Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a Case Report

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare congenital disorder charaeterized by a diluted, non- obstructive urinary bladder and hypoperistalsis of the gastro- intestinal tract, which is considered lethal. About 90 patients have been reported, predominantly female. We present the case of a female newborn with MMIHS in whom antenatal ultrasound was suggestive for the diagnosis, which was confirmed after delivery. Diagnostic features by antenatal ultrasound are described.

Key words: MEGACYSTIS; MIOROCOLON; HYPOPERISTALSIS

INTRODUCTION

Megacystis-microcolon-intestinal hy poper istals is syndrome (MMIHS) is characterized by abdominal distension, a dilated, non- obstructive urinary bladder, microcolon and bypoperistalsis of the gastrointestinal (GI) tract. Since Rerdon and colleagues first described it in 1976, about 90 cases have been reported in the literature1. Prenatal diagnosis is difficult and a genetic locus has not yet been identified2.

Case REPORT

At a gestational age of 36 weeks 6 days, a female infant was born to a primiparous mother. There was no consanguinity. At gestational age ol 30 weeks the ultrasound scan revealed an increased amount of amniotic fluid with a markedly distended bladder extending up to the diaphragm in the absence of dilatation of the ureters and renal pelvis (Figure 1). Amniocentesis was performed, which showed a normal karyotype (46XX).

During labor the fetus passed meconium. Physical examination showed a distended abdomen. Abdominal ultrasound imaging revealed an enlarged urinary bladder with bilateral hydronephrosis. A urethral catheter was inserted, which drained 600 ml of urine.

A water-soluble contrast enema showed a microcolon and a study of the upper (71 showed a malrotation and hypoperistalsis of the distal esophagus and stomach.

During admittance meconium did not pass and enterai feeding was not possible because of vomiting and persistent bilious drainage. On the seventh day of life a laparotomy was performed. The findings included dilated small intestine with a sudden change in distension and a malrotation. An ileostomy was made. Diagnostic biopsies were taken from different locations of the intestines and bladder.

Total patenterai nutrition (TPN) was started. A trial with different prokinetics was unsuccessful. The ileostomy also failed to pass fcces.

The histology of the intestines and the bladder showed normal ganglionosis, a very thin muscular layer, vacuolic degeneration, collagen proliferation and a decreased coloring of actin. These findings confirmed our suspected diagnosis of MMIHS. At 5 weeks TPN was discontinued and at 6 weeks of age she died.

Figure 1 Antenatal ultrasound image

DISCUSSION

Although the etiology of MMIHS is unknown, no abnormalities in ganglionic cells are found and the possibility of a smooth muscle myopathy is considered5.

MMIHS is the most severe form of functional intestinal obstruction3. Although a genetic locus has not yet been identified, an autosomal recessive inheritance has been suggested2,3.

Treatment is supportive and involves an ileostomy to defunction the colon, with TPN. MMIHS is usually lethal within the first year of life, typically due to TPN complications, renal failure and sepsis. Multivisceral transplantation as an experimental treatment has been reported in three patients with TPN-induced liver failure, of whom only one survived and was living at home with a functional graft 17 months after transplantation4.

Prenatal diagnosis of MMIHS is possible by antenatal ultrasound and needed for early postnatal investigations. We suggest that the triad of a female fetus with an enlarged urinary bladder and normal amniotic fluid is pathognomonic for MMIHS. In males with fetal megacystis, the most likely diagnosis is early urethral obstruction syndrome. Clinical genetic counseling is indicated for further pregnancies. We reviewed the tape of an ultrasound examination of this case at a gestational age of 16 weeks by the referring hospital. These images demonstrated a slightly increased amount of amniotic fluid, a normal-sized bladder and the absence of hydronephrosis, but a huge dilated stomach. These observations have to be taken into account when counseling parents for the exclusion by ultrasound of the described anomaly in future pregnancies at an earlier stage.

REFERENCES

1. Berdon WE, Baker DH, Blane WA, et al. Megacystistnicrocolon- intestinal hypoperistalsis syndrome: A new cause of intestinal obstruction in the new horn. Report of radiological findings in five newborn girls. Am J Roentgeno! 1976;126:957-64

2. White SM, Chamberlain P, Hitchcock R, et al. Megacystismicrocolon-intestinal hypoperistalsis syndrome: the difficulties with antenatal diagnosis. case report and review of the literature. Prenat Diagn. 2000;20:697-700

3. Rolle U, O’Briain S, Pearl RH, Puri P. Megacystis- microcolonintestinal hypoperistalsis syndrome: evidence of intestinal myopathy. Pediatr Surg Int 2002;18:2-5

4. Masetti M, Rodriguez MM, Thompson JF, et al. Multivisceral transplantation for megacystis microcolon intestinal hypoperistalsis syndrome. Transplantation 1999;68:228-32

S. C. A. T. Verbruggen1, R. M. H. Wijnen2 and P. van den Berg3

1 Department of Pediatrics, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands

2 Department of Pediatric Surgery, UMC St. Radboud, Nijmegen, The Netherlands

3 Department of Gynecology, UMC St. Radboud, Nijmegen, The Netherlands

Correspondence: Dr R. M. H. Wijnen, Department of Pediatric Surgery, UMCN St. Radboud, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

Received 12-11-03 Revised 22-12-03 Accepted 06-02-04

Copyright CRC Press Aug 2004

Giving Justice to Aging: Geriatric Jurisprudence in America

“Geriatric jurisprudence” is one of the academic mouthfuls that thicken the tongue and glaze the eye of otherwise lively intellects. Yet, the concept is at the center of a little-understood movement to bring the justice system of the United States into the age of longevity. This “In Focus” section touches on today’s efforts to adapt the U.S. judicial system to an aging population.

There are many difficult pronlems to broach: What is the best way to protect those with cognitive impairments while still respecting their remaining capacity to participate in decisions about their future? How can the United States best deal with its aging prison population, especially the growing number of older women behind bars? What must judges and lawyers know to remove barriers between the courts and elders? And how can U.S. courtrooms benefit from the growing ranks of older volunteers who can offer a vital new resource to the American system of justice?

Geriatric jurisprudence? Aging Today’s version of Winged Justice appearing on this page might emphasize-sounding a bit like the late Gray Panther founder Maggie Kuhn- “That means justice for all”.

Paul Kleyman, Editor

Aging Today

Copyright American Society on Aging Sep/Oct 2004

Is Dressler Syndrome Dead?*

Post-acute myocardial infarction (AMI) syndrome was first described by Dressler in 1956. Its incidence has decreased in the reperfusion era, most likely because of the extensive use of thrombolysis and coronary balloon angioplasty, therapies that dramatically decreased the size of myocardial necrosis. The authors suggest that drugs that have been prescribed in previous decades as the post-AMI “standard-of-care,” such as angiotensin-converting enzyme inhibitors, β-blockers, and statins, may also play an important role in the disappearance of Dressler syndrome due to their immunomodulatory effects. (CHEST 2004; 126:1680-1682)

Key words: inflammatory reaction; myocardial necrosis; pericardial effusion

Abbreviations: ACE = angiotensin-converting enzyme; AMI = acute myocardial infarction; DS = Dressler syndrome

Dressler’s description,1 > 40 years ago, of a clinical entity following an acute myocardial infarction (AMI) continues to be indelibly evoked at bedside and in the standard cardiology literature. Clinical features of this post-AMI syndrome include fever, chest pain, pericarditis, pleurisy occurring 2 to 3 weeks after the AMI and a tendency for recurrence.2 Prior to the reperfusion era, the reported incidence of Dressier syndrome (DS) ranged from 1 to 5% of patients with AMI.2-5 The incidence of DS, however, has decreased in the reperfusion era, most likely due to the widespread use of therapy with thrombolysis6,7 and balloon angioplasty.8 Supporting this, in a prospective study of 201 patients with AMI who had undergone thrombolysis, Shahar et al9 found that no patient showing clinical signs of early reperfusion had DS. The only patient who developed DS in the latter study had had an extensive anterior AMI without evidence of reperfusion. Before the reperfusion era. Lichstein and colleagues10 suggested that the decreased incidence of DS was related to the modification of the treatment of patients with AMI. The use of novel therapies, such as nonsteroidal antiinflammatory agents, steroids, and salicylates, and the decreased use of oral anticoagulants were evoked. In addition to the two mechanisms discussed above, which may account for the observed decrease in the incidence of DS,9-10 the authors propose a third hypothesis. We think that drugs that have been prescribed in previous decades as post-AMI “standard-of-care” may also play an important role in the disappearance of DS.

ETIOLOGY OF DS

Before the Era of Coronary Reperfusion

Several pathogenic mechanisms have been proposed for DS, including local inflammation,11 autoimmune reaction,12 and latent viruses.13 Irritant pericarditis due to the presence of blood in the pericardial space induced by anticoagulation therapy was at that time anticipated as a likely mechanism.1 However, anticoagulation therapy could not be related to all cases since > 25% of patients in the original report of Dressier1 did not receive anticoagulants.2 In addition, nowadays, a significant number of patients still receive anticoagulants after experiencing anterior AMIs,14 yet DS is not observed in this patient population. These two facts seem to rule out anticoagulants as the drugs playing a major role in the pathogenesis of DS.

Since the Era of Coronany Reperfusion

The decrease of the incidence of DS has been viewed as another beneficial effect of early and aggressive coronary reperfusion therapy, which decreased mortality and improved cardiac function.9 It was postulated9 that the diminution of the infarct size and the shortened time of exposure of the myocardial antigens to the immune system accounted for the decreased incidence of DS. Although the reduction in both the number of patients with AMI and in the infarct size following coronary reperfusion may play a role in the observed decrease of the incidence of DS,15,16 this can hardly explain the quasi-complete disappearance of the syndrome. Indeed, even in the reperfusion era, a significant number of patients will develop large AMIs due to unsuccessful or late reperfusion. The quasi-absence of DS in this patient population calls for another mechanism to explain their protection against DS.

The Author’s Hypothesis

DS is a recurrent immunoinflammatory syndrome that has similarities with other syndromes occurring after myocardial injury, such as postcardiotomy syndrome and posttraumatic pericarditis.17 Following myocardial injury or AMI, myocardial antigens are exposed and/or released, and, in some cases, an immune complex can form. This immune activation triggers a local inflammatory reaction, and may involve remote organs such the pleura and synovia, due to molecular mimicry and immune cross-reactions.12 The time needed for the immune reaction to develop may account for the observed latency period of 2 to 3 weeks between the AMI and the onset of DS. The duration of DS may be explained by the limited time during which myocardial antigens are exposed to the immune system and corresponds grossly to the time necessary for the myocardium to heal after an AMI. Interestingly, the hypothesis proposed herein suggests that this immune reaction has been minimized by novel therapies administered in the last 1 or 2 decades in the vast majority of patients who have experienced AMIs. These therapies include the use of angiotensin-converting enzyme (ACE) inhibitors, statins, and β-blockers. All of these drugs have been proposed to carry immunomodulatory properties.18-22 These drugs also lower the risk of recurrent AMI in addition to their effect on all-cause mortality. A direct relationship between systemic inflammation and myocardial ischemia has been highlighted by several authors.23-27 Interestingly, Gullestad et al19 have shown that circulating levels of proinflammatory cytokines were reduced by high doses of ACE inhibitors in patients with heart failure. Other authors demonstrated that ACE inhibitors reduced myocardial injury in cell cultures and in isolated hearts.18 In similar studies, β- blockers have been shown to decrease circulating levels of proinflammatory cytokines.20,22 Statins, a new class of lipid- lowering drugs that reduces cardiovascular-related morbidity and mortality,28,29 are now widely used for treatment after an AMI. Although these agents have not directly been shown to decrease the levels of systemic proinflammatory mediators in patients with AMI, they carry unequivocal protective antiinflammatory and immunomodulatory properties.21 Moreover, statin therapy has been found to lower levels of C-reactive protein,25,30 and Nahrendorf et al31 have demonstrated that left ventricular remodeling after AMI was profoundly changed by statin treatment in rats.

Another explanation for the post-AMI syndrome could be the close proximity between the myocardium and the pericardium. The inflammatory process that affects the cardiac muscle could propagate a nonspecific inflammatory response to the neighboring pericardium. However, the usual latency period of 2 to 3 weeks between the AMI and the onset of DS makes this hypothesis less likely, and corresponds more to the pathogenesis of the acute pericarditis observed within the 5-day period after the AMI.

SUMMARY

Historically, attempts to understand the quasicomplete disappearance of the DS have focused on early coronary reperfusion therapy, and less attention has been given to drugs with immunomodulatory properties. We hypothesize that the most likely disappearance of DS following a correctly treated AMI is related to drugs that have a strong defensive effect by virtue of diverse antiinflammatory effects.

* From the Divisions of Surgical Intensive Care (Dr. Bendjelid) Medical Intensive Care (Dr. Pugin), Geneva University Hospitals, Geneva, Switzerland.

REFERENCES

1 Dressler W. A post-myocardial infarction syndrome: preliminary report of a complication resembling idiopathic, recurrent, benign pericarditis. JAMA 1956; 160:1379-1383

2 Dressler W. The post-myocardial infarction syndrome. Arch Intern Med 1959; 103:28-42

3 Davidson CO, Oliver MF, Robertson RF. Post-myocardial infarction syndrome. BMJ 1961; 2:535-539

4 Welin L, Vedin A, Wilhelmsson C. Characteristics, prevalence, and prognosis of postmyocardial infarction syndrome. Br Heart J 1983; 50:140-145

5 Northcote RJ, Hutchison SJ, McGuinness JB. Evidence for the continued existence of the postmyocardial infarction (Dressler’s) syndrome. Am J Cardiol 1984; 53:1201-1202

6 GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronaryartery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329:1615-1622

7 Ross AM, Coyne KS, Moreyra E, et al. Extended mortality benefit of early postinfarction reperfusion: GUSTO-I Angiographic Investigators; Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Trial. Circulation 1998; 97:1549-1556

8 Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002; 346:957-966

9 Shahar A, Hod H, Barabash GM, et al. Disappearance of a syndrome: Dressler’s syndrome in the era of thrombolysis. Cardiology 1994; 85:255-258

10 Lichstein E, Arsura E, Hollander G, et al. Current incidence of postmyocardial infarction (Dressler’s) syndrome. Am J Cardiol 1982; 50:1269-1271

11 Thadani U, Chopra MP, Aber CP, et al. Pericarditis after acut\e myocardial infarction. BMJ 1971; 2:135-137

12 Earis JE, Marcuson EC, Bernstein A. Complement activation after myocardial infarction. Chest 1985; 87:186-190

13 Kossowsky WA, Lyon AF, Spain DM. Reappraisal of the postmyocardial infarction Dressler’s syndrome. Am Heart J 1981; 102:954-956

14 Weinreich DJ, Burke JF, Pauletto FJ. Left ventricular mural thrombi complicating acute myocardial infarction: long-term follow- up with serial echocardiography. Ann Intern Med 1984; 100:789-794

15 Correale E, Maggioni AP, Romano S, et al. Comparison of frequency, diagnostic and prognostic significance of pericardial involvement in acute myocardial infarction treated with and without thrombolytics: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI). Am J Cardiol 1993; 71:1377-1381

16 Oliva PB, Hammill SC, Talano JV. Effect of definition on incidence of postinfarction pericarditis: it is time to redefine postinfarction pericarditis? Circulation 1994; 90:1537-1541

17 Versey JM, Gabriel R. Soluble-complex formation after myocardial infarction. Lancet 1974; 2:493-494

18 Linz W, Wiemer G, Scholkens BA. ACE-inhibition induces NO- formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts. J Mol Cell Cardiol 1992; 24:909-919

19 Gullestad L, Aukrust P, Ueland T, et al. Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol 1999; 34:2061- 2067

20 Prabhu SD, Chandrasekar B, Murray DR, et al. Betaadrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation 2000; 101:2103 2109

21 Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399-1402

22 Ohtsuka T, Hamada M, Hiasa G, et al. Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J Am Coll Cardiol 2001; 37:412-417

23 Neumann FJ, Ott I, Gawaz M, et al. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995; 92:748-755

24 Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836-843

25 Ridker PM, Rifai N, Clearfield M, et al. Measurement of C- reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344:1959- 1965

26 Cusack MR, Marber MS, Lambiase PD, et al. Systemic inflammation in unstable angina is the result of myocardial necrosis. J Am Coll Cardiol 2002; 39:1917-1923

27 Kinlay S, Timms T, Clark M, et al. Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia. Am J Cardiol 2002; 89:1205-1207

28 Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285:1711-1718

29 Olsson AG, Schwartz GC. Early initiation of treatment with statins in acute coronary syndromes. Ann Med 2002; 34:37-41

30 Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactixe protein levels: the pravastatin inflammation/ CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64-70

31 Nahrendorf M, Hu K, Hiller KH, et al. Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction: an experimental serial cardiac magnetic resonance imaging study. J Am Coll Cardiol 2002; 40:1695-1700

Karim Bendjelid, MD, MS; and Jr Pugin, MD

Manuscript received December 13, 2003; revision accepted April 16, 2001.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

Correspondence to: Karim Bendjelid, MD, MS, Chef de Clinique Scientifique, Surgical Intensive Care Division, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland; e-mail: [email protected]

Copyright American College of Chest Physicians Nov 2004

Sarcoidosis Diagnosed in Elderly Subjects*: Retrospective Study of 30 Cases

Study objective: This study investigated the clinical features and disease course of sarcoidosis diagnosed in patients > 70 years of age.

Methods: A retrospective analysis was made of cases treated at the University Hospital in Nantes, France, between 1986 and 2000. The diagnosis of sarcoidosis was confirmed histopathologically. Cases involving progressive cancer and active tuberculosis were excluded.

Results: Thirty white patients with sarcoidosis diagnosed after age 70 years (mean, 74 years) were included. An alteration of general health (asthenia and/or anorexia and/or weight loss) was frequent (53%) and characteristic of the systemic form of the disease. Dyspnea was a fairly common sign (23%). The intrathoracic form of sarcoidosis was most frequent (43.3%). Diagnosis was difficult and lengthy, and symptomatology was atypical. Accessory salivary gland biopsy was an important contributing factor to diagnosis (70.6% were positive). Oral corticosteroid therapy was often required (60.7%). The disease course was satisfactory overall (81.8% of cases), but only for 50% of patients in intrathoracic stage IV.

Conclusions: The clinical presentation of sarcoidosis in elderly subjects is mainly characterized by an alteration of general health. Diagnosis is difficult and should include accessory salivary gland biopsy. Therapy frequently involves corticosteroids. Overall prognosis is similar to that for young subjects. (CHEST 2004; 126:1423-1430)

Key words: accessory salivary gland biopsy; elderly subjects; sarcoidosis

Abbreviation: ACE = angiotensin-converting enzyme

Sarcoidosis is a systemic granulomatous disease generally affecting the young and most often involving the lungs and mediastinum. Although sarcoidosis is infrequent in elderly persons, the clinical features and course of the disease can be determined as well as the possible benefit of diagnosis and treatment.

MATERIALS AND METHODS

Study Population

This retrospective study concerned all patients > 70 years of age who received a diagnosis of sarcoidosis after admission to the University Hospital in Nantes, France.

Diagnontic Criteria

Sarcoidosis can affect almost any organ or tissue, but the lungs and mediastinum are involved in most cases. All of the following criteria were required for patients included in this study: age ≥ 70 years at diagnosis; absence of any known history of sarcoidosis; suspected intrathoracic or visceral involvement (according to clinical data and/or imaging), with one positive biopsy result, or with two positive biopsy results in different regions; absence of toxic or medicinal etiology; absence of concomitant progressive neoplasia; and diagnosis of sarcoidosis by the attending physician as a function of clinical involvement and disease course. Cases of isolated granulomatous hepatitis were not included because of their uncertain nosology. Granulomatous diseases of infectious etiology (notably active tuberculosis) or those associated with other dysimnmne diseases responsible for granulomatous reactions (Crohn disease, rheumatoid arthritis, celiac disease) were also excluded.

Biopsies

The presence of noncaseathing grannlomas, with little or no necrosis, was required for diagnosis, hut not specific for sarcoidosis.

Staging of Mediastinum-Lung Involvement

Chest radiographs allowed intrathoracic involvement to be rated aecording to the customary four stages: normal radiography (stage 0), mediastinal adenopathy (stage II), parenchymal involvement associated with mediastinal adenopathy (stage II), infiltrating lung disease without mediastinal adenopathy (stage III), and pulmonary fibrosis (stage IV).1,2

Data Collection

Information on patients treated for sarcoidosis alter 1995 was provided by the data processing department of the Nantes University Hospital from an institutional database (Programme de Mdicalisation du Systme d’Information). For previous years, the files of each department concerned were consulted. As certain departmental files did not indicate a diagnosis of sarcoidosis, some patients were identified on the basis of complementary data in files maintained by histopathology laboratories. To ensure satisfactory exhaustiveness the year 1986 was chosen as the beginning of the investigation period.

RESULTS

Data were collected on cases diagnosed over a 14-year period (1986 to 2000).

General Population Characteristics

Thirty white patients (21 women and 9 men; mean age, 74 years; range, 70 to 81 years) satisfied the inclusion criteria (Table 1). The diagtiosis of sarcoidosis was made after 75 years of age in 23.3% of cases (n = 7). Mean follow-up was 37.8 months. Eighty- three percent of patients were treated in internal medicine, geriatrics, pneumology, and mixed-care departments. Six cases of possible sarcoidosis were excluded because of associated cancer (n = 3), associated active tuberculosis (n = 1), lack of histopathologic studies (n = 1 ), and known history of sarcoidosis before age 70 years (n = 1).

Table 1-Baseline Characteristics of Patients and Clinical Forms*

Table 2-Initial Clinical Signs and Radiologic Abnormalities

History of Tuberculosis of Autoimmune Disease

Four of the included patients (13.3%) had a known history of tuberculosis: one primary infection in adolescence, and three pulmonary tuberculosis (two before diagnosis of sarcoidosis at age 40 years). Two patients with a recent contagion (

Clinical Forms

The clinical form (Table 1) was defined according to the main area of involvement observed. Intrathoracic forms were dominant (43.3%), followed by systemic forms (20%). The latter were characterized by an obvious alteration of general health (asthenia and/or anorexia and/or weight loss).

Clinical or Radiologic Signs Suggestive of Sarcoidosis

An alteration of general health was observed in 53% of cases (Table 2). Asthenia was frequent (43%), notably in intrathoracic and systemic forms. Anorexia was found in 23% of cases. Weight loss (n = 8) was characteristic of systemic forms, which mimicked (asthenia and fever) progressive tuberculosis or neoplasm. Dyspnea and cough were quite characteristic of the intratlioracic form, which was often revealed by recurrent bronchial episodes (38%).

Dryness syndrome was noted initially in 16% of cases (n = 5), either as xerostomia (n = 4) or xerophthalmia (n = 1). In two cases, parotid uptake was observed in scintigraphy, and the parotid gland wtis enlarged in one case.

Ocular involvement was not searched for systematically. A single patent involvement of panuveitis type, with bilateral retinal lesions, was noted in the intratlioracic form. Systematic examinations detected signs of old iridocyclitis in one case and sequelae of bilateral retinal lesions in another.

Three patients had pericardial effusion, and three patients had a pacemaker implanted after severe conduction disorders. There were no asymptomatic cases. Alteration of general health (53%) and dyspnea (23%) were the main signs revealing the disease in these elderly subjects.

Diagnostic Process

The fact that most of the cases required a long interval (mean, 31.2 months; range, 3 to 168 months) before essential evidence was established for a diagnosis of sarcoidosis is indicative of the difficulties encountered with elderly subjects. The evidence came from the clinical history, biological examinations, imaging studies, biopsies (quite decisive in this type of pathology), and disease course. In the diagnostic process, a positive biopsy result in conjunction with clinical involvement or suggestive imaging concerned 17 patients. Twelve other patients had positive biopsy results in two different regions. In one case, the diagnosis related to two doubtful biopsy results and failure of antituberculous therapy.

In addition to these sources of evidence, other elements were taken into account, ie, lymphocytic BAL, elevated angiotensin- converting enzyme (ACE) levels, suggestive gallium scintigraphy, failure of antituberculous therapy, search for negative Mycobacterium tuberculosis culture, and negative tuberculin skin test.

Biological Abnormalities

Lymphopenia, defined as a decrease in lymphocytes

Table 3-Diagnostic Elements Suggestive of Sarcoidosis

Exclusion of Active Tuberculosis

The possibility of active tuberculosis was a major concern for the clinician. Only 9.1% of patients had no culture in specific medium. Stomach intubation was the most frequent examination (15 patients for 22 exploitable files), and the polymerase chain reaction technique was used once. Empi\ric antituberculous therapy was sometimes used as a diagnostic tool (n = 5, 22.7%), even though none of these patients had a positive tuberculin skin test result.

Tuberculin Skin Test

The tuberculin skin test result was very often negative (73%), but the number of positive cases was still substantial (27%). No reaction was phlyctenular (Tables 3, 4).

Table 4-Description of Involvement (According to Clinical Form) and Disease Course*

Biopsies Performed

Sixty-three biopsies were performed (66.7% of results were positive). Ten patients (33.3%) underwent at least three biopsies (three to five biopsies) for sarcoidosis diagnosis, probably because of uncertainties and frequent negative results in histopathology (Table 3).

The accessory salivary gland was sampled most often (27% of all biopsies for 56.7% of patients), and the results were quite satisfactory (70.6% were positive). This biopsy was performed early in only 17% of cases. Positive results concerned all clinical forms, and were a major factor in the diagnosis for 12 patients. The biopsy result was positive five of eight times in thoracic forms, and thus was more efficient than unguided procedures (Table 3).

Results for bronchial biopsies were less satisfactory (38% were positive), as were those for transbronchial biopsies. However, biopsies directed at morphologic or clinical abnormalities (skin, adenopathy, mediastinal tissues, etc.) were quite useful.

Mediastinum-Lung Involvement

Mediastinum-lung involvement (56.7%) can suggest sarcoidosis or confirm other evidence of the disease (Table 3). A chest CT scan (n = 18) was performed for 85% of intrathoracic forms, and nearly always when intrathoracic involvement was suspected on the basis of clinical or radiologic evidence. CT scan performed after chest radiograph guided diagnostic strategy and could confirm a process of pulmonary fibrosis.

Gallium scintigraphy was useful in six cases, showing at least suggestive intrathoracic uptake. Two of these cases corresponded to intrathoracic stage 0.

Description of Clinical Forms According to Dominant Clinical Involvement

Intrathoracic Form (n = 13): The intrathoracic form was often revealed by dyspnea or recurrent bronchial episodes (n = 4). Pleural effusion (n = 2) was exudative and massive and associated in one case with florid parenchymal involvement (stage II) [Table 4]. In another case, sarcoidosis (stage II, salivary gland biopsy positive) was revealed by obstructing bronchial aspergillosis treated by inhaled corticosteroids and oral itraconazol. The intrathoracic form of sarcoidosis was often severe (four stage IV, and two deaths directly imputable to the course of pulmonary fibrosis). Stages III and IV represented 54% of intrathoracic forms (26.6% of all cases).

Systemic Form (n = 6): The systemic form of sarcoidosis associated an alteration of general health (often febrile) with a complex clinical picture. Weight loss (n = 5) was marked (> 10 kg in three cases). Fever was noted in three cases (> 38.5C in two patients). Deep or superficial extrathoracic adenopathy and/or hepatomegaly were frequent (n = 4). Mediastinal and lung involvement was found in three cases. A pseudomyalgia rheumatica syndrome with peripheral arthritis was the cause in one case. Acute articular involvement was noted in two cases. In another case, the clinical picture was associated with neuropathy of the lower limbs, facial nerve palsy, and intercostal pain. Gallium scintigraphy showed mediastinal uptake, and neuromuscular and salivary gland biopsies revealed granulomatous inflammation. Granulomatous hepatitis was noted in another case. Diarrhea was observed in two cases, but no specific lesions were detected in colonoscopy (aspecific subacute colitis in one case). Exudative pleural effusion and medullary granulomas were found in one of these cases.

Articular Fonn (n = 3): Articular sarcoidosis was characterized by subacute or chronic inflammatory polyarthralgia affecting essentially large (n = 3) and small (n = 2) joints. One case was revealed by a granulomatous subpalpebral swelling and another by superficial adenopathy and an enlarged parotid gland. Diffuse muscular involvement occurred in the third case, causing severe musculotendinous sequelae. Granulomas were found in muscle and synovial biopsies.

Node Form (n = 3): The node form was characterized by cervical adenopathy (n = 3), together with supraclavicular adenopathy in two cases. Involvement of different node groups may have been successive. Xerostomia was noted in two cases (parotid involvement documented by scintigraphy in one case).

Forms Revealed by Cutaneous Manifestations (n = 3): In one case, aspecific erythema nodosum had developed over a 4-year period (positive salivary gland biopsy), and two other cases showed specific erythematous and squamous as well as papular granulomatous lesions.

Renal Form (n = 1): Renal sarcoidosis, characterized by rapidly progressive renal failure, showed granulomatous interstitial nephropathy in histopathologic studies. The blood calcium level was normal. The response to corticosteroid therapy was transient, and terminal renal failure developed.

Lacrimal Form (n = 1): Granulomatous swelling of the lacrimal gland was associated with lymphocytic BAL in the absence of radiologic signs of intrathoracic involvement. A sulivary gland biopsy result was positive.

Course of Clinical Patients

Sixty-one percent of patients received general corticosteroid therapy (usually starting at 1 mg/kg/d of prednisone equivalent) [Table 4]. This treatment was administered to 67% of patients with the intrathoracic form of sarcoidosis and 56% of those with other forms. Another immunosuppressant (azathioprine) was used in two cases of intrathoracic sarcoidosis. One patient was treated with inhaled corticosteroids. Other patients received hydroxychloroquine (n = 3), thalidomide (n = 1), and potassium iodide (n = 1) for skin or joint involvement.

Overall, the course was considered satisfactory in 82% of cases (improvement in 64% and stabilization in 18%). When a patient was treated by general corticosteroid therapy, improvement or stabilization was observed in 81% of cases overall, 71% for all intrathoracic forms, and 50% for stage IV intrathoracic sarcoidosis. The form was considered severe for 26.6% of all patients because of marked intrathoracic or other involvement (renal, peripheral nervous system, or ocular). The intrathoracic form of sarcoidosis had a more severe prognosis: four deaths vs one death for the other forms. Two deaths were directly attributable to chronic respiratory failure secondary to fibrosis (stage IV). Among stage IV cases, only one patient improved under treatment (after 12 months of follow-up); another was considered stable (but died of an unstated cause); and two others had a worsening of their respiratory problems. Corticosteroid therapy for fibrosis appeared to be inefficient, despite association of azathioprine in two cases. The patient with bronchial aspergillosis improved with inhaled corticosteroids followed by itraconazole. As the course of the renal form of sarcoidosis was unfavorable, peritoneal dialysis was considered. The complications related to treatment are difficult to evaluate retrospectively, but seem to have been essentially infectious: lung disease caused by cytomegalovirus, tuberculous abscess (in a patient with stage IV sarcoidosis who died from pulmonary fibrosis), and Alternaria infection.

DISCUSSION

Sarcoidosis generally affects young subjects and is relatively rare in older persons.3-5 A retrospective series (from 1951 to 1986) reported by Stadnyk et al3 found 17 elderly patients (7.8%) among 219 reviewed cases of biopsy-proven sarcoidosis. This is the only published series concerned specifically with the clinical characteristics and course of sarcoidosis in patients > 65 years of age (mean age, 70.9 years; vs 74 years in our series). Women were preponderant, as in our scries, although it would appear that the onset of sarcoidosis is earlier in men.6

There were no asymptomatic cases in our series, whereas fortuitous discovery is common in the young,6-8 probably because of a greater frequency of systematic radiologie examinations. General signs are the primary indicators in older people. However, alteration of general health, a major sign in our series (53% of patients), was less frequent in other nongeriatric series (6.3% for Judson et al,9 16% for Chapelon et al,6 and 13.7% for Garret et al8) and often led to empiric antituberculous therapy.8 Sarcoidosis is also a possible etiology for unexplained prolonged fever in elderly subjects.01 Pulmonary functional signs (46.3%) were prominent “organ symptoms,” as cleark documented in other studies,3,4,9 and patients showed dyspnea, cough, chest pain, hemoptysis, and recurrent infection. Mediastinum-lung involvement (57% of cases) was less frequent than in other series (90% for Garret Pt al,8 83% for Chapelou et al,8 and 82% for Stadnyk et al3), which tends to confirm the symptomatic atypia and diagnostic difficulty encountered in older persons. Articular involvement consisted especially of chronic, subacute, or acute inflammatory polyarthralgias or polyarthritis affecting particularly the large joints, as classically described.11,12 However, acute articular manifestations were less frequent in our series, and chronic manifestations more frequent.6,11 Renal, neurologic, or muscular localizations are uncommon, often difficult to diagnose, and not always susceptible to corticosteroid therapy.6,13-19 Lacrimal involvement has been documented in older subjects.20 Dryness syndrome often exists, and its importance is probably underrated. This symptom is more often related to parotid than lacrimal involvement. Although ocular involvement was only reported three times in our series, sarcoidosis is a frequent etiologic diagnosis for uveitis in older persons.24 Retinal periphlebitis (one case\) is also an acknowledged complication.23 Pericarditis is not the most frequently reported form of cardiac involvement.24 Cardiac sarcoidosis is especially characterised by conduction and rhythm disorders.25 Three cases of pericarditis occurred in our series, but three other patients underwent pacemaker implantation for conduction disorders that may have been sarcoidosis related.

Little is known about the relations between sarcoidosis and tuberculous or other mycobacteria. Their mutual involvement seems likely,26,27 and an association between sarcoidosis and tuberculosis has been reported.6,8 A history of tuberculosis was fairly frequent in our patients (13%), and retrospective collection of data probably underestimated this aspect. One patient acquired tuberculosis while receiving corticosteroid therapy (negative tuberculin skin test result).

Biopsies are essential to the diagnosis of sarcoidosis. The accessory salivary gland biopsy is simple to perform and relatively uninvasive, but is not used systematically.6,28 Results were positive in 70.6% of cases in our series, and were more informative than bronchial biopsies. Sensitivity was slightly better than in most published series concerning younger subjects.6,29-31 The diagnosis of sarcoidosis can be reached by mediastinoscopy, which is highly informative when imaging shows accessible adenopathy. In such cases, transbronchial biopsies can prove inadequate. Recourse to mediastinoscopy is not exceptional in the older subject,3 but accessory salivary gland biopsy should be performed first.28 Guided biopsies are also quite informative and can facilitate earlier diagnosis.6,9,28

Cutaneous reaction to tuberculin was often negative (73% of cases). These results are in agreement with those of published studies.6 A rise in ACE was observed in only 44.4% of cases in our series, 58% in that of Chapelon et al,6 and 32% in that of Garret et al.8 As the frequency of renal failure and diabetes is high in elderly subjects (thereby increasing ACE levels, especially in those with diabetic retinopathy32), the ACE assay is of little value in the diagnostic process. BAL and gallium citrate scintigraphy were rarely used in our series, but are of interest for the diagnosis of sarcoidosis.6,8,33 BAL fluid was lymphocytic in intrathoracic sarcoidosis, even when the chest radiograph was normal (n = 1).34 Hypergammaglobulinemia has been reported in sarcoidosis,35 and lymphopenia is common,36 as in our series. However, lymphopenia is not an efficient diagnostic tool because of numerous possible etiologies (tuberculosis, denutrition, etc.).

The disease was not always easy to control, but the results were generally satisfactory. Only two patients had clearly progressive disease (stage 4), and both died of a mediastinum-lung form, the major pathogenesis for sarcoidosis deaths.3,37-39 The follow-up period was not yet sufficiently long for some stage III or IV patients. The disease course was considered satisfactory (improvement or stabilization) in 82% of cases in our series vs 82% (for 554 cases, all ages combined) in that of Chapelon et al.6 Sixty- one percent of our patients received general corticosteroid therapy, which is comparable to data reported in studies concerning young patients.6,8 The course of sarcoidosis in elderly subjects is probably no more critical than in the young, but treatment is required especially for severe cases of mediastinum-lung or extrapulmonary involvement.40

This retrospective series reviewed 30 cases of sarcoidosis in older persons treated over a 14-year period at the University Hospital in Nantes, France. Intrathoracic and systemic forms of sarcoidosis accounted for 63% of all clinical forms.

Sarcoidosis has a different presentation in elderly than young subjects. An alteration of general health is the major sign, except for intrathoracic forms in which pulmonary functional signs reveal the disease.

If sarcoidosis is suspected, an accessory salivary gland biopsy should be included in initial examinations, regardless of clinical form. This simple biopsy can clarify the diagnosis and avoid any need for more onerous investigations. Guided biopsies are also useful in the case of a clinical or morphologic abnormality. BAL, gallium scintigraphy, and antituberculous therapy can also be helpful in difficult cases.

Although the prognosis for sarcoidosis is life threatening in 27% of cases, organ involvement does not seem to be more severe in the older subject. The disease course is generally similar to that of young subjects, and stage IV intrathoracic forms and some types of organ involvement remain difficult to treat.

Thus, sarcoidosis is not a disease exclusively of the young. In older patients, suitable treatment leads to improvement or stabilization of the disease in > 80% of cases. Once the very particular clinical signs of the disease are recognized, the older patient can benefit from treatment and improved quality of life.

* From the Federation of Geriatric Medecine, Department of Geriatric Medecine (Drs. Chevalet and Brisseau), Hpital Lon Bellier; and Departments of Geriatric Medecine (Drs. Clment and Rodat), Pathology (Dr. Moreau), and Pulmonary Diseases (Dr. Clarice), Nantes University Hospital, Nantes, France.

REFERENCES

1 De Remee RA. The roentgenographic staging of sarcoidosis. Chest 1983; 1:128-133

2 Berkmen YM. Radiologic aspects of intrathoracic sarcoidosis. Semin Roentgenol 1985; 20:356-375

3 Stadnyk AN, Rubinstein I, Grossman RF, et al. Clinical features of sarcoidosis in elderly patients. Sarcoidosis 1988; 5:121-123

4 Young KR Jr, Merrill WW. Interstitial lung diseases in the elderly patient. Clin Geriatr Med 1986; 2:385-410

5 Margolis ML, Israel HL. Sarcoidosis in older patients: clinical characteristics and course. Geriatrics 1983; 38:121-128

6 Chapelon C, Uzzan B, Piette JC, et al. Sarcoidosis in internal medicine: a cooperative study of 554 cases [in French]. Ann Md Interne (Paris) 1984; 135:125-131

7 Siltzbach LE, James DC, Neville E, et al. Course and prognosis of sarcoidosis around the world. Am J Med 1974; 57:847-852

8 Garret M, Sicard D, Pquignot H, et al. Sarcoidosis at the Cochin University Hospital Center from 1975 to 1982 [in French]. Ann Md Interne (Paris) 1984; 135:133-138

9 Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest 2003; 123:406-412

10 Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993; 41:1187-1192

11 Eschard JP, Etienne JC. Osteoarticular manifestations of sarcoidosis [in French]. Rev Md Interne 1994; 15:305s-307s

12 Mathur A, Kremer JM. Immunopathology, rheumatic features, and therapy of sarcoidosis. Curr Opin Rheumatol 1992; 4:76-80

13 Muther RS, McCarron DA, Bennett WM. Renal manifestations of sarcoidosis. Arch Intern Med 1981; 141:643-645

14 Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis: signs, course and treatment in 35 confirmed cases. Medicine (Baltimore) 1990; 69:261-276

15 Haleem MA, Myopathies in the elderly. Geront Clin (Basel) 1972; 14:361-377

16 Meysman M, Sennesael J, Vanderniepen P, et al. Renal failure in sarcoidosis: case report of granulomatous interstitial nephritis and review of the literature. Acta Clin Belg 1993; 48:115-118

17 Gardner-Thorpe C. Muscle weakness due to sarcoid myopathy. Neurology 1972; 22:917-928

18 Stjenberg N, Cajander S, Truedsson H, et al. Muscle involvement in sarcoidosis. Acta Med Scand 1981; 209:213-216

19 Wolfe SM, Finals RS, Aelion JA, et al. Myopathy in sarcoidosis: clinical and pathologic study of four cases and review of the literature. Semin Arthritis Rheum 1987; 16:300-306

20 Peterson EA, Hymas DC, Pratt DV, et al. Sarcoidosis with orbital tumor outside the laerimal gland: initial manifestation in 2 elderly white women. Arch Ophthalmol 1998; 116:804-806

21 Chatzistefanou K, Markomichelakis NN, Christen W, et al. Characteristics of uveitis presenting for the first time in the elderly. Ophthalmology 1998; 105:347-352

22 Kosmorsky GS, Meisler DM, Rice TW, et al. Chest computed tomography and mediastinoscopy in the diagnosis of sarcoidosis- associated uveitis. Am J Ophthalmol 1998; 126:132-134

23 Obenauf CD, Shaw HE, Sydnor CF, et al. Sarcoidosis and its ophthalmic manifestations. Am J Ophthalmol 1978; 86:648-655

24 Kinney E, Murthy R, Ascunce GL, et al. Pericardial effusion in sarcoidosis. Chest 1979; 76:476-478

25 Silverman KJ, Hutchins GM, Bulkey BH. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978; 58:1204-1211

26 Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336:1224-1234

27 Fidler HM, Rook GA, Johnson NM, et al. Mycobacterium tuberculosis DNA in tissue affected by sarcoidosis. BMJ 1993; 306:546-549

28 Tarpley TM Jr, Anderson L, Lightbody P, et al. Minor salivary gland involvement in sarcoidosis: report of 3 cases with positive lip biopsies. Oral Surg Oral Med Oral Pathol 1972; 33:755-762

29 Michon-Pasturel U, Hachulla E, Bloget F, et al. Role of biopsy of the accessory salivary glands in Lofgren’s syndrome and other forms of sarcoidosis [in French]. Rev Md Interne 1996; 17:452-455

30 Mayock RL, Bertrand P, Morrison CE, et al. Manifestations of sarcoidosis: analysis of 145 patients with a review of nine series selected from the literature. Am J Med 1963; 35:67-89

31 Marx RE, Hartman KS, Rethman KV. A prospective study comparing incisional labial to incisional parotid biopsies in the detection and confirmation of sarcoidosis, Sjgren’s disease, sialosis and lymphomea. J Rheumatol 1988; 15:621-629

32 Lieberman J, Sastre A. Serum angiotensin-converting enzyme: elevations in diabetes mellitus. Ann Intern Med 1980; 93:825-826

33 Rossman MD, Dauber JH, Cardillo ME, et al. Pulmonary sarcoidosis: correlation of serum angiotensin-converting enzyme with blood and bronchoalveolar lymphocytes. Am Rev Respir Dis 1982; 125:366-369

34 Wallaert B, Ramon P, F\ournier E, et al. Bronchoalveolar lavage, serum angiotensin-converting enzyme, and gallium-67 scanning in extrathoracic sarcoidosis. Chest 1982; 82:553-555

35 Gupta SK, Gupta S. Sarcoidosis in India: a review of 125 biopsy-proven cases from Eastern India. Sarcoidosis 1990; 7:43-49

36 Hunninghake G, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 1981; 305:429-434

37 Perry A, Vuitch F. Causes of death in patients with sarcoidosis: a morphologic study of 38 autopsies with clinicopathologic correlations. Arch Pathol Lab Med 1995; 119:167- 172

38 Gideon NM, Mannino DM. Sarcoidosis mortality in the United States, 1979-1991: an analysis of multiple-cause mortality data. Am J Med 1996; 100:423-427

39 Poe RH, Utell MJ. Diagnosis and management of pulmonary sarcoidosis. Compr Ther 1989; 15:35-42

40 Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care Med 1994; 149:893- 898

Pascal Chevalet, MD; Renaud Clment, MD; Olivier Rodat, MD; Anne Morean, MD; Jean-Marie Brissean, MD; and Jean-Patrick Clarke, MD

Manuscript received April 22, 2003; revision accepted May 5, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

Correspondence to: Pascal Chevalet, MD, Department of Geriatric Medecine, Hpital Lon Bellier, 41 rue Curie, BP 84607, 44046 Nantes Cedex 1, France; e-mail: [email protected]

Copyright American College of Chest Physicians Nov 2004

Oral Purified Bacterial Extracts in Chronic Bronchitis and COPD*: Systematic Review

Background: Oral lyophilized extracts of bacteria species have been used since the early 1970s to improve symptoms and to prevent exacerbations in COPD patients. The value of these treatments, which are thought to be immunomodulating, is poorly understood. Our aim was to quantify the efficacy of oral bacteria extracts in patients with chronic bronchitis and COPD.

Design: Systematic review of randomized trials.

Data sources: Electronic databases, bibliographies, and contact with authors and manufacturers.

Review methods: Randomized comparisons of oral purified bacterial (active) extracts with placebo or no treatment (control) were selected. Meta-analyses were performed using fixed and random- effects models, and the results were expressed as relative risk (RR), odds ratio (OR), number needed to treat for one to benefit (NNTB), or number needed to treat for one to be banned (NNTH), with 95% confidence interval (CI).

Results: Thirteen trials (1,971 patients), most of which were of low quality, tested OM-85BV (Broncho-Vaxom; OM Pharma; Geneva, Switzerland), LW-50020 (Luivac; ALTANA Pharma; Bad Homburg, Germany), or SL-04. Two trials (731 patients) had appropriate methodologies and reported on exacerbations. The RR in favor of the oral bacterial extract (active) was 0.83 (95% CI, 0.55 to 1.25), and the NNTB was 15.4 (95% CI, 5.5 to ∞; NNTH, 27.5). Five trials (591 patients) reported on observer-assessed improvement of symptoms RR in favor of active extracts was 0.57 (95% CI, 0.49 to 0.66), and the NNTB was 4 (95% CI, 2.8 to 5.4). Two trials (n = 344), reported on patient-assessed improvement (RR, 0.44; 95% CI, 0.31 to 0.61) [NNTB, 4; 95% CI, 3.0 to 5.9]. In two trials (163 patients), the average duration of an exacerbation was shorter with the active extracts (weighted mean difference, -2.7 days; 95% CI, -3.5 to – 1.8). Itching or cutaneous eruptions was reported in 3.3% of patients (four trials; 802 patients) who received active extracts compared with 1.0% of control subjects (OR, 2.94 95% CI, 1.12 to 7.69) [NNTH, 50; 95% CI, 14 to 161]. Urologic problems (two trials; 671 patients) were reported in 8% of patients who received active extracts compared with 3.0% of control subjects (OR, 2.62; 95% CI, 1.35 to 5.11) [NNTH, 22; 95% CI, 10 to 61].

Conclusions: Oral purified bacterial extracts improve symptoms in patients with chronic bronchitis and COPD. There is not enough evidence to suggest that they prevent exacerbations. Cutaneous and urologic adverse effects are common. (CHEST 2004; 126:1645-1655)

Keywords: bronchitis; COPD; exacerbation; immunotherapy; LW- 50020; meta-analysis; OM-85 BV; SL-04; systematic review

Abbreviations: CI = confidence interval; NNTB = number needed to treat for one to benefit; NNTH = number needed to treat for one to be harmed; OR = odds ratio; RR = relative risk; WMD = weighted mean difference

A cute exacerbation of respiratory symptoms is a common complication in patients with chronic bronchitis and COPD. Exacerbations are associated with significant morbidity, mortality,1- 3 and costs. In the United States, the annual direct health-care cost of acute COPD exacerbations has been estimated at $18 billion (US dollars),4 and in an average UK Health Authority with a population of 250,000, there are 200 general physician’s consultations and 680 hospital admissions for acute exacerbations per year.5

Strategies that reduce the frequency of acute exacerbations and their severity have clinical, public health, and economic implications. Smoking cessation, vaccination against influenza and pneumococcal pneumonia, antibiotic therapy, and a short course of systemic corticosteroids are the most important strategies to prevent and control exacerbations.2,6-8 Based on two randomized trials8,9 showing a 20% reduction of exacerbations, the Global Initiative for Chronic Obstructive Lung Disease2 also recommended long-term therapy with inhaled steroids for patients with moderate- to-severe COPD who were experiencing recurring exacerbations.

Potentially interesting alternative strategies for an improved control of symptoms and exacerbations in COPD include the use of mucolytic, antioxidant, and immunomodulator agents. For instance, there is evidence from systematic reviews10,11 that mucolytic agents reduce the risk of exacerbations.

Since the early 1970s, oral lyophilized (active) extracts of bacteria species, which are frequently responsible for lower respiratory tract infections in patients with COPD. have been used. These remedies are thought to enhance specific and nonspecific immune responses through humoral and cellular immunomodulating activities.12-15 One large randomized placebo-controlled trial performed in 1997,16 the Prevention of Acute Respiratory Infection by an Immunostimulant study, found that treatment with oral purified bacterial extracts reduced the seventy of exacerbations and the rate of hospitalizations in COPD patients. However, the total number of exacerbations was similar in both groups. Based on these findings, we performed a systematic review to learn more about the efficacy and harm of these potentially useful drugs in patients with chronic bronchitis and COPD.

MATERIALS AND METHODS

Data Sources

We searched without language restriction in the databases MEDLINE, Premedline, EMBASE, Lilacs, Biosis, CINAHL, HealthStar, Inspec, and the Cochrane Controlled Trials Register, using combinations of the terms “OM-85 BV,””Broncho-Vaxom,””SL-04,””LW- 50020,””bacterial AND lysate,””immunotherapy,” COPD,” and “bronchitis.” Searches were limited to controlled clinical trial” and “human.” The last electronic search was made in July 2003. Searches were completed through the screening of bibliographies of included reports and relevant reviews. We also contacted authors of the included reports and two manufacturers of bacterial lysates (OM Pharma; Geneva, Switzerland; and Sankyo Pharma; Faellanden, Switzerland), and asked for information on additional trials including unpublished data.

Study Selection

Reports were considered for review if they described randomized comparisons of an oral bacterial (active) extract with placebo or no treatment (control) in adults with chronic bronchitis and COPD. and it they had reported on efficacy or harm. Studies on the prevention of acute respiratory tract infections in otherwise healthy subjects and on immunologic parameters were not considered. There was au intention to consider data from the abstracts of scientific meetings if the study methods were clearly described and data reporting was adequate.

Validity Assessment and Data Extraction

One author (CS) screened all retrieved reports and selected those that were potentially valid. There was an n priori agreement that reports without randomization would be excluded. All authors independently assessed the selected studies for methodological quality.17 Information was sought for the following six criteria: adequacy of patient enrollment; sequence generation: concealment of allocation; blinding (of patient, caregiver, outcome assessment, and data-analysis); a statement on how dropouts were handled; and the use of an intention-to-treat analysis. We arbitrarily assigned 1 point for each fulfilled criterion (maximum, 6 points). A quality score of > 3 was considered to be adequate by us. Authors met to compare assigned scores, and discrepancies were resolved by discussion.

Information about bacterial lysate regimens (ie, drug, dose, route of administration, and duration of treatment), the number of patients enrolled into the study and analyzed. the length of follow- up, sponsorship, and outcome measures were entered in standard collection sheets. This was done by one investigator (CS), and the work was cross-checked by the others. The primary outcome measure was the prevention of exacerbation. Definitions of exacerbation were taken as reported in the original trials. Secondary outcome measures were the duration of the exacerbation, the improvement of symptoms as assessed by observers and patients, the rate of hospitalization due to exacerbation, and adverse effects.

Statistical Analysis

Dichotomous data on efficacy and harm were abstracted into 2 2 tables. Heterogeneity was assessed graphically using forest plots, and statistically using the χ^sup 2^ test. We planned to perform meta-analyses in which data from individual studies would be pooled using a fixed-effects model if no statistical heterogeneity (p > 0.05) was detected. We explored the causes of heterogeneity by studying the features of populations (ie, inclusion and exclusion criteria), interventions (ie, drug regimens), outcomes (ie, clinical heterogeneity), and study quality (ie, methodological heterogeneity). In case of statistical heterogeneity, we decided to pool data using a random-effects model. Consequently, the pooled results would be interpreted with caution. We also planned to examine the influence of individual studies (for instance, small trials or those with inadequate study quality) on the summary effect estimate. The results were presented as relative risks (RRs) or odds ratios (ORs), the number needed to treat for one to benefit (NNTB) or the number needed to treat for one to be harmed (NNTH), with corresponding 95% confidence intervals (CIs).18 For continuous data (ie, duration of exacerbat\ion), we calculated the weighted mean differences (WMDs), taking into account study size and SDs as reported in the individual trials. Statistical analyses were carried out using a statistical software package (Stata, version 7.0; Stata Corp; College Station, TX).

RESULTS

We retrieved 71 potentially relevant reports, and 58 were subsequently excluded (Fig 1). Four potentially relevant reports19- 22 contained data from already published studies, but we only considered the original publications.20,21,23 One trial24 studied patients with recurrent airway infections. We used data on adverse effects only from this study. Two randomized trials25,26 did not provide information on our predefined primary or secondary outcome measures. In one study,27 the number of patients per group was unknown. The other excluded reports were on children,28-41 were performed in other clinical settings,42-48 were not on randomized trials,20,49-64 or contained immunology data only.12,65-71

FIGURE 1. Study selection process for the systematic review of oral purified bacterial extracts in chronic bronchitis and COPD patients.

We analyzed data from 13 randomized placebo-controlled trials from seven countries (Switzerland, three trials; Germany, two trials; Yugoslavia, two trials; France, two trials; Egypt, two trials; Canada, one trial; and Italy, one trial) that had been published from 1981 to 1998(16,22,24,72-81) (Table 1). Six trials were published in English, three each in French and German, and one in Italian. From four trials,24,79-81 only data on adverse drug reactions could be analyzed. One trial80 studied adults and children, and we extracted the data on adults only. No additional data, published or unpublished, were retrieved through contacts with manufacturers or authors. A total of 2,121 patients were randomized, and the original investigators analyzed 1,971 patients. The median dropout rate was 5% (range, 0 to 22%). The median number of analyzed patients was 104 (range, 19 to 381).

Table 1-Oral Bacterial Extracts: Description of Included Randomized Controlled Trials*

Methodological Quality

All trials were placebo-controlled, and there were no head-to- head comparisons. In general, the methodological quality of the studies was poor (Table 2). The median score was 2, with one trial scoring 6 and two scoring 4 (Table 2). One study16 only (7.7%) reported on consecutive patient enrollment, and two studies16,78 (15.4%) reported on the details of the generation of random sequences and of the concealment of treatment allocation. Four studies16,22,75,78 (30.8%) included a statement on how they had dealt with dropouts, and five studies16,22,73,77,79 (38.5%) used an intention-to-treat analysis. Only two studies,73,76 however, did not provide details about the blinding of patients and caregivers. Seven trials24,72,73,77,80 (53.8%) acknowledged sponsorship by a manufacturer, and in five (38.5%) one or several authors were the collaborators of a manufacturer.

Regimens

Ten studies16,22,72-74,76-79,81 tested OM-85BV (Broncho-Vaxom; OM Pharma). The usual regimens were one 7-mg capsule daily for 1 month, followed by one capsule daily for 10 days during the second and third month, or one capsule daily during the first 10 days of each month for 3 months. Two studies24,80 tested LW-50020 (Luivac; ALTANA Pharma; Bad Homburg, Germany), 3 mg daily for 2 to 3 months. One trial75 tested SL-04, 1 mL per day during the first 20 days of each month for 3 months. The observation period was 6 months in nine trials16,23,24,72-75,78,81 (69%), 3 months in one trial,77 4 months in two trials,79,80 and 12 months in one trial76 (Table 1).

Table 2-Quality Assessment*

Patients

In trials that reported on demographic data, there were more male patients than female patients (median, 60%; range, 43 to 80%). The inclusion criteria were COPD in 6 trials, chronic bronchitis in 10 trials, and more than three episodes of exacerbation within the previous year in 8 trials (Table 1). In the seven studies that reported on smoking habits, almost half of the analyzed patients (median, 48%; range, 23 to 93%) were smokers or ex-smokers. Lung function was reported in five trials (mild-to-moderate COPD, four trials; severe COPD, one trial).

Outcome Measures

There was a large variety in the reported end points. No more than five trials reported on the same efficacy end point.

Prevention of Exacerbation

Three trials (731 patients) reported on the prevention of exacerbation with OM-85BV16,78 or SL-04,75 and the observation period was always 6 months. A relationship between study quality and treatment efficacy became apparent (Fig 2). One large trial16 with good quality did not show any beneficial effect with the use of active extracts. Another large trial78 with lower quality, hut still acceptable quality, was significantly in favor of the use of active extracts. The largest treatment effect was with the smallest trial,75 which also had the lowest quality score. When all three trials were combined, the data were heterogeneous (p

Average Duration of Exacerbation

Three trials (223 patients) reported on the average duration of exacerbation with OM-85 BV73,74 and SL-04.75 The observation period was always 6 months. In all three trials, the duration of exacerbation was significantly shorter with treatment with active extracts compared with the control substance (WMD, -3.3 days [in favor of bacterial extracts]). Again, a small, low-quality trial75 showed the largest benefit. When this trial was excluded from the combined analysis, the WMD was -2.7 days (95% CI, -3.5 to -1.8) [Fig 3].

Improvement Assessed by Observers

Five trials22,72,73,76,77 (591 patients) of relatively poor quality reported on the improvement of symptoms assessed by the observers at the end of the study period. All trials tested OM- 85BV, and the study periods were 3 months,77 6 months,22,72,73 and 12 months.76 The event rate scatter suggested consistent superiority with bacterial extracts, relative homogeneity, and little variability in event rates. When all five trials were combined, the data were homogeneous (p = 0.6), and the difference between active extracts and placebo was statistically significant in favor of bacterial extracts (RR, 0.57; 95% CI, 0.49 to 0.66) [NNTB, 4; 95% CI, 2.8 to 5.4] (Fig 4).

FIGURE 2. Forest plot showing RRs for the prevention of COPD exacerbations. Estimates of RRs from individual studies reporting on the effectiveness of OM-85BV in the prevention of exacerbation alter > 6 months of follow-up in patients with COPD and chronic bronchitis. The Forest plot indicates that lower study quality is associated with higher effect size.

Improvement Assessed by Patients

Two trials72,76 reported on the improvement of symptoms assessed by the patients at the end of the study period. Both trials tested OM-85BV. In one trial,72 the observation period was 6 months, and in the other76 it was 12 months. Improvement was reported by 148 of 185 patients (80%) receiving active extracts compared with 86 of 156 control subjects (55%) [RR, 0.44; 95% CI, 0.31 to 0.61] (NNTB, 4; 95% CI, 3.0 to 5.9).

Hospitalization

Data on hospital admission tor respiratory problems came from one trial with an observation period of 6 months.16 Hospital admission was reported in 31 of 191 patients (16.2%) receiving OM-85-BV and in 44 of 190 patients (23.2%) receiving placebo (HR, 0.70; 95% CI, 0.46 to 1.06) [NNTB, 14; 95%, CI, 8.0 to ∞; NNTH, 72].

Adverse Effects

Skin itching or cutaneous eruptions were reported in 13 of 399 patients (3.3%) receiving OM-85BV,16,79 LW-50020,24 or SL-04,75 and in 4 of 403 control subjects (1%) [OR, 2.94; 95% CI, 1.12 to 7.69] (NNTH, 44; 95% CI, 14 to 161). Urologic problems, which in one trial78 were specified as lower urinary tract infections, were reported in 27 of 338 patients (8%) receiving OM-85BV,16,78 and in 10 of 333 control subjects (3%) [OR, 2.62; 95% CI, 1.35 to 5.11] (NNTH, 20; 95% CI, 10 to 61). Abdominal problems (eg, gastroenteritis, nausea, upper abdominal pain, diarrhea, and gastric upset) were reported in 46 of 801 (5.7%) patients receiving OM- 85BV16,73,77-79,81 and LW-50020,24,75,80 and in 37 of 735 control subjects (5.0%) [OR, 1.24; 95% CI, 0.78 to 1.95]. Allergic reactions (eg, asthma and rhinitis) were reported in 4 of 341 patients (1.2%) receiving OM-85BV77 or LW-50020,24,80 and in 1 of 291 control subjects (0.3%) [OR, 2.75; 95% CI, 0.47 to 16.3]. Study withdrawal due to adverse reactions was reported in 3 of 213 patients (1.4%) receiving OM-85BV777 or LW-50020,24 and in 2 of 208 control subjects (1.0%) [OR, 1.46; 95% CI, 0.25 to 8.50].

FIGURE 3. The WMD in the average duration of exacerbations with OM-85 BY over an observation period of 6 months. In the two trials, the duration of an exacerbation was significantly shorter with the use of active extracts compared with control substances (WMD, -2.7 days; 95% CI, -3.5 to -1.8).

FIGURE 4. Improvement assessed by observers. Five trials (591 patients) reported on the improvement of symptoms assessed by the observers at the end of the study period. All trials tested OM-85.

DISCUSSION

Our systematic review was unable to provide strong evidence that oral immunostimulation with bacterial extracts prevents exacerbations in patients with COPD and chronic bronchitis. Regarding the secondary end points, however, we found an improvement of symptoms, as rated by both patients and observers, and a shortening of the average duration of exacerbations of approximately 3 days when pooling the results of studies with li\mited methodological quality. Hospitalization due to respiratory problems was reported in one high-quality trial. This was the largest of all trials (381 patients), and it provided some evidence that the risk of hospital admission may be reduced with the use of bacterial extracts.16 Although our systematic review could not find an effect on the prevention of exacerbations, it has to be considered that both a decrease in severity and a reduction in the duration of exacerbations are relevant in the management of COPD patients.2 For instance, a decrease in the duration of an exacerbation might have an economic impact. Also, it should be taken into account that this therapy is relatively cheap and can be applied intermittently.

In patients for whom data on lung function were available, the majority had mild-to-moderate COPD. Therefore, we do not know whether bacterial extracts would be effective in reducing exacerbations in patients with severe COPD. Strictly speaking, the results from these analyses apply to patients with mild-to-moderate COPD only.

Regarding safety, we could not identify any difference in adverse GI symptoms and study withdrawals due to drug-related adverse effects compared to placebo. However cutaneous eruptions, itching, and lower urinary tract infections are common. We do not know whether one of those adverse effects was severe enough to stop patients from receiving the treatment. The main problem with the use of bacterial extracts max be the increased risk of lower urinary tract infections.

Robustness of Results

Our systematic review has some important limitations, and all are related to the relatively quality and limited validity of the original trials. However, it is important to know about methodological weaknesses in the original trials, since only then can such weaknesses be avoided in future trials.

We made strenuous efforts to minimize the risk of selection bias. Relevant reports were searched systematically and without language restriction. Four duplicate reports were identified and excluded from further analysis. The main risk is that biases in the original trials may lead to an overestimation of treatment effect. Indeed, the overall quality of the trials was poor. The included trials, however, reported on clinically homogenous settings, treatment regimens and periods were standardized (in most trials, the observation periods were 6 months), and information on the underlying risk suggested that study populations were comparable. Also, most trials used adequate methods of blinding, minimizing the risk of observer bias. Nevertheless, important methodological items such as patient enrollment, the generation of random sequences, the concealment of treatment allocation, and details about the statistical analysis were seldom reported. Furthermore, most trials were of limited size. The problem with small trials is that they may generate treatment effects by random chance. One of the smallest trials generated the most beneficial effect in favor of bacterial extract, both for the prevention and duration of exacerbation.75 Heterogeneity of the results was largely explained by this trial. When in sensitivity analyses that trial was excluded, treatment effects moved toward equality.

Pharmaceutical companies sponsored hall of the trials. Often, coauthors were the collaborators of a manufacturer. An association between competing interests and authors’ conclusions has been shown repeatedly.82 In our meta-analysis, however, authors conclusions per se were not considered. We do not know how potential competing interests may influence the way a clinical trial is designed and conducted, and the way the data are analyzed and reported.

The trials reported on a large variety of different end points. It was impossible to combine outcome data from more than five trials. The main end point, prevention of exacerbation, was reported in three trials only, and one of those trials was of limited size and quality. Finally, the data were too sparse to allow for formal sensitivity analyses, addressing, for instance, the relative efficacy of different bacterial extracts or the impact of the duration of treatment.

Future Research

A question that should be examined in further trials is whether or not bacterial extracts are more effective in preventing exacerbations of COPD in high-risk patients with severely impaired lung function. Further relevant end points to consider are hospital admission, duration of disease-free intervals, saved days of absence of work, and the need for concomitant medications, especially antibiotics and systemic corticosteroids, as all these factors contribute to cost. It may also be of interest to know whether there was an additive or even synergistic effect when different treatments are given concomitantly in these patients, for instance, bacterial extracts with the use of inhaled steroids or mucolytic agents.

In conclusion, given the high prevalence of COPD, the impact of exacerbations on quality of life, and the costs incurred, effective ways for the prevention of exacerbations, and for reductions in the severity and duration of COPD symptoms are needed. So far, there is no strong evidence that oral bacterial extracts reduce the frequency of exacerbations, however, they seem to have a favorable effect on the severity of symptoms. Consequently, the agenda is one of further research rather than of clinical recommendations.

ACKNOWLEDGMENT: We thank Dr. P. Estermann from the Library Service of the Zurich University Hospital for his help in searching electronic databases, and Professor E. Tassonyi for translating Hungarian studies.

* From the Medical Policlinic (Dr. Steurer-Stey), Department of Internal Medicine, University Hospital, Zurich, Switzerland; Horten Centre for Patient Oriented Research (Drs. Bachmann und Steurer), University of Zurich, Zurich, Switzerland; and the Department of Anesthesiology, Pharmacology, and Surgical Intensive Care (Dr. Tramr), Division of Anesthesiology, Geneva University Hospitals, Geneva, Switzerland.

This study was supported by Programme for Social Medicine and Preventive and Epidemiologic Research grant No. 3233-051939.97/2 from the Swiss National Research Foundation (to MRT).

REFERENCES

1 Strassels SA, Smith DH, Sullivan SD, et al. The costs of treating COPD in the United States. Chest 2001; 119:344-352

2 Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 163:1256-1276

3 Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157(suppl):1418- 1422

4 Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000; 117(suppl):5S-9S

5 Pearson MG, Littler J, Davies PD. An analysis of medical workload: evidence of patient to specialist mismatch. J R Coll Physicians Lond 1994; 28:230-234

6 British Thoracic Society. BTS guidelines for the management of chronic obstructive pulmonary disease: the COPD Guidelines Group of the Standards of Care Committee of the BTS. Thorax 1997; 52(suppl):S1-S28

7 American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152(suppl):S77-S121

8 The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000; 343:1902-1909

9 Burge PS, Calverley PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320:1297-1303

10 Stey C, Steurer J, Bachmann S, et al. The effect of oral N- acetyleysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J 2000; 16:253-262

11 Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. BMJ 2001; 322:1271-1274

12 Emmerich B, Pachmann K, Milatovic D, et al. Influence of OM- 85 BV on different humoral and cellular immune defense mechanisms of the respiratory tract. Respiration 1992; 59(suppl):19-23

13 Lusuardi M, Capelli A, Donner CF. Lung immune defences after stimulation of gut-associated lymphoid tissue with OM-85 BV: a double-blind study in patients with chronic bronchitis. Eur Respir Rev 1996; 6:182-185

14 Mauel J. Stimulation of immunoprotective mechanisms by OM-85 BV: a review of results from in vivo and in vitro studies. Respiration 1994; 61(suppl):8-15

15 Keul R, Roth M, Papakonstantinou E, et al. Induction of interleukin 6 and interleukin 8 expression by Broncho-Vaxom (OM-85 BV) via C-Fos/serum responsive element. Thorax 1996; 51:150-154

16 Collet JP, Shapiro P, Ernst P, et al. Effects of an immunostimulatiug agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease: the PARI-IS Study Steering Committee and Research Group; Prevention of Acute Respiratory Infection by an Immunostimulant. Am J Respir Crit Care Med 1997; 156:1719-1724

17 Centre for Reviews and Dissemination. Undertaking systematic reviews of research on effectiveness: CRD’s guidance for those earning out or commissioning reviews. 2nd ed. CRD Report No. 4. York, UK: Centre for Reviews and Dissemination, 2001

18 Altman DG. Confidence intervals for the number needed to treat. BMJ 1998; 317:1309-1312

19 Debbas N, Derenne JP. Preventive effects of an immunostimulating product on recurrent infections of chronic bronchitis in the elderly. Lung 1990; 168(suppl):737-740

20 Ahrens J, Wiedenbach M. Efficacy of the immunostimulant Broncho-Yaxom. Schweiz Med Wochenschr 1984; 114:932-934

21 Orcel B, Delclaux B, B\aud M, et al. Oral immunization with bacterial extracts for protection against acute bronchitis in elderly institutionalized patients with chronic bronchitis. Eur Respir J 1994; 7:446-452

22 Keller R. Multicenter double blind trial of Broncho-Vaxom in chronic bronchitis. Schweiz Med Wschr 1984; 114:934-937

23 Keller R, Hinz G. Effect of an oral polyvalent bacterial lysate (Broncho-Vaxom) in chronic bronchitis. Prax Klin Pneumol 1984; 38:225-228

24 Fischer H, Eckenberger HP, van Aubel A, et al. Prvention von Infektrezidiven der oberen und unteren Luftwege. Atemw Lungenkrkh 1992; 4:146-155

25 Hutas I, Kraszko P, Boszormenyi NG. Immunomodulation therapy in chronic bronchitis (multicenter study). Orv Hetil 1994; 135:1251- 1254

26 Xinogalos S, Duratsos D, Varonos D. Clinical effectiveness of broncho-vaxom (BV) in patients with chronic obstructive pulmonary disease. Int J Immunother 1993; 9:135-142

27 Kaspar P, Petro W. Inhalative immunostimulation in patients with chronic bronchitis. Z Hautkr 1988; 63(suppl):64-66

28 Baretto DG, De La TC, Alvarez A, et al. Safety and efficacy of OM-85-BV plus amoxicillin/clavulanate in the treatment of subacute sinusitis and in the prevention of recurrent infections in children. Allergol Immunopathol (Madr) 1998; 26: 17-22

29 Collet JP, Ducruet T, Kramer MS, et al. Stimulation of nonspecific immunity to reduce the risk of recurrent infections in children attending day-care centers: the Epicreche Research Group. Pediatr Infect Dis J 1993; 12:648-652

30 Collet JP, Boissel JP. OM-85 BY: primary versus secondary prevention. Respiration 1994; 61(suppl 1):20-23

31 Goldschiuidt O, Kahl L. Klimek L. et al. Specific anti- infective immune therapy: an effective way to treat recurrent tonsillitis in childhood [abstract]. Drugs 1997; 54(suppl):38

32 Gutierrez-Tarango MD, Berber A. Satety and efficacy of two courses of OM-85 BY in the prevention of respiratory tract infections in children during 12 months. Chest 2001; 119: 1742-1748

33 Jara-Perez JV, Berber A. Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial. Clin Ther 2000; 22:748-759

34 Losa GA, Maestroni GJ. Clinical and immunobiological action of an orally administered bacterial extract. Schweiz Med Wochenschr 1984; 114:930-932

35 Maestroni GJ, Losa GA. Clinical and immunobiological effects of an orally administered bacterial extract. Int J Immunopharmacol 1984; 6:111-117

36 Martin du Pan RE, Martin du Pan RC. Clinical study concerning the prevention of infections of the upper respiratory tract of preschool children. Schweiz Rundsch Med Prax 1982; 71:1385-1389

37 Moratti G, Canepa GS, Scelsi F, et al. The use of bacterial lysates in postoperative immunodeficiency in ENT. Otorinolaringol Pediatr 1999l 10:81-88

38 Paupe J. Immunotherapy with an oral bacterial extract (OM-85 BV) for upper respiratory infections. Respiration 1991; 58:150-154

39 Riedl-Seifert RD, van Aubel A, Kmmereit A, et al. Infektrezidive im Kindesalter- noch immer iene Crux medicorum? Ergebnisse einer plazebokontrollierten Doppelblindstudie mit einem oralen Bakterienlysat bei infektanflligen Kindern. J Pharmacol Ther 1993; 3:108-117

40 Schaad UB, Mutterlein R, Goffin H. Immunostimulation with OM- 85 in children with recurrent infections of the upper respiratory tract: a double-blind, placebo-controlled multicenter study. Chest 2002; 122:2042-2049

41 Zayar S, Lofler-Badzek D. Broncho-Vaxom in children with rhinosinusitis: a double-blind clinical trial. ORL J Otorhinolaryngol Relat Spec 1988; 50:397-404

42 Bergmann ChK, Dehnert I, Eckert H, et al. Klinische wirksamkeit eines polyvalenten bakterinsprays: eine plazebo- kontrollierte doppelblindstudie. Atemw Lungenkrkh 1983; 9:126-130

43 Czerniawska-Mysik G, Adamek-Guzik T, Dyczek A, et al. Double- blind clinical study with Broncho-Vaxom in the treatment of recurrent acute bronchitis and bronchial asthma. Int J Immunother 1992; 8: 153-159

44 Geiser G. Prevention des maladies respiratoires une grande enterprise industrielle: etude en double-aveugle du Broncho-Vaxom. Acta Ther 1983; 9:289-303

45 Heintz B, Schlenter WW, Kirsten R, et al. Clinical efficacy of Broncho-Vaxom in adult patients with chronic purulent sinusitis; a multicentric, placebo-controlled, double-blind study. Int J Clin Pharmacol Ther Toxicol 1989; 27:530-534

46 Schlenter WW, Blessing R, Heintz B. Clinical efficacy of Broncho-Vaxom in adult patients with chronic purulent sinusitis: a multicentric, placebo-controlled, double-blind study. Laryngorhinootologie 1989; 68:671-674

47 Sequiera RB. Immunobiotherapy with Broncho-Vaxom in the prevention of postoperative respiratory infection. Med Hyg 1980; 38:2752-2753

48 Tielemans C, Gastaldello K, Husson C. et al. Efficacy of oral immunotherapy on respiratory infections in hemodialysis patients: a double-blind, placebo-controlled study. Clin Nephrol 1999; 51:153- 160

49 Anthonisen NR. OM-SBV for COPD. Am J Respir Crit Care Med 1997; 156:1713-1714

50 Basacopol A. Broncho-Vaxom in the treatment of chronic pulmonary lesions. Pneumoftiziologia 1992; 41:25-30

51 Bergemann R, Brandt A, Zoellner U, et al. Preventive treatment of chronic bronchitis: a meta-analysis of clinical trials with a bacterial extract (OM-85 BV) and a cost-effectiveness analysis. Monaldi Arch Chest Dis 1994; 49:302-307

52 Chyerek-Borowska S. Moniuszko T, Szymanski W, et al. Broncho- Vaxom in the treatment and prophylaxis of recurrent respiratory tract infections in bronchial asthma. Pneumonol Alergol Pol 1992; 60(suppl):117-119

53 Collet JP. Immunomodulators and primary prevention of respiratory infections: methodological considerations. Dev Biol Stand 1902; 77:159-165

54 Collet JP, Ducruet T, Haider S, et al. Economic impact of using an immunostimulating agent to prevent severe acute exacerbations in patients with chronic obstructive pulmonary disease. Can Respir J 2001; 8:27-33

55 Dahan R, Costantini D, Caulin C, et al. Clinical trials with C 1740. an immunomodulator compound proposed for prevention of acute infections exacerbations in chronic bronchitis. Methods Find Exp Clin Pharmacol 1986; 8:41-43

56 Debelic M. Eckenberger HP. Prevention of recurrent infection of the upper and lower airways. Multicenter, open study over three months. Fortschr Med 1002; 110:565-570

57 Derenne JP, Delclaux B. Clinical experience with OM-85 BV in upper and lower respiratory tract infections. Respiration 1992: 59(suppl):28-31

58 Farine JC, Meredith M. Clinical evaluation of a bacterial immunomodulator in chronic bronchitis. In: Advances in immunostimulation. Rome, Italy: Pythagora Press, 1988; 403-408

50 Grevers G, Palacios OA, Rodriguez B, et al. Treatment of recurrent respiratory tract infections with a polyvalent bacterial lysate: results of an open, prospective, multinational study. Adv Ther 2000; 17:103-116

60 Hajicek VL, Hajicek V. Utilisation du Broncho-Vaxom(R) dans le traitement de la bronchite asthmatiforme. Acta Ther 1980; 6:167-176

61 Palma-Carlos AG, Palma-Carlos ML, Inacio FF, et al. Oral chemotherapy with lyophilized bacterial lysate in patients with recurrent respiratory tract infections. Int J Immunother 1987; 3:123- 130

62 Panagiotou A, Loukides S, Georgiades G, et al. Broncho-Vaxom, an oral immunotherapy for the maiianement of acute exacerbations of chronic bronchitis in adults. Acta Ther 1993; 19:397-400

63 Spiropoulos K, Lymberopoulos D, Ginopoulos P, et al. Effect of ling term therapy with oral Broncho-Vaxom in spirometry of chronic bronchitis patients. Lotta Tuberculosi Mal Polm Sociali 1995; 65:167- 171

64 Wiedey KD. Rezidivierende atemwegsinfektionen. Fortschr Med 1987; 105:176-180

65 Emmerich B, Emslander HP, Milatovic D, et al. Effect of a bacterial extract on local immunity of the lung in patients with chronic bronchitis. Lung 1990; 168(suppl):726-731

66 Emmerich B, Emslander HP, Pachmann K, et al. Local immunity in patients with chronic bronchitis and the effects of a bacterial extract. Broncho-Vaxom, on T lymphocytes, macrophages, gamma- interferon and secretorv immunoglobulin A in bronchoalveolar lavage fluid and other variables. Respiration 1990; 57:90-90

67 Lusuardi M, Capelli A, Carli S, et al. Local airways immune modifications induced by oral bacterial extracts in chronic bronchitis. Chest 1993; 103:1783-1791

68 Malolepszy J, Chyerek-Borowska S, Siwinska-Golebiowska HK, et al. Multicenter clinical trial of Broncho-Vaxom in chronic bronchitis and asthma. Acta Ther 1991; 17:273-282

69 Rossi ME, Lega L, Azzari C, et al. Effect of a polyvalent bacterial preparation on natural killer cell activity in children with recurrent respiratory infections. J Immunother 1993; 9:225-233

70 Spiropoulos K, Lymberopoulos D, Garantziotis G, et al. Salivary immunoglobulin A production in chronic bronchitis patients given an orally administered bacterial extract. Respiration 1993; 60:313-318

71 Weiss S, Fnux T. Effect of Broncho-Vaxom on serum IgE and IgG levels in patients with bronchial asthma and chronic obstructive lung disease. A placebo-controlled double-blind study. Schweiz Med Wochenschr 1987; 117:1514-1518

72 Ahrens J. Clinical effects of oral immunotherapy. Atemw Lungenkrkh 1983; 9:424-427

73 Cvoriscec B, Ustar M, Pardon R, et al. Oral immunotherapy of chronic bronchitis: a double-blind placebo-controlled multicentre study. Respiration 1989; 55:129-135

74 Djurie O, Mihailovic-Vucinic V, Stojcic V. Effect of Broncho- Vaxom on clinical and immunological parameters in patients with chronic obstructive bronchitis: a double-blind, placebo-controlled study. Int J Immunother 1989; 5:139-143

75 Germouty J. Immunotherapy of recurrent respiratory infections. Double-blind study of a new immunomodulator in 60 patients. Rev Pneumol Clin 1986; 42:207-213

76 Khedr MS. Clinical and immunological efficacy of Broncho- Vaxom in chronic bronchitis: a double-blind study. Acta Ther 1993; 19:49-60

77 Messerli C, Michetti F, Sauser-HallP, et al. Effect of a bacterial lysate (Broncho-Vaxom) in the therapy of chronic bronchitis: multi-center double-blind clinical trial. Rev Med Suisse Romande 1981; 101:143-146

78 Orcel B, Delclanx B, Band M, et al. Preventive effect of an immunomodulator, OM-85 BV, on acute exacerbations of chronic bronchitis in elderly patients: Preliminary results at six months in 291 patients. Rev Mal Respir 1993; 10:23-28

79 Orlandi O, Bruna S, Bagnasco G. Immunostimulation treatment with a bacteriolysate in recurring bacterial infections in chronic bronchitics. Min Pneumol 1983; 22:461-464

80 Rutishanser M. Pitzke P, Grevers G, et al. Use of a polyvalent bacterial lysate in patients with recurrent respiratory tract infections: results of a prospective, placebo-controlled, randomized, double-blind study. Adv Ther 1998; 15:330-341

81 Tag El Din MA, Ashmawi S, Emam WEM. Effect of a polyvalent bacterial extract. Broncho-Vaxom, in the prophylaxis of acute exacerbations of chronic bronchitis. Eur J Clin Res 1993; 4:99-105

82 Kjaergard LL, Als-Nielsen B. Association between competing interests and authors’ conclusions: epidemiological study of randomised clinical trials published in the BMJ. BMJ 2002; 325:249

Claudia Steurer-Stey, MD; Lucas M. Bachmann, MD, PhD; Johann Steurer, MD; and Martin R. Tramr, MD, DPhil

Manuscript received January 15. 2004; revision accepted April 20, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

Correspondence to: Claudia Steurer-Stey, MD, Medical Policlinic, University Hospital, Raemistrasse 100, CH-8091 Zurich, Switzerland; e-mail: [email protected]

Copyright American College of Chest Physicians Nov 2004

The Beached Whale Diet

I’ve been “on a diet” for as long as I can remember. I honestly think I’m obsessed with the word. Whether it is a joke or serious, I say “diet” way too often.

For everyone who goes through this, I know how hard it is to change old habits. For example, yesterday I went to pre-basketball practice and was so excited I thought to myself, “Perfect opportunity to lose weight in a very natural way.”

So what did I do when I went home? Sat in front of the TV with root beer and leftover Halloween candy, and watched “Uptown Girls.”

I honestly tried not to eat the M&Ms, but just sitting there, knowing that I had to go work out after the movie, one piece after another just found its way into my mouth. Although I said that’s all I was going to eat, I soon found myself looking at the candy instead of the TV. About 10 minutes later I reached for another and found nothing. There were no more M&Ms in the dish.

After that I felt like something out of “Bridget Jones’s Diary,” because I felt humiliated, depressed, and most of all, like a whale. I realized I had just eaten the entire bowl of M&Ms.

Dieting isn’t easy, especially around the holidays. Thanksgiving is the best because of the turkey, potatoes, stuffing and rolls, but also one of the most depressing holidays. I eat so much that keeping my eyes open becomes a chore, and I unfortunately never learn from my mistakes, because I find myself inhaling food again the next year.

I’ve been trying to do the South Beach Diet, but to my despair potatoes aren’t allowed, so I’m not able to stick to it. I don’t care if they’re mashed, baked, twice baked, diced, cubed, scalloped; it doesn’t matter. I am the most pathetically in-love-with-potatoes person you’ll ever meet.

I’m not proud to say I’ve been practicing the Beached Whale diet, but I have been. Why does that seem to be the only one I can actually stick with? Oh yeah, because that’s where you forget about veggies and go overboard on junk food.

I wish all of you the best of luck with dieting, and maybe someday I’ll have enough self-control to let myself really diet, but until that day, I’m going to enjoy the coming holiday by eating myself sick with my grandma’s fabulous cooking.

Besides, I wouldn’t want to injure her pride by not eating three helpings. After Thanksgiving I plan to ask my aunt, who happens to be a dietitian, for some tips to help me to lose weight in a fun, healthy way.

Like I said, it won’t be happening until after Thanksgiving.

Mice Deficient in Methylenetetrahydrofolate Reductase Exhibit Tissue- Specific Distribution of Folates1

ABSTRACT

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S- adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent methylation reactions. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. To assess how impaired MTHFR activity affects folate metabolism in various tissues in vivo, we used affinity/HPLC with electrochemical detection to analyze the distribution of folates in plasma, liver, and brain of /Mthfr- deficient mice. The most pronounced difference in total folate was observed in plasma. In Mthfr -/- mice, plasma total folate levels were -25% of those in wild-type (Mthfr +/+) mice. Only 40% of plasma folate in Mthfr -/- mice was comprised of 5-methylTHF, compared with at least 80% in the other 2 genotype groups. In liver and brain, there were no differences in total folate. However, the proportion of 5-methylTHF in both tissues was again markedly reduced in mice with the Mthfr -/- genotype. In this genotype group, 5-methylTHF is likely derived from the diet. Our study demonstrated reduced total circulatory folate and altered distribution of folate derivatives in liver and brain in Mthfr deficiency. Decreased methylfolates and increased nonmethylfolates would affect the flux of one-carbon units between methylation reactions and nucleotide synthesis. This altered flux has implications for several common disorders, including cancer and vascular disease. J. Nutr. 134:2975-2978, 2004.

KEY WORDS: * folate distribution * methyltetrahydrofolate * formylated-folates * MTHFR deficiency

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR;3 EC 1.5.1.20) catalyzes the irreversible reduction of 5,10- methylenetetrahydrofolate (5,10-methyleneTHF) to 5- methyltetrahydrofolate (5-methylTHF). This reduction is crucial because it serves several biological reactions as follows: 1) 5- methylTHF provides the methyl group for the remethylation of homocysteine to methionine. Methionine is a precursor of S- adenosylmethionine (SAM), the universal methyl donor for many methylation reactions including DNA, proteins, lipids, hormones and others (1-3). 2) The substrate 5,10-methyleneTHF is also used in thymidylate synthesis or converted to 10-formylTHF for purine synthesis (4). Because the MTHFR reaction is irreversible, it diverts folate coenzymes to 5-methylTHF, and potentially to the trapping of folate coenzymes (5). 3) It provides 5-methylTHF (monoglutamates), which serves in the transport and trafficking of folate in and out of peripheral tissues (6).

Severe deficiency of MTHFR results in the inborn error of metabolism, homocystinuria, a relatively rare disorder for which >25 different mutations in MTHFR were identified (7). A mild deficiency of MTHFR, a more common condition, is present in 10-15% of many North American and European populations, due to homozygosity for a polymorphism (677C[arrow right]T) that encodes a thermolabile enzyme with reduced activity (8). We generated Mthfr knockout mice, providing a model with which to study the consequences of a disturbance in folate metabolism (9). The homozygous knockout mice (Mthfr -/-) have a 10-fold elevation in plasma homocysteine (~ 30 vs. ~3 mol/L in wild-type mice), altered SAM and SAH levels, and decreased DNA methylation in several tissues. The heterozygous knockout mice (Mthfr +/-) have moderate changes in the above parameters; their plasma homocysteine values are ~5 mol/L. Due to the above features, the Mthfr -/- and Mthfr +/- mice are considered good animal models for severe and mild MTHFR deficiency in humans, respectively.

Because MTHFR deficiency should result in the absence of newly synthesized 5-methylTHF, the present study was undertaken to determine how this deficiency affects plasma folate, which is normally made exclusively of 5-methylTHF (monoglutamate). Moreover, because plasma 5-methylTHF is considered to be the transport species across the cell membrane, this study also investigated folate distribution in peripheral tissues. Because our earlier report of these mice demonstrated that peripheral tissues from Mthfr- deficient mice did contain some 5-methylTHF (9), we also investigated potential sources of this folate form.

MATERIALS AND METHODS

Mthfr-deficient mice. Mice with severe (Mthfr -/-) and mild (Mthfr +/-) deficiency were generated and housed as described previously (9). Mice were progeny from matings of Mthfr +/- mice that had been backcrossed for at least 10 generations from 129/ SvBALB/c F1 heterozygotes (9) to BALB/cAnNCrlBR (Charles River Canada). Animal experimentation was approved by the Animal Care Committee of the Montreal Children’s Hospital and complied with the guidelines of the Canadian Council for Animal Care. The mice were fed standard mouse food (Harlan Teklad LM-485 Mouse, code 7012). After overnight food deprivation, blood was collected from the tail vein in vacutainer tubes containing EDTA. Plasma was obtained after centrifugation at 2000 g for 5 min and stored at -70C until analysis. Mice were killed and liver and brain tissues were immediately removed and also stored at -70C until analysis. Mthfr genotypes were determined by a PCR-based method as previously described (9).

Analysis of folate distribution. Folate distribution was determined in liver, brain, and plasma using the affinity/HPLC method with electrochemical (coulometric) detection (10) with minor modifications. Briefly, plasma was diluted 10-fold with extraction buffer (0.05 mol/L potassium tetraborate, 1% sodium ascorbate, pH 9.2), heat extracted (100C for 15 min) and centrifuged for 15 min at 36,000 g. Liver and brain samples were homogenized with extraction buffer MES (0.05 mol/L MES, 0.1 mol/L DET, 1% sodium ascorbate, pH 6.0), heat extracted (100C for 15 min), and centrifuged for 15 min at 36,000 g. Conjugase from folate-free rat plasma was added to the supernatant and incubated at 37C for 1.5 h. The samples were then heated at 100C for 5 min, and centrifuged for 20 min at 36,000 g. The supernatant fraction (2 mL) was injected into the affinity column (10 4.6 mm), which contained purified milk folate binding protein covalently bound to AffiPrep 10 support (BioRad). After washing the affinity column sequentially with 0.05 mol/L potassium phosphate (pH 7) and water, folate in the affinity column was eluted onto the analytical column (Betasil Phenyl, 250 4.6 mm, Keystone Scientific) with an acid mobile phase (0.028 mol/L dipotassium phosphate and 0.06 mol/L phosphoric acid in water). Folate was then eluted from the analytical column using the same aqueous mobile phase at a flow rate of 1 mL/min for 6 min followed by a linear gradient over 50 min of the same mobile phase containing 20% acetonitrile (v:v). This elution separates folates both on the basis of their pteridine ring structure and on their number of glutamate residues. Folate forms elute in the following order: tetrahydrofolate (THF), 5-methylTHF, 5- and 10-formylTHF, 5,10- methenylTHF, dihydrofolate (DHF), and folic acid (pteroylglutamate). Folate activity was determined using an ESA Four Channel Coularray Detector with channels 1 through 4 set at 0, 300, 500, and 600 mV, respectively. Quantification and identification of individual folates were achieved by comparison with external folate standards of known concentration. To simplify the comparison of various folate forms, the values of 5,10-methenylTHF were added to those of the corresponding 10-formylTHF and 5-formylTHF, and referred to as formylated-THF. 5-MethylTHF and total folate in the mouse diet were determined using the combined affinity and ion-pair chromatography detection as described previously (11,12).

Statistical analysis. All values are reported as means SEM. Differences among groups were evaluated by ANOVA. When the ANOVA was significant (P

RESULTS

Folate in plasma from the Mthfr +/+ and Mthfr +/- mice consisted primarily (82-94%) of 5-methylTHF (Table 1). In mice with the Mthfr – /- genotype, however, plasma folate consisted of more nonmethylated (60%) and less methylated (40%) folate. The percentage of 5- methylTHF in plasma of Mthfr +/- mice tended to be lower (82.1%) than that in Mthfr +/+ mice (93.6%; P = 0.06). Another important difference between the genotypes was the significant decrease, ~75% lower, in total plasma folate in mice with the Mthfr -/- genotype, compared with total plasma folate in mice with the other 2 Mthfr genotypes (Table 2).

In liver, the chromatogram peak for 5-methylTHF was barely discernible in mice with the Mthfr -/- genotype; it comprised only 0.5% of total folate, compared with 7.7-9.1% in extracts from mice with the +/- and +/+ genotypes (Table 1). In spite of these differences in the relative proportion of 5-methylTHF, tot\al folate in liver extracts did not differ among the 3 genotypes (Table 2).

As in plasma and liver, the peak in brain corresponding to 5- methylTHF was attenuated in mice with the Mthfr -/genotype and was 13% of the total folate, compared with the other genotypes in which the proportion of 5-methylTHF was 30-35% of the total (Table 1). Extracts from brains contained significantly higher percentages of 5- methylTHF compared with liver, irrespective of the genotype, and a lower percentage of THF and formylTHF (P

Mthfr +/- mice had lower 5-methylTHF in plasma, compared with the Mthfr +/+ group; the decrease in 5-methyl-THF levels also tended to occur in liver and brain of this genotype (P

Because of the presence of 5-methylTHF in extracts of mice that lack MTHFR, we conducted an HPLC analysis of the folate in their standard mouse food. This analysis revealed that the food contained 231 g 5-methylTHF and 6.7 mg folic acid/kg diet (data not shown).

TABLE 1

Percentage of individual folate forms in total folate from plasma, liver and brain of mice stratified by Mthfr genotype1

TABLE 2

Total folate in plasma, liver and brain of mice stratified by Mthfr genotype1

DISCUSSION

In the present study, we demonstrated that the absence of MTHFR activity is associated with altered distribution of folate, i.e., a decrease in methylated folates and an increase in unsubstituted THF or formylated THF. Nevertheless, tissue from mice with the Mthfr -/- genotype did contain traces of 5-methylTHF that amounted to 40% in plasma, 0.5% in liver, and 13% in brain, compared with mice with the +/+ genotype (94% in plasma, 9% in liver and 35% in brain). We found that the mouse food used in this study contained a substantial amount of 5-methylTHF. Therefore the 5-methylTHF detected in tissues of Mthfr -/- mice must be derived from the diet (13) because Mthfr – /- mice were already shown to have undetectable Mthfr mRNA and enzymatic activity (9). There was also a trend toward lower 5- methylTHF in Mthfr +/mice in the 3 tissues examined (P = 0.08 for the overall trend). It is likely that these mice were also obtaining 5-methylTHF from dietary sources and therefore not exhibiting a more significant decrease as might be expected for a mutant allele. As suggested for humans with mild MTHFR deficiency, the Mthfr +/- mice may require low-folate diets to manifest a disruption in folate and homocysteine metabolism.

In our original report on Mthfr-deficient mice, we examined the percentage of 5-methylTHF in liver and brain of mice with the 3 genotypes. We observed a similar trend i.e., a decreased percentage of 5-methylTHF in the Mthfr -/- genotype, although the absolute values were different (9). In that report, the mice were newly generated animals; consequently, they were of a mixed genetic background. The mice examined in this report were of a uniform BALB/ c background. Consequently, our measurements across the 3 genotypes in this study reflect changes due to Mthfr deficiency alone, rather than to other unidentified strain-related factors.

Another feature of mice with the Mthfr -/- genotype is the lower concentration of plasma total folate, 75% lower, than that in mice with the +/+ genotype. Usually 5-methyl-THF is the predominant circulatory form. With the decrease in plasma 5-methylTHF, unsubstituted THF becomes the predominant form in Mthfr -/- mice. Under normal circumstances, THF may be less efficiently released from body stores into the circulation or it is degraded in plasma due to its susceptibility to oxidative cleavage. However, despite the fact that the concentration of plasma folate in Mthfr -/- mice was substantially lower than that in the +/+ genotype, peripheral tissues were able to maintain sufficient levels of total folate. This would suggest either that the transport of nonmethylated folate is enhanced to maintain intracellular stores or that the folate concentration in plasma of the wild-type mouse is excessive, beyond that required for saturable tissue transport.

We found a higher proportion of formylated-THF in the liver compared with the brain, independently of Mthfr genotype. In contrast, the proportion of 5-methylTHF in the brain relative to that in the liver was significantly higher in mice with all 3 Mthfr genotypes [ratio (mean SEM): +/+, 3.89 3;+/-, 3.84 1.5 vs.-/-, 26.6 13; P

Bagley and Selhub (14) reported higher formylated-THF in RBC of individuals homozygous for the 677C[arrow right]T mutation, and implied impaired conversion to methylated folates in immature RBC. As mentioned above, the tissue/cell type may determine the requirement of certain folate forms for a particular pathway such as cellular methylation. Recent studies by Stover and co-workers reported enzymatic competition between thymidylate synthase and MTHFR for one-carbon units (15,16). Scott and Weir (17) suggested that a shift in folate distribution may create a competition among folate metabolic pathways, which may play a regulatory role between the DNA synthesis and methionine synthesis pathways. These metabolic variations may contribute to disturbances in methylation (18) or homocysteine elimination (8), with an effect on certain pathological conditions such as cancer and vascular diseases, and can provide additional insights into the role of MTHFR deficiency in these and other common disorders (19,20).

ACKNOWLEDGMENTS

We thank Paul Jacques (Tufts University) for assistance with the statistical analyses, and Abbey Johnston and Qing Wu for technical assistance.

1 Supported by operating funds and a Senior Scientist Award from the Canadian Institutes of Health Research (CIHR) to R.R. and by funds from the U.S. Department of Agriculture under agreement no. 581950-9-001 to J.S. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not reflect the view of the USDA.

3 Abbreviations used: DHF, dihydrofolate; FA, folie acid; 10- formylTHF, 10-formyltetrahydrofolate; 5,10-methenylTHF, 5,10- methenyltetrahydrofolate; 5-methylTHF, 5-methyltetrahydrofolate; 5,10-methyleneTHF, 5,10-methylenetetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; SAM, S-adenosylmethionine; THF, tetrahydrofolate.

LITERATURE CITED

1. Selhub, J. (1999) Homocysteine metabolism. Annu. Rev. Nutr. 19: 217-246.

2. Clarke, S. (1993) Protein methylation. Curr. Opin. Cell Biol. 5: 977-983.

3. Shane, B. (1995) Folate chemistry and metabolism. In: Folate in Health and Disease (Bailey, L. B., ed.), pp 1-22. Marcel Dekker, New York, NY.

4. Shane, B. (1989) Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitam. Norm. 45: 263-335.

5. Selhub, J. & Miller, J. W. (1992) The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S- adenosylmethionine of the remethylation and trassulfuration of homocysteine. Am. J. Clin. Nutr. 55:131-138.

6. Suh, J. R., Herbig, A. K. & Stover, P. J. (2001) New perspectives on folate catabolism. Annu. Rev. Nutr. 21: 255-282.

7. Rosenblatt, D. & Fenton, W. A. (2001) Inherited disorders of folate and cobalamin transport and metabolism. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. (Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, K.W. & Vogelstein, B., eds.), pp. 3897-3933. McGraw-Hill, New York, NY.

8. Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J., den Heijer, M., Kluijtmans, L. A., van den Heuvel, L. P. & Rozen, R. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10: 111-113.

9. Chen, Z., Karaplis, A. C., Ackerman, S. L., Pogribny, I. P., Melnyk, S., Lussier-Cacan, S., Chen, M. F., Pai, A., John, S. W., Smith, R. S., Bottiglieri, T., Bagley, P., Selhub, J., Rudnicki, M. A., James, S. J. & Rozen, R. (2001) Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum. Mol. Genet. 10: 433-443.

10. Bagley, P. J. & Selhub, J. (2000) Analysis of folate form distribution by affinity followed by reversed-phase chromatography with electrical detection. Clin. Chem. 46: 404-411.

11. Bagley, P. J. & Selhub, J. (1997) Analysis of folates using combined affinity and ion-pair chromatography. Methods Enzymol. 281: 16-25.

12. Pfeiffer, C., Rogers, L. M. & Gregory, J. F., 3rd (1997) Determination of folate in cereal-grain food products using trienzyme extraction and combined affinity and reversed-phase liquid chromatography. J. Agric. Food Chem. 45: 407-413.

13. Rong, N., Selhub, J., Goldin, B. R. & Rosenberg, I. H. (1991) Bacterially synthesized folate in rat large intestine is incorporated into host tissue folyl polyglutamates. J. Nutr. 121: 1955-1959.

14. Bagley, P. J. & Selhub, J. (1998) A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc. Natl. Acad. Sci. U.S.A. 95: 13217-13220.

15. Oppenheim, E. W., Adelman, C., Liu, X. & Stover, P. J. (2001) Heavy chain ferritin enhances serine hydroxymethyltransferase expression and de novo thymidine biosynthesis. J. Biol. Chem. 276:19855-19861.

16. Herbig, K., Chiangs, E. P., Lee, L. R., Hills, J., Shane, B. & Stover, P. J. (2002) Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J. Biol. Chem. 277: 38381- 38389.

17. Scott, J. M. & Weir, D. G. (1998) Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. J. Cardiovasc. Risk 5: 223-227.

18. Friso, S., Choi, S.W., Girelli, D., Mason, J. B., Dolnikowski, G. G., Bagley, P. J., Olivieri, O., Jacques, P. F., Rosenberg, I. H., Corrocher, R. & Selhub, J. (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc. Natl. Acad. Sci. U.S.A. 99: 5606-5611.

19. Ma, J., Stampfer, M. J., Giovannucci, E., Artigas, C., Hunter, D. J., Fuchs, C., Willett, W. C., Selhub, J., Hennekens, C. H. & Rozen, R. (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 57: 1098-1102.

20. Schwahn, B. & Rozen, R. (2001) Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am. J. Pharmacogenom. 1: 189-201.

Haifa Ghandour, Zhoutao Chen,* Jacob Selhub, and Rima Rozen*2

Vitamin Metabolism and Aging, Jean Mayer U.S. Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, MA and * Departments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research Institute, Montral, QC, Canada

2 To whom correspondence should be addressed. E-mail: [email protected].

Copyright American Institute of Nutrition Nov 2004

Nutrition 2: a Vital Consideration in the Management of Skin Wounds

Abstract

The first part of this review focused on the essential biological features of human skin, their origins and cellular relationships as a basis for understanding nutritional requirements in health and disease (see Vol 13(19;Tissue Viabil Suppl): S22-S28). The second part will discuss the importance of a good, well-balanced diet sufficient in proteins (amino acids), fats, carbohydrates, vitamins and minerals in the management of skin wounds. Evidence is drawn from clinical trials, case studies of patients with known genetic deficiencies affecting dietary metabolism and metabolic studies. Experimental studies in laboratory animals have provided limited information on the role of nutrient deficiencies in wound repair. There is still an urgent need for prospective controlled studies on the importance of key nutrients at principle phases in the wound- healing cascade and how uptake and metabolism is regulated by growth factors, cytokines and hormones.

Key words: Skin and skin disorders * Nutrition and diet * Wounds * Genetic disorders

Current focus on wound-bed preparation in the management of chronic wounds focuses upon re-establishing the ‘balance of growth factors, cytokines, proteases and their natural inhibitors as found in acute wounds’ (Schultz et al, 2003). At the meeting of the European Tissue Repair Society and Wound Healing Society in 2002, the expert working group summarized the clinical components of wound- bed preparation and the cellular environment at each stage. Although the authors of the report recognized the importance of water/ moisture balance, changing pH and oxygen tension in wound care, they failed to appreciate the importance of correct nutrient balance in the wound as an essential feature of the wound environment (Schultz et al, 2003). Earlier experimental evidence demonstrated that as wounds heal (acute wounds at least), requirements for different nutrients change to reflect the needs of building materials for enzymes and structural syntheses (Lansdown et al, 1999).

Table 1 lists the main nutrients currently known to fulfil roles as structural components, enzyme co-factors or physiological mediators in skin repair and regeneration.The evidence is drawn from epidemiological studies in populations with traditional dietary habits, case studies with patients with known genetic disorders of nutrient uptake, reports of nutrient deprivation and experimental studies. Although experimental animals do have greatly differing dietary needs from humans, they have proved useful in demonstrating how certain toxic factors in the diet can block the uptake and availability of key minerals, vitamins or amino acids, thereby impairing wound repair or leading to reduced tensile strength in re- epithelialized tissues.

Table 1. Essential nutrients for a healthy skin and repair following injury

Other metals like lead, aluminium, mercury and cadmium may be identified in the skin of some people through environmental or topical exposure (Lansdown, 1995, 2000). These have no nutritional role and occur in the tissues as contaminants. Nickel and chromium are regarded as trace metals in human nutrition but their precise role in metabolic processes is not -well defined (Lansdown, 1995). Chromium may have a multifactorial role but available evidence suggests that it interacts with insulin in glucose metabolism. The role of nickel in metabolic processes is also poorly understood, but it is implicated in cell-membrane function, regulation of prolactic release, blood flow and nucleic acid metabolism. Both metals fulfil the criteria that they are essential in some way (albeit at exceedingly low concentrations) for a fundamental physiological process in the human body.

As part of its protective role, the skin serves to eliminate toxic substances and excess quantities of essential trace minerals through the hair of sweat (i.e. iron, zinc, sodium). Silver may be deposited in the skin following ingestion of silver nitrate or colloidal silver as an oral mouthwash or to treat gastrointestinal infections (Tomi et al, 2004;Van Hasselt et al, 2004). Resulting skin discolorations (argyria) are cosmetically undesirable, but the silver sulphide deposits are of no nutritional role and are nontoxic (Lansdown and Williams, 2004). Some silver absorbed from sustained silver-release wound dressings may interact with trace metals like zinc, copper and calcium. This may advance reepithelialization (Lansdown et al, 1997).

Essential nutrients for skin wound repair

Proteins and amino acids

Proteins and amino acids constitute the largest portion of the human diet and form the main building blocks for tissue growth, cell renewal and repair systems following injury (Munro, 1974). In a tissue like the skin, with its high metabolic rate, regular replacement of cells and functional requirements as a protective shield, deficiencies in proteins and specific amino acids like cysteine, proline, etc. will adversely influence homeostasis and healing in wounds, leading to thin, fragile skin with reduced tensile strength. Nitrogen balance is a critical feature of wound repair, and protein synthesis must increase at wound sites during the repair process if normal healing is to occur (Levenson and Demetriou, 1992). An imbalance or deficiency in certain amino acids has singular effects on protein synthesis and healing, as it does on growth (Levenson and Demetriou, 1992).

Discussion of the needs for proteins and specific amino acids in isolation is difficult in view of the intricate relationships that exist with other nutrients. Protein uptake, metabolism and usage is dependent on the availability of vitamins and trace metals as co- factors in metabolizing enzymes (e.g. copper in lysyl oxidase, zinc in metalloproteinases, etc).

In well-nourished patients, the skin requires adequate amounts of protein and amino acids for:

* Ribonucleic acid (RNA) and deoxyribose nucleic acid (DNA) synthesis

* Collagen and elastic tissue formation

* Nutrition of the immune system

* Epidermal growth and keratinization.

Kwashiorkor (protein-calorie malnutrition common in Third-World countries) is one of the most prevalent causes of protein-energy malnutrition in impoverished societies (Miller, 1989). It is more widely linked to deficiencies in trace metals, vitamins and essential amino acids (Prasad and Oberleas, 1976). Erythema, cracking and scaling, discoloration, inflammation, susceptibility to damage and impaired wound repair reported in cases of kwashiorkor are part of a more general reduction in body health. Although ethically undesirable these days, kwashiorkor-like symptoms have been produced experimentally in young baboons fed protein-energy deficient diets (Coward and Whitehead, 1972). These animals exhibited sparse hair, oedema and flaky paint-like skin lesions resembling those seen in severely malnourished children in Uganda. Marasmus is a similar wasting condition related to protein malnutrition and skin ulceration and hyperkeratinization (scaling) are reported (Miller, 1989).

In patients subject to prolonged protein malnutrition, the skin becomes thinner and wrinkled as epidermal and dermal cell renewal systems decline, and immune resistance to bacterial infection is reduced. Protein-energy malnutrition in diabetic patients is an added risk for limb or digit amputations (Kay et al, 1987; Eiieroth et al, 2004). Numerous experimental studies with generalized protein deficiencies, reduction in specific amino acids, and known amino- acid antagonists have shown impaired angiogenesis, decreased rates of wound contraction, impaired re-epithelialization and low tensile strength (Alvarez et al, 1982; Levenson and Demetriou, 1992).

In wound repair, protein and amino-acid deficiencies are manifest in events in all of the four principle phases in healing (haemostasis, inflammation/granulation tissue formation, cell proliferation, tissue reorganization and ‘normalization’). Collagen synthesis is particularly sensitive to proline deficiency (Bailey, 1978), but insufficiencies in cysteine, cystine, methionine, argentine, tyrosine, histidine and glycine are additional causes of delayed wound healing. Fortification of diets with amino acids can be a means of solving some nutritional problems associated with wound healing (Altschul, 1974). This area is in urgent need of clinical research.

Carbohydrates

Carbohydrates are the principle source of energy for the human body with the high energy releasing pentose-phosphate shunt mechanism being vital in sustaining the high metabolic activity needed in proliferating epidermal cells, especially during re- epithelialization and regeneration (Coulton, 1977). Fibroblasts also seem to be sensitive to glucose deficiencies; concentrations of at least 1.8mM/l were shown to be necessary for stimulating growth and proliferation in culture media (Han et al, 2004). Glucose concentrations in normal human sera vary greatly but available figures suggest that the normal range is 3.9-6.7 mM/1 rising to 4.4- 8.3 mM/1 for people over 70 years of age. Appreciably lower levels of 0.6-5.9 mM/1 or even 0.3-1.2 mM/1 have been recorded in chronic wound patients (Trengrove et al, 1996; James, personal communication, cited by Han et al, 2004). This suggests that the glucose enhancement may be clinically attractive in the treatment of non-healing wounds. Personal observations h\ave shown that epidermal cells in the hyperplastic epidermis following reepithelialization are frequently rich in glycogen granules.

Diabetes has special significance in human skin -wounds. Foot and leg ulcers in diabetic patients show a high incidence of nonhealing and susceptibility to infection, peripheral neuropathy and necrosis leading to possible amputation (Edrnonds and Foster, 2000). Infections with Staphylococcus aureus and Candida albicans are more common in diabetic patients and may in part contribute to the wound indolence (Eneroth et al, 2004). Otherwise, the mechanisms underlying impairment in wound healing in diabetic patients are complex, probably involving circulatory problems, hyperglycaema and osmotic changes, disturbances in vitamin A and zinc metabolism, growth factor imbalances, acidosis and inflammatory changes.

The complexities in diabetic wound healing have been revealed through a large number of experimental studies using streptozotocin- induced diabetes in the rat (Goodson and Hunt, 1977; Barr and Joyce, 1989). In human diabetes, particular attention is given to the vascular pathology involving the proliferation of endothelial cells and obstruction of arterioles, venules and capillaries (Huntley, 1982; Sibbald and Schachter, 1984). Eneroth et al (2004) examined the possibility of using nutritional supplementation to improve the healing patterns in diabetic wounds in a blind clinical trial. Patients with diabetes mellitus and foot ulcers of at least 4-weeks dviration were given oral dietary supplementation with Fortimel (Nutrica AB) daily for 6 months. Although the authors experienced some practical difficulties in this approach and made some interesting observations, they were not able to demonstrate that the dietary intervention significantly improved wound repair.

Fats

Fats and fatty acids provide additional sources of energy in the human. Fats provide building blocks for many components of epidermal and dermal tissues, as well as sources of energy in cell proliferation, maturation and homeostasis (Skog and Jgerstad, 1998). Clinical reports on the influence of fatty-acid deficiency in wound repair are not numerous, but experimental evidence in rats suggests that it can impair wound healing (Hulsey et al, 1980). Certain unsaturated fatty acids like linoleic acid and arachidonic acid which are necessary in inflammatory reactions and prostaglandin synthesis, are not synthesized naturally in the human body and are derived from the diet. Evening primrose oil is a well known source of gamma-linoleic acid.

Fats and fatty acids contribute to wound healing in the following ways:

* Cell membrane synthesis

* Phospholipids in the epidermal barrier layer

* Inflammatory reactions

* Synthesis of intercellular matrix.

Vitamins

Metabolic research has shown that the human body relies on at least 20 vitamins or vitamin-like substances for normal health and physiological functions (Widdowson and Mathers, 1992). Many are low molecular weight substances required by tissues at low concentrations. Excess concentrations of some, like vitamin A, are toxic and can have detrimental effects on the skin and its appendages.

Vitamin A: this is a fat-soluble substance derived from carotene in green vegetables which shows a predilection for epithelial tissues. In its active form – retinol, it plays a central role in epidermal cell proliferation and maturation through binding to cell surface receptors. It enters into a complex sequence of events in normal skin, involving intercellular adhesion, communication and transcription of messenger-RNA (Chytil, 1984). Additionally, vitamin A may interact in the regulation of numerous enzyme systems involved in glycoprotein and glycolipid synthesis, prostaglandins production and cell membrane metabolism (Matter et al, 1980).

Excess vitamin A is harmful and can be a cause of irritation with scaling and roughness of the skin, dry fragile hair and a variety of metabolic changes, some of which are relevant in treating damaged skin (Cunliffe and Miller, 1984). Although vitamin A analogues have been widely researched as possible therapies for a range of skin ailments ranging from idiopathic hyperplasia, acne, photo-damaged tissue, and skin cancers in recent years, none seem to have been clinically suitable or sufficiently safe for patients (Moy et al, 1985; Kotrajaras and Kligman, 1993).

Vitamin A is required for wound healing, possibly in promoting the early inflammatory response and infiltration of macrophages, monocytes and fibroblasts leading to angiogenesis and collagen formation. As expected, vitamin A at appropriate concentrations is essential for epidermal cell growth and re-epithelialization, even though its regulation is unclear. Experimental evidence indicates that a derivative of vitamin A (trans-retinoic acid) can enhance the epidermal growth response through epidermal growth factors (EGF) and transforming growth factor-beta (TGF-β) (Tong et al, 1990), but much research is urgently needed in this area (Saurat, 1988). A detailed review on the pharmacology, clinical and laboratory work on vitamin A and its analogues is provided by Cunliffe and Miller (1984).

Vitamin A can influence dermal growth and excess retinoate inhibits the production of collagen and fibroblasts in culture (Bailley etal, 1990).

Vitamin B complex: the vitamins of the vitamin B complex are variously implicated in the metabolism of all major food requirements in the human patient. Normal body requirements are provided by a diet replete in dairy produce, vegetables, fish and cereals (Lansdown, 2003-2004). Deficiencies are likely to be manifest more through a general reduction in body health and this will reflect on the outward condition of the skin and its responses to normal wear-andtear and injury.

Vitamin C: (ascorbic acid) deficiency is probably best known as a cause of scurvy. The biochemistry of vitamin C in the human body is complex, but in the skin at least, its role in metabolism of trace metals (calcium, magnesium, iron) is relevant. Vitamin C serves several essential roles in wound healing in the skin (Ringsdorf and Cheraskin, 1982; Lansdown, 200Ib, 2002b) (Table 2).

Table 2. The role of vitamin C in wound healing in the skin

The first report showing that hypovitaminosis C was a cause of impaired wound repair was that of Lanman and Ingalls in 1937, but competent and clinically relevant studies did not appear until several years later when hypovitaminosis became linked to defects in the uptake and metabolism of essential amino acids (phenylalanine, tyrosine and praline) required in collagen production, metal ion metabolism, and enzyme activation (Levine, 1986). Current views are that hypovitaminosis manifests by inflammation of hair follicles, coiled hairs on the arms and back, possible bleeding, swollen gums and low serum concentrations (normal range 17-94 mM/1), should be indicative of dietary supplementation. This should be 300-1000 mg/ day given orally in addition to protein-rich food (Levine, 1986).

The role of hypovitaminosis C on wound healing has been extensively researched experimentally in the guinea pig which is naturally scorbutic (unable to synthesize ascorbic acid). Defective fibroblast responses, collagen defects and abnormal scar tissue formation have been reported (Wolbach and Howe, 1926; Bourne, 1944;Abercrombie et al, 1956).Vitamin C plays a major role in the natural defences of the body against infectious agents. Low resistance in patients low on vitamin C has been attributed to the factors listed in Table 3.

Proline and hydroxyproline metabolism were affected through dysfunction of iron-dependent enzyme systems (Lansdown, 200Ib). Clearly, vitamin C is an important aspect of nutrition in wound management particularly when local concentrations quickly become depleted in skin injuries including burn wounds.

Vitamin D: closely associated with the uptake and metabolism of calcium in the body and the action of dietary phosphate, calcitonin and parathyroid hormone (Lansdown, 2002b).The skin is of unique importance in human physiology as it is a principle site for synthesis and storage of vitamin D and its release into the circulation. Vitamin D is synthesized in the presence of sunlight with UV-radiation (wavelength 290-320 nm). The daily need for vitamin D in an adult person is estimated to be 400 iu (Matsuoka et al, 1988). Long-term irradiation might be expected to lead to excessive levels of vitamin and toxic complications associated with high calcium (headaches, anorexia and diarrhoea).

Vitamin E: interacts metabolically with selenium in controlling the metabolism of unsaturated fatty acids required for energy production in the human body (Green and Bunyan, 1969; Putnam and Comben, 1987). As such, it is presumed to fulfil the following main functions:

* An anti-oxidant protecting unsaturated fats from degradation

* Unspecified functions in general metabolism other than as

an anti-oxident (Green and Bunyan, 1969).

The selenium-dependent enzyme glutathione oxidase interacts with vitamin E in inhibiting the breakdown of fattyacid components of cell membranes and ensures stability in tissues (Putnam and Comben, 1987).

While the exact role of vitamin E or its analogues in the skin is ill defined in human wounds, inhibition in the peroxidation of fatty acids has been shown experimentally to promote the expression of a vascular endothelial growth factor and to advance repair in diabetic wounds (Altavilla et al, 2001). Other evidence has been seen to show that vitamin E interacts with other growth factors involved in collagenesis, immune responsiveness and graft rejection. Ehrlich et al (1972) actually claim that vitamin E can inhibit collagen formation and wound repair, but it is unclear at the moment how much vitamin is required for normal growth and repair and what levels in the human body are detrimental. Prospective assessments on theimportance of fruit and vegetable consumption on the health and vitality of a study of 271 adults have substantiated the view that increases in vitamins C and E through beneficial diets may stimulate the physical health status of socioeconomically deprived adults (Steptoe et al, 2004), and by inference will improve responses to injury.

Table 3. Factors attributed to low resistance in patients low in vitamin C

Vitamin K: a fat-soluble substance derived from vegetable foods, and may be synthesized by bacteria in the intestine. In human nutrition, vitamin K has a special importance in haemostasis with vitamin-deficient patients becoming susceptible to haemorrhages, impaired wound repair, and infection (Goskowicz and Eichenfield, 1993; Jenkins et al, 1998; Oehme and Rumbeiha, 1999). Although the importance of vitamin K is not well documented in the dermatological literature, biochemical studies have demonstrated its critical role in activating key proteins in the haemostatic phase, particularly those involved in the production of prothrombin and the clotting factors VII, IX and X. Thus, circulating levels of vitamin K will be significant in the haemostatic phase of wound healing and probably the release of growth factors. Patients with burn injuries exhibit multiple risk factors for development of vitamin K deficiency, including malabsorption, limited enterai uptake, antibiotic therapy and surgical procedures Qenkins et al, 1998). These authors demonstrated a direct relationship between the serum vitamin K level and prothrombin time (vitamin K dependent clotting factors) in 48 burned children. Patients with malabsorption syndromes or dietary vitamin K deficiency may be treated with oral doses of about 10mg/ day of the water-soluble analogue – menadiol sodium phosphate (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2004). Phytomenadione is given to neonatal cases of hypovitaminosis (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2004).

Table 4. Minerais in the nutrition and physiology of the human skin

Anticoagulants used as quick-acting rodenticides (for use in pest control) impair the availability of vitamin K in the body and its ability to stem bleeding.They inhibit the formation of essential clotting factors and damage blood capillaries (Oehme and Rumbeiha, 1999). Oral vitamin Kl (phytomenadione) can be used as an antidote, or in severe cases, patients may require blood transfusion (Jenkins et al, 1998; British Medical Association and Royal Pharmaceutical Society of Great Britain, 2004).

Minerals

At least 16 minerals and trace elements are now known to be important for the health of the human body (Underwood, 1971). Table 4 shows the principle minerals necessary for maintenance of characteristic skin appearance and its functional roles of protection, thermoregulation, homeostasis and excretion, as well as tissue repair following injury (Lansdown, 1995). A detailed analysis by Lansdown and Sampson (1997) of the actions and interactions of metal ions of nutrient status shows their importance to be:

* As structural components of cells or intracellular fluids

* Components or co-factors of key metalloenzyme systems

* Electrolytes and physiological components in the function of epidermal cells, skin glands and cell membrane exchange.

The importance of metals in biological systems in humans, experimental animals and cells in defined media has attracted considerable attention over many years, and the scientific literature on the subject is enormous. In the present review, the nutrient roles of key metals will be reviewed with special reference to their function in skin injury, outward signs and manifestations of deficiency, and possible therapeutic means of treatment.

Calcium

Calcium is the most intriguing metal in the human body and possibly the most difficult to analyse. Not only is calcium the most abundant mineral nutrient with at least 99% of the total body content residing in the skeleton and muscle mass (Lansdown, 2002b), but also it is present as a structural component, enzyme co-factor and growth factor/regulator in many soft tissues, including the skin. Although its central role in the growth and function of normal skin is well documented, its importance in wound healing is frequently overlooked as a feature of management (Lansdown, 2002b).

Calcium gradients are best illustrated with reference to the epidermis, where an exceedingly low calcium concentration in cells of the basal layer is held to promote proliferation. Although the inherent mechanism is not fully understood, there is a progressive increase in calcium concentrations in the post-mitotic maturing cells of the stratum spinosum up to and including the granular layer which is rich in keratohyalin granules and represents the terminal phase in keratinocyte maturation. In normal skin, this is a ‘cut off point for calcium; no calcium can be demonstrated in the stratum corneum under normal circumstances. Most of the early studies were conducted in murine (pertaining to rodents) skin aided by sophisticated techniques in histochemistry and molecular biology, but the observations are entirely relevant to human skin (Lansdown, 2002b).

All living cells in the skin are sensitive to environmental calcium concentrations with keratinocytes being at least 100 times more sensitive than fibroblasts in cell culture (Menon and Elias, 1991). In each case, local calcium concentrations serve to up- regulate calcium-binding proteins on cell membranes and activate intercellular calcium metabolism. At least 50 calciumbinding proteins involved in this process have been identified on cell membranes (e.g. cadherin), intercellular fluids and matrices (e.g. calbindin, calmodulin) and subcellular constituents. At the moment, little is known concerning the regulation of calcium metabolism in normal skin physiology and little appears in the literature concerning the distribution of the calcium-binding proteins in wounded tissue. However, a sharp rise in calcium follows wounding and this persists throughout the healing period and into the normalization phase (Lansdown et al, 1999). Further studies are necessary to determine the mechanism promoting this rise in calcium and the possible involvement of parathyroid hormone, calcitonin and phosphate levels.

If calcium is so important in normal skin physiology and the mere act of wounding is sufficient to disturb local concentrations and gradients, should a nurse consider calcium management in skin care? Calcium is not well absorbed through the skin except in the case of injury and to the authors knowledge the only wound care preparation currently available releasing calcium ion into the wound bed is calcium-sodium alginate and related products (e.g. Kaltostat, ConvaTec). Calcium ions released through ion exchange with sodium in wound exudates contribute in haemostatsis as factor IY The alginate fibres hydrate and are eventually absorbed into the tissue with minimal local reaction as they are ’tissue friendly’ (Lansdown and Payne, 1994). Nothing is presently published to show whether, or to what extent, this free calcium ion is absorbed into wounded tissue and contributes to re-establishment of calcium gradients or other cellular modulators. A lot has yet to be explained regarding the role of calcium in wound repair and how it might be controlled in wound management.

Zinc

Zinc is an essential trace element in all living cells in animal and plant systems (Kaulin, 1869). In human cells, it is a component of at least 70 major enzyme systems, notably those involved in nucleic-acid synthesis, collagenesis, inflammatory reactions, immune responses, and in the metalloproteinases prevalent in early wounds (Lansdown, 1996). Zinc concentrations are naturally highest in tissues undergoing active proliferation including the skin, intestinal mucosa and testis, and functional development of these organs is a good indication of sufficiency in zinc (Prasad and Oberleas, 1976; Lindemann and Mills, 1980; Strain et al, 1996).

Many different views have been expressed on the roles of zinc in human skin physiology including its role in the stabilization of cell membranes, maturation and growth, mobilization of vitamins (especially A and C) and carbohydrate metabolism. Zinc concentrations in the skin tend to be proportional to levels of mitotic activity, thus at least six times more zinc is seen in the epidermis than dermis in normal skin (Henzel et al, 1970). Following acute injury, local zinc concentrations rise by at least 15% and stay high through inflammation and proliferation and into the normalization phase (Lansdown et al, 1999).

The inherent regulatory mechanisms for tissue zinc concentration are not known but are likely to involve the cystine-rich protein – metallothionein (Lansdown, 2002a). This binds zinc, copper, selenium and a variety of non-nutrient metals like gold, silver, cadmium and mercury. By implication, excess levels of these non-trace metals in the circulation or in the wound environment can interfere with the metabolism of essential trace metals and their role in wound repair (Lansdown and Sampson, 1996; Lansdown et al, 1997, 2001). Zinc is applied topically as a mild antiseptic and anti-inflammatory agent in wound therapy; it induces the formation of metallothionein and binds to it. Histochemical demonstration of metallothionein provides a good marker for zinc activity in a tissue (Lansdown et al, 1997; Lansdown, 2002a).

Clinical evidence for the value of zinc in wound management is provided by the rare lethal mutation – acrodermatitis enteropathica (Moynahan, 1974).The condition manifests early in life and affected children exhibit characteristic symptoms of erythema, dermatitis, alopecia, hypogonadism, exceptionally thin skin, failure to thrive and impaired wound repair (Moynahan, 1974). The causation of this hypozincaemia is no\t fully understood. Originally, it was attributed to an inherent defect or toxic material (oligopeptide) in the gut affecting zinc absorption; zinc ion was irreversibly bound or ‘chelated’ by this material and not available for uptake. An alternative and more plausible explanation is that of an inherent defect in the absorptive apparatus in the mucosal cell. Early clinical treatments for acrodermatitis-like symptoms included injection of the drug diodoquin. Although diodoquin was effective in increasing blood zinc, its toxic action on the retinal epithelium of the eye (also seen with related drugs like chloroquin) precluded its therapeutic acceptability. Oral zinc sulphate tablets proved to be a safer and satisfactory alternative.

Further illustrations of zinc deficiency are highlighted in the classical studies of Prasad in Egypt and the Middle East (Prasad, 1978). These workers documented evidence of severe hypozincaemia in populations feeding high-fibre diets rich in histidine, phytate and proteins that bind zinc (Prasad, 1966; Pories et al, 1967; Prasad and Oberleas, 1976). Oral zinc sulphate was used successfully in treatment of these and other cases of dermatitis linked to dietary zinc malabsorption, which can arise not only through substances present in the diet, but also through drugs (e.g. penicillamine), toxic metals (cadmium, mercury, etc.), and gastrointestinal infections (Shakespeare, 1982; Lansdown and Sampson, 1996; Lansdown et al, 2001). In the chronic wound situation, it is not known to what extent defects in the metabolism of zinc underlie non-healing syndromes, or indeed whether oral or topical administration of zinc is beneficial.

Hair and serum analyses can give a good idea of the zinc status in the body, where up to 20% is located in the skin and its appendages (20-678 g/g dry weight) (Molokhia and Portnoy, 1969). Estimates of serum or tissue zinc vary greatly according to the date of the work and the accuracy of the analytical method used, but Halstead et al (1974) analysed 26 reports and concluded that normozincaemia was in the range 70-130 g/100 ml and that this decreases with advancing age. Oral zinc therapy has been used to treat cases of hypozincaemia but topical zinc oxide creams would seem to be a suitable and safe alternative for topical wound therapy. Pories et al (1967) recorded that 150mg oral zinc sulphate reduced the healing time of pilonidal cysts by up to 60%. Zinc absorption from medicated bandages has been shown to be 5 g/cm^sup 2^ per hour over 48 hours. Numerous zinc preparations are available for topical use including water-based pastes, creams and emollients in amphiphilic vehicles, to improve local zinc concentrations, but care has to be taken in the amount applied. Excessive amounts of zinc may impair calcium-related events, possibly leading to retarded healing (Heng et al, 1993). This has to be demonstrated clinically.

In experimental studies, a 1% zinc oxide cream was shown to advance the healing of open skin wounds without complication (Lansdown, 1993). Zinc was absorbed percutaneously (it is better from lipid solvents than aqueous solvents) and penetrates epidermal cells leading to increased mitosis and more rapid reepithelialization. Wounds remained free of infections through the mild antiseptic properties of zinc ion.

Copper

Copper was recognized as an essential trace element in all living cells as long ago as 1816 (Bucholz, 1816) but is now known to be a co-factor for many key enzyme systems. Copper has many similarities to zinc in human nutrition and physiology and like zinc it induces and binds metallothionein. Characteristic features of copper deficiency include hair and nail defects, reduced skin thickness through impaired collagen and elastic tissue synthesis, reduced immunological reactivity, and lowered resistance to infection.

Biochemical studies indicate that copper metabolism is intimately linked to that of iron, such that anaemia is a frequent manifestation of deficiency (hypocuprinaemia) (Hart et al, 1928). In skin physiology, lysyl oxidase necessary in the ‘cross-linking’ of collagen and elastic tissue fibres, is probably the best known of the cuproenzymes (Kagen and Li, 2003). Local copper concentration increases in wound sites, commensurate with the demand for the metal in systems like lysyl oxidase, prolyl oxidase, etc. involved in collagen formation in scar tissue. The inherent regulation of copper absorption, involvement in the carrier-protein caeruloplasmin, and serum concentration is not known but conceivably, cytokines, growth factors and other modulators in the wound bed are implicated.

Copper deficiencies in humans and other species are rare but manifest in terms of dietary deficiencies or inherited defects in intestinal absorption. Illustrations include ataxia and swayback in farm animals, Wilson’s disease, and Menke’s ‘kinky hair’ syndrome (Goodman et al, 2004). In Menke’s disease, the X-linked inherited copper deficiency syndrome is a cause of impaired keratin formation in hair papillae. Affected infants exhibit retarded growth and show clinical symptoms of cytochrome oxidase, lysyl oxidase, tyrosinasae and other cuproenzyme deficiencies. Blood vessel formation is reduced.

Intestinal absorption of copper is influenced by other trace elements including zinc, molybdenum, iron, manganese, cobalt and nickel, and may be inhibited by penicillamine and drugs and food additives that bind the free ion. Excess copper is voided in hair, nails and aged keratinocyte sloughed from the skin surface; ‘green hair’ is a sign of excessive copper in the diet and the hair as a route of detoxification (Verbov, 1990; Tosti et al, 1991; Turnlund et al, 2004). Penicillamine is a powerful chelator of trace metal ions and should be avoided in patients with skin wounds (Shewmake et al, 1988; Gosling et al, 1995). Any rapid depletion of essential trace metals is predictably a cause of chronicity and patient discomfort. In the case of copper, low circulating levels are known causes of impaired skin woundhealing with reduced tensile strength in re-epithelialized tissue attributable to defective collagen and elastic tissue formation (Shewmake et al, 1988; Gosling et al, 1995).

Iron

Iron is characteristically linked to the formation of haemoglobin and in the uptake and metabolism of oxygen radicals.The outward appearance of the skin and its appendages provide a useful guide to the iron status of the body. Although less well documented in the dermatological and woundhealing literature, iron performs a large number of fundamental roles in intracellular metabolism in most cells involved in normal skin physiology and those which adopt a special responsibility in wound repair (keratinocytes, fibroblasts, neutrophils) (Sato, 1991; Lansdown, 200Ia).

The iron content of the human body is estimated to be 3-5 g, with recommended daily intake 91-2 mg varying greatly according to the state of health and age of the individual (Scrimshaw and Young, 1976). Intestinal absorption of iron is influenced by substances present in the diet -which chelate free ion, but vitamin C is important in all aspects of iron metabolism. Deficiencies of iron and/or vitamin C are diagnosed through hair loss, inflammatory changes in the hair follicle and interfollicular skin, abnormal keratinization and impaired wound healing (tensile strength) (Green et al, 1968; Lansdown, 200Ib). Vitamin C supplementation is recommended as a therapy for pressure ulcers, particularly those associated with haemolytic anaemia (Ringsdorf and Cheraskin, 1.982). Iron uptake following topical application in intact skin is probably low; most of the iron required in skin physiology and repair systems will be provided from the plasma pool, with some being recycled (and conserved) within the tissue.

The highest iron content in human skin occurs in those areas with highest vasculature and highest cell turnover. Although most of the iron content is present in the dermal tissues, epidermal cells, hair papillae, sweat glands and melanocytes are also sensitive to iron levels (Sato, 1991). Severe iron deficiency occurring in patients with anaemia is recognized not only by general malaise but also skin irritancy, eczema, nail deformities (Beau’s lines) and hair loss (Handfield-Jones and Kennedy, 1988; Lansdown, 200Ib). Loss of skin ‘tone’, reduced resistance to infection and impaired wound healing are complications. The role of ferro-enzymes in proliferating tissue and skin physiology has been reviewed in detail elsewhere (Lansdown, 2001 a,b).

Iron fulfils the following basic requirements in mammalian skin (Brock, 1984):

* Oxygen transport

* Oxidation-reduction processes

* Mitochondrial respiration.

These are appreciated through cell ‘turnover’, nucleic-acid synthesis, cell-membrane stability and cell viability.Transferrin is the principle iron-binding carrier protein and conditions that reduce its availability or effectiveness (toxic metal ions, chelating agents, etc.) will reflect in iron-deficiency syndromes.

Iron deficiencies through malnutrition, disease or inherited conditions are a potential cause of impaired wound repair mainly through defects in oxygen supply to repairing tissues. Collagen formation in scar tissvie is impaired as is the ability to withstand the effects of local infections (Knighton et al, 1981; Bullen and Griffiths, 1999). Neutrophils and macrophages infiltrating wound sites show a high affinity for iron and their cell membranes are well adapted to absorb (phagocytose) irontransferrin complexes. This profound ability to absorb iron in the wound bed enables the neutrophils to deprive bacteria of an essential ‘growth factor’. Patients deficient in macrophages or neutrophils exhibit a marked reduction in resistance to infective organisms and their immune function is also less than normal.

Oxygen

Oxygen is a prerequisite for normal growth, physiological function and me\tabolism in most tissues in the human body – the skin is no exception (Tandara and Mustoe, 2004). In wound healing, the role of oxygen, tissue vascularity and signalling growth factors and gene expression have received considerable attention in recent years; as such it is well appreciated now that whereas the function and regeneration of certain tissues (epidermal cells) is dependent upon appropriate oxygen gradients, other tissues respond to hypoxic situations (angiogenesis, macrophages). Thus, Falanga et al (2002) demonstrated that low oxygen tension stimulates collagen synthesis and transcription of several genes. Human fibroblasts are sensitive to local oxygen tensions in vitro and respond to activation through growth factors (especially transforming growth factor-beta). It seems that the hypoxia present in the early wound provides the necessary stimulus for collagen synthesis, angiogenesis and scar tissue formation. Further, as wound healing progresses from one state to another in the healing cascade, so requirements for oxygen change.

Hyperbaric oxygen is a therapy used in chronic wound therapy. It is considered to be an important adjunct in the management of diabetic ulcers, ischaemic wounds and major surgery (Zamboni et al, 2003; Niinikoski, 2004). It is recommended for the treatment of problem wounds that fail to respond to traditional medicine and surgical techniques.

The most obvious effects of hyperbaric oxygen therapy are listed in Table 5 (Niinikoski, 2004).

Table 5. The obvious effects of hyperbaric oxygen therapy

Niinikoski (2004) recommended exposing patients to oxygen pressures of 2-2.5 ATA for 90 minutes once or twice daily, and that transcutaneous oximetry provides a convenient means of assessing levels of oxygen diffusion and tissue oxygenation. Hyperbaric oxygen can provide a cost-effective means of improving oxygen tension in indolent wounds, providing a more favourable environment for repair and regenerative systems to proceed (Heyneman and Lawless-Liday, 2002).

Water

The relevance of water as a nutrient is frequently over looked in wound care even though considerable attention is given to the selection and application of hydrofibres, alginates, hydrocolloids and polyurethane-containing dressings to control wound moisture and regulate gaseous exchange (Bale and Harding, 1991; Thomas and Loveless, 1991; Scherr, 1992; Banks et al, 1994; Robinson, 2000).

George Winter in the early 1960s provided much impetus to the study of water relations in the skin and the healing acute wound, control of wound exudates, and provision of a suitably moist environment for wound closure and re-epithelialization (Winter, 1962, 1964). (It is unfortunate that much of the information that he provided on role of water control in the acute wound has inappropriately been applied to human chronic wounds which differ substantially.) He demonstrated using a porcine model that re- epithelialization progressed more rapidly in a moist environment under a semipermeable dressing than under exposed or fully occluded wounds (Figure 1). Hydration with adequate oxygenation favours cell proliferation and migration along the chemotactic gradients provided by metal ions (zinc and calcium), growth factors and cytokmes, whereas dehydration promotes keratinization and hardening of the epidermis and possibly necrosis in exposed dermal tissues, obstrvicts re-epithelialization (Lansdown, 1985a,b). In practice, wounds that dry out tend to become cracked and painful for a patient, and are more prone to infection with aerobic bacteria and fungi (Keye, 2002).

Under normal conditions, water control in intact skin is the function of the epidermal layer of phospholipids (stratum lucidum). This provides a form of ‘water-proofing’ while limiting the penetration of materials coming into contact with the skin surface. On the practical side, removal of natural phospholipids through washing in soaps and lipid solvents greatly enhances water uptake, hydration of deeper epidermal tissues, and susceptibility to infection (Grasso and Lansdown, 1972; Idson, 1978). In the maturation of keratinocytes of the stratum spinosum, cysteine molecules aggregate in pairs and release a molecule of water in the production cystine (see Figure i).This process proceeds with successive layers of cells becoming more dehydrated. The surface of the skin normally contains least water, but it is effectively a ‘dead’ tissue. In the case of skin injury, cells of whatever layer exposed to the open environment become dehydrated and hardened to form a protective layer.

As repair mechanisms proceed, water provides (Enoch and Handing, 2003; Schultz et al, 2003):

* A structural component of the cytoplasm of epidermal and dermal cells

* A medium for enzyme-motivated events in regeneration and repair pathways

* An environmental component motivating the migration and maturation of epidermal cells.

Figure 1. Diagrammatic illustration of the influence of dressings upon epidermal cell migration in full-thickness acute wounds. The dressing retains moisture In the wound site and prevents dehydration. Epidermal ceils move laterally. In open wounds dehydration occurs, a hard mass of wound debris and exudate obstructs migrating cells which migrate beneath the ‘scab’ (adapted from Winter, 1962).

Regulation of-water balance in the wound-healing cascade is critical in achieving optimal healing in the acute wound and possibly the chronic wound as well (Winter, 1962, 1964). Although in wound management excessive exudates and wound fluid is frequently undesirable and embarrassing for a patient, excessive water loss is contraindicated as wound healing is delayed and patient comfort is compromised (Katz et al, 1986).

Summary

The present review has examined the available clinical and experimental evidence illustrating the importance of essential nutrients in the development, physiology and functional capacity of the skin and repair systems following injury. Table 6 provides practical guidance in understanding nutrition as a cause of wound repair.

It is entirely reasonable to expect that many wounds which are colloquially ‘stuck’ at some stage in the wound healing cascade, are in fact deprived of one or more essential nutrients or means of adequately metabolizing them. It is incumbent upon the -wound care nurse to appreciate the nature of the deficiency through analysing overt signs and using laboratory resources to analyse key body tissues – hair, nail, blood/serum for evidence of nutritional or metabolic defect. It is possible that cost implications, lack of time, or educational directives are contributory to non-utilization of essential back-up facilities.

Table 6. Practical guidance in understanding nutrition as a cause of impaired wound healing

The importance of any nutrient in the general health of the skin and its appendages is dependent not on the actual quantity supplied in the diet but in the amount delivered and ‘available to’ the epidermal cells that need it. This nutrient availability may be influenced by the factors listed in Table 7.

Correction of a nutritional defect identified as a potential cause of impaired wound may involve dietary attention, or intraparenteral injections (trace metals, vitamins). Appropriate preparations of vitamin complexes, trace meta preparations and dietary supplements are readily available commercially with recommendations for administration and monitoring. Alternatively, topical application of nutritional supplements like zinc may be administered, either in the form of medicated bandages (e.g. Zincaband, SSL Laboratories), creams or emollients. Substances applied topically are absorbed more readily by intact skin at least from amphiphilic vehicles with fat and water solubility (Grasso and Lansdown, 1972).

Evidence is presented to illustrate that impaired wound healing in older people is in part attributable to nutritional causes. As the body ages, so mechanisms for maintaining trace metals and sensitivities to vitamins, fats, and amino acids decline. Zinc levels are lower. Defects in the synthesis and stability of lipids in cell membranes and the epidermal barrier function render the skin more susceptible to dehydration and defects in repair processes dependent upon a suitably moist environment.

Table 7. Factors influencing nutrient availability

Understanding nutritional factors as a cause of indolence in skin wound repair is complex. Nutrients exhibit a large level of interaction and interdependency, with defects in the availability of some substances having a knock-on effect in the uptake and usage of others.The importance of the nutritionally balanced diet is illustrated with reference to mineral metabolism. The composition of the diet and the presence of substances like plant fibre, drvigs and environmental containments may influence absorption of nutrients and contribute to retarded wound repair. Suitable enquiries into a patient’s dietary habits and nutritional preferences may yield important clues as to why that patients wounds are failing to heal and how the attending nurse can provide inexpensive and practical help.

Nutrition should be considered as an essential feature of wound bed preparation. Unavailability or inability to use a particular nutrient through some inherited condition or disease state may represent the elusive ‘block’ in the progression of events of the wound healing profile of chronic wounds re-emphasized by the expert committee of the Wound Healing Society in its reference to wound bed preparation (Schultz et al, 2003). Clearly, a lot of further research is still required to give the practising nurse unequivocal markers for nutrient deficiencies in wound management, and acceptable treatments for their relief.

KEY POINTS

* It is impractical to consider nutrients individually in the human body; nutrients interact to a great extent in health and disease, particularly minerals and vitamins.

* Pr\oteins and amino-acids form the main building blocks for tissue growth, cell renewal and repair systems following injury.

* Fats provide building blocks for many components of epidermal and dermal tissues and as well as sources of energy in cell proliferation, maturation and homeostasis.

* The human body relies on at least 20 vitamins or vitamin-like substances for normal health and physiological functions.

* At least 16 minerals and trace elements are now known to be important for the health of the human body.

Abercrombie M, Flint MH, James DW (1956) Wound contraction in scorbutic guinea pigs. J Embrol Exp Morphol 4: 167-75

Altavilla D, Daitta A, Cucinotta D et al (2001) Inhibition of lipid peroxidation restores vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes 50: 667-74

Altschul AMD (1974) Fortification of foods with amino-acids. Nature 248: 643-6

Alvarez M, Mertz PM, Eaglstein WH (1982) The effect of the proline analogue l-azetidine-2-carboxylic acid (LACA) on epidermal and dermal wound repair. Plast Reconstr Surg 69: 284-9

Bailey AJ (1978) Collagen and elastic fibres.J Clin Pathol 31(Suppl 12): 49-58

Bailley C,Drezc S.Asselineau D et al (1990) Retinoic acid inhibits the production of collagenase by human epidermal keratinocytes.J Invest Dermatol 94: 47-51

Bale S, Harding K (1991) Foams still find favour; wound management using foam dressings. Prof Nurse 6: 510-8

Banks V, Bale S, Harding KG (1994) The use of two dressings for moderately exuding pressure sores.J Wound Care 3(3): 132-4

Barr LC, Joyce AD (1989) Microvascular anastomoses in diabetes: an experimental study. BrJ Plast Surg 42: 50-3

Bourne GH (1944) Effect of vitamin C deficiency on experimental wounds: tensile strength and histology. Lancet 1: 688-92

British Medical Association and Royal Pharmaceutical Society of Great Britain (2004) British National Formulary. BMA/RPSFB, London

Brock JH (1984) The biology of iron. In: De Souza JH, Brock JH, eds. Iran in Immunity, Cancer and Inflammation. John Wiley, Chichester: 35-53

Bucholz CF (1816) Reports in pharmacology. Rep Pharmacol 2: 235

Bullen JJ, Griffiths E (1999) Iron in Infection: Molecular, Physiological and Clinical Aspects. 2nd edn. Wiley, Chichester

Chytil F (1984) Retinoic acid: biochemistry, pharmacology and therapeutic use. Pharmacological Review 36: 93s-100s

Coulton LA (1977) Temporal relationship between glucose-6- phosphate dehydrogenase activity and DNA-synthesis. Histochetnistry 50: 207-15

Coward DG.Whitehead RG (1972) Experimental protein-energy malnutrition in baby baboons. BrJ Nutr 28: 223-37

Cunliffe WJ, Miller AJ (1984) Retinoid Therapy. MTP Press, Lancaster

Ecker RL, Schroeter AL (1978) Acrodermatitis and acquired zinc deficiency. Arch Dermaiol 114: 937-9

Edmonds ME, Foster AVM (2000) Managing the Diabetic I’oot. Blackwell Science Publications, Oxford

Eneroth M, Larsson J, Oscarsson C et al (2004) Nutritional supplementation for diabetic foot ulcers: the first RCTJ Wound Care 13: 230-4

Enoch S, Harding KG (2003) Wound bed preparation: the science behind removal of barriers to healing. Wounds 15: 213-29

Ehrlich HP.Tarver H, Hunt TK (1972) Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 175: 235-40

Falanga V, Zhou L, Yufit T (2002) Low oxygen tension stimulates collagen synthesis and COLIAl transcription through the action ofTGF- betal. J Cell Physiol 191: 42-50

Goodman VL, Brewe GJ, Merajver SD (2004) Copper deficiency as an anticancer strategy. Endocrine-Related Cancer 11: 255-63

Goodson WH, Hunt TK (1977) Studies on wound healing in experimental diabetes J Surg Res 22: 221-7

Goskowicz M, Eichenfield LF (1993) Cutaneous findings of nutritional deficiencies in children. Curr Opin Pediatr 5: 441-5

Gosling P, Rothe HfVl, Sheehan TM et al (1995) Serum copper and zinc concentrations in burns in relation to surface area. J Burn Care Rehabil 16: 481-6

Grasso P, Lansdown ABG (1972) Methods for measuring and factors affecting percutaneous absorption. J Soc Cosmet Chem 23: 481-452

Green I, Bunyan J (1969) Vitamin E and the biological antioxidant theory. Nntr Abstr Rev 39: 321-45

Green R, Charlton RW, Seftel H et al (1968) Body iron excretion in man. A collaborative study. AmJ Med 45: 336-53

Halstead JA, Smith JC, Irwin MI (1974) A conspectus of research on zinc requirements of man. J Nutr 104: 347-78

Han J, Hughes MA, Cherry GW (2004) Effect of glucose concentration on the growth of normal human dermal fibroblasts in vitro. J Wound Care 13: 140-53

Handfield-Jones SE, Kennedy CT (1988) Nail dystrophy associated with irondeficiency anaemia. Clin Exp Dermatol 13: 54

Hart EB, Steenbock H,Waddell J et al (1928) Iron in nutrition (VII): copper as a supplement to iron for haemoglobin building in the rat.J Biol Chem 77: 792

Heng MK, Song M, Heng MC (1993) Reciprocity between tissue calmodulin and cyclic AMP levels: modulation by excess zinc. BrJ Dermatol 129: 280-5

Henzel JH, DeWeese MS, Lichti EL (1970) Zinc concentrations within healing wounds. Arch Surg 100: 349-57

Heyneman CA, Lawless-Liday C (2002) Using hyperbaric oxygen to treat diabetic foot ulcers: safety and effectiveness. Grit Care Nurse 22: 52-60

HulseyTK, O’Niell JA, NeblettWR et al (1980) Experimental wound healing in fatty acid deficiency. J Pediatr Surg 15: 505-8

HuntleyAC (1982) The cutaneous manifestations of diabetes mellitus.J Am Acad Dermatol 7: 427-55

Idson B (1978) Hydration and percutaneous absorption. Curr Probl Dermatol 7: 132-41

Jenkins ME, Gottlschlich MM, Kopcha R et al (1998) A prospective analysis of serum vitamin K in severely burned pediatrie patients.J Bum Care Rehabil 19: 73-81

Kagen HM, LiW (2003) Lysyl oxidase properties and biological roles inside and outside of the cellj Cell Biochem 88: 660-72

Katz S, McGinley E, Leyden JJ (1986) Semipermeable occlusive dressings: effects on growth of pathogenic bacteria and re- cpithelialization of superficial wounds. Arch Dermatol 122: 58-62

Kay SP, Moreland JR, Schmitter E (1987) Nutritional status and wound healing in lower extremity amputations. CKn Orthop 217: 253-6

Keye G (2002) The management of traumatic wounds. The Oxford European Wound Healing Course Handbook. Positif Press, Oxford: 165- 70

Knighton DR, Silver IA, Hunt TK (1981) Regulation of wound healing angiogenesis: effect of oxygen gradients and inspired oxygen concentration. Surgery 90: 262-70

Kotrajaras R, Kligman AM (1993) The effect of topical tretinoin on photodamaged skin: the Thai experience. BrJ Dermatol 129: 302-9

Lanman TH, Ingalls NW (1937) Vitamin C deficiency and wound healing: experimental and clinical study. Ann Surg 105: 616-25

Lansdown ABG (1985a) Morphological variations in keratinizing epithelia in the beagle. Vet Rec 116: 127-30

Lansdown ABG (1985b) The mammalian skin: structural variations and responses to injury. The Biologist (London) 23: 253-60

Lansdown ABG (1993) The influence of zinc oxide on the closure of open skin wounds: an experimental study. Int J Cosmet Sci 15: 83-5

Lansdown ABG (1995) Physiological and toxicological changes in the skin resulting from the action and interaction of metal ions. CRC Crit Rev Toxicol 25: 397-462

Lansdown ABG (1996) Zinc and the healing wound. Lancet 347: 706- 7

Lansdown ABG (2000) Lead in hair dyes: short-term appeal vs. long- term risk. IntJ Cosmet Sci 22: 167-8

Lansdown ABG (200Ia) Nutrition and the healing of skin wounds. Wound Care Society (Educational Booklet) 8(2): 15

Lansdown ABG (200Ib) Iron: a cosmetic ingredient but an essential nutric-nt for healthy skin. Int J Cosmet Sci 23: 129-37

Lansdown ABG (2002a) Metallothioneins: potential therapeutic aids for wound healing in the skin. Wound Repair Regen 10: 130-2

Lansdown ABG (2002b) Calcium: a central regulator in wound healing m the skin. Wound Repair Regen 10: 271-85

Lansdown ABG (2003-2004) Nutrition: a critical consideration in the management of wounds. Hospital Healthcare Europe: T3-5

Lansdown ABG, Payne MJ (1994) An evaluation of the local reaction and biodgradation of sodium-calcium-alginate (Kaltostat) following subcutaneous implantation in the rat. J R Coll Surg Edinb 39: 284-8

Lansdown ABG, Sampson B (1996) Dermal toxicity and percutaneous absorption of cadmium in rats and mice. LabAnim Sci 46: 549-54

Lansdown ABG, Sampson, B. (1997) Trace metal in keratinising epithelia in the beagle dog. Vet Rec 141: 571-2

Lansdown ABG, Sampson B, Lautattarakasem P et al (1997) Silver aids healing in the sterile wound: experimental studies in the laboratory rat. Br J Dermatol 137: 728-35

Lansdown ABG, Sampson B, Rowe AM (1999) Sequential changes in trace metal, metallothionein and calmodulin in healing skin wounds. J Anat 195: 375-86

Lansdown ABG, Sampson B, Rowe AM (2001) Experimental observations on the influence of cadmium on skin wound repair. IntJ Exp Pathol 82: 35-42

Lansdown ABG, Williams A (2004) How safe is silver in wound care? J Wound Care 13: 131-7

Levenson SM, Demetriou AA (1992) Metabolic factors. In: Cohen IK, Diegelmann R, Lindblad WJ, eds. Wound Healing: Biochemical and Clinical Aspects, Saunders, Philadelphia: 248-73

Levine M (1986) New concepts in the biology and biochemistry of ascorbic acid. New Engt J Med 314: 892-902

Lindemann RD, Mills BJ (1980) Zinc homeostasis in health and disease. Mineral Metabolism 3: 223-36

Matsuoka LY, Wortsman J, Hanifan N et al (1988) Chronic sunscreen use decreases circulating concentration of 25-hydroxyvitamin D: a preliminary study. Arch Dermatol 124: 1802-4

Matter A, Muller-Salamin L, Lasmtski I et al (1980) Ultrastructural analysis of the retinoid-induced reversal of epithelial hyperplasia and metaplasia. VirehowArch B Cell Pathol 33: 199-212

Menon GK, Elias PM (1991) Ultrastructural localisation of calcium in psoriatic and normal human epidermis. Arch Dermatol 127: 57-63

Miller SJ (1989) Nutritional deficiency and the skm.J Am Acad Dermatol 21: 1-30

Molokhia MM, Portnoy B (1969) Neutron a\ctivation analysis of trace elements in skin: III. Zinc in normal skin. BrJ Dermatol 81: 759-62

Moy RL, Kingston TP, Lowe NJ (1985) Isotretinoin vs etrinate therapy in generalized pustular and chronic psoriasis. Arch Dermatol 121: 1297-301

Moynahan JJ (1974) Acrodermatitis enteropathica: a lethal inherited human zinc deficiency disorder. Lancet I: 399-400

Munro HN (1974) Report of a conference on protein and amino-acid needs for growth and development. AmJ CHn Nutr 27 (Special Issue): 55-8

Niinikoski JH (2004) Clinical hyperbaric oxygen therapy, wound perfusion and trancutaneous oximetty. World J Surg 28: 307-11

Oehme FW, Rumbeiha WK (1999) Veterinary toxicology. In: Ballantyne B, Marrs T, SyversenT, eds. General and Applied Toxicology. Macmillan, Basingstoke: 1509-26

Prasad AS (1966) Zinc Metabolism. Charles C Thomas, Springfield, Illinois

Prasad AS (1978) Trace Elements and Iron in Human Metabolism. Plenum Press, New York

Prasad AS, Oberleas D (1976) Trace Elements in Human Health and Disease. Academic Press, New York

Pories WJ, HenzelJH, Rob CG, StrainWH (1967) Acceleration of wound healing in man with zinc sulphate given by mouth. Lancet I: 121-4

Putnam ME, Conrben N (1987) Vitamin E. Vet Rec 121: 541-5

RaulinJ (1869) Etudes cliniques sur vegetation. Ann Sd Nat Botan Biol Veget 11: 39-299

Riley PA (1997) Epidermal melanin; sunscreen or waste disposal? Biologist (London) 44: 408-11

Ringsdorf WM, Cheraskin E (1982) Vitamin C and wound healing. Oral Suig Oral Med Oral Pathol 53: 231-6

Robinson BJ (2000) The use of a hydrofibre dressing in wound management. J Wound Care 9: 189-91

Sato S (1991) Iron deficiency: structural and micro-chemical changes in hair, nails and skin. Semin Dermatol 10: 313-9

Saurat J-H (1988) How do retinoids work on human epidermis? A breakthrough and its implications. The Dowling Oration, March 1988. Clin Exp Dermatol 13(6): 360-4

Scherr GH (1992) Alginates and alginate fibres in dinical practice. Wounds 4: 74-80

Schultz GS, Sibbald, RG, Falanga V et al (2003) Wound bed preparation: a systematic approach to wound management. Wound Repair Regen 11: 1-28

Scrimshaw NS, Young VR (1976) The requirements of human nutrition. Sci Am 235:51-64

Shakespeare PG (1982) Studies on serum levels of iron, copper, zinc and urinary excretion of zinc after burn injury. Bums lnd Therm In J 8: 358-64

Shewmake KB, Talbert GE, Bowser-Wallace BH et al (1988) Alterations in copper, zinc and caeruloplasmin m patients with thermal trauma. J Burn Care Rehabil 9: 13-7

Sibbald RG, Schachtcr RK (1984) Skin and diabetes mellitus. IntJ Dermatol 23: 567-83

Skog KI, Jgerstad M (1998) Toxicants in food: generated during cooking. Nutrition and Chemical Toxicology, loannides and Wiley, Chichester: 59-79

Steptoe A, Perkins-Porras L, Hilton S et al (2004) Quality of life and self-rated health in relation to changes in fruit and vegetable intake and in plasma vitamins C and E in a randomized trial of behavioural and nutritional education counselling. BYJ Nutr 92: 177-84

Strain WH, Steadman LT, Coleman GL, Wedig JH (1996) Analysis of zinc levels for diagnosis of zinc deficiency in man. J Lab Clin Mal 68: 244-49

Tandara AA, Mustoe TA (2004) Oxygen in wound healing – more than a nutrient. World J Surgery 28: 294-300

Thomas S, Loveless P (1991) A comparative study of the properties of six hydrocolloid dressings. Pharmacological Journal November: 67- 5

Tomi NS, Krnke B, Aberer W (2004) The silver man. Lancet 363: 532

Tong PS, Horowitz MS, Wheeler LA (1990) Trans-retinoic acid enhances the growth response of epidermal keratinocytes to epidermal growth factor and transforming growth factor beta.J Invest Dermatol 94: 126-31

Tosti A, Mattoli D, Miscialli C (1991) Green hair caused by copper in cosmetic plant extracts. Dermatologica 182: 204

Trengrove NJ, Langten SR, Stacey MC (1996) Biochemical analysis of wound fluid from non-healing and healing chronic leg ulcers. Wound Repair Regen 4: 234-9

Turnlund JR, Jacob RA, Keen CL et al (2004) Long-term high copper intake: effects of indexes of copper status, antioxidant status, and immune function in young men. AmJ Clin Nutr 79: 1037-44

Underwood JE (1971) Trace Elements in Human and Animal Nutrition. 3rd edn. Academic Press, New York

Van Hasselt P, Gashe BA, Ahmad J (2004) Colloidal silver as an antimicrobial agent; fact or fiction? J Wound Care 13: 154-5

Verbov J (1990) Green hair due to copper in spectacle metal. Clin Exp Dermatol 15: 234

Widdowson EM, Mathers JC (1992) The Contribution

Wegener’s Granulomatosis and Subglottic Stenosis: Management of the Airway

Abstract

Wegener’s granulomatosis is a multisystemic disease characterized by foci of necrotizing vasculitis and granuloma formation. Subglottic stenosis may occur either as a presenting feature or a late-stage manifestation of the disease, but will occur in approximately 10-20 per cent of cases.

We present a series of seven cases of Wegener’s granulomatosis with subglottic stenosis and discuss our management of this condition. Where there is active disease, tracheostomy is the first- line surgical treatment of respiratory obstruction, as an adjunct to full medical therapy. More aggressive or elaborate surgical treatments should be reserved for non-active cases in which patients have not required medical treatment for one year.

Keywords: Wegener’s granulomatosis; Constriction, Pathologic; Trachea; Tracheostomy

Introduction

Wegener’s granulomatosis is a necrotizing, granulomatous vasculitis that affects primarily the upper and lower respiratory tracts and kidneys.1 Besides these sites, there may be lesions in the oral cavity, larynx and trachea, ulceration of the skin, polyarthritis, and orbital involvement. Cranial nerve palsies may also occur. Laryngeal involvement is uncommon, but if present the subglottis and upper trachea are most commonly involved, with a risk of circumferential scarring and critical narrowing of the airway.

Subglottic stenosis occurs in approximately 10 to 20 per cent of patients with Wegener’s granulomatosis,2 who may present with this manifestation of the disease.3 It may be the only indication of disease, as was the case in half of the series of Langford et al.1 Symptoms range from cough and shortness of breath to life- threatening stridor. Initial diagnosis may be confused with the respiratory symptoms from co-existent pulmonary disease, and the stridor can easily be misdiagnosed as the wheeze of bronchial asthma. Where glottic involvement occurs, the voice may change.

The test for anti-neutrophil cytoplasm antibody (ANCA) is useful in diagnosis and is particularly helpful in unexplained subglottic stenosis. A positive ANCA test confirms the cause.4 C-anti- neutrophil cytoplasm antibody is cytoplasmic-staining and has a specificity of 99 per cent and a sensitivity of 91 per cent in active multisystem disease. P-anti-neutrophil cytoplasm antibody indicates perinuclear staining and is less commonly positive (between 20 and 40 per cent).5

We report a series of seven cases of Wegener’s granulomatosis with subglottic stenosis. The optimum treatment of such patients has not been formally ascertained, due mainly to the small number of sufferers.4 This uncontrolled, retrospective study looked at the airway management used, in an attempt to justify the rationale of our approach in light of published data concerning the natural history and alternative treatments for the condition. The study also looked at the correlation of the biopsy results with the ANCA test results during the course of the illness.

Materials and methods

The cases studied had been sent as secondary or tertiary referrals to the Queen Elizabeth Medical Centre, a regional teaching hospital in the United Kingdom. Wegener’s granulomatosis has long been a special clinical interest of the senior author, and cases were entered into a database (Paradox). Seven cases were treated over a 13-year period, all involving the subglottis. These were assessed retrospectively in an attempt to further characterize this unusual disease entity and to construct a rationale for diagnosis and management of the compromised airway. To this end, the existing literature on the subject was critically evaluated.

In order to identify relevant papers, a computer search (Medline) was used. Search criteria were Wegener’s granulomatosis (all fields) and subglottic stenosis (all fields).

Results

Seven cases that fitted the inclusion criteria were referred to our department during a 13-year period. The diagnosis was made by histopathological examination of either nasal or renal biopsy tissue. Four patients had a positive C-ANCA test on presentation. Two of the patients had a negative ANCA test initially, but these became positive later in the disease. One patient had a positive P- ANCA test. The findings are summarized in the Table and in the case summaries.

No patient had isolated subglottic involvement. There were six female patients and one male patient. The age range of the group was between 20 and 62 years. Two patients had laryngeal symptoms at the time of presentation and five subsequently developed them between one and 12 years after the initial diagnosis of Wegener’s granulomatosis.

In two of the cases of delayed subglottic involvement the complication occurred despite the patient being on chemotherapy (case 4 was receiving cyclophosphamide and prednisolone and case 5 azathioprine and prednisolone). In the third case, the subglottis became involved after a long period of remission.

The diagnosis of subglottic stenosis was made on flexible pernasal laryngoscopy and confirmed by radiological imaging of the larynx. The severity of the subglottic stenosis was determined from clinical history, endoscopie examination, radiological measurement of the length of the stenosed segment and flow loop studies (the latter in two patients).

The severity of the patient’s symptoms, general health, activity of the Wegener’s granulomatosis and assessment of the severity of subglottic stenosis determined the further management plan.

All seven patients had active disease, and immunosuppressant and steroid treatment was needed almost continuously from the time of diagnosis. Four patients required a tracheostomy to relieve the airway obstruction. These patients had subglottic stenosis that was refractory to maximal drug therapy. Three patients who had less severe symptoms were treated with medical therapy alone and with regular clinic surveillance of their subglottic stenosis.

TABLE I

CLINICAL PRESENTATION AND AIRWAY MANAGEMENT OF THE PATIENTS

Case histories

Case 1

A female patient aged 32 years presented in 1989 with shortness of breath, nasal obstruction, tinnitus, deafness and arthralgia. A diagnosis of Wegener’s granulomatosis was established by nasal biopsy and a positive C-ANCA test. One year later, she developed voice changes and shortness of breath and was clinically diagnosed with subglottic stenosis. The subglottic stenosis was treated conservatively. The CANCA test remained positive throughout the illness. Initially, prednisolone and cyclophosphamide were used to treat the systemic manifestations of the disease. Her subsequent course was one of relapses and remissions treated by methotrexate and prednisolone. She received this combination therapy intermittently due to repeated relapses. She was treated by continuous methotrexate for five years. The patient continued to have repeated chest infections, arthralgia and blocked nose. Her C- ANCA test continued to be positive. The methotrexate was stopped two years ago and she was treated with prednisolone only because she was attempting to conceive. At the time of writing the patient was receiving prednisolone 5 mg on alternate days.

Case 2

A female patient aged 34 years presented in 1993 with a hoarse voice and nasal obstruction with no other systemic symptoms. Nasoendoscopy showed subglottic stenosis and congested vocal cords. A PANCA test was positive for one year, following which it became negative. Nasal biopsy showed inflammatory granulation tissue without any granuloma formation. Magnetic resonance imaging (MRI) revealed a 3-cm segment of subglottic stenosis. Six months later the patient developed headache, weakness and paraesthesia of both the upper and lower limbs. In view of the severity of the breathing symptoms, tracheostomy was performed three years after the diagnosis. The patient’s medical treatment involved prednisolone and cyclophosphamide until she moved house and was transferred to another hospital’s care. During her follow-up period she experienced active ENT symptoms, with stridor, nasal blockage and recurrent epistaxis.

Case 3

A female patient aged 53 years presented in 1998 with shortness of breath, hearing loss and nasal obstruction. An ENT examination revealed perforation of the right tympanic membrane and granulation tissue in the nose. The patient had ankylosing spondylitis. The C- ANCA test was positive and nasal biopsy showed typical necrotizing granulomata. Three years later she developed voice changes and a diagnosis of subglottic stenosis was established. An MRI scan revealed tracheal and subglottic stenosis. Tracheostomy was performed after attempts to treat the patient with laryngcal and trachal dilatation failed. The patient was also treated with prednisolone and cyclophosphamide and she continued to have repeated relapses. At the time of writing, her most recent treatment regime was weekly methotrexate injection and daily oral cyclosporine and prednisolone.

Case 4

A female patient aged 66 years presented in 1990 with left-sided nasal obstruction and discharge. The clinical diagnosis was left- sided pansinusitis. Biopsy of the nasal granulation tissue showed typical necrotizing granulomatosis of Wegener. A C-ANCA test was negative at the time of presentation but became positive two years later. One year after presentation the patient developed respiratory and renal manifest\ations. At the age of 64 years the patient developed subglottic stenosis. A computerized tomography (CT) scan confirmed the diagnosis of mild subglottic stenosis. The patient received prednisolone and cyclophosphamide for four years and a tracheostomy was not required. The patient died in 1994 due to renal and pulmonary complications of the disease.

FIG. 1

Computed tomography scans of the larynx and trachea of case 6. (a) Severe subglottic stenosis on the axial section; (b) the stenosis is shown to have an overall length of 3 cm. This patient was managed by tracheostomy.

Case 5

A male patient aged 55 years presented in 1992 with weakness of the limbs, paraesthesia and renal impairment. He also had bilateral sensorineural hearing loss. One year later he developed voice changes, and the diagnosis of subglottic stenosis was established clinically. The diagnosis of Wegener’s granulomatosis was confirmed by renal biopsy. Tests for C-ANCA were negative for the first six years after presentation but later became positive. Tracheostomy was not performed. At the time of writing, the patient continued to receive prednisolone and azathioprine and had developed marked stridor.

Case 6

A female patient aged 58 years presented in 1981 with acute renal failure due to glomerulonephritis. The C-ANCA test was positive and renal biopsy revealed Wegener’s granulomatosis. Twelve years later the patient presented with breathing difficulties, a hoarse voice and nasal obstruction. She was treated with prednisolone and azathioprine. Nine years after the diagnosis of Wegener’s granulomatosis, and with worsening breathing symptoms, laryngeal CT scan showed a severe 3-cm length of Wegener’s granulomatosis (see Figure). A tracheostomy under general anaesthesia was performed because of the severity of respiratory obstruction. Post- operatively, the patient continued to receive azathioprine and prednisolone.

Case 7

A female patient aged 59 years presented in 1997 with nasal obstruction and rhinorrhoea, left-sided hearing loss, voice changes and mild stridor. Examination of the nose revealed a perforated nasal septum and fibre-optic endoscopy showed subglottic stenosis. The C-ANCA test was positive. Histopathological examination of the nasal septum and subglottic area showed non-specific inflammatory changes. The patient was diagnosed as having Wegener’s granulomatosis and treated with azathioprine and diclofenac. Her past history revealed chronic rheumatoid arthritis and coeliac disease, diagnosed 10 years before developing Wegener’s granulomatosis. Larynx MRI and CT scans confirmed the subglottic stenosis. Upon increasing stridor, a tracheostomy was performed three years after the diagnosis of Wegener’s granulomatosis. The patient developed severe voice changes and complete loss of voice two years later. Repeated dilatations of the subglottic area temporarily improved the voice for a few months. Laser excision was not attempted because of difficulty in performing tracheoscopy due to severe subglottic stenosis and also because of the patient’s cervical spine problems due to her rheumatoid arthritis. At the time of writing, the patient continued to receive azathioprine and diclofenac and was followed-up six-monthly.

Discussion

Immunosuppression with drugs such as prednisolone, cyclophosphamide and azathioprine has revolutionized the treatment of Wegener’s granulomatosis, with a dramatic reduction in mortality. However, patients continue to suffer considerable morbidity from the disease itself and its treatment. The risk of relapse is high.3

Although over 90 per cent of patients with Wegener’s granulomatosis will have positive ENT findings at some stage in their disease,6,7 subglottic stenosis will occur in 10 to 20 per cent of all cases.2,7 Although two of the seven cases reported here presented with subglottic stenosis, none had disease confined purely to the subglottis. The sexes are equally afflicted by the generalized condition.3 However, we found that women greatly outnumbered men (6:1). A similar ratio has been noted previously.7,8 The reasons for this are unclear and suggest heterogeneity.

The differential diagnosis of subglottic stenosis includes carcinoma, tuberculosis, syphilis and other infectious diseases, lymphoma, and prolonged intubation.7,9 Tuberculosis may occur in susceptible individuals, such as patients receiving immunosuppression therapy, and we have encountered both diseases in one patient who had pulmonary tuberculosis in addition.

We found that C-ANCA was only positive in 4/7 cases at presentation; two cases became positive later. This was not constant throughout the course of the disease and was modified by medical therapy. The P-ANCA test was positive in one further case and mirrors the findings of a previous report.1 This suggests that both P-ANCA and C-ANCA should be routine tests and should be repeated when there is diagnostic uncertainty; they complement the biopsy.

A CT scan provides accurate assessment of tracheal lesions and was performed in five patients. The reformatted coronal image is particularly useful to evaluate vocal cord involvement.10 Stenoses measured up to 3 cm distal from the subglottis to extend substantially into the cervical trachea; this is similar to the experience of others.9

The diagnosis of isolated subglottic stenosis may be difficult histologically. Macroscopically, Wegener’s granulomatosis appears as a reddish, friable, circumferential narrowing just below the vocal cords. Histological section will typically show a more non-specific pattern of inflammation, as opposed to biopsies from other sites.9,11 Biopsy yield is low (5 per cent sensitivity).1 We found that histological confirmation was obtained most commonly from the nasal mucosa.

The subglottic lesion is atypical in a number of other ways. It is frequently resistant to systemic immunosuppressive therapy and fibrosis may develop during aggressive treatment. Systemic immunosuppression may not be indicated in isolated subglottic stenosis because of this.1 Although all our patients received medical treatment, there was no reliable long-lasting benefit to the course of the subglottic stenosis, and periods of remission were short-lived. This reinforces the opinion that subglottic stenosis can occur independently of the systemic disease and its treatment.

The goal is to eradicate airway obstruction whilst retaining natural airway anatomy. Mild or reversible lesions require no surgical intervention. Fixed lesions tend to require surgery, either tracheostomy, resection or dilatation. We found that tracheostomy was required in 4/7 cases, as was the case in another study (60 per cent).3 Decannulation is challenging because of continued disease activity and restenosis. There are limited reports of resection and re-anastomosis. In one report, successful healing was not followed by decannulation.12 In another report of three segmentai resection and re-anastomosis procedures, decannulation was only achieved in one case. Fears appear unfounded that immunosuppression interferes with wound healing, reactivates local disease and disturbs the anastomosis.8

Intralesional glucocorticoid has been used to treat subglottic stenosis and may reduce the need for systemic therapy. It is a safe and effective treatment when used in conjunction with intratracheal dilatation. It should ideally be used without concomitant systemic immunosuppression in local disease.1 However, multiple treatments are required, and this modality was not suitable for our patients. Results of laser excision are varied but generally do not allow decannulation of the patient.

Conclusion

We have found that subglottic Wegener’s granulomatosis is unpredictable and atypical because it targets women. The C-ANCA test was not always positive initially and should be repeated if the diagnosis is suspected. A combination of clinical, immunological and histopathological tests is needed to establish the diagnosis, and CT scanning helps to define its extent. The stenosis may extend 3 cm into the cervical trachea.

Surgical relief of the airway is not always necessary. A subset of patients has subglottic stenosis that is neither prevented by nor responsive to aggressive immunosupprcssant medication, and so tracheostomy should be performed promptly in these cases. Surgical resection by laser or reconstruction should be limited to the patients who are in remission and require no immunosuppressive therapy for at least a 12-month period. In our limited experience, laryngotracheal dilatation alone is not a reliable form of airway management. Combined therapy of intralesional corticosteroids and dilatation does offer the best hope for decannulation in isolated Wegener’s granulomatosis, but we have no experience of this.

* Subglottic stenosis and upper tracheal stenosis are well known complications of Wegener’s granulomatosis

* This uncontrolled, retrospective series reports the management of seven cases

* Conclusion: subglottic involvement may be difficult to diagnose and manage. Patients may not respond to immunosuppression; in such cases prompt surgical intervention may be required

References

1 Langford CA, Sneller MC, Hallahan CW, Hoffman GS, Kammerer WA, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum 1996; 39:1754-60

2 Waxman J, Bose WJ: Laryngeal manifestations of Wegener’s granulomatosis: case report and review of the literature. J Rheumatol 1986;13:408-11

3 Hoffman OS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98

4 Hoare TJ, Jayne D, Rhys Evans P, Croft CB, Howard DJ. Wegener’s granulomatosis, subglottic stenosis and antineutrophil cytoplasm antibodies. J Laryngol Otol 1989; 103:1187-91

5 Roland NJ, McRae RDR, McCombe AW. Key Topics in Otolaryngology,2nd edn. Oxford: Bios, 2001:17\0-1

6 Aozasa K, Ohsawa M, Tajima K, Sasaki R, Maeda H, Mastsunaga T, et al. Nation-wide study of lethal mid-line granuloma in Japan: frequencies of Wegener’s granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions. Int J Cancer 1989; 44:63-6

7 Lebovics RS, Hoffman GS, Leavitl RY, Kerr GS, Travis WD, et al. The management of subglottic stenosis in patients with Wegener’s granulomatosis. Laryngoscope 1992:102:1341-5

8 McDonald TJ, Neel HB 3rd, DeRemee RA. Wegener’s granulomatosis of the subglottis and the upper portion of the trachea. Ann Otol Rhinol Laryngol 1982;91:588-92

9 Herridge MS, Pearson FG, Downey GP. Subglottic stenosis complicating Wegener’s granulomatosis: surgical repair as a viable treatment option. J Thorac Cardiovasc Surg 1996; 111:961-6

10 Screaton NJ, Sivasothy P, Flower CD, Lockwood CM. Tracheal involvement in Wegener’s granulomatosis: evaluation using spiral CT. Clin Radiol 1998;53:809-15

11 Yumoto E, Saeki K, Kadota Y. Subglottic stenois in Wegener’s granulomatosis limited to the head and neck region. Ear Nose Throat J 1997;76:571-4

12 Arauz JC, Fonseca R. Wegener’s granulomatosis appearing initially in the trachea. Ann Otol Rhinol Laryngol. 1982;91:593-6

A. ALAANI, F.R.C.S.ED., F.R.C.S.I., R. P. HOGG, M.PHIL., F.R.C.S. (O.R.L.-H.N.S.), A. B. DRAKE LEE, M.M.ED., PH.D., F.R.C.S.

From the Department of ENT, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK.

Accepted for publication: 13 June 2004.

Address for correspondence:

Mr A.B. Drake Lee,

Consultant ENT Surgeon,

Department of ENT,

Queen Elizabeth Hospital,

Edgbaston,

Birmingham B15 2TH, UK.

E-mail: [email protected]

Mr A. B. Drake Lee takes responsibility for the integrity of the content of the paper.

Competing interests: None declared

Copyright Royal Society of Medicine Press Ltd. Oct 2004

TB: Keeping an Ancient Killer at Bay

Laboratorians have been on the front lines in the fight against tuberculosis (TB) ever since Dr. Robert Koch announced his discovery of the tuberculosis bacillus in 1882. The bacillus Mycobacterium tuberculosis (M tuberculosis) has a high concentration of lipids in the cell wall, which makes it the ultimate survivor. It is impermeable to stains and dyes, resistant to many antibiotics, resistant to killing by acidic and alkaline compounds, resistant to osmotic lysis via complement deposition, and resistant to lethal oxidations and survival inside of macrophages. The bacillus also grows slowly compared to many of the other pathogenic bacteria; M tuberculosis divides every 16 to 20 hours as compared to Escherichia coli, which can divide every 20 minutes. This has been a major problem historically in identifying the organism because weeks, and sometimes months, were required to complete the “culture and susceptibility” laboratory testing.

“Ebola with wings”

According to Dr. Lee Reichman, executive director of the New Jersey Medical School National Tuberculosis Center and co-author of Time Bomb. The Global Epidemic of Multi-Drug-Resistant Tuberculosis, “In an era of concern over bioterrorism, it is important to remember that the disease of mass destruction is tuberculosis. According to the World Health Organization (WHO), over 2 million people died in 2003. Putting this in perspective, last year there were 813 deaths from SARS, 244 from Ebola, and five from anthrax in 2001; one cow died from mad cow disease; and there were no deaths at all due to smallpox. Paradoxically, TB is 100% preventable and curable.”

Dr. Lee Reichman, international expert on MDR-TB.

Of the world’s 6 billion people, 2 billion have latent TB. M tuberculosis infects many individuals, yet causes disease in relatively few. After the bacillus enters the lungs, the cellular arm of the immune system cannot kill the organism completely. It can, however, usually isolate it safely in the lungs. The bacteria frequently live inconspicuously for years or decades. During this latent infection, the victim generally suffers no obvious disease symptoms and cannot pass on the germ to others. Notwithstanding, if the immune system weakens (usually from old age, poor nutrition, or other diseases), the live bacteria can emerge from their hiding places and cause active TB.

While ordinary TB can be treated in a developing country with antimicrobials that cost roughly $10, sadly, TB has now returned as the leading infectious killer worldwide. “In an era of high tech, it is ludicrous that we have not had a new TB drug in 35 years,” comments Dr. Reichman, who was recently in Romania assessing the global outbreak of multidrug-resistant tuberculosis (MDR-TB).

MDR-TB is defined by its resistance to isoniazid and rifampiii. A recent global review showed that the prevalence of MDR-TB is 3.2% among new TB cases. The mechanism of resistance is man-made and reflects the problem of incomplete therapy. “When the HIV epidemic hits the pool of latent TB infections, there is going to be an explosion of MDR-TB. TB and HLVare like gasoline and a match,” says Dr. Reichman. HLV patients, who have diminished cellular immunity, have little defense against the bacteria and can easily infect others with TB, which is spread through the air like the common cold. TB has been referred to by Richard Bumgarner, former deputy director of the WHO’s global TB program, as “Ebola with wings.”

Figure 1 Reported TB cases, United States, 1982-2003. The resurgence of TB in the mid-1980s was marked by several years of increasing case counts followed by an even steeper rise. The total number of TB cases peaked in 1992. From 1992 until 2002, the total number of TB cases decreased 5% to 7% annually, and 2003 marked the 11th year of decline in the total number of TB cases reported in the United States since the peak of the resurgence.

Ending neglect

After antituberculosis drugs became widely available in the 1950s, tuberculosis began to recede from public consciousness. Since the 1960s, it has been largely ignored as a public health threat. Funding was cut and programs were closed until the killer returned in the mid-1980s, along with the first treatment-resistant strains. The subsequent increase in TB-control activities brought the number of new anil existing cases in the United States to an all-time low.

In May 2000, the Institute of Medicine report, “Ending Neglect: The Elimination of Tuberculosis in the United States,” warned another cycle of resurgence was likely if the United States failed to take decisive action to eliminate TH (see Figure 1). The report offered a plan detailing a number of intertwined steps involving all levels of government and the private sector, and identified clinical laboratory and TR testing as major areas of focus. The U.S. elimination goal was less than one case per million population by the target year of 2010.

TB: An impoited disease

TB has become an imported disease. In 2001, the proportion of TR cases among foreign-born persons living in the United States reached 50%. Most U.S. cases are occurring in persons from Asian, Latin American, and African countries, where TB rates are five to 30 times those of the United States. Since nearly one-third of the world’s population is infected with the organism, TB elimination in the United States is not possible without a substantial reduction in the global burden of TB. Dr. Reichman notes that 500 million international travelers passing through 5,000 international airports each year increases the risk for everyone. “To control TB anywhere, you have got to control it everywhere.”

The future of TB laboratory services

The Association of Public Health Laboratories (APHTy) just published a new report entitled “The Future of TB Laboratory Services: A Framework for Integration, Collaboration and Leadership,” which says, “The critical next step will be to develop an integrated system that ensures timely laboratory testing and timely flow of information among laboratorians, clinicians, and TB controllers.” John Ridderhof, Dr PH, chief, Office of Laboratory Systems Development Division of Laboratory Systems, Public Health Practice Program Office, at the Centers for Disease Control and Prevention (CDC), gives numerous suggestions as to how laboratories can better work together to speed up the process and provide better turnaround times. For example, if a laboratory has already identified M tuberculosis from a specimen, the next specimen could be sent to a full-service laboratory to avoid delay in reporting back to the clinician and TB-control personnel, and to reduce delay in treatment.

Another tip is to send broth cultures along with slants. Subculture from slants can cause delays of several days. Dr. Ridderhof states that laboratories should concentrate on the already existing CDC guidelines’ for acid-fast bacillus (AFB) smear, culture, and drug-susceptibility testing. For instance, does the laboratory receive specimens for TB testing within one day of specimen collection? Are smear results reported to a patient’s provider within one day of specimen receipt? Are results reported to the local health department within one working day from the time they are reported to the specimen submitter? A recent report2 showed that in California, laboratory reporting to the specimen submitter was delayed for 26.9% of smear-positive patients and 46.8% of smear- negative patients.

A visit to a hospital network

Susan Whittier, PhD, D(ABMM), chief of Clinical Microbiology Service at Meridian Health Systems in Neptune, NJ, oversees mycobacteriology testing for the entire hospital system. “We are really very fortunate since our microbiology laboratory at Jersey Shore University Medical Center serves as the core lab for our hospital system. We consolidated three very active and diverse labs and have been able to reap numerous benefits. We function as a Level- 3 lab, and we are able to definitively identify over 90% of our isolates. We use the Gen-Probe Accuprobe system to identify M tuberculosis, M avium complex, M gordonae, and M kansasii. All others are sent to our reference laboratory – ARUP in Salt Lake City. Since our core lab is just a few miles from the beach, a frequent isolate we send for identification is M marinum. In general, our level of service is perfectly matched to the patients we encounter.

Rick Valdez, MT (AMT), and Dr. Susan Whittier in Mycobacteriology Laboratory at Jersey Shore University Medical Center.

Rick Valdez, MT (AMT), manipulates TB cultures while working safely in a Biological Safety Cabinet with gloves, gown, and disposable respirator.

“Even though we are not in a metropolitan area, we see our share of tuberculosis cases. We serve patients who have emigrated from endemic regions throughout the world, and our beaches attract many people from New York City during the summer. All of our hospitals ‘think TB.’ When a patient presents to our emergency department at 3 o’clock in the morning, appropriate airborne precautions are put into place immediately. We process samples once a day, seven days a week. ‘Rule-out’ TB patients remain in isolation until we are able to turn around three negative AFB smears. When we do have a positive smear or culture, we notify the physician, the floor, the infection- control practitioner, and our state department of health. We do not wait for growth on solid med\ia to run our probes; we will always try to expedite results by testing the broth as soon as it is flagged as positive for AFB.”

ARUP Mycobacteriology Group. L to R (front), Gail L. Woods, MD, Haleina Neal. L to R (back), Joshua Kunz, Geremy Smith, and Joseph Strasburg.

TB testing at the large commercial laboratories and large medical centers

Gail L. Woods, MD, is the medical director of ARUP’s Specialty Microbiology and Microbial Antigen Detection Laboratories, which serve clients in all 50 states. The large commercial laboratories, such as LabCorp, Quest Diagnostics, and ARUP, provide excellent systems that bring specimens to the laboratory in a timely fashion and that employ electronic reporting capabilities. Dr. Woods states that to get specimens into the laboratory from all across the United States takes approximately 24 hours, with smear results having a 15- hour-or-less turnaround time. ARUP phones the referring laboratory with any positive TB results and directly reports any positives originating in Utah to that state’s TBcontrol program. Client laboratories are then directed to notify their own local or state health departments. It is the client laboratory’s responsibility to notify the clinician treating the patient and the TB-control program in the state where the TB patient resides. This may be a weak link in the chain. Dr. Woods believes thai the future holds more molecularbased testing and less biochemistry; that probes work well and have helped accelerate identification; and that susceptibility testing will utilize short-incubation liquid-based systems.

Pennsylvania Department of Health, Bureau of Laboratories, Microbiology Group L to R, Nancy G. Warren, PhD, assistant director; Gisela S. Withers, Microbiologist 3, Supervisor, Bacteriology section; lsmail Dirie, Alfred Logan, Melanie Solomon, Donna Krouse, and William Sweimler, all Microbiologist 2 level; Wayne Chmielecki, Microbiologist 3, Supervisor, Molecular Microbiology section; and Bruce Kleger, Dr PH, director.

A visit to Pennsylvania’s Bureau of Laboratories

Bruce Kleger, Dr PH, the director, and Nancy G. Warren, PhD, the assistant director of the Pennsylvania Department of Health, Bureau of Laboratories in Lionville, PA, explain the essential role of public health laboratories in TB testing. “Public health laboratories have always been at the forefront of TB testing – it is one of the core public health functions that our laboratory supports. Common to all clinical, commercial, and public health laboratories is the potential for TB testing. Typically, all three may perform primary detection methods, such as smear, culture, and even PCR, but it is usually public health and the larger reference laboratories that confirm identification, spciale other mycobacteria, and perform drug-susceptibility testing,” says Kleger. “Usually, public health laboratories facilitate and provide confirmatory and essential epidemiology support through expanded drug-susceptibility testing and genotyping. Communications remain a strong requirement of any successful control program. Any laboratory performing TB testing should be vigilant in reporting positive findings to its state TB-control program. When TB reporting fails, control measures will not be implemented, and the cycle of disease remains unchecked.”

Dr. Kleger relates that, during the TB resurgence of the 1990s, the laboratory accepted more specimens for testing and enhanced working relationships with state TB-control and HTV program staff. Additionally, revisions to the state’s communicable disease law now require that TB isolates be submitted by clinical labs to provide the opportunity for uniform culture confirmation and drug- susceptibility testing.

Current methodologies for identification of TB

According to Dr. Warren, the laboratory scientists at Pennsylvania’s Bureau of Laboratories explain that cultures of M tuberculosis are routinely identified by biochemical and nucleic acid probes. Biochemical testing is the more familiar, conventional approach; M tuberculosis produces niacin, while most other mycobacteria do not have this ability. Nucleic acid probes that detect TB ribosomal RNA have been in use for some time now. These probes are a dependable method for culture identification and eliminate the need to handle the chemicals used in biochemical testing. Both methods have pros and cons. Conventional testing definitely identifies M tuberculosis, but cultures must be several weeks old before the tests can be performed. Probes can be performed much earlier in the culture process, can provide answers within two hours, and can be combined with liquid culture methods. Probes are not able to separately identify all members of the “tuberculosis complex,” because probes will yield positive results when tested against M tuberculosis, Mycobacterium bovis, bacillus Calmette- Guerin, Mycobacterium africanum, and Mycobacterium microti. Overall, the rapid turnaround time achievable with probes generally far outweighs the need to subdivide the tuberculosis complex; if this level of identification is needed, probe positive isolates can be sent to a reference lab.

Current methodologies for TB-susceptibility testing

Currently, drug-susceptibility testing (DST) is performed by two general methods. Conventional methods use solid media, such as the Middlebrook agar used in the United States, with drugs incorporated into the agar. DST in liquid media is another accepted method and provides a much faster turnaround time (one week vs. three weeks). Liquid-media DST also can be supported by instrumentation – making reading, incubating, and interpreting results less laborious. DST is often sent to public health laboratories. In those laboratories that perform DST, liquid-media testing is quite common and isolates are usually not tested by solid-media methods unless a question arises or drug resistance is detected and results confirmation is needed.

New trends in TB identification and susceptibility testing

Dr. Kleger and Dr. Warren explain that new developments in recent years are having an impact on TB testing. The need for faster identification of new cases of TB has led to a real push for faster lab testing. Amplified DNA assays are now available to detect TB directly in respiratory secretions, so waiting for culture is not as critical. Culture and susceptibility testing have been improved by semiautomated broth methods, but the area of identification is where the most recent improvements have been seen. Methods have been developed that provide identification by high-performance liquid chromatography and 16S sequencing. In comparison to conventional methods, results are obtained faster, more species can be detected, and testing is better controlled. The combination of liquid culture and new identification methods has helped us identify many new mycobacterial species, and more species may be detected in the future.

Donna Krouse, MT(ASCP), analyzing mycolic acids by high- performance liquid chromatography (HPLC) to identify M tuberculosis at the Pennsylvania Department of Health, Bureau of Laboratories.

DST is on the cusp of new discovery right now. Liquid-media DST has certainly been a time improvement over conventional solid media, but neither provides the most rapid path to detecting drug resistance. As a result of the 1990s TB resurgence, more attention is now focused on the problem of dealing with drug-resistant and multidrug-resistant organisms. Improving the time it takes for lab tests to detect drag resistance is a step towards managing the complicated disease, and reports in the scientific literature today point to efforts to do just that. Amplified probe methods and molecular beacons are just two of the new tests being evaluated. In the next few years, laboratorians can anticipate that these tests will move out of the research lab and into the clinical lab for routine use.

Detection of mutations with a molecular beacon

(Loop portion contains wild-type sequence)

Figure 2

Molecular beacons

Edward Desmond, PhD, of the Microbial Diseases Laboratory Branch of the California Department of Health Services, describes the use of molecular beacons. Longstanding guidelines from the CDC and the APHL have given laboratories a time frame of two to four weeks to detect the presence of M tuberculosis in a culture and determine whether the strain is susceptible or resistant to commonly used anti- TB drugs, such as isoniazid, rifampin, and ethambutol. This requires growing a culture of these slowgrowing organisms twice – once for initial isolation and once in the presence and absence of the drugs to determine susceptibility. In many cases, this long turnaround time has no detrimental effects if patients are put on standard therapy before laboratory results are available and if their infecting organisms are susceptible to the standard therapy. With an initial treatment regimen of isoniazid, rifampin, ethambutol, and pyrazinamide, and the prevalence of resistance to isoniazid close to 10% and to rifampin at around 1% to 2%, the standard regimen will usually treat tuberculosis successfully or at least keep the infection in check until the drug-susceptibility results are available. In some cases, however, this conventional turnaround time is not nearly fast enough.

Quick drug-susceptibility results are always better in order to guide the TE patient’s treatment regimen, help him to get better quickly, and reduce further spread of TB. Sometimes, quick results are especially important, however, when a culture-positive patient – for example, a healthcarc worker, teacher, or child-care worker – has exposed a susceptible group of people to TB. Some of the exposed people may show signs of infection, like a positive skin test. TB- control guidelines call for treatment of infected people with a preventive drug regimen, such as isoniazid. If the culture-positive patient who exposed others has an isoniaz\id-resistant strain, preventive therapy with this drug will be ineffective; another preventive regimen or strategy will need to be chosen.

Dr. Desmond explains that another situation in which it is imperative to obtain the quickest possible drug-susceptibility result is when a critically ill patient, i.e., a patient with another illness like AIDS or cancer, contracts TB. If the patient has drug-resistant TB, and the initial regimen is ineffective, the patient could die or become seriously worse before the two- to four- week turnaround time of the conventional culture-based methods. On the other hand, blind treatment of such a patient’s TB with second- line drugs would entail the greater toxic effects of these drugs.

These clinical situations provide a setting for selective use of rapid molecular testing to detect drug resistance. One such method is a real-time PCR assay using molecular beacons.3 Molecular beacons are DNA probes designed with a structure that lets them “light up” in a real-time PCR reaction if there is amplification of their specific target (see Figure 1). The probe or loop region of the molecular beacon will bind to the normal DNA sequence of an M tuberculosis gene, such as catalase (katG) or RNA polymerase (rpoB), separating the fluorescent moiety from the quencher moiety of the beacon, resulting in fluorescence. Mutations in these genes have been associated with resistance to isoniazid and rifampin, respectively, the most effective drugs commonly used to treat TB. In a PCR reaction in which selected segments of the katG or rpoB gene are amplified, molecular beacons can discriminate between the presence of the wild-type sequence associated with drug susceptibility or a mutated sequence at specific sites associated with drug resistance. Figure 2 shows the output of a molecular beacons experiment, looking for mutations in the katG gene associated with isoniazid resistance. The nonmutated strains will show a rise in fluorescence with time as the molecular beacon probes bind to their complementary sequence in the amplified product, separating the fluorescent moiety from the quencher. Resistant strains with mutations in the probe region will not bind to the molecular beacons, so their fluorescence pattern stays flat throughout the amplification.

Commercial test kits are not available at present for performing molecular beacons testing to determine TB drug-susceptibility or resistance. Dr. Desmond predicts that because molecular beacons are so quick and generally provide clearcut results, their use in the future will likely become more widespread. For phenotypic, culture- based testing, these methods – besides being slow – involve the need for rigorous control of growth-medium composition, inoculum size, and metabolic status of the inoculum to permit accurate results to be obtained. These factors, in the long run, may make molecular testing more practical than phenotypic testing for most laboratories.

TB genotyping

Dr. Desmond highlighted other tools created in the laboratory for TB epidemiology. Before the development of molecular strain typing of tuberculosis in the 1990s, tuberculosis-control personnel often relied on interviewing patients and looking for TB cases in the patients’ close contacts people who shared social or work settings or living facilities – to trace the spread of this disease. A recent study has shown that strain typing, with follow-up interviews for cases with the same strain type, can expand the understanding of transmission, including in settings outside the traditional concentric-circle approach.4 Genotyping, thus, has the potential for identifying new circumstances and places where TB transmission can occur.

New PCR-based genotyping methods, including spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units (MlRU) typing, can provide straintyping information from cultures within a month or sometimes less from the time the specimen is collected from a patient. The CDC has contracted with two laboratories (Michigan State Laboratory for the eastern half of the United States and the California [Microbial Diseases] Laboratory for the western half) to provide genotyping services for all culture-positive U.S. patients. These laboratories accept pure broth or solid-medium cultures of M tuberculosis complex organisms submitted through participating state laboratories. The Michigan and California laboratories use MTRU and spoligotyping, and report results within two weeks of receiving the culture in most instances. Reports, including a cumulative database, are sent to the tuberculosis-control program in each state. Universal genotyping with rapid results offers the possibility of new knowledge and rapid response to developing outbreaks of TB.

Francine Arroyo works on MIRU with capillary sequencer.

TB genotyping has been useful in answering specific questions related to suspected outbreaks of TB in institutions, such as hospitals, schools, and prisons. In California, for example, a renal- dialysis clinic reported five cases of tuberculosis in a year’s time. It was suspected that transmission of TB was taking place at the clinic and that more rigorous control measures would need to be implemented. TB genotyping showed, however, that the five patients had different strains so that transmission at the clinic was effectively ruled out. Conversely, after an outbreak in a prison was thought to be under control, a new case was found to be the outbreak strain again, leading to further control measures.

When used together for strain typing, spoligotyping and MIRU provide a powerful combination of tools that can discriminate strains which are not part of the same chain of transmission or the same cross-contamination event. Occasionally, however, unrelated strains could have the same spoligotyping and MIRU numbers. For this reason, a third technique, insertion sequence 6110 restriction fragment length polymorphism (RFLP) is available in the regional laboratories. When it is suspected that cultures from patients with matching spoligotyping and MTRU numbers may be unrelated epidemiologically, TB-control programs can request that RFLP testing be done as well. RFLP is a lengthier and more labor-intensive method than the PCR-based methods, so about three weeks is required after RFLP is requested before results are available.

The CDC and the National Tuberculosis Controllers Association prepared a Genotyping Guide – 80 pages long – which is available at http://web-tb.forum.cdc.gov. After registering for this website, users can access the Genotyping Guide, which includes an introduction to the methods and case studies, along with information on how to access, interpret, and use gene-typing services. Rapid TB genotyping by regional laboratories will unfold new possibilities for improving tuberculosis control. TB-control programs can rapidly discover patterns of transmission in developing outbreaks, and new situations in which TB is spread from one person to another are likely to be found by universal application of these techniques.

A view of the future from a pioneer in rapid TB testing

Becton Dickinson (BD) Fellow Salman H. Siddiqi, PhD, is considered the “father” of the first rapid semiautomated liquid- medium-based TB-culture system, which he helped develop at the University of Maryland. Historically, there had been no new significant development to improve laboratory testing for TB until 1980 when BD introduced the BACTEC 460 TB Radiometrie System. This technology led to a shortened turnaround time for detection and drugsusceptibility testing of TB from months to weeks. BACTEC 460 became a gold standard worldwide and the workhorse of the mycobacteriology laboratory. The new nonradiometric BACTEC MGIT 960 System is a fully automatic system and, thus, has helped not only standardize testing but has also helped save labor costs. While a liquid-culture system has replaced conventional solid media in developed countries, culture-based diagnosis in general, and rapid liquid-culture systems in particular are being adopted as the resources are more readily available in developing countries.

BD’s “father of rapid TB testing,” Dr. Salman Siddiqi, is shown with a row of the “workhorse” BACTEC 460 instruments in the background with the new BACTEC MGIT 960 in the front.

According to Dr. Siddiqi, the National Committee for Laboratory Standards (NCCLS) has placed streptomycin in the second line of anti- TB drugs (NCCLS, M24-A). This decision will not have any significant impact on BACTEC 460 or BACTEC MGIT 960 testing because both systems have the ability to test five drugs for susceptibility, and any drug combination may be tested on these instruments. Most overseas laboratories, as well as many laboratories in the United States, are still testing streptomycin. As medical and laboratory practices evolve in the next few years, the packaging for the drug combination will also evolve accordingly.

Microarray-chip technologies

Dr. Siddiqi says that he sees the new trends are toward achieving faster and faster results. In developed countries, molecular technologies are further reducing testing time from weeks to days or even hours. Results of molecular tests, however, are still used in conjunction with the conventional culture-based techniques. Microarray-chip technologies are developing quickly, and this new approach may one day also become a gold standard in carrying out multiple TB testing on a single chip and would have a great impact on the management and control of the disease. The concern is that these new state-of-the-art technologies are complex and expensive and are not suitable for low-resource developing countries where 95% of the global burden of tuberculosis is located. In many of these countries, AFB smear is the only test that can be afforded. It may take decades before newer technologies become widely accessible in these countr\ies. At present the culture-based techniques may be the only hope for diagnosis of the disease in high-burden developing countries.

Biosafety: OSHA withdraws the proposed new TB standard

Laboratorians working with M tuberculosis have always been at risk for becoming occupationally infected with the organism. After a decade of intense debate, on December 31, 2003, the Occupational Safety and Health Administration (OSHA) withdrew the proposed new TB standard and also eliminated the interim TB standard 29 CFR 1910.139. An Institute of Medicine report entitled “Tuberculosis in the Workplace” warned that the OSFIA standard may not allow organizations reasonable flexibility to adopt TB-control measures appropriate to the level of risk that workers face. Many other infection-control groups, including the Society for Healthcare Epidemiology of America and the Association for Professionals in Infection Control and Epidemiology (APIC), agreed with that assessment. OSHA decided that a number of factors have emerged in the past decade that alleviate the necessity of developing a TB- specific regulation. For example, there has been a steady decrease in the number of TB cases nationwide. OSHA determined that occupational risk was lower than originally reflected because of greater implementation of TB controls and greater compliance with the CDC’s guidelines. It concluded that a new rule would not substantially reduce the spread of TB from undiagnosed sources.

OSHA has introduced a new mandate applying the General Industry Respiratory Protection Standard to M tuberculosis.5 This mandate beeame effective July 1, 2004, and requires the annual fit-testing of respirators in healthcare settings. Many infection-control groups have been working diligently to overturn this new ruling. APIC has long opposed the notion of mandatory annual fit-testing, because its membership believes there is no solid scientific justification for this practice. Jeanne Pfeiffer, RN, MPH, CIC, the current president of APIC, responded to an August 15, 2004, Washington Post article on the issue, “rather than mandating unproven, unreliable, and unnecessary ritualistic practices such as annual fit-testing, the federal government should instead focus on ensuring dedicated funding for TB-control efforts at the public health level – efforts that are proven to be effective.” The jury is still out on the validity of respirator fit-testing and TB.

The authoritative standard for biosafety in the clinical laboratory remains the Biosafety in Microbiological and Biomedical Laboratories (BMBL) 4th Edition published by the CDC and the National Institutes of Health in 1999. Freely available on the Internet at www.cdc.gov/od/ohs/biosfty/ bmbl4/bmbl4toc.htm, the book contains helpful and practical information about how to work safely with M tuberculosis, warns that all aerosol-generating activities must be conducted in a Class I or II biological safety cabinet, and recommends the use of a slide-warming tray, rather than flame- drying, for slides. The incidence of tuberculosis in laboratory personnel working with M tuberculosis was three times higher than that of those not working with the agent before workers focused on biosafety issues.

Making decisions about TB testing

Clinical laboratories today must decide how they will handle requests for TB tests. If testing is to stay in-house, then what extent of testing will be performed? Will an AFB smear result provide the physician with immediate information needed? Is it necessary to perform culture in-house, or can this be referred? What identification methods should be used to provide the fastest answers?

With personnel costs and unique instrumentation requirements, the best choice may be to refer specimens to another laboratory. Choose your reference laboratory carefully, and ask critical questions, such as:

* Are instructions provided for specimen collection, storage, and transport?

* What are the criteria for rejecting a specimen?

* How is information communicated back to the submitting laboratory?

* Does the reference laboratory participate in an approved proficiency-testing program?

* How does the reference laboratory maintain proficiency in performing requested mycobacteriology tests?

* What testing methods are used?

* What are the expected turnaround times?

* How are positive cultures stored and retained?

* Is there a disaster plan in case testing cannot be done?

CE test on TB: KEEPING AN ANCIENT KILLER AT BAY

MLO and Northern Illinois University (NIU), DeKaIb, IL, a re co- sponsors in offering continuing education units (CEUs) for this issue’s article on TB: KEEPING AN ANCIENT KILLER AT BAY. CEUs or contact hours are granted by the College of Health and Human Sciences at NIU, which has been approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS PAC. E. prog ram (Provider No. 0001) and by the American Medical Technologists Institute for Education (Provider No. 121019; Registry No. 0061). Approval as a provider of continuing education programs has been granted by the state of Florida (Provider No. JP0000496), and for licensed clinical laboratory scientists and personnel in the state of California (Provider No. 351 ). Continuing education credits awarded for successful completion of this test are acceptable for the ASCP Board of Registry Continuing Competence Recognition Program. After reading the article on page 8 answer the following test questions and send your completed test form to NIU along with the nominal fee of $20. Readers who pass the test successfully (scoring 70% or higher) will receive a certificate for 1 contact hour of P.A.C.E. credit. Participants should allow four to six weeks for receipt of certificates.

The fee for each continuing education test will beS20.

All feature articles published in MLO are peer-reviewed.

Learning objectives and CE questions prepared by Donna M. Falcone, MSM, MT(ASCP), CLS(NCA), Project Consultant, Geneva, IL.

1. The bacillus Mycobacterium tuberculosis (M tuberculosis)

a. is susceptible to many antibiotics.

b. has a high concentration of lipicls in the cell wall.

c. is permeable to stains and dyes.

d. is susceptible to osmotic lysis via complement deposition.

2. One major problem in identifying M tuberculosis is that

a. it can divide every 20 minutes.

b. culture and susceptibility testing can be completed very rapidly.

c. it is a very slow grower, dividing every 16 to 20 hours,

d, None of the above.

3. Of the world’s 6 billion people, it is estimated that the number of those that have latent TB is

a. 2 million,

b. 6 million,

c. 1 billion,

d. 2 billion.

4. Multidrug-resistant tuberculosis (MDR-TB)

a. is defined by resistance to isoniazid and rifampin.

b. shows a prevalence of 3.2% among new TB cases,

c. reflects the problem of incomplete therapy,

d. All of the above.

5. In 2001, the proportion of TB cases among foreign-born persons living in the United States reached

a. 50%.

b. 25%.

c. 15%.

d. 5%.

6. PCR-based genotyping methods

a. include spacer oligonucleotide typing (spoligotyping).

b. include mycobacterial interspersed repetitive units (MIRU) typing,

c. can provide strain-typing information from cultures within a month of specimen collection,

d. All of the above.

7. Methods that provide identification of TB by high-performance liquid chromatography and 16S sequencing

a. detect fewer species than conventional methods,

b. are less controlled than conventional methods,

c. provide faster results than conventional methods,

d. are not useful in the clinical laboratory.

8. According to Dr. GaM Woods, future TB testing

a. will be confined to biochemical testing,

b. will use more molecular-based testing,

c. will not involve probe assays,

d. None of the above.

9. In 1980, laboratory testing for TB improved significantly due to the development of

a. the BACTEC 460 TB Radiometrie System.

b. molecular testing.

c. the BACTEC MGIT 960 System.

d. microarray-chip technology.

10. When choosing a reference laboratory for TB testing, it is important to consider

a. if the reference laboratory participates in an approved proficiency-testing program,

b. whether the reference laboratory provides instructions for specimen collection, storage, and transport,

c. how the reference laboratory stores and retains positive cultures,

d. All of the above.

11. In general, public health laboratories

a. are usually unable to confirm TB identification,

b. can speculate mycobacteria.

c. are unable to perform drug-susceptibility testing,

d. cannot provide TB genotyping.

12. The percentage of the global burden of TB that resides in lowresource developing countries is

a. 95%.

b. 75%.

c. 50%.

d. 25%.

13. Most often, the standard treatment regimen that can successfully keep a tuberculosis infection in check while drug- susceptibility testing is being performed includes

a. isoniazid.

b. rifampin.

c. ethambutol and pyrazinamide.

d. All of the above.

14. Nucleic acid probes

a. require cultures that are several weeks old.

b. can definitively identify M tuberculosis.

c. can provide answers within two hours.

d. are unable to be combined with liquid culture methods.

15. The CDC/NIH publication Biosafety in Microbiological and Biomedical Laboratories (BMBL), 4th Edition published in 1999

a. has practical information on how to work with M tuberculosis,

b. states that all aerosol-generating activities must be conducted in a Class I or Il biological safety cabinet,

c. recommends the use of a slide-warming tray rather than flame- drying for slides,

d. All of the above.

16. In a PCR reaction in which selected segments of the katG gene are amplified, one would expect the fluorescent pattern of a nonmutated strain to

a. remain flat throughout the amplification,

b. show a rise in fluorescence with time,

c. show a small rise and then remain flat,

d. None of the above.

17. Drug susceptibility testing for TB is currently performed using

a. solid m\edia,

b. liquid media,

c. both a and b.

d. neither a nor b.

18. The two laboratories used by the CDC for genotyping all culture-positive patients in the USA are

a. Michigan State Laboratory and California (Microbial Diseases) Laboratory.

b. Michigan State Laboratory and Florida State Laboratory,

c. Maryland State Laboratory and California (Microbial Diseases) Laboratory,

d. Maryland State Laboratory and Florida State Laboratory

19. The General Industry Respiratory Protection Standard to M tuberculosis introduced by OSHA calls for respirators in healthcare settings to be fit-tested

a. semiannually.

b. every two years,

c. every five years,

d. annually.

20. The insertion sequence 6110 RFLP (restriction fragment length polymorphism) technique

a. can be used when unrelated TB strains have the same spoligotyping and MIRU numbers.

b. is a more labor-intensive method than PCR-based methods,

c. is available in regional laboratories,

d. All of the above.

CE CONTINUING EDUCATION

To earn CEUs, see test on page 20.

LEARNING OBJECTIVES

Upon completion of this article, the reader will be able to:

1. Describe multidrug-resistant tuberculosis and why eliminating tuberculosis in the United States is a global effort.

2. List the pros and cons of the two methods used routinely in TB identification.

3. Discuss the trends in TB-susceptibility testing.

4. Describe how TB genotyping can aid epidemiologists in tracking cases in a suspected outbreak.

5. Recognize the biosafety issues associated with working with Mycobacterium tuberculosis, and discuss some measures that can be taken to reduce the risk of becoming occupationally infected.

In an era of concern over bioterrorism, it is important to remember that the disease of mass destruction is tuberculosis.

TB spreads through the air like the common cold and has been referred to as “Ebola with wings.”

500 million international travelers passing through 5,000 international airports each year increases the risk for everyone.

References

1 CDC. Laboratory practices for the diagnosis of tuberculosis. 1995. MMWR, 44(R111.1-48.

2 Pascopella L, Kellam S, Ridderhof J, Chin DP, Reingold A, Desmond E, Flood J, Royce S. 2004. Laboratory Reporting of Tuberculosis Test Results and Patient Treatment Initiation in California. J Clin Microbiol. 2004. 42(91:4209-4213.

3 Lin S-Y, Probert W, Lo M, Desmond E. 2004. Rapid detection of isoniazid andrifampin resistance mutations in Mycobacterium tuberculosis complex from cultures or smear-positive sputa by use of molecular beacons. J CHn Microbiol. 42(9):42044208.

4 van Deutekom H, Hojing S, de Haas P, Langendam M, Horsman A, van Soolingen D, Coutinho R. 2004. Am J Resp CritCare Med. 169:806- 810.

5 Federal Register. 2003 Dec 31; Volume 68: 75776-75780. Respiratory Protection For M. Tuberculosis – Final Rules. U.S. Department of Labor, OSHA.

By James W. Brown, PhD, HCLD

James W. Brown, PhD, HCLD, and dean of the division of Health Sciences and Human Performance at Ocean County College in Toms River, NJ, is pictured here in Guatemala in September 2004 with his newly adopted daughter, Abby Carmelina. Many internationally adopted children have positive Mantoux tests, some of which are due to infection with M tuberculosis.

Copyright Nelson Publishing Nov 2004

Join the Club ; Here Are Five Tips to Keep in Mind Before You Sign That Gym Membership. You Might Feel Some Serious Workouts Calling Your Name After That Thanksgiving Feast, but Be Sure to Test Out a Gym and Look into Other Options Before Joining One.

There’s good reason Bally Total Fitness has proclaimed today “Feeling Fat Friday” and is allowing anybody to use its gyms for free.

If you ate a traditional Thanksgiving meal Thursday, you’re probably avoiding mirrors and promising yourself you’ll start working out today – or tomorrow.

A modest helping of hors d’oeuvres, turkey, stuffing, gravy, mashed potatoes, cranberry sauce, pie and a drink is approximately 2,700 calories and 144 grams of fat, said Silvia Veri, a dietitian for Beaumont Hospitals in Detroit.

That’s equivalent to about 6 1/2 Quarter Pounders with Cheese from McDonald’s and more than the USDA recommends you eat in an entire day.

“And you’re probably eating more than one meal on Thanksgiving,” Veri said.

To burn 2,700 calories you’d have to walk from the Tacoma Dome to the Capitol dome in Olympia. Suddenly trying to find the right gym doesn’t seem so daunting.

So, as an early Christmas present we, with the input of local fitness pros, are giving you five tips that will make it even easier to find a comfortable place to work out.

1. The white glove test

Heather Ancheta, co-manager of the Puyallup Athletic Club, says pay attention to your senses as soon as you walk through the door.

“What’s your first impression?” Ancheta said. “How does it smell? Then head straight to the locker room.”

In the locker room, check the corners of the showers and the restroom stalls, and under the toilets to see how thoroughly the gym is cleaned.

“If the locker room isn’t clean, you’re probably going to pick up a foot icky,” Ancheta said.

David Simia, a district manager for Bally, says also check the equipment.

“It’s OK if some equipment is down, but if a lot it is down it’s a sign of poor maintenance,” Simia said.

Check for cleaning spray and towels to wipe the community sweat off the machines before and after your workout.

And Steve Triller, associate executive of the Tacoma YMCA, says checking the pool can also tip you off if the gym is cleaned and well-maintained.

“If the pool is shut down, that can be a bad sign,” Triller said.

2. Does the gym feel right?

A gym has to have the exercise equipment, facilities and classes you need. Some gyms have pools, some have basketball courts, some have climbing walls, and some are equipped to handle disabled clients.

Others are not.

“Some gyms are geared toward families,” Triller said. “Others are geared toward people who work out three hours per day. People who are new to working out and surround themselves with super-fit people start to get self-reflective and think, ‘I’m not good enough to be here.’

“You need to find the gym that makes you feel most comfortable.”

In an attempt to broaden its appeal, Tacoma’s Morgan Family YMCA recently removed some mirrors in exercise areas.

“New exercisers sometimes don’t want to see themselves,” Triller said.

Also, the pros suggest touring the gym at the time of day you are most likely to work out so you can get the truest feel for how crowded the gym is, how loud the music is and who else is there.

Also, Ancheta said, geography is a big deal. Try to find a gym within 10 miles of your house so “it’s too far away” doesn’t become an excuse.

3. Check out the staff

If you are new to exercise – or it’s been so long you’ve forgotten how – you’ll likely need some pointers from the gym staff or its personal trainers.

“Picking a gym with a friendly and trained staff is key to becoming a long-term exerciser,” Triller said.

If the staff is huddled around the reception desk chatting, this might be a good sign they aren’t going to help you much, the pros say.

“You should have access to professional trainers for basic training without an additional charge,” said Darcy Celletti, the senior program director for adult fitness at the Morgan Family YMCA. “Once you get into advanced training and sports-specific training you should expect to pay extra.”

Ancheta suggests interviewing employees and trainers as if they are applying for a job with you. What’s their experience? Who trained them? How long have they been working there?

When picking a trainer, it is important to find out if they are certified by a reputable company. Larger gyms offer in-house trainer certification programs, but should also require outside certification after about three months, Simia said.

“And trainers should meet you where you are,” Celletti said. “They need to help you meet your goals, not their goals.”

4. Is the gym current?

If a gym doesn’t offer Pilates or yoga, it’s probably stuck in the dark ages.

These are the most popular workout classes, and Simia says you want to pick a gym that is on the cutting edge.

Other fashionable classes include spinning (group stationary cycling) and core training.

“There is less emphasis on dancing workouts and more on basic functional stuff,” Ancheta said.

Gyms should also regularly update their equipment. Triller says check to see if the equipment is new and well maintained.

“There should be no gunk on the guide rods of the weight machines,” Triller said. “If there is, the machine will not work smoothly.”

A good gym will have cardiovascular equipment (treadmills, elliptical trainers, etc.) and plenty of it because almost everybody will use these machines in their workouts.

Simia says don’t forget to make sure the training room’s equipment is up-to-date, too. One device he recommends asking for is a Bosu. The half-ball balance trainer is one of the hottest training tools on the market.

5. Will your wallet lose weight?

Gyms can be like cell phone companies – they want your signature on a long-term contract.

“But finally gyms are starting to offer memberships that don’t lock you into long-term contracts,” Ancheta said.

Ancheta says it’s to your advantage to avoid these long-term agreements.

Simia says you should be wary of processing fees and other hidden costs.

“You should pay a base fee to get started and a monthly fee,” Simia said. “Read the fine print.”

Some gyms charge fees for lockers, towel service and equipment rentals.

Others charge fees to participate in workout classes, but Simia says most classes should be included in your membership. He says only about 5 percent of gym activities should charge an additional fee.

“You have to make sure the gym fits your budget,” Ancheta said. “If it doesn’t, you’re going to have an excuse to stop going.”

So, how can you be certain a gym is a good fit after one 10- minute tour?

You can’t.

Ask for a trial membership. Most clubs will let you try out their gym for a week or two at no charge.

“Really use that trial membership before you make your decision,” Ancheta said. “If the gym won’t give you a trial membership, I’d really question that. That’s a pretty big red flag.”

– – –

Craig Hill: 253-597-8742

[email protected]

– – –

SIDEBAR: ALPHABET SOUP

If you plan to use a personal trainer at your new gym, make sure he or she is certified by a reputable instructor. There are hundreds of companies that certify trainers, but they are not created equal. Local fitness pros say keep these seven acronyms in mind:

ACSM – American College of Sports Medicine

ACE – American Council on Exercise

NSCA – National Strength and Conditioning Association

NASM – National Academy of Sports Medicine

AFAA – Aerobics and Fitness Association of America

IFPA – International Fitness Professionals Association

ISSA – International Sports Sciences Association

Individuality Good for Couples

It seems a contradiction to say that in order to have a closer relationship we need to be more ourselves.

TRADITIONAL wisdom has suggested in contrast that giving up individual will and developing a collective will is essential for a marriage or long-term relationship to survive.

It’s certainly the case that two people have to learn to be able to work together to maintain closeness long term.

That alliance does not have to mean losing individuality; in fact quite the opposite applies. To lose a sense of self as an individual may mean the death-knell for the relationship and particularly your sex life.

There is, however, a big difference between the immature self- centredness that is an inevitable developmental stage for children or adolescents and mature individuality.

The latter involves delving deep into yourself again and again over time to find your unique full self, thinking for yourself with consideration for your partner, acting with self-respect and integrity, and bringing the fullest, most caring, passionate you into relationship with your partner.

This is clearly a two-person process, but even if your partner refuses to act in this way, one of you doing it can lead the way to a better relationship.

Every relationship problem offers an opportunity to develop these skills. Rather than becoming embattled with each of you digging in your toes and defending your stance at all costs, consider the possibility of sitting side by side as you each express your perspective on the matter.

There’s no judging who is right and who is wrong as you’re both clear that as two unique individuals, of course you’ll have two different views.

In fact, each of you is interested in this ongoing learning opportunity involving someone you love who sees the world through different eyes than you.

Once you have the two perspectives laid out clearly in front of you then together you can begin generating possible joint solutions to the problem.

Each of you needs to be connecting to your love for your partner and your generosity while maintaining and communicating a clear sense of what is important to you.

You also need to be doing a good job of soothing your own anxiety as there’s no doubt this is a challenging process. There may be a need for professional help here in developing the required skills.

David Schnarch (Resurrecting Sex) suggests that it is in working our way through these emotional knots that we have the opportunity to discover the most we can be.

Couples coming to sex therapists often have a clear and detailed understanding of what is wrong with their partner and have spent insufficient time examining their own contribution to the problem. In fact as no one is perfect, joining together in close relationship with your partner requires being willing to rub all the rough edges off yourself.

Of course when a relationship begins this involves a delightful sense of closeness for most people. High levels of lust, dizzying excitement, the joyful state of feeling in love, loved and wanted. For some people this stage lasts only days, for others it continues pleasurably for some years.

It is important to realise this state is partly based on the illusions you have about each other. You can’t possibly know each other well, so into that gap goes all your hopes and dreams about the ways in which the right loving partner will make you and your life whole and worthwhile.

Once this stage is passed through, unless both partners are very mature, couples tend to either move into a state of fusion where the relationship is the new identity or a state of merger where individual boundaries are ignored and the identity of one partner is subsumed by the other. Both share the responsibility for getting into either of these states: for every person who dominates there’s one who submits.

There’s likely to be more conflict with merger as in this situation couples share all activities and physical space and tend to be of one mind.

One danger here is that if you freeze in your individual development then this chill is likely to extend to your sex life.

So there’s a need to move on, and this is where some important progress toward becoming an individual can come in.

Couples need to confront the reality of their differences, their aloneness.

Some drift apart back to separate identities or in search of someone else who will make them whole, fulfil their fusion fantasies.

Others work hard on themselves to achieve the task of becoming an individual (Schnarch calls this differentiation) in relationship.

This task involves integrating individuality with compassion, empathy and honour for your partner’s differences.

To get to this ultimate stage requires the passion of the early relationship, the struggle out of merger or fusion, the pain of differentiation (including grieving lost fantasies) and the establishment of connections that honour differences, rather than just tolerating them.

For the many people who are perplexed at how exactly to connect given these differences, working with a skilled sex therapist can help to transform long-term commitment into a bridge over which passions can travel.

* Robyn Salisbury is a clinical psychologist and director of Sex Therapy New Zealand, a referral network. To seek professional help with any sexual relationship problem phone 354-2449 or visit www.sextherapy.co.nz.

Meditation and Health: An Annotated Bibliography

Anne Haynes, Guest Columnist

Meditation is clearly moving into the mainstream. Evidence of this is the August 4, 2003, cover story in Time magazine, which explored the research on the physiological and psychological aspects of meditation. Since then, numerous stories have been published on the scientific findings relating to the benefits of meditation. Recent research conducted by scientists at the Laboratory for Affective Neuroscience at the University of Wisconsin at Madison demonstrated that meditation activates the part of the brain that is associated with positive emotions.1 A study released in March 2004 by the Medical College of Georgia found that two fifteen-minute meditation sessions daily (one at school, one at home) helped teenagers lower their blood pressure.2 This study also reported other favorable outcomes for the teens who meditated, including decreased absenteeism and a reduction in behavioral problems. Meditation is becoming more common in American classrooms. Some middle schools in Detroit have practiced meditation for more than six years.3 A recent article in Barron’s highlighted a plan by parents to propose that transcendental meditation be offered in New York City public schools.4

Interest in this topic is likely to grow as meditation increases in popularity. The number of adults in the United States who meditate on a regular basis has doubled in the past ten years, and is estimated to total ten million.5 This column focuses on meditation research, specifically on studies that have been done linking meditation with improved physical health and increased mental well-being. There is growing evidence that meditation, used as a mind-body medicine, is effective alone and as a complement to allopathic medicine in relieving stress, pain, and other physical and mental conditions. The scope of the article includes spiritual and secular meditation, including breathing practices, mantra meditation, Buddhist mindfulness, Qigong, and other forms of meditation. Researchers in medicine, psychology, and sociology became interested in meditation during the twentieth century, and research has flourished, especially in the past three decades. As meditation research has evolved, the standard of research has become more rigorous. The author has focused on scholarly rather than popular works on the topic. Among the resources included are books, review articles, Web sites, and organizations. Haynes’s column will assist public, academic, medical, and seminary libraries interested in meditation.

Haynes has been a reference librarian in the Indiana University- Bloomington Main Library Reference Department since 2000. She provides library instruction and research assistance in many disciplines and coordinates library services for the campus’ distance students. Her previous library experience was in acquisitions and cataloging. She is active within the Machine- Assisted Reference Section (MARS) of the Reference and User Services Association, serving most recently as editor of “Messages from MARS,” the section’s newsletter. She has also served on the MARS Executive Committee and the MARS Publications Committee. Haynes has also been active in other ALA divisions. A meditator, she has studied and practiced several different types of meditation.-Editor

Meditation is a state of heightened mental awareness and inner peace that brings mental, physical, and spiritual benefits. It is a useful self-help technique and can be practiced without adherence to any religion or philosophy.6

Meditation has almost as many definitions as there are writers, scholars, and practitioners in the field. For many of us, the term conjures up images of people in loose robes sitting for hours in lotus position, eyes closed, in silence. Meditation can also be practiced while walking, engaging in exercise, chanting, working in the garden, or sitting at one’s desk. It can be solitary or accomplished in a room full of fellow practitioners. Time spent in meditation can be a few minutes a day to hours a week, but is usually somewhere in between. Meditation has its roots in spirituality, and for most people in the world who practice some form of it, spiritual growth is its purpose.

Meditation is defined by Shapiro and Walsh as “a family of practices that train attention and awareness, usually with the aim of fostering psychological and spiritual well-being and maturity.”7 Meditation can take many forms and can be used for either sacred or secular purposes-often both-and a number of these forms have been, and continue to be, investigated for their roles in improvement of both physical and psychological health. Rubin defines two main types of meditation as “concentrative and insight. In concentrative meditation we focus on a single object . . . with wholehearted attentiveness. . . . In insight meditation, we attend without attachment or aversion to whatever thoughts, feelings, fantasies, or somatic sensations are being experienced.”8 Yet another definition separates meditation into two other types, focused and unfocused.9

Western medicine has traditionally separated the mind from the body, while in traditional cultures the mind, spirit, and body have long been recognized to be integrally connected. In the last half- century many mindbody interventions, including meditation, have been demonstrated to have positive effects on various aspects of health and emotional well-being. The introduction to the United States and Europe in the 1950s and 1960s of certain forms of meditation practiced mainly in India and East Asia marked the beginning of the popularization of meditation in the Western world. This popularization brought with it a surge in interest in research linking meditation with positive health effects. In a much- publicized study, Richard Davidson and Jon Kabat-Zinn recently collaborated in the first study that linked brain and immune function changes produced by Mindfulness-Based Stress Reduction (MBSR).10 Meditation is practiced widely in India, China, and other Asian countries for spiritual reasons; but it is also practiced worldwide by athletes, secretaries, students, corporate executives, and truck drivers to promote better concentration and higher performance levels, and by individuals seeking improved health.11 It has been successfully taught to prison inmates (for example, in India and New York state), to quell violent behavior and promote peaceful states of mind.12 Meditation rooms can even be found in airports.13 The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (NIH) (U.S.) and other health organizations around the world have been supporting research to investigate the link between meditation and mental and physical health. A search on the keyword “meditation” in the Complementary Medicine section of PubMed (www.nlm.nih.gov) in January 2004 resulted in 972 articles, the vast majority of which address meditation in medical studies. Meditation research has opened up possibilities for healing that were, until the 1970s or 1980s, not widely recognized in this country.

The volume of articles in the medical and psychology literatures demonstrates the surge of interest in meditation during the past thirty to forty years. Many scientific journals publish articles on meditation research. Among those are Perceptual & Motor Skills, Psycho-Oncology, Psychological Reports, Alternative Therapies in Health and Medicine, Psychosomatic Medicine, Tidsskrift for Den Norske Laegeforening, American Journal of Psychiatry, Australian Family Physician, British Medical Journal, Indian Journal of Physiology and Pharmacology, Journal of Psychosomatic Research, International Journal of Neuroscience, International Journal of Psychosomatics, and Journal of Clinical Psychology. Proquest’s Digital Dissertations shows 450 dissertations with the word “meditation” in the title, and the majority of these are about current research in meditation.

In researching this topic in the journal literature, in books, and on the Web, various keywords and subject terms were used in locating the appropriate resources, including Library of Congress and MESH subject headings. Citation and full-text databases such as Medline, Journals@OVID, ISI’s Web of Science, ATLA Religion Index, PsycINFO, PsycARTICLES, Ingenta, and many others covering medicine, nursing, religion, psychology, and sociology were searched for review articles on this topic. Library catalogs, personal libraries, WorldCat, RLIN Eureka, Books in Print online, and bookstores were searched for book titles. The catalogs included those of certain research libraries, medical libraries, Library of Congress, National Library of Medicine, and others known to have collections in mind- body medicine or meditation. Bibliographies found in these books and articles were then used as leads to other works. The Web was used as a tool for seeking out medical schools, meditation societies, and other organizations with an interest in promoting meditation research. Colleagues knowledgeable in this field were consulted.

Criteria for inclusion in this survey were an emphasis on the scientific research on meditation, thoroughness of coverage of the subject, length and/or depth of bibliographic references, and number of times cited by other authors. An attempt was made to include representation of variou\s major schools of meditation, but there are so many methods of meditation that it would not be possible in an article of this length to include any but those most popularly practiced. English language resources were used for the purposes of this article, because most of the contemporary research studies found have been reported in, or translated into, English, though some of the bibliographies contain references to works in other languages. An effort was made to include some works that the lay reader will find enjoyable and informative, as well as some of a more scholarly nature. All demonstrate a basis in, or reference to, scientific research.

Books

Benson, Herbert. The Relaxation Response. New York: Avon, 1976. (ISBN 0-380-00676-6). The Relaxation Response was a bestseller and was subsequently published in various countries, languages, formats, and editions. It is included here because it was the first popular, practical book for the lay reader on the health applications of meditation practice. Benson was an early promoter of his own method of relaxation for improved health soon after the 1960s popularization of the Transcendental Meditation (TM) method in the United States and elsewhere in the West. Benson is a physician and professor at the Mind/Body Medical Institute in Massachusetts and a researcher of TM. He has published numerous studies, including some with R. Keith Wallace, a well-known TM researcher. Benson challenged the idea that TM was the only or best way to practice a calming type of meditation. He claimed that based on his research, the secret mantras and established training program used in teaching the TM method were not necessary to achieve what he called the “relaxation response,” which could counter-act stress and its effects, such as high blood pressure and certain forms of heart disease. This book is controversial among those who believe that the spiritual elements of meditation are necessary to reap its benefits; that is why it is an important part of any meditation collection. In print; also available in large print, VHS videotape, and audiotape.

Orme-Johnson, David W., and John T. Farrow, eds. Scientific Research on the Transcendental Meditation Program: Collected Papers. 2nd ed. Weggis, Switzerland: Maharishi European Research University Press, 1977-90. (ISBN 3-88333-001-9).

This is the complete official collection of research papers on Transcendental Meditation (TM) published by the TM organization. This edition is the compilation of the reports of the 508 research studies on the TM method and TM-Sidhi Program (a program for advanced practitioners), with some that are not included in the first edition of the papers. TM is a method of meditation originating in India and taught by Maharishi Mahesh Yogi throughout the world beginning in the late 1950s. Thousands of teachers were trained in a standardized instruction method and thus made the course widely available to the public. Some of these papers were first published in professional journals. Some were carried out under the auspices of the TM organization, and others are based on research done at other universities and research institutions. There is a wide variation in the degree of thoroughness applied to the research design, sample sizes, and other aspects of the studies, according to many researchers, but it is generally accepted that this huge body of TM research laid the groundwork for more recent meditation research, and it demonstrates the positive effects of meditation on many aspects of human physiology and psychological health. These volumes are available for purchase from the TM organization’s Web site (http://mumpress.com/p_b01-5.html). A Summary of Research found in these volumes has been compiled by David Orme-Johnson, Dean of Research, Maharishi University of Management, and is found on the Web at: www.mum.edu/tm_research/ summary_tm_res.html.

Shapiro, Deane H., and Roger N. Walsh, eds. Meditation, Classic and Contemporary Perspectives. New York: Aldine, 1984. (ISBN 0-202- 25136-5).

The Shapiro and Walsh book is included here for its historic value as the first scholarly compilation of meditation research up to about 1980 in the United States and several other countries. Unlike the other meditation bibliographies discussed here, it is a collection of reprints of many journal articles, including review articles and reports of research studies. Included are substantial introductory sections by Shapiro and Walsh, well-known academic researchers in psychology and psychiatry. The articles in this volume are ones the editors considered to be the most important contributions to meditation literature up to that time-not only research in such areas as drug abuse and stress, but elegant treatises on Buddhism, the meditative experience, and states of consciousness. The interested reader can have access to the actual studies, including the tables, charts and graphs, with the convenience of not having to locate copies of the articles. And unlike the collected papers on TM research, this volume also discusses various other forms of meditation, including Zen, yoga, and insight meditation. This book was considered a foundational work in meditation research at the time it was published, and should be in every library’s meditation collection. If your library holds it, this is one to keep. Out of print, but available from out-of-print booksellers.

Jarrell, Howard R. International Meditation Bibliography 1950- 1982. Metuchen, N.J.: Scarecrow Press, 1985. ATLA Bibliography Series 12. (ISBN 0-8108-1759-4).

The International Meditation Bibliography 1950-1982, the first international meditation bibliography published, differs from the two Murphy bibliographies in that it covers resources on the subject of meditation in general, and is not restricted to meditation research. Part of the American Theological Library Association Bibliography Series, it is a list of sources with very brief descriptions, not annotations, of some of the entries. Many of the works listed are about the Transcendental Meditation (TM) method, but also included are the subjects of yoga meditation, Christian meditation, Zen Buddhist meditation, and other relaxation techniques. The sources included are books; journal and magazine articles; dissertations; theses; motion pictures; sound recordings; and societies and associations. There are author, title, and subject indexes, making this an unusually well-indexed work. Citations for books written in English, French, German, Spanish, Portuguese, Italian, and Dutch are included. Though dated, this very well organized book is of particular interest because it includes works not included in later bibliographies or in collections of purely research studies. This factor makes it historically significant, and it is an important work for any library’s collection on meditation. In print and available.

Murphy, Michael, and Steven Donovan, eds. The Physical and Psychological Effects of Meditation: A Review of Contemporary Meditation Research with a Comprehensive Bibliography, 1931-1988. San Rafael, Calif.: Esalen Institute Study of Exceptional Functioning, 1988. (ISBN 0-9621232-0-X).

This book was the first such work to review a large international body of research in English on the scientific study of meditation. The first half of the book is a survey of the research on meditation’s effect on each of a number of specific body systems, including the cardiovascular system, the cortical system, blood chemistry, the metabolic and respiratory systems, and others; and behavioral effects, including chapters titled “Perceptual and Cognitive Abilities,””Empathy,””Creativity and Self- Actualization,””Anxiety,” and “Psychotherapy and Addiction.” Particular studies are discussed in this section. The second half is the bibliography itself, containing more than 1,200 citations of published research in journals of many disciplines. This book is an important resource for anyone interested in the meditation research literature. Updated by, but an important addition to, the second edition by Murphy, Donovan, and Eugene Taylor, discussed later in this article. In print and available from online booksellers.

Goleman, Daniel. The Meditative Mind: The Varieties of Meditative Experience. London: Thorsons, 1996. (ISBN 0-7225-3427-2).

Goleman began this book in 1971 when he was in the Himalayas pursuing his personal interest in Eastern spiritual practices, and it emerged in 1988 as a compilation of articles he had written for various journals. The book-an updated edition of the author’s 1977 Varieties of the Meditative Experience-is in four parts; the first three present a survey of various meditative paths and some of their theory and practice, and point out what the different methods have in common. Chapter 4, “Meditation Paths: A Survey,” is a brief but excellent overview for the lay reader of some of the most well known meditative practices of the world, including Hindu Bhakti, Jewish Kabbalah, Christian Hesychasm, Sufism, Transcendental Meditation, Patanjali’s Ashtanga Yoga, Indian Tantra and Kundalini Yoga, Tibetan Buddhism, Zen, Gurdjieff’s Fourth Way, and Krishnamurti’s Choiceless Awareness. Goleman indicates that the synopses in chapter 4 are intentionally brief and meant to be an introduction for the uninitiated. The fourth section covers psychology and research in this field. This book has many references and does have a significant chapter on “The Psychology of Meditation,” including meditation research. The Meditative Mind stands out in this collection because it includes brief sections on Jewish and Christian meditation, not usually included in general works on meditation. It also is an excellent introductory exploration of the topic of meditation for the uninitiated lay reader. Includes suggested readings and substantial bibliography on meditation, mysticism, and consciousness studies. Goleman, a psyc\hologist, has been associated with Harvard University, has been a reporter on the behavioral sciences for the New York Times, and is internationally known for writing and speaking about the brain and behavior. In print; copies are available through online booksellers. Recommended for any meditation collection.

Kabat-Zinn, Jon. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness. New York: Delta, 1990. (ISBN 0-385-30312-2).

This book describes the first eleven years of the Stress Reduction and Relaxation Program (SR&RP) at the University of Massachusetts Medical Center, founded in 1979. This is the pioneering clinic where mindfulness meditation (based on Buddhist meditation) is used as complementary medicine to help patients suffering from stress, pain, and various illnesses. Jon Kabat-Zinn, featured in Bill Moyers’ public television documentary Healing and the Mind, is the founder and former director of the clinic (now called the Stress Reduction Clinic [SRC]; www.umassmed.edu/cfm/srp) and is currently a professor in the Division of Preventive and Behavioral Medicine at the University of Massachusetts Medical School. The SRC is the oldest clinic of its kind in this country. The patients at the clinic commit to an eight-week course in mindfulness, or awareness, training. I have included this book, even though its reading list is brief, because it describes work that is based on academic study: “[M]ore than 13,000 people referred by more than 1,800 physicians have completed this eight week, ten session program.”14 The SRC has been used as a model for hundreds of similar programs worldwide. In print.

Goleman, Daniel. Healing Emotions: Conversations with the Dalai Lama on Mindfulness, Emotions, and Health. Boston: Shambhala, 1997. (ISBN 1-570-62212-4).

This book reports on a series of dialogues between His Holiness Tenzin Gyatso, the fourteenth Dalai Lama of the Tibetan people, and ten Western scholars, which took place in 1991. It was the third meeting in the series of “Mind and Life” conferences, which began in 1987 (www.mindandlife.org/books.pubs_section.html). The purpose of these dialogues was “to increase mutual understanding and facilitate the emergence of new insight into the relationship” between health and emotions, which according to Goleman has been documented since the eleventh century by Tibetan Buddhists. Western scientists have only been exploring this relationship for about thirty years, but Buddhists have been using meditation to help heal the body and mind for about two thousand years, the editor claims. The other distinguished scholars participating in the dialogues were Daniel Brown, Richard Davidson, Jon Kabat-Zinn, Sharon Salzberg, Clifford Saron, Francisco Varela, and Lee Yearley-representing the fields of philosophy, psychology, physiology, and behavioral medicine. Jon Kabat-Zinn’s description of the successful use of mindfulness meditation in his stress reduction clinic at the University of Massachusetts goes to the heart of the topic discussed here.

This is a very readable presentation for the lay reader of a scientific approach to understanding meditation. There is no bibliography, but there is an extremely useful glossary (contained in the notes) that explains terminology associated with Buddhism and other Eastern spiritual practices. In print.

Austin, James H. Zen and the Brain: Toward an Understanding of Meditation and Consciousness. Cambridge, Mass.: MIT Press, 1998. (ISBN 0-262-01164-6).

As the title indicates, this tome of 844 pages, written by a neurologist, is dedicated to Zen Buddhism practice and its confluence with science. It is an exploration into the questions of how the brain functions and what happens in the brain during meditation or altered states. It is rare for an academic scholar, particularly a neuroscientist, to make public his own experience with meditation and altered states of mind, and relate them to science. That is what makes this an unusual book. Austin’s experience with Zen led him to study its relationship with the workings of the brain. He combines his personal interest and long experience with zazen, or a kind of Zen sitting meditation, with his scientific quest for understanding the relationship between meditation and the pathways of the brain. Austin recounts his own fascinating experience of Zen training in Japan, and his ultimate experience eight years later of kensho-a brief occurrence of enlightenment achieved by some after a great deal of practice. A detailed table of contents reveals eight parts in the body of the book, divided into 158 short sections discussing the history and practice of Zen meditation, EEG patterns and alpha waves, physiological changes during meditation, development and anatomy of the brain, the study of sleep states and their relationship to Zen, pharmacology, and much more, in great depth. This remarkable book is written in language that is accessible by the lay person, and while it may be too long for most people to want to read from cover to cover, parts of it will undoubtedly appeal to many. Includes glossary and a 112-page References and Notes section. In print; also available as an e-book.

Lu, Zuyin. Scientific Qigong Exploration: The Wonders and Mysteries of Qi. Trans. Hui Lin; ed. Ming Dao. Malvern, Pa.: Amber Leaf Press, 1997. (ISBN 0965-7135-71).

Qigong, qi gong, or qi kung (pronounced “chee-gung”), the term given to a broad category of Chinese training exercises for the mind and body, has been practiced for several thousand years.15 Certain forms of qigong have been believed to have healing powers for illnesses of the body and mind. The NCCAM classifies qigong as a form of energy therapy, more specifically, a “biofield therapy.”16 One example of healing qigong is chi-lel qigong.17 Qigong is included in this collection of meditation literature because it is a relaxation technique and often produces a meditative state. However, it was not studied scientifically as a healing method until the 1970s. Due to political repression of discussion about qigong in China, it has been difficult for researchers to exchange knowledge and ideas on this subject until very recently. This book, originally published in Chinese as Qigong Tansuo in 1994, discusses scientific research into “external qi” up to 1982, but with greater emphasis on the author’s involvement in this research since that time. “External qi,” according to the author, a physics researcher, is an “invisible and untouchable” force, or energy, emitted by practitioners of qigong. In 1977 it was discovered that this external qi was capable of effecting changes in an infrared spectrometer and creating magnetic field measurements on a magnetometer. News of this created a renewed interest and increased Chinese people’s practice of qigong. The author’s experiments in collaboration with Dr. Yan Xin included work on the effects of external qi on DNA and radioactive isotopes. This is a substantial collection of research in a field in which it is difficult to obtain information on research at all. In print.

Murphy, Michael, and Steven Donovan. The Physical and Psychological Effects of Meditation: A Review of Contemporary Research with a Comprehensive Bibliography, 1931- 1996. 2nd ed. Ed. and with an introduction by Eugene Taylor. Sausalito, Calif.: Institute of Noetic Sciences, 1997. With Annotated Update, September 2002. (ISBN 0-943951-36-4).

This book is more than just an update of the 1988 bibliography of similar title edited by Murphy and Donovan. Included is a thirty- two-page introduction by Eugene Taylor presenting a history of the modern developments in meditation research. This introduction is a significant piece of work that adds great interest to this edition. Subheadings such as “The Americanization of Meditation,””TM and the TM-Sidhi Project,””Herbert Benson: The Mind/ Body Medical Institute,””Government Research and Medical Science,””Difficulties of Research with Religious Adepts,””The Cortical System,” and “The Qi Gong Database” show the scope of this very readable and informative introduction. As in the first edition, the next several chapters are devoted to a narrative survey of the studies done in each of the many areas of physical and psychological research. A strong feature of this book and its update is that both strengths and limitations in meditation research methodologies, and the reasons for them, are noted. The bibliography contains the citations plus almost four hundred new studies since the first edition. The twenty-four-page 2002 update, printed separately, consists of a number of the latest research citations, all annotated. Subsequent editions of this book would be welcome and important to the continuing documentation of meditation research. In print; available from the Institute of Noetic Sciences by phone: (707) 779-8217, or e- mail: [email protected]. A searchable online version of the bibliography is also found at www.noetic.org/research/medbiblio/ index.htm.

Review Articles

Sandlund, E. S., and T. Norlander. “The Effects of Tai Chi Chuan Relaxation and Exercise on Stress Responses and Well-Being: An Overview of Research.” International Journal of Stress Management 7, no. 2 (2000): 139-49.

Sandlund and Norlander present an overview of the research published between 1996 and 1999 (located through PsycLit and Medline) on tai chi chuan and its relationship to stress management. Tai chi chuan, or tai chi, originated in China as long as nine hundred years ago and is practiced worldwide.18 The practice incorporates five principles: relaxation, separating yin and yang, turning the waist, keeping the back erect, and total body involvement. Some of the findings of this article are that tai chi research is very new; that more is known about tai chi’s benefits for senior adults than other age groups; and that there is great promise in studying tai chi further in \relation to other forms of stress management techniques, gender differences, length of experience in practice, and effects on the immune system.

Shapiro, Shauna L., and Roger Walsh. “An Analysis of Recent Meditation Research and Suggestions for Future Directions.” Humanistic Psychologist 31, no. 2/3 (2003): 86-114.

This article reviews the recent literature (approximately the past five to six years) of meditation research, including the most well designed (in their view) studies on meditation. The authors discuss the psychological, physiological, and transpersonal aspects, dividing meditation into two basic types: concentration and awareness. They discuss the limitations present in pioneering meditation studies, how these first studies laid a foundation for later research, and include a significant section on suggestions for future research.

Baer, Ruth A. “Mindfulness Training as a Clinical Intervention: A Conceptual and Empirical Review.” Clinical Psychology: Science and Practice 10 (Summer 2003): 125-43.

This review is a summary of the literature of mindfulness meditation as a clinical treatment from the 1970s to the present. The author acknowledges the increasing popularity of mindfulness meditation as an intervention and discusses both its success as an intervention and the ways in which empirical research methodology could be improved. Readers of Baer’s article should also read Jon Kabat-Zinn’s commentary on this article in the same issue of this journal, “Mindfulness-Based Interventions in Context: Past, Present, and Future,” (144-56).

Organizations, Conferences, and Web Sites

Meditation research is a dynamic, rapidly advancing field. The research done in earlier years has suggested the current research initiatives that are continuing with greater insight and improved methods. The recent use of the Web to disseminate such information is helping to promote global awareness of this current research interest. The information about the Web sites and organizations provided here is current as of this writing, though it is in the nature of both Web sites and organizations to change, particularly in a field that is evolving so rapidly.

Stress Reduction Clinic at the University of Massachusetts Medical School

www.umassmed.edu/behavmed/clinics

The Web site of the Stress Reduction Clinic founded by Dr. Jon Kabat-Zinn and described above in the annotation of Full Catastrophe Living. Also describes the Center for Mindfulness in Medicine, Health Care, and Society (CFM) at the University of Massachusetts.

National Center for Complementary and Alternative Medicine (NCCAM) (U.S. National Institutes of Health)

http://nccam.nih.gov

As of this writing, there are four clinical trials on meditation being conducted by this Center. These trials are studying cardiovascular disease in older blacks and in older black women, coronary heart disease, and binge eating disorder. Another trial, “Mindfulness-Based Art Therapy for Cancer Patients,” is in progress, as are three studies on tai chi and one on qigong (Chinese exercise systems incorporating meditation). Details of the studies and links to related articles can be found at this Web site. The NCCAM also funds many studies based in university medical schools.

Mind/Body Medical Institute, Harvard University and Beth Israel/ Deaconess Medical Center

www.mbmi.org

Herbert Benson is the president of this institute, incorporated in 1988, which seeks to study and teach mind/body medicine.

“CAM on PubMed”

www.nlm.nili.gov/nccam/camonpubmed.html

CAM is a search engine at the NCCAM site that limits searches to the complementary and alternative subset of PubMed, a medical database providing free access to Medline.

Investigating the Mind. The McGovern Institute, MIT. September 13- 14, 2003 (conference).

http://web.mit.edu/mcgovern/html/Events_and_Seminars/ investigating_mind. shtml

The McGovern Institute at the Massachusetts Institute of Technology is investigating the relationship between thought and emotion and how they relate to the physical brain. The “Investigating the Mind” conference was jointly sponsored with the Mind and Life Institute (see later entry in this list), and was the eleventh such meeting involving the Dalai Lama and a group of Buddhist meditators and scientists in dialogue.

Health Emotions Research Institute, University of Wisconsin www.healthemotions.org

This site provides descriptions of state-of-the-art research facilities and descriptions of current research projects, including a recent study of mindfulness meditation.

Institute of Noetic Sciences

www.noetic.org

This nonprofit organization supports research and education in consciousness studies, including meditation research. Its quarterly journal, Shift: At the Frontiers of Consciousness, communicates to both scientific and lay readers.

Mind and Life Institute

www.mindandlife.org

This is the institute responsible for the publication of the books in the Mind and Life Series described above in the bibliography section. This organization works to create a collaborative research partnership between Buddhism and science. They have published a series of books on this subject and sponsor conferences and a Summer Research Institute.

Transcendental Meditation (TM) organization

www.tm.org

TM is a yogic meditation technique practiced by several million people throughout the world. The program (see previous citations on the scientific research) was developed by Maharishi Mahesh Yogi and brought to the West in the form of an education program. In addition to the meditation course, the TM organization runs three schools: one for K-12, a liberal arts university offering advanced degrees, and a continuing education school for adults. The Web site is extensive and includes the TM Summary of Research, edited by David Orme-Johnson (www.mum.edu/tm_research/summary_tm_res.html).

The Qigong Institute

www.qigonginstitute.org

This is a nonprofit organization devoted to research and education. A number of scientific papers in full text, describing research on qigong, are found on this site; also a list of dissertations written about qigong, a qigong database with 3,500 abstracts of articles and conference papers, and other resources. The database is available for purchase from this Web site.

References

1. Michael W. Robbins, “Meditation Apparently Activates Positive Areas within the Brain,” Discover 25 (Jan. 2004): 45.

2. Daniel Lee, “Meditation Impacts Teen Blood Pressure,” Associated Press Online (Apr. 2, 2004). Retrieved from the Lexis Nexis Academic database on Apr. 20, 2004.

3. Robin Goldwyn Blumenthal, “Move Over, Medication, Meditators May Be Coming,” Barron’s 84 (Mar. 8, 2004): 11.

4. Ibid.

5. Joel Stein, “Just Say Om,” Time 162 (Aug. 4, 2003): 48-56.

6. Anne Woodham and David Peters, DK Encyclopedia of Healing Therapies, 1st American ed. (New York: Dorling-Kindersley, 1997), 174.

7. Shauna L. Shapiro and Roger Walsh, “An Analysis of Recent Meditation Research and Suggestions for Future Directions,” Humanistic Psychologist 31, no. 2/3 (2003): 86-114.

8. Jeffrey B. Rubin, “Close Encounters of a New Kind: Toward an Integration of Psychoanalysis and Buddhism,” American Journal of Psychoanalysts 59, no. 1 (1999): 5-24.

9. Michael Murphy and Steven Donovan, The Physical and Psychological Effects of Meditation: A Review of Contemporary Research with a Comprehensive Bibliography, 1931-1996, 2nd ed., ed. and with an introduction by Eugene Taylor. (Sausalito, Calif.: Institute of Noetic Sciences, 1997).

10. Richard J. Davidson and Jon Kabat-Zinn, “Alterations in Brain and Immune Function Produced by Mindfulness Meditation: Three Caveats: Response,” Psychosomatic Medicine 66 (Jan./Feb. 2004): 149- 52.

11. Murphy and Donovan, The Physical and Psychological Effects of Meditation, 1.

12. Sudip Mazumdar, “Nirvana Behind Bars,” Newsweek (Atlantic Edition) 136 (Sept. 18, 2000): 49; Mark Hays, “Unlocking Spirituality for Prisoners,” Natural Health 31 (Jan./Feb. 2001): 33.

13. Stein, “Just Say Om,” 48-56.

14. University of Massachusetts Division of Preventive and Behavioral Medicine. Accessed Mar. 29, 2004, www.umassmed.edu/ behavmed/clinics.

15. Richard H. Lee, ed. Scientific Investigations into Chinese Qigong (San Clemente, Calif.: CHI Institute, 2001).

16. National Center for Complementary and Alternative Medicine (NCCAM) (U.S. National Institutes of Health). Accessed Mar. 29, 2004, http://nccam.nih.gov/health/whatiscam/index.htm.

17. Chi-Lel Qigong Web site. Accessed Mar. 29, 2004, www.chilel- qigong.com.

18. Damien Keown, ed., A Dictionary of Buddhism (New York: Oxford Univ. Pr., 2003) Oxford Reference Online. Accessed Mar. 18, 2004, www.oxfordreference.com/views/ ENTRY.html?subview=Main&entry=t108.e1129.

Diane Zabel

EDITOR

Correspondence concerning this column should be addressed to Diane Zabel, Endowed Librarian for Business, Schreyer Business Library, Pennsylvania State University, University Park, PA 16802; e- mail: [email protected]. Anne Haynes is Reference Librarian, Reference Department, Indiana University-Bloomington Libraries, Bloomington, Indiana. The author gratefully acknowledges Betty Jo Irvine, David Frasier, and Christopher Haynes for their critical readings of drafts, and the Indiana University-Bloomington Libraries for granting her a research leave to write this article.

Copyright American Library Association Fall 2004

Florida Passes Three-Strikes Law for Doctors: ; Three Malpractice Judgments Would Result in Loss of Medical License

The Associated Press

TALLAHASSEE, Fla. – Florida voters this month approved a three- strikes law unlike any other state’s – a measure aimed not at killers and thieves but at doctors who foul up.

The newly approved amendment to the Florida Constitution would automatically revoke the medical license of any doctor hit with three malpractice judgments. The law is backed by doctors’ foremost antagonists – lawyers – and the ramifications could be huge.

Legal experts say the measure could let loose a flood of malpractice suits. Doctors say it will scare some physicians away from Florida while forcing others to reach quick malpractice settlements to avoid a “strike” against them.

“It has branded the state as probably the most unfriendly state for physicians,” said Robert Yelverton, a Tampa doctor.

The three-strikes law is just one salvo in a fierce battle between doctors and trial lawyers that is playing out across the country and in Congress. While several states have taken steps to limit malpractice awards, the fight is especially intense in Florida, where the cost of malpractice insurance higher than in most states.

Doctors this year put their own malpractice measure on the ballot that limits how much of a malpractice award an attorney can take as a fee. There are already such limits, but the amendment, which also passed, further reduces the lawyer’s percentage.

Doctors claim that with less chance for a big payday, lawyers will be more selective about which cases they take and will perhaps avoid frivolous ones.

Lance Block, a lawyer who makes his living mostly by representing malpractice victims, said the doctors’ campaign to limit attorney fees was motivated purely by enmity.

“I don’t think there’s any question that the purpose of this amendment is to drive lawyers away from medical-negligence cases,” Block said.

Lester Brickman, a professor of legal ethics at the Cardozo School of Law of Yeshiva University in New York, said the lawyers “trumped the doctors” with the three-strikes amendment, because lawyers will rush to sue in hopes doctors will settle to avoid a “strike” on their record.

“You’ll see hundreds of these claims,” Brickman said. “In the next 10 years virtually every doctor in the state of Florida will have been sued.”

The three-strikes law has yet to take effect. It was put on hold by a judge who said the Legislature needs to spell out just how it will work.

The number of doctors who would have their licenses revoked by the three-strikes rule is extremely small, perhaps a dozen or so at the most, experts say. Florida has just under 30,000 active doctors.

Yelverton is among the physicians caught in the middle of the fight.

Like thousands of other Florida doctors, he has never gotten in trouble for making a mistake. He has delivered more than 10,000 babies in his 33-year career – enough, he notes, to make a “whole little town.”

But the 63-year-old increasingly feels it was just not worth it to be a doctor in this state, and he now works in the front office of his practice to develop procedures to reduce the risk of medical mistakes.

One reason he stopped seeing patients and delivering babies was the increase of the cost of his malpractice insurance, and the feeling that at any time he could lose a bundle in a lawsuit, whether it had merit or not.

“The hardest thing about giving up a very successful practice of 33 years is that your patients have come to rely on you for what they consider quality medicine and they have to find someone else,” Yelverton said. “And it’s one less experienced doctor.”

Jay Wolfson, a professor of health law at the University of South Florida College of Public Health, has watched with frustration the back and forth between doctors and lawyers. He said the ultimate result is that patients become mere pawns.

Wolfson said the three-strikes amendment is like many other efforts to “fix” the medical malpractice situation: “It doesn’t do a darn thing to protect patients from the very small number of bad doctors.”

Marijuana’s Potential Exciting Researchers ; Might Treat ALS, Parkinson’s Disease, Obesity

SAN DIEGO – A decade ago, when Daniele Piomelli went to scientific conferences, he was often the only researcher studying cannabinoids, the class of chemicals that give marijuana users a high.

His work often drew snickers and jokes – but no more. At the annual Society for Neuroscience conference this month, scientists here delivered almost 200 papers on the subject.

Why the attention? Many scientists believe marijuana-like drugs might be able to treat a wide range of diseases, far beyond the nausea and chronic pain typically treated with medical marijuana.

Researchers here presented tantalizing evidence that cannabinoid drugs can help treat amyotrophic lateral sclerosis, known as ALS or Lou Gehrig’s disease, Parkinson’s disease and obesity. Other researchers are studying whether the compounds can help victims of stroke and multiple sclerosis.

Although the chemicals work on the same area of the nervous system, the new drugs are much more refined and targeted than marijuana, with few of its side effects.

“Cannabinoids have a lot of pharmaceutical potential,” said Piomelli, a neuroscientist at the University of California at Irvine. “A lot of people are very excited.”

Although the federal government opposes the use of medical marijuana, it generally doesn’t restrict cannabinoid research, most of which doesn’t involve the cannabis plant itself. Scientists who use Marinol, a legal but tightly regulated marijuana-like drug, do need government permission.

Because the cannabinoid system wasn’t discovered until the late 1980s – decades after serotonin, dopamine and other neurotransmitters -researchers still know relatively little about how it works.

Like all neurotransmitter networks, the cannabinoid system consists of a series of chemical pathways through the brain and nervous system. Marijuana produces its effects by activating this pathway, primarily through the effects of tetrahydrocannabinol, or THC, the drug’s main active ingredient.

Over the past decade, researchers have been following these abundant trails to determine their real purpose. “You don’t have them there to get stoned. So there must be internal reasons,” said Andrea Giuffrida, a neuroscientist at the University of Texas Health Sciences Center in San Antonio.

Researchers have learned that endogenous cannabinoids – internal brain chemicals that activate the system – play a role in tissue protection, immunity and inflammation, among other functions. The cannabinoid system also appears to exert wide influence, modulating the release of dopamine, serotonin and other neurotransmitters.

Giuffrida and others believe cannabinoids can treat degenerative disorders such as Parkinson’s disease and ALS.

At the conference, Giuffrida announced that a cannabinoid drug wards off Parkinson’s-like effects in mice.

The disorder, which afflicts more than 1 million Americans, destroys neurons in a key part of the brain, causing patients to lose control over movement.

Giuffrida, with colleagues David Price and James Roberts, injected mice with a chemical called MPTP, which mimics Parkinson’s damage. When some of the animals subsequently received a drug that blocks cannabinoid receptors, their nerve cells suffered far less damage than did the cells of the other mice. This was the first demonstration that a cannabinoid drug can have this effect.

Although he is not sure how the anti-cannabinoid compound works, Giuffrida suspects it protects neurons by reducing inflammation, a key component in Parkinson’s.

Cannabinoids might also slow down ALS, which destroys neurons that control muscles until victims become paralyzed, unable to breathe on their own.

Neuroscientist Mary Abood first became interested in cannabinoids after hearing about ALS patients who got some relief from smoking marijuana. So she began animal experiments at the California Pacific Medical Center in San Francisco.

In her study, mice with a variant of ALS were given a combination of THC and cannabidiol, another compound found in marijuana. Both substances are cannabinoid agonists, chemicals that activate the cannabinoid system.

Abood measured the course of the ailment by testing how long the mice could stand on a rod that was slowly rotating.

The treatment delayed disease progression by more than seven days and extended survival by six days. In human terms, this would amount to about three years. That’s a significant improvement over the only existing ALS drug, riluzole, which extends life by two months. “I was very excited when I got my initial results,” Abood said.

Also at the conference, researchers at the Institute of Neurology in London announced results that corroborated her findings. Cannabinoids have also helped some human ALS patients in one small trial. and Abood is trying to get funding for a larger one.

If cannabinoids can shield human neurons from harm, researchers say, they might prove useful against other neurological diseases, including mental illness. Scientists are looking at whether cannabinoids can treat multiple sclerosis, epilepsy and Huntington’s disease, while Giuffrida is beginning a study of their effect on schizophrenia.

Advocates of medical marijuana have long argued that the drug can be useful for treating many conditions, particularly chronic pain, nausea and glaucoma (in the latter, marijuana works by temporarily decreasing pressure around the eye).

Although they don’t dispute this view, most researchers believe there are better, more precise ways to stimulate the cannabinoid system. They believe marijuana has too many negatives to be a truly effective drug, with side effects that include memory problems, decreased immunity and possibly addiction. (Some researchers dispute this.)

Marijuana has another drawback. From a scientific standpoint, Giuffrida says, it’s “a very dirty drug.”

It contains more than 300 compounds, 60 of which affect the cannabinoid system. Scientists don’t understand what most of these substances do or how they work together. This complexity makes it hard for researchers to pinpoint marijuana’s effects.

One cannabinoid, Marinol, is available legally. The compound, which contains THC in a pill form, is usually prescribed for nausea and for appetite loss among AIDS patients.

But Marinol has the same psychoactive effects as marijuana. So the key, Piomelli says, is “getting the effects without the side effects.”

To that end, Piomelli has developed a compound called URB597, which doesn’t flood the body with cannabinoids, as Marinol and marijuana do. Instead, it slows the breakdown of the cannabinoids in the system. He thinks the drug may help treat pain, anxiety and even depression without making patients stoned and forgetful. He and others are testing it on animals.

Adult Day Care an Aid for Victims of Parkinson’s

TODAYQ: My closest friend and colleague has Parkinson’s disease. Her husband has been the primary caregiver for the past five years. He seems exhausted yet is doing the best he can. Although he clearly needs assistance, he refuses to get help in the house and only occasionally drives his wife to a physical therapist. I don’t think my friend is getting optimal care. She is becoming more isolated, unsteady, thinner and increasingly dependent. What really is Parkinson’s and what can be done to help a person? Is there anything I can do, besides worry?

— D.H.

Dear D.H.:

You are faced with a very frustrating situation.

First, a little bit about the disease from the Parkinson’s Disease Foundation and the American Parkinson Disease Association (APDA).

Parkinson’s disease, among a group of conditions called movement disorders, is neurologically based. It is chronic and progressive. Approximately 1 million people suffer from Parkinson’s. And about 40,000 cases are diagnosed each year.

The incidence of the disease increases with age, and, unfortunately, the cause is unknown. Symptoms can be mild without affecting daily activities. In other cases, the symptoms can be aggressive, leading to physical limitations and disability.

Here is some information about what happens when someone has this disease:

A group of cells in the brain (substania nigra) produces a chemical called dopamine. These cells begin to malfunction and eventually die.

Dopamine is a neurotransmitter or a “chemical messenger” that conveys signals to parts of the brain that control movement and coordination. When the brain cells begin to die, there is less dopamine produced. The result is an impairment of movement with tremors, lack of balance and stiffness.

In addition to medication, what can be done?

The APDA recommends activity, good nutrition and creating the right physical environment. There are techniques and aids that can assist a person to remain independent and as safe as possible. For example, the bedroom should be free of clutter; throw rugs should be removed or taped to the floor. Casters should be removed from furniture. Shoes and small objects should be off the floor, particularly at night.

Suggestions for bathroom safety, grooming, the kitchen, mealtime, walking, stairs and getting in and out of a car are published by the ADPA in Being Independent. The publication is available at HealthLinks, a consumer resource library of the new West Tower of the Torrance Memorial Medical Center (310-517-4711).

Here is an option you might suggest that will give the caregiver a rest and your friend with Parkinson’s an opportunity to function at her best — Adult Day Care. Individuals are not patients, clients or customers. They are participants.

I recently had the opportunity to visit Family Adult Day Health Care in Lomita. The environment was light, bright and positive.

To attend, people need to be referred by their physician. They then are evaluated by the day-care staff, and a plan of care is developed. That plan may include physical therapy, occupational therapy, speech and maintenance therapy, nutritional counseling and/ or psychological counseling. The final plan is discussed with the family.

During the day, participants continue with their regular medications under the supervision of a nursing staff.

What do participants do? They engage in exercise classes and small group activities organized according to their abilities. These activities might include art, music and dance. They take trips and have opportunities to learn and express themselves. For example, one individual learned to use the computer and access the Internet; another writes poetry.

Owner Charity Abracosa says, “Participating in adult day health care programs can help avoid inappropriate nursing home admissions. The emphasis is for individuals to stay with their families and be given opportunities and support to function at their highest level.” For more information, call the center at 310-602-0123.

For more about adult day care, contact or visit Healthlinks and request materials called “Adult Day Services.” Approximately 20 are listed, with a guide on how to select the one that’s most appropriate.

D.H., perhaps your primary role is to be a good friend. Visit often, stay in contact and consider recommending some tips to your friend’s husband. At least you know that you’ve given it your best shot — because you care.

Thank you for your good question and best wishes.

Helen Dennis is a specialist in aging, with academic, corporate and nonprofit experience. Send her your questions and concerns in care of the Daily Breeze Today section, 5215 Torrance Blvd., Torrance, CA 90503-4077; or fax to 310-540-7581, or e-mail to [email protected].

Give Patients a Hand – a Clean Hand

An infection control program at Austin Health in Melbourne to improve hand hygiene practices among health care workers has achieved sustained improvement in hand hygiene, coinciding with a reduction of nosocomial (hospital-acquired infections) and transmission of MRSA in health care settings, according to an infection control nurse.

The DeBug Infection Prevention Program (DIPP) promoted an alcohol- chlorhexidine hand rub first pioneered by Professor Didier Pittet from the University of Geneva Hospital, Switzerland.

His studies demonstrated hand hygiene compliance was associated with a significant reduction in nosocomial infections.

Following the success of the project in using an alcohol- chlorhexidine hand rub in place of traditional hand washing practices at Austin Health, it has now been adopted as a pilot project by the Victorian Quality Council (VQC).

Clinical Research Coordinator RN Timothy Brown said the project focused on using alcohol-chlorhexidine based hand disinfection at the bedside, while providing education to health care workers to facilitate change management in hand hygiene practices.

‘Hand hygiene is the single most important measure to prevent cross-transmission of microorganisms from one patient to another,’ Mr Brown said.

‘Several studies have demonstrated reductions in nosocomial infection rates after hand hygiene practice improvement.

‘But efforts to improve rates of hand hygiene compliance by health care workers have generally been ineffective or poorly sustained. There is a range of reasons for this: it may be related to understaffing and high patient acuity allowing insufficient time for staff to wash their hands.

‘It could be avoidance if people have previously experienced skin irritations and dryness from other hand-hygiene solutions, or related to infrastructure, if sinks are inconveniently located.’

Other factors affecting compliance could be inadequate knowledge of guidelines or protocols for hand hygiene; lack of positive role models; and a perception that glove use negates the need for hand hygiene, Mr Brown said.

Alcohol-chlorhexidine hand rubs are considered to be superior to soap and water because they require less time to use; they are more effective in reducing micro-organisms; are less irritating to the skin; and can be made readily accessible to health care workers.

The health services and clinical research nurses participating in the pilot project are: Western Health (Jeffrey Brooks), Peninsula Health (Kaye Bellis), Melbourne Health (Celene McMullan), St Vincent’s Health (Katie Taylor), North-East Health Wangaratta (Roger Gregory), and Bendigo Health Care Group (Meryanda Jodoin). Each of the health services will pilot the rub, then introduce the practice from May 2005.

For more information, visit: www.debug.net.au.

Copyright Australian Nursing Federation Nov 2004

Test and Treat Helicobacter Pylori Before Endoscopy

Abstract

Background Helicobacter pylori may have major implications for patients’ wellbeing and future health. If a patient is found to be H. pylori positive it is important that the infection is eradicated because of the risk of associated peptic ulcers and gastric cancers. There are, however, great demands on NHS gastroenterology and endoscopy services and following the introduction of recent guidelines for dyspepsia some of these issues may be addressed. The literature suggests that a strategy of test and treat before endoscopy referral will benefit patients and be cost-effective.

Conclusion There is evidence that, over a period of time, it is more prudent to test and treat H. pylori first and then review the patient’s condition before endoscopy is performed (if no other symptoms are identified).

Key words

* Endoscopy

* Gastrointestinal system and disorders

* Microbiology

* Peptic ulcers

These key words are based on the subject headings from the British Nursing Index. This article has been subject to double- blind review.

EVIDENCE suggests that Helicobacter pylori, a species of Gram- negative bacteria, has major implications not only for patients’ wellbeing and future health but also for gastroenterology and endoscopy services. If a patient is H. pylori positive then it is necessary to eradicate the infection because of the risk of associated peptic ulcers and gastric cancer. The ‘test and treat’ strategy involves testing patients for H. pylori using a breath test or serology followed by H. pylori eradication in those with H. pylori (Box 1) and symptomatic therapy for the remainder. A number of management trials have demonstrated that the test and treat strategy is as effective as endoscopy in determining therapy for dyspepsia (British Society of Gastroenterology (BSG) 2002).

H. pylori is associated with symptoms that come under the general heading of dyspepsia. Koch and Lancaster Smith (2003) describe two types of dyspepsia: ‘ulcer-like’ and ‘dysmotility-like’ dyspepsia. Ulcer-like symptoms include a burning epigastric pain or discomfort that often occurs at night and improves after eating, while dysmotility-like dyspepsia relates to a sensation of fullness, nausea, bloating and vomiting. Dyspepsia is extremely common in western society with a prevalence of 25-40 per cent over a six to 12 month period – 25 per cent of patients consult a doctor and 2 per cent of the UK population undergo upper gastrointestinal endoscopy (Koch and Lancaster Smith 2003).

Helicobacter pylori

H. pylori is a Gram-negative micro-aerophillic rodshaped bacterium (Roderick et al 2003). Evidence shows that it resides in the gastric mucosa and causes chronic active inflammation (Asaka et al 1995). Once acquired in childhood, it has been shown to be prevalent for several years (Blaser 1998, Danesh et al 2000, Figura et al 1998). H. pylori was discovered as early as 1906 (Caiman 1996). Originally called Campylobacter pylori its name was changed when it was realised that the bacteria’s ribonucleic acid (RNA) structure did not contain any of the characteristics of Campylobacter RNA. One of the most recent events in the field of gastroenterology was the cultivation of H. pylori in 1981.

The main causes of dyspepsia are functional and non-functional dyspepsia (greater than 50 per cent), peptic ulcer disease (20 per cent), gastrooesophageal reflux (20 per cent), and gastric carcinoma (less than 2 per cent) (Lassen et al 2000). H. pylori contributes to several of these conditions, for example, 90 per cent of duodenal ulcers and 70 per cent of gastric ulcers are thought to be associated with H. pylori infection (Axon et al 1997). The other cases of ulcer disease are associated with polypharmacology and related side effects, in particular aspirin and non-steroidal antiinflammatory drugs (NSAIDs) (Roderick et al 2003).

Box 1. Suggested Helicobacter pylori eradication regimens

Helicobacter pylori and cancer

H. pylori infection has been linked to gastric cancer due to changes in the mucosal lining in the stomach, which promotes an anti- inflammatory response and alters the stomach’s ability to protect itself against hydrochloric acid (Figura et al 1998). Research into the relationship between the two is ongoing, however, Forman et al (1991) suggested that between 35 and 55 per cent of all gastric cancers may be related to H. pylori infection.

The risk of gastric cancer in patients under the age of 45 is rare (Christie et al 1997). A total of 319 cases of gastric cancer were examined. Of these patients, only 25 were less than 55 years and of these, 24 presented with alarm symptoms. Christie et al (1997) concluded that the prevalence of gastric cancer in patients presenting with uncomplicated dyspepsia in the under 55 age group is very low. In a similar study, Williams et al (1988) researched patients who had already been diagnosed with gastric cancer and found that all patients under 45 years had presented to the GP with alarm symptoms.

Approach

The aim of this literature review was to establish when H. pylon should be treated. Sreedharan et al (2004) showed that a test and treat strategy is effective in reducing the number of referrals to endoscopy in patients under the age of 40 from 33.4-34.6 per cent to 23.2-26.2 per cent during a five-year period.

Data for this article were gathered from textbooks, journals and the internet. Athens programmes including Ovid, ScienceDirect and British Medical Journal sties have been used in research collection. The keywords used included dyspepsia, Helicobacter pylori, and test and treat. Documents were also obtained from organisations such as the National Institute for Clinical Excellence (NICE), the British Society of Gastroenterology (BSG) and Scottish Intercollegiate Guidelines Network (SIGN).

The endoscopy unit at the University Hospitals of Coventry and Warwickshire NHS Trust is modernising its services: this involves the redesign of endoscopy services, increasing the number of endoscopists and tackling variation in existing approaches to care. For the open access service provided – it is a GP-led service – referral of patients with dyspepsia is high. Currently, all patients referred for upper gastrointestinal endoscopy under this system are referred before treatment of symptoms, regardless of age, gender or social background. This has put staff at the endoscopy unit under pressure to achieve the number of endoscopies required to meet the demand and has created long waiting lists. A new strategy was therefore needed to accommodate these patients.

In accordance with the Dyspepsia Management Guidelines (BSG 2002) and NICE (2004) guidelines, a protocol was developed, in conjunction with the primary care trust (PCT), to recommend medical management of all patients under the age of 55 with new onset dyspepsia who do not have alarm symptoms. Under this regimen all patients would be automatically tested for H. pylori and treated accordingly. They would only be referred for endoscopy and further investigation if symptoms persisted or if consultant referral was required, for example, in cases of unexplained anaemia associated with dyspepsia or anxiety in relation to fears about cancer. If a patient, regardless of age, presents with alarm symptoms related to a suspicion of gastric cancer, he or she should be automatically referred to endoscopy via the two-week referral system for patients with suspected cancers, ensuring prompt investigation. The alarm symptoms identified by the BSG (2002) are listed in Box 2.

NICE produced guidelines for the treatment of dyspepsia in August 2004. These guidelines state that: ‘any patient of any age presenting without alarm symptoms does not need routine endoscopie investigation’. Consideration is, however, given to patients over the age of 55 whose symptoms persist despite H. pylori testing and acid suppression therapy. In this category of patient a history of previous gastric ulcer or surgery should be considered. Consideration should also be given to the long-term need for NSAIDs or increased risk of gastric cancer or anxiety about cancer (NICE 2004).

Findings

For practice in relation to H. pylori to change throughout the NHS, the strategy adopted must satisfy patients, provide effective testing and be cost-effective. Dyspepsia is a frequent and costly problem. In 1998, 1.1 billion was spent by the NHS on managing dyspepsia and 450,000 patients had an endoscopy (Delaney et al 2001).

At present, primary care pays the cost of patients’ treatment for dyspepsia and endoscopic procedures. Therefore, the impact of the test and treat strategy for H. pylori on consultation time and budgets would be considerable. There is evidence, however, that it is more prudent to test and treat H. pylori first, then review the patient’s condition post-eradication or if symptoms persist.

Jones et al (1999) performed a trial of a test and treat strategy for H. pylori-positive dyspeptic patients in the primary care setting. For the trial, patient referrals were restricted to those under 45 years of age with no alarm symptoms. A total of 165 patients entered the study. Eradication therapy was administered if the patients were positive for H. pylori. Patients were followed up after one year and information was gathered in audit format. The results were that the test and treat strategy is clinically appropriate and cost-effective during the fir\st year of follow-up. The cost saving of avoiding endoscopy offsets the initial cost of eradication therapy over the one-year period.

Box 2. Patients in whom diagnostic endoscopy is appropriate

Another outcome was that there was no evidence that serious lesions were missed using this approach. Manes et al (2003) identifies that test and treat is as safe and efficient as endoscopy when dealing with dyspepsia. They also found no evidence that gastric cancer was either missed or diagnosed in the 219 patients studied. After a one-year period, symptoms of dyspepsia had been eradicated in 60 per cent of patients.

In contrast to the findings of Manes et al’s (2003) study, Axon et al (1997), on studying the incidence of recurring ulcers post- eradication of H. pylori, found that patients already had ulcers of at least 5mm in diameter, but did not have other active upper gastrointestinal disease, cardiovascular, renal or liver disease. Of the 172 patients with benign ulcers, 19 were found to have cancer when the ulcer was biopsied at follow-up endoscopy. Axon et al (1997) advocate repeat endoscopy of patients found to have gastric ulcers, even post-eradication of H. pylori.

Effectiveness

Delaney et al (2001) examined the comparison of endoscopy and H. pylori testing for dyspepsia in the primary care setting. Patients were chosen who were under the age of 50 and had presented to the GP complaining of dyspepsia for a period of more than four weeks. Exclusion criteria included patients who had undergone endoscopy or a barium meal in the past three years, or patients who were unable to give consent or were unfit for endoscopy. One of the areas for examination was the cost-effectiveness of managing dyspepsia, the other was the effectiveness of the regimen.

A total of 478 patients entered the trial of which 285 were randomised to test and endoscopy, and 193 to empirical management (eradication therapy). Forty per cent of the patients tested were found to be H. pylori-positive. Total mean costs for test and endoscopy were 367.85 compared with 253.16 for the usual management. The study showed that the test and endoscopy method was less cost- effective but there were no significant differences found in the effectiveness of the routes of treatment.

Delaney et al (2001) also focused on the effectiveness of treatments. This was assessed by patients’ interpretation of symptoms using the Birmingham Dyspepsia Symptom Score. This enabled the researchers to measure patient satisfaction in terms of quality of life, pain, emotion and social function. Delaney et al (2001) concluded that test and endoscopy does not improve dyspeptic symptoms or quality of life compared with empirical management.

Heaney et al (1999) performed a study comparing test and treat for H. pylori with endoscopybased management in a hospital setting. Patients included in the research were 45 years of age or under and presented with symptoms of dyspepsia. Exclusion criteria for patients included alarm symptoms, symptoms of gastro-oesophageal reflux disease, regular use of NSAIDs, pregnancy or patients who had been treated for H. pylori in the past two weeks. The Glasgow Dyspepsia Severity Score (Medical Algorithms Project (MAP) 2004a) was used to assess dyspeptic symptoms. This is considered to be a valid and reproducible means of evaluating the severity of dyspepsia in patients. The SF36 health survey questionnaire (MAP 2004b) was used to assess quality of life and the Crown Crisp experimental index – another questionnaire -was used to measure the individual’s response or likelihood of attributing his or her somatic symptoms and distress to physical illness. Symptoms were reviewed frequently and quality of life was reviewed at five months. A total of 104 patients were enlisted, 52 were randomised to test and treat, the other 52 received endoscopy. Over a period of 12 months, 73 per cent of endoscopy referrals were avoided, however, dyspeptic symptoms were not eradicated in all patients in either group. Forty three per cent of the test and treat group and 30 per cent of the endoscopy group were, however, asymptomatic at 12 months. More recent research suggests that, although superficial epithelial damage recovers within weeks, it may take several years for chronic inflammatory cells to disappear (Koelz et al 2003).

The Glasgow Dyspepsia Severity Score was also used by McColl et al (2002) as an indicator for H. pylori status following eradication. A total of 114 patients were referred to the trial who, on endoscopy, were found to have active duodenal and/or gastric ulcers. H. pylori status was checked using the C-urea breath test, endoscopy and biopsy. If these tests were positive, then the patient was given eradication therapy. The dyspepsia score was completed before and after eradication. When reassessed, 47 per cent of patients experience complete, or almost complete, resolution of symptoms. According to McColl et al (2002) this was directly related to the successful eradication of H. pylori. In 43 out of 44 patients whose dyspeptic symptoms had resolved H. pylori was found to have been eradicated.

However, Talley et al (1999) found there was little difference in the symptom scores of 370 patients post-eradication of H. pylori. Patients who had had dyspepsia for more than three months and were found to be H. pylori positive after an endoscopy were enrolled in the study. An extensive list of exclusion criteria is provided, for example, patients with duodenal ulcers or Barrett’s oesophagus. Patients were then randomised; one group (n=182) received H. pylori eradication therapy, the other group (n=188) received a placebo. Following treatment, or not, patients were followed up in regular clinics for up to 12 months. Diary cards used a Likert scale with seven markers. These ranged from none to very severe to establish and determine the severity of symptoms. A quality of life form was completed at the six and 12 months visits. A repeat endoscopy at three and 12 months was performed and biopsies were taken.

On evaluating the results, Talley et al (1999) found ‘no convincing evidence that successful eradication of Helicobacter pylori relieves or reduces symptoms in patients with functional dyspepsia over 12 months’. However, they advocate using the test and treat strategy in patients under 45 years and point out that only a small number of patients are likely to have long-term symptomatic relief from H. pylori eradication therapy.

Patient satisfaction

Patient satisfaction is another important factor when implementing strategies that change their care pathway; however, literature on this aspect of care is poor and evidence is limited. Lassen et al (2000) found that 12 per cent of their study group – identified as patients over 18 years who had a clinical history of dyspeptic symptoms for less than two weeks but which were severe enough to require investigation or treatment – were not satisfied when assigned to the test and treat strategy, and concluded that this strategy makes the process less efficient.

They enrolled 500 patients presenting to the GP with a two-week history of dyspepsia without alarm symptoms. A total of 250 patients were randomised to the test and treat strategy and the remainder were referred for endoscopy. H. pylori status was obtained using the C-urea breath test. Diary cards were used as a data collection tool, with a four-stage Likert scale, and a questionnaire was completed after one month and at the annual follow-up. In view of the findings, Lassen et al (2000) advocate test and treat for H. pylori as a safe and efficient alternative to endoscopy, but they point out that patients may still request invasive procedures.

On examining the effectiveness of endoscopy in the management of dyspepsia (Figure 1), McColl et al (2002) studied 208 patients referred directly from the GP to endoscopy. They looked specifically at the comparison of test and treat for H. pylori with endoscopy management. Patients were excluded for various reasons, for example, patients over the age of 55, those on certain medications such as NSAIDs, and patients with alarm symptoms.

Figure 1. Management of dyspepsia

The severity of dyspeptic symptoms was assessed using the Glasgow Dyspepsia Severity Score (MAP 2004a) six months before the trial, and quality of life was evaluated using the SF36 health survey questionnaire (MAP 2004b). Sinister perceptions of what the patient believed to be wrong (for example, cancer) were recorded on a Likert scale of 0-10. The study showed that the most anxious patients received equivalent reassurance from endoscopy management and the test and treat strategy. In contrast to Lassen et al (2000), McColl et al (2002) conclude that test and treat is as effective and safe as prompt endoscopy, with patients being satisfied on both counts.

If the test and treat strategy is to take place then reassurance is necessary for the patient to be satisfied that the outcomes of the test are safe and reliable, and that no serious underlying cancer will be missed. Patients who remain anxious about their health may experience distress and could, potentially, become a further strain on NHS resources. Some patients may require further consultations to reassure them of test results.

Lucock et al (1997) state that anxious patients can misinterpret patient-doctor communication. They performed a quantitative study observing 50 patients, aged between 18 and 74, referred for gastroscopy. The results demonstrated the importance of patients receiving reassurance, and emphasised the need for patients to receive a positive explanation of the symptoms and test results in acceptable, understandable language. Thus giving the patient confirmation of diagnosis and followup implications will help to reduce the number of consultation appointments with medical staff.

Discussion

The current demands on endoscopy services are high and are likely to \increase. This is partly due to new national screening programmes such as colorectal screening (Cairns and Scholefield 2002), and the throughput of patients requiring endoscopy. The NICE (2004) guidelines on dyspepsia will help to address some of the problems of capacity and demand in endoscopy services.

At the University Hospital of Coventry and Warwickshire NHS Trust the PCT has a key role in changing the care pathway for patients experiencing dyspepsia. Without the trust’s involvement change will not occur. Members of the PCT will need to allow for extra consultation time and a possible initial increase in the budget. This would eliminate the need for endoscopy in patients under the age of 45 unless the patient is concerned or anxious about their symptoms.

Under the trust’s protocol, patients presenting with alarm symptoms would automatically be referred under the two-week urgent referral system for suspected cancer. However, in a study of 25 patients who had no alarm symptoms Christie et al (1997) found one patient with gastric cancer. Two reports on patient satisfaction highlight the fact that this is an area that requires further examination (Lassen et al 2000, McColl et al 2002). The common theme throughout these two studies was the need for patients to be fully informed, reassured and to participate in their health care, otherwise the implementation of the test and treat strategy may not be as effective as previously thought.

It is well known that increasing age is associated with an increased risk of cancer (National Institute of Aging 2004). Age and H pylori are major factors associated with gastric cancer. The safest way to identify cancer early may be to perform endoscopies on those patients at greater risk rather than waiting for acid suppressant medication to take effect or referring for endoscopy at later stages of the disease.

Conclusion

From the evidence provided in this article, H. pylori has a major impact on co-morbidity and pathophysiology. Research suggests that the strategy of test and treat before endoscopy referral is costeffective, although it will take time before the benefits become evident. The effectiveness of a test and treat strategy appears to be the same as endoscopy management

Livett H (2004) Test and treat Helicobacter pylori before endoscopy. Nursing Standard. 19, 8, 33-38. Date of acceptance: June 22 2004.

Online archive

For related articles and author guidelines visit our online archive at: www.nursing-standard.co.uk and search using the key words above.

Implications for practice

* Test and treat for Helicobacter pylori before endoscopy can be a cost-effective alternative

* More research needs to be conducted into how satisfied patients are with this strategy

* Primary care needs to allow for extra consultation time and possible budget increases to adopt a test and treat strategy

REFERENCES

Asaka et al (1995) Relationship between Helicobacter pylori infection, atrophie gastritis and gastric carcinoma in a Japanese population. European Journal of Gastroenterology and Hepatology. 7, Suppl 1, S7-S10.

Axon A et al (1997) Randomised double-blind controlled study of recurrence of gastric ulcer after treatment for eradication of Helicobacter pylori infection. British Medical Journal. 314, 7080, 565-568.

Blaser M (1998) Clinical review. Science, medicine and the future. Helicobacter pylori and gastric diseases. British Medical Journal. 316, 7143, 1507-1510.

British Society of Gastroenterology (2002) Dyspepsia Management Guidelines, www.bsg.org.uk/pdf_ word_docs7dyspepsia.doc (Last accessed: October 21 2004.)

Cairns S, Scholefield J (2002) Guidelines for colorectal cancer screening in high risk groups. Gut. 51, Suppl 5, V1-2.

Caiman J (1996) Clinician’s Guide to Helicobacter pylori. London, Chapman and Hall.

Christie J et al (1997) Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 41, 4, 513-517.

Danesh J et al (2000) High prevalence of potentially virulent strains of Helicobacter pylori in the general male population. Gut. 47, 1, 23-25.

Delaney B et al (2001) Randomised controlled trial of Helicobacter pylori testing and endoscopy for dyspepsia in primary care. British Medical Journal. 322, 7291, 898.

Elliot D (2002) The treatment of peptic ulcers. Nursing Standard. 16, 22, 37-42.

Figura N et al (1998) cagA positive and negative Helicobacter pylori strains are simultaneously present in the stomach of most patients with non-ulcer dyspepsia: relevance to histological damage. Gui. 42, 6, 772-778.

Forman D et al (1991) Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. British Medical Journal. 302, 6788, 1302- 1305.

Heaney A et al (1999) A prospective randomised trial of a ‘test and treat’ policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut. 45, 2, 186-190.

Jones R et al (1999) A trial of a test-and-treat strategy for Helicobacter pylori positive dyspeptic patients in general practice. International Journal of Clinical Practice. 53, 6, 413-416.

Koch K, Lancaster Smith M (2003) Dyspepsia. Fast Facts. Second edition. Oxford, Health Press.

Koelz H et al (2003) Treatment of Helicobacter pylori in functional dyspepsia resistant to conventional management: a double- blind randomised trial with a six-month follow-up. Gut. 52, 1, 40- 46.

Lassen A et al (2000) Helicobacter pylori test and eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet. 356, 9228, 455-460.

Lucock M et al (1997) Responses of consecutive patients to reassurance after gastroscopy: results of self-administered questionnaire survey. British Medical Journal. 315, 7108, 572-575.

Manes G et al (2003) Empirical prescribing for dyspepsia: randomised controlled trial of test and treat versus omeprazole treatment. British Medical Journal. 326, 7399, 1118.

McColl K et al (2002) Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia. British Medical Journal. 324, 7344, 999-1002.

Medical Algorithms Project (2004a) Gastroenterology. Glasgow Dyspepsia Severity Score. www.medal.org/ch10.html (Last accessed: October 19 2004.)

Medical Algorithms Project (2004b) Gastroenterology. Dyspepsia- related Health Scale Questionnaire. www.medal.org/ch 10/(Last accessed: October 19 2004.)

National Institute on Aging (2004). Cancer Facts for People Over the Age of 50. www.niapublications. org/engagepages/cancer.asp (Last accessed: October 19 2004.)

National Institute for Clinical Excellence (2004) Scope for the Development of a Clinical Guideline on the Primary Management of Dyspepsia. www.nice.org.uk/article.asp?a=16738 (Last accessed: October 1 2004.)

Roderick P et al (2003) The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model. Health Technology Assessment. 7, 6, 1-86.

Sreedharan A et al (2004) Cost-effectiveness and long-term impact of Helicobacter pylori ‘test and treat’ service in reducing open access endoscopy referrals. European Journal of Gastroenterology and Hepatology. 16, 10, 981-986.

Talley N et al (1999) Eradication of Helicobacter pylori in functional dyspepsia: randomised double-blind placebo controlled trial with 12 months follow-up. British Medical Journal. 318, 7187, 833-837.

Scottish Intercollegiate Guidelines Network (2003) Dyspepsia. www.sign.ac.uk/pdf/qrg68.pdf (Last accessed: October 8 2004.)

Williams B et al (1988) Do young patients with dyspepsia need investigation? Lancet. 2, 8624, 1349-1351.

Helen Livett RGN, BSc, is nurse endoscopist, University Hospitals Coventry and Warwickshire NHS Trust, Coventry.

Email: [email protected]

Copyright RCN Publishing Company Ltd. Nov 3-Nov 9, 2004

A Five-Year Followup of Hand Function and Activities of Daily Living in Systemic Sclerosis (Scleroderma)

ABSTRACT: The purpose of this study was to identify hand factors that change over a five-year period that may be risk factors for the development of functional disability in persons with systemic sclerosis (scleroderma). Sixty individuals with scleroderma were administered assessments of grip and pinch strength, joint range of motion, and pain, and were observed for the presence of digital ulcers, digital scars, calcium deposits, puffy fingers, and tendon friction rubs. Matched-pairs chi square analyses and Fisher’s exact tests were performed to compare variables at year 1 and five years later. Grip and pinch strength increased as did joint motion except for the wrist and thumb carpometacarpal joint. There were also significant increases in the presence of scars, friction rubs, calcium deposits, and puffy fingers. Regression analysis was done to determine which variables predicted functional ability. Only puffy fingers predicted functional disability. In conclusion, hand impairment persisted over time while functional ability decreased.

J HAND THER. 2004;17:407-411.

Systemic sclerosis or scleroderma is a multisystem disease with two major subtypes: diffuse and limited cutaneous scleroderma. In diffuse scleroderma, the classic form of the disease, there is symmetrical and generalized (diffuse) involvement of skin affecting the trunk face, proximal and distal extremities, and visceral involvement that develops relatively early.1 In the limited cutaneous variant, skin thickening is generally restricted to the face and hands, and visceral manifestations may not be present for a prolonged period.1

The hands in individuals with both subtypes of scleroderma show skin thickening, tendon friction rubs (tendon sheath inflammation in the flexor and extensor tendons), digital pitting scars on the fingertips, digital ulcers, puffy or swollen fingers, Raynaud’s phenomenon, and subcutaneous calcium buildup.1-4 Palmer et al.3 described the hands in individuals with scleroderma as showing characteristic “claw” deformities, a loss of flexion at the metacarpophalangeal joins, and a loss of extension at the proximal interphalangeal joints. However, they did not follow individuals over a time period to determine whether the finger deformities increased or decreased during the course of the disease or led to functional disability.

The long-term ability to perform activities of daily living is of interest to hand therapists who play a role in preventing deformities and preserving hand function in persons with scleroderma.5,6 Poole and Steen7 measured a number of factors observed clinically to be associated with the ability to perform daily tasks. The presence of puffy fingers, joint pain and swelling, and measures of grip strength, thumb palmar abduction, wrist extension, and composite index and middle finger motion all correlated with the ability to dress, eat, brush teeth, reach, and grasp. Poole8 also reported that grip strength, thumb palmar abduction, wrist extension, digital sores, calcium deposits, and tendon friction rubs correlated with the ability to hold four common objects ( glass, saucepan handle, key, coin). Thus, it appears that hand involvement in individuals with scleroderma is associated with overall functional ability. Due to the progressive nature of scleroderma, it may be instructive to examine hand involvement at different points irv time. Although prognosis in systemic sclerosis is largely dependent on the degree of visceral involvement, Medsger9 reported that hand dysfunction was also related to morbidity. He estimated that hand impairment increased in the first five years after diagnosis and then plateaus in diffuse scleroderma. In the limited cutaneous subset, hand dysfunction continues to increase throughout the course of the disease. The purpose of this study was to identify the hand factors that change over a five-year time period that may be risk factors for the development of functional disability in persons with both types of scleroderma.

METHODS

This was a prospective or cohort study where participants were tested at two points in time, five years apart.

Participants

Participants for this study consisted of 60 individuals who fulfilled American College of Rheumatology criteria for scleroderma.10 Information on age, sex, educational level, and occupation was collected at the beginning of the study. At the beginning of the study, 16 participants were classified as having limited cutaneous scleroderma, 39 as diffuse, and five as unclassified. Five years later, 15 cases were classified as limited, 40 as diffuse, and five unclassified.

There were 52 women and eight men. The ages of the participants ranged from 19 to 86 years at completion of the study with a mean of 51.06 and a median of 52.5 years. Disease duration ranged from five to 47 years with a mean of 14.4 and a median of 12.5 years. It was found that 1.7% (1/60) had not completed high school, 60% (36/60) had completed high school, 30% (18/60) had some education beyond high school such as college, and 8.3% (5/60) had an unknown education level. At the beginning of the study, participants reported their occupations were as follows: 20% (12/60) were clerical workers, 18.3% (11/60) were private household workers or service workers, 18.3% (11/60) were housewives, 8.3% (5/60) were professional or technical workers (e.g., nurses, teachers, technicians), 6.6% (4/60) were sales workers, 6.6% (4/60) were operative and kindred workers (e.g., dress makers, bus drivers, taxi drivers); 5% (3/ 60) were managers, officials, or proprietors; and 5% (3/60) were craftsmen or foremen. The occupations of seven cases were unknown.

Procedures

The plausible risk factors selected for this study represent factors that correlated with disability.7,8 Additional factors represent a spectrum of clinically important items that may be related to hand involvement, such as educational level and occupation. We did not control for medications because information was not available for all participants. Participants were evaluated at the beginning of the study ( year 1, time 1) and were reevaluated five years later (time 2).

Physical Examination

The presence or absence of the following factors was recorded: digital ulcers, digital scars, calcium deposits, puffy fingers, and tendon friction rubs. Grip strength was measured with a vigorimeter, a rubber bulb attached to a meter. Pinch strength was measured with a pinchmeter. For both grip and pinch strength, three consecutive measurements were taken, alternating the right hand with the left hand. The average of the three measurements for each hand was recorded. Pain was assessed with the pain visual analogue scale on the Health Assessment Questionnaire.10 Active range of motion (ROM) for each joint in the hand and wrist was measured with a goniometer and served as determination of deformity. Based on these ROM measurements, five deformity measures were calculated: the number of extension contractures (flexion less than or equal to 45 degrees) at the metacarpophalangeal (MCP) joints, the number of flexion contractures ( finger flexed 45 degrees or greater) at the proximal interphalangeal (PIP) joints, the distance in centimeters from the fingertip to distal palmar crease for each finger (FTOP), thumb palmar abduction in degrees of motion, and number of amputations.

Severity of skin thickness was used as measure of disease severity. Skin thickness of the hand and fingers was rated according to the scale of described by Clements et al.” With this scale, the skin on the dorsal surface of the fingers and hand is pinched. The ability to make a skinfold is rated from O (uninvolved) to 3 (severe skin thickening). Disease subtypes, diffuse or limited cutaneous scleroderma, were also recorded.

The outcome measure for this study, functional disability, was measured by the Health Assessment Questionnaire Disability Index (HAQ). The disability index of the HAQ was designed to measure functional ability in rheumatic disease patients.10 The HAQ consists of eight components of daily living (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and outside activity). Questions in each component are scored on a four-point scale, from “without difficulty” to “unable to do.” A disability index was calculated by summing the highest score in each component and dividing by the number of components answered. The mean disability index for individuals with systemic sclerosis was determined to be 0.92.7 Concurrent validity of the HAQ in scleroderma was established by comparing an individual’s self-report responses with actual performance of selected items on the HAQ.12 Support for construct validity was provided by Poole and Steen7 because the HAQ differentiated individuals with the diffuse and limited cutaneous subtypes of the disease.

Data Analysis

Variables were described using means, medians, and frequency distribution. Additionally, cross-tabulations were calculated matching independent variables with improvement from time 1 (year 1) to time 2 (five years later). Categorical variables were scars, ulcers, friction rubs, calcium, Raynaud’s phenomenon, and puffy fingers. Continuous variables were grip strength, lateral pinch, palmar pinch, wrist extension, thumb abduction, measures of each fingertip to the palmar crease \(FTOP 2-5), and thumb flexion. Matched-pairs chi square analysis ( for categorical variables) as well as Fisher’s exact tests and paired t-tests (for continuous variables) were performed to compare variables at time 1 and time 2. Regression analysis was performed to determine which variables predicted changes in HAQ scores. Multiple logical regressions were used to predict improvement over time by the significant risk factors determined from the univariate analysis.

RESULTS

Table 1 demonstrates the results of comparisons from time 1 and time 2 for all risk factors broken down by continuous variables. Grip and pinch strength increased. In general, joint motion of the fingers increased while CMC and wrist motion decreased. However, the only continuous variables showing significant change were lateral pinch, and palmar pinch. Table 2 shows the results of comparisons from time one to time two for the categorical variables. The percentages of all these variables increased in the five year period. However, the categorical variables showing significant changes were the presence of scars, tendon friction rubs, calcium deposits, and puffy fingers. The mean HAQ score was 0.73 at time 1 and 0.81 at time 2. Thus, disability increased, but not significantly.

The continuous and categorical variables that significantly changed over time were entered into the regression analysis. The regression analysis revealed that only puffy fingers predicted change in total HAQ disability scores.

DISCUSSION

In general, joint motion and strength were relatively unchanged over the five-year period. Interestingly, pinch strength increased significantly. Palmer pinch, where the thumb opposes the pads of the index and middle fingers, has been reported to be the most commonly used pinch for both picking up and using small objects. 3’14 Lateral pinch is the second most commonly used pinch pattern. It has been reported that 2.5 Ib of pinch is all that is needed to perform 90% of tasks of daily living.15 The increase in pinch strength might reflect a decrease in disease activity, which might explain why functional disability did not decrease. However, the presence of the variables related to the disease itself increased. These findings are different from those reported by Medsger and Steen,16 who reported a significant increase for calcium deposits but a decrease in puffy fingers and tendon friction rubs. The smaller sample size in our study may account for this difference in results. Although grip strength, joint motion, calcium deposits, and ulcers correlate with functional ability,7,8 in this study, only puffy fingers predicted disability. Several explanations are possible. First, participants in this study, as compared with published data on other persons with scleroderma, had minimal disability/'” In addition, the participants had minimal joint involvement and skin thickness. Although there were no significant differences in the variables for diffuse and limited participants, findings might be very different if the sample had been more severely involved and disabled. A second reason that other variables did not predict disability may be that the outcome measure, the HAQ, was not sensitive to changes in hand function. Silman et al.17 suggest that the HAQ includes areas that are not considered major problems in scleroderma. Using a different outcome measure that emphasizes hand function, such as the Scleroderma Functional Ability Questionnaire17 or the Hand Function Disability Scale,18,19 might yield different results. Third, although hand function was of particular interest to us, scleroderma involves other parts of the body as well, including the internal organs. The combination of impairments from many bodily systems may predict disability beyond hand function. Altman et al20 showed that proximal muscle weakness, joint swelling, and deformity early in the course of the disease were related to decreased survival.

TABLE 1. Mean Values for Continuous Variables for Time 1 and Time 2

TABLE 2. Percent Response for Categorical Variables for Time 1 and Time 2

Most studies examining disability in scleroderma have examined the presence of clinical disease variables. Only two studies did performance-based evaluations of hand function.7,8 However, whereas those studies only assessed hand function at one point in time, they did find that hand function was related to disability. The present study was the first to examine changes in performance outcomes in the hand over time. Although in our study the participants had minimal hand contractures, contractures occur frequently in the hand.21 Our criteria for a contracture may have been too severe. We identified a PIP contracture as flexed to 45 degrees or greater and an MCP contracture as less than 45 degrees of flexion. if we had used less strict criteria or used total joint motion, our results might have been different.

The participants in our study did not report receiving occupational or physical therapy during the five years of this study. However, the participants did receive therapy when their condition was first diagnosed. They also received care at a major medical center from physicians specializing in scleroderma. Thus, the most up-to-date treatment may have contributed to the reason why hand variables did not decrease significantly.

Clearly, persons with scleroderma have significant hand involvement.16,21 Yearly assessments with newly diagnosed cases could identify sequential stages of disease progression to determine optimal time for therapeutic intervention such as occupational or physical therapy. Further studies using larger sample sizes and outcomes specific to hand function should also be preformed.

Acknowledgments

The authors acknowledge the assistance of Timothy Sypolt, Camen Scolieri, Mary Lucas, and Carol Brewer, MS, OTR/ L, in collecting data; Aysa Alseayleck and Beena Suri foiassistance with data input and analysis; and Thomas A. Medsger, Jr., MD, and Virginia Steen, MD, for providing continued support. Supported in part by the University of Pittsburgh Research Development Fund and the Western Pennsylvania Chapter of the Arthritis Foundation. Portions of this manuscript were presented at the Annual Conference of the Association of Rheumatology Health Professionals, Orlando, Florida, October 1996.

REFERENCES

1. Masi AT, Rod nan GP, Mcdsger TA Jr, et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581-90.

2. Entin MA, Wilkinson RD. Scleroderma hand : a reappraisal. Orthop Clin North Am. 1973;4:1031-8.

3. Palmer DG, Hale GM, Grennan DM, Pollock M. Bowed fingers: a helpful sign in the early diagnosis of systemic sclerosis. J Rheumatol. 1981;8:266-72.

4. Steen V, Contc C, Medsger TA Jr. Twenty-year incidence survey of systemic sclerosis (scleroderma). Arthritis Rheum. 1988;31:S57.

5. Melvin JL (1996). Scleroderma (systemic sclerosis): Treatment of the hand. In Hunter JM, Mackin EJ, Callahan AU (eds). Rehabilitation of the Hand: Surgery and Therapy. St. Louis, MO: Mosby, 1996, pp 1385-97.

6. Poole JL. Occupational and physical therapy. In: Clements PJ, Purst DE (eds). Systemic Sclerosis. Baltimore, MD: Williams 6 Wilkins, 1995, pp 581-90.

7. Poole J, Steen V. The use of the health assessment questionnaire (HAQ) to determine physical disability in systemic sclerosis. Arthritis Care Res. 1991;4:27-31.

8. Poole JL. A description of grasp pattern variations seen in scleroderma. Am J Occup Ther. 1994;48:46-54.

9. Medsger TA Jr. Systemic sclerosis (scleroderma). In: Fries JF, Ehrlich GE (eds). Prognosis: Contemporary Outcomes of Disease. Bowie, MD: Charles Press Publishers, 1982, pp 378-80.

10. Fries JF, Spitz PV, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23:137-25.

11. Clements PJ, Lachcnbruch PA, Seibold JR, Tee B, Steen V, Brennan P. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 1993;20:1892-6.

12. Poole J, Williams C, Bloch D, Hollak B, Spitz P. Concurrent validity of the health assessment questionnaire disability index in scleroderma. Arthritis Care Res. 1995;8:189-93.

13. Harty M. The hand of man. Phys Ther. 1974;51:777-9.

14. Taylor CL, Schwarz RJ. The anatomy and mechanics of the human hand. Artif Limbs. 1955;3:22.

15. Swanson AB. Evaluation of impairment of hand function. In Hunter JM, Mackin EJ, Callahan AD (eds). Rehabilitation of the Hand: Surgery and Therapy. St. Louis, MO: Mosby, 1996, pp 115-25.

16. Medsger TA Jr, Steen V. Classification, prognosis. In: Clements PJ, Furst DE (eds). Systemic Sclerosis. Baltimore, MD: Williams & Wilkins, 1995, pp 51-64.

17. Silman A, Akesson A, Newman J, et al. Assessment of functional ability in patients with scleroderma: a proposed new disability assessment instrument. J Rheumatol. 1998;25:79-83.

18. Duruz MT, Poiraudeau S, Fermanian J, et al. Development and validation of a rheumatoid hand functional disability scale that assesses functional handicap. J Rheumatol. 1996;23:1167-72.

19. Brower LM, Poole JL. Reliability and validity of the Duruz Hand Index in persons with systemic sclerosis (scleroderma). Arthritis Care Res. (In press).

20. Altman RD, Medsger TA, Bloch DA, Michel BA. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum. 1991;34:403-13.

21. Melone CP, McLoughlin JC, Beldner S. Surgical management of the hand in scleroderma. Cur Opin Rheumatol. 1999;11:514-20.

Janet L. Poole, PhD, OTR/L

Departments of Orthopaedics and Rehabilitation

Occupational Therapy Graduate Program

University of New Mexico

Albuquerque, New Mexico

Valerie J.M. Watzlaf, PhD, FAHIMA, RHIA

Department of Health Information Management

School of Health and Rehabilitation Sciences

University of Pittsburgh

Pittsburgh, Pennsylvania

Frank D’Amico, PhD

Department of Mathematics and Computer Science

Duquesne University

Pittsbu\rgh, Pennsylvania

Correspondence and reprint requests to Janet L. Poole, PhD, OTR/ L, Occupational Therapy Graduate Program, Department of Orthopaedics and Rehabilitation University of New Mexico, MSC 09 5240, Albuquerque, NM 87131-0001; e-mail: .

Copyright Hanley & Belfus, Inc. Oct-Dec 2004

The Management of Nausea and Vomiting in Palliative Care

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Summary

For patients with terminal illness, nausea and vomiting can be very distressing symptoms and can have a negative effect on their quality of life. This article discusses the nursing management of these symptoms, with a view to improving quality of life for these patients.

Keywords

* Nausea

* Terminal care

* Terminal care: symptom relief

These key words are based on subject headings from the British Nursing Index. This article has been subject to double-blind review.

Aim and intended learning outcomes

The aim of this article is to provide greater insight into the issues surrounding nausea and vomiting for palliative patients, including guality of life issues, treatment of symptoms and nursing care. After reading this article you should be able to:

* Recognise the effect of nausea and vomiting on quality of life.

* Understand the causes of nausea and vomiting.

* Describe the emetic process.

* Outline the pharmacological and non-pharmacological approaches to the management of nausea and vomiting.

* Explain the significance of nursing care to the patient with nausea and vomiting.

Introduction

For a patient with a progressive, incurable disease such as cancer, maintaining quality of life is paramount. Nausea and vomiting can have a profoundly negative impact on quality of life. If these symptoms are to be managed effectively, nurses need to understand how debilitating and distressing they can be for the patient and his or her family.

There are many nursing, medical and practical measures that can be used in the management of nausea and vomiting, but it is essential before attempting any of these measures that the cause or causes of these symptoms are identified and also that the emetic process is understood.

Before discussing the management of nausea and vomiting, it is appropriate to define palliative care. Nurses need to have a firm grasp of the concept and principles of palliative care and, therefore, understand the importance of quality of life when the quantity is uncertain. In this way, the negative effect that these symptoms have on quality of life can be appreciated more fully.

Palliative care

The most common definition of palliative care was provided by the World Health Organization (WHO) in 1990 and updated in 2002: Palliative care is an approach that improves the quality of life of patients and their families facing the problems associated with life- threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual. Palliative care:

* Provides relief from pain and other distressing symptoms.

* Affirms life and regards dying as a normal process.

* Intends neither to hasten nor postpone death.

* Integrates the psychological and spiritual aspects of patient care.

* Offers a support system to help patients live as actively as possible until death.

* Offers a support system to help the family cope during the patient’s illness and in their own bereavement.

* Uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated.

* Will enhance quality of life, and may also positively influence the course of illness.

* Is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications.’

Twycross and Wilcock (2001) describe four cardinal principles of palliative care:

* Respect for patient autonomy (patient choice).

* Beneficence (do good).

* Non-maleficence (minimise harm).

* Justice (fair use of available resources).

The National Institute for Clinical Excellence (NICE) (2004) guidance Improving Supportive and Palliative Care for Adults with Cancer identifies a difference between general and specialist palliative care service provision, taking into account the qualifications and experience of staff involved in the care as well as the healthcare setting. It also recognises that patients should play a central role in decision making and that, as the main care providers, families and carers need to be included.

Palliative care focuses on the quality of life of the patient but also takes into account the needs of the patient’s family and carers. Using a team approach while also recognising that the patient will need to have one key worker is essential – it is frequently the ward or community nurse that takes this role.

Nausea and vomiting

Nausea and vomiting are two symptoms that frequently accompany each other. However, some patients will experience nausea without ever vomiting while others will only feel nauseated immediately before vomiting.

Nausea can be described as the sensation that immediately precedes vomiting. A cold sweat, increased salivation, a lack of interest in one’s surroundings, loss of gastric tone, duodenal contractions and the reflux of intestinal contents into the stomach often accompany nausea (Morrow and Rosenthal 1996).

Vomiting (or emesis) is the rapid and forceful evacuation of the stomach contents up to and out of the mouth caused by the powerful sustained contraction of the abdominal and chest wall muscles (Morrow and Rosenthal 1996).

These two symptoms, the unpleasant sensation created by nausea followed by the physical effort of vomiting, can have a profound impact on quality of life (Mannix 1998).

Vomiting is one of the body’s involuntary defence mechanisms that is used to expel toxic or harmful substances. The process occurs as follows (Baines 2000):

* A deep breath is taken, the glottis is closed, the larynx is raised to open the upper oesophageal sphincter and the soft palate is elevated, closing off the posterior nares.

* The diaphragm contracts downwards, creating negative pressure, which opens the oesophagus and distal oesophageal sphincter.

* While the diaphragm moves down, the abdominal muscles are contracted to squeeze the stomach and raise intragastric pressure. The pylorus closes to leave the oesophagus as the only route of exit for the stomach’s contents.

Causes of nausea and vomiting

Before treating nausea and/or vomiting, a full assessment should be undertaken to ascertain the possible causes. Without assessment, any treatment offered will at best be trial and error, wasting valuable time and quality of life for the patient, who may have a limited prognosis (a life expectancy of weeks to months). Twycross (1999) states that it is usually possible to determine the cause of nausea and vomiting from the patient’s history and a clinical examination.

The causes of nausea and vomiting in patients with cancer can be broken down into two main areas (Box 1). Many of these are either reversible or temporary, so when beginning anti-emetic therapy the causes should also be addressed. For example:

* Treat constipation with more appropriate laxatives.

* Drain ascites.

* Give antitussive for cough.

Polypharmacy is an ongoing issue for patients receiving palliative care – overprescribing of medication because of a lack of careful review may lead to unnecessary drug interactions. Where this is not an issue, many patients find the volume of oral medication overwhelming. Some drugs can be converted to slow-release formulation, other drugs may be replaced by a more potent version, while many drugs are used solely to treat the side effects of existing medication.

Table 1 provides a list of regular medication that a patient with metastatic lung cancer and spinal cord compression may be taking. Table 2 indicates the medication for the same patient following a review by the palliative care team. By making some simple changes, the palliative care team was able to reduce the patient’s daily medication intake by 21 doses.

Replacing a 12-hourly morphine formulation with a daily version is one way to reduce oral intake without affecting pain control. COX- 2 non-steroidal antiinflammatory drugs were developed specifically to reduce gastrointestinal toxicity (Flower 2003). Etoricoxib falls into this category; it has fewer side effects and, as a daily formulation it reduces oral medication for the patient. Co-codamol, as a step 2 analgesic, is unnecessary when step 3 analgesics are already in use (WHO 1986). Co-danthramer is a combination of a contact laxative and a faecal softener and is, therefore, a more appropriate approach to opioid-induced constipation than is a combination of senna and lactulose (Twycross et al 2002).

Box 1. Causes of nausea and vomiting in patients with cancer

Anti-emetic therapy

Assessment of nausea and vomiting Nausea is a subjective experience and only the patient is aware of its severity – a consistent and systematic approach to assessment is necessary for nurses to understand this.

Assessment tools should measure the severity of nausea experienced, the frequency and duration of vomiting and the distress this causes the patient (Miller and Kearney 2004). The Edmonton Symptom Assessment System uses a visual analogue scale to assess a range of symptoms including naus\ea, vomiting, pain, anxiety and depression (Bruera et al 1991). The information given by the patient is then transferred to a graph to provide a measurable record of the impact of symptom control interventions.

Table 1. Medication taken by a patient with metastatic lung cancer and spinal cord compression

Table 2. Medication taken by a patient with metastatic lung cancer and spinal cord compression after review by the palliative care team

Other tools focus solely on nausea and vomiting, for example, the Rhodes Index (Saltzman et al 2003), but perhaps by isolating these symptoms with one assessment tool other symptoms may be overlooked.

Before introducing a tool, its reliability, validity and practicality in the clinical setting should be considered. However, the assessment tool ‘must not be a substitute for a good patient/ doctor/nurse relationship’ (Ripamonti and Bruera 2002).

Before choosing an anti-emetic:

* Determine the possible causes of the nausea and vomiting.

* Treat reversible causes.

* Review current medication.

* Ascertain the most appropriate route for administration of the anti-emetic.

* Ensure that the patient understands and agrees with the treatment plan.

It has been shown that nausea and vomiting can be controlled in up to 70 per cent of patients by treating with anti-emetics according to the receptor site thought to contribute to the symptom (Lichter 1993). Figure 1 shows the receptor sites in the brain and gut that contribute to nausea and vomiting.

The most commonly used drugs for treating nausea and vomiting and the route of action are shown in Table 3 (Twycross et al 2002). The cause of these symptoms is not always immediately obvious, and in this circumstance the choice of an appropriate anti-emetic can be almost haphazard. However, Twycross and Wilcock (2001) have provided a fourstep anti-emetic ladder that provides a logical and methodical approach to the drug treatment of nausea and vomiting (Figure 2).

Subcutaneous administration There are two types of syringe drivers commonly used in palliative care for delivering drugs subcutaneously:

* The Graseby MS16A syringe driver (blue) – which delivers in millimetres per hour.

* The Graseby MS26 syringe driver (green) – which delivers in millimetres per 24 hours.

Of these two syringe drivers, the MS26 is recommended for use in palliative care, because it is the simplest to use (Dickman and Littlewood 1998). The MS26 requires only the ability to measure the distance that the plunger needs to travel over 24 hours when setting the rate, unlike the MS16A, which requires the nurse to calculate the rate per hour and then convert that to a rate over 24 hours. A combination of up to three drugs can usually be administered safely (provided that compatabilities have been checked), with the main advantage over oral administration being that vomiting will not adversely affect absorption because as the drugs are given subcutaneously the gut is not involved. Coackley and Skinner (2003) make two recommendations for giving anti-emetic drugs via the subcutaneous route:

* For vomiting of more than 24 hours’ duration.

* For moderate-to-severe nausea unresponsive to oral antiemetics for more than 48 hours.

Continuous administration of subcutaneous drugs allows for improved symptom management with minimal discomfort and inconvenience for the patient. Regular intramuscular or subcutaneous injections are painful, intravenous administration requires access and can become an infection risk, and the rectal route is rarely appropriate or acceptable (Dickman 2003).

While this type of syringe driver is commonly recognised as simple to use, complications can arise. Nurses caring for a patient with this equipment in situ should be able to manage it competently, recognise complications quickly and problem solve efficiently. As Lugton (2002) explains: ‘Patients and relatives feel more relaxed even when symptoms are not alleviated, if nurses are perceived to be available and confident in their approach.’

Table 3. Common anti-emetics and mode of action

Figure 1. Receptor sites contributing to nausea and vomiting

Common complications associated with syringe drivers Painful injection site This can result from irritation caused by the needle being in place for several days, an allergic reaction to the needle or an irritant drug combination. Consideration should be given to using a non-metal needle, a review of the drug combination, increasing the dilution of the drugs or adding hyaluronidase (1,500 units) (which enhances the diffusion of subcutaneous infusions) to the infusion, increasing the rate of absorption of subcutaneous drugs (Twycross et al 2002).

Infusion rate problems This is usually as a result of an incorrect syringe measurement or an incorrect rate setting. When using a Graseby MS26 syringe driver to set the rate, measure the length of the syringe driver (after the line has been primed) in millimetres. The length in millimetres is then the rate that is set (Twycross et al 2002).

The start/test button is often referred to as the boost button – if this is frequently used the infusion will finish early. It is recommended that this button is only used when starting an infusion because it will not give a large enough bolus to provide additional symptom relief (Twycross et al 2002). Pressing the button once will move the syringe plunger forward by 0.23mm. This means that in a 20ml syringe with 150mg cyclizine a dose of less than 1.5mg would be given. It is more effective to have an anti-emetic available as required (PRN) to be given as a subcutaneous injection. Additional doses are then recorded, providing evidence of the efficacy of the current anti-emetic regimen.

Patient refuses to have a syringe driver There is a common misconception that syringe drivers are only used when death is approaching. While it is true that this approach is often used during terminal care, it is not the only reason for doing so. This is where nursing care is invaluable for the patient who may have been prescribed a recommended drug combination to alleviate the symptom, but is too frightened to co-operate. By spending time with the patient, explaining why this approach to symptom management is being used and exploring his or her anxieties, the nurse is ensuring that physical and emotional needs are being met.

Bowel obstruction

Bowel obstruction can be caused by intrinsic or extrinsic pressure by either a primary bowel cancer or metastatic abdominal and/or pelvic disease (Ripamonti and Bruera 2002). It can be a temporary problem but for many patients this may also signal that they are entering the terminal phase of illness.

Figure 2. The anti-emetic ladder

Assessment Patients will often describe a gradual worsening of symptoms rather than sudden onset. This may include a history of worsening constipation and colic, followed by loss of appetite, increasing nausea, fatigue and eventually vomiting (Rawlinson 2001).

Diagnosis Adding the patient’s history to abdominal swelling, intermittent abdominal pain (colic) and reduced (or even a complete absence of) bowel sounds will often be enough to suspect a bowel obstruction (Rawlinson 2001). However, radiological investigation should be considered to differentiate between constipation and malignant obstruction, and also to identify those patients who may be suitable for surgical intervention.

Surgery Palliative surgery should be considered for every patient with malignant bowel obstruction. However, not all patients are well enough to undergo this procedure or will live long enough afterwards to reap the potential rewards. Before offering surgery, the following should be considered (Hung 2000):

* Co-morbid conditions.

* Other metastases.

* Nutritional status.

* The presence of ascites.

* Recent chemotherapy.

* Recent pelvic or abdominal radiotherapy.

* The patient’s motivation and willingness to have surgery.

For the patient who is considered fit enough for surgery, there is still a risk of post-operative complications, including infection, poor healing and formation of fistulas (Rawlinson 2001).

Intubation The insertion of a nasogastric tube may be used as an adjunct to surgery. For those patients where this is not an option and who consequently have a poorer prognosis this is an invasive procedure. The use of antisecretory drugs – such as octreotide to reduce gastric secretions – and antiemetics frequently negate the need for intubation but where the obstruction is high or at multiple levels complete control of nausea and vomiting may be impossible to achieve. The option of intubation needs to be discussed with the patient who may prefer to undergo an invasive procedure rather than face the prospect of regular emesis (Baines 1998).

There are a small number of patients for whom a venting gastrostomy is an option, again where the obstruction is high or at multiple levels. However, the number of patients deemed inoperable but fit enough for this procedure is small.

For those patients where the obstruction cannot be removed or bypassed surgically, then control of physical symptoms and support during emotional distress become paramount. While most patients are aware of the palliative nature of their disease, a bowel obstruction may emphasise the enormity of this situation. These patients will have some important decisions to make.

Nutrition This can often provoke family conflict where the absence of eating can be seen to hasten death. This issue needs to be explored sensitively with the patient and his or her family. If the patient still enjoys eating normally and is prepared to accept vomiting afterwards, then he or she should continue to do so. However, if postprandial emesis and the resulting colic distress the patient, then to continue to eat will only reduce his or her quality of life.

Hydration This is another potential source of family conflict, which requires close consultation and emotional support from themultidisciplinary team. Artificial hydration should be considered if the patient’s prognosis is likely to be measured in weeks and if the frequency of vomiting inhibits oral hydration (Baines 1998).

Pharmacological management Control of pain, nausea and vomiting are the main objectives of any drug treatment offered. If the obstruction is thought to be incomplete, there is an absence of colic and the patient is still passing flatus, a combination of a corticosteroid (dexamethasone) and a prokinetic drug such as metoclopramide (which increases gastric emptying and reduces gastric volume) should be considered (Rawlinson 2001). As well as having an anti-emetic effect, dexamethasone will reduce peritumour oedema and potentially improve the patency of the bowel lumen (Twycross and Wilcock 2001). For a patient with a complete bowel obstruction, a prokinetic anti-emetic will increase colic and a corticosteroid will serve only to increase gastric acid production, causing the patient further discomfort (Baines 1998).

At this time, emesis may be inevitable but the size and frequency of any vomits can be reduced, pain can be managed and nausea reduced to the brief periods before vomiting. While bulk-forming, osmotic and stimulant laxatives (such as lactulose, senna and co- danthramer) should be stopped, it may still be necessary to offer a faecal softener and phosphate enemas to reduce any discomfort from the bowel below the obstruction (Rawlinson 2001).

The drugs that should be considered for managing symptoms in malignant bowel obstruction are outlined in Table 4. Figure 3 highlights the use of hyoscine butylbromide (an anticholinergic) and octreotide (a somatostatin analogue) in the management of bowel obstruction.

Table 4. Drugs for managing symptoms in malignant bowel obstruction

Case study

Alan was a 73-year-old man with squamous cell carcinoma of the lung and bone metastases. He was admitted a week after completion of five fractions of palliative radiotherapy to the lumbar spine with lower back pain, colic, constipation (bowels not open for seven days) and a three-day history of nausea and vomiting.

His medication included:

* Morphine sulphate tablets slow-release (30mg twice daily (BD)).

* Morphine sulphate solution immediate-release (10mg as required (PRN)).

* Diclofenac (50mg three times a day (TDS)).

* Cyclizine (50mg TDS).

* Lactulose(10ml BD).

Alan’s treatment Radiotherapy to the lumbar spine is a frequent cause of nausea and vomiting (Hoskin 1998). However, Alan had been given ondansetron 8mg daily for the duration of his radiotherapy and, as a result, had coped well with the treatment.

Blood tests revealed dehydration and hypercalcaemia. An abdominal X-ray showed constipation rather than an obstruction.

The initial treatment Alan received was:

* Intravenous (IV) hydration for 12 hours followed by IV zoledronic acid 4mg to treat the dehydration and hypercalcaemia, respectively.

* Administration of subcutaneous analgesia and anti-emetics. The syringe driver contained:

* Diamorphine 20mg

* Cyclizine 150mg.

* Diamorphine 5mg and levomepromazine 6.25mg were available subcutaneously as required.

Figure 3. Use of hyoscine butylbromide and octreotide in managing bowel obstruction

* All oral medication was stopped.

By day two, the patient’s nausea and vomiting had settled and pain control had improved. This early improvement in symptoms permitted the use of oral and rectal measures. The following were added to his prescription:

* Co-danthramer (dantron and poloxamer) 10ml BD.

* Daily phosphate enemas.

On day three, Alan’s appetite began to return and his bowels had been opened. As there had been no vomiting for the past 24 hours, it was safe to return to oral medication. This time the following drugs were prescribed:

* Fentanyl patch 25mcg.

* Morphine sulphate (Oramorph) 10mg PRN.

* Cydizine 50mg TDS.

* Etoricoxib 90mg OD.

Day four arrived with no new problems and so, after consultation with Alan and the oncologist, he was discharged home. A referral to the local specialist palliative care team was made and he was asked to have blood taken every two weeks to monitor his calcium levels.

On reflection it was easy to see why Alan had become so unwell and on assessment was displaying such distressing symptoms:

* Radiotherapy to the lumbar spine, incorporating a large area of the abdomen with an associated risk of nausea and vomiting. Ondansetron 8mg was prescribed to prevent this.

* This meant that Alan was on two constipating drugs (morphine sulphate and ondansetron), one drug causing gastric irritation (diclofenac) and with only lactulose available to prevent constipation.

* Increasing hypercalcaemia will also cause nausea, vomiting, dehydration and constipation (Bower et al 1998).

Rationale for Alan’s treatment For a patient who is already vomiting, oral anti-emetics will have no positive effect. It will also be virtually impossible to provide pain control if the absorption of the oral analgesics is compromised. Bypassing the oral route will ensure that the chosen drug regimen can be properly evaluated.

Once the treatment of the nausea, vomiting and pain has been optimised, the patient will feel able to take oral laxatives, to cope with rectal measures and to spend enough time on the toilet to have his bowels open. It would be unfair to ask a nauseated patient with poor pain control to attempt this.

Conversion to oral medication after 24 hours can be considered if nausea is no longer present and the patient is able to tolerate food. Transdermal fentanyl can be considered once pain has been controlled and studies have shown that it is approximately half as constipating as morphine sulphate (Evans 2003, Ripamonti and Dickerson 2001).

Co-danthramer is a stimulant and softener laxative and therefore is a more appropriate drug for a patient taking opioid analgesics (Twycross et al 2002). Etoricoxib, as a member of the new group of COX-2 anti-inflammatory drugs, will offer a reduced risk of gastrointestinal side effects.

Less common treatments

Not suprisingly, a heavy reliance is placed on antiemetics in the management of nausea and vomiting but this is a science that many patients can find bewildering. Non-drug therapies, as well as acting as adjuvant anti-emetics will also enhance the patient’s sense of control and provide an opportunity to actively participate in his or her treatment.

Diet Constipation is a major problem and good dietary advice can prevent it becoming so again. Taste changes are a common side effect of oncological treatments (Ventafridda et al 1998) and different foods need to be tried to see what is acceptable to the patient.

Smells from certain foods may need to be avoided and a side room may be helpful for these patients. Some patients will find carbonated drinks helpful in releasing trapped wind; others have experienced the positive effects of ginger as a herbal remedy (Ernst and Pittler 2000).

Complementary therapies Complementary therapies are used alongside orthodox therapies and are generally given to provide relief of physical and emotional symptoms.

There remains a paucity of randomised controlled trials with good data to support the use of therapies such as reflexology, guided imagery and acupuncture. More qualitative data are available but visit any day hospice and you will also be provided with plenty of anecdotal evidence (NICE 2004).

Cognitive therapy has been used to reduce the psychological morbidity associated with nausea and vomiting, and techniques such as progressive muscle relaxation and guided imagery can provide the patient with coping mechanisms (Kohn 1999).

Cannabis There is much anecdotal evidence about the benefits and pitfalls of using this drug. It is difficult to encourage its use when it is illegal and unpredictable in its strength and efficacy. However, patients may ask about this drug and enquiries should be handled sensitively.

The nearest comparative drug is nabilone, which is classed as a cannabinoid. Tramer et al (2001) conducted a quantitative systematic review of the use of these drugs in nausea and vomiting induced by chemotherapy. They concluded that they were often superior to conventional anti-emetics after chemotherapy but that the side- effect profile – drowsiness, euphoria, inability to concentrate – would limit their use.

Oral hygiene

One of the most basic but also one of the most important aspects of nursing care is oral hygiene (Macmillan Practice Development Unit 1995), yet this task is frequently allocated to junior or unqualified staff (Crosby 1989).

Simple but regular measures can have a significant impact on oral hygiene, without resorting to complex regimens with strong- flavoured oral rinses (Yarbro et al 1999).

Frequent exposure of the oral mucosa and teeth to the acidic contents of the stomach as a result of prolonged and repetitive emesis may lead to further symptoms and a deterioration in quality of life.

Oral assessment, prompt recognition and treatment of problems, and good oral hygiene should be undertaken to prevent potentially life-threatening infections and maintain the patient’s quality of life (Honnor and Law 2002). Dental implications from repeated vomiting include loss of enamel and, in severe cases, exposure of the nerves leading to temperature sensitivity and pain.

Oral hygiene goals should include cleanliness, comfort and prevention of infection caused by uncontrollable side effects of therapy. To achieve these goals, nurses should identify patients with the potential to develop oral complications as early as possible. When developing a plan of care for the patient, the nurse should ensure that it is simple and realistic (Madeva 1996). This needs to take into account what the patient feels able to tolerate and how soon after vomiting the oral hygiene takes place.

Conclusion

Nausea and vomiting can have many causes including various oncology treatments, medication and disease progression. The\re will be times when a combination of these is responsible for the symptoms; however, for the patient they will all have an impact on quality of life.

Patients experiencing nausea often feel too ill to complain, so the first indication for healthcare professionals that there is a problem may be when vomiting starts.

Nausea and vomiting require careful assessment to identify the often multiple causes. A plan of action that the whole multidisciplinary team works to, daily reassessment of the patient and a strategy for future prevention and management are essential to effective management of nausea and vomiting. Accurate assessment of the patient is the key to good practice, spending time with the patient to gain an understanding of his or her perception of the symptoms and the effectiveness of the treatment offered is also important.

Nurses are often the healthcare professionals closest to the patient so are in a position to carry out and assess the treatment plan, but more importantly to explain it and offer support to patients and their families

Test your knowledge and

This self-assessment questionnaire (SAQ) will help you to test your knowledge. Each week you will find ten multiple-choice questions broadly linked to the continuing professional development (CPD) article. The answers might not be found in the article itself and you may wish to use reference books to assist you.

Note: There is only one correct answer for each question.

How to use this assessment

There are several ways that you can make use of this assessment.

* You could test your subject knowledge by attempting the questions before reading the article, and then go back over them to see if you would answer differently.

* Alternatively, you might like to read the article to update yourself before attempting the questions.

* The answers will be published in Nursing Standard in two weeks’ time.

Prize draw

Each week there is a draw for correct entries. If you wish to enter, send your answers on a postcard to:

Nursing Standard, The Heights, 59-65 Lowlands Road, Harrow-on- the-Hill, Middlesex HA1 3AE, or via email to: [email protected]

Ensure you include your name and address and the SAQ number. This is SAQ No 266. Entries must be received by 10am on Tuesday November 16. This week’s successful entrant will receive 50 in book tokens.

* When you have completed your self-assessment, cut out this page and add it to your professional portfolio. You can record the amount of time it has taken you, and don’t forget to include any time spent consulting other sources to find answers. Space has also been provided for you to add any comments and additional reading you might have undertaken.

* If you wish to further your professional development, you might consider writing a practice profile, see page 56.

Online archive

For related articles visit our online archive at: www.nursing- standard.co.uk and search using the key words above.

NS266 Thompson I (2004) The management of nausea and vomiting in palliative care. Nursing Standard. 19, 8, 46-53. Date of acceptance: September 24 2004.

TIME OUT 1

Reflect on a patient you have cared for who was experiencing nausea and vomiting. Compare the care that was given for the physical aspects of these symptoms with the emotional and psychological support the patient received.

TIME OUT 2

Try to remember the last time you experienced nausea and vomiting. Write down how you felt physically and emotionally at the time.

TIME OUT 3

List what you perceive to be the advantages, disadvantages and potential complications associated with using a subcutaneous syringe driver to administer anti-emetics.

TIME OUT 4

Read the case study. Before reading on, list what measures should be undertaken in the first 24 hours of Alan’s admission to find the cause of his symptoms and to gain effective management of them.

TIME OUT 5

Consider what practical measures a nurse can implement to support the patient with nausea and vomiting. This could include addressing issues of privacy, oral hygiene and the ward environment.

TIME OUT 6

List what you consider to be the actual and potential implications of nausea and vomiting for terminally ill patients. This should include the physical and psychological effects and the implications for ongoing disease management.

TIME OUT 7

Now that you have completed the article you might like to write a practice profile. Guidelines to help you are on page 56

REFERENCES

Baines M (2000) The ABC of Palliative Care. London, BMJ Books.

Baines M (1998) The pathophysiology and management of malignant intestinal obstruction. In Doyle D et al (Eds) Oxford Textbook of Palliative Medicine. Second edition. Oxford, Oxford University Press.

Bonwick H (2003) Guidelines for the Management of Bowel Obstruction in Advanced Cancer. The Liverpool and Cheshire Palliative Network Audit Group. Standards and Guidelines. Second edition. Liverpool, Marie Curie Centre.

Bower M et al (1998) Endocrine and metabolic complications of advanced cancer. In Doyle D et al (Eds) Oxford Textbook of Palliative Medicine. Second edition. Oxford, Oxford University Press.

Bruera E et al (1991) The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. Journal of Palliative Care. 7, 7, 6-9.

Coackley A, Skinner J (2003) Guidelines for the Management of Nausea and Vomiting in Palliative Care. The Liverpool and Cheshire Palliative Network Audit Group. Standards and Guidelines. Second edition. Liverpool, Marie Curie Centre.

Crosby C (1989) Method of mouth care. Nursing Times. 85, 35, 38- 41.

Dickman A (2003) Care of the Dying: A Pathway to Excellence. Oxford, Oxford University Press.

Dickman A, Littlewood C (1998) The Syringe Driver in Palliative Care. Fifth edition. Oxford, Oxford University Press.

Ernst E, Pittler M (2000) Efficacy of ginger for nausea and vomiting: a systematic review of randomised clinical trials. British Journal of Anaesthesia. 84, 3, 367-371.

Evans R (2003) The effectiveness of transdermal fentanyl in palliative care. Nursing Times. 99, 41, 24-25.

Flower R (2003) The development of COX2 inhibitors. Nature Reviews. Drug Discovery. 2, 3, 179-191.

Honnor A, Law A (2002) Mouth care in cancer nursing: using an audit to change practice. British Journal of Nursing. 11, 16, 1087- 1096.

Hoskin P (1998) Radiotherapy in symptom management. In Doyle D et al (Eds) Oxford Textbook of Palliative Medicine. Second edition. Oxford, Oxford University Press.

Hung W (2000) Management of gastrointestinal obstruction in advanced cancer. Palliative Care Today. 9, 3, 39-41.

Kohn M (1999) Complementary Therapies in Cancer Care: Abridged Report of a Study Produced for Macmillan Cancer Relief. London, Macmillan Cancer Relief.

Lichter I (1993) Results of anti-emetic management in terminal illness. Journal of Palliative Care. 9, 2, 19-21.

Lugton J (2002) Communicating with Dying People and Their Relatives. Oxford, Raddiffe Medical Press.

Macmillan Practice Development Unit (1995) Managing Oral Care Problems Through the Cancer Illness Trajectory, London, Macmillan Cancer Relief/The Royal Marsden.

Madeva M (1996) Oral complications from cancer therapy. Part two. Nursing implications for assessment and treatment. Oncology Nurses Forum. 3, 5, 808-819.

Mannix K (1998) Palliation of nausea and vomiting. In Doyle D et al (Eds) Oxford Textbook of Palliative Medicine. Second edition. Oxford, Oxford University Press.

Miller M, Kearney N (2004) Chemotherapy-related nausea and vomiting: past reflections, present practice and future management. European Journal of Cancer Care. 13, 1, 71-81.

Morrow G, Rosenthal S (1996) Models, mechanism and management of anticipatory nausea and vomiting. Oncology. 53, Suppl 1, 4-7.

National Institute for Clinical Excellence (2004) Improving Supportive and Palliative Care for Adults with Cancer. London, NICE.

Rawlinson F (2001) Malignam bowel obstruction. European Journal of Palliative Care. 8, 4, 137-140.

Ripamonti C, Bruera E (2002) Gastrointestinal Symptoms in Advanced Cancer Patient. Oxford, Oxford University Press.

Ripamonti C, Dickerson E (2001) Strategies for the treatment of cancer pain in the new millennium Drugs. 61, 7, 961.

Saltzman E et al (2003) Measuring nausea, vomiting and retching: the Modified Rhodes Index of Nausea and Vomiting Short Version for Research and Clinical Use. Oncology Nursing Forum. 30, 2, 127.

Tramer M et al (2001) Cannabinoids for control of chemotherapy- induced nausea and vomiting. British Medical Journal. 323, 7303, 13- 16.

Twycross R (1999) Guidelines for the management of nausea and vomiting. Palliative Care Today. 5, 4, 32-33.

Twycross R, Wilcock A (2001) Symptom Management in Advanced Cancer. Third edition. Abingdon, Radcliffe Medical Press.

Twycross R et al (2002) Palliative Care Formulary. Second edition. Oxford, Radcliffe Medical Press.

Ventafridda V et al (1998) Mouth care. In Doyle D et al (Eds) Oxford Textbook of Palliative Medicine. Second edition. Oxford, Oxford University Press.

World Health Organization (1990) Cancer Pain Relief and Palliative Care. Technical Report Series 804. Geneva, WHO. www.who.int/cancer/palliative/ definition/en/ (Last accessed: October 25 2004.)

World Health Organization (1986) Cancer Pain Relief. Geneva, WHO.

Yarbro C et al (1999) Cancer Nursing: Principles and Practice. Fourth edition. Massachusetts, Jones and Bartlett.

In brief

Author

Iain Thompson RGN, is Macmillan palliative care clinical nurse specialist, Clatterbridge Centre for Oncology, Wirral.

Email: [email protected]

Copyright RCN Publishing Company Ltd. Nov 3-Nov 9, 2004

The Metamorphosis of the Quality Professional

Perhaps I’m about to preach to the faithful, but I really sense not too many quality professionals are actively pursuing continual professional development.

If what I’m going to say is old stuff to you, I apologize. However, you might stay with me a while longer and see if there is a gem or two worth noting. The rest will find most of the suggestions strike a bell-the bell of negligent indifference.

We are all in the midst of the most impactful, world shaking changes ever to confront the people on planet Earth. Look around you. Who isn’t in fear of something, be it war, the weather, dealing with technology that appears to change every nanosecond, out-of- sight medical costs, stronger strains of virulent diseases and possible job loss? Add religious, political and family turmoil-and the list goes on.

The following captures the essence of what faces each of us as a new day dawns:

Every morning in Africa, a gazelle wakes up knowing it must run faster than the fastest lion or be killed.

Every morning a lion awakens knowing it must outrun the slowest gazelle or starve to death.

It doesn’t matter if you are a lion or a gazelle, when the sun comes up, you’d better be running.

Martis Jones’

You owe it to yourself and to any others for whom you provide financial support to stay on top of your game, foresee the world and local events that could upset your equilibrium and take a proactive approach to being ready. What does this mean for the quality professional?

First, I predict the roles of quality professionals (quality manager, quality engineer, quality inspector and so on) will nearly disappear within the next eight to 10 years. The duties not taken over by advanced technology will be absorbed into the product or service realization processes. Quality as an entity will be subsumed, with only tiny vestiges remaining of the now multiarmed profession.

In terms of the Kano model,2 quality will move (if it hasn’t already) from being a delighter to being a “must have” and an integral part of the mainstream value chain-much as the factory installed cup holder first delighted auto buyers, then gradually moved into the must-have category.

Quality managers and quality engineers will, if they are prepared, metamorphose to project managers, executive positions or roles in other functional areas. To make the transition, survivors from the present quality profession will have to learn a new language -the language of management-and acquire new competencies.

Competency consists of five factors (see Figure 1, p. 24):3

* Knowledge: Formal education, degrees, educational certifications, professional certifications and self-study achievements.

* Experience: Years spent applying knowledge and skills in types of organizations, kinds of industries and jobs and positions held.

* Skills: Skill certifications, training received and demonstrated proficiency in use of pertinent tools and equipment.

* Aptitude: Natural talent, capability, capacity, innate qualities, deftness, knack, adaptability to change, natural ability to do things requiring hand-eye coordination and fine-motor-skills.

FIGURE 1 The KESAA Factors

FIGURE 2 KESAA Requisites Analysis

FIGURE 3 Overall Competence

* Attitude: Manner of showing one’s feelings or thoughts, disposition, opinion, mood, ideas about an issue, belief, demeanor, condition of mind, reaction, bias, inclination, emotion, temperament, mental state and ease in accepting and adopting new or changed plans and practices.

Using the KESAA Factors, complete a KESAA Requisites Analysis for your present position ( see Figure 2).

This KESAA Requisites Analysis represents your baseline. Begin your strategic planning for your future position or work role. Look ahead five to 10 years from today. Take some time to think through what KESAA Factors will have to change to meet your future goal, and do one or more KESAA Requisites Analyses for each of the potential future positions you will hold on your journey to your goal.

The difference between where you are today and where you plan to be in the future represents the gap you need to work on. Let’s now use the mind maps in Figures 3 through 8 to look at some of the additional competence requisites you may wish to consider:

* Overall competence categories.

* Technical competence.

* Business competence (p. 26).

* People competence (p. 29).

* HR competence (p. 30).

* Environmental competence (p. 31).

Caution: The maps are not intended to be all-inclusive but merely indicative of the range of competence.

FIGURE 4 Technical Competence

Technical Competence

The technical competence area is very fluid-changing rapidly as new technologies are added or replace existing technologies. Figure 4 maps some of the technologies known at this time.

It will be important to promptly add new or changed technologies to your competence bank as each becomes pertinent to your professional development. As a quality professional, you should be familiar with most of these current technologies.

Business Competence

As you emerge from your present cocoon, you will need to expand your competence range from the current narrow, quality oriented perspective. It will be increasingly important for you to acquire competencies in how businesses are planned, managed and measured. You will need to understand and speak the language of management.

In the book used to assist individuals in preparing to take the ASQ certified quality manager examination,4 there is advice to:

* Think of yourself as a corporate director of quality for a multifacility business entity.

* Think of yourself as having to integrate the needs of the quality assurance function with the needs of the management team and all other business processes.

* Always think plan-do-check-act.

* Develop an understanding of how all the elements of the certified quality manager body of knowledge are interrelated.

Quality expertise is or should be inherent in every line listed on Figure 5 (p. 26). Areas that loom large for the near term are developing competencies in project management, customer relations management, lessening the negative impact of outsourcing to other countries and supply chain management.

More and more organizations will be built around projects. Some businesses are already entirely project oriented. Developing your competency in project planning, project management, and project measurement and evaluation is an excellent way to break out of the purely quality oriented milieu.

FIGURE 5 Business Competence

Serving first as a project team member and ultimately positioning yourself to assume a project manager role helps you:

* Gain exposure to a wider range of business functions and the people responsible for these activities.

* Build your knowledge and hone your skills in planning and managing a business within the business.

* Be in the spotlight by being associated with a project important to achieving the strategic objectives of the organization.

* Become an executive-in-training for that bigger and better role in the future.

With the dwindling of middle management positions, ask yourself, where do you get the training and competencies needed to become a vice president or president of an organization? Project management competency is an excellent step in the right direction.

Accounting and finance in general were never your thing? Can’t make sense of an annual report? Well, dear reader, if you’re aspiring to a role beyond quality control, you’ll need to know more than how to balance your checkbook and establish a household budget (you do know how to do that, right?).

Money enables the business to carry on its work. Budgeting enables the appropriate allocation of monies to the activities of the business. Investing enables the procurement of additional funds beyond those generated by business operations. Investing also enables warehousing of funds through interest producing entities for future contingencies.

Accounting aids in keeping track of how the business’s money has been used and provides measurement information for executive decision making. Accounting also provides the analysis and reports that are officially made to the business owners, government and the public (if the business is publicly owned).

Does your business have a strategic plan? If so, have you seen and read it? Establishing strategy and the plans to carry out the activities that will fulfill the strategic needs is a primary function of senior management. Understanding the strategic planning process, as it is practiced and could be practiced and the influence it has or should have on the entire organization is key to your professional development. Every activity engaged in by the organization should be traceable to the strategic objectives. (This is not always the case, leaving an opportunity for improvement.)

It is important to understand and appreciate relations with customers, suppliers, employees and business owners. Without the synergy among these constituencies, business would not function, or not well.

It is vital to understand the basic functions of the business: marketing, engineering, production and support functions, such as finance, HR and legal affairs, and the interaction among these functions.

If a model doesn’t exist, create one of your business and plan to gain some level of competency in each function. Understand how your business organization is structured, what characterizes its culture, how the culture developed a\nd what the predominant managing style is.

Pay attention to the effect of mergers, acquisitions, divestitures and closings. Understand the ramifications of these extreme events on the future well-being of the organization and the people affected. These decisions, often financially driven and made by top level executives, are seemingly executed without a thorough risk assessment of the impact on customers, suppliers, employees and the owners if the company is public.

Know and understand the principal metrics used for high level decision making.

Traditionally, business decisions have been based on past experience, intuition and financial data. Reliance was placed on indicators that were lagging behind reality (experiences of a bygone time and reports detailing financial data at least one and a half to three months old). What was needed was more emphasis on a balance between lagging and leading indicators.

Additionally, financial figures reflect only one perspective of business. Robert S. Kaplan and David P. Norton proposed a balanced scorecard5 that integrated the scorecard with managing business strategy. The elements measured and presented in the scorecard represent the best elements needed to present a balanced view of the business, for example:

* Financial factors.

* Customer factors.

* Internal factors.

* Organizational learning factors.

Richard Y. Chang and Mark W. Morgan have presented a measurement process they call performance scorecards.6 Clearly, scorecards, sometimes called dashboards, recognize the need for making decisions based on a balanced perspective of the business.

Mark T. Czarnecki reviews a number of measurement processes and programs leading to the concept of benchmarking measurement programs with other businesses and ultimately reengineering an organization’s programs for greater effectiveness.7

The term “language of business” is steadily creeping into the literature. What does this mean? In Quality Progress, Stephen George, following the thinking of J.M. Juran, discusses what matters most to senior management and how quality professionals can align their actions with those of executives by speaking the same language of business.8

Look again at the list in Figure 5 and ask yourself two questions:

1. Do I have a working competence in all these elements of business?

2. In what areas should I develop a competency to position myself for future changes?

There are two examinations for business management certifications you may wish to investigate:9

1. The certified associate business manager focuses on helping individuals master business management principles and can serve as a diagnostic tool to determine strengths and weaknesses in business management knowledge. With content on a level of a bachelor’s degree course of study, the four-hour exam covers 200 questions and touches on 98 topics.

2. The certified business manager focuses on advanced business applications. The three-part, nine-hour exam has 400 questions covering 168 topics. The content is at master’s degree level.

People Competence

Developing your competence in communicating with people is at least as important as technical and business competence.

Consider two examples from Simplified Project Management for the Quality Professional.10 Naive Harry demonstrates a basic lack of people competence. Paula displays a relatively uncommon understanding of human behavior and attitude.

Harry is a newly hired graduate quality engineer in his first week on the job. He observes a major bottleneck in his employer’s order fulfillment process. As an avid student of the theory of constraints and the techniques involved, he knows without any doubt a change could shorten cycle time from two weeks to three days.

Harry scribbles a few notes on paper and tells his boss about his great new idea. He is stopped short as the boss tells him, “You’re too new on the job to be messing with that stuff; that’s not your job.”

Harry is shot out of the water before getting to the third sentence. What mistakes did this now disillusioned but initially enthusiastic quality engineer make? He:

* Presented it as his brilliant idea.

* Did not have a plan to seek his boss’s viewpoint on the bottleneck situation before mentioning the idea.

* Had no facts to substantiate the idea.

* Had no rationale for spending time on something not his official job or concern.

* Had little concept of what it might take to implement the change or its potential impact, either negative or positive.

* Had poor timing (too little time on the job to build a good performance record).

* Had not taken the time and effort to understand what the boss might view as important, what the boss’s needs might be and on what criteria the boss was measured by his superior (for example, finding the hot button).

* Was too new to have gained friends in the organization and therefore had no known supporters for the idea.

* Had no knowledge, skill or experience in planning and managing a project and therefore would have been an unlikely person to be allowed to run the project if he had gotten that far.

Assuming the zealous engineer’s perception was correct, but a plan did not get off the ground, who lost out? Harry did and the company did. They both lost because Harry did not know how to create and sell the vision.

If it were possible to compile a list of the rejected opportunities passed up by organizations because the ideas and visions were never sold properly, the list would startle all of us.

Another example is Paula, a quality engineer at Omega Bearings, who learned approval for a new expenditure of any magnitude required making a presentation to the president and his direct reports (top management). Paula was not high in the organization’s hierarchy.

However, Paula took a very proactive approach to her job and constantly looked for ways Omega could improve both its quality and productivity. For example, in performing a quality management system process audit, Paula observed a deficiency in the audited process that often resulted in mistakes in communicating customer order requirements.

Over several weeks of performing her regular duties, Paula found time to talk with some of the people involved in the process in question, gathered some opinions and facts and got support for a change, provided she took the initiative to propose the change. She analyzed her data, spoke with the finance people about how to estimate the value of the change and picked up some pointers on how to present the financial impact.

Paula discussed the observations with her boss, received his suggestions and gained his support, including permission to contact top management. She then visited “all the president’s men” and solicited their suggestions on what to do. Out of five top management members, Paula was able to gain committed support for her vision from three. Paula then asked the art department for help in creating presentation materials.

With a mock-up of her presentation, Paula went separately to her boss and the three top level supporters to give each a run-through of what they could see at the next funding meeting. She emphasized how she had incorporated their suggestions. After receiving constructive criticism and making finishing touches, Paula gave her boss a trial run of the presentation and asked him to arrange an appointment for her to present the proposal to top management. The project was approved, and Paula was designated project manager.

What happened? All the president’s direct reports had been exposed to the vision in advance and had been asked for suggestions and support. During the meeting it was clearly evident that three of them had immediately bought in and were supporting the vision from the outset. Following Paula’s presentation, the remaining two top management members nodded their approval. The president approved the initiation of the project. A done deal.

Paula, virtually unknown to top management, successfully sold her vision by carefully covering the bases up front. Intuitively or otherwise, she knew you couldn’t spring something new on people, especially if you were an unknown, without doing your homework first. She also knew she needed hard facts to prove her case and that those numbers must correlate with the criteria by which the people she was selling the idea were evaluated. And, she needed full support from her boss.

These two real situations (names disguised) point out people competence is the combination of knowledge plus experience plus skills plus attitude plus aptitude. While you may not yet have matured sufficiently to have the experience for addressing a particular task, you need the people skill to seek out those who do have the experience to help you.

Further, you must always stop and consider answering the spoken or unspoken question from the people whom you ask for support: “What’s in it for me?”

W. Edwards Deming’s system of profound knowledge” contains four interrelated parts:

1. Appreciation for a system.

2. Knowledge about variation.

3. Theory of knowledge.

4. Psychology.

People live within systems and their behavior is influenced by these systems. As quality professionals we, I hope, acknowledge the presence of variation in everything. The theory of knowledge predicts future outcomes, with the potential risk the prediction may be wrong. Further, Deming teaches information is not knowledge, and integrating psychology facilitates understanding people and the interactions between them.

FIGURE 6 People Competence

Because of differences among people, people learn differently. They express love and devotion differently. They are motivated by different events, words and actions-differently at different times and in different situations.

FIGURE 7 HR Competence

The phrase “Different strokes for different folks” sums it up. What do you need to do to build your people competency? Look at the brief but developing list in Figure 6 (p. 29) and note the area\s for which you need to gain competency to reach your goals.

HR Competence

You will need to develop a modicum of competency in the legalities and the consequences for not abiding by the law as this relates to HR. You will need expertise in making quality selections of people as well as training. It is not enough to have knowledge in these areas; you need application experience-for example:

* Can you conduct an in-depth needs analysis to determine training required?

* Can you design a training program or select an external provider’s training program that will produce the desired outcomes from the trainees?

* Can you differentiate between skills training and management training and know why there is a difference?

* Can you effectively evaluate the outputs and outcomes of a training program?

Do you have competency in determining the relative effectiveness of various approaches to recognition and rewards? And, how would you prepare yourself to aid in the professional development of people for whom you have responsibility? Do you comprehend the relative merits and disadvantages of the myriad compensation systems and schemes?

Check the list in Figure 7 for areas in which you need to develop further competence, and make your plans to do so.

Environmental Competence

At first mention, people tend to think of this area of competency as pertaining mostly to air, trees, water and land use. It’s much more. We live and work in the environment. We affect and are affected by the environment. What we learn and experience about this environment enables us to adjust to changes.

A process called environmental scanning equips the astute person and organization with the competence to cope with the rapid changes that, if not detected, can mean unpreparedness, disasters or missed opportunities.

Make it your practice to spend some time each day scanning the environment. Newspapers, radio, TV, the Web, internet forums and magazines are just some of the ways to stay in touch with the environment. Read widely, listen closely and observe behavior.

Figure 8 provides a mind map of world, political, geographical and competitive environments that should be of concern.

Reinvent Yourself

I’ve taken you on a long trip and into many areas not normally your area of expertise or interest. Do I feel strongly you should develop some level of competency in each of the five areas? Yes, I do. Do I believe the areas I’ve presented are the only ones that will be important to you five to 10 years along your journey? No, I don’t.

Certainly whole new areas will be added, some will be replaced along the way, and others will be dropped entirely or subsumed into another area. Furthermore, your personal professional objectives will change.

The modus operandi I’ve adopted is to constantly reinvent myself to meet new and emerging opportunities. The current statistics indicate the average college graduate will face 13 job changes and seven profession or career changes during his or her worklife. I’ve already held more than 13 jobs but am only in my sixth career. Guess I’m a little behind on career changes.

I am continually dismayed with a number of my quality profession colleagues, especially the younger ones, who can’t seem to see the changes occurring and fail to prepare themselves. You owe it to yourselves and your families to continually broaden your perspective.

It’s never too late, so stop ignoring the obvious and do something about it.

FIGURE 8 Environmental Competence

Please comment

If you would like to comment on this article, please post your remarks on the Quality Progress Discussion Board at www.asq.org, or e-mail them to [email protected].

In 50 Words Or Less

* Quality professionals must not ignore the obvious changes that will affect them.

* Their roles will nearly disappear or be subsumed into other processes within the next 10 years.

* These changes demand continual development to increase technical, business, people, HR and environmental competence.

Gain exposure to a wider range of business functions and the people responsible for these activities.

If it were possible to compile a list of the rejected opportunities passed up by organizations because the ideas and visions were never sold properly, the list would startle all of us.

REFERENCES AND NOTES

1. Martis Jones, The Prodigal Principle, Worth Publishers, 1995.

2. Professor Noriaki Kano’s ideas concerning the three definitions of quality were published in Japan in 1984. Terry G. Vavra describes Kano’s analysis and classification scheme in Improving Your Measurement of Customer Satisfaction, ASQ Quality Press, 1997.

3. “KESAA Factors,” 2003 R.T. Westcott & Associates.

4. Duke Okes and Russell T. Westcott, editors, The Certified Quality Manager Handbook, second edition, ASQ Quality Press, 2001.

5. Robert S. Kaplan and David P. Norton, The Balanced Scorecard, Harvard Business School Press, 1996.

6. Richard Y. Chang and Mark W. Morgan, Performance Scorecards: Measuring the Right Things in the Real World, Jossey-Bass, 2000.

7. Mark T. Czarnecki, Managing by Measuring: How To Improve Your Organization’s Performance Through Effective Benchmarking, Amacom, 1999.

8. Stephen George, “How To Speak the Language of Senior Management,” Quality Progress, May 2003.

9. Information about the exams and the Assn. of Professionals in Business Management organization may be obtained at www.cbmexam.com, [email protected] or 323-903-6757.

10. Russell T. Westcott, Simplified Project Management for the Quality Professional, ASQ Quality Press, 2004.

11. W. Edwards Deming, The New Economics: For Industry, Government, Education, second edition, Massachusetts Institute of Technology, Center for Advanced Educational Services, 1994.

RUSSELL T. WESTCOTT is president of the Offerjost-Westcott Group, a division ofR.T. Westcott & Associates, in Old Saybrook, CT, specializing in providing work life planning, guidance and coaching. Westcott wrote Stepping Up to ISO 9004:2000 and co-edited The Certified Quality Manager Handbook, second edition, the Certified Quality Manager section Refresher Training Course and The Quality Improvement Handbook. He is an ASQ Fellow, certified quality auditor and certified quality manager. He serves on the ASQ Thames Valley section’s executive board as newsletter editor and job leads chair.

Copyright American Society for Quality Oct 2004

Biochemical Recovery Time Scales in Elderly Patients With Osteomalacia

SUMMARY

Osteomalacia is not rare in the UK and climatically similar countries, particularly in elderly people and those of Asian descent. Overt clinical osteomalacia is usually treated with a loading dose of vitamin D, followed by a regular supplement. However, little is known of the time taken to reach a stable biochemical state after starting treatment. Such information would shed light on the duration of the bone remineralization phase and guide decisions on the length of follow-up. To address this we conducted a 2-year follow-up study of 42 patients (35 female, mean age 80.8 years) with biopsy proven osteomalacia treated with a standard replacement regimen and general nutritional support.

Although normocalcaemia was attained within 4 weeks the mean values continued to rise, to a mid-range plateau at 52 weeks. The phosphate and alkaline phosphatase values also took at least a year to reach a stable mean, with a slight further trend towards the mid- range for the entire 104 weeks. The mean serum albumin also rose throughout the first 52 weeks, indicating an effective response to the general nutritional support measures.

Our observations suggest that the dynamic relationship between calcium, phosphate and bone requires at least a year, and probably longer, to reach an equilibrium after treatment for osteomalacia in elderly patients. The findings emphasize the need for close medical and social follow-up in this clinical context.

INTRODUCTION

Osteomalacia is a generalized disorder of bone in which impairment of mineralization results in the accumulation of unmineralized osteoid. Vitamin D deficiency is the major cause, usually as a result of dietary lack, inadequate exposure to sunlight, or both. In childhood this leads to classical rickets, now rare in the UK and similar developed northern countries because of improved nutrition. Conversely, osteomalacia in adults is not an uncommon condition, and there is ample evidence that frail elderly patients arc particularly at risk,1,2 mainly as a result of suboptimal skin exposure to sun.3,4 Elderly Asians living in Britain probably have an even higher prevalence of osteomalacia because of an adverse diet, darker skin and traditional dress codes.5 Osteomalacia predisposes to bone fracture, skeletal deformity and bone pain.4 The underlying low levels of active vitamin D also lead to muscle weakness, myalgia and symptomatic hypocalcaemia.6 Furthermore, less overt manifestations of vitamin D undernutrition, such as persistent low-level muscle aching, can occur in patients over a wide range of ages and skin pigmentation levels in northerly latitudes.7 Even in areas of high average sunlight duration, frail patients and people with poor nutrition and low skin exposure are at high risk.8

Though osteoporosis is the main risk factor for fracture of the neck of the femur, a proportion of such patients prove to be osteomalacic-less than 1% in one study where strict histomorphometric criteria were applied.9 The gold standard for the diagnosis of osteomalacia is a bone biopsy showing an excess of osteoid and subnormal number of calcification fronts. The usual criteria are an osteoid scam width of greater than 13 microns, osteoid surfaces more than 24% and mineralizing surfaces less than 60%.10 Supportive biochemical changes include low serum calcium and phosphate concentrations, a low serum 25-hydroxyvitamin D and high blood levels of parathyroid hormone and alkaline phosphatase. Patients do not always have all these findings,11 and the usefulness of serum 25-hydroxyvitamin D assays in elderly individuals has been questioned on the grounds that low levels are found in patients with and without osteomalacia.12 Nevertheless, there is evidence that vitamin D subnutrition, defined in terms of an abnormally low scrum 25-hydroxyvitamin D, is a predisposing factor for accelerated osteoporosis in elderly people in developed countries.13

When a patient is proven to have osteomalacia in the context of fractured neck of femur it is mandatory to treat the deficient state with vitamin D replacement. If the deficiency is due to dietary lack and/or low sunlight exposure the usual regimen is an intramuscular loading dose of 300 000 units (7.5 mg) vitamin D followed by an oral supplement of 400-800 units daily, though recommendations vary and large-scale trial evidence is lacking. Certainly such doses will return serum 25-hydroxyvitamin D concentrations to the normal range and in most patients normalize the serum calcium and phosphate concentrations.14 However, there are no published data about the pattern of recovery of serum calcium, phosphate and alkaline phosphatase, and the associated symptoms and mobility, over subsequent months. Such information would help to guide nutritional support regimens. Therefore, we conducted an open observational longitudinal study of the rate and duration of the recovery phase of those biochemical indices in elderly patients with fractured neck of femur and proven osteomalacia surviving at least 2 years after the fracture while receiving standard vitamin D replacement and nutritional support.

METHODS

We prospectively studied 42 patients (35 female) with a mean age of 80.8 years (range 66-99). All were admitted to hospital urgently for a fractured neck of lemur and underwent operative management. Patients were selected consecutively from a group of patients who had a bone biopsy performed at the time of operation for diagnostic purposes because of a suspicion of osteomalacia or malignancy. Patients were included in the study if they had a biopsy positive for osteomalacia (according to the criteria specified in the Introduction), a low serum calcium (corrected to the equivalent at a scrum calcium of 40g/L) and a raised scrum alkaline phosphatase at presentation. For the purposes of analysis, only patients surviving the 2-year follow-up were included. The total number of patients admitted with a fractured neck of femur was 4050 over a 9-year period, 222 (5.5%) of whom were suspected of being vitamin D deficient on radiological, clinical and/or biochemical grounds. 77 (1.9%) were proven to have ostcomalacia by bone biopsy and 42 (1.03%), the study group, survived and attended the 2-year follow- up. We excluded patients with chronic renal failure (serum crcatinine >200 mol/L), coeliac disease or overt malabsorption, severe co-pathologies likely to result in an early death, phenytoin therapy and known primary parathyroid disorders.

The study group had measurements made of serum calcium, phosphate, albumin, alkaline phosphatase, haemoglobin, urea, sodium and potassium at presentation (week 0) and at 2, 4, 6, 8, 12, 24, 36, 52, 76 and 104 weeks, during inpatient treatment and subsequent follow-up in a day hospital or clinic. The timing of the follow-up biochemical samples began with the first dose of vitamin D. All received a starting replacement dose of 7.5 mg (300 000 IU) vitamin D by intramuscular injection at the beginning of the study period, a mean of 6 days postoperatively. In most cases this was on clinical suspicion of osteomalacia while biopsy confirmation was awaited. This was followed by an oral supplement of 800 IU daily in the form of calcium and vitamin D combined tablets (plain vitamin D was not available). All were given general nutritional information and advice, with support in the form of meals-on-wheels, luncheon clubs and assisted shopping when appropriate, and with reinforcement during follow-up contacts. All patients proceeded down our usual rehabilitation track for fractured neck of femur, with a wide range of functional outcomes. We also obtained narrative data from the case notes and during follow-up about pre-fracture and post- treatment mobility and symptoms.

The data were analysed by use of SPSS software. A normal parametric distribution about the mean was assumed and the t test was applied to identify statistically significant differences.

RESULTS

The blood indices are shown in Table 1 and the morphology of the curves over time is illustrated in Figure 1. The mean value of corrected serum calcium rose into the normal reference range (2.20- 2.67 mmol/L) and was significantly higher by week 4, but continued on a rising trend to reach an apparent plateau at about 52 weeks. Similarly, the mean phosphate concentration rose within the normal range (0.80-1.40 mmol/L), reaching a significantly different value at 12 weeks and then showing a steadily rising trend throughout the 104 weeks of follow-up. The alkaline phosphatase response was more complex. The baseline levels were high, probably partly as a result of the underlying osteomalacia; there was a peak at 6 weeks in response to the fracture and the vitamin D loading dose, after which values declined gradually into the normal range (25-115 IU/L) by 52 weeks. A slight downward trend was still apparent at 104 weeks. Rising trends with time were also observed for haemoglobin and albumin, reaching statistical significance in the case of albumin at 36 weeks. The low mean haemoglobin at week 0 was probably due to blood loss at the time of the trauma and operation; some patients received a blood transfusion, hence the higher mean value by week 2. Renal function and electrolyte homoeostasis were remarkably stable throughout the follow-up, though there was a s\light rising trend in the mean urea.

Table 1 Changes in mean (1 SD)* values of various blood indices over time of patients with osteomalacia after treatment

Figure 1 Morphology of the curves over time

Analysis of the narrative data showed that, before the fracture, 66% of patients had been experiencing bone and muscle pain or aching, mainly in the legs and pelvis, whereas at the end of the follow-up period the proportion with such symptoms was only 21%. The figures for independent walking were 59% and 84% respectively. The fact that the mean body weight rose by only 0.3 kg in men and 0.1 kg in women from the time of admission to week 104 suggests that calorie under-nutrition was not a major pre-fracture feature in most of the study group.

DISCUSSION

We have found that, in elderly patients with osteomalacia, the serum calcium returns to the normal range within about 4 weeks of starting treatment with a standard vitamin D replacement regimen. This is consistent with expectations in this clinical context.15 The mean phosphate concentration was within the normal range throughout but rose to the mid-range after treatment. This finding is in keeping with the observation that older people tend not to be as hypophosphataemic as younger people with osteomalacia, probably because of the reduced urinary phosphate excretion in older age as glomerular filtration rate declines. More interestingly, we showed that the mean values of serum calcium, phosphate and post-fracture alkaline phosphatase continue to change towards the mid-normal range for at least a year after vitamin D repletion and the start of a general nutrition programme. One explanation might be that the initial dose of 300 000 IU of vitamin D was too low or that the daily oral dose was inadequate. This is unlikely since those doses are known to achieve sustained normal blood 25-hydroxyvitamin D levels within four months of the loading dose.14 More likely, the process of establishing a stable chemical relationship between bone, calcium, phosphate, calcitonin and parathyroid hormone requires at least a year, and possibly as much as 2 years, in severely vitamin D depleted individuals receiving adequate replacement therapy. This is consistent with a histomorphometric study which showed a reduction in osteoid volume over a mean period of 2 years in patients receiving treatment for osteomalacia.16 Such an explanation is supported by the observed reduction of transformation of vitamin D to the active metabolites in old age and relative resistance to its effect in the intestine and on bone.17 It could be argued that our study should have included measurements of serum 25-hydroxyvitamin D and parathyroid hormone. These were not available to us for routine clinical use when the study began and were omitted for that reason. Furthermore, the diagnosis of osteomalacia was established histologically, so parathyroid hormone was not required for that purpose. Also, the probable unreliability of 25-hydroxyvitamin D measurement for confirming the diagnosis of osteomalacia has been mentioned above. There is no doubt that an additional insight into the time-scale of the recovery of bone metabolism to a homoeostatic state would have been gained by tracking the changes in parathyroid hormone over the 104 week period. The importance of our observations to clinical practice lies in the apparently long duration of the bone metabolic recovery period in this context. This indicates that a sustained attempt to keep osteomalacic patients adequately nourished and vitamin D replete is required, with adequate medical and social follow-up. The continued rise in the mean albumin concentration over the first 52 weeks highlights the need for general nutritional support of frail elderly individuals in these clinical circumstances. The cost of providing vitamin D supplements is low in comparison with the potential health benefits, which are established for bone risk and mobility. Furthermore, there is some evidence that vitamin D deficiency carries an excess risk of prostate, colon and breast cancers, though the explanation for this probably lies with associated general nutritional and lifestyle patterns.18

REFERENCES

1 Egsmose C, Lund B, McNair P, et al. Low scrum levels of 25- hydroxyvitamin D in institutionalized old people: influence of solar exposure and vitamin D supplementation. Age Ageing 1987;16:35-40

2 McKenna MJ. Differences in vitamin D status between countries in young adults and in the elderly. Am J Med 1992;93:69-77

3 Bell NH, Key LL. Acquired osteomalacia. Curt Ther Endocrinol Metab 1997;6:530-3

4 Francis RM, Selby PL. Osteomalacia. Clin Endocrinol Metab 1997;11:145-163

5 Solanki T, Hyatt RH, Kemm JR, et al. Are elderly Asians in Britain at a high risk of vitamin D deficiency and osteolamacia? Age Ageing 1995;24:103-7

6 Allain TJ, Dhesi J. Hypovitaminosis D in older adults. Gerontology 2003;49:273-8

7 Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463-70

8 Nowson CA, Diamond TH, Pasco JA, et al. Vitamin D in Australia. Issues and recommendations. Aust Fam Physician 2004;33:133-8

9 Compston JE, Vedi S, Croucher PI. Low prevalence of osteomalacia in elderly patients with hip fracture. Age Ageing 1991;20:132-4

10 Hordon LD, Peacock M. Osteomalacia and osteoporosis in femoral neck fracture. Bone Mineral 1990;11:247-59

11 Peacey SR. Routine biochemistry in suspected vitamin D deficiency. J R Soc Med 2004;97:322-5

12 Thompson SP, Wilton TJ, Hosking DJ, et al. Is vitamin D necessary for skeletal integrity in the elderly? J Bone Joint Surg 1990;72B:1053-6

13 Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327: 1637-42

14 Wu F, Staykova T, Horne A, et al. Efficacy of an oral, 10-day course of high-dose calciferol in correcting vitamin D deficiency. NZ J Med 2003;116:U536

15 Hamdy RC, Coles JA, Downey LJ. A comparative study of cholecalciferol, dihydrotachysterol and alfacalcidol in the treatment of elderly patients with hypocalcaemia. Age Ageing 1987;16:178-80

16 Parfitt AM, Rao DS, Stanciu J, et al. Irreversible bone loss in osteomalacia. Comparison of radial photon absorptiometry with iliac bone histomorphometry during treatment. J Clin Invest 1985;76: 2403-12

17 Simon J, Leboff M, Wright J, et al. Fractures in the elderly and vitamin D. J Nutr Health Aging 2002;6:406-12

18 Eriksen FF, Glerup H. Vitamin D deficiency and aging: implications for general health and osteoporosis. Biogerontology 2002;3:73-7

S C Allen MD FRCP S Raut MD MPhil

J R Soc Med 2004;97:527-530

Department of Medicine and Geriatrics, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, UK

Correspondence to: Professor S C Allen

E-mail: [email protected]

Copyright Royal Society of Medicine Press Ltd. Nov 2004

Sturge-Weber Syndrome and Paroxysmal Hemiparesis: Epilepsy or Ischaemia?

Transient neurological deficits experienced by patients with Sturge-Weber syndrome can be caused by epilepsy, or may result from temporary ischaemia of the cortex underlying the vascular malformation. To show the difficulty in distinguishing seizures from ischaemic symptoms, two male children with episodes of acute unilateral weakness are presented here as well as a review of the literature. The first child presented at 2 years of age with a sudden increase in his pre-existing right hemiparesis accompanied by screaming. Ictal epileptiform activity was recorded at the moment of the attack, and subsequent seizures were controlled by adjustment of antiepileptic drug treatment. The second child presented at 4 years of age with attacks of vomiting and a coinciding increase in the pre- existing paresis of the left leg. Electroencephalogram (EEG) recording did not show ictal epileptiform activity. The origin was presumed to be vascular. Treatment with aspirin led to control of these transient ischaemic attacks. Ictal EEG is needed to differentiate between an epileptic and an ischaemic origin of transient focal deficit. Treatment with aspirin should be considered if an ischaemic origin cannot be excluded.

Sturge-Weber syndrome (SWS) is a congenital neurocutaneous disorder, typically characterized by telangiectatic venous angiomas of the leptomeninges, an ipsilateral facial angiomatous nevus involving at least the first branch of the trigeminal nerve sensory distribution, and a choroidal angioma (Gomez and Bebin 1987). At pathological examination, a paucity of normal superficial cortical veins is often found. One factor contributing to the development of cerebral damage is a lack of efficient outflow of venous blood, resulting in hypoperfusion and impaired neuronal metabolism (Maria et al. 1998b).

Epilepsy is the most common, and often presenting, symptom of SWS seen with its onset in childhood. Other neurological symptoms include learning disability*, focal deficits, such as a chronic hemiparesis and hemianopia, and stroke-like episodes which consist of transient visual field defects or unilateral weakness (Garcia et al. 1981, Maria et al. 1998a). As epilepsy is the most common symptom of SWS, ictal epileptiform activity or postictal depression of activity is usually considered causative where there are transient neurological symptoms. However, these symptoms can also be caused by temporary ischaemia of the cortex underlying the vascular malformation. Therefore, the occurrence of episodes of a transient focal deficit pose a diagnostic challenge to the clinician. Adequate differentiation between epileptic and ischaemic origins of these events is of utmost importance, as this will have consequences for therapy.

We report on two children with episodes of acute unilateral weakness which highlight the difficulty in distinguishing seizures from ischaemic symptoms. We also present a review of the literature.

Case report

CHILD 1

This male was born after an uneventful pregnancy and delivery. At birth, a port wine nevus in the first branch of the left trigeminal nerve was noticed, leading to the diagnosis of SWS. Seizures, lasting 1 minute and consisting of lowered consciousness and deviation of head and eyes to the left, occurred from the age of 5 months and were resistant to antiepileptic drugs, including vigabatrin, valproic acid, and clobazam. From the age of 1 year psychomotor development was delayed. A right hemiparesis became manifest. Cerebral magnetic resonance imaging (MRI) showed atrophy in the left temporo-parieto-occipital region (Fig. 1a). At the age of 2 years he was admitted to the University Medical Centre, Utrecht, the Netherlands, with daily attacks of screaming (as if in pain). During attacks he grabbed for his head but was not nauseous. A coincidental sudden exacerbation of his right hemiparesis was noticed during the majority of attacks, lasting for up to several hours. An electroencephalogram (EEG) performed during an attack showed ictal epileptiform activity, consisting of spike-waves and spike activity, in the left centro-temporo-parietal region (Fig. 2a). EEGs performed before and after attacks did not show any epileptiform activity. The dose of valproic acid was increased, since which the hemiparetic attacks have not been observed during the last 2 years. Attacks of impaired consciousness, considered to be seizures, still occur with a low frequency. The child’s development is now progressing.

Figure 1a: Cerebral T^sub 2^-weighted MRI of child 1, demonstrating atrophy of left temporo-parieto-occipital region.

Figure 1b: Cerebral T^sub 2^-weighted MRI of child 2, demonstrating atrophy of right frontoparietal region.

CHILD 2

This male was born after a twin pregnancy that was complicated by hypertension and intrauterine growth retardation. No facial nevus was present at birth. The first seizures occurred at the age of 5 months and consisted of left hemiconvulsions, preceded by a sudden left hemiparesis. Cerebral computerized tomography, showing atrophy and calcifications in the left frontoparietal region, led to the diagnosis of SWS. Despite administration of several antiepileptic drugs, including carbamazepine, valproic acid, and phenytoin, cessation of seizures could not be achieved. The child was admitted to our hospital for evaluation for functional neurosurgery for epilepsy. Neurological examination revealed psychomotor delay with a mild left hypertonic hemiparesis. Cerebral MRI showed atrophy of the right frontoparietal region (Fig. 1b). Multiple lobectomy was considered. Surprisingly, following yet another change in medication, seizure frequency reduced substantially. Furthermore, psychomotor development improved. At the age of 4 years, he presented with paroxysmal events with a different semiology. Once every 1 to 3 weeks, he vomited and a sudden increase of the preexisting paresis of the left leg occurred. Positive phenomena, e.g. tingling, were absent. The paresis recovered during the following day. An EEG performed during one of these attacks did not show ictal epileptiform activity (Fig. 2b). The underlying mechanism of these attacks was, therefore, considered to be ischaemic, and a course of aspirin (1mg/kg/day) was prescribed. Thereafter, the paroxysmal events stopped and have not occurred in the last 1 years of follow-up.

Discussion

We present two children with apparently comparable episodes of a sudden increase in severity of a pre-existing unilateral paresis, illustrating the diagnostic problem of acute focal deficits in individuals with SWS. In the first child, the attacks were caused by focal epileptic seizures, whereas the attacks in the second child appeared to have an ischaemic origin.

Although stroke-like episodes in those with SWS have been acknowledged for many years (Garcia et al. 1981), reports are scarce and the definition of these episodes is poor. Two previous studies (Maria et al. 1998a, b) defined stroke-like episodes as the sudden onset of unilateral weakness with or without seizure activity. Unfortunately, differences in duration and accompanying features between the seizures and stroke-like events were not analyzed. Furthermore, ancillary investigations to confirm the origin of the events were not performed.

In most cases, seizures can be distinguished from ischaemic events on clinical grounds. Positive phenomena, such as tingling, may occur in transient ischaemic attacks, but tend to arise at the same time in all affected parts of the body, whereas during focal seizures they usually spread from one part to another (Warlow et al. 2001). Accompanying features, such as eye blinking, smacking, and other automatisms, are absent during an ischaemic attack. Furthermore, consciousness is almost invariably maintained in transient ischaemic attacks, whereas it may be lowered during a seizure. However, half of the patients with SWS have learning disabilities and, therefore, altered behaviour during the attacks maybe difficult to interpret.

Figure 2a: Ictal EEG (double banana montage) of child 1, showing continuous epileptiform discharges in left centro-temporo-parietal region.

Figure 2b: Ictal EEG (double banana montage) of child 2, showing asymmetry of background activity. No epileptiform activity is demonstrated.

Hemiplegic migraine due to vascular phenomena around the angioma has been reported in one individual with SWS presenting with a transient hemiparesis (Dora and Balkan 2001). As demonstrated by the children in this report, differentiation by semiology may be impossible when attacks consist of sudden focal deficits without positive phenomena. In these cases, ancillary investigations should be performed.

In most people with SWS an interictal EEG is misleading, as interictal epileptiform activity may occur in those with stroke- like episodes, and may be absent in those with SWS (Jansen et al. 2002). EEG recording during an attack is often diagnostic.

In our first patient, an EEG showed ictal epileptiform activity during an attack, which lead to the diagnosis of epilepsy as the cause of his attacks. In child 2, however, EEG recordings at time of the attack did not show ictal epileptiform activity. Based on this finding, together with the clinical signs, an ischaemic cause was assumed.

Although diffusion-weighted MRI has p\roved useful for the evaluation of those with acute cerebral ischaemia (Roberts and Rowiey 2003) as well as for patients with partial status epilepticus (Lansberg et al. 1999), its use for differentiating between ischaemic or epileptic causes of a hemiparesis is probably limited. In both acute focal cerebral ischaemia and status epilepticus, diffusion-weighted MRI demonstrates cortical hyperintensity and corresponding hypointense areas may be found on apparent diffusion coefficient maps (Lansberg et al. 1999, Roberts and Rowiey 2003). Both in individuals with partial status epilepticus and in those with transient ischaemic attacks, diffusion-weighted MRI abnormalities disappear in the subsequent days orweeks (Lansberg et al. 1999, Schulzetal. 2003).

The extent and severity of glucose asymmetry detected by 2-deoxy- 2 [18F] fluoro-D-glucose positron emission tomography (FDG PET) has proved a sensitive marker for seizure severity and cognitive decline in SWS (Lee et al. 2001). With use of single photon emission computed tomography (SPECT), cerebral blood flow was found to be lower in the region of the cortex involved in the vascular malformation in patients who had experienced seizures compared with patients who had not (Pinton et al. 1997). To date, both FDG PET and SPECT scanning have not been used to differentiate between ischaemia and epilepsy in individuals with SWS, probably also because of large logistical barriers of ictal scanning.

The value of aspirin in patients with SWS and transient focal deficits has been suggested previously. In one study of 14 patients, a 65% decrease of stroke-like events was found after administration of aspirin (Maria et al. 1998b). Additionally, in a different study, Maria et al. (1998a) reported one patient who developed stroke-like episodes after discontinuation of aspirin. In the present study, the response in the second patient is in keeping with the proclaimed potential benefit of aspirin. Therefore, we suggest that treatment with aspirin should be considered for individuals with manifestations of a paroxysmal hemiparesis without ictal epileptiform activity on EEG.

Additionally, prevention of neurological deterioration after the start of aspirin treatment has been suggested (Roach et al. 1985). Persistent or progressive neurological deficits in individuals with SWS may be caused by two mechanisms (Aylett et al. 1999); the deleterious effect of recurrent seizures, and venous hypertension leading to progressive ischaemia. Local venous thrombosis has been suggested to be involved in this process (Probst 1980). When seizures occur a vicious circle may develop (Bebin and Gomez 1988). The epileptic activity increases the metabolic rate and, thus, the demand for oxygen and glucose; as blood circulation is already disturbed the demand is not fulfilled and more damage may occur, leading to progressive atrophy and calcification in the affected hemisphere, and, consequently, to an increased propensity to develop epileptic seizures (Ito et al. 1990).

Antiplatelet therapy has proved to reduce the risk of deep-vein thrombosis in high-risk patients (Hankey and Eikelboom 2003), and may also benefit people with SWS. Therefore, it would be useful to test the efficacy of aspirin in a large randomized trial of individuals with SWS, even in the absence of seizures.

In conclusion, differentiation between ischaemia and epilepsy as causes of paroxysmal focal deficits in people with SWS can be difficult. Clues can be obtained from a careful targeted history of events. An attempt should be made to perform an EEG at the moment of the attack, as this is often diagnostic. If ischaemia cannot be excluded, administration of aspirin should be considered. A randomized clinical trial is warranted to investigate the value of aspirin in the prevention of neurological deterioration in individuals with SWS.

DOI: 10.1017/S0012162204001343

Accepted for publication 4th March 2004.

* US usage: mental retardation.

References

Aylett SE, Neville BGR, Cross JH, Boyd S, Chong WK, Kirkham FJ. (1999) Sturge-Weber syndrome: cerebral haemodynamics during seizure activity. Dev Med Child Neurol 41: 480-485.

Bebin EM, Gomez MR. (1988) Prognosis in Sturge-Weber disease: comparison of unihemispheric and bihemispheric involvement. J Child Neurol 3: 181-184.

Dora B, Balkan S. (2001) Sporadic hemiplegic migraine and Sturge- Weber syndrome. Headache 41: 209-210.

Garcia JC, Roach ES, McLean WT. (1981) Recurrent thrombotic deterioration in the Sturge-Weber syndrome. Child’s Brain 8: 427- 433.

Gomez MR, Bebin EM. (1987) Sturge-Weber syndrome. In: Gomez MR, Bebin EM, editors. Neurocutaneous Diseases: A Practical Approach. Boston: Butterworths Publishers.

Hankey GJ, Eikelboom JW. (2003) Antiplatelet drugs. Med J Aust 178: 568-574.

Ito M, Sato K, Ohnuki A, Uto A. (1990) Sturge-Weber disease: operative indications and surgical results. Brain Dev 12: 473-477.

Jansen FE, van Huffelen AC, Witkamp T, Couperas A, Teunissen N, Wieneke GH, van Nieuwenhuizen O. (2002) Diazepam-enhanced beta activity in Sturge Weber syndrome: its diagnostic significance in comparison with MRI. Clin Neurophysiol 113: 1025-1029.

Lansberg MG, O’Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW (1999) MRI abnormalities associated with partial status epilepticus. Neurology 52: 1021-1027.

Lee JS, Asano E, Muzik O, Chugani DC, Juhasz C, Pfund Z, Philip S, Behen M, Chugani HT. (2001) Sturge-Weber syndrome: correlation between clinical course and FDG PET findings. Neurology 57: 189- 195.

Maria BL, Neufeld JA, Rosainz LC, Ben-David K, Drane WE, Quisling RG, Hamed LM. (1998a) High prevalence of bihemispheric structural and functional defects in Sturge-Weber syndrome. J Child Neurol 13: 595-605.

Maria BL, Neufeld JA, Rosainz LC, Drane WE, Quisling RG, Ben- David K, Hamed LM. (1998b) Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression. J Child Neurol 13: 606-618.

Pinton F, Chiron C, Enjolras O, Motte J, Syrota A, Dulac O. (1997) Early single photon emission computed tomography in Sturge- Weber syndrome. J Neurol Neurosurg Neuropsych 63: 616-621.

Probst FP (1980) Vascular morphology and angiographic flow patterns in Sturge-Weber angiomatosis: facts, thoughts and suggestions. Neuroradiology 20: 73-78.

Roach ES, Riela AR, McLean WT, Stump DA. (1985) Aspirin therapy for Sturge-Weber syndrome. Ann Neurol 18: 387.

Roberts TP, Rowley HA. (2003) Diffusion weighted magnetic resonance imaging in stroke. Eur J Radiol 45: 185-194.

Schulz UG, Briley D, Meagher T, Molyneux A, Rothwell PM. (2003) Abnormalities on diffusion weighted magnetic resonance imaging performed several weeks after a minor stroke or transient ischaemic attack. J Neurol Neurosurg Psychiatry 74: 734-738.

Warlow CP, Dennis MS, van GiJn J, Hankey GJ, Sandercock PAG, Bamford JM, Wardlaw JM. (2001) Is it a vascular event and where is the lesion? Identifying and interpreting the symptoms and signs of cerebrovascular disease. In: Stroke: A Practical Guide to Management. Oxford UK: Blackwell Science, p 73.

Floor E Jansen* MD, Department of Child Neurology;

H Bart van der Worp MD PhD, Department of Neurology;

Alexander van Huffelen MD PhD, Department of Clinical Neurophysiology;

Onno van Nieuwenhuizen MD PhD, Department of Child Neurology, University Medical Centre, Utrecht, the Netherlands.

* Correspondence to first author at Department of Child Neurology, C03236, University Medical Centre, PO Box 85500, 3508 GA, Utrecht, the Netherlands.

E-mail: [email protected]

Copyright Mac Keith Press Nov 2004

Effect of an Exercise Program on Functional Performance of Institutionalized Elderly

Abstract-

This study determined the effectiveness of a 6-month program of regular exercises for the improvement of functional performance of the elderly living in a nursing home. The 40 subjects aged 60 to 99 who took part in this trial were assigned either to a comparative group or an exercise group. The following variables were measured: functional performance with the use of an obstacle course, a lower- limb function test, and a 6-minute walk test (gait velocity); isometric strength of the knee extensors; proprioception of the lower limbs; mental status through the Mini-Mental State Examination (MMSE); and depression symptoms with the use of the Geriatric Depression Scale (GDS). In the exercise group, 19 subjects completed the program and attended an average of 32 (68%) sessions. At the end of the trial, the exercise subjects showed significant performance improvement in quantitative and qualitative obstacle course scores, lower-limb function test, gait velocity test, knee extensors strength, and the GDS, while the nonexercise subjects showed significant decrease in qualitative obstacle course score, lower- limb function, gait velocity, MMSE, and the GDS.

Key words: depression, elderly, exercise, functional performance, institutionalization, mental status, proprioception, strength.

Abbreviations: GDS = Geriatric Depression Scale, IKES = isometric knee extensors strength, MMSE = Mini-Mental State Examination, OCQLS = obstacle course qualitative score, OCQTS = obstacle course quantitative score, 6-MIN = 6-minute walk test.

INTRODUCTION

The elderly population has grown proportionally faster than any other age group in Brazil [1]. In 2020, when life expectancy will have reached 75.5 years, the Brazilian population will consist of an estimated 23.5 percent young people (aged 18 or younger) and 7.7 percent, an estimated 16.2 million, the elderly (aged 60 or older) [2]. As the population ages, a trend of health problems and functional disability increases [3], with a significant impact on rehabilitation service needs, such as home care and nursing homes, especially for those aged 85 and older [4]. In the United States, approximately 5 percent of the elderly are institutionalized, and this statistic is unlikely to decline in the coming years. As a result, the demand for long-term care institutions for the elderly will increase [5,6]. In Brazil, census information and research data on institutionalized elderly are scarce. In 1984, Jean Louis Hot, a French sociologist, quoted the only study known. At the time, he believed that, in Brazil, around 0.6 to 1.3 percent of the elderly were institutionalized [7].

The institutionalized elderly are high-risk patients. The loss of functional mobility has been shown to be associated with 50 percent mortality rate among nursing home patients within 6 to 12 months [8]. Evidence from several studies indicates that this decline in physical functionality as such is due only partly to the aging process, and to a large extent, it is due to the decrease in or lack of physical activity [9-11].

Exercise is an accessible form of prevention of physical decline. Several studies have found that adherence to a regular exercise program can improve muscle strength [9,12-19], reaction time [9,12], balance control [9,12,20], and gait velocity [21-23] significantly. Also some trial evidence has shown that exercise programs may enhance cognitive performance and effective states of the elderly as well [24-26], mainly of frail institutionalized elderly, given their lack of exercise and life stimuli [25,27].

Although sufficient evidence exists to recommend that older people should exercise and the findings just described suggest that exercise can increase function in the elderly, further studies are required to elucidate its role in improving function in institutionalized elderly patients. This research has important practical implications, since the primary goal of rehabilitating the elderly is to contribute to a better life quality by maintaining physical function [28-30].

In this study, we have attempted to address this issue by undertaking a long-term controlled exercise program trial with 40 elderly subjects living in a nursing home. Our aim was to assess the adherence of institutionalized elderly to an exercise program and to determine whether regular exercise has beneficial effects on their functional performance, muscle strength and proprioception of the lower limbs, and cognitive and affective status.

METHODS

Subjects

This study was conducted in a nursing home, which hosts 670 people. Of the residents, 85 percent are older than 60 years and among these, only 20 percent are independent.

Initially, among the nursing home residents who had been referred to the exercise program, 40 were selected to participate in this study after a personal interview. Subjects were assigned either to an exercise group, those who wanted to attend the exercise sessions, or to a comparative group, those who did not want to attend the exercise sessions but who volunteered to participate in the study. The subjects were consenting and informed volunteers, mentally capable of understanding and performing the tests proposed, and ambulatory with and without aids.

Inclusion criteria included the subjects being able to perform the functional “get-up and go” test described by Mathias and colleagues [31], without any evidence of risk of falling during the test or at any other time, as considered “normal” in the test’s scale. Performing the test also meant that they could follow commands.

Subjects were also medically examined by Healthcare practitioners to identify any condition that precluded their participation in the exercise program, such as imminent fall risk, symptomatic coronary insufficiency, and uncontrolled chronic disease-diabetes, chronic obstructive pulmonary disease, congestive heart failure, hypertension. Exclusion criteria included not living in the institution, not meeting medical criteria, and unwillingness to participate in the study. The Ethics and Research Committee of the Medical School of the University of So Paulo approved this study.

Exercise Program

The experimental subjects participated in a 1-hour exercise session, twice a week for 6 months. The sessions consisted of mobility exercises involving ankles, knees, hips, spine, and shoulders. Subjects performed strengthening exercises with weights on the ankles and hands, closed-kinetic chain exercises (standing and sitting on a chair, climbing stairs), a 15-minute walk, and a 5- to 10-minute relaxation (cooldown) to simulate daily activities.

Exercises were undertaken in group activities, with emphasis on social interaction and enjoyment. The comparative subjects continued their daily nursing home routine, without participating in any organized physical activity.

Assessment Procedures

Assessments were made before subjects began the exercise program and after a 6-month period. Assessments included three functional performance tests: an obstacle course (based on an obstacle course quantitative score [OCQTS] and an obstacle course qualitative score [OCQLS]), a lower-limb function test, and a gait velocity test. Isometric knee extensors strength (IKES), lowerlimb proprioception, depressive symptoms, and cognitive status were also measured. All tests were done in the same amount of time, with the exception of the obstacle course and the 6-minute walk test (6-M1N), which were done in a separate setting. Each subject test session took approximately 1 hour. The same person assessed all tests.

Obstacle Course

This test, validated in 1996, consists of a series of 12 stations at which functional tasks or simulations of common functional conditions encountered in and around the environment are presented. The three sections of the obstacle course included four stations with different floor textures, two ramps, two sets of stairs, and four discrete functional tasks (opening a door, rising from a chair, walking around, and stepping over obstacles) [32,33]. The course was set up in an existing physical therapy room (6.8 m 15.0 m). The stations were set up within a different area from the one described, with minor variations in the obstacle course configuration and the corresponding interobstacle distances.

The subjects were asked to walk the course at a comfortable pace and the elapsed time was recorded based on OCQTSs. OCQLSs were assigned according to specific criteria. A physical therapist guided the test, and the subjects were not allowed to walk the course before the actual test.

Lower-Limb Function

We assessed lower-limb function by measuring standing balance, walking speed, and the ability to rise from a chair [34]. For standing balance tests, the subjects were asked to attempt to maintain their feet side-by-side, in semitandem (the heel of one foot beside the big toe of the other foot), and tandem (the heel of one foot directly in front of the other foot) positions for 10 s each. The subjects received a score of “1” if they could hold a sideby-side standing position for 10 s, but were unable to hold a semitandem position for 10 s; a score of “2” if they could hold a semitandem posi\tion for 10 s, but were unable to hold a full tandem position for more than 2 s; a score of “3” if they could stand in the full tandem position foot from 3 s to 9 s; and a score of “4” if they could stand in full tandem position for 10s.

A 2.4 m walk at the subject’s normal pace was timed, and the participants were scored according to quartiles for the time length required to complete the test. The time of the faster of two walks was used for scoring as follows: 5.7 s, a score of 1; 4.1 s to 5.6 s, a score of 2; 3.2 s to 4.0 s, a score of 3; and 3.1 s, a score of 4.

The subjects were asked to stand up from a chair and to sit down five times, as fast as possible. Quartiles for the length of time of this measure were used for scoring as follows: 16.7 s, a score of 1; 13.7 s to 16.6 s, a score of 2; 11.2 s to 13.6 s, a score of 3; and 11.1 s, a score of 4.

We created a performance score profile by adding the three test scores. The subjects were allowed to use their aids if necessary.

6-Minute Walk Test

The subjects were instructed to walk for 6 minutes in the space determined, from one side to the other, and to try to cover as much ground as possible, continuously if possible, but without being concerned if they felt an urge to slow down or to stop. A physical therapist accompanied the subjects and measured the time, giving encouragement as necessary [35]. The distance covered was then measured in meters, with the use of a tape measure.

Isometric Knee Extensors Strength

The modified sphygmomanometer was used to measure the IKES [36]. It consists of a sphygmomanometer folded bladder inside a sewn bag, as described by Helewa et al. [37]. The sphygmomanometer was inflated to a baseline reading on the aneroid scale (20 mmHg). The tester placed the sphygmomanometer on the subject’s leg, and the subject was asked to attempt to induce movement by exerting force against the tester. A “break” in movement or a tremor indicated maximal isometric contraction. Measurements were made in triplicate and the greatest force was recorded (mmHg).

Proprioception

Proprioception was measured with the use of an apparatus modified by Lord et al. [38]. This test measured the subject’s ability to match the position of the lower limbs. The subjects attempted to simultaneously place the right big toe on the right side of a sheet and the left big toe on the corresponding position on the left side of the sheet in an orthostatic position, without looking to the feet. Error in matching the two toes was measured with a protractor. The test score was the mean error.

Mini-Mental State Examination

The Mini-Mental State Examination (MMSE) was administered to assess the subject’s cognitive level in items related to orientation, capability of registration, attention and calculation, recall, and language [39].

The maximum score possible is 30. A score below 24, which indicates cognitive impairment, is not considered normal for older people. A score of 21 implies mild intellectual impairment, a score from 16 to 20 reflects moderate impairment, and a score below 15 is considered severe impairment. No adjustment for subject characteristics was made because MMSE was not used as an exclusion criterion, and only the means of the differences obtained by subtracting the baseline from the follow-up values was compared across groups.

Geriatric Depression Scale

We used the GDS to measure depressive symptoms. It includes 30 questions to which subjects answer “yes” or “no” [40], such as-

* “Are you basically satisfied with your life?”

* “Do you frequently feel like crying?”

* “Do you often feel helpless?”

Statistical Analysis

All variables were considered continuous because measurements varied within a certain scale. Baseline differences in group characteristics were analyzed with the use of an unpaired two- tailed t-test for age and with the Mann-Whitney Latest for institutionalization time. Pearson correlation coefficients were calculated comparing data from different variables at baseline. We used the one-tailed t-test, Wilcoxon test, and Mann-Whitney test to assess differences between the exercise and nonexercisc group means, and after the trial, we subtracted the baseline value from the follow-up value and compared the means. In addition, improvement in the performances of the subjects with and without chronic conditions in the exercise group was compared with the Wilcoxon test. A p- value

Table 1.

Characteristics of study group at baseline.

RESULTS

Of the 40 subjects initially recruited into the study, 3 failed to complete the program: 1 from the exercise group, due to medical conditions that caused discontinuation of participation in the exercise class and 2 from the nonexercise group (1 who died and another who left the institution). The characteristics of the study group are described in Table 1. Chronic conditions considered were those found to compromise the performance of the subjects in the physical function tests.

No significant difference was found between the groups at baseline in relation to age. But compared to the exercise group, the nonexercise group had a significantly longer institutionalization time.

The total number of sessions in the 6-month period was 47. The mean number of sessions attended by the 19 subjects who adhered to the exercise program was 32 (68%), in the range of 20 to 47 sessions (43% to 100%); 16 subjects (84%) attended 30 (64%) or more sessions. The mean number of subjects per session was 14 (74%), in the range of 8 to 19 subjects (42% to 100%); over 10 (53%) subjects attended 46 (98%) of the sessions.

Mean values and standard deviations of test measures before and after trial are shown in Table 2. The comparison of these values reveals that the exercise group performed significantly better in functional tests (OCQTS and OCQLS), lower-limb function, gait velocity, strength, and the GDS. The nonexercise group had a significantly diminished functional performance (only OCQLS), lower- limb function, gait velocity, MMSE, and the GDS.

The correlation between baseline variables is shown in Table 3. The highest coefficients were found among functional tests. The proprioception test, MMSE, and GDS had a weak correlation with the remaining tests, except for a moderate correlation between MMSE and lower-limb function tests.

Table 2.

Mean standard deviations of test measures-baseline and 6-month follow-up.

Table 3.

Pearson correlation coefficients (r) of different baseline variables.

When comparing the means of the differences obtained subtracting baseline from follow-up values of the exercise and nonexercise groups, we found that the exercise group performed significantly better in all the tests, except for the proprioception one, as shown in Table 4.

DISCUSSION

This study evaluated the effectiveness of an exercise program on functional performance, mental status, and depressive symptoms in the institutionalized elderly. Strength and balance measurements were included because they are prerequisites fur successful functional activity performance [41,42]. Proprioception assessment, joint position sense, was used as an indirect balance cvaluation [43]. The finding that proprioception was not significantly better in the exercisers compared with the nonexercisers is consistent with a previous study by Lord et al. [44]. They reported that their subjects showed negligible effects on proprioception after a 12- month exercise intervention, suggesting that exercising may have minimal effect on peripheral sensory systems.

Table 4.

Mean standard deviations of differences between baseline and follow-up values for exercise and nonexercise groups.

According to Rogers and Evans [45], the very old and frail elderly experience skeletal muscle atrophy of Type H fibers as a result of disuse, disease, undernutrition, and the effects of aging per se. However, several studies have shown that elderly men and women retain the capacity to adapt to progressive resistive exercise training with significant and clinically relevant muscle hypertrophy and increased muscle strength [46-49]. Our study supports this finding, showing a significant performance improvement in the strength test in the exercise group compared to the nonexercise group.

Few other studies that addressed adaptation to resistance training in the institutionalized elderly reported improvement in strength, irrespective of the use of a high-intensity resistance program [14], a combination of isometric training and low-intensity weight-lifting exercises [50,51], seated resistance exercises [18,26], and rowing exercises for restrained nursing home residents [52]. Although high-intensity exercise clearly may elicit sizable gains in strength [14], less strenuous programs (similar to the one described in this study) have demonstrated significant gain in muscle strength [53,54].

Some studies have considered changes in functional ability in older people after training [19,21,26,51,55-58]. In our study, we found significant improvement in the three functional indicators used. It is important to point out their strong correlation shown by the Pearson correlation coefficients, which corroborate their validity.

When considering relevant improvements in functional tasks, one should consider the type of training exercises used. Skelton et al. [59], in a study with task independent training exercises (i.e., training exercises specific to increase strength of major muscle groups) and avoidance of those that mimic functional tasks, reported only minimal improvements in 2 out of 12 functional ability tests, despite significant increase in strength and muscle power. In contrast, Skelton and MacLaghlin [21] found significant improvements in chair-rise, timed-up-and-go, stair-climbing time, and Moor rise- time tests, in an 8-week study, with a training program mirroring daily activities. They concluded that it might be more benefi\cial to train using movements that closely mirror daily activities rather than to train to increase strength and the power of individual muscle groups per se.

Rantanen et al. have also suggested that usual daily activities may represent a large proportion of maximal strength for older individuals and, therefore, be an adequate overload [60]. In accordance with that, Schnelle et al. reported a study in which nurses in a nursing home bladder/bowel training program spent an extra 6 minutes helping extremely frail residents exercise every time they got the residents up to toilet [61]. The residents would push their wheelchairs, do sit-to-stands, or try to walk a couple of extra minutes. After 8 weeks, their levels of daily living activity improved significantly; they could walk and propel their wheelchairs further and stand up more easily, which showed that even simple interventions can translate into physical benefits.

The psychological effects of exercise, described elsewhere [62,63], have been confirmed in this study by GDS improvements. Nevertheless, the issue of whether or not exercise affects cognitive function remains controversial [19,25,26,64-66]. In our study, the exercisers showed no significant effect on MMSE performance improvement by the end of the program. However, we would like to note that the comparative group showed a significant decrease in MMSE after the 6-month period.

The mechanism underlying the connection between exercise and mental health is still unknown, but many theories have been proposed to try to explain it [25,67]. There is evidence that exercise enhances the activity of monoamines in the brain; stimulates the release of endorphins, especially in the elderly population; and increases oxygen transport capacity, blood circulation, and energy supply to different parts of the body, including the brain. This last effect has been emphasized in relation to cognitive changes. Powell suggested that the deterioration of cognitive processes among psychogeriatric patients hospitalized for many years may result from disuse or disinterest and that exercise therapy may lead to a revitalization of those mental activities, or at least to the maintenance of cognitive level [68]. According to Barry and Eathorne [69], the social interaction offered by an exercise program provides mental and intellectual stimulation that is often missing. In this study, the lack of association between MMSE and GDS with the remaining tests implies that the psychological and cognitive level of the subjects in this sample had no influence on the physical tests.

Some methodological problems relevant to the evaluation of the effects of an exercise program have not been considered in this study. First, owing to resource limitations, a blind observer did not assess the exercise group, and therefore, observer bias possibly may have intervened. However, poststudy measurements were made without reference to baseline values. Additionally, according to Morgan [70], it is necessary to distinguish between effects caused by exercising and confounding effects caused by social or personal consequences of participating in supervised activities. In practical terms, a need exists to include control interventions, which mimic the exercise program as close as possible, except for the exercise program itself. In this particular study, a control group with an intervention that mimics the exercise program only in the social aspects was not accomplished. McMurdo and Rennie studied a group of elderly who exercised in comparison to those who participated in reminiscence sessions [19]. Those in the exercise group demonstrated significantly better strength scores, but cognitive status declined in both groups. Even though the decline was larger in the reminiscence group, it was not statistically significant.

This study had an interesting finding, despite the initial difficulty to motivate the subjects to attend the exercise program sessions during the subject selection step. This finding was that the subjects’ enthusiasm for the exercise sessions was apparent from their expressed hope for continuation of the program.

CONCLUSION

Our results suggest that an exercise program can produce benefits with regard to functional improvement, reduction of depressive symptoms, and prevention of decline in mental status in the institutionalized elderly, thus contributing to a better quality of life. However, to conclusively confirm these benefits, investigators need to conduct randomized controlled studies with large subject samples and better assessment conditions.

REFERENCES

1. Camargo ABM, Yazaki LM. Caracteristicas demogrficas e socioeconmicas da populao idosa. In: Fundao SHADE. O Idoso na Grande So Paulo. So Paulo: Coleo Realidade Paulista; 1990. p. 41-100 (Brazil).

2. Machado CC. Projees multirrcgionais da populao: o caso brasileiro (1980-2020) (thesis). Belo Horizonte: CEDEPLAR/ Universidade Federal de Minas Gerais; 1993 (Brazil).

3. Ramos LR. A exploso demogrfica da terceira idade no brasil: uma questo de sade pblica. Gerontologia. 1993; 1(1):3-8 (Brazil).

4. Lewis CB, Bottomley JM. Understanding the demographics of an aging population. In: Mehalik CL, Ryan EC, Kelly MJ, editors. Geriatric physical therapy: A clinical approach. Connecticut: Appleton & Lange; 1994. p. 3-22.

5. Brocklehurst JC, Tallis RC, Fillit RM. The geriatric service and the day hospital in the United Kingdom. In: Brocklehurst JC, editor. Textbook of geriatric medicine and gerontology. 4th ed. Edinburgh: Churchill Livingstone; 1993. p. 1005-15.

6. Brocklehurst JC, Butler RN, Hyer K, Schechter M. The elderly in society-An international perspective. In: Brocklehurst JC, editors. Textbook of geriatric medicine and gerontology. 4th ed. Edinburgh: Churchill Livingstone; 1993. p. 980-92.

7. Bom T, Abreu CMG O cuidado ao idoso em instituio de longa permanncia. Gerontologia. 1996;4(4):7-14 (Brazil).

8. Clark LP, Dion DM, Barker WH. Taking to bed: rapid functional decline in an intermediate care facility. J Am Geriatr Soc. 1990;38:967-72.

9. Lord SR, Castell S. Effect of exercise on balance, strength and reaction time in older people. Aust J Physiother. 1994; 40:83- 88.

10. Schroll M. The main pathway to musculoskeletal disability. Scand J Med Sci Sports. 1994;4:3-12.

11. Porter MM, Vandcrwoort AA, Lexell J. Aging of human muscle: structure, function and adaptability. Scand J Med Sci Sports. 1995;5:129-42.

12. Lord SR, Ward JA, Williams P, Strudwick M. The effect of a 12- month exercise trial on balance, strength, and falls in older women: a randomized controlled trial. J Am Geriatr Soc. 1995;43(11):1198- 206.

13. Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans WJ. Strength conditioning in older men: skeletal muscle hypertrophy and improved function. J Appl Physiol. 1988;64:1038-44.

14. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA, Evans WJ. High-intensity strength in nonagenarians: Effects on skeletal muscle. JAMA. 1990;263:3029-34.

15. Morey MC, Cowper PA, Feussner JR, DiPasquale RC, Crowlcy GM, Samsa GP, Sullivan RJ Jr. Two-year trends in physical performance following supervised exercise among community-dwelling older veterans. J Am Geriatr Soc. 1991;39(10):986-92.

16. Charette SL, McEvoy L, Pyka G, Snow-Harter C, Guido D, Wiswell RA, Marcus R. Muscle hypertrophy response to resistance training in older women. J Appl Physiol. 1991; 70(5):1912-16.

17. Nichols JF, Omizo DK, Peterson KK., Nelson KP. Efficacy of heavy-resistance training for active women over sixty: muscular strength, body composition, and program adherence. J Am Geriatr Soc. 1993;41(3):205-10.

18. Grimby GA, Aniansson A, Hedberg M, Henning GB, Grangard U, Kurst H. Training can improve muscle strength and endurance in 78- to 84-yr-old men. J Appl Physiol. 1992;73(6):2517 23.

19. McMurdo MET, Rennie LM. Improvements in quadriceps strength with regular seated exercise in the institutionalized elderly. Arch Phys Med Rehabil. 1994;75:600 603.

20. Parsons D, Foster V, Harman F, Dickinson A, Oliva A, Westerlind K. Balance and strength changes in elderly subjects after heavy-resistance training. Med Sci Sports Exerc. 1992;24(Suppl 5):S21.

21. Skelton DA, MacLaghlin AW. Training functional ability in old age. Physiotherapy. 1996;82(3):159-67.

22. Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA, Evans WJ. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330(25):1769-75.

23. Judge JO, Underwood M, Gennosa T. Exercise to improve gait velocity in older persons. Arch Phys Med Rehabil. 1993;74:400-406.

24. Christensen H, Mackinnon A. The association between mental, social and physical activity and cognitive performance in young and old subjects. Age Ageing 1993;22(3): 175-82.

25. Netz Y, Jacob T. Exercise and the psychological state of institutionalized elderly: a review. Percept Mot Skills. 1994; 79(3 Pt 1): 1107-18.

26. McMurdo ME, Rennie L. A controlled trial of exercise by residents of old people’s homes. Age Ageing. 1993;22:11-15.

27. Deps VL. A ocupao do tempo livre sob a tica de idosos residentes cm instituies: anlise de u ma cxperincia. In: Neri AL. Qualidade de vida e idade madura. Campinas, Sn Paulo (Brazil): Papirus; 1993.

28. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303:130-35.

29. Katz S, Branch LG, Branson MH, Papsidero JA, Beck JC, Greer DS 1. Active life expectancy. N Engl J Med. 1983; 309(20): 1218-24.

30. Grimby G, Grimby A, Frndin K, Wiklund I. Physically fit and active elderly people have a higher quality of life. Scand J Med Sci Sports. 1992;2:225-30.

31. Mathias S, Nayak USL, Isaacs B. Balance in elderly patients: the “get-up and go” test. Arch Phys Med Rehabil. 1986;67(6):387-89.

32. Means KM. The obstacle course: a tool for the assessment of functional balance and \mobility in the elderly. J Rehabil Res Dev. 1996;33(4):413-28.

33. Means KM, Rodell DE, O’Sullivan PS. Use of an obstacle course to assess balance and mobility in the elderly: a validation study. Am J Med Rehabil. 1996;75:88 95.

34. Guralnik JM, Ferruci L, Simonsick EM, Salive ME, Wallace RB. Lower-extremity function in persons over age of 70 years as a predictor of subsequent disability. N Engl J Med. 1995;332:556-61.

35. Tappen RM, Roach KE, Buchne D, Barry C, Edelstein J. Reliability of physical performance measures in nursing home residents with Alzheimer’s disease. J Gerontol Biol Sci Med Sci. 1997;52(1):PM52-55.

36. Giles C. Modified sphygmomanometer: instrument to objectively assess muscle strength. Physiother Can. 1984; 36:36-41.

37. Helewa A, Goldsmith CH, Smythe HA. The modified sphygmomanometer-instrument to measure muscle strength: a validation study. J Chronic Dis. 1981;34(7):353-61.

38. Lord SR, Clark RD, Webster W. Postural stability and associated physiological factors in a population of aged persons. J Gerontol. 1991;46(3):M69-76.

39. Folstein MF, Folstein SE, McHugh PR. Mini mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98.

40. Yesavage JA, Brink TL. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982-83;17(1):37-49.

41. O’Neil MB, Wooddard M, Sosa V, Hunter L, Mulrow CD, Geroty MB, Tuley M. Physical therapy assessment and treatment protocol for nursing home residents. Phys Ther. 1992;72:596-604.

42. Buchner DM, Wagner EH. Preventing frail health. Clin Geriatr Med. 1992;8:1-17.

43. Duncan PW, Chandler J, Studenski S, Hughes M. How do physiological components of balance affect mobility in elderly men? Arch Phys Med Rehabil. 1993;74:1343-49.

44. Lord SR, Gideon AC, Ward JA. Balance, reaction time, and muscle strength in exercising and nonexercising older women: a pilot study. Arch Phys Med Rehabil. 1993;74(8): 837-39.

45. Rogers MA, Evans WJ. Changes in skeletal muscle with aging: effects of exercise training. Exerc Sport Sci Rev. 1993;21:65-102.

46. Coleman EA, Buchner DM, Cress ME, Chan BKS, Lateur BJ. The relationship of joint symptoms with exercise performance in older adults. J Am Geriatr Soc. 1996;44:14-21.

47. Tracy BL, Ivey FM, Hurlbut D, Martel GF, Lemmer JT, Siegel EL, Metler EJ, Fuzard JL, Fleg JL, Hurley BF. Muscle quality. II. Effects of strength training in 65- to 75-yrold men and women. J Appl Physiol. 1999;86(1):195-201.

48. Sipil S, Suominen H. Effects of strength and endurance training on thigh and leg muscle mass and composition in elderly woman. J Appl Physiol. 1995;78(1):334-40.

49. Judge JO, Whipple RH, Wolfson LI. Effects of resistive and balance exercises on isokinetic strength in older persons. J Am Geriatr Soc. 1994;42:937-46.

50. Fisher NM, Pendergast DR, Calkins E. Muscle rehabilitation in impaired elderly nursing home residents. Arch Phys Med Rehabil. 1991;72:181-85.

51. Brill PA, Drimmer AM, Morgan LA, Gordon NF. The feasibility of conducting strength and flexibility programs for elderly nursing home residents with dementia. Gerontologist. 1995;35(2):263-66.

52. Schnelle JF, MacRae PG, Giacobassi K, MacRae HSH, Simmons SF, Ouslander JG. Exercise with physically restrained nursing home residents: maximizing benefits of restraint reduction. J Am Geriatr Soc. 1996;44:507-12.

53. Agre JC, Pierce LE, Raab DM, McAdams M, Smith EL. Light resistance and stretching exercise in elderly woman: effects upon strength. Arch Phys Med Rehabil. 1988;69(4): 273-76.

54. Vandervoort AA, Hayes KC, Belaner AY. Strength and endurance of skeletal muscle in the elderly. Physiother Can. 1986;38:167-73.

55. Okumiya K, Matsubayashi K, Wada Tomoko, Kimura S, Doi Y, Ozawa T. Effects of exercise on neurobehavioral function in community-dwelling older people more than 75 years of age. J Am Geriatr Soc. 1996;44:569-72.

56. Sipila S, Multanen J, Kallinen, M, Era P, Suominen H. Effects of strength and endurance training on isometric muscle strength and walking speed in elderly women. Acta Physiol Scand. 1996; 156:457- 64.

57. Thompson RF, Crist DM. Effects of physical exercise for elderly patients with physical impairments. J Am Geriatr Soc. 1988;36:130-35.

58. Harada N, Chiu V, Fowler E, Lee M, Reuben DB. Physical therapy to improve functioning of older people in residential care facilities. Phys Ther. 1995;75(9):830-38.

59. Skelton DA, Young A, Greig CA, Malbut KE. Effects of resistance training on strength, power and selected functional abilities of women aged 75 and over. J Am Geriatr Soc. 1995;43:1081- 87.

60. Rantanen T, Era P, Heikkinen E. Physical activity and the changes in maximal isometric strength in men and women from the age of 75 to 80 years. J Am Geriatr Soc. 1997;45: 1439-45.

61. Schnelle JF, MacRae PG, Ouslander JG, Simmons SF, Nitta M. Functional incidental training, mobility performance, and incontinence with nursing home residents. J Am Geriatr Soc. 1995;43(12):1356-62.

62. Brandon JE, Loftin JM. Relationship of fitness to depression, state and trait anxiety, internal health locus of control, and self- control. Percept Mot Skills. 1991;73(2):563-68.

63. Taunton JE, Martin AD, Rhodes EC, Wolski LA, Donelly M, Elliot J. Exercise for the older woman: choosing the right prescription. Br J Sports Med. 1997;31(1):5-10.

64. Molloy DW, Richardson LD, Crilly RG. The effects of a three- month exercise programme on neuropsychological function in elderly institutionalized women: a randomized controlled trial. Age Ageing. 1988;17(5):303-10.

65. Singh NA, Clements KM, Fiatarone MA. A randomized controlled trial of the effect of exercise on sleep. Sleep. 1997;20(2):95-101.

66. Paffenbarger RS Jr, Hyde RT, Wing AL, Lee IM, Jung DL, Kampert JB. The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med. 1993;328:538-45.

67. Butler RN, Davis R, Lewis CB, Nelson ME, Strauss E. Physical fitness: benefits of exercise for the older patient. 2. Geriatrics. 1998;53(10):46-62.

68. Powell RR. Psychological effects of exercise therapy upon institutionalized geriatric mental patients. J Gerontol. 1974; 29(2):157-61.

69. Barry HC, Eathorne SW. Exercise and aging: Issues for the practioner. Med Clin North Am. 1994;78(2):357-76.

70. Morgan K. Trial and error: evaluating the psychological benefits of physical activity. Int J Geriat Psychiatr. 1989;4: 125- 27.

Submitted for publication January 21, 2003. Accepted in revised form February 19, 2004.

Alessandra de Carvalho Bastone, MS, PT; Wilson Jacob Filho, PhD

The University of So Paulo, So Paulo, Brazil; D. Pedro II Hospital, So Paulo, Brazil; National Council of Scientific and Technological Development (CNPq), Brasilia, Brazil

This material was based on work supported by the National Council of Scientific and Technological Development, Edifcio Nazir I, Brasilia, Brazil.

Address all correspondence to Alcssandra dc Carvalho Bastone, R. Frei Leopolde, 173, Apt 104, Bairro Ouro Preto-Pampulha, Belo Horizonte-M.G., Brazil, CEP 31310-190; 55-31-3498-7430; fax: 55-31- 3441-3678; email: [email protected].

DOI: 10.1682/JRRD.2003.01.0014

Copyright Superintendent of Documents Sep/Oct 2004

Increased Insulin-Like Growth Factor-I Levels in Women With Polycystic Ovary Syndrome, and Beneficial Effects of Metformin Therapy

Key words: INSULIN, INSULIN-LIKE GROWTH FACTOR-I, METFORMIN, POLYCYSTIC OVARY SYNDROME, REGULAR MENSES

ABSTRACT

We aimed to investigate whether metformin would reverse the endocrinopathy of polycystic ovary syndrome (PCOS), allowing resumption of cyclic ovulation and regular menses, and whether metformin causes any change in the serum concentration of insulin- like growth factor-I (IGF-I) in patients with PCOS. Fifty-eight women with PCOS participated in the study and received metformin at a dose of 850 mg three times a day (total 2550 mg)for 16 weeks. Serum concentrations of luteinizing hormone, follicle stimulating hormone, estradiol, free testosterone, total testosterone, 17- hydroxyprogesterone, dehydroepiandrosterone sulfate, fasting insulin, IGF-I, sex hormone binding globulin and insulin-like growth factor binding protein-1 (IGFBP-1) were evaluated before and after metformin treatment. Patients were divided into two groups as responders and non-responders according to the achievement of regular menstrual periods. The mean IGFI levels decreased significantly on metformin therapy. After 16 weeks of metformin treatment, 55.17% of PCOS patients achieved regular menses. Only the change in serum levels of progesterone and IGF-I on metformin were statistically significant between responders and nonresponders; metformin-induced decremental change in IGF-I levels were greater in responders. In conclusion, we observed that elevated IGF-I levels may have a crucial role in many consequences of PCOS in addition to hyperinsulinemia. By decreasing insulin and IGF-I levels, metformin therapy offers additional beneficial effects in resumption of regular menses. Thus, in PCOS patients with elevated levels of IGF- I, metformin may be considered as an appropriate agent to be used for the regulation of menstrual cycles.

INTRODUCTION

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies, affecting approximately 5-10% of women of reproductive age . This syndrome, in addition to chronic anovulation and hyperandrogenemia, is also characterized by several metabolic aberrations, including insulin resistance and compensatory hyperinsulinemia, as well as possible dysregulations of the insulin- like growth factor-I (IGF-I) system. Because the majority of women with PCOS are obese, it seemed initially that their insulin resistance could be accounted for on this basis alone; however, the studies of Dunaif and colleagues2-4 firmly established that the magnitude of insulin resistance is greater in women with PCOS than in their controls, matched for total and fat-free body mass. The current consensus is that both lean and obese women with PCOS may show evidence of decreased insulin sensitivity5. The resultant hyperinsulinemia enhances androgen levels by stimulating ovarian androgen synthesis and by lowering circulating concentrations of sex hormone binding globulin (SHBG).

The discovery that insulin resistance has a key role in the pathophysiology of PCOS has led to a novel and promising therapy in the form of insulinsensitizing drugs. Among the various agents, metfbrmin is the most widely tested. Metfbrmin has several mechanisms of action that tend to result in improvements in hyperinsulinemia in women with PCOS. The major effect is seen in the liver, where it suppresses hepatic glucose output. Metformin may also improve peripheral insulin resistance6. For many patients, metfbrmin therapy results in measurable weight loss, presumably secondary to the induction of sufficient abdominal discomfort to decrease appetite. The results of various studies of metfbrmin in patients with PCOS are variable. Not all studies have demonstrated a beneficial effect that could be clearly separated from that of weight loss7-9.

Several studies have suggested that IGF-I may play an important role in the regulation of ovarian follicular maturation and steroidogenesis10-12. It has been postulated that elevated levels of insulin and IGF-I along with elevated levels of luteinizing hormone (LH), acting on the thecal component m vivo, contribute to the hyperandrogenemia observed clinically in PCOS patients. While it is evident that IGF-I plays a role in PCOS, only a few studies have focused on the effects of metfbrmin therapy on IGF-I levels in PCOS patients13,14. The present study aimed to investigate whether metfbrmin would reverse the endocrinopathy of PCOS, allowing resumption of cyclic ovulation and regular normal menses. The second aim was to investigate whether metfbrmin causes any change in the serum concentration of IGF-I in patients with PCOS.

SUBJECTS AND METHODS

Fifty-eight women with clinical and biochemical evidence of PCOS were enrolled into this study. Mean age of the patients was 24.9 2.3 (range 19-31 years). The study protocol was approved by the Institutional Review Board of the Department of Obstetrics and Gynecology, and informed consent was obtained from each woman before starting the study. Subjects were recruited consecutively between February 2001 and June 2002 from our out-patient clinic. Diagnosis of PCOS was based on the presence of oligomenorrhea or amenorrhea and hyperandrogenemia. Free testosterone (FT) concentrations were determined in the local laboratory using radioimmunoassay. We considered that a patient had elevated FT if the concentration exceeded 3.2 pg/ml. Oligomenorrhea was defined as fewer than six cycles per year and amenorrhea as the absence of periods for ≥ 6 months. A baseline ultrasound scan was applied to all patients to evaluate the uterus and the ovaries. However, the polycystic ovarian morphology detected by ultrasound was not considered an essential criterion for the diagnosis of the syndrome, since abnormal ovarian appearance is a prevalent but not a universal feature of PCOS15.

Thyroid dysfunction, hyperprolactinemia, hypercortisolism and late-onset congenital adrenal hyperplasia were all excluded, using the appropriate tests. In order to exclude diabetes mellitus, a standard 2-h, 75-g oral glucose tolerance test (OGTT) was performed in all women, with normal results. None of the patients had taken oral contraceptives or any other steroid medication during the preceding 3 months. To gain entry to the study, body weight had to remain stable for at least 2 months before the study, and subjects participating in a dietary or exercise program for weight reduction were excluded.

Study design

All patients were evaluated between days 3 and 6 of spontaneous menstruation or at any time if amenorrhea was present. At the initial visit, a medical history was obtained and a physical examination was conducted with measurement of height and weight for the calculation of body mass index (UMI). Before the metfbmiin treatment, patients were screened for blood count, serum electrolytes, liver and renal functions, and lipid profile; basal blood samples for LH, follicle stimulating hormone (FSH), estradiol, FT, total testosterone (TT), 17-hydroxyprogcsterone (17OHP), dehydroepiandrosterone sulfate (DHEAS), fasting insulin (FI), IGF- I, SHBG and insulin-like growth factor binding protein-1 (IGFBP-I) were obtained at 08.00 after an overnight rest and fast.

After baseline study, all patients received metformin (metformin hydrochloride, Glucophage retard tablet; Merck, Germany) at a dose of 850 mg three times a day (total 2550 mg), 1 h after meals. All the patients were instructed to continue taking the medication for 16 weeks without modifying their physical activity and usual diet. At the end of the 16 weeks, the baseline protocol was repeated, and changes in the BMI and menstrual pattern were also recorded. We divided the patients into two groups as responders and non- responders according to the achievement of regular menstrual periods defined as two or more sequential menstrual cycles encompassing 21- 35 days. Spontaneous ovulation was detected by blood sampling between days 20 and 24 of the last menstruation. A progesterone serum level of ≥ 5 ng/ml was considered an ovulatory level. Since it is accepted that metformin treatment is not associated with episodes of hypoglycemia, glucose serum levels were not monitored during treatment16.

Hormonal assays

Serum glucose level was determined enzymatically using the glucose oxidase method on a Hitachi 747 autoanalyzer (Hitachi, Tokyo). Serum DHEAS level was measured by electrochemiluminescence immunoassay (Elecsys Systems 1010/2010/ Modular Analytics E170, Roche Diagnostics GmbH, Mannheim, Germany; normal range 70-300 g/dl in females). 17-OHP and FT were measured by radioimmunoassay (RIA), using ^sup 125^I RIA kits (17OHP kit: ICN Biomedicals, Inc., Diagnostic Division, Costa Mesa, CA, USA; normal range 0.1-0.8 ng/ ml in the fbllicular phase; FT kit: DSL-4900, Diagnostic System Laboratories, TX, USA; normal range 0.45-3.2 pg/ml). Serum LH and FSH levels were measured by immunometric assay (IMMULITE 2000, Diagnostic Products Corporation, Los Angeles, CA, USA; normal range in fbllicular phase 2.5-12.00 mIU/ml and 1.98-11.60 mIU/ml, respectively). Estradiol, progesterone and TT were measured by competitive immunoassays using available kits (IMMULITE 2000, Diagnostic Products Corporation; normal range 26-161 pg/ml, 0.12- 1.7 ng/ml in fbllicular phase, and 5.76-77 ng/ml, respectively). Insulin was measured by R\IA using a Coat-A-Count kit (Diagnostic Products Corporation, Los Angeles, CA, USA). For the insulin measurement, intraassay coefficients of variation (CVs) were 9.3% and 5%, and interassay CVs were 10% and 4.9% for low and high values, respectively. IGF-I was measured by using an immunoradiometric assay kit (Immunotech, Marseille, France; normal range 232-385 ng/ml, for 20-30 years of age). Intraassay CVs were 7.4% and 4.1% for the low and high values, and interassay CVs were 15.5% and 12.9% for the low and high values of IGF-I, respectively. SHBG was measured by RIA by using the BC 1020 kit (Biocode, Schlessin, Germany). For SHBG, the intra-assay CVs were 5.6% and 4.9%, and interassay CVs were 7.6% and 6.9% for the low and high values, respectively. IGFBP-1 was measured by RIA (Bio-Source, Nivelles, Belgium). Intra-assay and interassay CVs were less than 10%.

Statistical analysis

The pre- and post-treatment data were evaluated using the Wilcoxon rank sum test. The results between the responders and non- responders were analyzed using the Mann-Whitney U test. Correlations were estimated using simple regression analysis. A value of p

RESULTS

The effects of metformin on endocrine and clinical indices are presented in Table 1. The mean BMI of the patients did not change significantly during the study period. After 16 weeks of metformin therapy, there was a significant reduction of LH levels (11.15 3.02 vs 8.67 2.92 miIU/ml; p

Table 1 Clinical and hormonal data of 58 women with polycystic ovary syndrome before and after 16-week metformin treatment

After 16 weeks of metformin treatment, 32 of 58 PCOS patients achieved regular menses (55.17%) To determine the effects of metformin on menstrual regularity, we divided the patients into two groups according to menstrual changes: responders (n = 32) and non- responders (n = 26) (Table 2). These two groups did not differ from each other in terms of mean age and BMI. Twenty-one out of 32 (65.6%) patients with regular menses had a serum progesterone level within the ovulatory range (3.0-28 ng/ ml) which was statistically significant (p

The baseline study showed statistically significant correlations between insulin and TT, FT, IGF-I, HOMA-R index and BMI (Table 3). We failed to find any correlation between insulin and other studied hormonal parameters. Unlike insulin, IGF-I was not statistically related to testosterone levels. After 16 weeks of metformin therapy, we did not find any significant correlation between decrease in serum fasting insulin level and the changes in other studied hormonal and clinical parameters. As shown in Table 4, the change in IGF-I on metformin therapy was inversely correlated with the change in progesterone level (r=-0.41; p = 0.002), and was positively correlated with the change in LH level (r = 0.29;p = 0.023). The relationships of the change in IGF-I to the change in other variables were examined also, but no statistically significant correlations were observed.

Table 2 Comparison of the differences of the clinical and hormonal data between responders and nonresponders to metformin treatment in 58 women with polycystic ovary syndrome

Table 3 Significant correlations between insulin and other parameters at study entry in 58 patients with polycystic ovary syndrome

Table 4 Significant correlations between changes on metformin in 58 patients with polycystic ovary syndrome

After starting on metformin treatment, 22 of 58 women reported minor gastrointestinal problems including abdominal discomfort, meteorism, nausea and diarrhea that did not necessitate discontinuation of the treatment. These side-effects resolved spontaneously within a few weeks when the drug was taken at mealtime.

DISCUSSION

Although PCOS is the most common pathological cause of anovulation, the pathogenesis of this syndrome has not been AUIy defined. Current studies suggest that abnormalities of the insulin and IGF systems, including hyperinsulinemia, insulin resistance and increased IGF-I, may be involved18-20. These findings prompted the testing of insulinsensitizing agents, such as metfbrmin or troglitazone, for the treatment of both the metabolic and the endocrine abnormalities of women with PCOS ” .

In this respect, there were two main findings of the present study: first, 16 weeks of metfbrmin administration reduced IGF-I levels and ameliorated insulin resistance and hyperandrogenemia, with no significant changes in BMI; and second, metfbrniininduced decrements in IGF-I levels were greater in women with PCOS who achieved regular menstruation after metfbrmin therapy.

In our study, we observed higher insulin concentrations in all PCOS women, in agreement with the literature21,22. After metfbrmin therapy, we observed a significant reduction in FI, TT and FT concentrations together with decreased insulin resistance (decreased HOMA-R), whereas change in BMI did not reach statistical significance. There are several studies on metfbrmin therapy in patients with PCOS, but the results are inconsistent5,7,9,19. Currently, it is still not clear whether the reduction in FI concentration is a direct effect of metfbrmin action or an indirect result of the weight loss in the group of PCOS patients. Ehrmann and colleagues did not observe any beneficial effect of metfbrmin treatment on body weight . Additionally, they reported that hyperinsulinemia and hyperandrogenism did not improve after metfbrmin treatment, which is in constrast to our findings. They concluded that there was no direct effect of nictfbrmin on gonadotropin or ovarian steroid production that could be independent of weight loss9. However, contrary to the results of Ehrmann et al., Morin-Papunen and colleagues did not observe a significant change in BMI after 4-6 months of metformin treatment, and they also observed a statistically significant decrease in fasting insulin concentrations and free testosterone levels23. These data are in agreement with the results obtained in our study. Thus, it was demonstrated that the effects of metfbrmin on PCOS were due to actions independent of weight loss, and BMI should not be the sole predictor of the success of mctformin therapy.

In the present study, metfbrmin treatment was associated with a reduction in androgen serum levels, partly due to a reduction in insulin levels. Hyperinsulinemia enhances androgen concentration by direct stimulation of ovarian androgen synthesis, or by enhancing LH secretion and by lowering the concentration of SHUG14. Since the serum levels of SHBG were within normal limits at the beginning of the study and did not change significantly after metfbrmin treatment, the last factor is most probably not the major responsible mechanism for insulin-mediated hyperandrogenism observed in our study. In the current study, insulin was more strongly correlated with TT and FT than with LH. Supporting the finding of our study, m i//(m studies have shown that thecal cells from polycystic ovaries were more sensitive to insulin; the same concentrations only slightly affected testosterone production in controls” .

More recent studies have focused on the ability of metformin to improve menstrual regularity and documented ovulation ^ “” . Morin- Papunen and colleagues reported that 69% of Finnish PCOS women with menstrual disturbances developed regular menstrual cyclicity on metfbrmin 1500 mg/day for 6 months “. Diamanti-Kandarakis cf a/, reported that seven of 16 (44%) Greek women with PCOS resumed normal menstruation on metfbrmin, 1700 mg/day for 6 months””. Nestler ff a/ , reported that 12 of 35 obese women (34%) ovulated after 35 days on nietfbrmin 1500 mg/day, versus one of 26 (4%) given placebo” . In the present study, parallel to the previous reports, with metfbrmin of 2550 mg/day, 32 of 58 (55.17%) previously oligomenorrheic/ amenorrheic PCOS women resumed normal menstrual cyclicity, labeled as responders. It was demonstrated that, in subjects experiencing regular menses after metfbrmin treatment, improvement was observed within 4 months” ” . In our opinion, a dose of metfbrmin 850 nig three times per day is important in the achievement of regular menses. Although we could not assess how many of the cycles were ovulatory during therapy, after 16 weeks of treatment, 21 of 32 (65.6%) women who resumed regular menses had a serum progesterone level within the ovulatory range. As a result, consistent with the novel theoretical models of PCOS, we can state that hyperinsulinism and resultant hypcrandrogenism chronically alter gonadotropin secretion, increasing LH, disrupting the normal pituitary-ovarian axis, leading to oligomenorrhea and amenorrhea26,32. Thus, when metfbrmin reduces insulin levels, this leads directly to consequent decrements inandrogens with restoration of the normal pituitaryovarian feedback system23,25,28-30,33. However, in the current study, we demonstrated that only the change in scrum levels of progesterone and IGF-I on metfbrmin were statistically significant between responders and non-respondcrs; metfbrmin- induced decrements in IGF-I levels were greater in responders. Therefore, whether all of the therapeutic effects of metfbrmin in women with PCOS are mediated solely by its insulin-lowering effects remains to be determined. Hence, we can speculate that the decrements in IGF-I on metfbrmin therapy may also play a part in achievement of a normal pituitary-ovarian axis; i.e. resumption of ovulatory menses.

There is evidence suggesting that PCOS is associated with an increase in the level of IGF-I, possibly because of a decrease in IGFBP-I, a hepatic product the synthesis of which is inhibited by insulin13,34,35. We showed a significant correlation between IGF-I and insulin and insulin resistance, supporting the suggestion that IGF-I could play a role in the pathogenesis of PCOS. However, the situation is likely to be complex, and the physiology of how IGF-I contributes to hyperandrogenemia is not fully defined. While it is evident that IGF-I plays a role in PCOS, there are a limited number of studies showing the precise effect of metfbrmin therapy on IGF-I levels. Kowalska and colleagues reported that the IGF-I level remained unchanged, and the IGFBP-1 concentration showed a tendency to increase, which did not reach statistical significance after 4-5 months of metfbrmin treatment in the PCOS group14. Similarly, De Leo and colleagues observed that IGF-I concentrations did not change after 30-32 days of metfbrmin treatment, with a significant increase in serum IGFBP-1 levels in patients with PCOS13. In our study, we observed a statistically significant decrease in IGF-I levels after 16 weeks of metfbrmin treatment. Additionally, as we expected, the IGFBP-I level showed a tendency to increase. However, it did not reach statistical significance. This finding may be explained by the fact that the response to metfbrmin in PCOS patients is not entirely uniform. The decrement in IGF-I levels was significantly greater in women who resumed regular menses. We also found a significant correlation between change in IGF-I concentrations and changes in progesterone and LH levels. We can speculate that, despite the significant decrease in serum insulin levels in both responders and nonresponders, improvement in menstrual cyclicity following metfbrmin treatment in the responder group may be primarily related to the overwhelming decrease in the IGF-I levels in this group of PCOS women. In agreement with our data, in a recent study, Duleba and colleagues showed that IGF-I increased the number of thecal- interstitial cells more potently than insulin35. This important finding offers another, complementary, explanation of hyperandrogenism seen in PCOS patients.

In summary, we observed that elevated IGF-I levels may have a crucial role in many consequences of PCOS in addition to hyperinsulinemia. By decreasing insulin and IGF-I levels, metfbrmin therapy offers additional beneficial effects in resumption of regular menses. Thus, in PCOS patients with elevated levels of IGF- I, metfbrmin may be considered as an appropriate agent that could be used for the regulation of menstrual cycles, but large randomized trials are needed. With increasing understanding of the IGF system and its roles in ovarian physiology, future therapeutic modalities will be developed to treat such disturbances in ovarian physiology as anovulation and disorders of androgen excess, and treatment modalities for the infertile couple will be expanded.

References

1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz K. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998;83:3078-82

2. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499-507

3. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165-74

4. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774-800

5. Ehrmann DA. Insulin-lowering therapeutic modalities for polycystic ovary syndrome. Endoainol Metab Clin North Am 1999;28:423- 38

6. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998; 338:867-72

7. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovaiy syndrome? Fertil Steril 1996;65:946-9

8. Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M. Effects of diet and metformin administration on sex hormone- binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endoainol Metab 1995;80:2057-62

9. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovaiy syndrome. J Clin Endoainol Metab 1997;82:524-30

10. Thierry van Dessel HJ, Lee PD, Faessen G, Fauser BC, Giudice LC. Elevated serum levels of free insulin-like growth factor I in polycystic ovaiy syndrome. J Clin Endocrinol Metab 1999;84:3030-5

11. Stadtmauer LA, Toma SK, Riehl RM, Talbert LM. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril 2001;75:505-9

12. Tiitinen AE, Laatikainen TJ, Seppala MT. Serum levels of insulin-like growth factor binding protein1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease. Fertil Steril 1993;60:58-62

13. De Leo V, La Marca A, Orvieto R, Morgante G. Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovaiy syndrome. J Clin Endoainol Metab 2000;85: 1598-600

14. Kowalska I, Kinalski M, Straczkowski M, Wolczyski S, Kinalska I. Insulin, leptin, IGF-I and insulindependent protein concentrations after insulinsensitizing therapy in obese women with polycystic ovaiy syndrome. EwJ Endocrinol 2001;144:509-15

15. Battaglia C, Regnani G, Artini PG, et al. Polycystic ovaiy syndrome: a new ultrasonographic and color Doppler pattern. Gynecol Endocrinol 2000;14:417-24

16. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 1994-11:223-41

17. Mather KJ, Hunt AE, Steinberg HO, et al. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab 2001;86:5457-64

18. Taylor AE. Insulin-lowering medications in polycystic ovary syndrome. Obstet Gynecol Clin North Am 2000;27:583-95

19. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovaiy syndrome. Fertil Steril 2000;73: 1149- 54

20. Velazquez EM, Mendoza S, Hamcr T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-54

21. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogemsm with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980; 50:113-16

22. Dunaif A, Fincgood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942-7

23. Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998;69:691-6

24. Nestler JE, Jakubowicz DJ, de Vargas AF, Bnk C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J CHn Endocrinol Metab 1998:83:2001-5

25. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. EurJ Endocrinol 1998;138:269-74

26. Glueck CJ, Wang P, Fontaine R, Tracy T, SieveSmith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 1999;48:511-19

27. Morin-Papunen EC, Koivunen RM, Tomas C, Ruokonen A, Martikainen HK. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:2566-8

28. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:6l7-23

29. Velazquez E, Acosta A, Meiidoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392-5

30. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876-80

31. Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double- blind, placebocontrolled 6-month trial, followed by open, longterm clini\cal evaluation. J Clin Endocrinol Metab 2000;85:139-46

32. Pasquali R, Filicori M. Insulin sensitizing agents and polycystic ovary syndrome. Eur J Endocrinol 1998;138:253-4

33. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in serum plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997;46:454- 7

34. Homburg R, Pariente C, Lunenfeld B, Jacobs HS. The role of insulin-like growth factor-1 (IGF-I) and IGF binding protein-1 (IGFBP-I) in the pathogenesis of polycystic ovary syndrome. Hum Reprod 1992;7:1379-83

35. Duleba AJ, Spaczynski RZ, Olive DL. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca- interstitial cells. Fertil Steril 1998;69:335-40

B. Berker, R. Emmi*, C. Demirel, D. Corapcioglu*, C. Unlu and K. Kose[dagger]

Department of Obstetrics and Gynecology; * Department of Endocrinology; [dagger] Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey

Correspondence: Dr B. Berker, Hseyinonat Sokak 10/6 Sahinbey Ap. Asagi ayranci , 06540-Ankara, Turkey

Tel: +90-312-466 28 70 Fax: +90-312-3203553 e-mail: [email protected]

Copyright CRC Press Sep 2004

Prevalence of Gestational Diabetes Mellitus and Pregnancy Outcomes in Asian Women With Polycystic Ovary Syndrome

Key words: GESTATIONAL DIABETES MELLITUS, HYPERTENSIVE DISORDER IN PREGNANCY, POLYCYSIC OVARY SYNDROME, PREMATURE DELIVERY

ABSTRACT

The aim of this study was to determine the prevalence of gestational diabetes mellitus (GDM) and the pregnancy outcomes in Asian women with polycystic ovary syndrome (PCOS). The retrospective cohort study was performed to compare pregnancy outcomes of 47 pregnancies in 41 PCOS women with 264 pregnancies in 222 women with normal menstruation. Logistic regression was used to assess the risk of PCOS on GDM, hypertensive disorder in pregnancy (HDP) and premature delivery. The mean age of both groups was 31 years. The mean body mass index (BMI) and proportion of BMI of > 25 kg/m^sup 2^ were significantly higher in the PCOS than in the control group. There was no difference in the prevalence of GDM between the PCOS women and the high-risk group of the controls. The prevalence of HDP and premature delivery was significantly greater in PCOS women (21.3 and 13.3%) than in the controls (6.4 and 5.4%), respectively. PCOS was demonstrated as a risk factor for GDM ami HDP with borderline statistical significance, but not for premature birth. The Cesarean section rate was higher in the PCOS than in the control group. In conclusion, the prevalence of GDM in Asian women with PCOS is high and comparable to those of a high-risk group.

INTRODUCTION

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, characterized by menstrual irregularities and hyperandrogenism1. It is well accepted that insulin resistance (IR) is an important pathogenesis of PCOS2. IR is the cause of abnormal glucose tolerance”, therefore type 2 diabetes mellitus (I)M) and impaired glucose tolerance (IGT) can be found in PCOS women. IGT in 25-31% and 7.5-15.2% of type 2 DM in these women has been reported recently4-6.

Because pregnancy induces IR , pregnant women with PCOS may be at increased risk for gestational DM (GDM) and IGT. However, there have been contradictory results in the prevalence of GDM when compared between PCOS and control women8-12.

In addition, there is evidence that IR is associated with hypertension and hypertensive disorder in pregnancy (HDP)13. PCOS women may also be at risk for HDP. The prevalence of HDP and pre- eclampsia in PCOS has been reported to be higher than in controls8,9,14. By contrast, there have been studies that did not show this increased risk10,12.

Recently, some studies showed that the IR of Asian ethnic women who lived in Western countries was not lower than that of Caucasian women15. The fact that the prevalence of IGT and type 2 DM in Asian women ‘ was reported to be comparable to those in Caucasians4,5 provided evidence that there may be no difference in IR between the two ethnic groups. Like other ethnic populations, Asian pregnant women with PCOS would be at risk for GDM as well. However, there is no report on GDM in Asian women with PCOS. Therefore, the aim of this study was to determine the prevalence of GDM and pregnancy outcome in Asian women with PCOS.

METHODS

Between 3 June 1996 and 31 May 2002, 41 PCOS women with 47 pregnancies who were treated in the Reproductive Endocrinology and Infertility Unit were enrolled in the study. The criteria for the diagnosis of PCOS according to Homburg16 were as follows: menstrual irregularities; clinical hyperandrogenism such as acne, seborrhea and hirsutism; and typical ultrasound presentation of bilateral polycystic ovaries with ten or more follicles of 2-8 mm in diameter, as described by Adams and colleagues17. Of the 47 pregnancies, six were conceived spontaneously and 17 were conceived after ovulation induction with clomiphene citrate (CC). The remaining were CC- resistant PCOS women, and pregnancies occurred after laparoscopic ovarian drilling, ovulation induction with metformin, and in vitro fertilization and embryo transfer in 15, eight and one women, respectively.

Starting from October 1997, the protocol for GDM screening in all pregnant women with PCOS was established. These pregnant women had a 3-h, 100 g oral glucose tolerance test (OGTT) performed at 24-28 weeks of gestation, according to the one-step method of the American Diabetic Association (ADA)18.

GDM was diagnosed if two or more plasma concentrations were at or exceeded the levels according to the ADA18 as follows: fasting, ≥ 95 mg/dl; 1 h, ≥ 180 mg/dl; 2 h, ≥ 155 mg/ dl; and 3 h, ≥ 140 mg/dl.

Both gestational hypertension and pre-eclampsia are components of HDP and were considered in this study. Gestational hypertension was defined as blood pressure of ≥ 140/90 mniHg with no proteinuria, and pre-eclampsia was diagnosed when hypertension was accompanied by proteinuria ( ≥ 300 mg/24 h)19. Delivery at

The controls had normal menstruation, were matched for age ( 2 years) and registered on the same day. The women who were at risk for GDM also had an OGTT performed at 24-28 weeks of gestation according to the one-step method of the ADA18. The pregnant women who delivered elsewhere or who did not receive antenatal care in this hospital or suffered a miscarriage before 20 weeks of gestation were excluded from the study.

All parameters of pregnancy outcomes were collected from medical records of both the pregnant women and the neonates. This study was approved by the ethical committee of our institute.

Unpaired t test, χ^sup 2^ test and Fisher’s exact test were used to compare the groups, where indicated. Univariate and multivariate logistic regressions were used to analyze risk factors for GDM, HDP and premature delivery. A value of p

RESULTS

There were 288 pregnancies in 246 women who were used as the controls. Of these, 24 pregnancies in 24 women were excluded from the study because 21 delivered elsewhere or did not receive antenatal care in this institute and three miscarried. The remaining 264 pregnancies of the control group and 47 of the study group were analyzed.

The mean age of both groups was 31 years. The proportion with age > 35 years was not different between the groups. The mean pre- pregnancy body weight, body mass index (BMI) and prevalence of obesity (BMI > 25 kg/m^sup 2^) were significantly higher in the PCOS than in the control group (p = 0.000). However, gestational weight gain was not different between the groups. Nulliparity was more prevalent in the PCOS women than in the controls (p = 0.004), whereas the multiple pregnancy rate was not different. All multiple pregnancies in this study were twin pregnancies. Four out of five twin pregnancies were premature. The Cesarean section rate was high in both groups, and significantly greater in the PCOS than in the control group (p = 0.004, Table 1).

Thirty-six (76.6%) of PCOS women and 100 (37.9%) of the controls received an OGTT. Eight and 18 women were diagnosed as GDM in the PCOS and in the control group, respectively. The prevalence of GDM did not differ between the PCOS women and the controls who had an OGTT (Table 2). After analysis by logistic regression, PCOS and the family history of DM were independent risk factors for GDM, with an odds ratio (OR) of 3.3 (95% CI 1.1-9.7) and 9.3 (95% CI 3.2-26.9), respectively, whereas age, BMI and parity were not in the singleton pregnancies (Table 3).

Ten (21.3%) of PCOS women and 17 (6.4%) of the controls were diagnosed with HDP. Of ten in the PCOS group, eight (17%) had gestational hypertension and two (4.3%) had pre-eclampsia. One case of pre-eclampsia was detected in the control group (Table 2). Using logistic regression, PCOS, age and GDM were the risk factors with borderline statistical significance in the singleton pregnancies (Table 4).

Table 1 Patients’ characteristics and maternal pregnancy outcomes

Table 5 shows the comparison of the neonatal outcomes of singleton pregnancies between the groups. Gestational age was significantly lower (p = 0.027) and premature rate was higher (p = 0.046) in women with PCOS than in the controls. Analysis of risk factors for premature delivery of the singleton pregnancies indicated that HDP was an independent risk factor (Table 6).

Two (4.3%) perinatal deaths occurred in PCOS women. One was a dead fetus in utero at 27 weeks of gestation. The cause of death could not be established in this case after the investigation. The other was a preterm neonate of a twin pregnancy at 22 weeks of gestation. One died of respiratory distress syndrome (RDS) 5 days after birth, and the another also had RDS but survived after intensive treatment.

Table 2 Prevalence of gestational diabetes mellitus (GDM) and hypertensive disorder in pregnancy (HDP) between the group with polycystic ovary syndrome (PCOS) and the control group

Table 3 Risk factors for gestational diabetes mellitus in the singleton pregnancies

Table 4 Risk factors for hypertensive disorder in pregnancy in the singleton pregnancie\s

DISCUSSION

This study has demonstrated that GDM was more frequently found in the PCOS group than in the control group, as has been found by others8,10. More than one decade ago, Gjonnaess14 reported that the incidence of GDM in PCOS women who conceived after laparoscopic ovarian drilling was 8.1%, which was more than that of the general population at that time. Subsequent studies showed that the prevalence of GDM in PCOS women was around 20%8,10, whereas it was 3- 9% in controls.

Although most studies have shown a higher prevalence of GDM in PCOS than in controls, a few studies, in contrast, did not demonstrate a difference in GDM rate between PCOS and controls11,12. In the study of Wortsman and colleagues , there was a difference of GDM rate between PCOS and the control women (16.7% in 22 and 6.7% in 44), but this did not reach statistical significance. With the small number of these populations studied, the power of testing was only 0.159, which could certainly not show a difference. Moreover, some authors demonstrated recently that the rate of GDM was not statistically different between PCOS and control women .

PCOS has been demonstrated as a risk factor for GDM with borderline statistical significance10. This could be explained, in part, by the increased IR and hyperinsulinemia in the pregnant PCOS women compared with the control women7,22 . Likewise, PCOS was a predictive factor for GDM in this study; IR in Asian women with PCOS may not be different from the other ethnic groups15.

Family history of DM is one of the indications for an OGTT according to the ADA18 and was more frequently found in PCOS women12. However, it was not considered as a risk factor in previous studies10,12. In this study, it was demonstrated as an independent risk factor for GDM

Mikola and colleagues10 reported that obesity was an independent predictor for GDM, but this was not shown in our study. There were some controversial reports about obesity as risk factors for GDM in women with PCOS. Some studies showed that the prevalence of GDM was increased by BMI10,14. In contrast, a study from Turkey demonstrated not only that the prevalence of GDM was higher in PCOS than in controls, but also that the differences occurred merely between the lean PCOS and the lean control women when compared between subdivided groups8.

Table 5 Comparison of neonatal outcomes of singleton pregnancies between the group with polycystic ovary syndrome (PCOS) and the control group

Table 6 Risk factors for pretcrm delivery in the singleton pregnancies

There have been reports of the risk of PCOS on HDP8,9,14. Some studies have shown a risk of PCOS on pre-eclampsia9,14, and some on gestational hypertension8. By contrast, Mikola and colleagues did not show the risk of PCOS on pre-eclampsia. In agreement with most of the previous studies, HDP and gestational hypertension were significantly more frequent m PCOS women than in the controls in this study. The risk of PCOS on HDP was more than three times that with respect to the controls. The risk of PCOS on HDP can be explained by the existence of IR. Previous studies showed that the pregnant women who developed HDP had hyperinsulinemia22. Moreover, there was a report of an increased risk for HDP among women with GDM23, supporting the finding in this study.

Although Urman and colleagues demonstrated that a low birth weight was more frequent in PCOS than in controls, other studies showed no differences in any parameters of neonatal outcomes comparing the singleton pregnancy between both groups10,12. On the other hand, this study showed the gestational age at birth was lower and the rate of prematurity was higher in the PCOS than in the control group. However, PCOS was not indicated as a risk factor for premature delivery. This finding was consistent with that of others8,10. It is well documented that pre-eclampsia is an important risk factor for preterm delivery . Therefore, HDP may, in part, be a risk factor that accounts for premature delivery in pregnant women with PCOS.

There was a report of one neonatal death with respiratory syndrome 20 h after a Cesarean section for abruptio placentae14. Urman and colleagues also reported one perinatal death in a PCOS woman with abruptio placentae, and one in the control group. In the current study, there were two perinatal deaths: one fetal death in utero and one of the twins with severe pre-eclampsia that died of respiratory distress syndrome. It can be seen that perinatal deaths in PCOS women were associated with severe pre-eclampsia and prematurity. Therefore, we cannot assume that PCOS is a risk for poor neonatal outcome.

The Cesarean section rate was high, both in the PCOS group and in the control group, and higher with respect to the other reports . This may be due, first, to the fact that there was no policy or protocol for vaginal birch after Cesareaii section (VBAC). It is known that VBAC policy can reduce the rate of Cesarean delivery. In this study, one-fourth of PCOS women and 40% of the controls had had a previous Cesarean delivery. This finding was consistent with a previous survey24. second, the high rate of Cesarean delivery might be due to the attitude, as in some individuals, that Cesarean delivery is better for the baby25. In addition, the difference in Cesarean section rates between the PCOS group and the control group could not be explained by the maternal and fetal complications. Instead, infertility may be the factor that, in part, explains this difference.

In conclusion, it was shown that the prevalence of GDM, HDP and premature delivery was higher in Asian women with PCOS than in the control women. PCOS was a risk factor for GDM and HDP, but not a potential risk factor for premature birth. However, it cannot be concluded that PCOS poses a risk on neonatal outcome.

References

1. Frank S. Polycystic ovary syndrome. N Engl J Med 1995;333:853- 61

2. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implications for pathogenesis. Endocr Rev 1997; 18:774-800

3. Weyer C, Tataranni PA, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2001;24:89-94

4. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endomnol Metab 1999; 84:165-9

5. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:14l-6

6. Weerakiet S, Srisombut C, Bunnag P, et al Prevalence of type 2 DM and impaired glucose tolerance in Asian women with polycystic ovary syndrome, hit J Gynecol Obstet 2001 ;75:177-84

7. Knopp RH, Montes A, Childs M, et al. Metabolic adjustments in normal and diabetic pregnancy. Clin Obstet Gynecol 1981;24:21-49

8. Urman B, Sarac E, Dogan L, et al. Pregnancy in infertile PCOD patients: complications and outcome. J Reprod Med 1997;42:501-5

9. Radon PA, McMahon MJ, Meyer WR. Impaired glucose tolerance in pregnant women with polycystic ovary syndrome. Obstet Gynecol 1999;94: 194-7

10. Mikola M, Hiilesmaa V, Halttunen H, et al. Obstetric outcome in women with polycystic ovarian syndrome. Hum Reprod 2001; 16:226- 9

11. Wortsman J, de Angeles S, Futterweit W, et al. Gestational diabetes and neonatal macrasomia in the poly cystic ovary syndrome. J Rcp rod Med 1991;36:659-61

12. Turhan NO, seckin NC, Aybar F, et al. Assessment of glucose tolerance and pregnancy outcome of polycystic ovary patients, Int J Gynecol Obstet 2003;81:163-8

13. Roberts R. Hypertension in women with gestational diabetes. Diabetes Care 1998;21 (Suppl 2):B27-1332

14. Gjonnaess H. The course and outcome of pregnancy after ovarian electrocautery in women with polycystic ovarian syndrome: the influence of bodyweight. Br J Obstet Gynaecol 1989;96:714-19

15. Wijeyaratne CN, Balen AH, Barth JH, et al. Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? CHn Endocrinol (Oxf) 2002;57:343-50

16. Homburg S. Polycystic ovary syndrome from gynaecological curiosity to multisystem endocrinopathy. Hum Reprod 1996; 11:29-39

17. Adams J, Poison DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J 1986;293:355-9

18. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2001;24(Suppl 1):s77-s79

19. National high blood pressure education program: working group report on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:sl-s22

20. Creasy RK, lams JD. Preterm labor and delivery. In: Creasy RK, Resnik R, eds. Maternal- Fetal Medicine, 4th edn. Philadelphia: WB Saunders, 1999:498-531

21. Casey BM, Mclntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med 2001 ;344:467-71

22. Hamasaki T, Yasuhi I, Hirai M, et al. Hyperinsulinemia increases the risk of gestational hypertension. Int J Gynaecol Obstet 1996;55:141-5

23. Suhonen L, Teranio K. Hypertension and preeclampsia in women with gestational glucose intolerance. Acta Obstet Gynecol Scand 1993;72: 269-72

24. Chanrachakul B, Herabutya Y, Udomsubpayakul U. Epidemic of cesarean section at the general, private and university hospitals in Thailand. J Obstet Gynaecol Res 2000;26:357-61

25. YangX, Hsu-HageB, ZhangH, tal. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care 2002;25:1619-24

S. Weerakiet, C. Srisombut, A. Rojanasakul, P. Panburana, A. Thakkinstian* and Y. Herabutya

Department of Obstetrics and Gynecology; *Clinical Epidemiology Unit; Faculty of Medicine, Ramathibodi Hospital, Mahidol U\niversity, Bangkok, Thailand

Correspondence: Dr S. Weerakiet, Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 10400

Copyright CRC Press Sep 2004

JOHN L. SMITH: Daughter”S Struggle Against Cancer Provides Lesson in Being Thankful

This Thanksgiving I find myself more thankful than at any time in my life.

We are in the middle of what many people would call a horrible experience, our 8-year-old daughter Amelia’s medical treatment for a cancerous brain tumor.

“Thankful?” you ask. “For a brain tumor?”

It’s awful, of course. It’s painful and frightening, and I would give anything for it not to have happened.

But you can’t turn back the clock or become mired in the unthinkable possibilities the future might bring. The present is all we have, and so that is where we’re focused. I’m thankful for that lesson.

There is pain, but there is also something incredible going on. I’ve been given an opportunity to be part of the life of a brave little girl who just happens to be my daughter. I’m awed by this opportunity — even though what I’ve seen has sometimes been almost too much to bear.

Pushing a chemotherapy stand behind her the other day, I watched Amelia stoop as she took the slow, painful steps of an old woman. At that moment, she might have been 100. Her back ached from a spinal tap, her chest hurt from a surgically implanted medical port in her chest, and I ached along with her. But I was awed by her strength.

It was then I made sure to remind myself to be thankful — thankful because a battery of tests came up negative for the spread of cancer from her brain to her spine, thankful because that medical port would nearly end the need for all the painful needles in her arms, hands and neck. Thankful because she was winning a fight other children in the pediatric ward of St. Joseph’s Hospital in Phoenix were losing.

Two days later, Amelia was energetic enough to walk to the pediatric playroom, where the kids congregate whenever possible to play games, practice arts and crafts, and visit with people more their own size and age.

I was thankful that she was walking at all, for the little boy we’d met earlier in the day had been born with spina bifida and would be wheelchair-bound all his life. His parents had stood by him through dozens of surgeries. Although he was just a small boy, he’d been using his wheelchair for so long that his tiny hands were knots of muscle. That young kid was tougher than most of the professional athletes I’ve ever met.

Amelia and the boy had had minor surgeries on the same morning, and they had that in common — that, and an affinity for Sponge Bob – – and became instant friends.

Later, when the effects of her chemotherapy treatment made her quiet, lethargic and queasy, I saw the color drain from her face and felt my heart sink. But she has improved steadily, and the doctors and nurses smile when they see her. Neurosurgeons and oncologists love a success story in the making.

This process is teaching us that not all angels play harps and float on clouds. Plenty of them work 12-hour shifts disguised as pediatric nurses.

It’s great that our nurses are professionals, some of whom specialize in caring for chemo kids, but their kindness is what makes them so remarkable. They don’t have to share their supper, hand-craft a little girl a pair of earrings, dress her in hospital scrubs like a miniature doctor, or invite her horseback riding as an incentive for getting well soon, but they’ve done that and a hundred other things.

Only a fool wouldn’t be thankful.

These days, Amelia loses her beautiful golden strands with every brush stroke, but I am thankful because I know her hair will grow back one day.

One day, when her chemotherapy and radiation treatments are finally over. One day, when the memories of all the needle sticks and morning booster shots and nauseating medicine are a thing of the past.

One day, when she’s well again.

Just a few years ago a malignant tumor in such a precarious place in the brain might have been inoperable, or at best caused irreparable damage during surgery. As unfortunate as we might sometimes want to feel, we’re incredibly blessed to be living in an age of medical possibilities.

Slowly, a painful step at a time, she’s getting better.

How could I be anything but thankful for that?

John L. Smith’s column appears Tuesday, Wednesday, Friday and Sunday. E-mail him at [email protected] or call 383-0295.

Last Night’s Television: More Than Just a Schoolboy Crush ; Chubby Chasers ITV1 Full On Food BBC2

ANNA HAD lost eight stone for her impending marriage, the kind of achievement that would usually be the occasion for joyous celebration. But Anna was worried. Now that she was a mere 33 stone, would her future husband Tony still find her sexually attractive? The problem was that Tony was an FA, or a “Fat Admirer”, and though he swore that it was Anna’s personality that had finally persuaded him to settle down to the married life, she couldn’t entirely shake the suspicion that his devotion might be blubber deep. You could understand her anxiety. In the circles Anna moved in (very slowly and with her kneecaps further apart than seemed humanly possible) nobody was exactly lissom. In fact they all looked as if they’d got contraband Space Hoppers concealed about their persons. But Anna was earthshaking, so humungously obese that she’d had to have a tracheotomy so that she could breathe. And Fat Admirers seemed to take a “more is more” approach when it came to erotic satisfaction. They begin, as Tony had, with mere “Plumpers” and then steadily work themselves up to SSBBWs (Super Size Big Beautiful Women). So what happens when the portions get smaller?

Chubby Chasers, which described the internet-enabled connection between big women and their fans, never quite explained the appeal of enormity. “There’s just more of everything,” said one man. It sounded logical, but aren’t they fussy about where the “more” goes? The biggest of these women looked like badly stuffed beanbags. As for bilateral symmetry… well, you could forget that altogether. Another chubby chaser tentatively offered a less starkly physical explanation. “Larger women seem to be a lot more easy-going than other girls,” he said, which sounded like a diplomatic version of that coarse but ancient proposition that “fat girls are always grateful”. Watching one of the men making a futile attempt to put his arms around his partner, I did wonder whether there might be something about infancy going on here – and the consoling expanse of the maternal body – but this wasn’t going to go much beyond cosmetic superficialities, so no one put the impertinent question.

These women were grateful, however politically incorrect that sounds. But in several cases, years of self-loathing had been replaced by a sense of sexual value, and they seemed happy to settle for that. One interviewee, whose previous partner had paid an ex- girlfriend to attend a Christmas party with him rather than publicly acknowledge his relationship with an overweight woman, had discovered that she was the centre of attention at BBW meetings, and she visibly glowed in the knowledge. “I assumed it was a fetish,” said another, in a tone of voice that suggested she’d been silly to think any such thing. And since this was what most of us will have been thinking at the time, the line forced you to think about definitions. Sexual attraction which centres at first on specific details of physical appearance? A sense that one’s desires are independent of social convention? Perhaps it is a fetish, but then what isn’t?

Full On Food, BBC2’s new food magazine programme, isn’t quite done yet. The ingredients are all fine and the method is tried and tested. Assemble an audience in a large shed, chop the script up finely and divide it between two presenters, sprinkle with specialist news items, jaunty filmed packages and plenty of rhetorical questions (“Now, do you have a problem with peas?”). It works like a treat on Top Gear, whatever you might think of Jeremy Clarkson. Top Gear, though, has a marksman’s eye for its demographic: lads of all sexes who like to talk about torque. Here the community isn’t as easy to identify. Anyone who eats, or seriously dedicated foodies? I’m sure it will be fine in the end, but at the moment it’s like a jelly that won’t quite set.

STARVED TWINS PAIR ARE JAILED ; Police Shocked As Children Found in Squalor

A DOCTOR who treated twin babies rescued from a life of ‘utter squalor’ said they were ‘the worse case of malnutrition he had ever seen outside the developing world’.

A judge was told how police officers who brought five children out of the terraced house in Sheffield in June had difficulty not being physically sick in the excrement-smeared bedrooms and kitchen.

Sheffield Crown Court heard that one of the 12-month-old twin boys was critically ill and close to death. The other was also seriously ill.

But officers were astonished to find a neatly-kept lounge, filled with state-of-the art electrical appliances – a room ‘equipped for adult leisure’. Yesterday the children’s parents, David Askew and Sarah Whittaker, both 24, were each jailed for seven years after admitting five counts of cruelty.

The court heard the horror at the three-bedroom house was discovered when Whittaker phoned for an ambulance in June because one of the twins was ‘lifeless’.

Paramedics found he was skeletal and grey.

The youngster was taken to hospital with his brother where he was put on a ventilator.

Andrew Hatton, prosecuting, said the boy was suffering from hypothermia, hypoglycaemia (deficiency of glucose in the bloodstream) and was badly malnourished.

He said both twins weighed just over four kilograms (8.8lbs), less than when they were nine-months-old.

They were 40 per cent of the weight expected for a one-year-old.

Mr Hatton said the most seriously ill twin was passing live maggots into his nappy which were later identified as the larva of the common housefly.

Both boys’ growth was consistent with a four to fivemonth-old, he said.

Mr Hatton said: ‘One doctor said it was the worse case of malnutrition he had ever come across in the UK or outside of the developing world’.

The other children in the house – now aged eight, four and three – were also living in terrible conditions. Police found dog and human excrement smeared on the bedroom floors, walls and windows. The children were sleeping on urine soaked mattresses.

The three-year-old boy seemed to be locked in his room. The officers found him huddled in a corner wearing soiled underpants.

His elder sisters were in a similar state, the court heard. Mr Hatton said the officers found the kitchen in a state with a food cupboard containing just a tin of mushy peas, baked beans and corned beef.

The fridge had two cartons of milk in it and the freezer contained only a few sprouts and three fishcakes. They did find some powdered baby milk.

But Mr Hatton told the judge the living room was a ‘complete contrast’ to the squalor in which the children were allowed to live.

It was a room which was equipped for ‘adult leisure’.

Postoperative Spondylodiscitis From Aspergillus Fumigatus in Immunocompetent Subjects/Comment

J. LENZI, A. AGRILLO, A. SANTORO, N. MAROTTA, G. P. CANTORE

Department of Neurosciences – Neurosurgery “La Sapienza ” University of Rome, Rome, Italy

The authors describe a case of spondylodiscitis from Aspergillus fumigatus which occurred subsequent to surgery for lumbar disc herniation in a non-immunodepressed patient. The results obtained by combined medical and surgical treatment are discussed.

KEY WORDS: Spondylodiscitis * Aspergillus fumigatus * Infectious disease * Tomography, emission computed * Biopsy * Surgery.

Aspergillus is an ubiquitous fungus in nature with more than 350 known species; only a few of these are pathogenic for men.1, 2

Aspergillosis is the most frequent of the skeletal micoses whereas Aspergillus fumigatus is the one more often responsible for osteomyelitis and micotic vertebral spondylodiscitis.1-3

Vertebral localizations of aspergillosis occur predominantly in immunologically impaired subjects, although some rare cases have been described in healthy subjects.4-6

The authors describe a case of spondylodiscitis from Aspergillus fumigatus which occurred subsequent to surgery for lumbar disc herniation in a non-immunodepressed patient. The results obtained by combined medical and surgical treatment are discussed.

Case report

This 50-year-old woman was referred to us for acute left low back pain which had begun about 1 month before admission and a deficit of dorsal flexion of the left foot which appeared 15 days later. Lumbar- sacral MRI documented a large, left, meclian-paramedian disc herniation at L4-L5. The patient was submitted to surgery which consisted of a L4-L5 microdiscectomy and clecompressive foraminotomy of the left root of L5. At the end of the procedure an antiscarring agent (Adcon) was applied around the root (Figures IA, B).

The early postoperative period was uneventful and the patient was discharged on the 3rd postoperative clay and remained in good health until about 2 weeks later. In fact, on the 151’1 day after surgery, she experienced the sudden onset of intense left paravertebral pain. After a brief period of bed-rest, the patient was advised to undergo kinesitherapy. However, after the first sitting, her painful symptoms worsened considerably, assuming the typical features of discitis. At 1-month follow-up, MRI with gadolinium detected hypointensity of the spongiosa of the L4 and L5 bodies with irregularity of the somatic borders on Tl sequences; on T2, there was market! contrast enhancement and a modest amount of esophytic tissue at L4-L5. Values of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were high. The patient was fitted with an orthopedic vest and prescribed wide-spectrum antibiotic therapy (piperacillin), (Figures 2A, B).

Despite this treatment, her symptoms continued to worsen and the low back pain and sciatica returned. Another MRI demonstrated an increase of the esophytic component, of the T2 hyperintensity at L4- L5 and of contrast enhancement, all consistent with discitis (Figures 3A, B).

We decided to submit the patient to a 2nd operation to remove the esophytic component of the discitis and to take a sample for culture.

Figure 1.-Lumbar sacral MRI showed in sagittal (A) and axial (B) view a large, left, median-paramedian disc herniation at L4-L5.

Diagnosis was spondylodiscitis from Aspergillus fumigatus and specific antibiotic therapy with Itraconzaol was begun. Twenty clays later the patient’s clinical conditions improved with normalization of VES values.

Three months after the 1st operation, the patient was free of pain and no longer taking antibiotics.

Discussion

Aspergillus is a saprophyte of the airways described for the first time by Micheli in 1729.1 Aspergillosis is a rare disease which, in healthy subjects, is often responsible for allergy-based conditions of the respiratory system, although other localizations have been observed in the skin, paranasal sinuses, orbits, skeleton/ bones or in the CNS.1,2

Aspergillosis may be primary, developing in healthy patients in the absence of pulmonary involvement, or secondary to predisposing factors such as leukemia, AIDS, chronic and/or neoplastic diseases or immunosuppressive therapy as well as in patients with general impairment of immunological status.

In 74% of Aspergillus infections 7 the localization is skeletal. The majority of vertebral infections from aspergillosis occur in immunologically impaired patients, although some very rare cases have been described in healthy subjects.4-6,8

In subjects without immunological impairment, a vertebral localization of Aspergillus infection is generally attributable to iatrogenic causes related to surgical treatment9 and the pathogenetic mechanism appears to be inoculation of the spores present in the air into the disc space during operation. When the discitis is secondaiy to a hematic dissemination,9,10 the vascularized vertebral borders are infected first and the infection subsequently spreads to the disc space. Cases of vertebral infection from Aspergillus due to contiguous dissemination of pseudoaneurysms following aortic bypass surgery have also been described.

Figure 2.-MRI with gadolinium documented hypointense of the spongiosa of the L4 and L5 bodies with irregularity of the somatic borders on T1 sequences (A) and a modest amount of esophytic tissue at L4-L5 on T2 sequences (B).

Of the 30 patients with discitis from Aspergillus reported in the literature, 80% had an immune-suppressed status.8 The clinical, biological and radiological characteristics of discitis from Aspergillus are exactly the same as those of discitis from piogens.9

The case described here demonstrates that infection of the intervertebral disc space may also occur in immunologically normal patients following surgery for lumbar disc herniation.

Features suggestive of discitis are a combination of intense pain in the area involved by the infection, a high velocity of erithrosedimentation and a radiological finding of hypointensity of the spongiosa of the vertebral bodies with irregular somatic borders on T1 and disc hyperintensity on T2 as well as marked contrast enhancement.

In our opinion, the treatment of choice should be both medical and surgical, as demonstrated by the case described here. However, in the literature there are reports of cases treated by pharmacological therapy alone, via needle-biopsy,11 as well as others in which surgical treatment was only taken into consideration following either a poor response to antimicotic therapy or neurological deterioration.10,12,13 The purpose of explorative surgery is essentially to obtain a precise diagnosis 5-9, 11-14 since needle-biopsy does not always achieve this.10 Accurate diagnosis is, in fact, the key point of treatment for discitis of micotic nature, since wide-spectrum antibiotic therapy does not resolve clinical symptoms, on the contrary to the bacterial forms of discitis. In this type of discitis, delicate curettage of the vertebral plates and removal of the esophytic component that is often present allow a more rapid recovery.

Figure 3.-Another MRI demonstrated an increase of the esophytic component, T2 hyperintensity at L4-L5 (A) and contrast enhancement on T1 sequences (B).

Moreover, it is almost impossible to make a differential diagnosis between bacterial and fungal discitis solely on the basis of neuroradiological data: this is demonstrated by our case in which wide-spectrum antibiotics were administered at the first suspicion of discitis but failed to bring about any improvement in the patient’s conditions.

The pharmacological treatment of choice for discitis is still a matter of debated Standard treatment comprises, besides itmconazol, anfotencin B and 5 flucitosin, administered at a dosage of 0.5 mg/ kg/die and 60-100 mg/kg/die, respectively.5 Itroconazol undoubtedly has the advantage of oral administration, lower toxicity and less side-effects. The advised dose is 3-5 mg/kg/die.

Conclusions

To conclude, this case illustrates how discitis may develop as a complication of spinal surgery, even in patients without immunological impairment, and how diagnosis of this condition in the early stages is not straightforward due to the almost total absence of radiological signs couple with a clinical situation difficult to interpret.

References

1. Casey AT, Wilkins P, Uttley D. Aspergillosis infection in neurosurgical practice. Br J Neurosurg 1994;8:31-9.

2. Wood M, Anderson M. Neurological infections. London: W.B. Saunders; 1988.p.300.

3. Korovessis P, Repanti M, Katsardis T, Stamatakis M. Anterior decompression and fusion for aspergillus osteomielitis of the lumbar spine associated with paraparesis. Spine 1994;23:2715-8.

4. Deshpande DH, Desai AP, Dastur HM. Aspergillosis of the central nervous system. Neurology India 1975;23:167-75.

5. McKee DF, Barr WM, Biyan CS, Lunceford EM. Primary aspergillosis of spine mimicking Pott’s paraplegia. J Bone Joint Surg 1984;66A:1481-3.

6. Seligsohn R, Rippon JW, Lerner SA. Aspergillus terreus osteomyelits. Arch Intern Med 1977;137:918-20.

7. Cortet B, Richard R, Deprez X, Lucet L, Flipo R, Le Loet X et al. Aspergillus spondylodiscitis: successful conservative treatment in 9 cases. J Rheumatol 1994;21:1287-91.

8. Govender S, Rajoo R, Goga IE, Charles RW. Aspergillus osteomyelitis of the spine. Spine 1991;16:746-9.

9. Bridwe\ll K, Campbell JW, Barenkamp SJ. Surgical treatment of hematogenous vertebral aspergillus osteomyelitis. Spine 1990;15: 281- 5.

10. Assad W, Nuchikat P, Cohen L, Esguerra JV, Whittier F. Aspergillus discitis with acute disc abscess. Spine 1994;19:2226-9.

11. Holmes PF, Osterman DW, Tullos HS. Aspergillus discitis. Report of two cases and review of the literature. Clin Orth Rel Res 1988;226:240-6.

12. Van Ooij A, Beckers JMH, Helpers MJHM, Walenkamp GHIM. Surgical treatment of aspergillus spondylodiscitis. Eur Spine J 2000;9:75-9.

13. Castelli C, Benazzo F, Minoli L, Marone P, Seghezzi R, Carlizzi CN. Aspergillus infection of the L3-L4 disc space in an immunosop-pressed hearth transplant patient. Spine 1990;15:1369-73.

14. Mawk JR, Erickson DL, Chou SN, Seljeskog EL. Aspergillus infection of the lumbar disc spaces. Report of three cases. J Neurosurg 1983;58:270-4.

Received February 4, 2004.

Accepted for publication July 15, 2004.

Address reprint requests to: J. Lena, Via dei Fienili 58A, 00186 Roma, Italy. E-mail: [email protected]

Comment

In this well-written report, Lenzi et al. describe the case of a patient suffering from a postoperative spondylodiscitis caused by Aspergillus fumigatus.

The authors review the literature on this topic and provide the reader with relevant information on diagnosis and treatment of this fortunately rare condition.

An important message from this paper is the indication, in selected cases, to surgical exploration, with the 2-fold purpose of reducing the exophytic component of the infected disk, and to ascertain, in cases in which the CT-guided biopsy results negative, the correct etiological diagnosis permitting to start the most appropriate therapy.

Finally the authors call to our attention that micotic postsurgical infections may develop even in non-immunodepressed otherwise healthy patients.

I think this paper is suitable for publication with minor changes. I suggest the authors to make the “Discussion” section shorter condensing in a few sentences the general information they provide about aspergillosis, and referring the interested reader to the main papers dealing with the topic they quote.

Copyright Edizioni Minerva Medica Jun 2004

Internet Parent Support Groups for Primary Caregivers of a Child With Special Health Care Needs

Little is known about the efficacy of Internet Parent Support Groups (IPSGs). This exploratory study describes factors related to use of Internet Parent Support Groups (IPSGs) by primary caregivers of Children with Special Health Care Needs (CSHCN). An Internet survey was administered to 114 participants using stress and coping theory as a guide for measuring perceived satisfaction, Stressors, social support, personal characteristics, appraisal, positive and negative emotion, coping, timing, somatic health, physical functioning, family relationships, and well-being. The majority of participants not only obtained what they sought, but found more than expected in terms of insight and people to trust. The strongest outcome factor related to satisfaction was improved caregiver-CSHCN relationship, and nearly 90% of the sample suggested participating in an IPSG as soon as possible. Nurses may want to consider IPSGs as an adjunct for social support in this population.

Biomedical and technological advances have not only prolonged the life expectancy of children with previously terminal conditions, but the political and economic milieu has shifted the responsibility of caring for these children from hospital to home. Consensus among investigators using both quantitative and qualitative methods is that the impact on families caring for a child with chronic illness at home is both profound and prolonged, increasing the need for social support (Baumgardner & Burtea, 1998; Gravelle, 1997; Hayes, 1997; Newacheck & Halfen, 1998). A major deterrent in obtaining social support for primary caregivers of a Child with Special Health Care Needs (CSHCN) is the inability to find alternative caregivers (Bouchard, 1998). Computer mediated social support may be a viable option, but research is limited and focuses primarily on adult patient populations. This report summarizes a study that explored use of Internet Parent Support Groups (IPSGs) from the perspective of primary caregivers of a CSHCN.

Because participation in an IPSG is theorized to be part of the psychosocial adaptation of parents caring for a CSHCN at home, the Transactional Model of Stress, Coping and Adaptation (Lazarus & Folkman, 1984) was selected as a guide for formulating research questions. Figure 1 is an attempt to incorporate several linear models published by Lazarus, as well as his latest writings, which consider dynamic systems and complexity theories. Intrapersonal relationships are placed in circular rather than linear fashion to better portray the natural dynamic. The 2-way circular and time arrows are meant to depict the transactional, iterative, synergistic nature of individual adaptive responses over time. Table 1 is a summary of major concept labels and theoretical definitions.

Literature Review

A myriad of traditional self-help face-to-face support groups exist for parents. Groups cater to single parents, adoptive parents, abusive parents, parents of CSHCN, etc., but no research-based precedent for their efficacy was found. Preliminary evidence suggests that support groups in general may promote emotional recovery from life crises, but methodological limitations make results tentative. Over the last 20 years, over 1000 national and international support groups have become available through the Internet (White & Madara, 2000), but research on them is only beginning to be reported. The following review includes the only four studies that were found on Internet support groups involving parents of a CSHCN.

Man and Belcher (2001) used an online survey to explore aspects of computer-mediated support group use by 73 parents of children with cancer using three online self-help groups. They found computer group use was more common among persons with higher socioeconomic status. Perceived benefits included getting information, sharing experiences, receiving general support, venting, gaining accessibility, and using writings. Perceived disadvantages were off- topic chatter, negative emotions, large volume of email, and lack of physical contact and proximity.

Wright (1999) did a correlation study using an online survey of 148 participants in 24 computer mediated support groups (three with parenting issues) to identify social support, perceived stress, and coping. Those using coping strategies of “thought about problem, gathered information about it, and actually did something to solve it” and “sought emotional support from others” had higher online support network satisfaction scores (M=5.3 and M=5.7, respectively) than race-to-face support network satisfaction scores (M=4.7 & 3.8, respectively).

Figure 1. Incorporating Several Linear Models Published by Lazarus

Table 1. Concept Definitions of the Transactional Model of Stress and Coping

Fernsler and Manchester (1997) surveyed 54 users of CompuServe Information Service’s Cancer Forum, 7.4% of whom were parents of children with cancer. Primary reasons for seeking online support were similar experiences, information, emotional support, and encouragement of others. Most helpful topics included treatment and effects on the family. The primary constraints on participation were cost and time. Over 7% began participating before there was even a diagnosis of cancer, 48.1% began within 4 months after diagnosis, and 26% began more than 4 months after diagnosis.

Tetzlaff (1997) explored informatic requirements of 120 parents of children with cancer using a video based, non-interactive computer mediated support system. Concerns included details of managing day-to-day, conceptual information about disease and treatment, and management of psychosocial problems. Information was sought to solve problems and provide emotional support, but interest could create a conflict when material was threatening. Consumers were positive toward online solutions.

All four studies were descriptive, which is typical of preliminary research, but only one included correlations or any mention of a conceptual framework. Three of the four studies were restricted to children with cancer. No report indicated when it was best to begin participating in an IPSQ and the one study on satisfaction did not correlate it with types of online social support. Very little is known about what relates to well-being and no research was found on how to maintain or improve quality of IPSQs. In summary, since use of IPSQs appears to be increasing, more descriptive information is needed to educate nurses about when, why, and how online support groups may be appropriate. Questions included the following:

1. How do primary caregivers of a CSHCN rate and describe their reasons for participating in an IPSQ in terms of problem-focused and emotion-focused coping, and how does coping relate to support received?

2. How do primary caregivers rate their overall satisfaction with IPSGs, and how does satisfaction relate to support received?

3. How do primary caregivers of a CSHCN rank emotional support of IPSQs compared to other sources (family, other parents of CSHCN, nurses, clergy, religion, therapist, and face-to-face support groups), and what are primary correlates of emotional support?

4. How are reappraisal, emotion, somatic health, physical functioning, family relationships, and IPSG social support interrelated, and what factors are described as having the most long- lasting effect on subjective well being?

5. What is the optimum time to begin participating in an IPSG according to primary caregivers of a CSHCN, and are there significant differences between groups who recommend different times with respect to sociodemographics and coping strategies?

6. What are characteristics of recommended and nonrecommended IPSGs according to primary caregivers of a CSHCN, and what suggestions do they have for making IPSGs more efficient and effective?

Method

Design and setting. An exploratory, retrospective self-report design was employed using an Internet survey method, using HTML 3.2, a Web page was constructed on an IBM compatible computer where visitors obtained detailed information about the study. A direct link to the electronic survey was provided at the study Web site once a person consented to participate. The electronic survey was housed on a server administered by Surveypro.com, a public “do-it- yourself” survey service.

Sample. Power analysis for correlations with a moderate effect size required a minimum sample size of 85 (α = .05, β = .80). Qualifying criteria were contained in the first three questions and were designed to include a broad cross section of primary caregivers with a CSHCN at home who essentially manipulated their own independent variable by seeking social support through IPSGs. Only primary caregivers with a CSHCN at home who had participated in an IPSG were included in the study and English was the only language used to communicate with participants.

A sample of 114 primary caregivers, caring for 140 CSHCN, using over 100 different Internet parent support groups completed the Internet survey. The typical caregiver was a White, married, well- educated female in her late 30s from the United States. Most caregivers were Christian, living in towns or cities, making over $50,000/year, with 3-5 years’ experience caring for a CSHCN at home. The average number of people living at homewas four, with an average of two of those having disabilities. One quarter of the sample, some of whom were single women, dedicated their lives to caring for more than one CSHCN. A number of caregivers also cared for disabled adults in their homes or were disabled themselves. Of the CSHCN, 93 (66%) were male, and 47 (34%) were female. Overall, males were younger (males M=6.5 years; females M=8.7 years). Participants preferring not to answer did not affect validity of results. The number of participants who chose to withhold information about their religious preference (

Instrument. The Internet Survey was originally composed by the author (Baum, 2002) and administered via the Internet from. February through May of 2001. Out of a total of 75 questions, there were approximately 18 open ended questions, 41 questions using a Likert- type rating scale, 15 multiple-choice, and one ranking question. A personal dispositional coping style, optimism, was selected because of its known moderating effect on coping and was measured by the 10- item Life Orientation Test-Revised (LOT-R) (Scheier, Carver, & Bridges, 1994). Another personal characteristic, generalization, has been shown to predict depressive symptoms and was measured by the 4- item Attitudes Toward Self Test (ATS) (Carver, 1998). Five 2-item subscales of the Brief COPE were used to assess active coping, planning, positive reframing, and acceptance; all of which had previously published validity & reliability (Carver, Scheier, & Weintraub, 1989). see Table 2 for alpha reliabilities of these measures in this study.

Because “problem-focused coping” (see Figure 1) is defined as an attempt to alter the source of stress (see Table 1), questions having to do with finding usable ideas, decision support, people to trust, or greater insight were categorized as problem-focused coping and support (see Table 3). In contrast, “emotion-focused coping” is an attempt to reduce or manage the emotional response to perceived stress, as opposed to trying to change the stressor itself. Questions that related to validating or relieving negative feelings were therefore categorized as emotionfocused coping. seeking opportunities to help others was categorized as emotion-focused coping because it did not fit the definition of problem-focused coping and is usually associated with relief of negative feelings. One question had to do with reappraisal (change of view, Table 4) and nine questions focused on major categories of positive and negative feeling (see Table 5).

Table 2. Generalization, Optimism, and Coping Scores of Primary Caregivers

Table 3. Relationship Between Social Support Sought and Received from IPSGs

Table 4. Spearman Rho Correlations of Trust, Emotional Support, and Change of View as they Relate to Increased Positive Emotion

Formal pre-testing of the survey instrument included both “alpha” and “beta” tests. An alpha test involves assessing the survey for readability, clarity, logical flow, and length of time to complete it. Several people with varying levels of education were asked for feedback on the questionnaire, including five PhD prepared faculty members who provided judgment as to whether the survey instrument measured relevant constructs. Total time for completing the electronic survey was 35- 45 minutes.

A beta test is somewhat like a pilot test in which actual caregivers of a CSHCN are asked to give feedback about what it is like to complete the various versions of the survey. Adding a question at the end, “Is there anything else you would like to say” and a “comments” link on the Web page encouraged caregiver feedback throughout the survey. The beta test was run during January 2001 with four primary caregivers of a CSHCN (two mothers and two fathers) and eight adults with various browsers and Internet service providers (ISPs). Their feedback was very helpful in refining survey content, clarifying instructions, and improving the administration.

Table 5. Feelings Resulting from Participation in an IPSG

Table 6. Average rankings by parents of a CSHCN for various types of social support (N=113)

General limitations of Internet surveys include selection bias, possible electronic tampering with survey or data, and anonymity, which makes it more difficult to assure that a participant meets the inclusion criteria. (see Baum, 2002 for full explanation of these limitations and what was done to minimize them.)

Procedure. After approval of the project by the Institutional Review Board, a combined “push” and “pull” strategy was employed to obtain a purposeful nonprobability sample of information- rich cases. The push strategy entailed sending a study invitation directly to 30 caregivers who voluntarily offered their e-mail addresses to readers of seven issues of “The Matchmaker,” a newsletter distributed by Mothers united for Moral Support (MUMS). MUMS is an international online matching service for parents of a CSHCN. The pull strategy involved posting an invitation on one Web site and four listservs to which the targeted sample could then respond. The Web site was MUMS ([email protected]), where a hypertext link directly to the study Web site was placed. The four mailing lists (listservs) were [email protected], [email protected], ckmkstart_HIt409 56705shcn- [email protected], and [email protected]. A $200 contribution on behalf of all those who participated in the survey was made to MCJMS for their additional support.

Quantitative data extracted from the database were aggregated using SPSS version 10.0, and qualitative data were reduced into categories using QRS NUD*IST 4 software. Because most data was nonparametric, Spearman’s rho was used to explore relationships, Chi- square and Kruskall-Wallis Tests were used to test differences between groups, and the Mann-Whitney U Wilcoxon Test was used to detect where the differences were. The only research question producing extensive qualitative data was one asking participants to describe three things about IPSGs that had the most long-lasting effect on their sense of well-being. Published therapeutic factors of psychotherapy groups were used as a guideline for assigning codes. A colleague with a background similar to the author and who had no knowledge of results, was asked to code answers to the question on well-being, after a brief explanation of coding parameters. Inter-rater reliability was .95.

Results

Due to limited space and to reduce complexity, selected answers to research questions will be reported and discussed under major headings of the theoretical model. (see Baum, 2002 for full report of results organized under research questions.)

Stressors and social support. One hundred ten (79%) children had mild to moderate disability, and 54 (39%) children required some form of technology to maintain life or health. The two top diagnostic categories of the children were rare disorders (28%) and psychiatric disorders (28%); the latter being also the most prevalent comorbid condition. Only 18% of the families with insurance qualified for home nursing. Of the 10 families reporting 100 or more trips to clinics in the last year, only the highest user (227 visits) received any home care nursing, and that was limited to 4 hrs/week. Sixty-one families (54%) had one to eight hospitalizations in the last 12 months. Forty-one families (37%) carried more than one kind of insurance, 13 families had only Medicaid or Medicare, and 6 had no insurance at all.

The highest-ranking source of emotional support in this sample was family (52%), especially spouses, and 10 participants ranked both family and IPSGs #1. On the other hand, the number of those ranking family as zero emotional support (8%) was almost three times as many as those who ranked IPSGs as zero support (3%). Surprisingly, nurses and clergy were considered the least supportive (Table 6). Qualitative data revealed some of the possible reasons: “People have no idea how hard it is parenting a child with a chronic illness unless they have done it!””Most professionals are not going to tell you the down and dirty truth you are going to get from other parents who live this every day. Probably because they could never imagine what it is like;””Many times from the nurses/therapists/ doctors 1 get an answer that there is only one right way.” On the other hand, “Our list is run by an RN who has had this disease for years and really puts her heart and soul into it in a professional manner.”

Overall satisfaction with IPSGs was high (93%). The three strongest factors associated with satisfaction were (a) getting usable ideas (rho=.42, p

Optimism and generalization. Optimism scores (M=20.7) in this sample were considerably higher tha\n published norms for college students (M=14.3) or bypass patients (M=15.2) (see Scheier et al., 1994), and tendency to generalize (M=9.5) was lower than published norms for either men (M=IO.25) or women (M=Il.52) (see Carver, 1998). Although the overall sample scored lower on generalization, the 30% taking psychotropic medication for depression and anxiety scored higher than norms (M= 12.2). Results of Mann-Whitney CI tests indicated that caregivers who scored high on pessimism (part of the optimism scale) also scored significantly higher on generalization (z = -3.09, 1-tailed p=.001) and loss of sleep (z = -2.20, 1-tailed p=.01) than their optimistic counterparts.

Coping. As shown in Table 3, both problem-focused and emotion- focused coping were significantly and substantially related to obtaining what was sought (p

Participants scored relatively high on a wide variety of positive coping styles, as measured by the Brief COPE (Table 2); including acceptance, active coping, planning, positive reframing, and religious coping. Of the 114 participants, 19 people did not use religious coping at all, which was essentially equal to the number of people who said they had no religion. At least 26% used alcohol, tobacco, and recreational drugs to feel better and several mentioned using “a lot” of caffeine drinks during stressful times.

Reappraisal. One survey question had to do directly with reappraisal: “1 changed my viewpoint about something.” Sixty-four percent agreed that their viewpoint changed, 11% disagreed, and 25% were neutral. Qualitative data revealed some of the ways in which people changed their view as a result of IPSG participation. One lost her “rose colored glasses.” Others adjusted their general outlook on life, came to terms “with what will happen,” increased their confidence in giving advice or “proper care” for their child, and trusted their intuition more. One mother summed it up by saying, the “wealth of ideas and information shared has changed our lives.” Changing one’s view was strongly correlated with two long term outcomes: (a) improved relationships with CSHCN (rho=.38, p

Emotion. Survey questions addressed five positive and three negative feelings that could be generated by IPSQ participation (see Table 5). Typically, participants felt better as a result of participating in an IPSQ, especially more hopeful (87%) and relieved (83%), which according to qualitative data, was often related to new information regarding diagnoses and treatment, hearing “success stories,” and seeing others with more difficult situations (“I am blessed.”) Other important emotions from the qualitative data were increased compassion, confidence and patience, and decrease of guilt. Correlations among the emotion factors revealed that laughter was more associated with relief (rho=.43, p

Time. Nearly 90% of primary caregivers of a CSHCN recommended entering an IPSQ as soon as possible, within 1-3 months. One mother said she wished she had started IPSQ participation sooner because it “it would have helped with the guilt.” Another said 1-3 months “doesn’t let enough time slide so that helplessness or hopelessness slips in.” Some recommended starting even before the CSHCN was born. Factors associated with delaying participation longer than 3 months were technology dependent children and readiness of the caregiver to accept the situation, although IPSQs may facilitate acceptance of reality. One father commented that an IPSG was “a very rewarding private way of accepting the future.”

Outcomes. Only 15% of the sample agreed that IPSQ participation improved habits affecting somatic health. By contrast, 73% of the sample agreed that IPSQ participation increased efficient effective functioning, which was significantly related to all positive feelings (rho=.35 to.45, p

Outcomes that were perceived to have the most long-lasting effect on well-being were (a) finding people with similar challenges (79%), (b) receiving guidance and information (59%), (c) feeling understood and accepted (50%), (d) worldwide relatively anonymous access to information and support (24%), (e) the opportunity to help others (22%), (f) change in perspective that instilled hope and gratitude (20%), and (g) opportunity to vent (10%).

Discussion

Stressors and social support. Part of the purpose of gathering sociodemographic data was to describe demands and resources that have known moderating effects on adaptation and compare results from this sample with other research. Level of CSHCN impairment and female child gender has been found to predict parental distress (Canning, Harris, & Kelleher, 1996). All children in this sample had some kind of disability with even more impairment than was required by study criteria, and the only factor that may not have contributed to distress was that the typical CSHCN in this sample was male. Consistent with other research, health care utilization was enormous in this sample, and was inversely related to whether families qualified for home care nursing. It could also be related to having more than one disability per household. Administrators of managed care may want to rethink the cost/benefit of providing more home care nursing to high utilization families.

Greater control of the amount and type of social support as a motivator for participating in an IPSG was a unique, unanticipated finding, especially since increased sense of control has been found to be an important factor in psychological adaptation and quality of life in this population (Lubkin, 1998). One aspect of control provided by IPSGs is the advantage of bypassing usual norms that are found in face-to-face groups. Listening politely, for example, is not necessary in IPSGs. For people stranded in their homes with children requiring complex care, IPSGs were a “link to the outside world.” unlike one study that found lack of physical contact and proximity a disadvantage of online relationships (Han & Belcher, 2001), it seemed to be of little consequence in this sample. Some arranged to meet the friends they had made online, and others preferred the anonymity.

Optimism and generalization. Optimism has been shown to predict more adaptive types of coping than pessimism, such as acceptance, positive reframing, and humor (Scheier, Carver, & Bridges, 1994). Participants in this study were high in all three of those coping strategies (see Tables 2 & 5). If seeking online social support were perceived as an adaptive coping strategy, then it would attract optimistic people. Because optimism scores were unusually high in this sample, it could skew some results such as global evaluations, but it would not be expected to keep people from being forthright about actual events and processes such as reasons for participating or factors that had an impact on well-being.

If the percentage of people taking psychotropic medication is a valid indicator, the incidence of anxiety and depression was 10% higher in this sample than the best estimate 1-year prevalence of mental health dysfunction for the general population (U.S. Department of Health and Human Services,1999). This finding is consistent with other literature, which documents high levels of depression in families adapting to a CSHCN with disabilities (Lubkin, 1998), particularly if they generalize and tend to be pessimistic.

Coping, unlike other Internet samples, which are primarily male, age 20-30, the average participant in this sample was female and almost 40 years old. This is not surprising since most caregivers of a CSHCN at home are mothers. What is interesting is that the mothers were apparently willing to learn how to use a computer in order to obtain more social support. One mother commented, “…to think 3 years ago I was afraid to get online, now I’m a whiz thanks to my child’s needs.” High Brief COPE scores along with qualitative data in this sample indicated primary caregivers were not only acc\epting of their challenges, but preferred planning ahead and becoming actively involved in doing as much as possible for their children.

A surprising result of this study was that seeking an opportunity to help others was a stronger, more frequent motivator for participating in an IPSQ than any other emotion-focused coping strategy (see Table 3). This is consistent with others who observe how online “helper therapy” taps into a “deep altruistic impulse” people do not realize they have (White & Madara, 2000) that can be even more beneficial than receiving help for oneself.

Re/appraisal. Both quantitative and qualitative data suggested that IPSG participation serendipitously shifted paradigms. More information and insight can often change a person’s perspective so that situations previously perceived as painful become more tolerable, as implied by the fact that change in view was significantly related to relief and gratitude (see Table 4).

Emotion. The fact that IPSGs generated positive emotion in this sample (see Table 5) is an important finding. Since prolonged negative emotions and avolition are criteria for anxiety and mood disorders, IPSG participation may reduce anxiety and depression through laughter and increased motivation. Since laughter was strongly and significantly associated with relief and peace, it implies that, in some cases, IPSG participation may help restore emotional balance or stability. On the other hand, the one-fifth of the sample who were more sad and angry after IPSG participation is important if the ethic is “Do no harm,” but often anger was a result of increased awareness of social inequities, which parents said was an impetus for advocating more effectively for their CSHCN. An important finding in this study is that neither changing one’s view nor receiving emotional support had nearly as strong a relationship with positive emotion overall as finding trustworthy people. Evidently, finding people to trust was not only a pleasant, relatively unexpected outcome related to satisfaction, but it was also powerfully related to feeling better (see Table 4).

Time. Participating in an IPSG “as soon as possible” perhaps even as part of prenatal planning or in conjunction with genetic counseling is new and important information for nurses. Families whose children require technology, or who are having trouble accepting their situation, may need more time to adjust before participating in an IPSQ, but could be offered the information about online resources to be used later.

Outcomes. Although the majority of people did not agree that IPSQ participation improved their health habits, they did agree that they laughed and relaxed more (Tables 3 & 5), which certainly has implications for health. Improved functioning attributed to IPSG participation is particularly exciting, especially from the standpoint of health promotion. Notably, most participants did not agree that IPSQ participation interfered with sleep or family relationships.

A striking outcome of IPSQ participation in this sample was improved caregiver-CSHCN relationship. This is consistent with another study that found family-led self-help groups improved relationships with ill family members more than professional-led groups (Pickett, Heller, & Cook, 1998). This is important because mothers tend to experience greater distress when their chronically ill child does not respond positively to caregiving efforts (Holaday, Turner, Kanematsu, Krulik, & Wang, 1997), and if an IPSG can help mothers understand and deal with children who are fussy and irritable much of the time, or change their interpretation of the child’s behavior, it would be well worth participating.

Frequency data does not necessarily reflect what is most valued in terms of producing well-being. For example, seeking opportunity to help others through IPSG participation was the second most frequently used coping strategy (see Table 3), but only fifth in its perceived ability to produce a long-lasting effect on well-being. This is consistent with other research that found altruism to be unrelated to perceived helpfulness of the group.

Implications for Further Research

The role of high quality IPSGs in prevention, diagnosis, and treatment of psychosocial problems related to caring for a CSHCN is only beginning to be recognized and developed. It may also be productive to focus on what would be considered maladaptive coping online. The connection between neglecting the family due to IPSG participation and having a child with a rare disorder warrants further investigation. Other avenues of research suggested by this study include the need for developing new ways of defining and measuring spirituality and humor as coping strategies. A major contribution of this study is the preliminary evidence that trust and altruism play a major role in the relatively unexplored mechanism that links social support to well-being, and finally, the fact that altruism as a major coping strategy was not a part of the Brief COPE instrument, suggests that measurement of the concept needs to be developed.

Implications for Practice

Historically, nurses have taken the role of patient care advocate and are in a position to plan and coordinate greater continuity of care, particularly for parents of a CSHCN who have limited alternative caregivers. The strong recommendation of this sample to begin participating in an IPSQ “as soon as possible” is something nurses need to make part of their repertoire of resources for prenatal and discharge planning and may even be helpful in conjunction with genetic counseling. It is also important for clinicians to be aware of when it might be preferable to delay participation in an IPSG. Families whose children require technology, or who are having trouble accepting their situation, may need more time to adjust. One respondent suggested that family members could educate themselves about how to be more supportive to parents by browsing on an IPSQ, which has implications for nurses as well.

Many participants talked of “empowerment” gained from IPSG participation, which is also the theme of large governmental initiatives developed for families with CSHCN. It may be an important policy consideration to make the Internet more accessible to those of lower socioeconomic status. When evaluating public and private insurance programs, single parents of a CSHCN and people caring for more than one person with disabilities may need greater community support.

Although there seem to be many advantages to online support groups, it would be unwise to assume that no harm could come from them. Potential dangers include misinformation, expression of intense feelings that could overwhelm those struggling with pain and fear, different needs related to different stages of adaptation, untrained people who may offer therapy or untested products, and occasional pressure to adopt excessive or distorted group beliefs. Specialists in pediatric chronicity, rare disorders, or psychiatric mental health nursing are much needed and valued as IPSQ consultants or moderators. In summary, although participants said IPSGs were “here to stay” and often “fill a unique void,” there is much to be done both to educate people about IPSGs and to develop ways to promote and evaluate IPSG quality.

References

Baum, L. (2002). Factors related to use of Internet parent support groups by primary caregivers of a child with special health care needs (Doctoral dissertation, University of Utah, 2002). Dissertation Abstracts International, DAI-B 63/02, 734, Publication #AAT 3041616.

Baumgardner, D.J., & Burtea, E.D. (1998). Quality-of-life in technology-dependent children receiving home care, and their families-a qualitative study. Wisconsin Medical Journal, 97(8), 51- 55.

Bouchard, K. (1998). Issues in case management: Respite care…”hot issues in case management.” Pediatric Nursing, 24(3), 260.

Canning, R.D., Harris, E.S., & Kelleher, K.J. (1996). Factors predicting distress among caregivers to children with chronic medical conditions. Journal of Pediatric Psychology, 27(5), 735- 749.

Carver, C. S. (1998). Generalization, adverse events, and development of depressive symptoms. Journal of Personality, 66(4), 607-619.

Carver, C.S., Scheier, M.F, & Weintraub, J.K. (1989). Assessing coping strategies: A theoretically based approach. Journal of Personality and Social Psychology, 56(2), 267-283.

Fernsler, J.I., & Manchester, LJ. (1997). Evaluation of a computer-based cancer support network. Cancer Practice, 5(1), 46- 51.

Gravelle, A.M. (1997). Caring for a child with a progressive illness during the complex chronic phase: Parents’ experience of facing adversity. Journal of Advanced Nursing, 25(4), 738-745.

Man, H.R., & Belcher, A.E. (2001). Computer-mediated support group use among parents of children with cancer-an exploratory study. Computers in Nursing, 79(1), 27-33.

Hayes, V.E. (1997). Families and children’s chronic conditions: Knowledge development and methodological considerations. Scholarly Inquiry for Nursing Practice, 77(4), 259-98.

Holaday, B., Turner H.A., Kanematsu, Y, Krulik, T., & Wang, R. (1997). Stress in mothers of chronically ill children: A cross cultural study. Australian Paediatric Nurse, 6(1), 2-9.

Lazarus, R.S., & Folkman, S. (1984). Stress, appraisal, and coping. New York: Springer.

Lubkin, I.M. (1998). Chronic illness: Impact and interventions (2nd ed.). Boston: Jones & Bartlett.

Newacheck, P.W., & Halfen, N. (1998). Prevalence and impact of disabling chronic conditions in childhood. American Journal of Public Health, 88(U), 610-617.

Pickett, S.A., Heller, T., & Cook, J.A. (1998). Professional-led versus family-led support groups: Exploring the differences. Journal of Behavioral Health Services & Research, 24(4), 437-452.

Scheier, M.F., Carver, C.S., & Bridges, M.W. (1994). Distinguishing optimism from neuroticism (and trait anxiety, self- mastery, and selfesteem): A reevalu\ation of the Life Orientation Test. Journal of Personality and Social Psychology, 67(6), 1063- 1078.

Tetzlaff, L. (1997). Consumer informatics in chronic illness. Journal of the American Medical Informatics Association, 4(4), 285- 300.

U.S. Department of Health and Human Services (1999). Mental health: A report of the surgeon general. Rockville, MD: U. S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, National Institutes of Health, National Institute of Mental Health.

White, BJ., & Madara, EJ. (2000). Online mutual support groups: Identifying and tapping new I & R resources. Information & Referral: The Journal of the Alliance of Information and Referral Systems, 22, 63-82.

Wright, K.B. (1999). Computer-mediated support groups: An examination of relationships among social support, perceived stress, and coping strategies. Communication Quarterly, 47(4), 402-414.

Lynda S. Baum, PhD, APRN-BC Adult Pysch/Mental Health, is a clinician at VA Medical Center in Salt Lake City; Highland Ridge Hospital in Murray, ClT; and Copper Hills Youth Center in West Jordan, UT.

Note: Research partially funded by Gamma Rho chapter of Sigma Theta Tau.

Copyright Anthony J. Jannetti, Inc. Sep/Oct 2004

Hepatitis C in Children

Cathy, a 3-year-old girl adopted from China 3 months ago, is brought to the primary care office because her adoptive parents were notified that her biological mother was recently found to be infected with hepatitis C. Cathy has been apparently healthy, but her new parents want to know if she should be tested for hepatitis C and, if found to be positive, is there a treatment for this condition. The parents also expressed concern that hepatitis C might be contagious and wondered if there were any precautions they should take at home or that should be instituted at her daycare. They also want to know if there are any long-term complications from hepatitis C requiring ongoing monitoring and specialty care.

Significance of Hepatitis C Infection

Hepatitis C virus (HCV) was discovered in 1989 and was found to be the major cause of post-transfusion non-A, non-B hepatitis. HCV infection is the most common bloodborne pathogen in the united States (Center for Disease Control and Prevention [CDC], 1998) with a yearly incidence in the 1980s of 230,000 cases. With the advent of methods to screen the national blood supply, the yearly incidence has fallen to 25,000 cases annually. HCV is a ribonucleic acid (RNA) virus of the flavivirus family. It has nine genotypes that vary geographically, with genotype-1 being most prevalent in the united States. Genotyping of the virus is important because the response to treatment and long-term complications of cirrhosis vary by genotype, unfortunately, the virus tends to mutate rapidly in the host making it difficult for the host’s immune system to eradicate the virus resulting in chronic infection (Hochman & Balistreri, 2003). This mutation process also makes it difficult to develop an effective vaccine.

Epidemiology

Prevalence. The prevalence of HCV in the general population of the united States is estimated to be 1.8% (American Academy of Pediatrics [AAP], 2003). Although HCV is a reportable disease many individuals with acute infections are asymptomatic and, therefore, not diagnosed. Also, individuals at highest risk for infection (i.e., injection drug users) may not readily seek health care and diagnosis (Kirn, 2002). According to the National Health and Nutrition Examination Survey (NHANES), 3.9 million of the non- institutionalized or incarcerated population has been infected with HCV, and 74% of them have a chronic infection (Alter et al., 1999). In the pediatrie population under 12 years of age the seroprevalence is estimated to be 0.2%, and in adolescents between 12 and 19 years of age the seroprevalence is estimated to be 0.4% (AAP, 2003). Fifty to sixty percent of children with HCV develop persistent infections even though they are asymptomatic and do not have biochemical evidence of liver disease, but limited data indicates less than 10% (as compared to 60%-70% of infected adults) go on to develop chronic hepatitis and less than 5% develop cirrhosis (AAP, 2003). The long- term effects of persistent low level infection among children with HCV for 3, 4, and 5 decades is unknown at this time. In adults with chronic hepatitis C there is a l%-3% risk of hepatocellular carcinoma development after 30 years of infection (El-Serag, 2003), but the risk for individuals exposed during childhood verses adulthood are not known. Long-term cohort studies are needed to determine the risk and associated factors for these serious complications.

Risk factors. The major risk factor for virus acquisition is direct percutaneous exposure to blood from a HCV-positive individual. Hepatitis C is much less contagious than hepatitis B virus (HBV), with the risk of infection increasing significantly with either repeated percutaneous exposure to infected blood or infusion with large amounts of infected blood (U.S. Preventive Services Task Force [USPSTF], 2004). The average infection risk for HCV following a single parental exposure to HCV-positive blood is 1.9% as compared to a 30% infection risk following exposure to blood with HBV and a 0.3% risk of infection with a single exposure to blood with human immunodeficiency virus (HlV) (Henderson, 2003). Before 1990 blood transfusions or use of clotting factor concentrates were the most common routes of spread. Because of the exclusion of high-risk donors and testing of donated blood for hepatitis C antibodies, the risk of HCV from a transfusion is now less than 1 in a million transfused units of blood (AAP, 2003). All immune globulin products and clotting factor concentrates released in the united States are now also HCV negative.

Presently, the common risk factors for acquisition of HCV are parenteral drug abuse (60%-90% of infections), high-risk sexual behavior (1%-10% of infections), hemodialysis (10%-20 % of infections), and accidental exposure in health workers (1%) (AAP, 2003). Contamination of medical equipment for procedures in physician offices or specialty clinics resulting in outbreaks of HCV among treated patients has been reported due to ineffective sterilization procedures or reuse of syringes by medical personnel (CDC, 2003). Tattooing, body piercing, and use of shared razors have also been implicated in HCV transmission (Borkowsky, 2002). Perinatal transmission of HCV, although infrequent, is a significant cause of HCV in infants and young children, but many children and adolescents diagnosed with HCV have no identifiable source of infection (AAP, 2003).

Figure 1. Clinical sequelae of HCV. Acute HCV is generally benign; only 20% of infected children are symptomatic. However, 50- 60% of children with HCV develop persistent infection. Serious sequelae are infrequent but include cirrhosis (

In the united States the leading cause of HCV is the use of contaminated needles and equipment for illegal intravenous drugs. The prevalence of HCV infection among populations of injection drug users (IDUs) is estimated to be between 30%-90%, increasing with duration and frequency of use of parenteral drugs (Miller et al, 2002). use of contaminated needles and equipment also increases the risk of transmission of other blood-borne pathogens, especially HIV. It is estimated there are over 200,000 people with both HCV and HIV infections in the United States (Thomas, 2002). One study found that 88% of HIV-positive youth who were IDUs were also infected with HCV (Miller et al., 2002).

Perinatal HCV transmission. In pediatrics, maternal-fetal transmission accounts for most cases. The risk to the fetus of acquiring HCV from an HCV RNA positive mother at the time of birth is 5% (range, 0%-25%) versus a 95% risk of acquiring HBV from an HBVsAg positive mother (Hochman & Balistreri, 2003; Schwimmer & Balistreri, 2000). Fetal monitoring during labor and prolonged rupture of the membranes increase the risk of transmission of HCV. If the mother is co-infected with HIV then the risk of the infant acquiring HCV goes up to 14% (range 5%-36%) because HCV titers tend to be higher in women co-infected with HIV (Hochman & Balistreri, 2003). Mothers with HCV can breastfeed, as high HCV titers in breast milk have not been documented, but they should be counseled about its presence (AAP, 2003).

Clinical Manifestations of Infection

The incubation period for HCV infection averages 6 to 12 weeks (AAP, 2003). HCV RNA can usually be detected in serum 2 weeks after infection, and anti-HCV antibodies appear 4-8 weeks later. All people with HCV antibodies or HCV-RNA in their blood are considered to be infectious, but those individuals with higher titers are more infectious. Acute infections are usually clinically silent and symptoms, if present, indistinguishable from symptoms found with hepatitis A or B infection. Only 20% of affected individuals becoming jaundiced, and abnormalities in liver function tests (elevations in the serum aminotransferase levels) are usually less pronounced than found in people with acute hepatitis B infections (AAP, 2003). Infected children may complain of anorexia, malaise, fatigue, and abdominal pain during the acute phase. The acute phase is followed by resolution of symptoms although the serum aminotransferase levels may continue to fluctuate.

Persistent infection occurs in 50%-60% of infected children even in the absence of biochemical evidence of the liver disease (AAP, 2003). The clinical sequelae for HCV in children varies. The majority of children with chronic infections are asymptomatic, but a few (

Diagnostic Tests

Children complaining of abdominal symptoms, jaundice, or with a history of risk factors for hepatitis C should have a screening panel of blood work done including a complete blood count (CBC), sedimentation rate, amylase and lipase levels, and liver function tests (LFTs). LFTs determine the serum transaminases, which rise with any hepatocellular inflammation; the serum bilirubin levels that may increase if the hepatocytes are not able to metabolize bilirubin normally; the synthetic function of the liver as indicated by the serum albumin; the coagulation profile as reflected in the prothromin and partial thromboplastin times; and the metabolic functions of the liver as indicated by the serum glucose level (see Table 1). LFTs are usuallynormal in hepatitis C infections except for mild elevations of serum transaminase levels.

Table 1. Liver Function Tests (LFTs)

Table 2. Tests to Detect HCV

Specific screening test for HCV can be done in a child with known exposure or to determine the cause of elevated LFTs. The time from exposure to onset of viremia is generally 1 to 2 weeks, but there are no direct tests for the serum viral antigen of HCV. The two major types of tests available to detect for HCV infection are antibody assays for immunoglobulin (Ig) G anti-HCV (Alter, Kuhnert, & Finelli, 2003) (see Table 2). The initial screening for HCV is usually performed through an anti-HCV screening enzyme immunoassay (EIA) (USPSTF, 2004). Positive results should be confirmed by a recombinant immunoblot assay (RIBA). Both third generations of these tests are 97% sensitive and 99% specific (USPSTF, 2004). False negative results can occur early in the course of infection due to the possible long interval between exposure and seroconversion, and repeat testing may be indicated in children with high risk factors. At this time, the CJSPSTF recommends against routine screening for HCV infection in asymptomatic adults who are not at increased risk for infection. In addition, there is insufficient evidence to recommend for or against routine screening for HCV infection in adults at high risk for infection (CJSPSTF, 2004). These screening tests are unable to discriminate between persistent infection and resolved infection. No recommendations have been made for children regarding screening for HCV infection.

The Food and Drug Administration (FDA) has approved diagnostic Nucleic Acid Tests (NATs) for quantitative detection and genotyping of HCV RNA using reverse transcriptase-polymerase chain reaction (RT- PCR) (AAP, 2003). This test determines the presence of active viremia. HCV RNA can be detected in serum within 1 -2 weeks of exposure and before anti-HCV tests are effective or abnormalities in LFTs occur. Genotyping and quantifying viral load are important when assessing the possible value of antiviral therapy.

In infants born to anti-HCV-positive mothers, passively acquired maternal antibodies can persist for up to 18 months; therefore, infants must be retested after 18 months of age with either of these tests to determine active anti-HCV status. Consequently, HCV RNA testing is used to identify infection in infants early in life when maternal serum antibodies can interfere with other test results. Viral RNA may be detected intermittently early in the infection, so false negative results can occur.

Treatment

Children with acute HCV infection usually require only supportive care at home. Supportive care for the child with hepatitis includes rest, a healthy diet, avoidance of hepatotoxic drugs like acetaminophen and alcohol, and prevention of additional liver disease through active immunization against hepatitis A and B. Children with HCV should be followed every 6 to 12 months with serial LFTs to assess the degree of inflammation and measurement of serum alphafetoprotein (AFP) along with an abdominal ultrasound to screen for hepatocellular carcinoma. If the LFTs begin to rise, the viral load should be reassessed with a repeat RT-PCR. Children should not be excluded from daycare if they have HCV, but standard precautions regarding bloodborne pathogens should be practiced both in school and at home. Transmission among family members is uncommon but can occur from direct or inapparent percutaneous or mucosal exposure to blood (AAP, 2003). Adolescents should be educated about the risk of transmission of the infection to their sexual partners, the use of alcohol, and the hazard of parenteral drug use.

Most children infected with HCV will not have long-term complications. As stated before, only 50%-60% of children with HCV infection will develop persistent infection. Of these, less than 10% will develop chronic hepatitis, and fewer than 5% will develop cirrhosis. Therefore, the benefit of additional antiviral therapy is questionable at this time.

There are two specific therapies currently approved by the FDA for chronic hepatitis C infections in adults and recently approved for use in children with hepatitis C age 3 years and older.

Interferon therapy (interferon-alfa, pegylated interferon alfa- 2a, alfa-2b). Interferons are antiviral and immunomodulatory proteins. They are naturally produced by leucocytes in response to infectious agents and tumors. In virus-infected cells, interferons can produce antiviral proteins, inhibit synthesis of viral RNA, and allow recognition of the infected hepatocytes by cytotoxic T lymphocytes. It is manufactured by the recombinant method. The disadvantages of this drug are its parenteral route of administration and tolerable but frequent side effects (see Table 3). Its longer acting formulation, called pegylated Interferon, requiring once weekly infusion, is now available for adult use only (AAP, 2003; Hochman & Balistreri, 2003; Strader, Wright, Thomas, & seeff, 2004). Given by itself, interferon-alfa only resulted in a sustained decrease in viral load in 10%-20% of the adults treated, use of the pegylated interferon resulted in sustained response in 25%-39% of treated adults and lower rates for adults with genotype- 1, the most common genotype found in the united States (Fried et al., 2002). Treatment protocols require at least weekly infusions for 12 months.

Table 3. Adverse Effects of Interferon and Ribavirin

Ribavirin therapy. Ribavirin is a guanosine analogue. Although monotherapy showed no beneficial effects in the treatment of hepatitis C, it has a synergistic effect when used with interferon alfa-2b for the therapy of chronic hepatitis C. This combination therapy resulted in sustained response in 33% of adults with genotype 1 and approximately 80% of adults with genotypes 2 or 3 (AAP, 2003). An oral liquid formulation (Rebetol ), to be used in conjunction with interferon alfa-2b, has recently been approved by the FDA (Schering-Plough, 2004). Treatment for HCV genotype-1 virus requires 48 weeks and 24 weeks for genotype-2 virus.

To Treat or Not to Treat

There are several factors that make treatment of HCV in children controversial. In a follow-up study conducted in 460 children who underwent cardiac surgery before 1991 when blood donor screening was initiated, it was found that 15% of the children became anti-HCV positive (Vogt et al., 1999). Fifty-five percent of these positive children remained HCV RNA-positive indicating continued virus production, but only one child had abnormal liver enzymes. Forty- five percent of the children cleared the infection spontaneously. This study showed that over a 20-year time interval almost half the children had cleared the virus. In those who remained infected, the disease had a benign course. As stated before, the treatment is long (6-12 months) and involves the use of parenteral medications with frequent side effects that have to be closely monitored via blood tests.

There have been studies conducted recently that show that early treatment may give the best chance of eradicating the virus and preventing chronic hepatitis. In a small cohort of children with chronic hepatitis C, early initiation of antiviral treatment was associated with a sustained response rate independent of treatment type (Hartman, Berkowitz, Rimon, & Shamir, 2003). In a study of 44 adults treated with interferon, 42 of 43 patients treated within 3 months of acquiring infection or within 1 month of being symptomatic were able to eliminate the virus (Jaeckel, et al., 2001). Although this study did not include children, it highlights the importance of early diagnosis and referral of children to a pediatrie hepatologist for potential treatment.

Conclusion

There is no vaccine or universally effective treatment available for HCV. The prevalence of long-term complications of HCV acquired during childhood is unknown. Additional insults to the liver must be prevented whenever possible in children infected with hepatitis C. Due to the lack of effective treatment and the virus’s ability to mutate, universal screening is not currently recommended. Education against high-risk activities is the only available protection. Research into the management of HCV in children is currently active and should result in a better understanding of the risks associated with each virus genotype, the best practice guidelines for treatment, and, hopefully, an effective means of prevention. Combination therapies for hepatitis C that have improved treatment efficacy in adults should be tested in controlled clinical trials in children. Protease inhibitors, antisense oligonucleotides, and ribosomes are some of the alternative treatment modalities being explored.

Cathy’s adoptiue parents were told that giuen the maternal history of Hepatitis C infection Cathy should be screened for the presence of HCV infection with LFTs and an anti-HCV screening enzyme lmmunoassay (ElA). If the E/A test is positwe, she will be further screened with the RT-PCR to detect the level ofviremia and genotype. When the results of these tests are known, Cathy should be referred to a hepatologist for long-term follow-up. In the meantime, her parents should be reassured that there is minimal risk of contagion in the family or daycare setting, although uniuersal bloodborne pathogen precautions are recommended. The parents were also told that the frequency of long-term complications from HCV in children is thought to be low and careful follow-up will be instituted with these complications in mind. HCV does not alter a child’s growth or deuelopment.

References

Alter, MJ., Kruszon-Moran, D., Nainan, O.V., McQuillan, G.M., Gao, F., Moyer, L.A., et al. (1999). The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. New England Journal of Medicine, 34 7(8), 556-562.

Alter, M.J., Kuhnert, W.L., & Finelli, L. (2003). Guid\elines for laboratory testing and result reporting of antibody to hepatitis C virus. Morbidity and Mortality Weekly Report, 52(3), 1-13.

American Academy of Pediatrics (AAP). (2003). Hepatitis C. In L.K. Pickeringf Ed.), Red book: Report of the committee on infectious diseases (26th ed.Xpp. 336-340). Elk Grove Village, IL: AAP.

Borkowsky, W. (2002). Viral hepatitis. In Burg, F.D. & lngelfinger, J.R. (Eds.), Gellis & Kagan Current pediatrie therapy (17th ed.Xpp. 116-121). Philadelphia: W.B. Saunders.

Centers for Disease Control and Prevention (CDC). (1998). Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morbidity and Mortality Weekly Report, 47(19), 1-33.

Centers for Disease Control and Prevention (CDC). (2003). Transmission of hepatitis B and C viruses in outpatient settings – New York, Oklahoma and Nebraska, 2000-2002., Morbidity and Mortality Weekly Report, 52(38), 901-906.

El-Serag, H.B., (2003). Hepatocellular carcinoma and hepatitis C in the United States. Hepatology, 36(5), 74-83.

Fried, M.W., Shiftman, M.L., Reddy, K.R., Smith, C., Marines, G., Goncales, F. et al. (2002). Pegylated alfa-2a- plus ribavarin for chronic hepatitis C virus infection. New England Journal of Medicine, 347(13), 975-982.

Hartman, C., Berkowitz, D., Rimon, N., & Shamir, R. (2003). The effect of early treatment in children with chronic hepatitis. Journal of Pediatrie Gastroenterology and Nutrition, 37(3), 252- 257.

Henderson, O.K. (2003). Managing occupational risks for hepatitis C transmission in the health care setting. Clinical Microbiology Review, 76(3), 546-568.

Hochman, J.A., & Balistreri, W.F. (2003). Chronic viral hepatitis: Always be current. Pediatrics in Review, 24(121,399-409.

Jaeckel, E., Cornberg, M., Wedemyer, H., Santantonio, T., Mayer, J., Zankel, M. et al. (2001). Treatment of acute hepatitis C with Interferon alfa-2b. New England Journal of Medicine, 345(20), 1452- 1457.

Kim, W.R. (2002). The burden of hepatitis C in the United States. Hepatology, 26(5), 30-34.

Miller, C.L., Johnson, C., Spittal, P.M., Li, K., LaLiberte, N., Montaner, J. S., et al. (2002). Opportunities for prevention: Hepatitis C prevalence an incidence in a cohort of young injection drug users. Hepatology, 36(3), 737-742.

Schering-Plough. (2004). FDA approves Rebetol (ribavarin} oral solution for treatment of children with chronic hepatitis C. Kenilworth, NJ: Schering-Plough. Retrieved from www.scheringplugh.com/schering_ plough/news/ release.jsp?releaselD=485964.

Schwimmer, J.B., & Balistreri, W.F. (2000). Transmission, natural history, and treatment of hepatitis C virus infection in the pediatrie population. Seminars in Liver Disease, 20(1), 37-46.

Strader, D.B., Wright, T., Thomas, D.L. & seeff, L.B. (2004). Diagnosis, management, and treatment of hepatitis C. Hepatology, 39(4), 1147-1171.

Thomas, D.L. (2002). Hepatitis C and immunodeficiency virus infection. Hepatology, 26(5), 207-209.

U.S. Preventive Services Task Force (USPSTF). (2004). Screening for hepatitis C: Recommendation Statement. Rockville, MD: Agency for Healthcare Research and Quality. Retrieved from www.ahrq.gov/ clinic/ Srduspstf/hepcrs.htm.

Vogt., M., Lang, T., Frosner, G., Klinger, C., Sendl, A., Zeller, A. et al. (1999). Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. New England Journal of Medicine, 347(121,866-870.

Sona Sehgal, MD, is Pediatrie Gastroenterology/Hepatology Service Clinical Fellow, Yale-New Haven Hospital, New Haven, CT.

Patricia L. Jackson Alien, MS, RN, PNP, FAAN, is Professor, Yale university School of Nursing, New Haven, CT.

The Primary Care Approaches section focuses on physical and developmental assessment and other topics specific to children and their families. If you are interested in author guidelines and/or assistance, contact Patricia L. Jackson Alien at [email protected].

Copyright Anthony J. Jannetti, Inc. Sep/Oct 2004

Sudden Death Secondary to Fulminant Intracranial Aspegillosis in a Healthy Teenager After Posterior Fossa Surgery: the Role of Corticosteroids and Prophylactic Recommendations/Comments

R. D. DICKERMAN, Q. E. J. STEVENS, S. J. SCHNEIDER

Department of Neurosurgery North Shore University-Long Island Jewish Health System New Hyde Park, NY, USA

Postoperative complications from corticosteroids in neurosurgical patients are not uncommon. Too often the deleterious immunosuppressive effects of corticosteroids are overlooked in neurosurgery patients and can lead to serious and lethal infections. Experimental design: case report of a 16-year-old healthy male who presented for elective resection of a recurrent juvile pilocytic astrocytoma of the posterior fossa 4 years after initial resection. Setting: major University institutional practice. Intervention/ results: a standard suboccipital craniotomy with gross total resection. Postoperatively, the patient suffered from posterior fossa syndrome and diminished gag reflex requiring nasogastric feeds with progressive improvement. While awaiting transfer to a rehabilitation center on postoperative day 12 he suffered a sudden temperature spike followed by neurological decline. A stat computed tomography scan of the brain revealed a diffuse miliary process with severe cerebral edema. Sputum and cerebrospinal fluid cultures identified Aspergillus. Despite immediate therapy to combat the malignant cerebral edema, the patient died within 24 hours of onset of the symptoms. Corticosteroids are used routinely in neurosurgery to combat cerebral edema without much consideration for the immunosuppressive effects. This case demonstrates how the immunosuppressive effects of corticosteroids can lead to a fulminant lethal fungal infection. Neurosurgeons should be aware of the anticatabolic medications now available to combat the deleterious side effects of corticosteroids.

Key words: Anabolic – Catabolic – Decadron – Steroids – Immune system – Oxandrin.

Corticosteroids are routinely used in neurosurgery for there ability to decrease cerebral edema.1 Corticosteroids have been shown to have a multitude of other effects on multiple systems both beneficial and deleterious.2, 3 A few cases have been reported on catastrophic immunosuppression occurring with routine doses of Corticosteroids in postoperative patients.4-8 We present a tragic case of rapid neurological decline and death secondary to fulminant Aspergillus infection occurring after successful posterior fossa surgery for resection of brain tumor.

Case report

Sixteen-year-old male with history of juvenile pilocytic astrocytoma C)PA) resection 4 years prior at an outside institution was seen in the Neurosurgery Clinic for evaluation of radiographie evidence for recurrent tumor and new growth. The patient was an otherwise healthy male, neurologically intact, developmentally normal and very active in sports. The family requested elective surgery for resection of the recurrent tumor. The patient underwent a standard suboccipital approach, with intraoperative neuronavigation assistance due to recurrent tumor growth occurring in the 4th ventricle and attaching to the dorsal brainstem. The patient tolerated the procedure very well and postoperatively suffered posterior fossa syndrome with akinetic mutism and a diminished gag reflex. The patient was on standard postoperative corticosteroid therapy, Dexamethasone 4 mg every 6 hours with a slow taper. A CT scan of the brain was performed on postoperative day 8 as a routine predischarge scan which demonstrated normal postoperative changes (Figure 1). Due to the diminuished gag reflex the patient was nourished with a nasogastric tube until appropriate swallowing reflexes returned. While the diminished gag reflex persisted, the patient progressively improved over the next 2 postoperative weeks and was preparing for discharge to a rehabilitation facility. On postoperative day 12 the patient developed a temperature of 102.S degrees and a chest X-ray was performed while blood and urine cultures were sent for analysis. A small right middle lobe effusion appeared on the radiograph and the patient began to have labored breathing. He was transferred to the Pdiatrie Intensive Care Unit and intubated for airway protection with a presumptive diagnosis of aspiration pneumonia. Approximately 12 hours later the neurosurgery team was notified that the patient had an abnormal pupillary response and an emergent CT scan of the brain was performed (Figure 2). A diffuse miliary process was evident on the CT scan with a yet to be determined etiology. Based on the head CT, a chest CT was also performed demonstrating a similar process of multiple cavitary lesions. A lumbar puncture was performed which was negative for any organisms. Despite aggressive medical intervention for cerebral edema, ventriculostomy, and prophylactic antifungal coverage, the patient developed malignant cerebral edema and died within 24 hours.

Figure 1.-Postoperative day 8, routine predischarge computed tomography .scan demonstrating no hydrocephalus or postoperative hemorrhage.

Figure 2.-Postoperative day 12, emergent computed tomography scan demonstrating a diffuse miliary process with significant cerebral edema.

Discussion

Postoperative death from corticosteroid-induced immunosuppression in neurosurgery patients is a rare occurrence but surgeons must be aware of the serious deleterious effects of corticosteroids.4,7-9 The immunosuppressive effects of corticosteroids are well documented and often utilized to treat many autoimmune diseases.1,3 Neurosurgical catastrophies secondary to Aspergillus have thus far involved cerebrovascular events such as aneurysmal rupture and diffuse subarachnoid hemorrhage.9-12 This is the first case of fulminant Aspergillus occurring in a postoperative neurosurgical patient secondary to immunosuppression. It is unlikely that the patient suffered an occult immunosuppressive illness to predispose him to this process, with the history of previous posterior fossa surgery and exposure to corticosteroids. We did not use any synthetic dura/grafts that may have predisposed him to infection. It is possible that the combined immunosuppressive effects of corticosteroids and surgical stress may have allowed a fungal infection to become overwhelming.

A recent study from the National Institutes of Health demonstrated an increasing incidence of Pneumocystis carinii pneumonia in brain tumor patients, without HIV, receiving Decadron and recommended prophylactic antibiotics.6 Previous studies on brain tumor patients receiving corticosteroid therapy have also demonstrated an increased risk for immunocompromised infections and recommended both prophylactic antibiotics and antifungals.2, 8 We recently reported on a 38-year-old male on corticosteroids for systemic sarcoidosis who developed an isolated intracranial infection with Mycobacterium avium which we attributed to corticosteroid immunosuppression.13 Based on these reports and our experience, we are now routinely utilizing an anticatabolic/ anabolic agent Oxandrin (BTG Pharmaceutical, NJ, USA) which is indicated to combat the deleterious effects of corticosteroids.14- 16 Oxandrin has anabolic properties that can assist with protein metabolism essential for proper immune function and postoperative healing while also combating the catabolic effects of corticosteroids. Our experience thus far with Oxandrin has been successful in assisting with wound-healing in patients undergoing neurosurgery in our practice, especially the compromised patients such as elderly and diabetics. We feel that this medication may have been helpful in combating the immunosuppression in this case.

Lastly, nosocomial causes for aspergillosis infections have been implicated in the past, specifically ongoing hospital construction.17 There was no construction occurring during this patients admission and there were no other patients suffering from a pneumonia in the patients vicinity. In addition, no cases of Aspergillus pneumonia have been reported at the hospital since this patients death 18 months ago. A recent study provided the term “immunoparalysis” for patients that are immunocompetent and subsequently succumb to infections that are usually found in chronically immunosuppressed patients.18 The authors reported on 4 immunocompetent patients that acquired invasive aspergillosis and hypothesized that the patients immune system responded to their initial insult with the expected hyperinflammatory phase followed by the anti-inflammatory phase, it is during this anti-inflammatory phase that the patient suffers “immunoparalysis” and is susceptible to the opportunistic infections.18 Thus, it is plausible that corticosteroids enhanced the anti-inflammatory phase in our patient making him more susceptible to opportunistic infections.

Conclusions

The deleterious effects of corticosteroids are too often underestimated in the field of neurosurgery due to there routine use. This case demonstrates that routine utilization of corticosteroids can lead to catastrophe even in a healthy 16-year- old male. Surgeon awareness of the immunosuppressive effects of corticosteroids is imperative along with education on nutritional and pharmaceutical modalities available to prevent/combat immunosuppression in patients receiving corticosteroids.

References

1. Boumpas DT. Glucocorticoidtherapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993;119:1198-208.

2. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol 2001;33:289-94.

3. Roubenoff R, Roubenoff RA, Ward LM, Stevens MB. Catabolic effects of high-dose corticosteroids persist despite therapeutic benefit in rheumatoid arthritis. AmJ Clin Nutr 1990;52:1113-7.

4. DeMaria EJ, Reichman W, Kenney PR, Armitage JM, Gann DS. Septic complications of corticosteroid administration after central nervous system trauma. Ann Surg 1985;202:248-52.

6. Russian DA, Levine SJ. Pneumocystis carinii pneumonia in patients without HIV infection. AmJ Mecl Sei 2001;321:56-65.

7. Sharma RR, Gurusinghe NT, Lynch PG. Cerebral infarction clue to Aspergillus arteritis following glioma surgery. Br J Neurosurg 1992;6:485-90.

8. Slivka A, Wen PY, Shea WM, Loeffler JS. Pneumocystitis cannii pneumonia during steroid taper in patients with primary brain tumors. AmJ Med 1993;94:2l6-9.

9. Endo T, Tominga T, Hidehiko K, Yoshimoto T. Fatal subarachnoid hemorrhage, with brainstem and cerebellar infarction, caused by Aspergillus infection after cerebral aneurysm surgery: case report. Neurosurgery 2002;50:1147-51.

10. Corvisier N, Gray F, Gherardi R, Lebras F1 Anc CM, Nguyen JP at al. Aspegillosis of the ethmoid sinus and optic nerve, with arteritis and rupture of the internal carotid artery. Surg Neurol 1987;28:311-5.

11. Piotrowski WP, PiIz P, Chuang IH. Subarachnoid hemorrhage caused by a fungal aneurysm of the vertebral artery as a complication of intracranial aneurysm clipping. J Neurosurg 1990;73:962-4.

12. Takahashi Y, Sugita Y, Shigemori M. Fatal hemorrhage from rupture of the intracranial internal carotid artery caused by Aspergillus arteritis. Neurosurg Rev 1998;21:198-201.

13. Dickerman RD, Stevens EJ, Nguyen TT. Isolated intracranial infection with Mycobacterium avium complex. J Neurosurg Sei 2003;47:1-5.

14. Hart DW, Wolf SE, Herndon DN. Anabolic effects of oxandrolone after severe burn. Ann Surg 2001;233:556-64.

15. Langer CJ, Hoffman JP, Ottery FD. Clinical significance of weight loss in cancer patients: rationale for the use of anabolic agents in the treatment of cancer-related cachexia. Nutrition 2001; 17:11-20.

16. Spungen AM, Rasul M, Cytiyn AS, Bauman WA. Nine clinical cases of nonhealing pressure ulcers in patients with spinal cord injury treated with an anabolic agent: a therapeutic trial. Adv Skin Wound Care 2001;14:139-44.

17. Cooper EE, O’Reilly MA, Guest DI, Dharmage SC. Influence of building construction work on Aspergillus infection in a hospital setting. Infect Control Hosp Epidemiol 2003;24:472-6.

18. Hartemink KJ, Paul MA, Spijkstra JJ, Girbes AR, Poklerman KH. Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003;24:15-20.

Received March 26, 2004.

Accepted for publication July 15, 2004.

Address reprint requests to: R. D. Dickerman, D.O., Ph.D., Department of Neurosurgery, 260-12 74th Avenue, Glen Oaks, NY 11004, USA. E-mail: [email protected]

Comments

This report of intracranial aspergillosis alerts us to a very rare complication of surgery, obviously related to the immunosuppressive effect of corticosteroids. Corticosteroids are of course indispensable in neurosurgical practice, but every effort should be made control their side effects. However there is no hard evidence that the use of anabolics, like oxandrolone, as suggested by the authors, reduces the incidence of opportunistic infections. Their help seems to be limited to muscular wasting and wound healing in immunosuppressed patients.

P. Mariatos

Athens – GR

It seems quite impossible to disagree with the objective and conclusions of the paper of Dickerman et al.: the immunosuppressive effects, often deleterious, of corticosteroids are too frequently overlooked in neurosurgery. The cue for these considerations is represented by the case of a young boy who, after a surgical resection of a pilocytic astrocytoma of the cerebellum and subsequent steroid administration, presented a diffuse intracranial fungal infection rapidly lethal.

Corticosteroids are routinely used in neurosurgery with great benefit so that at the end of the ‘5Os began the “steroid era”. Postoperative courses and the entire management of brain tumors radically changed. But corticosteroids have been shown to have many other effects both beneficial and deleterious: cutaneous effects, electrolyte abnormalities, hypertension, hyperglicemia, pancreatitis, hematologie effects, adrenal insufficiency, gastrointestinal, hepatic, ophthalmologic, immunologie effects, i.e. immunosuppression with patients becoming prone to bacterial and fungine infection.

Surgeon awareness of adverse effects of corticosteroids, the immunosuppressive too, is imperative along with education on nutritional and pharmaceutical modalities to prevent or combat immunosuppression.

G. Andrioll

Genoa -1

A 16-year-old neurologically intact patient underwent surgery owing to progression of growth of a cerebellar pilocytic astrocytoma, that had been (partially?) removed 4 years earlier. Following extirpation of a tumor located in the 4th ventricle and implanted on the dorsal brain stem, a routine corticosteroid therapy (Dexamethasone, 4 mg every 6 hours) was started.

On the 12th postoperative day the patient developed high fever followed by neurological deterioration. Multiple cavitary lesions within the brain and the lungs were revealed by CT scan. On the basis of cultures of sputum and cerebrospinal fluid a diagnosis of aspergillosis was made.

The patient died within 24 hours. It was assumed that the infection was consequent to immunosuppression secondary to corticosteroid therapy.

This article is rather untidy and somewhat confusing, with the results of the cultures being reported only in the summary. Immunological pattern and autopsy records are lacking. The cause- effect relationship is conjectural, owing to the shortage of available findings. However, this case report can be a reminder of possible complications following intracranial surgery.

G. Viale

Genoa – I

Copyright Edizioni Minerva Medica Jun 2004

Using the Health Belief Model to Reveal the Perceptions of Jamaican and Haitian Men Regarding Prostate Cancer

OBJECTIVE: The purpose of this study was to determine the knowledge and perceptions of Jamaican and Haitian men regarding prostate cancer. METHODS: A qualitative design was used and ethnographic accounts were collected. RESULTS: The Jamaican men were knowledgeable of the signs, symptoms, and risks for prostate cancer. They believed early detection was associated with positive outcomes. All of the Jamaican men had been screened within the past five years. The Haitian men were less knowledgeable, had more misconceptions than the Jamaican men, were less optimistic that prostate cancer could be cured, and were less likely to have been screened. CONCLUSIONS: While qualitative findings cannot be generalized, language and cultural differences appear to have a negative impact on the level of knowledge that Haitian men have regarding prostate cancer, and their perception of the severity and outcomes. These same factors hinder efforts to recruit Haitian men as research participants.

KEYWORDS: Health Care Seeking Behavior; Prostate Cancer.

Jamaican men, have the highest rate of prostate cancer in the world (304/100,000) (Glover et al., 1998). Due to the prevalence of infectious diseases, the life expectancy for men living in Haiti is only 49.7 years, with only 8.4% of the men expected to live past 60 years (World Health Organization [WHO], 2001a). For black men, the age-specific risk for prostate cancer increases at age 45 years (American Cancer Society [ACS], 2001a; American Urological Association [AUA], 2001). Therefore, few men living in Haiti survive into the years associated with increased risk, and the incidence of prostate cancer among black men living in Haiti is unknown. However, relocating from Haiti to the United States (US) extends life expectancy by 19 years (WHO, 2001b), thereby giving Haitian-born men living in the US the opportunity to experience age-related prostate changes.

The term “African-American” has been broadly used to describe all black people living in the US. Use of such sweeping categorization pays little regard to the existence of subcultures within the black community. There is much diversity within this broad population, and there are attributes of ethnicity that exceed the limitations of the definition of race. While members of the black race may share similar genetic characteristics, skin color cannot be equated with behavior (Kleier, 2003).

Identifying the perceptions of prostate cancer of African- American men is important, and interventions based on these perceptions would logically be effective for African-American men. However, it would be inappropriate to then build interventions for all black men based on findings from studies of African-American men.

Table 1 Characteristics of the Sample

PURPOSE OF THE STUDY

The purpose of this study was to determine the knowledge and perceptions of Jamaican and Haitian men living in South Florida regarding prostate cancer. Specifically, this study explored knowledge levels, cues which would cause health care seeking behavior, perceptions of susceptibility, perceptions of the severity of the effects of prostate cancer, barriers to having prostate examinations, and perceived benefits of such examinations. Knowledge included awareness of risk factors for developing prostate cancer, possible signs of prostate cancer, and the decade of life when prostate screening should commence (Price, Colvin, & Smith, 1993). Once barriers have been identified, practical and tailored interventions can be formulated to correct misconceptions and encourage prostate screening.

THEORETICAL FRAMEWORK

The Health Belief Model was developed as a means to explain and predict preventive health behavior. The concepts of the Health Belief Model as related to prostate cancer screening include (a) perceived susceptibility to prostate cancer, (b) perceived severity of having prostate cancer, (c) perceived benefits of being screened for prostate cancer, (d) perceived barriers to being screened for prostate cancer, (e) cues to action to seek screening for prostate cancer, and (f) self-efficacy, or the confidence in one’s ability to take action (ETR Associates, 2002; Rosenstock, 1974). According to this model, the likelihood that an individual will take action to prevent illness depends on the person’s perception that they are personally vulnerable to the condition, the consequences of the condition would be serious, the precautionary behavior effectively prevents the condition, and the benefits of reducing the threat of the condition exceed the costs of taking action (Redding, Rossi, Rossi, Velicer, & Proschaska, 2000). Modifying factors incorporated in the model include demographic variables and knowledge. Once an individual perceives a threat to his health and is cued to action and the perceived benefits outweigh the perceived barriers, the individual is likely to engage in the preventive health action.

LITERATURE REVIEW

Cognizant of the increased risk for prostate cancer among black males, there have been studies focused on determining which factors influence the health care seeking behavior of members of the African- American community (Boyd, Weinrich, Weinrich, & Norton, 2001; Florida Prostate Cancer Task Force, 2000; Moul, 2000; Price et al., 1993; Shelton, Weinrich, & Reynolds, 1999; Stallings et al., 2000; Thomas et al., 1999; US Department of Health and Human Services (DHHS), 2000; Weinrich, Reynolds, Tingen, & Star, 2000). However, few of these studies have discriminated for subculture and ethnic diversity within the total population of African-American men.

Only one study regarding the beliefs and health care seeking behavior of African- Caribbean immigrants living in the US was found. The New York Task Force on Immigrant Health (2001) used the focus group approach to assess the perceptions, knowledge, and attitudes of immigrant groups to cancer prevention, detection, and treatment. One focus group included 13 English-speaking Caribbean participants; three were males (28.1%). Of the 13 participants, six were age 40 or older (46.2%); the gender of these older participants was not reported. The 13 participants reported their country of origin as Jamaica (n = 2, 15.4%), St. Vincent (n = 5, 38.5%), Grenada (n = 1, 7.7%), Haiti (n = 1, 7.7%), and Trinidad and Tobago (n = 4, 30.8%). Although country of origin was reported, the race of the participants was not. It appears there may have been a racial mix since the report specified that concerns were expressed by “black Caribbeans” (p. 13). Participants attributed good health to nutritional intake and health maintenance including exercise, rest, and avoiding cigarettes. They indicated that the biggest impediment to access of health care resources was the inability to pay. It was noted that black Caribbeans expressed concern that they would receive bad news from doctors and therefore avoided health care visits. Overall, these participants had a basic understanding of the risk for cancer, although they equated the word with negative consequences.

The focus group which consisted of 20 Haitian individuals was equally under represented. Of the 20 participants, two (12.5%) were over the age of 40; neither the gender nor the race of these older participants was reported. The Haitian participants, too, believed that nutrition, exercise, rest, hygiene, and avoiding smoking and drinking were essential components of a healthy life style. However, the Haitians seemingly placed equal emphasis on non-physical components of health and illness. They connected attitude, self- discipline, and self-respect to a healthy state. They relied on being aware of their bodies to determine sickness, used prayer to prevent illness and/or injury, and utilized such natural remedies as medicinal teas as the initial step in illness treatment. The Haitian group was found to have substantially less accurate knowledge regarding cancer risk factors, prevention, detection, and treatment than the English-speaking Caribbean group. They equated cancer with death and attributed the cause of cancer to numerous products associated with industrialization and/or biological factors. Participants believed cancer could be treated but that treatment was painful and expensive treatment was reserved for the wealthy. They expressed doubt that cancer therapy was effective. They claimed to have regular medical screening for cancer but were unlikely to have followed up on the results of such tests for fear of receiving bad news. The men correctly identified the age at which the risk of prostate cancer increases; however, they relied on self-monitoring to detect symptoms of illness. Regarding the cause of prostate cancer, one man attributed it to “sitting on cool objects after long walks” (New York Task Force on Immigrant Health, 2001, p. 26).

Based on the findings of the New York Task Force on Immigrant Health (2001), it is evident that there is incomplete understanding of the knowledge and perceptions of prostate cancer among the immigrant populations examined. It is additionally clear that the participants in these studies lacked knowledge of prostate cancer and had misconceptions regarding the causes of the disease\. They did not participate in screening for early detection of the disease, and, when they did experience symptoms indicative of obstructive uropathy, they either did not recognize the significance of the symptoms or were reluctant to have them evaluated.

Table 1 Characteristics of the Sample

METHOD

This study mirrors work done by Price et al. (1993) to determine the perceptions of African American males regarding prostate cancer. A qualitative design was used, and ethnographic accounts were collected for the purpose of discovering concepts and relationships in raw data and then organizing these into themes that provided conceptual order and insight into the knowledge and perceptions regarding prostate cancer unique to Jamaican and Haitian men living in South Florida.

PROCEDURE

Data was collected at various sites in Broward County, Florida. According to the US Census Bureau (2000), Broward County had a total population of 1,623,018. There were 60,241 (4%) residents who reported to have been born in Jamaica, and 47,445 (3%) who reported to have been born in Haiti. It must be acknowledged that the numbers reported in the census are not reflective of the likely large number of undocumented immigrants living in the area. Sites were selected based on the likelihood of a high concentration of the target population, the availability of a private interview area, and permission from property managers.

Using convenience sampling, ethnically matched research assistants (RA) recruited 20 male volunteers (10 Jamaican and 10 Haitian) to respond to a structured, audio taped interview. Interviews were conducted in the participant’s language of choice. Selection criteria included self-identification as either Jamaican or Haitian and being aged 45 years and older.

Description of the Sample

The men in the Jamaican cohort were most receptive to participating in the study. Over approximately 20 hours, 19 men were approached, 10 of whom who met the inclusion criteria and agreed to participate. Men who refused to be interviewed did so because they did not feel comfortable with either the topic or going into the private room with the RA.

Recruitment of Haitian men was exceedingly difficult. Two RAs spent approximately 70 hours and approached 44 men before 10 agreed to be interviewed. Younger men were more inclined to participate than were older men. Some men said they were not interested in the subject, while others expressed a fear of learning about a problem they did not know they had. Three (30%) interviews were conducted in Haitian Creole and translated into English for analysis. Table 1 provides a detailed description of the characteristics of the sample.

Data Analysis

The interviews were transcribed and categorized by questions. Interpretation was based on themes which emerged from the data and were supported by select quotes. Descriptive data was entered into SPSS for Windows (1999) for quantitative analysis.

Trustworthiness of the Data

To maximize the trustworthiness of the data and enhance credibility, triangulation, member checks, and search for disconfirming evidence were incorporated into the data collection and analyses procedures. Data was collected at different sites on different days of the week and at different times of the day. The interviews were conducted by culturally matched RA who also participated in the analysis of the data. At the conclusion of each interview the RA engaged the participant in summarization of the points which had emerged from the interview and validated the RA’s impressions. In the process of analysis, the research team searched for data that seemed to be contrary to, or to be an alternative explanation to, an emerging theme. Efforts were made to explain those who had a minority view.

FINDINGS

Findings are discussed according to the concepts of the Health Belief Model and the themes identified within each construct. The modifying factor of “knowledge” was included in the inquiry.

A. THE JAMAICAN COHORT

Knowledge

The Jamaican men interviewed were impressively knowledgeable regarding prostate cancer. The majority (n = 6, 60%) had an idea of the location of the prostate gland and stated that it could impact on urinary flow. Two (20%) did not respond to the question, and two (20%) attributed the production of semen or process of ejaculation to the prostate gland. Nine men (90%) were aware prostate screening should begin sometime around the age of 40 years. When asked about the signs and symptoms of prostate cancer, six men (60%) mentioned urinary symptoms as dribbling of urine, urinary frequency, difficulty starting the stream and having to get up in the night to urinate; however, other symptoms mentioned included urinary burning and testicular pain, and three men (30%) stated that they had no idea of the signs and symptoms.

Perceived Susceptibility

Responses to questions regarding perceived susceptibility also showed the Jamaican men to be knowledgeable. Four (40%) stated that susceptibility increased with age starting at 40 years, and one man (10%) identified that being black increased the risk.

Three of the Jamaican men (30%) stated that they did not know the risk factors for prostate cancer. Of those who responded, three (30%) thought that dietary intake of fatty, greasy foods, red meat, alcohol, and caffeine was a major factor. One (10%) participant associated prostate cancer with extremes in sexual activity: “If you are overly sexually active, that could be a factor, and if you are not. I have heard both sides of it so I am not really sure.” One (10%) participant identified hereditary as a possible risk factor.

Regarding cause, seven of the Jamaican men (70%) said they did not know what caused prostate cancer. This line of inquiry led to speculation regarding the relationship between dietary intake, hereditary, and prostate cancer.

Perceived Severity

The men were asked what happened if a person had problems with the prostate gland. Two (20%) did not know what happened; seven (70%) identified urinary symptoms as frequency of urination, difficulty starting the urinary stream, and nocturia; and one (10%) associated prostate problems with a decline in sexual drive.

All participants agreed that prostate cancer could be a serious threat to health and could lead to death. Two (20%) participants simply said that the words prostate cancer brought to mind “death.””Because I just feel once its cancerous, don’t care the surgery, you don’t survive it.” But others were not so pessimistic. Four (40%) participants acknowledged that early detection and prompt treatment could be effective. One man said, “Just try to get rid of it; there are cures out there for it, like surgery, whatever, depends on the severity.” Another man clarified, “If caught early enough there should be help but if not, it could lead to death.” A third man elaborated, “I mean it doesn’t bound to be terminal but…if you catch it in time, they say you can be saved. But if it is not taken in time, it means death.”

Four men (40%) could not identify any problems associated with prostate cancer. Others identified pain and metastasis as problems. One (10%) participant mentioned issues of sexual dysfunction and resultant relationship problems, “If a person is married it could affect the function with their spouse.” While only one participant mentioned sexual problems directly, another participant hinted that sexual functioning could be affected, “Those are ‘well known’ problems (chuckle), you know what I’m saying?”

Perceived Benefits of Taking Action

The participants agreed that the benefit of having a prostate examination was “peace of mind,” early detection of prostate cancer, and the possibility of extension of life. “Just peace of mind that you don’t have cancer.””Benefit is you know if your body is functioning right, if your prostate is good. Give you peace of mind.””If you do have a problem then it might be taken in time. As the old saying goes, a stitch in time saves nine.”

Perceived Barriers to Taking Action

None of the participants identified any barrier to seeking a prostate examination. Indeed, all participants claimed to have been screened within the past five years.

Cues to Action

The symptoms that would motivate the participants to seek an evaluation of their prostate gland centered on urinary symptoms as nocturia, urinary frequency, urinary incontinence, and difficulty starting the urinary stream. Only one person (10%) was unable to state a symptom that would lead him to seek evaluation.

Sources of Information

The participants were asked how they usually got information about health and whose advice they usually followed regarding health care. Six of the Jamaican men (60%) stated they got health information from their doctor, and nine (90%) said they followed their doctor’s advice. Other sources of information included reading, television, and radio. The participants expressed appreciation for the patient/physician relationship and the desire to maintain privacy concerning health matters, “With males, when you have a problem, you don’t go about spreading it. No one needs to know about it but the doctor.”

B. THE HAITIAN COHORT

Knowledge

The Haitian men interviewed were less knowledgeable regarding the prostate gland and prostate cancer. When asked where the prostate gland was located and what it did, five men (50%) were unable to respond, four (40%) had an idea where the gland was located and that it could impact on urinary flow, and one (10%) believed it produced sperm. Eight (80%) stated that prostate screening should begin sometime around age of 40 to 50 years; however, one (10%) thought screening should begin in the mid-30s, and one (10%) did not know. As for the signs and symptoms of prostate cancer, seven (70%) mentioned urinary symptoms as difficulty urinating, bleeding with urination, urinary retention, and urinary frequency. One man stated “If I walk a mile or two, I feel lik\e going to the bathroom.” Three (30%) stated that they did not know the symptoms of prostate cancer.

Perceived Susceptibility

Three of the Haitian men (30%) stated that susceptibility increased with age starting at 40 to 60 years, and one (10%) stated that being black increased the risk of prostate cancer. Seven (70%) were unable to identify any risk factors for prostate cancer, one (10%) stated that age was an important risk factor; two (20%) connected increased risk with dietary intake high in “grease” and “improper” sexual activities. Only one (10%) ventured to identify a cause of prostate cancer; he believed that if a young man had untreated gonorrhea, it would lead to a chronic problem.

Perceived Severity

The Haitian men were not highly verbal when asked questions to determine their perception of the severity of prostate cancer. Their responses were short and to the point. Terms equated with the words “prostate cancer” were: scary, uncomfortable, very bad, and death. Early detection was associated with a more positive outcome, but only one man (10%) thought that prostate cancer was a potentially curable disease. Problems associated with prostate cancer focused on urinary symptoms (40%) and sexual dysfunction (30%). Three (30%) stated they did not know what problems were associated with prostate cancer.

Perceived Benefits of Taking Action

The benefits of having a prostate exam were identified by four (40%) as “knowing where you stand” and “not wondering whether you have a problem or not.” Four (40%) identified early detection as the primary benefit, “The sooner…you check, the better it’s gonna be. Like that you might cure the problem.” One (10%) participant did not identify any benefits, and one (10%) thought that screening would help solve infertility problems.

Perceived Barriers to Taking Action

Five (50%) of the Haitian men said that embarrassment and the pain/discomfort of a digital rectal examination were primary barriers to seeking screening. One man (10%) said that he was afraid to know. Four men (40%) said there were no reasons they would not be screened for prostate cancer.

Cues to Action

Seven of the Haitian men (70%) identified urinary symptoms as cues that would cause them to seek an evaluation of their prostate. “Any problem with urination, like pain, or if I see any blood…would…motivate me to see a doctor.” Three (30%) did not identify any cues; one of these men said, “You don’t need symptoms to seek an evaluation….You’re supposed to have your prostate checked every year.”

Sources of Information

Physicians and nurses were overwhelmingly identified as sources of information by the Haitian participants. They viewed these providers as knowledgeable and responsible. “One of the ways that I usually…I mean, the easiest way is for me to talk to my nurse…she provides me usually with good information, reliable information. And if she has doubt, I go to my doctor.” Besides healthcare professionals, the Haitian participants relied heavily on their personal experience of their bodies. One man said, “I listen to my body.””I listen to myself.”

DISCUSSION

Jamaican men in this sample were well aware of the signs and symptoms of prostate cancer despite a misconception that the prostate gland was involved in fertility and sexual function. The majority knew the risk factors for prostate cancer. The group was polarized with respect to the severity of prostate cancer. They believed that early detection was beneficial, and all Jamaican participants claimed to have been examined within the past five years.

Haitian men were less aware of the signs and symptoms, and there was a more pervasive perception that problems with the prostate gland were directly tied to sexual function and indiscretion. While Haitian men thought that screening was useful for early detection, they were less optimistic that the outcome would be positive. Embarrassment and discomfort were primary barriers to being screened. Although urinary symptoms were identified as cues to action, they also relied on self-awareness. Fewer of the Haitian men than the Jamaican men had ever been screened for prostate cancer, and those who had been screened were screened less recently. Of the five that had never been screened, two were interviewed in the Haitian Creole language.

None of the men in either group identified transportation or financial difficulties as barriers to being screened. Neither did they attribute prostate cancer to supernatural causes or violation of religious mores or natural laws. Both groups strongly identified physicians and nurses as their primary resource for healthcare information and indicated they would follow their advice in these matters.

The findings of this study point to the isolating effect that subcultures experience from an inability to use the dominate language of an area. English is the official language in Jamaica. Jamaicans have more easily assimilated into the American culture, are more knowledgeable regarding prostate cancer and, to some degree, ascribe to American values associated with healthcare. The official language in Haiti is French; however, not all Haitians are literate in French. Most Haitians speak Haitian Creole but are unable to read it (Colin & Paperwalla, 1998). Haitian men are less knowledgeable regarding prostate cancer, are less likely to have been screened for prostate cancer, and are more likely to retain traditional beliefs regarding healthcare practices. They repel intrusion into their personal lives, particularly in areas they believe are connected to reproductive and sexual function.

IMPLICATIONS

It is undeniable that there is disparity in the healthcare outcomes for members of sub-cultural groups in the US. Agencies such as the ACS (2001b) and the US Department of Health and Human Services (2000) have mandated that this disparity be narrowed and actively support methods by which this can be accomplished. However, for interventions to be worthwhile, they must be congruent with the healthcare beliefs, values, and practices of the particular subcultures.

Both Jamaican and Haitian men report that they rely on physicians and nurses for healthcare information and guidance. However, engagement with these providers is limited if these men only present for episodic illness. Indeed, prostate cancer is likely to be advanced by the time symptoms occur. Nurses are in an excellent position to maximize on opportunities to provide Healthcare education, correct misconceptions, and encourage Healthcare maintenance.

There is a need for Healthcare educational materials to be developed in both written and oral Haitian Creole. This material should be available at community locations frequented by men. The presentational design of such materials should be reflective of the private and personal nature of the problem.

FUTURE RESEARCH

Qualitative studies are limited in that they typically involve very small samples and the results cannot be generalized. Language and receptiveness limit the ability to carry out qualitative research involving the Haitian community. Haitian men are reluctant to be interviewed on a face-to-face basis and provide narrative- type data. Data must be collected in the participant’s language of choice then French or Haitian Creole data must be translated into English for analysis. There is a need for transcultural adaptation of appropriate research instruments so that quantitative data can be collected from larger samples while allowing anonymous participation.

REFERENCES

American Cancer Society (2001a). African-American men need early prostate cancer screening. Retrieved March 19, 2004, from http:// www.cancer.org/docroot/nws/content/nws_1_1x_african-

rican_men_need_early_screening_and_treatment_for_prostate_cancer.asp

American Cancer Society (2001b). Cancer statistics, 2001. Retrieved March 19, 2004, from http://www.cancer.org/docroot/pub/ content/pub_3_8x_cancer_statistics_2001.asp

American Urological Association (2001). Policy statements: Early detection of prostate cancer. Retrieved March 19, 2004, from http:// www.auanet.org/aboutaua/policy_statements/services.cfm

Boyd, M. D., Weinrich, S. P., Weinrich, M., & Norton, A. (2001). Obstacles to prostate cancer screening in African-American men. Journal of National Black Nurses Association, 12(2), 1-5.

Colin, J. M., & Paperwalla, G. (1998). Haitian-Americans. In L. D. Purnell, & B. J. Paulanka, (Eds.). Transcultural health care (computer disk). Philadelphia, PA: Davis.

ETR Associates (2002).Theories and approaches: Health belief model. Retrieved March 19, 2004, from http://www.etr.org/recapp/ theories/hbm/

Florida Prostate Cancer Task Force Report (2000). Increasing awareness about prostate cancer: Recommendations of the Florida prostate cancer task force. Retrieved March 19, 2004, from hup:// www.moffitt.usf.edu/pctf/text.pdf

Glover, F. E., Coffey, D. S., Douglas, L. L., Cadogan, M., Russell, H., Tulloch, T., et al. (1998). The epidemiology of prostate cancer in Jamaica. Journal of Urology, 159, 1984 – 1987, 1998.

Kleier, J. A. (2003). Prostate cancer in black men of African- Caribbean descent. Journal of Cultural Diversify, 10(2), 56 – 61.

Moul, J. W. (2000). Screening for prostate cancer in African Americans. Current Urology Report, 1(1), 57-64.

New York Task Force on Immigrant Health (2001). Attitudes and knowledge of cancer prevention, detection, and treatment among five immigrant communities in New York City: A focus group approach. Retrieved on March 19, 2004, from http://www.med.nyu.edu/cih/docs/ FocusGroupRep.pdf

Price, J. L., Colvin, T. L., & Smith, D. (1993). Prostate cancer: Perceptions of African-American males. Journal of the National Medical Association, 55(12), 941 – 947.

Redding, C. A., Rossi, J. S., Rossi, S. R., Velicer, W. F., & Proschaska, J. O. (2000). Health behavior models. The International Electronic Journal of Health Education, 3(Special Issue), 180-193.

Rosenstock, I. \M. (1974). Historical origins of the Health Belief Model. In M. H. Becker, The Health Belief Model and personal health behavior (pp. 1 – 8). Thorofare, NJ: Slack.

Shelton, P., Weinrich, S., & Reynolds, W. A. (1999). Barriers to prostate cancer screening in African American men. Journal of National Black Nurses’ Association, 10(2), 14-28.

SPSS, Inc. (1999). SPSS 10.0 for windows user’s guide. Chicago, IL: SPSS.

Stellings, F. L., Ford, M. D., Simpson, N. K., Fouad, M., Jernigan, J. C., Trauth, J. M., et al. (2000). Black participation in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Controlled Clinical Trials, 21(6), 3795 – 389S.

Thomas, S. M., Holleran, S. A., Hayden, J., Sullivan, J. W., Pollard, S., & Sartor, O. (1999). Enhancing recruitment of African- American men to a prostate cancer screening event. American Society of Clinical Oncology. Retrieved on November 4, 2002, from http:// 208.243.117.238/cgibin/prof/abstracts.pl?absno=1227&div_guc&year_9 9abstracts

United States Census Bureau (2000). South Florida Regional Planning Counsel: South Florida Census 2000 Resource Center. Retrieved April 1, 2004 from http://www.sfrpc.com/ftp/pub/census/ SF3Broward.pdf

United States Department of Health and Human Services (2000). Healthy People 2010 Issues: Health issues impacting healthy people 2010 objectives for the black American population. Retrieved March 19, 2004, from http://rcwww.omhrc.gov/healthy2000book/tab8.html

Weinrich, S. P, Reynolds, W. A., Tingen, M. S., & Star, C. R. (2000). Barriers to prostate cancer screening. Cancer Nursing, 23(2), 117 – 121.

World Health Organization (2001a). WHO statistics: Haiti. Retrieved March 19, 2004, from http://www. who. int/country/hti/en/

World Health Organization (2001b). The world health report archives 1995- 2001. Retrieved March 19, 2004, from http:// www.who.int/whr2001/2001/archwes/1995/state.him

Jo Ann Kleier, EdD, PhD, ARPN, CURN

Jo Ann Kleier, EdD, PhD ARNP, CURN, Associate Professor, Barry University School of Nursing, Miami Shores, Florida.

Copyright Riley Publications, Inc. Center for the Study of Multiculturalism and Health Fall 2004

Immunology of Tuberculosis

Tuberculosis is a major health problem throughout the world causing large number of deaths, more than that from any other single infectious disease. The review attempts to summarize the information available on host immune response to Mycobacterium tuberculosis. Since the main route of entry of the causative agent is the respiratory route, alveolar macrophages are the important cell types, which combat the pathogen. Various aspects of macrophage- mycobacteriiim interactions and the role of macrophage in host response such as binding of M. tuberculosis to macrophages via surface receptors, phagosome-lysosome fusion, mycobacterial growth inhibition/killing through free radical based mechanisms such as reactive oxygen and nitrogen intermediates; cytokine-mediated mechanisms; recruitment of accessory immune cells for local inflammatory response and presentation of antigens to T cells for development of acquired immunity have been described. The role of macrophage apoptosis in containing the growth of the bacilli is also discussed. The role of other components of innate immune response such as natural resistance associated macrophage protein (Nramp), neutrophils, and natural killer cells has been discussed. The specific acquired immune response through CD4 T cells, mainly responsible for protective ThI cytokines and through CD8^sup +^ cells bringing about cytotoxicity, also has been described. The role of CD-I restricted CD8^sup +^ T cells and non-MHC restricted γ/ δ T cells has been described although it is incompletely understood at the present time. Humoral immune response is seen though not implicated in protection. The value of cytokine therapy has also been reviewed. Influence of the host human leucocyte antigens (HLA) on the susceptibility to disease is discussed.

Mycobacteria are endowed with mechanisms through which they can evade the onslaught of host defense response. These mechanisms are discussed including diminishing the ability of antigen presenting cells to present antigens to CD4^sup +^ T cells; production of suppressive cytokines; escape from fused phagosomes and inducing T cell apoptosis.

The review brings out the complexity of the host-pathogen interaction and underlines the importance of identifying the mechanisms involved in protection, in order to design vaccine strategies and find out surrogate markers to be measured as in vitro correlate of protective immunity.

Key words immunology – Mycobacterium tuberculosis – tuberculosis

Tuberculosis (TB) remains the single largest infectious disease causing high mortality in humans, leading to 3 million deaths annually, about five deaths every minute. Approximately 8-10 million people are infected with this pathogen every year1. Out of the total number of cases, 40 per cent of cases are accommodated in South East Asia alone. In India, there are about 500,000 deaths occurring annually due to TB2, with the incidence and prevalence being 1.5 and 3.5 millions per year.

This review summarizes the information available on host immune response to the causative bacteria, complexity of host-pathogen interaction and highlights the importance of identifying mechanisms involved in protection.

Pathogcnesis of TB

Roule and site of infection: Mycobacterium tuberculosis is an obligatory aerobic, intracellular pathogen, which has a predilection for the lung tissue rich in oxygen supply. The tubercle bacilli enter the body via the respiratory route. The bacilli spread from the site of initial infection in the lung through the lymphatics or blood to other parts of the body, the apex of the lung and the regional lymph node being favoured sites. Extrapulmonary TB of the pleura, lymphatics, bone, genito-urinary system, meninges, peritoneum, or skin occurs in about 1 5 per cent of TB patients.

Events following entry of bacilli: Phagocytosis of M tuberculosis by alveolar macrophages is the first event in the host-pathogen relationship that decides outcome of infection. Within 2 to 6 wk of infection, cell-mediated immunity (CMI) develops, and there is an influx of lymphocytes and activated macrophages into the lesion resulting in granuloma formation. The exponential growth of the bacilli is checked and dead macrophages form a caseum. The bacilli are contained in the caseous centers of the granuloma. The bacilli may remain forever within the granuloma, get re-activated later or may get discharged into the airways after enormous increase in number, necrosis of bronchi and cavitation. Fibrosis represents the last-ditch defense mechanism of the host, where it occurs surrounding a central area of necrosis to wall off the infection when all other mechanisms failed. In our laboratory, in guineapigs infected with M. tuberculosis, collagen, elastin and hexosamines showed an initial decrease followed by an increase in level. Collagen stainable by Van Gicson’s method was found to be increased in the lung from the 4th wk onwards.3

Macraphage-Mycobacterium interactions and the role of macrophage in host response can be summarized under the following headings: surface binding of M. tuberculosis to macrophages; phagosome- lysosome fusion; mycobacterial growth inhibition/killing; recruitment of accessory immune cells for local inflammatory response and presentation of antigens to T cells for development of acquired immunity.

Binding of M. tuberculosis to monocytes macrophages: Complement receptors (CRl, CR2, CR3 and CR4), mannose receptors (MR) and other cell surface receptor molecules play an important role in binding of the organisms to the phagocytes4. The interaction between MR on phagocytic cells and mycobacteria seems to be mediated through the mycobacterial surface glycoprotein lipoarabinomannan (LAM)5. Prostaglandin E2 (PGE2) and intcrleukin (IL)-4, a Th2-type cytokine, upregulate CR and MR receptor expression and function, and interferon-γ (IFN-γ) decreases the receptor expression, resulting in diminished ability of the mycobacteria to adhere to macrophages6. There is also a role for surfactant protein receptors, CD14 receptor7 and the scavenger receptors in mediating bacterial binding8.

Phagolysosome fusion: Phagocytosed microorganisms are subject to degradation by intralysosomal acidic hydrolases upon phagolysosome fusion9′. This highly regulated event10 constitutes a significant antimicrobial mechanism of phagocytes. Hart et al11 hypothesized that prevention of phagolysosomal fusion is a mechanism by which M. tuberculosis survives inside macrophages11. It has been reported that mycobacterial sulphatides12, derivatives of multiacylated trehalose 2-sulphate13, have the ability to inhibit phagolysosomal fusion. In vitro studies demonstrated that M. tuberculosis generates copious amounts of ammonia in cultures, which is thought to be responsible for the inhibitory effect14.

How do the macrophages handle the engulfed M. tuberculosis?: Many antimycobacterial effector functions of macrophages such as generation of reactive oxygen intermediates (ROI), reactive nitrogen intermediates (RNl), mechanisms mediated by cytokines, have been described.

Reactive oxygen intermediates (ROI): Hydrogen peroxide (H^sub 2^O^sub 2^), one of the ROI generated by macrophages via the oxidative burst, was the first identified effector molecule that mediated mycobactericidal effects of mononuclear phagocytes15. However, the ability of ROI to kill M. tuberculosis has been demonstrated only in mice16 and remains to be confirmed in humans. Studies carried out in our laboratory have shown that M tuberculosis infection induces the accumulation of macrophages in the lung and also H^sub 2^O^sub 2^ production17. Similar local immune response in tuberculous ascitic fluid has also been demonstrated18. However, the increased production of hydrogen peroxide by alveolar macrophages is not specific for TB19. Moreover, the alveolar macrophages produced less H^sub 2^O^sub 2^, than the corresponding blood monocytes.

Reactive nitrogen intermediates (RNI): Phagocytes, upon activation by IFN-γ and tumor necrosis factor-α (TNF- α), generate nitric oxide (NO) and related RNI via inducible nitric oxide synthase (iNOS2) using L-arginine as the substrate. The significance of these toxic nitrogen oxides in host defense against M. tuberculosis has been well documented, both in vitro and in vivo, particularly in the murine system20. In genetically altered iNOS gene knock-out (GKO) mice M. tuberculosis replicates much faster than in wild type animals, implying a significant role for NO in mycobacterial host defense21.

In our study, rat peritoneal macrophages were infected in vitro with M. tuberculosis and their fate inside macrophages was monitored. Alteration in the levels of NO, H^sub 2^O^sub 2^ and lysosomal enzymes such as acid phosphatase, cathepsin-D and – glucuronidase was also studied. Elevation in the levels of nitrite was observed along with the increase in the level of acid phosphatase and -glucuronidase. However, these microbicidal agents did not alter the intracellular viability of M. tuberculosis22.

The role of RNI in human infection is controversial and differs from that of mice. 1, 25 dihydroxy vitamin D3 [1, 25-(OH)7D3] was reported to induce the expression of the NOS2 and M. tuberculosis inhibitory activity in the human HL-60 macrophage-like cell line23. This observation thus identifies NO and related RNI as the putative antimycobacterial effectors produced by human macrophages. Thisnotion is further supported by another study in which IFN- γ stimulated human macrophages co-cultured with lymphocytes (M, tuberculosis lysate/IFN-γ primed) exhibited mycobactericidal activity concomitant with the expression of NOS2(24). High level expression of NOS2 has been detected immunohistochemically in macrophages obtained by broncho alveolar lavage (BAL) from individuals with active pulmonary TB25.

Other mechanisms of growth inhibition/killing’. IFN-γ and TNF-α mediated antimycobacterial effects have been reported. In our laboratory studies, we were unable to demonstrate mycobacterial killing in presence of IFN-γ, TNF-α and a cocktail of other stimulants26.There is lack of an experimental system in which the killing of M. tuberculosis by macrophages can be reproducibly demonstrated in vitro. The reports of the effect of IFN-γ treated human macrophages on the replication of M. tuberculosis range from its being inhibitory27 to enhancing28. Later it was demonstrated that 1,25-(OH)^sub 2^D^sub 3^, alone or in combination with IFN-γ and TNF-α, was able to activate macrophages to inhibit and/or kill M. tuberculosis in the human system29. In our comparative study of immune response after vaccination with BCG, in subjects from Chengalput, India and London, M. bovis BCG vaccination did not enhance bacteriostasis with the Indians, but did so with the subjects from London.

Macrophage apoptosis

Another potential mechanism involved in macrophage defense against M. tuberculosis is apoptosis or programmed cell death. Placido et al30 found that using the virulent strain H37Rv, apoptosis was induced in a dose-dependent fashion in BAL cells recovered from patients with TB, particularly in macrophages from HIV-infected patients. Klingler et al31 have demonstrated that apoptosis associated with TB is mediated through a downregulation of bcl2, an inhibitor of apoptosis. Within the granuloma, apoptosis is prominent in the epithelioid cells as demonstrated by condensed chromatin viewed by light microscopy or with the in situ terminal transferase mediated nick end labeling (TUNEL) technique32.

Molloy et al33 have shown that macrophage apoptosis results in reduced viability of mycobacteria. The effects of Fas L- mediated or TNF-α-induced apoptosis on M. tuberculosis viability in human and mouse macrophages is controversial: some studies report reduced bacterial numbers within macrophages after apoptosis34 and others indicate this mechanism has little antimycobacterial effect35.

Evasion of host immune response by M. tuberculosis

M. tuberculosis is equipped with numerous immune evasion strategies, including modulation of antigen presentation to avoid elimination by T cells. Protein secreted by M. tuberculosis such as Superoxide dismutasc and catalase are antagonistic to ROI36. Mycobacterial components such as sulphatides, LAM and phenolic- glycolipid I (PGL-I) are potent oxygen radical scavengers37,38. M tuberculocsis-infected macrophages appear to be diminished in their ability to present antigens to CD4^sup +^ T cells, which leads to persistent infection39. Another mechanism by which antigen presenting cells (APCs) contribute to defective T cell proliferation and function is by the production of cytokines, including TGF- β, IL-10(40) or IL-68(41). In addition, it has also been reported that virulent mycobacteria were able to escape from fused phagosomes and multiply42.

Host immune mechanisms in TB

Innate immune response: The phagocytosis and the subsequent secretion of IL-12 are processes initiated in the absence of prior exposure to the antigen and hence form a component of innate immunity. The other components of innate immunity are natural resistance associated macrophage protein (Nramp), ncutrophils, natural killer cells (NK) c/c. Our previous work showed that plasma lysozyme and other enzymes may play an important role in the first line defense, of innate immunity to M. tuberculosis43. The role of CD-I restricted CDS’ T cells and nonMHC restricted T cells have been implicated but incompletely understood.

Nramp: Nramp is crucial in transporting nitrite from intracellular compartments such as the cytosol to more acidic environments like phagolysosome, where it can be converted to NO. Defects in Nramp production increase susceptibility to mycobacteria. Newport et al44 studied a group of children with susceptibility to mycobacterial infection and found Nramp I mutations as the cause for it. Our laboratory study on pulmonary and spinal TB patients and control subjects suggested that NRAMP1 gene might not be associated with the susceptibility to pulmonary and spinal TB in the Indian population45.

Nuertrophils: Increased accumulation of neutrophil in the granuloma and increased chemotaxis has suggested a role for neutmphils46. At the site of multiplication of bacilli, neutmphils are the first cells to arrive followed by NK cells, γ/δ cells and α/β cells. There is evidence to show that granulocytemacrophage-colony stimulating factor (GM-CSF) enhances phagocytosis of bacteria by neutmphils^. Human studies have demonstrated that neutmphils provide agents such as defensins, which is lacking for macmphage-mediated killing'”. Majeed et al49 have shown that neutmphils can bring about killing of M. tuberculosis in the presence of calcium under in vivo conditions.

Natural killer: ISK cells are also the effector cells of innate immunity. These cells may directly lysc the pathogens or can lyse infected monocytes. NK culture with live M tuberculosis brought about the expansion of NK cells implicating that they may be important respondcrs to M. tuberculosis infection m vivo50. During early infection, NK cells are capable of activating phagocytic cells at the site of infection. A significant reduction in NK activity is associated with multidrugresistant TB (MDR-TB). NK activity in BAL has revealed that different types of pulmonary TB are accompanied by varying degrees of depression51. IL-2 activated NK cells can bring about mycobactericidal activity in macrophages infected with M. avaim complex (MAC) as a non specific response52. Apoptosis is a likely mechanism of NK cytotoxicity. NK cells produce IFN-γ and can lyse mycobacterium pulsed target cells53. Our studies54 demonstrate that lowered NK activity during TB infection is probably the ‘effect’ and not the ’cause’ for the disease as demonstrated by the follow up study. Augmentation of NK activity with cytokines implicates them as potential adjuncts to TB chemotherapy54.

The Toll-like receptors (TLR): The recent discovery of the importance of the TLR protein family in immune responses in insects, plants and vertebrates has provided new insight into the link between innate and adaptive immunity. Medzhitov et a!55 showed that a human homologue of the Drosophila Toll protein signals activation of adaptive immunity. The interactions between M. tuberculosis and TLRs are complex and it appears that distinct mycobacterial components may interact with different members of the TLR family. M. tuberculosis can immunologically activate cells via either TLR2 or TLR4 in a CD 14-independent, ligand-specific manner56.

Acquired immune response

Humoral immune response: Since M. tuberculosis is an intracellular pathogen, the serum components may not get access and may not play any protective role. Although many researchers have dismissed a role for B cells or antibody in protection against TB57, recent studies suggest that these may contribute to the response to TB58.

Mycobacterial antigens inducing humoral response in humans have been studied, mainly with a view to identify diagnosticalIy relevant antigens. Several protein antigens of M. tuberculosis have been identified using murine monoclonal antibodies59. The immunodominant antigens for mice include 71, 65, 38, 23, 19, 1.4 and 12 kDa proteins. The major protein antigens of M leprae and M. tuberculosis have been cloned in vectors such as Escherichia coli. Not all the antigens identified based on mouse immune response were useful to study human immune response.

In our laboratory a number of M. tuberculosis antigens have been purified and used for diagnosis of adult and childhood TB60’66. Combination of antigens were also found to be useful in the diagnosis of HIV-TB6768 Detection of circulating immune complex bound antibody was found to be more sensitive as compared to serum antibodies. The purified antigens were evaluated for their utility in diagnosing infection6970.

Cellular immune response

T cells: M. tuberculosis is a classic example of a pathogen for which the protective response relies on CMI. In the mouse model, within 1 wk of infection with virulent M. tuberculosis, the number of activated CD4^sup +^ and CD8^sup +^ T cells in the lung draining lymph nodes increases71. Between 2 and 4 wk post-infection, both CD4^sup +^ and CD8^sup +^ T cells migrate to the lungs and demonstrate an effector/memory phenotype (CD44^sup hi^CD45^sup lo^CD62L^sup -^); approximately 50 per cent of these cells are CD69^sup +^. This indicates that activated T cells migrate to the site of infection and are interacting with APCs. The tuberculous granulomas contain both CD4^sup +^ and CD8^sup +^ T cells72 that contains the infection within the granuloma and prevent reactivation.

CD4 T cells: M. tuberculosis resides primarily in a vacuole within the macrophage, and thus, major histocompatibility complex (MHC) class II presentation of mycobacterial antigens to CD4^sup +^ T cells is an obvious outcome of infection. These cells are most important in the protective response against M. tuberculosis. Murine studies with antibody depletion of CD4^sup +^T cells73, adoptive transfer74, or the use of gene-disrupted mice75 have shown that the CD4^sup +^T cell subset is required for control of infection. In humans, the pathogenesis of HIV infection has demonstrated that \the loss of CD4^sup +^T cells greatly increases susceptibility to both acute and reactivation TB76. The primary effector function of CD4^sup +^T cells is the production of IFN-γ and possibly other cytokines, sufficient to activate macrophages. In MHC class II-/- or CD4-/- mice, levels of IFN-γ were severely diminished very early in infection73. NOS2 expression by macrophages was also delayed in the CD4^sup +^T cell deficient mice, but returned to wild type levels in conjunction with IFNy expression75.

In a murine model of chronic persistent M. tuberculosis infection77, CD4 T cell depletion caused rapid re-activation of the infection. IFN-γ levels overall were similar in th lungs of CD4^sup +^ T celldepleted and control mice, due to IFNγ production by CD8^sup +^ T cells. Moreover, there was no apparent change in macrophage NOS2 production or activity in the CD4^sup +^T cell-depleted mice. This indicated that there are IFN-γ and NOS2-independent, CD4^sup +^T celldependent mechanisms for control of TB. Apoptosis or lysis of infected cells by CD4^sup +^T cells may also play a role in controlling infection32-. Therefore, other functions of CD4^sup +^T cells are likely to be important in the protective response and must be understood as correlates of immunity and as targets for vaccine design.

CD8^sup +^t.cells: CD8^sup +^ cells are also capable of secreting cytokincs such as IFN-γ and IL-4 and thus may play a role in regulating the balance of ThI and Th2 cells in the lungs of patients with pulmonary TB. The mechanism by which mycobacterial proteins gain access to the MPIC class 1 molecules is not fully understood. Bacilli in macrophages have been found outside the phagosome 4-5 days after infection78, but presentation of mycobacterial antigen by infected macrophages to CDS T cells can occur as early as 12 h after infection. Reports provide evidence for a mycobacteria-induccd pore or break in the vesicular membrane surrounding the bacilli that might allow mycobacterial antigen to enter the cytoplasm of the infected cell79.

Yu et al80 analyzed CD4 and CDS populations from patients with rapid, slow, or intermediate regression of disease while receiving therapy and found that slow regression was associated with an increase in CDS’ cells in the BAL. Taha et al81 found increased CDS^sup +^T cells in the BAL of patients with active TB, along with striking increases in the number of BAL cells expressing IFNγ and IL-12 mRT\IA. These studies point to a potential role for CD8^sup +^T cells in the immune response to TB. Lysis of infected human dendritic cells and macrophages by CDl- and MHC class !- restricted CD8^sup +^T cells specific for M tuberculosis antigens reduced intracellular bacterial numbers82. The killing of intracellular bacteria was dependent on perforin /granulysin83. Lysis through the Fas/Fas L pathway did not reproduce this effect82. At high cffector-to-target ratio (50:1), this lysis reduced bacterial numbers84. It is shown that IFN-γ production in the lungs by the CD8T cell subset was increased at least four-fold in the perforin deficient (P-/-) mice, suggesting that a compensatory effect protects P-/- mice from acute infection85.

Studies defining antigens recognized by CD8^sup +^T cells from infected hosts without active TB provide attractive vaccine candidates and support the notion that CD8^sup +^T cell responses, as well as CD4^sup +^T cell responses must be stimulated to provide protective immunity.

T cell apoptosis: A wide variety of pathogens can attenuate CMI by inducing T cell apoptosis. Emerging evidence indicates that apoptosis of T cells does occur in murine86 and human TB87. In m vitro studies using peripheral blood mononuclear cells (PBMC) from tuberculous patients88, the phenomenon of T cell hypo- responsiveness has been linked to spontaneous or M tuberculosis- induced apoptosis of T cells. The observed apoptosis is associated with diminished M tuberculosis-stimulated IFN-γ and IL-2 production. In tuberculosis infection, CD95-ediatcd ThI depletion occurs, resulting in attenuation of protective immunity against M. tuberculosis, thereby enhancing disease susceptibility89. Detailed analysis of para formaldehyde-fixed human tuberculous tissues revealed that apoptotic CD3′, CD45RO’ cells are present in productive tuberculous granulomas, particularly those harbouring a necrotic centre90. Studies carried out in our laboratory have demonstrated the ability of mycobacterial antigens to bring about apoptosis in animal models91. In addition, increased spontaneous apoptosis, which is further enhanced by mycobacterial antigens, has also been shown to occur in pleural fluid cells92.

Nonclassically retricted CD* T cells: CD1 molecules are nonpolymorphic antigen presenting molecules that present lipids or glycolipids to T cells. There is evidence of a recall T cell response to a CD1-restricted antigen in M. tuberculosis-exposed purified protein derivative (PPD) positive subjects93. CDl molecules are usually found on dendritic cells m vivo94, and dendritic cells present in the lungs may be stimulating CDl-restricted cells in the granuloma that can then have a bystander effect on infected macrophages. Further investigation of the processing and presentation of mycobacterial antigens to CD1-restricted CD8 T cells is necessary to understand the potential contribution of this subset to protection.

γ/δ: T-cells in TB: The role of γ/δ T cells in the host response in TB has been incompletely worked out. These cells are large granular lymphocytes that can develop a dendritic morphology in lymphoid tissues; some γ/δ T cells may be CD8+. In general, γ/δ T cells are felt to be non-MHC restricted and they function largely as cytotoxic T cells.

Animal data suggest that γ/δ cells play a significant role in the host response to TB in mice and in other species95, including humans. M. tuberculosis reactive γ/δ T cells can be found in the peripheral blood of tuberculin positive healthy subjects and these cells are cytotoxic for monocytes pulsed with mycobacterial antigens and secrete cytokines that may be involved in graiuiloma formation96. Studies97,98 demonstrated that γ/ δ cells were relatively more common (25 to 30% of the total) in patients with protective immunity as compared to patients with ineffective immunity. Our study in childhood TB patients showed that the proportion of T cells expressing the γ/δ T cell receptor was similar in TB patients and controls99. Thus γ/ δ cells may indeed play a role in early immune response against TB and is an important part of the protective immunity in patients with latent infection100.

Th1 and Th2 dichotomy in TB: Two broad (possibly overlapping) categories of T cells have been described: Th1 type and Th2 type, based on the pattern of cytokines they secrete, upon antigen stimulation. ThI cells secrete IL-2, IFN-γ and play a protective role in intracellular infections. Th2 type cells secrete 1L-4, IL-5 and IL-IO and are either irrelevant or exert a negative influence on the immune response. The balance between the two types of response is reflected in the resultant host resistance against infection. The type of ThO cells shows an intermediate cytokine secretion pattern. The differentiation of ThI and Th2 from these precursor cells may be under the control of cytokines such as IL- 12.

In mice infected with virulent strain of M. tuberculosis, initially ThI like and later Th2 like response has been demonstrated101. There are inconsistent reports in literature on preponderance of ThI type of cytokines, of Th2 type, increase of both, decrease of ThI, but not increase of Th2 etc. Moreover, the response seems to vary between peripheral blood and site of lesion; among the different stages of the disease depending on the severity.

It has been reported that PBMC from TB patients, when stimulated in vitro with PPD, release lower levels of IFN-γ and IL-2, as compared to tuberculin positive healthy subjects’02. Other studies have also reported reduced IFN0 -γ103 increased IL-4 secretion104 or increased number of IL-4 secreting cells105. These studies concluded that patients with TB had a Th2-type response in their peripheral blood, whereas tuberculin positive patients had a Th1-type response.

More recently, cellular response at the actual sites of disease has been examined. Zhang et al106 studied cytokine production in pleural fluid and found high levels of 1L-12 after stimulation of pleural fluid cells with M. tuberculosis. IL-12 is known to induce a Thl-type response in undifferentiated CD4+ cells and hence there is a ThI response at the actual site of disease. The same group107 observed that TB patients showed evidence of high IFNy production and no IL4 secretion by the lymphocytes in the lymph nodes. There was no enhancement of Th2 responses at the site of disease in human TB. Robinson el a/108 found increased levels of IFN-γ mRNA in situ in BAL cells from patients with active pulmonary TB.

In addition, reports suggest that in humans with TB, the strength of the Thl-type immune response relate directly to the clinical manifestations of the disease. Sodhi et al109 have demonstrated that low levels of circulating IFN-γ in peripheral blood were associated with severe clinical TB. Patients with limited TB have an alveolar lymphocytosis in infected regions of the lung and these lymphocytes produce high levels of IFN-γ54. In patients with far advanced or cavitary disease, no Thl-type lymphocytosis is present.

Cytokines

Interleiikin-12: IL-12 is induced following phagocytosis of M. tuberculosis bacilli by macrophages and dendritic cells110, which leads to development of a ThI response with production of IFN- γ. IL-I2p40-gens deficient mice were susceptible to infection and had increased bacterial \burden, and decreased survival lime, probably due to reduced IFN-γ production111. Humans with mutations in IL-l2p40 or the IL-12R genes present with reduced IFN- γ production from I cells and are more susceptible to disseminated BCG and M. avium infections112. An intriguing study indicated that administration of II,-12 DNA could substantially reduce bacterial numbers in mice with a chronic M. tuberculosis infection113, suggesting that induction of this cytokine is an important factor in the design of a TD vaccine.

McDycr et al114 found that stimulated PBMC from MDR-TB patients had less secretion oflL-2 and IFN-γ than did cells from healthy control subjects. IFN-γ production could be restored if PBMC were supplemented with IL-12 prior to stimulation and antibodies to IL-12 caused a further decrease in IFTN-γ upon stimulation. Taha et al81 demonstrated that in patients with drug susceptible active TB both lFN-γ and IL-12 producing BAL cells were abundant as compared with BAL cells from patients with inactive TB.

Interferon-γ IFN-γ, a key cytokine in control of M tuberculosis infection is produced by both CD4^sup +^ and CD8^sup +^T cells, as well as by NK cells. IFN-γ might augment antigen presentation, leading to recruitment of CD4^sup +^T-lymphocytes and/ or cylotoxic T-lymphocytes. which might participate in mycohacterial killing. Although lFN-γ production alone is insufficient to control M tuberculosis infection, it is required for the protective response to (his pathogen. IFN-γ is the major activator of macrophages and it causes mouse but not human macrophages to inhibit the growth of M /i/A(?rcz(/o.sv.s m vitro16. IL-4, IL-6 and UM-CSF could bring about in vitro killing of mycobactcria by macrophages either alone or in synergy with IFN-γ in the murine system115 IFN-γ GKO mice are most susceptible to virulent M tuberculosis116.

Humans defective in genes for IFN-γ or the IFN-γ receptor are prone to serious mycobacterial infections, including M. tuberculosis Although ll’N-γ production may vary among subjects, some studies suggest that IFN-γ levels are depressed in patients with active TB107,118 Another study demonstrated that M tuberculosis could prevent macrophages from responding adequately to IFN-γ119. This suggests that the amount of IFN-γ produced by T cells may be less predictive of outcome than the ability of the cells to respond to this cytokine.

Our study comparing the immune response to preand post- BCG vaccination, has shown that BCG had little effect in driving the immune response towards IFN-γ and a protective ThI response120. In another study on tuberculous pleuritis, a condition which may resolve without therapy, a protective ThI type of response with increased IFN-γ is seen at the site of lesion (pleural fluid), while a ThO type of response with both IFN-γ and IL-4 is seen under m vitro conditions121.

To determine if the manifestations of initial infection with M tuberculosis reflect changes in the balance of T cell cytokines, we evaluated in vitro cytokine production of children with TB and healthy tuberculin reactors122. IFN-γ production was most severely depressed in patients with moderately advanced and far advanced pulmonary disease and in malnourished patients. Production of IL-12, IL-4 and IL-IO was similar in TB patients and healthy tuberculin reactors. These results indicate that the initial immune response to M. tuberculosis is associated with diminished IFN- γ production, which is not due to reduced production of IL-12 or enhanced production of IL-4 or IL-10.

Tumor necrosis factor (TNF-α): TNF-α is believed to play multiple roles in immune and pathologic responses in TB. M. tuberculosis induces TNF-α secretion by macrophages, dendritic cells and T cells. In mice deficient in TNF-α or the TNF receptor, M. tuberculosis infection resulted in rapid death of the mice, with substantially higher bacterial burdens compared to control micc123 TNF-α. in synergy with IFN-γ induces NOS2 expression124′.

TNF-α is important for walling off infection and preventing dissemination. Convincing data on the importance of this cytokine in granuloma formation in TB and other mycobactcrial diseases has been reported123-125. TNF-α affects cell migration and localization within tissues in M. tuberculosis infection. TNF-α influence expression of adhesion molecules as well as chemokincs and chemokine receptors, and this is certain to affect the formation of functional granuloma in infected tissues.

TNF-α has also been implicated in immunopathologic response and is often a major factor in host-mediated destruction of lung tissue126. In our studies, increased level of TNF-α. was found at the site of lesion (pleural fluid), as compared to systemic response (blood) showing that the compartmentalized immune response must be containing the infection127.

Interleukin-1: IL-1, along with TNF-α, plays an important role in the acute phase response such as fever and cachexia, prominent in TB. In addition, IL-1 facilitates T lymphocyte expression of IL-2 receptors and IL-2 release. The major antigens of mycobacteria triggering IL-1 release and TNF-α have been identified128. IL-1 has been implicated in immunosuppressive mechanisms which is an important feature in tuberculoimmunity129.

Interleukin-2: IL-2 has a pivotal role in generating an immune response by inducing an expansion of the pool of lymphocytes specific for an antigen. Therefore, IL-2 secretion by the protective CD4 Th 1 cells is an important parameter to be measured and several studies have demonstrated that IL-2 can influence the course of mycobacterial infections, either alone or in combination with other cytokines130.

Interleukin-4: Th2 responses and IL-4 in TB are subjects of some controversy. In human studies, a depressed Th 1 response, but not an enhanced Th2 response was observed in PBMC from TB patients107-118. Elevated IFN-γ expression was detected in granuloma within lymph nodes of patients with tuberculous lymphadenitis, but little IL-4 mRNA was detected107. These results indicated that in humans a strong Th2 response is not associated with TB. Data from mice studies116 suggest that the absence of a Th 1 response to M. tuberculosis does not necessarily promote a Th2 response and an IFNγ deficiency, rather than the presence of IL-4 or other Th2 cytokines, prevents control of infection. In a study of cytokine gene expression in the granuloma of patients with advanced TB by in situ hybridization, IL-4 was detected in 3 of 5 patients, but never in the absence of IFN-γ expression131. The presence or absence of IL-4 did not correlate with improved clinical outcome or differences in granuloma stages or pathology.

Interleitkin-6: IL-6 has also been implicated in the host response to M. tuberculosis. This cytokine has multiple roles in the immune response, including inflammation, hematopoiesis and differentiation of T cells. A potential role for IL-6 in suppression of T cell responses was reported41. Early increase in lung burden in IL-6^sup -/-^ mice suggests that IL-6 is important in the initial innate response to the pathogen132.

Interleukin-10′. IL-10 is considered to be an antiinflammatory cytokine. This cytokine, produced by macrophages and T cells during M. tuberculosis infection, possesses macrophage-deactivating properties, including downregulation of IL-12 production, which in turn decreases IFN-γ production by T cells. IL-10 directly inhibits CD4^sup +^ T cell responses, as well as by inhibiting APC function of cells infected with mycobacteria133. Transgenic mice constitutively expressing IL-10 were less capable of clearing a BCG infection, although T cell responses including IFN-γ production were unimpaired134. These results suggested that IL-10 might counter the macrophage activating properties of IFN-γ.

Transforming growth factor-beta (TGF-β): TGF-β is present in the granulomatous lesions of TB patients and is produced by human monocytes after stimulation with M. tuberculosis135 or lipoarabinomannan136. TGF-β has important antiinflammatory effects, including deactivation of macrophage production of ROI and RNI137, inhibition of T cell proliferation40, interference with NK and CTL function and downregulation of IFN-γ, TNF-α and IL- 1 release138. Toossi et al 135 have shown that when TGF-β is added to co-cultures of mononuclear phagocytes and M. tuberculosis, both phagocytosis and growth inhibition were inhibited in a dosedependent manner. Part of the ability of macrophages to inhibit mycobacterial growth may depend on the relative influence of IFN- γ and TGF-β in any given focus of infection.

Cell migration and granuloma formation

A successful host inflammatory response to invading microbes requires precise coordination of myriad immunologic elements. An important first step is to recruit intravascular immune cells to the proximity of the infective focus and prepare them for extravasation. This is controlled by adhesion molecules and chemokines. Chemokines contribute to cell migration and localization, as well as affect priming and differentiation off cell responses139.

Granulona: CD4′ T cells are prominent in the lymphocytic layer surrounding the granuloma and CD8′ T cells are also noted140. In mature granulomas in humans, dendritic cells displaying long filopodia are seen interspersed among epithelioid cells. Apoptosis is prominent in the epithelioid cells32. Proliferation of mycobacteria in situ occurs in both the lymphocyte and macrophage derived cells in the granuloma141. Heterotypic and homotypic cell adhesion in the developing granuloma is mediated at least in part by the intracellular adhesion molecule (ICAM-1), a surface molecule that is up regulated b\y M. tuberculosis or LAM142. The differentiated epithclioid cells produce extracellular matrix proteins (i.e., ostcopontin, fibronectin), that provide a cellular anchor through integrin molecules143.

In our experience144, the iymph node biopsy specimens showing histological evidence of TR could he classified into four groups based on the organization of the granuloma, the type and numbers of participating cells and the nature of necrosis. These were (i) hyperplastic (22.4%) – a well-formed epithelioid cell granuloma with very little necrosis; (ii) reactive (54.3%) – a well-formed granuloma consisting of epithelioid cells, macrophages, lymphocytes and plasma cells with fine, cosinophilic cascation necrosis; (iii) hyporeactive (17.7%) – a poorly organized granuloma with macrophages, immature epithclioid cells, lymphocytes and plasma cells and coarse, predominantly basophilic cascation necrosis; and (iv) nonreactive (3.6%) unorganized granuloma with macrophages, lymphocytes, plasma cells and polymorphs with non caseating necrosis. It is likely that the spectrum of histological responses seen in tuberculous lymphadenitis is the end result of different pathogenic mechanisms underlying the disease144.

Chemokines: The interaction of macrophages with other effector cells occurs in the milieu of both cytokines and chemokines. These molecules serve both to attract other inflammatory effector cells such as lymphocytes and to activate them.

Interleukin-8: An important chemokine in the mycobacterial host- pathogen interaction appears to be IL-8. It recruits neutrophils, T lymphocytes, and basophils in response to a variety of stimuli. It is released primarily by monocytes/macrophages, but it can also be expressed by fibroblasts, keratinocytes, and lymphocytes145. IL-8 is the neutrophil activating factor.

Elevated levels of IL-8 in BAL fluid and supernatants from alveolar macrophages were seen in patients140. IL-8 gene expression was also increased in the macrophages as compared with those in normal control subjects. In a series of in vitro experiments it was also demonstrated that intact M. tuberculosis or LAM, but not deacylated LAM, could stimulate IL-8 release from macrophages146.

Friedland et al147 studied a group of mainly HIVpositive patients, and reported that both plasma IL-8 and secretion of IL-8 after ex vivo stimulation of peripheral blood leukocytes with lipopolysaccharide remained elevated throughout therapy for TB. Other investigators had previously shown that II,-8 was also present at other sites of disease, such as the pleural space in patients with TB pleurisy148.

Other chemokines: Other chemokines that have been implicated in the host response to TR include monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES), which both decrease in the convalescent phase of treatment, as opposed to IL-8. Chemokine and chemokine receptor expression must contribute to the formation and maintenance of granuloma in chronic infections such as TB. In in vitro and in vivo murine models, M. tuberculosis induced production of a variety of chemokines, including RANTES, macrophage inflammatory protein1- α (MIP-α), MIP2, MCP-1, MCP-3, MCP-5 and IP10(149) Mice over expressing MCP-1(150), but not MCP-/- mice151, more susceptible to M. tuberculosis infection than were wild type mice. C-C chemokine receptor 2 (CCR2) is a receptor for MCP-1, 3 and 5 and is present on macrophages and activated T cells. CCR2-/- mice are extraordinarily susceptible to M. tuberculosis infection and they exhibit a defect in macrophage recruitment to the lungs. The current literature indicates that TNF-α can uprcgulate expression of MIP1-α, MIP1-β, MIP2, MCP-1, cytokine-induced neutrophil chemoattractant (CINC) and RANTES152, and it can affect recruitment of neutrophils, lymphocytes and monocytes/ macrophages to certain sites.

RANTES, MCP-1, MIP1-α and IL-8 were released by human alveolar macrophages upon infection with M. tuberculosis in vitro153 and monocytes, lymph node cells and BAL fluid from pulmonary TB patients had increased levels of a subset of these chemokines compared to healthy controls153,154. In human studies, CCR5, the receptor for RANTES, MIP-α and MIPβ, was increased on macrophages following in vitro M. tuberculosis infection and on alveolar macrophages in BAL from TB patients155.

HIV-TB coinfection

Studies from many parts of the world have shown higher incidence of TB among HIV infected individuals, ranging from 5 to 10 per year of observation156, which is in sharp contrast to the lifetime risk of 10 per cent among people without HIV. Persons with HIV infection are at increased risk of rapid progression of a recently acquired infection, as well as of re-activation of latent infection. TB is the commonest opportunistic infection occurring among HIV-positive persons in India and studies from different parts of the country have estimated that 60 to 70 per cent of HIV positive patients will develop TB in their lifetime157. Differences in HIV-positive TB, as opposed to HIVnegative TB, include a higher proportion of cases with extra-pulmonary or disseminated disease, a higher frequency of false- negative tuberculin skin tests, atypical features on chest radiographs, fewer cavitating lung lesions, a higher rate of adverse drug reactions, the presence of other AIDS-associated manifestations and a higher death rate.

TB and HIV infections are both intracellular and known to have profound influence on the progression of each other. HIV infection brings about the reduction in CD4^sup +^ T cells, which play a main role in immunity to TB. This is reflected in the integrity of the cellular immune response, namely the granuloma. Apart from the reduction in number, HIV also causes functional abnormality of CD4^sup 1^ and CD8^sup +^ cells. Likewise, TB infection also accelerates the progression of HIV disease from asymptomatic infection to AIDS to death. A potent activator of HIV replication within T cells is TNF-α, which is produced by activated macrophages within granuloma as a response to tubercle infection158. Because the clinical features of HIV infected patients with TB are often non specific, diagnosis can be difficult. The method most widely used, detection of acid-fast bacilli by microscopic examination of sputum smears, is of little use, since 50 per cent of the HIV-TB cases are negative by acid fast staining159. Chest radiograph is normal in up to 10-20 per cent of patients with AIDS160. Alternative diagnostic tests, based on serology, using crude mycobacterial antigens161, purified lipid162 and protein antigens163, have been tried with varying results. Our results with purified 38, 30, 16 and 27kDa antigens to study the antibody response to different isotypes have yielded an improved sensitivity and specificity67,68.

Since the CD4^sup +^ receptors of the T cells are bound by the HIV through the gp120 antigen, interaction of these cells with APC presenting antigen in the context of Class II MHC molecules is impaired, which results in hypo-responsiveness to soluble tubercle antigens. HIV infection also downregulates the Th1 response, not affecting or increasing the Th2 response. In patients co-infected with TB and HIV, expression of IFN-γ, IL-2 and IL-4 in PBMCs is suppressed, but IL-10 levels do not differ from patients with HIV infection164. The suppressed Th 1 response paves the way for susceptibility to many intracellular infections. A role for NK cells also has been implicated in the immune response to HIV. It has been reported that NK cells from normal and HIV positive donors produce C- C chemokines and other factors that can inhibit both macrophage and T cell tropic HIV replication in vitro165. Another group reported a decline in NK activity, which strongly correlated with the disease progression in HIV patients166. Our studies demonstrate that even though there is no difference in the per cent of NK cells, there is lowered NK activity during TB and HIV-TB infection54.

Though most patients respond very well to antituberculous treatment initially, they develop other opportunistic infections and deteriorate rapidly within a few months. Further, recurrence of TB is more frequent than in immunocompetent population, due to both endogenous reactivation or exogenous reinfection.

Immunogenetics of TB

Yet another important area in understanding the immunology of TB is host genetics, which is briefly discussed here. Susceptibility to TB is multifactorial. Finding out the host genetic factors such as human leucocyte antigens (HLA) and non-HLA genes/ gene products that are associated with the susceptibility to TB will serve as genetic markers to understand predisposition to the development of the disease.

A number of studies on host genetics have been carried out in our laboratory. Our studies on HLA in pulmonary TB patients and their spouses revealed the association of HLA-DR2 (subtype DRBI * 1501) and -DQ1 antigens with the susceptibility to pulmonary TB167,168. Further studies on various nonHLA gene polymorphisms such as mannose binding lcctin (MBL)169, vitamin D receptor (VDR)170,171, TNF- α and β172, IL-1 receptor antagonist170 and Nramp45 genes revealed that functional mutant homozygotes (FMHs) of MBL are associated with the susceptibility to pulmonary TB. The polymorphic BsmI, ApaI, TaqI and FokI gene variants of VDR showed differential susceptibility or resistance with male or female subjects. These studies suggest that multicandidate genes are associated with the susceptibility to pulmonary TB.

The role of HLA-DR2 and the variant genotypes of MBL on the immunity to TB revealed that in a susceptible host (HLA-DR2, FMHs of MBL-positivc subjects) the innate immunity (lysozyme, mannose binding lectin. etc.) play an important role173-176. If the innate immunity fails. HLA-DR2 plays an importa\nt role on the specific immune response against the pathogen.

Conclusion

The protective and pathologic response of host to M. tuberculosis is complex and multifaceted, involving many components of the immune system. Because of this complexity, it becomes extremely difficult to identify the mechanism(s) involved in protection and design surrogate markers to be measured as in vitro correlate of protective immunity. A clear picture of the network of immune responses to this pathogen, as well as an understanding of the effector functions of these components, is essential to the design and implementation of effective vaccines and treatments for TB. The combination of studies in animal models and human subjects, as well as technical advances in genetic manipulation of the organism, will be instrumental in enhancing our understanding of this immensely successful pathogen in the future.

References

1. World Health Organization. The World Health Report: Making a difference: 1999 p. 110.

2. Revised National Tuberculosis Control Programme: Key facts and concepts. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare; 1999.

3. Jayasankar K. Ramanathan VD. Biochemical and histochemical changes relating to fibrosis following infection with Mycobactenium tuberculosis in the guineapig. Indian J Med Res 1999. 110: 91-7.

4. Schlesinger LS. Role of mononuclear phagocytes in M. tuberculosis pathogenesis. J Invest Med 1996; 44 : 312-23.

5. Schlesinger LS, Hull SR. Kaufman TM. Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. J Immunol 199-1; 152: 4070-9.

6. Barnes PL. Modlin RL. Ellner JJ. T-cell responses and cytokines. in: Bloom BR, editor. Tuberculosis: Pathogenesis, protection and control. Washington, DC: ASM Press; 1994 p. 417-35

7. Hoheisel G, Zheng L, Teschler H, Striz I, Costabel U. Increased soluble CD14 levels in BAL fluid in pulmonary tuberculosis. Chest 1995; 108 : 1614-6.

8. Gaynor C, McCormack FX, Voelker DR, McGowan SE, Schlesinger LS. Pulmonary surfactant protein A mediates enhanced phagotosis of Mycobacterium tuberculosis by a direct interaction with human macrophages. J Immunol 1995; 155 : 5343-51.

9. Cohn ZA. The fate of bacteria within phagocytic cells. I. The degradation of isotopically labeled bacteria by polymorphonuclear leucocytes and macrophages. J Exp Med 1963; 117 : 27-42.

10. Desjardins M, Huber LA, Parton RG, Griffiths G. Biogenesis of phagolysosomes proceeds through a sequential series of interactions with the endocytic apparatus. J Cell Biol 1994; 124 : 677-88.

11. Hart PD, Armstrong JA, Brown CA, Draper P. Ultrastructural study of the behaviour of macrophages toward parasitic mycobacteria. Infect Immun 1972; 5 : 803-7.

12. Goren MB, Hart PD, Young MR, Armstrong JA. Prevention of phagosome lysosome fusion in cultured macrophages by sulfatides of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 1976; 73 : 2510- 4.

13. Goren MB. Brokl O, Das BC. Sulfatides of Mycobacterium tuberculosis: the structure of the principal sulfatide (SL-1). Biochemistry 1976; 15 : 2728-35.

14. Gordon All, Hart PD, Young MR. Ammonia inhibits phagosome- lysosome fusion in macrophages. Nature 1980; 286 : 79-81.

15. Walker L, Lowrie DB. Killing of Mycobacterium microti by immunologically activated macrophages. Nature 1981; 293 : 69-70.

16. Flesch I, Kaufmann SH. Mycobacterial growth inhibition by interferon-gamma-activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis. J Immunol 1987; 138 : 4408-13.

17. Selvaraj P, Venkataprasad N, Vijayan VK, Prabhakar R, Narayanan PR. Alveolar macrophages in patients with pulmonary tuberculosis. Lung India 1988; 6 : 71-4.

18. Swamy R, Acharyalu GS, Balasubramaniam R, Narayanan PR, Prabhakar R. Immunological investigations in tuberculous ascites. Indian J Tuberc 1988, 35 : 3-7.

19. Selvaraj P, Swamy R, Vijayan VK, Prabhakar R, Narayanan PR. Hydrogen peroxide producing potential of alveolar macrophages and blood monocytes in pulmonary tuberculosis. Indian J Med Res 1988, 88 : 124-9.

20. Chan J, Flynn JL. Nitric oxide in Mycobacterium tuberculosis infection. In: Fang, FC, editor. Nitric oxide and infection. New York : Kluwer Academic Plenum; 1999 p. 281-310.

21. MacMicking JD. North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acd Sci USA 1997; 94 : 5243- 8.

22. Vishwanath V, Meeru R, Puvanakrishnan R, Narayanan PR. Fate of Mycobacterium tuberculosis inside rat peritoneal macrophages in vitro. Mol Cell Biochem 1997; 175 : 169-75.

23. Rockett KA, Brookes R, Udalova I, Vidal V. Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998; 66 : 5314-21.

24. Bonecini-Almeida MG, Chilale S, Boutsikakis I, Geng J, Doo H. He S, et al. Induction of in vitro human macrophage anti- Mycobacterium tuberculosis activity: requirement for IFN-gamma and primed lymphocytes. J Immunol 1998; 160 : 4490-9.

25. Nicholson S, Bonecini-Almeida HG, Lapae Silva JRL, Nathan C, Xie QW, Mumford R, et al. Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Me of 1996; 183 : 2293-302.

26. Vishwanath V, Narayanan S, Narayanan PR. The fate of Mycobacterium tuberculosis in activated human macrophages. Curr Sci 1998; 75 : 942-6.

27. Rook GA, Steele J, Ainsworth M, Champion BR. Activation of macrophages to inhibit proliferation of Mycobacterium tuberculosis: comparison of the effects of recombinant gamma-interferon on human nionocytes and murine peritoneal macrophages. Immunology 1986; 59 : 333-8.

28. Douvas GS, Looker DL, Vatter AG. Crowle AJ. Gamma Interferon activates human macrophages to become tumoricidal and leishmanicidal but enhances replication of macrophage-associated mycobacteria. Infect Immun 1985; 50 : 1-8.

29. Denis M. Killing of Mycobacterium tuberculosis within human monocytes: activation by cytokines and calcitriol. Clin Exp Immunol 1991; 84: 200-6.

30. Placido R, Mancino G, Amcndola A, Mariani F, Vendetti S, Piacentini M, et al. Apoptosis of human monocytes/ macrophages in Mycobacterium tuberculosis infection. J Pathol 1997; 181 : 31-8.

31. Klinglet- K, Tchou-Wong KM, Brandli O, Aston C, Kim R. Chi C. et al. Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes. Infect Immun 1997; 65 : 5272-8.

32. Keane J, Baleewicz-Sablinska MK. Remold HG, Chupp GL, Meek BB. Fenlon MJ, et al. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoplosis. Infect Immun 1997: 65 : 298-304.

33. Molloy A, Laochumroonvorapong P, Kaplan G. Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular bacillus CalmetteGuerin. J Exp Med 1994; IKH : 1499- 509.

34. Condos R, Rom WN, Liu Y, Schluger NW. Local immune responses correlate with presentation and outcome in tuberculosis. Am J Respir Crit Care Med 1997; 157 : 729-35.

35. Tan JS, Canada) DH, Boom WII, Balaji KN. Schwander SK. Rich EA. Human alveolar T lymphocyte responses to Mycobacterium tuberculosis antigens: role for CD4 and CD8 cytotoxic T cells and relative resistance of alveolar macrophages to lysis. J Immunol 1997; 159 : 290-7.

36. Andersen P. Askgaard D. Ljungqvist L, Bennedsen J, Heron I. Proteins released from Mycobacterium tuberculosis during growth. Infect Immun 1991; 59 : 1905-10.

37. Chan J. Fujiwara T. Brennan P. McNeil M. Turco SJ, Sibille JC. et al. Microbial glycolipids: possible virulence factors that scavenge oxygen radicals. Proc Natl Acad Sci USA 1989; 86 : 245.3- 7.

38. Chan J. Lan XD, Hunter SW, Brennan PJ, Bloom BR. Lipoarabinomannan. a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect Immun 1991: 59 : 1755-61.

39. Hmama Z, Gabathuler R, Jefferies WA, deJong G, Reiner NE. Attenuation of HLA-DR expression by mononuclcar phagocytes infected with Mycobacterium tuberculosis is related to intracellular sequestration of immature class 11 heterodimers. J Immunol 1998; 161: 4882-93.

40. Rojas RE, Balaji KN, Subramanian A, Boom WH. Regulation of human CD4^sup +^ αβ T cell receptor positive (TCR+) and γδ (TCR +T-cell responses to Mycobacterium tuberculosis by interleukin-10 and transforming growth factor β. Infect Immun 1999; 67 : 6461-72.

41. vanHeyningen TK. Collins HL, Russell DG. IL-6 produced by macrophages infected with Mycobacterium species suppresses T cell responses. J Immunol 1997; 158 : 303-7.

42. Moreira AL. Wang J. Tsenova-Berkova L, Hellmann W, Freedman VH, Kaplan G. Sequestration of Mycobacterium tuberculosis in tight vacuoles in vivo in lung macrophages of mice infected by the respiratory mute. Infect Immun 1997; 65 : 305-8.

43. Selvaraj P, Kannapiran M. Kurian SM, Narayanan. PR. Effect of plasma lysozyme on live Mycobacterium tuberculosis. Curr Sci 2001 ; 81 : 201-3.

44. Newport M, Levin M, Blackwell J, Shaw MA, Williamson R, Huxley C. Evidence for exclusion of a mutation in NRAMP as the cause of familial disseminated atypical mycobacterial infection in a Maltese kindred. J Med Genet 1995; 32 : 904-6.

45. Selvaraj P. Chandra. G, Kurian SM. Reetha AM, Charles N, Narayanan PR. NRAMP1 gene polymorphism in pulmonary and spinal tuberculosis. Curr Sci 2002; 82 : 451-4.

46. Edwards D, Kirkparick CH. The immunology of mycobacterial diseases. Am Rev Respir Dix 1986; 134 : 1062-71.

47. Fleisehmann J, Golde DW, Weisbart RH, Gasson JC. Granulocyte- macrophage colony-stimulating factor enhances phagocytosis of bacteria by human neutrophils. Blood 1986; 68: 708-11.

48. Ogala K, Linzer BA, Zuberi RI. Ganz, T. Lehrer RI, Catanzaro A. Activity of Defensins from human neutrophilic granulocytes against Mycobacterium \aviumMycobacterium intracellulare. Infect Immun 1992; 60 : 4720-5.

49. Majeed M, Perskvist N, Ernst JD, Orselius K, Stendahl O. Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosis in human nentrophils. Microh Pathog 1998; 24 : 309-20.

50. Esin S. Batoni G, Kallenius G. Gaines H. Campa M. Svenson SB, et al. Proliferation of distinct human T cell subsets in response to live, killed or soluble extracts of Mycobacterium tuberculosis and Mycobacterium avium. din Exp Immunol 1996; 104 : 419-25.

51. Ratcliffe LT, Lukey PT, Mackenzie CR, Ress SR. Reduced NK activity correlates with active disease in HIV patients with multidrug-resistant pulmonary tuberculosis. Clin Exp Immunol 1994; 97 : 373-9.

52. Bermudez LE, Young LS. Natural killer cell-dependent mycobacteriostatic and mycobactericidal activity in human macrophages. J Immunol 1991; 146 : 265-70.

53. Molloy A, Meyn PA, Smith KD, Kaplan G. Recognition and destruction of bacillus Calmette-Guerin-infected human monocytes. J Exp Med 1993; 177 : 1691-8.

54. Nirmala R, Narayanan PR, Mathew R, Maran M, Deivauayagam CN. Reduced NK activity in pulmonary tuberculosis patients with/without HIV infection: Identifying the defective stage and studying the effect of inlcrlcukins on NK activity. Tuberculosis 2001; 81 : 343- 52.

55. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997; 388 : 394-7.

56. Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 1999; 163 : 3920-7.

57. Johnson CM, Cooper AM, Frank AA, Bonorino CBC, Wysoki LJ, Orme IM. Mycobacterium tuberculosis aerogenic rechallenge infections in B cell-deficient mice. Tuber Lung Dis 1997; 78 : 257-61.

58. Bosio CM, Gardner D, Elkins KL. Infection of B celldeficient mice with CDC1551, a clinical isolate of Mycobacterium tuberculosis: delay in dissemination and development of lung pathology. J Immunol 2000; 164 : 6417-25.

59. lingers HD, Houba V, Bennedsen J, Buchanan TM, Chaparas SD, Kadival G, et al. Results of a World Health Organization sponsored Workshop to characterize antigens recognized by mycobacterium specific monoclonal antibodies. Infect Immun 1986; 51: 718-20.

60. Lima Devi KR, Ramalingam B, Brennan PL, Narayanan PR, Raja A. Specific and early detection of IgG, IgA and IgM antibodies to Mycobacterium tuberculosis 38kDa antigen in pulmonary tuberculosis. Tuberculosis 2001; 81 : 249-53.

61. Raja A, Uma Devi KR, Ramalingam B, Brennan PJ. Immunoglobulin G, A and M responses in serum and circulating immune complexes elicited by the 16kDa antigen of Mycobacterium tuberculosis. Clin Diagn Lab Immunol 2002; 9 : 308-12.

62. Uma Devi KR, Senthil Kumar KS, Ramalingam B, Raja A. Purification and characterization of three immunodominant proteins (38, 30, and 16 kDa) of Mycobacterium tuberculosis. Protein Expr Purif 2002; 24 : 188-95.

63. Raja A, Ranganathan UD, Bethunaickan R, Dharmalingam, V. Serologic response to a secreted and a cytosolic antigen of Mycobacterium tuberculosis in childhood tuberculosis. Pediatr Infect Dis J 2001; 20: 1161-4.

64. Ramalingam B, Uma Devi KR, Swaminathan S, Raja A. Isotype specific antibody response in Childhood tuberculosis against purified 38kDa antigen of Mycobacterium tuberculosis. J Trop Pediatr 2002; 48 : 188-9.

65. Uma Devi KR, Ramalingam B, Raja A. Qualitative and quantitative analysis of antibody response in childhood tuberculosis against antigens of Mycobacterium tuberculosis. Indian J Med Microbiol 2002; 20 : 145-9.

66. Senthil Kumar KS, Uma Devi KR, Raja A. Isolation and evaluation of diagnostic value of two major secreted proteins of Mycobacterium tuberculosis. Indian J Chest Dis Allied Sd 2002; 44 : 225-32.

67. Ramalingam B, Uma Devi KR, Raja A. Isotype specific anti-38 and 27kDa (mpt 51) response in pulmonary tuberculosis with human immunodeficiency virus coinfection. Scand J Infect Dis 2003; 35 : 234-9.

68. Uma Devi KR, Ramalingam B, Raja A. Antibody response to Mycobacterium tuberculosis 30 and 16kDa antigens in pulmonary tuberculosis with human immunodeficiency virus coinfection. Diagn Microbiol Infect Dis 2003; 46 : 205-9.

69. Raja A, Acharyulu GS, Selvaraj R, Khudoos A. Evaluation of antibody level to purified mycobacterial antigens for identification of tuberculous infection. Biomedicine 2001; 21: 63-9.

70. Senthil Kumar KS, Raja A, Uma Devi KR, Paranjape RS. Production and characterization of monoclonal antibodies to Mycobacterium tuberculosis. Indian J Med Res 2000; 112 : 37-46.

71. Feng CG, Bean AGD, Hooi H, Briscoe H, Britton W.I. Increase in gamma Interferon- secreting CDS+, as well as CD4 + T cells in lungs following aerosol infection with Mycobacterium tuberculosis. Infect Immun 1999; 67 : 3242-7.

72. Randhawa PS. Lymphocyte subsets in granulomas of human tube

Perspectives on Physical Activity in the Lives of Korean Women

OBJECTIVE: The purpose of this study was to explore what physical activity means to Korean women and to identify what factors influenced their decisions to engage in exercise. METHODS: Individual interviews were conducted with five Korean women in South Korea. Each interview was audiotaped and transcribed for later review. The transcription of interview was reviewed line by line to identify themes. RESULTS: The findings indicated that the Korean women understood that physical activity was related to exercise, labor, daily activity, and body movement. They believed that only exercise had any health benefits. For these women, the main determinants of exercise were availability of time, family support, financial security, concerns about safety, and the availability of community facilities for exercise. CONCLUSIONS: The findings in this study provided a better understanding of what physical activity means to Korean women and helped set the foundation for the more extensive study on physical activity.

KEY WORDS: Health Benefits; Korean Women; Physical Activity.

Physical activity, one of the most important of all health- promoting behaviours, has beneficial effects on the general functioning of both young and middle-aged women. For these women, a healthy lifestyle in their early years increases the likelihood that they will maintain good health and functional ability in later years. Studies show, however, that contemporary many Korean women lack the physical activity they need for good health. For example, among contemporary Korean females aged 15 years and older, 57.8 percent are regarded as sedentary (Lee, 1997). In comparison, only 30.5 percent of American women aged 18 and older had not engaged in any leisure-time physical activity in the previous month, as reported by the Behavioral Risk Factor Surveillance System (BRFSS) for Texas (U.S. Department of Health and Human Services, 2000). Although Korean and American women differ in many respects, it is clear that both groups activity must increased their levels of physical activity.

In any assessment of physical activity, it is important to take into account the cultural background of the individuals (Sternfeld, Cauley, Harlow, Liu, & Lee, 2000). For example, there are differences between Western and Asian cultures as to what “health” means. According to the more traditional Korean culture, health is considered immeasurable, because health reflects not only the individual’s current emotional and mental state but more generally his or her adaptation to conditions in the natural world (Yang, 2000). For good health, a human must be in harmony-or equilibrium- with nature. Good health is a given fact when the person is well adjusted to daily life; it is not a goal to be pursued by planned efforts (Yang, 2000). This view of health may affect one’s choices of health-promoting behaviors. For example, it may explain why Korean women are more likely to focus on symptom management rather than preventive management (Lum, 1995; Sarna, Tae, Kim, Brecht, & Maxwell, 2001). Korean women, however, are involved in physical activities, ranging from caring for the family at home to working at jobs outside the home. In fact, many Korean women insist that their household and occupational tasks give them a sufficient amount of activity (Shin & Shin, 1999) . The high rates of hypertension, heart disease, and diabetes mellitus that prevail among Korean women call (Korean National Statistical Office, 1998) for a radical change in the way Korean women perceive their current activity patterns.

Only a few studies have addressed what Korean women actually think of physical activity and its role in improving their health (Im & Choe, 2001). Yet, knowledge of their beliefs about physical activity could provide valuable insights into the choices Koreans women make regarding physical activity. Before those beliefs can be examined/however, there has to be some deeper understanding of what physical activity means to the women. Such an understanding, if it is to embrace a sufficient variety and richness of meanings, requires a more personal and direct approach to data gathering, that is, a more qualitative technique. Only by qualitative methods can we begin to interpret much of what we have learned from the plethora of statistically oriented studies.

The purpose of this study was to improve the understanding of what physical activity means to Korean women. The approach of the study was to gather insights from interviews with the women on how they perceive physical activity in their daily lives and to identify factors that determine whether or not they engage in physical activity and exercise. With this knowledge, perhaps we would be better prepared to promote healthy attitudes toward exercise within the larger population of Korean women.

METHODS

The hermeneutic phenomenological approach used for this study is frequently employed to explore the meaning of particular human experiences within situational contexts (Kahn, 2000). In open-ended interviews and direct observations in natural settings, the researcher invites informants to share their thoughts, dreams, expectations, rationales, and habits regarding some aspect of their lives. The researcher interprets the shared information and builds a coherent picture which helps make sense of the informant’s experience.

After the proposal for this study was approved by the Institutional Review Board of the University of Texas at Austin, eight informants were recruited through fliers posted inside a large apartment complex in South Korea and only five met the eligibility. To be eligible for this study, the informants had to be women, Korean nationals, native speakers of Korean, aged 25 to 65 years, free of chronic of illness or disabilities, and living independently in a home-based setting. Women were excluded from the study if they have severe disabilities or histories of cardiovascular disease. The researcher conducted an eligibility screening interviews with the informants by telephone. If the woman met the inclusion criteria, she and the researcher agreed to a time and place for a face-to- face interview.

Table 1. Interview Questions

The face-to-face interview with each woman took place in a quiet and comfortable setting, and it typically lasted about 40 minutes. The interview began with the researcher explaining the purpose and method of the study and obtaining the participant’s written informed consent before proceeding. Each interview was audiotaped and later transcribed. The principal question in the interview was what physical activity meant to the informant, but the informant was also asked to identify factors that influenced her decision whether or not to engage in exercise, a specific form of physical activity. The interview questions used in each interview are shown in Table 1.

As soon as possible after meeting with the informant, the researcher reviewed the Korean-language transcription of the interview line by line several times. The purpose of these repeated reviews was to identify, bracket, and label distinct but emergent topics (Kahn, 2000). Those topics in turn were grouped into main themes. In addition, the informants’ definitions and examples were carefully examined. These definitions and examples were used to develop categories of physical activity.

After the analysis of the Korean transcripts, the transcript was translated from Korean into English. To ensure that the Korean and English versions corresponded closely in meaning and to reduce any bias in interpretation (Brislin, 1970; Dimmitt, 1996), two bilingual graduate students compared the versions for equivalence of content. The graduate students were given no demographic information or other indicators by which to identify the informants.

RESULTS

Of the eight Korean women who responded to the flyers, only five were eligible to participate in the study and five Korean women, whose ages ranged from 34 to 59 (mean 45.8 years), finished the interview. Five was an acceptable number of participants for this pilot study since the researcher was getting no new information by the fifth interview. Four were married, two were college educated, and two worked outside the home. Only one of the women was currently engaged in exercise. From the interviews with these Korean women and from the repeated analyses of the transcriptions, the researcher was able to obtain a clearer understanding of how the participants defined physical activity and what factors determined their decisions to take up an exercise program. These definitions and factors are discussed in the following sections.

Definition of physical activity

In general, the definition of “physical activity” given by these women was at odds with the concept of physical activity that prevails in the West. The Korean written character for “physical activity” derives from the Chinese character combining ideograms for “body” and “movement.” As a result, to the Korean women, physical activity was any movement of the body. This definition differs from that commonly taken for granted in academic studies in the West, which conceive of physical activity as leisure-time, occupational, or household activity (Bouchard & Shephard, 1994).

The Western view of ph\ysical activity seemed to be new to the women in this study. Whereas they defined “physical activity” broadly as daily activity and/or body movement, they made strong distinctions between daily activity, body movement, and labor, on one hand, and exercise, on the other hand. Note, for example, the distinctions made by the participants during their interviews:

Daily activity:

YH: Daily activity? Regular and natural living . . . wake up in the morning, make breakfast, help my husband go to work, make box lunches for my children . . . .

Body movement:

MY: I think it is about household activity and volunteering in church.

Labor:

SJ: Labor is a kind of obligation. I have to work. But it is not all for me. I have to work for my company, carry out household activities for my family, as well as for myself.

KS: From my experience, labor is not exercise, and it is not good for my health. I used to engage regularly in exercise at a health club, but sometimes I couldn’t go there because of personal reasons. Then I would try to compensate for the missed day. At my workplace, I would purposely clean the floor to exercise my arms. Or I would climb stairs many times for leg exercise. Guess what? I spent the same amount of time doing those things as when I exercised at the health club. I was sweating, too. But I never felt the rush of good feeling that came after my regular exercise. I just felt some muscle pains. I just felt like soaked cotton [a limp rag]. I think household work is included in labor.

KS: From doing work, I can feel some sense of accomplishment, but I also feel the burden of having to continue to accomplish as time passes. I would call it stress. So I can’t say that labor is positively related to health. I teach children. People say my occupation is related more to the brain than the body. When I am teaching, I use my arm to write something on the blackboard, and I stand for a long time. I feel physically drained and exhausted at the end of the day. I feel some joy in teaching my students, but it easily fades away as I grow tired each day.

Exercise:

SJ: Exercise is a part of physical activity. I do exercise for my health with a constructive and optimistic mind. Physical activity, however, is just a part of my life. It is just for living. I don’t think my health is related to physical activity. I can enjoy exercising, though . . . .

EY: Exercise . . . is something for myself. I exercise for my health, for a better life, and for a better quality of later life. I think, however, it is a matter of priority in my life when I think of it, comparing it with other ordinary physical activity. I love to exercise I believe that, if I am healthy, it would be good for everyone around me, though.

In summary, when participants were asked about physical activity, they frequently related it to “daily activity” or “body movements” that were integrated into their daily lives, which encompassed all leisure-time, occupational, and household activities. Thus, they related physical activity to what they felt were obligations. When defined in Western terms, physical activity seemed to represent a burden to the participants. Some participants recognized that exercise was a form of physical activity, but they differentiated exercise from all other physical activities in that exercise had health benefits.

To obtain equivalent data in cross-cultural studies, therefore, we might have to decompose physical activity into “daily activity” and “exercise.” One fact is clear: the narrow and somewhat negative attitude of these five Korean women toward physical activity has implications for efforts to design any program to promote the health benefits of physical activity within this population.

DETERMINANTS OF EXERCISE

As mentioned, the women responded more specifically to the term “exercise” than to “physical activity” when discussing their purposes and effects on health. All five participants expressed their intention to exercise to improve their health in later life, to improve their mood, and to lose weight. Only one of the five informants, however, was actually engaged in exercise at the time of the interview.

The women identified several factors that influenced their decision whether to engage in exercise. These included availability of time, family support, safety, financial security, and availability of a facility for exercise. Each factor is discussed below.

Availability of Time

The women considered the lack of time because of family-care obligations as the main barrier to exercise. Family systems in Korea have been changing rapidly in recent decades, with an increase in the number of working mothers and a decrease in the number of extended traditional families (Kweon). It is common to see a third person, either a family member or a non-family member, taking care of children while the mother works outside the home. Therefore, compared to women in more traditional roles, working mothers tend to regret the time they must deny their children or other family members. If the working mothers have spare time, they feel obligated to spending those hours with their family to compensate for absence during their working hours.

SJ: I can’t exercise . . . If I had free time, I would love to get some exercise with my husband. However, I have children and a mother-in-law to be taken care of. I have to work, so I have to ask someone else to take care of my children. My mother takes care of my daughter and my mother-in-law takes care of my son. Therefore, when I have a day off, I have to visit them. I believe if I had a strong enough resolution, I could probably make some time for myself, but it would be risky. It is not easy when I consider all the situations that involve my family and myself. Nobody’s going to tell me that I should get exercise when she or he is taking care of my children. I would not be comfortable doing that. I don’t know . . . I believe many people around me are so supportive of me generally, but I am still uncomfortable with the idea of taking the time to exercise.

YH: When I feel my health is beginning to fall apart, I think I need some exercise. Currently I am exercising everyday. However, when I lived with my parents-in-law, I couldn’t do it. . . .

Family Support

The participants felt that family support was important to their decision to engage in exercise. Because they lived close together, they needed assurance from their family members that they could take the time to exercise without feeling they were violating any family obligation.

MY: We live together, so someone else, like my husband or my mother-in-law, takes care of my household chores while I am getting exercise. If a family member helps me and gives me the time to get exercise, I can enjoy my exercise. The main reason I want to exercise is to be happy and refreshed . . . However, if I didn’t get such warm support from them, I would not be comfortable exercising. In fact, it might be stressful . . . I can’t make any time for my health . . . right now.

Concerns about Safety and Lack of Financial Security

One of the determinants was concern about safety while the women exercised. Interestingly, the participants had different opinions about using the same community facility. One woman reported that she felt safe there, and another woman reported that she did not. According to a participant’s comments, the playground at the elementary school was open to the public, but if a person needed to use that facility, she still had to have exercise partners to feel safe.

In addition, the participants indicated that financial concerns were a main barrier to exercise, because a safe place to exercise, such as a private health center, would cost more than they could afford.

YH: I see many people running and walking in the playground of the nearby elementary school even between 8 and 10 p.m. Therefore I feel I can run there safely . . . .

EY: I prefer to exercise in the morning. I rarely go out after dark. I can’t tell whether our neighborhood is safe or not. People need to have a partner when they want to get exercise.

EY: The school’s playground is open to the public, but I see few people there. Recently I heard that some bad things have happened in that area. If a woman has children, she has to bring them with her. If a woman has friends for exercise, she should bring them with her, too.

SJ: If there is some spare time or any emotional space to get exercise, it means that the person must feel comfortable with her living condition and economic circumstances.

Availability of a Facility in the Community

Three participants indicated that there were few exercise facilities available in the nearby neighborhood. This lack of facilities could be a barrier to exercise, especially for those who felt unable financially to exercise in a safe place, like a private health center.

SJ: We don’t have much ground in our neighborhood. All the roads around my neighborhood are paved in concrete, so my feet hurt after running. I prefer a health center . . . .

EY: These days there is a trend to make special courses available for jogging and to provide parks near large apartment complexes. However, there are not enough of these yet.

Even though the women in this study were not engaged in regular exercise, there was an important finding: the women compensated for their lack of formal exercise by resorting to various healthful practices in their daily routines. While they were busy in the many roles of their lives, they tried to improve their health in various ways even though they did not exercise, but they would not admit that labor was positively related to their good health.

SJ: When I clean my house, I don’t squat down. I try to use the long handled dust mop. In doing so, I avoid getting severe back pains. Also, it gives me some arm exercise. So, while it doesn’t bother my back, it would be good for my body. And it takes much less time than cleaning with my k\nees bent [that is, squatting herself down]. When I hang up washed clothes to dry, I purposely try to use my upper arms to give an article a good snap before hanging it up on the line. Sometimes I lie on the bed and put my baby on my legs and lift him up. It’s fun for the baby and it gives me some leg exercise.

KS: I described household chores as labor, but there is some enjoyment even in household chores, because I feel good when I see a clean house. If I could do my household chores in a suitable amount of time, depending on my physical ability, I believe, I would enjoy housework more.

SJ: I walk with my baby. I push the stroller and I walk at the same time. I am not bored at all because I am with my baby. At work, I try to walk or move as much as I can. I try to use stairs. I park a good-walk distance away from my building, though sometimes that’s not my intention, like when the parking lot is full of cars when I get there. Anyway, I walk pretty much.

DISCUSSION

In their interviews, the five Korean women, all live in South Korea, reported what physical activity meant to them. Several words appeared repeatedly in their descriptions of physical activity, such as exercise, labor, daily activity, and body movement. They often related physical activity to some form of obligation. In addition, the women believed that only exercise could have a positive influence on their health, even though numerous studies have shown the beneficial effects of physical activity in all its forms (U.S. Department of Health and Human Services, 1996). In light of this finding, researchers in cross-cultural studies should be aware that Korean women may not necessarily relate increased physical activity to better health. This difference in perceptions must be considered by researchers who attempt to compare physical activity data from Korea with data from Western cultures.

The Korean women indicated several determinants to exercise: availability of time, family support, financial security, concerns about personal safety, and the availability of community facilities for exercise. These determinants were similar to those of previous studies (Sherwood & Jeffery, 2000), even studies involving subjects from five different cultural groups. For example, a qualitative study (Eyler et al., 1998) of physical activity among minority women in the U.S. (Filipino Americans, Chinese Americans, American Indians, African Americans, and Mexican Americans) reported that the availability of time, environmental access, and safety issues were determinants to exercise. In contrast to the Eyler et al. study, however, the present study has focused on what physical activity means to Korea women living in their own culture.

Korean women regard physical activity through the prism of their cultural and social background. While they play the role of major caregivers in their families, they often feel they lack good judgment if they fail to take care of themselves properly. Thus, lack of time is a frustrating barrier to exercise, because Korean women also feel obligated to give that time to the care of children, parents, parents-in-law, and other family members. In addition, Korean women recognize that family support is important to their ability to engage in regular exercise. Without family support, they do not feel they would get any benefits from exercising, at least emotionally. This determinant could be related to the Korean concept of health, which is oriented mainly toward emotional and mental happiness and equilibrium with life’s circumstances.

Only one of five participants was currently engaging in exercise, but some of the other participants tried to compensate for their sedentary lifestyles by modifying their lives to promote healthful daily physical habits. Based on this study’s findings health professionals should advise Korean women to seek ways to incorporate physical activity into their daily activities as much as they can, to ensure better health.

For future studies, more interviews with more informants will be needed for a denser data field. With its small sample size, this exploratory study could do little more than suggest the attitudes of Korean women toward physical activity and exercise and to identify possible determinants for their engaging in exercise. Nevertheless, the findings in this study give us a better understanding of what physical activity means to Korean women and will help set the foundation for the more extensive study on physical activity. Most importantly, we can see the need for studies that take into account the cultural differences between Korean and Western populations. In addition, health professionals should advise Korean women of ways to incorporate physical activity into their daily activities and evaluate strategies to decrease factors that impede women’s ability to engage in exercise.

REFERENCES

Bouchard, C., & Shephard, R. J. (1994, 1994). Physical activity, fitness, and health: the model and key concepts. Paper presented at the Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement.

Brislin, R. (1970). Back-translation for cross-cultural research. Journal of Cross-cultural Psychology, 1(3), 185-216.

Dimmitt, J. (1996). Translation and reassessment of the adolescent self-perception profile for a rural, Mexican-American population. Journal of Nursing Measurement, 4(1), 5-18.

Eyler, A. A., Baker, E., Cromer, L., King, A. C., Brownson, R. C., & Donatelle, R. J. (1998). Physical activity and minority women: a qualitative study. Health Education & Behavior, 25(5), 640-652.

Im, E. O., & Choe, M. A. (2001). Physical activity of Korean immigrant women in the u.s.: Needs and attitudes. International Journal of Nursing Studies, 38(5), 567-577.

Kahn, D. (2000). How to conduct research. In M. Cohen, D. Kahn & R. Steeves (Eds.), Hermeneutic Phenomenological Research: A Practical Guide for Nurse Researchers (pp. 57-70). California: Sage.

Korean National Statistical Office. (1998). Prevalence of Disease. Retrieved April 13, 2003, from http://kosis.nso.go.kr/cgi- bin/

Kweon, S. (n.d.). The Extended Family in Contemporary Korea: Changing Patterns of Co-residence. Retrieved May 4, 2004, from http:/ /www. koreasociety.org/ks_curriculum/GKK/07_Sug-in_Kweon- contemporaryExtendedfamily.pdf

Lee, S. (1997). Leisure Time Physical Activities among Koreans and Its Relation to Health Risk Factor. Seoul National University, Seoul, Korea.

Lum, O. M. (1995). Health status of Asians and Pacific Islanders. Clinics in Geriatric Medicine, 11(1), 53.

Sarna, L, Tae, Y. S., Kim, Y. H., Brecht, M. L, & Maxwell, A. E. (2001). Cancer screening among Korean Americans. Cancer Practice, 9(3), 134-140.

Sherwood, N. E., & Jeffery, R. W. (2000). The behavioral determinants of exercise: Implications for physical activity interventions. Annual Review of Nutrition, 20, 21-44.

Shin, K. R., & Shin, C. (1999). The lived experience of Korean immigrant women acculturating into the United States. Health Care for Women International, 20(6), 603-617.

Sternfeld, B., Cauley, J. A., Harlow, S, Liu, G., & Lee, M. (2000). Assessment of physical activity with a single global question in a large, multiethnic sample of midlife women. American journal of epidemiology, 152(7), 678-687.

U.S. Department of Health and Human Services. (1996). Physical activity and health: A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Center for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion.

U.S. Department of Health and Human Services. (2000). 2000 BRFSS Summary Prevalence Report. Retrieved March 2, 2002, from http:// www.cdc.gov/nccdphp/brfss/pdg/2000prvrpt.pdf

Yang, J. (2000). Traditional concepts of health in Korea. Journal of Korean Academic Nursing, 30(1), 72-83.

Kyeongra Yang, MPH, RN, Doctoral Candidate

ACKNOWLEDGEMENT: The author thanks the Korean women who participated in this study. The author thanks Professor, Shirley C. Laffrey and Ms. Mary King for their invaluable inputs in this manuscript.

Kyeongra Yang, MPH, RN, Doctoral Candidate, The University of Texas, Austin.

Copyright Riley Publications, Inc. Center for the Study of Multiculturalism and Health Fall 2004

Accent on Taste: An Applied Approach to Multicultural Competency

“Multicultural competency is not a luxury or a specialty, but a requirement for every registered dietitian,” according to the American Dietetic Association.1 Practitioners who primarily treat clients with type 2 diabetes are familiar with the challenges of intercultural counseling. The prevalence of type 2 diabetes among African Americans, Asians/Pacific Islanders, Latinos, and American Indians/Alaska Natives is disproportionately high; it is 1.5-2 times greater than in the white population of the United States, with even higher rates in some subgroups.2

Similar trends are seen internationally, with prevalence rates in Russia and Japan exceeding those in the United States. The countries with the highest number of people with type 2 diabetes are India (35.5 million) and China (23.8 million).3

Today, diabetes specialists most likely work with at least some clients with backgrounds different from their own. In the near future, even more client-practitioner relationships may be intercultural. Type 2 diabetes is increasing worldwide, as is the need for multicultural competency.

We have identified three key proficiencies in multicultural competency. First, there is an attitude of acceptance. This includes respect for cultural differences, a tolerance for the ambiguities inherent in intercultural communication, and patience for the additional time and effort necessary for effective counseling. second, there is culturespecific knowledge of clients’ diets and traditional health beliefs and practices. This includes information on typical foods and meal patterns, special-occasion customs, food avoidances/additions necessary to well-being, common botanical remedies, and acculturation norms. Finally, intercultural counseling skills are necessary. These include verbal and nonverbal communication abilities and practical approaches to diet modification.

Discussion of these three complex proficiencies is beyond the scope of a single article, and other resources addressing them are available.4 In this overview, we instead address handson practice, with the assumption that diabetes specialists are familiar with the three key proficiencies. We provide an applied approach to multicultural competency through understanding the role of taste in food choices, and we introduce tools for successful intercultural diet modification.

The Importance of Taste

Researchers have identified numerous influences on food choices, including taste, cost, convenience, self-expression, well-being, and variety. These are outlined in the Consumer Food Choice Model (Figure I).4 People select foods from a domain of available items- the sum-total of those foods found in the garden or field, at the market, in the grocery store, or at food stands and other eateries. Individuals have little control over what is available in this domain; availability is typically determined by environmental, economic, political, and social constraints.

Figure 1. The Consumer Food Choice Model

In cultures where the dietary domain includes plentiful food, such as in the United States, taste is typically the most significant factor in selection decisions.5 Cost and convenience may be important to some people, or on certain occasions. Foods are sometimes chosen for self-expression (adolescents may eat fast foods; orthodox Jews may eat a Kosher diet; and southerners may eat fried chicken, grits, and greens) or to promote well-being (vegetarians may eat only fruits, vegetables, and grains for moral well-being; Hindus may avoid beef for spiritual well-being; athletes may load carbohydrates or eat meat for physical well-being). Variety can influence people who travel or eat often at restaurants. But in general, taste dominates choices within the dietary domain.

Taste, in its most narrow definition, is the stimulation of the receptors on the tongue for sweet, sour, salty, and bitter flavors. This form of taste is an innate sense. We have an inborn preference for sweets, hypothesized to be an evolutionary adaptation that encourages the consumption of calorie-dense foods in the natural environment (an advantage for our prehistoric ancestors who spent their days foraging).6 As we age, our desire for sweets diminishes, while an appetite for bitter flavors, such as those in broccoli, grapefruit, or coffee, increases.

In its broader definition, however, taste includes numerous sensory properties that are more cultural than physiological. Color, aroma, and texture are equally important to what tastes “good” to us. We have certain expectations regarding these properties, and differences may indicate that a food is poisonous or spoiled.

If we generally experience one of our staple foods, say, potatoes, as white or cream colored, we know they should not be consumed if they are green. Most staple foods are light in color, yet in Hawaii, taro root is pounded and fermented to make poi, a lavender-colored paste.

Similarly, the accustomed aroma for a food can stimulate our appetite, while an unexpected odor can cause revulsion. Europeans may salivate at the aroma of a ripe brie cheese, while many Latinos would be repulsed by it. Conversely, strong-smelling fermented meats, such as muktuk and/tog, are enjoyed by some Inuit and Filipinos, respectively, although many Americans would gag at the odor.

Texture, or “mouth-feel,” is also significant. It is the mouth- feel of fat that makes it well-liked in almost all societies worldwide. But other textures are more cultural in popularity. The mucilaginous property of okra is appreciated in the Southern United States, but disliked by people in other regions. Mashed potatoes are favorites with many Americans, but their thick, sticky texture is often unpopular with Asians.

Diabetes nutrition specialists who ignore the sensory taste properties of cultural foods may find that their recommendations are ignored.

The Role of Flavor

Most cultures also have expectations regarding the flavor of prepared dishes. Flavor is the quality in a food that imparts a particular taste in the palate. Every technique used in cooking foods, from preparation (i.e., washing, chopping, or leaching) to heating (i.e., roasting, grilling, or frying) or preserving (i.e., drying, pickling, curing, or fermenting) affects the flavor.

Most noteworthy, however, is how a food is seasoned. The herbs, spices, vegetables (onion or garlic, for example), and fats (such as butter, olive oil, or sour cream) associated with dishes can be used to classify cuisines culturally.7

A traditional combination of seasonings, called a flavor principle, is the most distinctive factor in a given ethnic cuisine. A fish sauted with tomatoes, onions, chile peppers, cilantro, and cumin is a Mexican recipe, whereas that same fish steamed with soy sauce, rice wine, scallions, and ginger root is a Chinese specialty. Vegetables cooked in vegetable oil and seasoned with garam masala (a curry blend that may include coriander, cumin, fenugreek, turmeric, cardamom, and other spices) is an Asian-Indian dish that differs from Greek vegetables cooked in olive oil, lemon juice, garlic, and oregano. Generally, cultures in which meats and protein foods are prominent in the diet tend to have fewer seasonings in their cuisine than cultures in which grains and vegetables are emphasized.

Regional differences are typically variations on the broader flavor principle. Although soy sauce, rice vinegar, and ginger root are a Chinese flavor principle, soybean paste, garlic, and sesame oil are added in the northern regions of China, and fermented black beans are included in the south. Even more locally, chile peppers, hot bean paste, or fagara pepper supplement the soy sauce, rice vinegar, and ginger root in Szechwan cooking, and red rice wine is the featured addition in Hakka cuisine.4

Understanding that a dish will not taste like a Samoan dish if the coconut cream is omitted or that a Nigerian dish made with corn oil instead of palm oil is no longer a Nigerian dish can direct diabetes nutrition specialists in making modifications satisfactory to their clients. Reductions in the amount or frequency of ingredients in a flavor principle are more acceptable than their elimination or the substitution of other seasonings.

Core and Complementary Foods

The sensory taste properties of food and flavor principles are united in the concept of core and complementary foods. The original model states that foods in each culture can be grouped according to intake frequency.8 Core foods are the foundation of the diet, the staples that are consumed almost daily. Examples include rice, corn, wheat, yams, cassava, taro, and other starches, although protein items are core foods in some cultures. Foods that are eaten widely and often (but not daily) in a culture are secondary core foods. In the United States, these might include chicken, apples, and carrots, for instance. Peripheral foods are those that are eaten sporadically and usually represent personal preference rather than cultural traditions.

An adapted model (Figure 2) includes a fourth category, complementary foods.9 Core foods tend to be bland in flavor and uniform in texture. Small amounts of complementary foods are added to boost taste, vary texture, and encourage consumption. It is hypothesized that not only do complementary foods improve the palatability of core foods, but they also increase nutritional value. Rice is often pre\pared with legumes and small amounts of meats in many cultures, for example, and leafy greens and abundant herbs, or tomato sauces, are added to rice, root vegetables, or pasta. The appropriate flavor principle is often used to season complementary foods.

Clients may be quite willing to eliminate some peripheral foods, or even some secondary foods, from their diet, but core foods and their complementary foods are so associated with most ethnic cuisines that clients may resist any attempt to change or modify these items. Familiarity with the core and complementary foods model for each client can reduce ineffective diet modifications.

The Influence of Age

As illustrated in the Consumer Food Choice Model, the importance of taste changes through the life cycle.

Taste is most significant to very young children, who consume food at an almost completely sensory level, often devoid of cultural and social inhibitions. Their dietary domain is totally dependent on what is provided by their parents, and they are often very resistant to new foods, especially those that are somewhat sour or bitter. Older children also focus on taste, and they are especially susceptible to advertising. Children modify their dietary domain through pressuring their parents to purchase certain foods or through selections at school lunch counters and snack kiosks.

Taste is also a significant factor in the food choices of adolescents. Teens are attracted to the sweet, salty, and fatty flavors found in inexpensive, processed foods and have a strong desire to eat whatever their peers are eating as a form of self- expression through differentiation from their parents and conformation with their group. Taste may be secondary in some cases, however, such as when a favorite traditional dish from their culture is rejected as a sign of independence or eaten only in the privacy of home.

Figure 2. The Core and Complementary Foods Model

Young adults continue to be concerned with taste, although cost and convenience issues become a factor in food selection, especially for families. A couple may be willing to give up the taste of a home- prepared meal for the speed and entertainment value of eating at a restaurant that caters to families with young children. And favorite, pricey foods may be consumed infrequently.

In middle age, income typically increases and cost issues diminish. Some adults enjoy their ability to purchase expensive tasty foods and beverages at this stage, with variety at a premium. For others, specific physical or spiritual concerns or a general interest in longevity may begin to influence food choices.

In old age, taste often becomes secondary to a diet that satisfies health needs. Limited income or physical disability may once again make cost or convenience important, as well.

Thus, age can affect how important taste will be to clients’ food choices, and diabetes nutrition specialists can make diet modification recommendations that recognize not only the role of taste, but also that of other influences in their clients’ food selections.

The Influence of Acculturation

The Consumer Food Choice Model describes the role of taste in food selection; it also mirrors the diet acculturation process. When people move from one culture to another, their food choices change in many ways, becoming over time or over generations more like the diet of the new culture than that of the culture of origin. The transformation can be immediate if no traditional ingredients are available in the new culture. But most often, it is a gradual process of adding new foods, substituting new ingredients for traditional ingredients if necessary, and rejecting some traditional items. Core and complementary foods and flavor principles are maintained if possible, while preferred sensory properties are also preserved as self-expression of cultural identity.

Changes are typically influenced mostly by taste. Most immigrants to the United States quickly accept the sweet, salty, and fatty flavors of processed foods, for example. Soft drinks, candy, cookies, doughnuts, breakfast cereals, mayonnaise and dressings, and meats (particularly beef) are some of the first foods added to the traditional diet. Foods that are strong in flavors that are uncommon in the new culture, such as variety cuts of meat in the United States, are often the first foods to be eliminated.

Similar to the changes in the role of taste during the life cycle, the role of taste also changes during acculturation. After the adoption of sweet, salty, and fatty foods, other items are slowly introduced into the diet dependent on the other influences on choice. Cost and convenience may be factors for some families, especially if traditional ingredients are expensive or difficult to obtain. Well-being, especially as expressed through foods eaten for good health or to cure illness, such as balancing hot-cold foods or yin-yang foods, may also significantly affect selection. And those immigrants who come from societies where food choice is limited may seek variety. Eventually, even the core foods most associated with an ethnic diet may be eliminated as the culture of origin becomes more distant and the new culture is incorporated. Thus, it is essential to know the degree of acculturation in clients’ diets when proposing diet modifications.

Summary

The influence of taste on cultural food choices should not be underestimated. Our physiological fondness for sweet, salty, and fatty flavors has backfired in our plentiful food environment, leading to overeating and the conditions associated with obesity, including type 2 diabetes.

Dietitians face the challenge not only of changing clients’ desire for such foods, but also of working within clients’ cultural tastes, with an awareness of sensory preferences, flavor principles, and core and complementary foods. Additionally, clients must be assessed for life cycle stage and degree of acculturation to determine the personal significance of taste in their diet.

Multicultural competency requires acquisition of the three key proficiencies-an attitude of acceptance, culture-specific knowledge, and intercultural counseling skills. The applied approach outlined here-understanding the role of taste in cultural food choices and using the tools of the flavor principles, the core and complementary foods model, and the Consumer Food Choice Model-can help diabetes nutrition specialists make effective diet modifications that are tasty and will contribute to a healthy lifestyle for their clients.

References

1 Curry KR: Multicultural competence in dietetics and nutrition. J Am Diet Assoc 100:1142-1143, 2000

2 National Institute of Diabetes and Digestive and Kidney Diseases: National diabetes statistics fact sheet: general information and national estimates on diabetes in the United States, 2003. Rev. ed. Bethesda, MD, U.S. Department of Health and Human Services, National Institutes of Health, 2004

3 World Health Organization: Diabetes Programme, Facts and Figures, 2000. Available online at www.who.int/diabetes/facts/en

4 Kittler PG, Sucher KP: Food and Culture. 4th ed. Belmont, Calif., Wadsworth/Thompson Learning, 2004

5 Drewnoski A: Taste, genetics and food choices. In Food Selection from Genes to Culture. Anderson H, Blundell J, Chiva M, Eds. LevalloisPerrett, France, Danone Institute, 2002, p. 27-39

6 Stubbs J, Ferres S, Morgan G: Energy density of foods: effects on energy intake. CrIt Rev Food Science Nutr 40:481-515, 2000

7 Rozin E: Ethnic Cuisine: The Flavor Principle Cookbook. New York, Hawthorne Books, 1973

8 Passin H, Bennett JW: Social process and dietary change. In The Problem of Changing Food Habits. Washington D.C., National Research Council Bulletin 108, 1943, p. 113-123

9 Mintz S, Schlettwein-Gsell D: Food patterns in agrarian societies: the “core-fringe-legume hypothesis,” a dialogue. Gastronomica 1:41-59, 2001

Pamela Goyan Kittler, MS, and Kathryn P. Sucher, ScD, RD

Pamela Goyan Kittler, MS, is a food, culture, and nutrition consultant in Sunnyvale, Calif. Kathryn P. Sucher, ScD, RD, is a professor in the Department of Nutrition and Food Science at San Jose State University, in San Jose, Calif.

Copyright American Diabetes Association Fall 2004

Multidrug-Resistant Tuberculosis

Multidrug-resistant tuberculosis (MDR TB) caused by Mycobacterium tuberculosis resistant to both isoniazid and rifampicin with or without resistance to other drugs is among the most worrisome elements of the pandemic of antibiotic resistance. Globally, about three per cent of all newly diagnosed patients have MDR-TB. The proportion is higher in patients who have previously received antituberculosis treatment reflecting the failure of programmes designed to ensure complete cure of patients with tuberculosis. While host genetic factors may probably contribute, incomplete and inadequate treatment is the most important factor leading to the development of MDR-TB. The definitive diagnosis of MDR-TB is difficult in resource poor low income countries because of non- availability of reliable laboratory facilities, (efficiently run tuberculosis control programmes based on directly observed treatment, short-course (DOTS) policy is essential for preventing the emergence of MDR-TB. Management of MDR-TB is a challenge which should be undertaken by experienced clinicians at centres equipped with reliable laboratory service for mycobactcrial culture and in vitro sensitivity testing as it requires prolonged use of expensive second-line drugs with a significant potential for toxicity. Judicious use of drugs, supervised individualised treatment, focussed clinical, radiological and bacteriological follow up, use of surgery at the appropriate juncture are key factors in the successful management of these patients. In certain areas, currently available programme approach may not be adequate and innovative approaches such as DOTS-plus may have to be employed to effectively control MDR-TB.

Key words Diagnosis – epidemiology – mullidrug-rcsistanl tuberculosis (MDR-TH) – predictors Tor development prognostic factors- treatment

Tuberculosis (TB) is as old as the mankind1-3. TB is the most common cause of death due to a single infectious agent worldwide in adults4. In 1993, the World Health Organization (WHO) took an unprecedented step and declared TB to be a global emergency4-6. According to the recent estimates, onethird of the human population (about 1.86 billion people) was infected with Mycobacterium tuberculosis worldwide in 19977(7) TB is principally a disease of poverty, with 95 per cent of cases and 98 per cent of deaths occurring in developing countries. Of these, more than half the cases occur in five SouthEast Asian countries7. In 1997, nearly 1.87 million people died of TB and the global case fatality rate was 23 per cent. This figure exceeded 50 per cent in some of the African countries where human immunodeficiency virus (HIV) is highly prevalent7. It is estimated that between 2002 and 2020, approximately 1000 million people will be newly infected, over 150 million people will get sick, and 36 million will die of TB if proper control measures are not instituted4.

Though the disease was known since ancient times, the organism causing TB was described only a century ago by Robert Koch on 24th March 1882(3). Until middle of the 20th century, there was no definitive treatment available for TB. With the availability streptomycin, isoniazid and paraaminosalicylic acid (PAS), in the mid 1940s, predictable, curative treatment for TB became a reality2. The introduction of rifampicin, pyrazinamide and ethambutol in the subsequent years ushered in the era of short-course treatment. Further, the fully supervised sanatorium based treatment of the earlier days also gave way to the totally unsupervised domiciliary treatment. Soon, it was felt that TB could be easily contained and possibly eradicated. The advent of HIV infection, the acquired immunodeficiency syndrome (AIDS) pandemic in the 1980s1,8,9, shuck a blow to this optimism and there has been a global resurgence of TB. Strains of M. tuberculosis resistant to both isoniazid and rifampicin with or without resistance to other drugs have been termed multidrug-resistant strains. Multidrug-resistant tuberculosis (MDR-TB) is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients that fail treatment have a high risk of death10-14.

RATIONALE FOR STRICT DEFINITION

Isoniazid, the most powerful mycobactericidal drug available, ensures early sputum conversion and helps in decreasing the transmission of TB. Rifampicin, by its mycobactericidal and sterilising activities is crucial for preventing relapses. Thus, isoniazid and rifampicin are keystone drugs in the management of TB. While resistance to either isoniazid or rifampicin may be managed with other first-line drugs, resistance to both isoniazid and rifampicin (MDR-TB) demands treatment with second-line drugs. These drugs have limited sterilising capacity and are not suitable for shortcourse treatment. Thus, patients with MDR-TB require prolonged treatment with drugs that are less effective and more toxic. Therefore, it is necessary to distinguish MDR-TB from mere drug- resistant tuberculosis by performing mycobacterial culture and sensitivity testing because the therapeutic implications are different.

It is possible to strictly define a given isolate of M.tuberculosis as multidrug-resistant only after performing mycobacterial culture and in vitro sensitivity testing. Under programme conditions, these facilities are usually not available and patients are labelled as “treatment failure”, “re-treatment failure” and “chronic cases” as per the guidelines issued by the WHO15. It is likely that several of these patients may be excreting multidrug- resistant organisms. Keeping these facts in mind, the term MDR-TB has been used in this review in the strict sense of the definition referring to isolates resistant to both isoniazid and rifampicin with or without resistance to other drugs.

TERMINOLOGY OF DRUG RESISTANCE

Primary resistance is that which has not resulted from the treatment of the patient with the drug concerned. It includes resistance in wild strains which have never come into contact with the drug (natural resistance) and the resistance occurring as a result of exposure of the strain to the drug but in another patient. Initial resistance is the resistance in patients who give a history of never having received chemotherapy in the past. It includes primary resistance and resistance to previous treatment concealed by the patient or of which the patient was unaware16,17.

The term “acquired resistance” has often been used with the implication that resistance has developed due to exposure of the strain to antituberculosis drugs and the consequent selecting out of resistant mutant bacilli. However, some of the drug-resistant isolates in previously treated patients may actually represent primary resistance among patients who remain uncured18,19. In the strict sense, the term “acquired resistance” can be used to refer to strains proven to have drug resistance in a reliable laboratory which were subsequently isolated from a patient in whom initial susceptibility testing was done to document the presence of a drug susceptible strain earlier18,19. If initial drug susceptibility testing has not been done, the term “resistance among previously treated patients” would be a more appropriate term than “acquired drug resistance”18,19. Susceptible strains are those that have not been exposed to the main antituberculosis drugs and respond to these drugs in a uniform manner. Resistant strains differ from the sensitive strains in their capacity to grow in the presence of higher concentration of a drug. Wild strains are those that have never been exposed to antituberculosis drugs. Naturally resistant strains are wild strains resistant to a drug without having been in contact with it. It is species specific and has been used as ataxonomic marker16,17.

EPIDEMiOLOGY

World

Though studies published from the developing world suggested that drug resistance was a potential problem20,21, it was the emergence of MDR-TB in USA in the 1990s which attracted the attention22,23. The global extent of the problem of drug-resistant tuberculosis is evident in the report by the WHOlnternational Union Against Tuberculosis and Lung Disease (IUATLD) Global Project on Antituberculosis Drug Resistance Surveillance between 1994 and 1997 which described the prevalence of resistance to four first-line antituberculosis drugs in 35 countries24. In this study24, resistance to antituberculosis drugs was found in all 35 countries surveyed suggesting that it is a global problem. The prevalence of acquired resistance to any drug ranged from 5.3 per cent in New Zealand to 100 per cent in Ivanovo Oblast, Russian Federation, with a median value of 36 per cent. Resistance to all four drugs among previously treated patients was reported in a median of 4.4 per cent of the cases (range 0-17%). The median prevalence of acquired MDR- TB was 13 per cent, with a range of 0 per cent (Kenya) to 54.4 per cent (Latvia). There are several “hot spots” around the world where MDR-TB prevalence is high and could threaten control programmes24. These include Estonia, Latvia and two Russian oblasts (territories) in Europe; Argentina and the Dominican Republic in the Americas; and Cte d’Ivoire in Africa.

This survey did not include temporal changes in the prevalence of resistance. Further, in some countries with high burden of TB, such as China, India, and Russia, surveys were conducted only in one administrative unit if, any and this was not representative of \the national scenario. Therefore WHO-IUATLD survey24 was extended to define this problem further25. Between 1996 and 1999, patients in 58 geographic sites were surveyed23. For newly diagnosed patients, the frequency of resistance to at least one antitubereulosis drug ranged from 1.7 per cent in Uruguay to 36.9 per cent in Estonia (median, 10.7%). The median prevalence of MDR-TB among new cases of tuberculosis was only 1.0 per cent, but the prevalence was much higher in Estonia (14.1%), Henan Province in China (10.8%), Latvia (9%), the Russian oblasts of Ivanovo (9%) and Tomsk (6.5%), Iran (5%), and Zhejiang Province in China (4.5%). A significant decrease in multidrug resistance was observed in France and the United States. In Estonia, the prevalence in all cases increased from 1 1.7 per cent in 1994 to 18.1 per cent in 199825. Results of resistance surveys from 64 countries, together with data predictive of resistance rates from 72 others suggest that an estimated 273,000 new cases of MDRTB occurred worldwide in 2000 and constituted 3.2 per cent of all new TB cases26.

India

Reliable data on the epidemiology of MDR-TB are lacking from India1. Though the problem of drug resistance was observed in the early studies from India2021, resistance to both isoniazid and rifampicin has been a recent phenomenon. It is felt that the phenomenon of MDR-TB is on the rise and is bound to reach much more menacing proportions27-44.

In India, prevalence of primary MDR-TB in newly diagnosed cases has been observed to be 3.4 per cent or less (Table I). Data meticulously collected at the Tuberculosis Research Centre (TRC), Chcnnai over the last three decades suggest that rifampicin resistance started appearing in the early 1990s and MDR-TB levels in newly diagnosed patients has been one per cent or less36.

Prevalence of MDR-TB among previously treated patients has been observed to be higher. In a study conducted at a referral tuberculosis hospital in Amargadh, Gujarat28, multidrug resistance in previously treated cases was observed to increase from 25.2 per cent in 1983 (n=305) to 33.8 per cent in 1986(n=260). In the North Arcot district, between 1988-89, six per cent of the 3357 patients initiated on antituberculosis treatment were found to have MDR- TB29. More recently, in a study from Gujarat 44, the patterns of drug resistance were studied among previously treated tuberculosis patients who remained symptomatic or smear-positive despite receiving antituberculosis drugs under the DOTS programme for a minimum period of five months. Of the 1472 patients studied, 804 (54.6%) were treatment failure cases and 668 (45.4%) were relapse cases; 822 patients (373 failure and 449 relapse) were culturepositive. Of these 822 patients, 482 (58.6%, 261 failure and 221 relapse) were resistant to one or more drugs. Resistance to rifampicin and isoniazid with or without resistance to other drugs was seen in 289 of the 822 patients (35.2%). However, caution has to be exercised in interpreting the prevalence figures published in studies with a small sample size because of inherent methodological concerns.

Table I. Prevalence of multidrug resistant M. tuberculosis isolates among new cases in India

The global epidemic of HIV infection/AIDS

Neville et al45 described the emergence of drugresistant TB as the third epidemic. It is generally accepted that patients with HIV infection/AIDS are at a greater risk of developing TB8,18,22,23,46. In persons with HIV infection/AIDS, factors such as increased vulnerability, increased opportunity to acquire TB (due to over crowding, exposure to patients with MDR-TB, increased hospital visits), and malabsorption of antituberculosis drugs resulting in suboptimal therapeutic blood levels inspite of strict adherence to treatment regimen have all been postulated as the possible causes for increased risk of acquiring MDR-TB. Data from published literature also support this view18,22,23,47,48.

BIOLOGIC AND MOLECULAR BASIS OF DRUG RESISTANCE

Spontaneous chromosomalIy borne mutations occurring in M. tuberculosis at a predictable rate is thought to confer resistance to antituberculosis drugs49-53. A characteristic feature of these mutations is that they are unlinked. Thus, resistance to a drug is usually not associated with resistance to an unrelated drug. A tuberculosis cavity usually contains 10(7) to 10(9) bacilli. If mutations causing resistance to isoniazid occur in about 1 in 106 replications of bacteria, and the mutations causing resistance to rifampicin occur in about 1 in10(8) replications, the probability of spontaneous mutations causing resistance to both isoniazid and rifampicin would be 10(6) 10(8)= 1 in 10(14). Given that this number of bacilli cannot be found even in patients with extensive cavitatory pulmonary tuberculosis, the chance of spontaneous dual resistance to rifampicin and isoniazid developing is practically remote49-53. Thus, the fact that mutations are unlinked formstlie scientific basis of antituberculosis chemotherapy. The primary mechanism of multiple drug resistance in tuberculosis is due to perturbations in the individual drug target genes.51,52 Table II lists the molecular mechanisms of drug resistance as they are understood today49-53.

Table II. Antitubcrculosis drugs and the gene(s) involved in their resistance

Scanty information is available regarding the molecular basis of drug resistance in India. In studies published from India54.55, in addition to the previously reported mutations, several novel mutations were also observed in the rpoB (rifampicin), kat/G and the ribosomal binding site of inhA (isoniazid), gyrA and gyrB (ofloxacin). and r/’A and rrs (streptomycin). Mani at al56analysed the mutations in 44 drugresistant and six drug-sensitive M. tuberculosis clinical isolates from various parts of India in the 81- bp rifampicin resistance-determining region (RRDR) of the rpoB gene by DNA sequencing. Fifty three mutations of 18 different kinds, 17 point mutations and one deletion, were observed in 43 of 44 resistant isolates. Three novel mutations and three new alleles within the RRDR, along with two novel mutations outside the RRDR, were reported by these workers56. These observations suggest that while certain mutations are widely present, pointing to the magnitude of the polymorphisms at these loci, others are not common, suggesting diversity in the multidrug-resistant M tuberculosis strains prevalent in this region. Further, it was observed that rifampicin resistance was found to be an important marker for checking multi-drug resistance in clinical isolates of M. tuberculosis54.

DIAGNOSIS OF MDR-TB

Conventional methods

Traditionally, Lowenstein-Jensen (LJ) culture has been used for drug sensitivity testing using (i) absolute concentration method; (ii) the resistance ratio method; and (m) the proportions method16,17 With the conventional methods, 6-8 wk time is required before sensitivity results are known.

In absolute concentration method, the minimal inhibitory concentration (MIC) of the drug is determined by inoculating the control media and drug containing media with a carefully controlled inoculum of M. tuberculosis. Media containing several sequential two- fold dilutions of each drug are used. Resistance is indicated by the lowest concentration of the drug which will inhibit growth (defined as 20 colonies or more at the end of four weeks)1617. In resistance ratio method, MIC of the isolate is expressed as a multiple of the MIC of a standard susceptible strain, determined concurrently, in order to avoid intra- and inter-laboratory variations. These two methods require stringent control of the inoculum size and hence are not optimal for direct sensitivity testing from concentrated clinical specimens. In the proportions method, the ratio of the number of colonies growing on drug containing medium to the number of colonies growing on drug free medium indicates the proportion of drug resistant bacilli present in the bacterial population. Below a certain proportion called critical proportion, a strain is classified as susceptible, and above that as resistant16-17.

Modern methods

Radiometrie methods have been developed for rapid drug- susceptibility testing of M. tuberculosis57-59. In the BACTEC-460 (BectonDickinson) radiometric method, 7Hl2 medium containing palmitic acid labelled with radioactive carbon (^sup 14^C-palmitic acid) is inoculated. As the mycobacteria metabolise these fatty acids, radioactive carbon dioxide (^sup 14^CO^sub 2)^ is released which is measured as a marker of bacterial growth. The proportions method has been modified by incorporating the BACTEC technique in place of the conventional Lowenstein-Jensen culture. With this modification, sensitivity results will be available within 10 days57,58.

The mycobacteria growth indicator tube (MGIT) system (Becton- Dickinson) is a rapid, nonradioactive method for detection and susceptibility testing of M. tuberculosis59,60. The MGIT system relies on an oxygen-sensitive fluorescent compound contained in a silicone plug at the bottom of the tube which contains the medium to detect mycobacterial growth. The medium is inoculated with a sample containing mycobacteria and with subsequent growth mycobacteria utilise the oxygen and the compound fluoresces. The fluorescence thus produced is detected by using a ultraviolet transilluminator. Studies carried out both with cultures and direct clinical samples showed comparable results with the GACTEC and the proportions method60.

Restriction fragment length polymorphism (RFLP) patterns used to categorise isolates of M. tuberculosis and to compare them, has facilitated the elucidation of molecular epidemiology of TB61. In this technique, DNA is extracted from the cultured bacilli. A restriction endonuclcase such as Pvull cleaves the element at base pair 461. Subsequent steps involve separation of DNA fragments by electrophoresis on an agarose gel, \transfer of the DNA to a membrane (Southern blotting), followed by hybridisation and detection with a labelled DNA probe. The DNA from each mycobacterial isolate is depicted as a scries of bands on an X-ray film to create the fingerprint. A banding pattern reflecting the number and position of copies of IS6110 (a 1361 base pair insertion sequence) within the chromosomes is obtained and this depends on the number of insertion sequences and the distance between them. As the DNA fingerprints of M. tubercoulosis have been observed not to change during the development of drug resistance, RFLP analysis has also been used to track the spread of drugresistant strains61. Recently, Goulding et al62 determined the value of fluorescent amplifiedfragment length polymorphism (FAFLP) analysis for genetic analysis of M. tuberculosis and suggested that FAFLP can be used in conjunction with IS6110 RFLP typing to further understand the molecular epidemiology of M. tuberculosis.

Ligase chain reaction (LCR) involves the use of an enzyme DNA ligase which functions to link two strands of DNA together to continue as a double strand. This can occur only when the ends are complementary and match exactly, and this method facilitates the detection of a mismatch of even one nucleotide63-65. Luciferase reporter assay is a novel reporter gene assay system for the rapid determination of drug resistance66-68. It is based on the gene coding for luciferase, an enzyme identified as the light producing system of fireflies. In the presence of adenosine triphosphate (ATP), it interacts with hicifcrin and emits light. The luciferase gene is placed into a mycobacteriophage. Once this mycohacleriopliage attaches to M. tuberculosis, the phagc ONA is injected into it and the viral genes are expressed. If M. tuberculosis is infected with luciferase reporter phage and these organisms are placed in contact with antituberculosis drugs, susceptibility can be tested by correlating the generation of light with conventional methods of (CStMTg. This technique has the potential to identify most strains within 48 h66-68.

FASTPIaqueTB-RIF, a rapid bactcriophage-based test, to identify rifampicin susceptibility in clinical strains of M.tuberculosis after growth in the BACTKC-460 semi-automated liquid culture system has also shown potential to rapidly aid in the diagnosis of MDR- TB69,70.

Polymerase chain reaction (PCR) based sequencing has often been employed to understand (he genetic mechanisms of drug resistance in mycobacteria71. This technique allows for detection of both previously recognised and unrecognised mutations. The PCR-based methods are not readily applicable for routine identification of drug resistance mutations because several sequencing reactions need to be performed for each isolate. However, for targets such as rpoB, where mutations associated with rifampicin resistance are concentrated in a very short segment of the gene, PCR-based sequencing is a useful technique71.

The Line Probe assay (LiPA; Inno-Genetics NV, Zwijndrccht, Belgium) has been used for rapid detection of rifampicin resistance7′. LiPA technique is based on the reverse hybridisation method, and consists of PCR amplification of a segment of the rpoB gene followed by denaturation and hybridisation of the biotinylated PCR amplicons to capture probes bound to a nitrocellulose strip and detection of the bound amplicons producing a colour reaction. The interpretation of the banding pattern on the strip allows the identification of M. tuberculosis complex and detection of rpoB mutations. DNA microarray technology used for mycobacterial species identification has also been used for rapid detection of mutations that are associated with resistance to antituberculosis drugs72,73. However, most of the modern diagnostic methods are confined to research laboratories and are several years away from being available for use in the field setting.

Role of multidrug transporters

Multidrug transporters comprise four families of transmembrane efflux proteins that actively pump out a broad range of structurally unrelated compounds from the interior of the cell, using either proton motive force or ATP supplied energy74. These proteins are expressed by all organisms ranging from prokaryotes to higher eukaryotes, including human cells. They mediate both intrinsic and acquired resistance to various drugs of a multitude of organisms such as Pseudomonas sp., Candida sp., Plasmodium sp. and cancer cells74. P-glycoprotein is a human analogue of these multidrug transporters and is expressed on immune effector cells75. It has been observed that infection of experimental cell lines by M. tuberculosis results in increased expression of Pglycoprotein and decreased accumulation of isoniazid inside the cells76. Apart from the up regulation of host cell P-glycoprotein, M. tuberculosis per se expresses at least three multidrug transporter proteins Tap, Lfr A and Mmr77-79. The potential contribution of these multidrug transporter proteins in the causation of MDR-TB merits further evaluation. These transmembrane efflux proteins also appear to be novel targets for drug therapy in future.

POTENTIAL CAUSES OF DRUG RESISTANCE

Various factors have been implicated in the causation of MDR- TB80. These are discussed below:

Genetic factors

Though there is some evidence to postulate host genetic predisposition as the basis for the development of MDR-TB, it has not been conclusive81-84. In a recent study from India83, patients with HLA-DRB1*13 and -DRB 1*14 were found to have two-fold increased risk of developing MDR-TB. Park et al84 found that susceptibility to MDR-TB in Korean patients was strongly associated with HLADRB1*08032- DQB1*0601 haplotypes. The exact role of these factors is not known. It is likely that these loci or the alleles linked with them play a permissive role in conferring increasing susceptibility to the development of MDR-TB.

Factors related to previous antituberculosis treatment

Incomplete and inadequate treatment: Review of published literature strongly suggests that the most powerful predictor of the presence of MDR-TB is a history of treatment of tuberculosis. TB patients in India get treated with DOTS regimens not only through the Revised National Tuberculosis Control Programme (RNTCP), but also receive treatment from private medical practitioners. Irregular, incomplete, inadequate treatment is the commonest mean of acquiring drug resistant organisms.

Mahmoudi and Iseman85 observed that among the 35 patients with MDR-TB patients, errors in management decisions occurred in 28 patients, at an average of 3.93 errors per patient85. The most common errors were the addition of a single drug to a failing regimen, failure to identify preexisting or acquired drug resistance, initiation of an inadequate primary regimen, failure to identify and address noncompliance and inappropriate isoniazid preventive therapy. Moreover, the group in which management errors occurred had more extensive acquired drug resistance compared to the group where there were no errors85.

Use of single drug to treat TB is another common predisposing cause in the Indian setting. This could have occurred because of ignorance, use of penicillin/ streptomycin combinations; use of rifampicin for other diseases, and economic constraints. Furthermore, there is a problem of using unreliable combinations with an appreciable failure rate such as thiacetazone/isoniazid as initial treatment. Another common error in prescription practice is the “addition syndrome”, if another drug is added to the existing regimen when the patient appears to deteriorate clinically and if resistance had developed to the drugs in use, adding another drug effectively amounts to monotherapy with the drug. There is also a risk of use of unreliable drugs with poor bioavailability (e.g., rifampicin, isoniazid, pyrazinarnide combinations). Use of antituberculosis drugs by unqualified persons or alternative medicine practitioners in bizarre regimens for inadequate periods is an important problem in our country. Free availability of antituberculosis drugs over the counter may contribute to this.

Inadequate treatment compliance: The change- over from fully supervised sanatorium treatment to unsupervised domiciliary treatment has affected compliance significantly. Poor compliance with treatment is also an important factor in the development of acquired drug resistance. In a study conducted in south India37, it was observed that only 43 per cent of the patients receiving short- course treatment (n=2306) and 35 per cent of those receiving standard chemotherapy (n=1051) completed 80 per cent or more of their treatment37.

Noncompliance with prescribed treatment is often underestimated by the physician and is difficult to predict. The drug defaulter, just like placebo reactor is not a consistent or readily identified person86. In the west, demographic factors such as age, sex, marital status, education level and socio-economic status have not been found to correlate with the degree of compliance. On the other hand, certain factors such as psychiatric illness, alcoholism, drug addiction and homelessness do predict noncompliance86,87. This may not be entirely true in the Indian context and the relevance of these factors in the Indian scenario merits further study.

Considering the changing epidemiological scenario DOTS is presently being advocated by the WHO to be the only effective way to control tuberculosis4,88,89. However, DOTS has not been adopted universally and the control programmes in several parts of the world are chaotic80.

Santha et al90 studied the risk factors associated with default, failure and death among TB patients treated in a newly implemented DOTS programme in south India. In this study, 676 patients were registered during the one year study period. In multivariate analysis, higher default rates were associated with irregular treatmen\t [adjusted odds ratio (AUR) 4.3; 95 per cent confidence intervals [(95% Cl) 2.5-7.4], male sex (AOR 3.4; 95%CI 1.5-8.2), history of previous treatment (AOR 2.8; 95% Cl 1.6-4.9), alcoholism (AOR 2.2; 95%CI 1.3-3.6), and diagnosis by community survey (AOR 2.1; 95%CI 1.2-3.6). Patients with MDR-TB were more likely to fail treatment (33 vs. 3%; f

Johnson et al91 in a study of 109 culture-positive pulmonary tuberculosis patients found a high incidence of drug resistance in previous treatment defaulters while only four of the 27 new incident cases had MDR-TB. The various reasons for default included travel to different places, symptom relief, adverse drug reactions and inability to afford treatment91.

Lack of laboratory diagnostic facilities

Good, reliable laboratory support is seldom available in developing nations. Unfortunately, these are the areas where MDR-TB is a major health hazard. When facilities for culture and sensitivity testing are not available, therapeutic decisions are most often made by algorithms or inferences from previous treatment. Guidelines such as those published by the WHO are often resorted to choose the treatment regimen.15

For patients categorised as treatment failure the WHO re- treatment regimen consists of three drugs (isoniazid, rifampicin, and ethambutol) for a period of eight months, supplemented by pyrazinamide during the first three months and streptomycin during the first two months15. If mycobacterial culture and in vitro sensitivity testing are not routinely performed, it is not possible to establish whether these patients are excreting multidrug- resistant bacilli. If this WHO re-treatment regimen is administered to treatment failure patients who actually have MDR-TB (resistance to rifampicin and isoniazid with or without resistance to other antituberculosis drugs), it is evident that during the last five months die patient will be receiving isoniazid, rifampicin and ethambutol only and this would amount to “monothcrapy” with ethambutol. Thus, “programmatic approach” to the management of “treatment failure” patients may fail in some settings as is evident from the following reports92-93. The programme of tuberculosis control using first-line therapy and DOTS was assessed in 467 patients with sputum-positive tuberculosis in a prison setting in Baku, Azerbaijan92. Drug resistance data on admission were available for 131 patients and 55 per cent of patients had strains of M. tuberculosis resistant to two or more drugs. Mortality during treatment was 11 per cent, and 13 per cent of patients defaulted. Overall, treatment was successful in 54 per cent of patients, and in 71 per cent of those completing treatment. One hundred and four patients completed a full treatment regimen and remained sputum- positive. Resistance to two or more drugs, a positive sputum result at the end of initial treatment, cavitary disease, and poor compliance were independently associated with treatment failure. The authors concluded that the effectiveness of a DOTS programme with first-line therapy fell short of the 85 per cent target set by WHO. First-line therapy may not be sufficient in settings with a high degree of resistance to antibiotics92.

Similar observations were made in another study with results of treatment with first-line drugs for patients enrolled in the WHO and the lUATLD’s global project on drug-resistance surveillance93. Patients with tuberculosis in the Dominican Republic, Hong Kong Special Administrative Region (People’s Republic of China), Italy, Ivanovo Oblast (Russian Federation), the Republic of Korea, and Peru were studied in this retrospective cohort study. Of the 6402 culture- positive cases evaluated, 5526 (86%) were new cases and 876 (14%) were re-treatment cases. A total of 1148 (20.8%) new and 390 (44.5%) retreatment cases were drug resistant, including 184 and 169 cases of MDR-TB, respectively. Of the new cases, 4585 (83%) were treated successfully, 138 (2%) died, and 151 (3%) experienced short-course chemotherapy failure. Overall, treatment failure and mortality were higher among new MDR-TB cases than among new susceptible cases. Even in settings using 100 per cent direct observation, cases with multidrug resistance had a significantly higher failure rate than those who were susceptible [10 vs 0.7%; relative risk (RR), 16.9; 95% CI, 6.6-42.7; P

PREDICTORS FOR THE DEVELOPMENT OF MDR-TB

Certain factors have been documented to be associated with the development of MDR-TB. In an analysis to identify determinants of drug-resistant TB, population-based representative data on new and previously treated patients with TB collected within an international drug resistance surveillance network were studied99. Of the 9,615 patients, 85.5 per cent were new cases and 14.5 per cent were previously treated cases. Compared with new cases, patients who received treatment in the past were more likely to have resistance to antitubercLilosis drugs. An approximately linear increase was observed in the likelihood of having MDR-TB as the total time of prior antituberculosis treatment measured in months increased. Multivariate analysis revealed that prior antituberculosis treatment but not HIV positivity, was associated with MDR-TB99. In a study from Saudi Arabia100, previous history of antituberculosis treatment and young age were found to be risk factors associated with the development of MDR-TB. In a study from New Delhi83, the presence of past history of tuberculosis, poor compliance to treatment, low socioeconomic status and body mass index (BMI, kg/m^sup 2^) ≤18 kg/m^sup 2^ were independent contributors to the risk of developing MDR-TB. In most of the published studies, previous history of tuberculosis and past history of antituberculosis treatment have been implicated in the causation of MDR-TB83,99-103.

MANAGEMENT

In the early reports of outbreaks of MDR-TB in HIV co-infected patients in hospitals and prisons, the mortality rate was very high ranging form 72 to 89 per cent104-108. However, subsequent studies have documented decreased mortality and improvement in clinical outcome for HIV-seropositive patients with MDR-TB who were started on at least two drugs with, in vitro susceptibility against the MDR- TB isolate96,109,110. Even in HIV seronegative patients, treatment of MDR-TB has been difficult and may only give response rates of the order of 50 per cent with a high mortality rate with persistent positive cultures95-97,111,112.

In resource-poor nations, the treatment of MDR-TB has been considered to be very expensive and available only at referral centres. In a recently published study113, results of community- based outpatient treatment of MDR-TB were reported form Peru. While the results of susceptibility testing were pending, the patients were treated empirically under direct observation with regimens containing at least five drugs to which the strains were likely to be susceptible. The definitive regimens, determined on the basis of the results of drug susceptibility, contained a minimum of five drugs and lasted for at least 18 months. Of the 66 patients who completed four or more months of therapy, 55 (83%) were probably cured (defined as at least 12 months of consecutive negative cultures during therapy). Five of these 66 patients (8%) died while receiving treatment. Only one patient continued to have positive cultures after six months of treatment. Low haematocrit [hazard ratio (HR) 4.09; 95% CI, 1.35 to 12.36] and a low BMI (kg/m^sup 2^) (HR, 3.23; 95% CI, 0.90 to 1 1.53) were found to be the predictors of the time to treatment failure or death. These observations suggest that community-based out-patient treatment of MDR-TB has the potential to yield high cure rates even in resource-poor settings113.

Sparse data are available from published literature regarding the treatment of patients with MDR-TB from India. In a study from New Delhi, additional administration of oral ofloxacin was found to be effective and safe for the treatment of MDR-TB10. In an uncontrolled study from Manipal, Karnataka114, pefloxacin, with its low cost and high safety profile was considered to be a useful companion drug in selected cases. A prospective uncontrolled study from New Delhi’115 reported that sparfloxacin, in combination with kanamycin (for the initial 3 to 4 months) and cthionamidc treatment was useful in achieving sputum conversion, clinical and radiological improvement in nine patients with pulmonary tuberculosis who had received adequate antituberculosis treatment with first-line drugs, including supervised category il treatment regimen as per WHO guidelines for five months, and were still sputum smear positive. In a study from Vellore, Tamil Nadu116 combination therapy containing ofloxacin was useful in achieving sputum conversion in 26 of 49 (53%) patients and culture conversion occurred in 16 of 26 (61.5%) patients. Clinical and radiological response was noted in 3 I (56%) and 13 (32.5%) out of 40 patients respectively.

Prognostic markers

Park et al96 reported that extra-pulmonary involvement was a risk factor for shorter survival, while a cavitary lesion on initial chest film and institutionof appropriate treatment were positive predictors of survival in patients with MDR-TB. In a recently published study from the United Kingdom112, overall median survival time was 1379 days (95% Cl 1336 to 2515). Median survival time was 858 days (95% Cl 530 to 2515) in immunocompromised individuals and 1554 (95% Cl 1336 to 2066) days in immunocompetent persons. Median survival in patients treated with three drugs to which the bacterium was susceptible on m W/ro testing was 2066 days (95% CI 1336 to 2515), whereas, in those not so treated survival was 599 days (95% Cl 190 to 969). Immunocompromised status, failure to culture the bacterium in 30 days or to apply appropriate treatment with three drugs to which the organism is susceptible, and age were significant factors in mortality. An immunocompromised patient was nearly nine times more likely to die, while application of appropriate treatment reduced the risk. Increasing age was associated with increasing risk of death (risk ratio 2.079; 95% Cl 1.269 to 3.402) suggesting that, for every 10 yr increase in age the risk almost doubled112. In a study from France117, in patients with MDR-TB, HIV-coinfection, treatment with less than two active drugs, and knowledge regarding the multidrug-resistant status at the time of diagnosis were found to be associated with a poor outcome. In study from Turkey118, older age and history of previous treatment with a larger number of drugs were found to be associated with a poor outcome.

Guidelines for the management of patients with MOR-TB

When MDR-TB is suspected on the basis of history or cpidemiological information, the patient’s sputum must be subjected to culture and antituberculosis drug sensitivity testing and the WHO re-treatment regimen15 or the empirical regimens employing second- line reserve drugs (Tables III and IV) suggested by the American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society of America (ATS/CDC/ IDSA)119 must be initiated pending sputum culture report. Further therapy is guided by the culture and sensitivity report. These guidelines clearly mention that a single drug should never be added to a failing regimen. Furthermore, when initiating treatment, at least three previously unused drugs must be employed to which there is in vitro susceptibility15,119.

When susceptibility testing reports are available and there is resistance to isoniazid and rifampicin (with or without resistance to streptomycin) during the initial phase, a combination of ethionamide, fluoroquinolone, another bacteriostatic drug such as ethambutol, pyrazinamide and aminoglycoside (kanamycin, amikacin, or capreomycin) are used for three months or until sputum conversion. During the continuation phase, ethionamide, fluoroquinolone, another bacteriostatic drug (ethambutol) should be used for at least 18 months after smear conversion15,119(Table IV). If there is resistance to isoniazid, rifampicin and ethambutol (with or without resistance to streptomycin) during the initial phase, a combination of ethionamide, fluoroquinolone and another bacteriostatic drug such as cycloserine or PAS, pyrazinamide, and aminoglycoside (kanamycin, amikacin, or capreomycin) are used for three months or until sputum conversion. During the continuation phase, ethionamide, ofloxacin, another bacteriostatic drug (cycloserine or PAS) should be used for at least 18 months after smear conversion15,119.

Table III. Daily dosage and toxicity status of second-line antituberculosis drugs

The recently published ATS/CDC/IDSA119 guidelines suggest that among the fluoroquinolones, levofloxacin is most suited for the treatment of MDRTB given its good safety profile with long-term use. These observations need to be confirmed in prospective studies with a large sample size.

When administering antituberculosis drugs by the parenteral route, proper precautions must be taken. This is particularly relevant in countries like India where, disposable syringes are not always available for giving the injections and the use of improperly sterilized needles would be a health hazard especially in patients with HIV infection and AIDS.

Second-line drugs are very difficult to obtain in small towns and rural areas in India. Therefore, reliable supply of drugs is a difficult problem. Moreover, there is a wide variation in the price range between different pharmaceutical brands. Reliable pharmacokinetic data regarding bioavailability of most of these formulations are not available and there is no assurance that the most expensive brand names have the best bioavailability profile. Even considering the cheapest brand names available, the cost of drug treatment alone is much beyond the means of the average Indian patient. Therefore, long-term compliance is not very good. All these factors constitute significant therapeutic challenges for the clinicians treating MDR-TB in the field setting. Population migration due to poverty to seek better job opportunities, natural disasters, wars, political instability and regional conflicts also create mobile populations. These factors make treatment of MDRTB difficult120,121.

DOTS-plus strategy

DOTS is a key ingredient in the tuberculosis control strategy. In populations where MDR-TB is endemic, the outcome of the standard short-course regimen remains uncertain. Unacceptable failure rates have been reported and resistance to additional agents may be induced80. As a consequence, there have been calls for well- functioning DOTS programmes to provide additional services in areas with high rates of MDR-TB. These “DOTS-plus for MDR-TB programmes”80’94121 may need to modify all five elements of the DOTS strategy: (i) the treatment may need to be individualized rather than standardised; (ii) laboratory services may need to provide facilities for on-site culture and antibiotic susceptibility testing; (iii) reliable supplies of a wide range of expensive second- line agents; (iv) operational studies would be required to determine the indications: and (v) financial and technical support from international organizations and Wstem governments would be needed in addition to that obtained from local governments. WHO has established a Working Group on DOTS-Plus for MDR-TB, to develop policy guidelines for the management of MDR-TB and to develop protocols for pilot projects intended to assess the feasibility of MDR-TB management under programme conditions. The WHO has also established a unique partnership known as the Green Light Committee (GLC) in an attempt to promote access to and rational use of second- line antituberculosis drugs for the treatment of MDR-TB121-125 DOTS- plus programmes are established, they may prove beneficial not only for patients with MDR-TB but for all patients with tuberculosis.

Table IV. Suggested treatment for patients with MDR-TB

Monitoring response to treatment

Patients receiving treatment for MDR-TB should be closely followed up. Clinical (e.g., fever, cough, sputum production, weight gain), radiological (c.,g\, chest radiograph) , laboratory (crytlirocyte sedimentation rate) and microbiological (e.g., sputum smear and culture) parameters should be frequently reviewed tu assess the response to treatment. In addition, considerable attention must be I’ocussed on monitoring the adverse drug reactions which often develop with the second-line antituberculosis drugs. A detailed description of these adverse drug reactions is beyond the scope of this review. Majority of the patients who respond to treatment begin to show favourable signs of improvement by about four to six weeks following initiation of treatment, failure to show positive trend may alert the clinician to resort to other measures outlined below.

Newer antitubcrculosis drugs

Currently available second-line drugs used to treat MDR-TB (Table 111) are four to ten times more likely to fail than standard therapy for drug-susceptible Kiberculosis94-98. After the introduction of rifampicin, no worthwhile antituberculosis drug with new mechanism(s) of action has been developed in over thirty years. Moreover, no new drugs that might be effective in treatment of MDR- TB are currently undergoing clinical trials. It appears that effective new drugs for tuberculosis are at least a decade away98. Recently, a series of compounds containing a nitroimidazopyran nucleus that possess antitubcrculosis activity have been described122. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antituberculosis drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static bacilli. Lead compound PA-824 showed potent bactericidal activity against multidrug- resistant M. tuberculosis and promising oral activity in animal infection models. It is being hoped that these nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis122.

Surgery

Various surgical procedures performed for patients with MDR-TB have ranged from segmental resection to pleuro-pneumonectomy126- 130. Based on the experience reported in the literature about surgery for MDR-TB, it can be concluded that the operation can be performed with a low mortality (

Thus, resectional surgery is currently recommended for MDR-TB patients whose prognosis with medical treatment is poor. Indications for surgery in patients with MDR-TB include: (i) persistence of culture-positive MDR-TB despite extended drug retreatment; and/or (ii) extensive patterns of drug resistance that are associated with treatment failure or additional resistance; and/or (iii) local cavitary, necrotic/destructive disease in a lobe or region of the lung that was amenable to resection without producing respiratory insufficiency and/or severe pulmonary hypertension. It should be performed after minimum of three months of intensive chemotherapeutic regimen, achieving sputum-negative status, if possible. The operative risks are acceptable and the long-term survival is much improved than that with continued medical treatment alone. However, for this to be achieved, the chemotherapeutic regimen needs to continue for prolonged periods after surgery also, probably for well over a year, otherwise recrudescence of the disease with poor survival is a real possibility.

Nutritional enhancement

Tuberculosis is a wasting disease. The degree of cachexia is most profound when MDR-TB occurs in patients with HIV-infection/AIDS131. While the mechanisms involved in weight loss are not well known, current evidence points to tumour necrosis factor-α (TNF- α) to be the cytokine responsible for this phenomenon. TNF- α, in addition to inducing immunopathological effects such as tissue necrosis and fever, is also thought to induce the catabolic response132. Further, several second-line drugs used to treat MDR- TB such as PAS, fluoroquinolones cause significant anorexia, nausea, vomiting and diarrhoea interfering with food intake, further compromising the cachectic state. Therefore, nutritional support is a key factor in the care of patients with MDR-TB, especially those undergoing major lung surgery. Though definitive evidence is not yet available, it is generally believed that malnourished patients are at a greater risk of developing post-operative complications126.

Nutritional assessment and regular monitoring of the nutritional state by a dietician are essential for the successful management of MDR-TB patients and should be an essential part of such programmes. When the routine measures are not able to improve the nutritional status and induce weight gain, nasogastric feeding may be employed to supplement the diet. When the patients are very sick and have severe nutritional deficit, feeding gastrostomy/ jcjunostomy may have to be performed.

Immunotherapy

Ever since the early attempts by Robert Koch, several workers have attempted to modify the immune system of patients with tuberculosis to facilitate cure133,134 The measure employed in the earlier days included heliotherapy, dietary supplementation including milk and cod-liver oil. It is likely that these interventions acted through 1,25 (OH)^sub 2^, D^sub 3^, which is now recognised to have significant effects on T-lymphocyte and macrophage function. Agents with potential for immuimtherapy are detailed below.

Mycobacterium vaccae vaccination: Transiently favourable results were observed when immunoenhancement using M, vaccae vaccination was used to treat drug-resistant tuberculosis patients who failed chemotherapy133,134. It was postulated that M. vaccae redirected the host’s cellular response from aTh-2 dominant to a Th-I dominant pathway leading to less tissue destruction and more effective inhibition ofmycobacterial replication133. However, subsequent reports from randomised controlled trials have not confirmed these observations135.

Cytokine theraphy: With further understanding of the molecular pathogenetic mechanisms of tuberculosis, several attempts have been made to try cytokines in the treatment of MDR-TB. Recent data, however, suggest that intcrfcron-γ (IFN-γ ) and interferon- α (IFN-α) may improve disease evolution in subjects affected with pulmonary tuberculosis caused by multidrug-resistant (IFN-γ ) and sensitive (IFN-α) strains. The mechanisms involved are not known, even though it has been reported that IFN- gamma-secreting CD4+ Th cells may possess antituberculosis effects. In addition, IFN-a can induce IFN-γ secretion by CD4+ Th cells, and both types of IFN may stimulate macrophage activities133.

Aerosolised lFN-γ (500 μg, thrice weekly) has been found to produce transient, but clinically encouraging responses in patients with MDR-TB in an open-label trial116. The observed benefits included unsustained sputum smear conversion to negative, delayed growth of cultures and shrinkage of cavities. Granulocytemacrophage colony-stimulating factor (GM-CSF) has been used simultaneously with IFN-γ in the successful treatment of a patient with refractory central nervous system MDR-TB137.

Giosue et al138, studied the usefulness of aerosolised IFN- α in the treatment of MDR-TB. In this study, seven patients who were non-rcsponders to a second-line antituberculosis treatment after six months of directly observed treatment were given aerosolised IFN-α. (3 MU, three times a week) for two months as adjunctive therapy. A transient decrease in the colony number per culture was observed. Preliminary data suggest that aerosolized IFN- α may be a promising adjunctive therapy for patients with MDR- TB. Optimal doses and schedules, however, require further studies.

Interleukin-2 (IL-2) has been used in the treatment of lepromatous leprosy and is believed to act by enhancing IFN-γ production. By the same analogy, IL-2 may be useful in the treatment of MDR-TB. Johnson et al139 reported the usefulness of low-dose recombinant human interleukin 2 (rhuIL-2) ad)unctive immunotherapy in MDR-TB patients. In this study MDR-TB patients on best available antituberculosis chemotherapy also received rhuIL-2 for 30 consecutive days (daily therapy), or for five days followed by a nineday rest, for three cycles (pulse therapy). Placebo control patients received diluent. The cumulative total dose of rhulL-2 given to each patient in cither rhuIL-2 treatment group was the same. Patient immunologie, microbiologie, and radiologie responses were compared. The three treatment schedules induced different results. Immuneactivation was documented in patients receiving daily rhuIL-2 therapy. Numbers of CD25+ and CD56+ cells in the peripheral blood were increased in these patients, but not in patients receiving pulse rhuIL-2 or placebo. In addition, 62 per cent patients receiving daily rhuIL-2 demonstrated reduced or cleared sputum bacterial load while only 28 per cent pulse rhuIL-2 treated and 25 per cent controls showed bacillary clearance. Chest radiographs of 58 per cent patients receiving daily rhuIL-2 indicated significant improvement over six weeks. Only 22 per cent pulse rhulL-2-treated patients and 42 per cent placebo controls showed radiologie improvement. The authors concluded that daily low dose rhuIL-2 adjunctive treatment stimulates immuneactivation and may enhance the antimicrobial response in MDR-TB.

Other Agents

Several agents have evoked interest as potential adjunctive treatment for patients with MDR-TB. Though very little information is available regarding their clinical usefulness, they are described here considering their therapeutic potential. Thalidomide48,140 and pentoxifylline141,142 have been shown to combat the excessive effects from TNF-α. These may be useful in limiting the wasting associated with MDR-TB. Other agents which have occasionally been considered include, levamisole143,144, transfer factor145, inhibitors of transforming growth factor-β (TGF-β)146 interleukin12 (IL-12)”interferon-α. (IFN-o.) and imiquimod an oral agent which stimulates the production of IFN-α147. Though there have been anecdotal reports of their usefulness, further studies are required to clarify their role.

Prevention of nosocomial transmission of MDR-TB

As MDR-TB poses a significant risk to health care workers, doctors and other patients, the CDC in Atlanta have made recommendations to try to prevent such nosocomial transmission148. These include isolation in a single room with negative pressure relative to the outside with six air exchanges per hour, the room to be exhausted to the outside; consideration of ultraviolet lamps or particulate filters to supplement ventilation; use of disposable particulate respirators for persons entering the room and during cough inducing procedures.

Preventive chemotherapy for contacts to MDR-TB cases and treatment of latent multidrug-resistant tuberculosis infection

For contacts thought to be infected with M tuberculosis resistant to both isoniazid and rifampicin, no satisfactory chemoprophylaxis is available. There is no consensus regarding the choice of the drug(s) and the duration of treatment. The CDC lias put forth guidelines for the management of persons exposed to multidrug- resistant tuberculosis149. The guidelines recommended that the likelihood that (i) the contact is newly infected; (ii) the infecting strain is multidrug-resistant; and (iii) the contact will develop active tuberculosis should be considered. The CDC recommendations149 also stress the importance of obtaining drug susceptibility results from the isolate of the presumed source case and the use of more than one drug, since the efficacy with drugs other than isoniazid has not been demonstrated in large trials\. Patients with risk factors for progression to active disease warrant treatment, although immunocompctent individuals may be observed closely without therapy for at least six months. The two suggested regimens for MDR-TB preventive therapy are149: (i) pyrazinamide (25 to 30 mg/kg daily) plus ethambutol (15 to 25 mg/kg daily), or (ii) pyrazinamide (25 to 30 mg/kg daily) plus a quinolone with antituberculosis activity (e.g., levofloxacin or ofloxacin). The recommended duration of therapy is 12 months for those with underlying immunosuppression and at least six months for all others. All patients should be closely followed for at least two years, and a low threshold for referral to a centre with experience in managing MDR-TB should be maintained.

It has been observed that prophylaxis with pyrazinamide and levofloxacin in solid organ transplant recipients possibly exposed to MDR-TB was associated with limited tolerability due to the high frequency of adverse events150. Very little is known regarding the usefulness of pyrazinamide and levofloxacin in the treatment of multidrug-resistant latent tuberculosis infection. In a study from Canada151, this combination was found to be poorly tolerated regimen as several patients developed severe adverse drug reactions. These issues merit further studies.

In conclusion, treatment of MDR-TB is a challenge which should be undertaken by experienced clinicians at centres equipped with reliable laboratory service for mycobacterial culture and m vitro sensitivity testing. Judicious use of second-line drugs, supervised individualised treatment, focussed clinical, radiological and bacteriological follow-up, judicious use of surgery at the appropriate juncture are key factors in the successful management of these patients. In certain areas, currently available programme approach may not be adequate and innovative approaches such as DOTS- plus may have to be employed to effectively control MDR-TB.

References

1. Mohan A, Shrami a SK. Epidemiology, lu: Sharma SK. Mohan A. editors. Tuberculosis. New Delhi: Jaypce Brothers Medical Publishers; 2001 p. 14-29.

2. Slianna SK. Mohan A. Multiclrug-rcsislant tuberculosis. Mediquest 1995. 13 . 1-11.

3. Mohan A. Sharnia SK. History. In: Sharma SK, Mohan A. editors. Tiiherculoxis. New Delhi: Jaypce Brothers Medical Publishers: 2001 p. 5-13.

4. World Health Organization. Tuberculosis fact sheet. Available from URI/: http://www.who.int/gtb/ puMicalions/facl.sheet/ inde.x.litm. Accessed on 1 July 2003.

5. Grange JM. Zumla A. The global emergency of tuberculosis: what is the cause? J R Soc Health 2002; 122 : 78-81

6. Raviglione MC. Snider 1)1; Jr. Kochi A. Global epidemiology of tuberculosis : morbidity and mortality of a worldwide epidemic. JAMA 1995;’273 : 220-6.

7. Dye C. Scheele S. Dolin P. Pathania V. Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring project. JAMA 1999: 282 : 677-86.

8. Sharma SK. Mohan A, Gupta R, Kuniar A, Gupta AK, Singhal VK. el cil. Clinical presentation of tuberculosis in patients with AIDS: an Indian experience. Indian J Chest Dis Allied Sa 1997: 39 : 213- 20.

9 Corbett EL. Wall C.I. Walker N. Maher D. Williams BG, Raviglione MC. el al. The growing burden of tuberculosis: global trends and interactions with the HlV epidemic. Arch Inlern Med 2003; 163 : 1009-21.

10. Sharma SK. Guleria R. Jain D, Chawla TC, Saha P, Mohan A. et al. Effect of additional oral ofloxacin administration in the treatment of multi-drug resistant tuberculosis Indian J Chest Dis Allied Sd 1996; 3M : 73-9.

11. Anderson RM The pandemic of antibiotic resistance. \cinire Med 1999: 5 : 147-9.

12. Seaworlh HJ. Multidrug-resislant tuberculosis. Inject Dis (Vm Xorlli Am 2002; 16 : 73-105.

13. Fisher M. Diagnosis of MDR-TB: a developing world problem on a developed world budget. Kxperl Rev MoI Diagn 2002; 2 ; 151-9.

14. Dye C, Williams HG, Kspinai A, Raviglione MC. !o!rasing the world’s slow slain: strategies to beat multidrug-resislant tuberculosis. Science 2002; 295 : 2042-6.

15. Crofton J. Chaulct P, Malier D, Grosse! J, Harris W, Home N. et al. Guidelines for the management of drugresistant tuberculosis. WHO/TB/96.2 IO Revl. Geneva: World Health Organi/.ation: 1997.

16. Vareldzis BP, Grosset J. de Kantor I, Crofton J. Faslo A. Feiten M, el cd. Drug-resistant tuberculosis : laboratory issues. World Health Organi/.ation recommendations. Tuber Lung Dis 1994; 75 ; 1-7.

17. Citron KM. Curling D.I. Tuberculosis. In: \Veatherall D.I, Ledingliam JGG, Warrel DA. editors.

18. Frieden TR, Sterling T. Pablos-Mendez A. Kilburn JO, Cauthen GM, Dooley SW. The emergence of drugresistant tuberculosis in New York City. N Engl J Med 1993; 328 : 521-6.

19. Frieden TR. Khatri GR. Multi-drug resistant tuberculosis. In: Narain JP. editor. Tuberculosis epidemiology and control. WHO/SHA/ TD/248.New Delhi: World Health Organi/.ation Regional Office for South-Fast Asia; 2002 p. 105-15.

20. Indian Council of Medical Research. Prevalence of drug resistance in patients with pulmonary tuberculosis presenting for the

Studies: Cord Blood Works Vs. Leukemia

Umbilical-cord blood, now used mostly to treat children with leukemia, could save thousands of adults with the disease each year who cannot find bone marrow donors, two big studies indicate.

A European study found that those who got cord blood were just as likely to be free of leukemia two years later as those who got marrow. A U.S. study looking at three-year survival yielded results almost as promising.

To Dr. Mary Horowitz of the Medical College of Wisconsin, senior author of the U.S. study, the message is clear: Umbilical cord blood can save adults.

Leukemia patients often undergo radiation or chemotherapy to kill their cancerous white blood cells – a treatment that wipes out their immune systems, too. To restore their immune systems, doctors give these patients an infusion of bone marrow or umbilical cord blood, both of which contain stem cells capable of developing into every kind of blood cell.

Cord blood offers an important advantage over marrow that makes it particularly valuable for use in transplants: Its stem cells are less likely to attack the recipient’s body. That allows a wider margin of error in matching up donors and recipients.

But up to now, cord blood has been considered suitable only for children, because each donation has only about one-tenth the number of stem cells in a marrow donation.

The two new studies, published in Thursday’s New England Journal of Medicine, suggest that is not a serious impediment.

In the European study, involving 682 patients, about one-third of both those who got matched marrow and those who got cord blood that did not quite match their own tissues were alive after two years. In the U.S. study of 601 patients, about one-third of those who got matched marrow were leukemia-free after two years, compared with about one-fifth of those who got cord blood or unmatched marrow.

Both studies were based on records from transplants in the late 1990s and early 2000s.

Using cord blood could improve the odds of getting a transplant for the 16,000 U.S. adult leukemia patients each year who cannot find a compatible marrow donor, said the U.S. study’s leader, Dr. Mary J. Laughlin of Case Comprehensive Cancer Center in Cleveland.

Still, Dr. Nancy Kernan, assistant chief of marrow transplantation at Memorial-Sloan-Kettering Cancer Center in New York, said cord blood transplants in adults should be done only as part of studies to look at and improve their effectiveness.

Public cord blood banks – where blood drawn from umbilical cords and placentas at birth is kept frozen – need to quadruple their supply to find a match for every leukemia patient who needs one. With 4 million births a year in this country, and most cord blood thrown away, that should not be a problem once more public money comes into play, doctors said.

A federal Institute of Medicine committee is already looking into the best way to set up a national cord blood supply, and is scheduled to complete its report in March.

“I know our committee will consume this study avidly,” said Kristine Gebbie, chairman of the group.

The first bone marrow transplants were done in the 1960s; cord blood transplants started in the 1990s. Stem-cell transplants save only 20 percent to 30 percent of the patients who hope to grow new immune systems. But without the treatment, virtually all of them would die.

Some researchers said techniques they have developed in the past two years, since the study ended, already have boosted their success.

Most doctors consider cord blood more appropriate for smaller people, because it contains fewer stem cells than marrow. In the two studies, cord blood recipients tended to weigh less than those who got marrow – an average of 22 pounds less in the U.S. research, about 18 in the European study.

There are two competing U.S. public cord bank systems, one holding about 38,000 vials, the other 27,000. Together, they do not add up to the supply kept by just one of the 20 or so private banks kept for paying families.

On the Net:

http://www.parentsguidecordblood.com

http://www.marrow.org

http://www.nationalcordbloodprogram.org

http://www.leukemia-lymphoma.org

http://www.cancer.org

Teaching Science to Students With Learning Problems in the Elementary Classroom

ABSTRACT:

Because of recent legislation, students with mild disabilities frequently receive science instruction in the general education classroom. Elementary teachers therefore have the challenge of teaching science to children with a wide range of abilities and preparing them to pass the federally mandated assessments in science. The emphasis in the general education science curriculum is on high-level cognitive skills which is challenging for students with learning problems. This article reviews characteristics of students with learning and behavior problems and then presents some ideas for practice to help these students and their teachers have a positive experience.

Key Words: instructional modifications, learning problems, mild disabilities, science

With the passage of the Education IOr All Handicapped Children’s Act of 1975 and its subsequent amendments, and the most recent education law of 2002, No Child Left Behind, there has been increasing emphasis on teaching students with disabilities in general education classes. Whether it is referred to as “mainstreaming,” placing children in the “least restrictive environment,” or using an “inclusive” model in the schools, the focus is on children with and without disabilities being taught together using the same general curriculum. This trend presents a challenge to teachers who will be responsible for instructing students of all levels and abilities. In addition the emphasis in science instruction on high level thinking skills, problem-solving, and an inquiry approach to teaching is challenging for many students and teachers and could present particular difficulties for students with learning problems (Palincsar, Magnusson, Collins, & Cutter, 2001).

Nevertheless, elementary teachers are responsible for instructing all students in the same curriculum and assuring that all students pass the federally mandated assessments developed by every state. The purpose of (his article is to address this challenge by reviewing characteristics associated with the high prevalence mild disabilities and suggesting some strategies and modifications for teaching science to children with learning and behavior problems.

Students With Mild Disabilities

Because of the recent legislation and the current emphasis on including children with special needs in the general education curriculum, children with learning, intellectual, and behavioral disabilities frequently receive science instruction in the general rather than special education setting. It is important for elementary teachers to be familiar with characteristics that many of these children exhibit so they are able to make appropriate modifications in science instruction.

Many students with mild disabilities are below their peers in the basic academic skills of reading, mathematics, and writing (Olson & Platt, 2004), which could interfere with science instruction. The science textbooks and related reading materials, for example, are often written 2 or 3 years above the actual reading levels of students with disabilities.

Problems in processing information are also typical of students with special needs. Memory problems, for example, are common among students with learning and intellectual disabilities (Raymond, 2000) and could interfere with recall of science information presented in lecture and class discussion. Other examples of processing deficits common among children with learning and other mild disabilities include problems with visual processing and auditory processing (Kirk, Gallagher, & Anastasiow, 2003). Visual processing problems make it difficult for students to understand science illustrations and demonstrations shown to the class, whereas auditory processing deficits interfere with the ability to follow class discussion of science experiments, hypotheses, results, and conclusions.

Organizational deficits are also symptoms of learning and behavioral disabilities (Kirk et al., 2003). This difficulty often leads to problems in science when students are required to follow certain rules and procedures for conducting experiments in the classroom. They may have trouble organizing the materials for an experiment, keeping their notes in the appropriate format, and putting materials in the proper locations for safety and efficiency in the classroom.

Attention problems are typical of many students with intellectual, learning, and behavioral disabilities (Olson & Platt, 2004). Students have trouble, for example, following directions for a science project, following through on all steps for the project, and attending to lessons that require extended periods of concentration.

Generalization is a difficult task for students with mild disabilities (Raymond, 2000). In science classes, it is often necessary to learn the steps of inquiry and then apply them throughout the year to various projects. A student who has trouble generalizing will not be able to apply these same steps in a variety of situations. The steps only seem applicable to the specific situation in which they were learned and first practiced.

Negative attitudes can also create difficulties for students with special needs. Because of their cycle of frustration and failure, they may have trouble staying motivated and focused on a task. They often learn early that school experiences are very difficult and then give up putting forth the effort needed to succeed (Olson & Platt, 2004). For many science assignments and tasks, a great deal of time and effort is often required over a long period of time. If a student gives up before he even understands the parameters of the assignment, he will not have a chance for success.

Many students with behavior and learning disorders have difficulty with social skills; they may have trouble establishing and maintaining relationships and may not be readily accepted by others (Olson & Platt, 2004). Very often in science classes, projects and experiments are conducted with partners or in small groups. This grouping creates problems for students with special needs because of their inability to be successful in social situations.

Finally, students with disabilities frequently have language disorders either receptive, expressive or both (Raymond, 2000). Science vocabulary, therefore, could be extremely difficult to understand. The complex, technical, and abstract wording could make the entire science lesson confusing and prevent accomplishment of related objectives.

Modifications for Science Instruction

Several strategies for teaching science have been researched and recommended for students with special needs. These ideas will help bridge the gap between the typical characteristics of students with learning and behavior problems and their need to master the general science curriculum in the elementary classroom.

In research studies conducted by Palincsar et al. (2001), with elementary science instruction, the conclusions supported collaboration between general and special education teachers. This team approach would bring together ideas about science content, science methods, and individual learner needs. The special education teacher can assist the students with learning problems who are having difficulty with vocabulary such as compound, mixture, and solution, and assist students with behavior deficits who are having difficulty working in groups to make mixtures. While the classroom teacher is an expert in the science content and methods, the special education teacher can ensure that all students understand the lesson and accomplish the objectives.

Presenting material in a variety of formats whenever possible will also help students with disabilities learn science. A science experiment on seed germination, for example, can often be presented using multiple senses: (a) listening to a discussion of factors necessary for germination (auditory), (b) observing results with seeds growing in various conditions (visual), (c) participating in the planting and recording of data (kinesthetic and tactile), and (d) discussing the conclusions (oral). In this way science can readily be taught using a multisensory approach often recommended for students with learning problems (Alexakos, 2001). Using tape recorded textbooks, either through a library or made by the teacher, is another way to present traditionally visual material in the textbook through another modality (Munk, Bruckert, Call, Stoehrmann, & Radandt, 1998).

Although it may be more complicated to effectively structure cooperative learning groups when students with disabilities are included, the benefits for social and science skills would make the effort worthwhile. The opportunities for success would be enhanced for students with disabilities especially if specific responsibilities are given to each student based on his or her ability level (Alexakos, 2001; Munk et al., 1998). Students who have oral language deficits could contribute to a project on health by creating the visuals illustrating the classification of food eaten over a period of time into the food groups; students with written language deficits could orally present the results of the project to the class.

Using themes, which is often recommended in science instruction, can be a valuable approach for students with disabilities. The themes focusthe content on a few main ideas, and therefore it would not seem overwhelming for students with processing and memory problems. Since themes such as earth, energy, and human growth cut across several subject areas and also incorporate several topics within the fields of science, this approach can help students generalize, which is often a problem (Cawley, Poley, & Miller, 2003). In addition, themes can foster understanding through relationships to familiar concepts and personal experiences in the real world (Salend, 1998).

Another strategy to keep the content and nature of science from seeming overwhelming to students with special needs is to break down the material so they will not have to focus on too much information at one time (Alexakos, 2001). Because of the memory, organizational, and attention problems of students with mikl disabilities, this focus on only a small amount of material will enable learning to occur with more success and positive attitudes.

Science lessons, incorporating student activity and involvement, recommended in science standards, have many benefits for students with special needs. This type of lesson enables the teacher to modify the paee according to student ability, to teach generalization (Cawley el al., 2003) and to improve memory of content, behavior, and focus which are all potential problems for students with disabilities (Bianchi, 1999). Furthermore, research by Mastropieri and others (1998) supports activity-based science lessons for improvement in achievement and attitudes of students with disabilities.

TABLE 1. Suggestions for Teaching Science to Students With Learning Problems

Learning strategies are recommended fur teaching students with mild disabilities and can be used for science instruction. Mnemonics is one example of a popular learning strategy that can be incorporated into science lessons to assist with the memorization of factual information, lists, steps, and difficult vocabulary words (Munk et al., 1998). Learning strategies are beneficial because they encourage students with disabilities to be more independent. They learn to monitor their work and develop active learning styles critical for student with disabilities (Scanlon, 2002).

Because many students with special needs have oral or written language deficits, it is important to modify lessons with their language levels in mind when using lecture format and science textbooks. Vocabulary can be taught and clarified prior to the lesson and outlines or study guides can be used to keep students’ focus on main points (Munk et al., 1998).

Evaluation of student performance in science can also be modified for students with disabilities. In addition to traditional science tests, teachers could use projects, oral and written reports, problemsolving activities, and portfolios to evaluate student achievement and mastery of content (Salend, 1998).

Conclusion

These recommendations for effective science instruction for elementary students with mild disabilities are summarized in Table 1. They represent a collection of ideas to help students with disabilities achieve science objectives. Although science standards recommend problem-solving and high level thinking skills, some degree of structure and explicit instruction will help students succeed (Bianchi, 1999; Gersten & Baker, 1998). These ideas are critical for students with special needs but will also be valuable for many students without disabilities. Finally these suggestions can be adjusted for other areas of the curriculum to ensure success in all subjects.

REFERENCES

Alexakos, C. (2001). Inclusive classrooms. Science Teacher, 68(3), 40-43.

Bianchi, L. (1999). Less-able children’s learning in science. Printarv Science Review, 60, 20-22.

Cawley, J. K, Foley, T. E., & Miller, J. (2003). Science and students with mild disabilities. Intervention in School and Clinic, J. (3), 160-171.

Gersten, R., & Baker, S. (1998). Real world use of scientific concepts: Integrating situated cognition with explicit instruction. Exceptional Children, 65(1), 23-35.

Kirk, S. A.. Gallaghcr. J. J., & Anastasiow, N. J. (2003). Educating exceptional children. Boston: Houghton Mifflin.

Mastropieri, M. A., Scruggs, T. E., Mantzicopoulos, P., Slurgeon. A., Goodwill. I,., & Cluing, S. (1998). A place where living things affect and depend on each other: Qualitative and quantitative outcomes associated with inclusive science teaching. Science Education, 82(2), 163-179.

Munk, D. D., Bruckert, J., Call, D. T., Stoehrmann, T., & Radandt, E. (1998). Strategies for enhancing the performance of students with LD in inclusive science classes. Intervention in School & Clinic, 34(2), 73-78.

Olson, J. L., & Platt, J. C. (2004). Teaching children and adolescents with special needs. Upper Saddle River, NJ: Merrill.

Palincsar. A. M., Magnusson. S. J., Collins, K. M., & Culler, J. (2001). Making science accessible to all: Results of a design experiment in inclusive classrooms. Learning Disability Quarterly; 24(1), 15-32.

Raymond, E. B. (2000). Learners with Mild Disabilities. Boston: Allyn & Bacon.

Salend, S. J. (1998). Using an activities-based approach to teach science to students with disabilities. Intervention in School & Clinic, 34(2), 67-72.

Scanlon, D. (2002). PROVE-ing what you know: Using a learning strategy in an inclusive class. TEACHING Exceptional Children, 34(4), 50-54.

Marree M. Steele is a professor in the Watson School of Education at the University of North Carolina at Wilmington.

Copyright HELDREF PUBLICATIONS Fall 2004

Breaking in a Social Climber’s Guide to Palm Beach Society

Jump on the ladder!

First, a few affectations to leave behind – wherever it is you came from.

– Illustrative or dramatic speech

– A Roman numeral after your name

– An invented name with “von” or a “de la”

– Swagger

“Most of these people don’t deliver and therefore last a few seasons and are history,” says James Sheeran, astute social observer and editor and publisher of Palm Beach Society. “They work and network for their personal aggrandizement, not for the cause. And discovery comes soon!”

Do you have to be filthy rich?

Publicist Carey O’Donnell says no. “Cash is not necessarily king when

someone with social aspirations turns their sights on Palm Beach. Grace and style is what matters inside the inner social circles, especially those with a social ‘legacy.’ If you’re rich as well, you’re in, baby! But remember, social climbing at this altitude is a real, live game of snakes and ladders. Choose your rungs carefully!”

Socialite in training

– Don’t rely on accomplishments in a previous life

– Have a pet. “In Palm Beach, a cute little poodle is dearer to a woman’s heart than her husband,” Sheeran says.

– Volunteer (See page 3)

– Be understated. Dress well, but be traditional. Decolletage will get looks from leering husbands but nothing more.

– Create a plan for marketing yourself with immediate and next- year objectives, but not beyond because the plethora of new players seeking the limelight changes quickly.

– Get a mentor. Someone older and wiser in the ways of Palm Beach, someone who knows what makes a difference, what really counts. Plan on total immersion for three to six months. The ultimate mentors: Nancy Sexauer Walsh, Jean Tailer, Helen Persson and Pauline Pitt.

– Write lots of personal notes to your mentor on Cartier or Tiffany stationery.

How the ladies who lunch work it

– Join a group that supports a cultural organization such as Miami City Ballet’s Artist Circle ($1,500 a year, includes priority seating, access to invitation-only events and a pair of pointe shoes signed by a member of the company) or Young Friends of the Kravis ($85 single, $120 couple).

– Start small. “Propose simple ways to raise money – dinner with an Astaire movie, readings, cooking classes, all in a private home for $10 a person with pizza or hamburgers – for a charity. No show biz, no overhead, little publicity.” – Sheeran.

– Volunteer: Work toward a position on a charity ball committee.

– Support causes that have a good product and need help. “Cancer, Heart, Dana Farber, Bascom Palmer are all great but a newcomer has to bench warm before gaining rank…Non-profs such as Center for Creative Education, Armory Art Center and School of the Arts teach young people the basics of living a good life and facilitating themselves as life rolls out.” – Sheeran

GENTS ONLY

“Men provide the elbows for the Palm Beach women to hold onto,” Island observer Kit Reed, a contributor to Palm Beach Illustrated magazine, says.

– Palm Beach is a matriarchal society. Granted most of the money is made by the men, but the women decide how it’s spent.

– Dress well, at least as well as possible when you’re limited to a tuxedo, fuzzy shoes and no socks. (See page 5)

– Be able to dance. So many marriages have suffered because the husband would rather slouch in his chair.

Better yet, be a singer, a musician, an artist or a writer. “Capote and Tennessee Williams were not screaming rich, but they were able to write up their hosts and the hosts’ guests,” said writer Joella Cain. “Gigolos and hangers-on can’t do that.”

– Have a pilot’s license.

– Keep a stock of Cuban cigars.

THE DAPPER MAN

“In Palm Beach the tuxedo is the most important suit,” said Palm Beach real estate wiz Bob Gordon, who heads the local chapter of the Chaine des Rotisseurs dining society. “You need at least two and preferably three, plus shirts with studs and cufflinks. Otherwise, a couple of blazers, an assortment of pants, sport jackets, suits and so forth.”

Gordon can get a tux from his a Hong Kong tailor for about $1,200. Expect to spend $3,500 and up at local stores for name brands.

TIP: “The best place for a man to buy is at a jewelry store with his wife. If he sees a nice pair of women’s earrings, they’ll change them over to a pair of cufflinks. Because she’s looking for bigger and better, she can’t say anything.”

Be a good host

Begin by hosting luncheons – plan on $40 a head with beverages, tax and tip.

Then, graduate to cocktail parties with food and drink for 100. You’ll need to add:

– Valet parking – $500. Your new friends can’t be expected to park and walk. This ballpark figure from Don Ryks at Fred Furtado Valet Service covers four valets for 4 1/2 hours.

– Photography – $150 per hour. If you make it this far, you’ll want a few for the scrapbook. Coverage for the average party at Lucien Capehart Photography is about $400.

– Flowers. At VM flowers, prices for party flowers range from $50 to $50,000 depending upon the host and the event.

Five hors d’oeuvre faux pas

– Boring food. Don’t make everyone suffer your low-carb diet.

– Big food. Tray-passed foods must be bite sized.

– Double dipping.

– Returns. If you touch it, keep it.

– Slow drinks. Make guests feel comfortable fast by putting a drink in their hand immediately.

– The White Apron Catering

Only in Palm Beach . . .

With so many parties, the best hosts find a way to stand out.

“One woman with incredible taste, 50-ish, did a tacky party just to get a laugh out of her friends,” VM flower’s Duane Murrell said. “For her birthday party, she painted the walls in her house gold and put all her guests’ names and ages on the cake. Some were amused, some weren’t. Waiters wore gold lame, she had plastic flowers for centerpieces. It was so much fun because it wasn’t serious. But those who walked in and said how beautiful it was, were never invited back.”

The full kit and caboodle

GOWNS: Sami Alpark’s salon is a hot stop for ready-to-wear gowns.

“We have dresses that range from $3,000 for something more simple and basic to $15,000 for something beaded, with special touches. But $5,000 is the median price point for gowns women wear to the charity balls,” Alpark says.

“For the chairwoman or someone on a committee, the price resistance lowers. It’s almost expected of them. So they may go to $7,000.

“We’re talking 20-30 functions a year, just here,” Alpark said. “They’ve gone fashion wild.”

JEWELRY: The most fashion conscious women prefer an unadorned neckline. But, for the jewelry case of the woman who wants it all, Graff Jewelers, who supplied Donald Trump’s “12-carat natural D flawless” diamond for fiancee Melania Knauss, has just the thing.

“Sometimes they just come in and buy a set of earrings for $200,000 – diamond waterfalls – let’s say $250,000 just to be safe,” manager Craig Miller said. “We have some that start at $100,000, a simple pair, that would be great for an evening. They also usually like a rather large ring – could be up to 40 carats, traditionally a large white diamond.”

“Between clothes and jewelry, they spend a million a year, easily.”

– Sami Alpark

– $3,000 and up for gowns

– $200,000 for diamond drop earrings for evening

– $700 and up for shoes (Manolo Blahniks, of course)

Alpark’s best dressed (listed alphabetically, of course)

Kathy Bleznak

Audrey Gruss

Darlene Jordan

Dorothy Kohl

Anka Palitz

Pauline Pitt

Hot property

You’ll need a home to rest and relax in between parties.

$75 million: Ron Perelman’s South Ocean estate

$36 million: The sea-to-lake estate of troubled Canadian publisher Conrad Black

$22.9 million: Nuestro Paradiso with 150 feet of oceanfront was featured in Sinatra’s Tony Rome

Less than $2.5 million: Not much left at that price, brokers say.

But don’t despair. Remember: Grace and style trump cash. Repeat this to yourself as you commute back and forth across the bridge.

TIP: If you’re not dining in your own personal seaside villa, the only restaurant with real waterfront dining in Palm Beach is at the Flagler Museum where lunch – Gilded Age style – is served daily in the Whitehall Cafe. Lemonade or tea, tea sandwiches and sweets including scones with cranberries are $18 including tax and gratuity.

Details of a fab life

– If you have jewelry, fine furs and couture and don’t have a safe room or hermetically sealed storage vault at home, rent vault space at a private bank.

– Whatever car you have, keep it up. Few things are worse than a valet parker calling a tow truck because your battery went dead.

– Keep fit. Get a gym or spa membership. All that dancing is tough.

– Watch your diet. Don’t stand at the hors d’oeuvres table and skewer shrimp for half an hour.

– If you’re invited to a reception, cocktail party or dinner always R.S.V.P. (you’d be surprised how many don’t), and always follow up with a thank-you note. E-mails and phone calls are out. A token gift for the hostess is always a nice gesture.

– Keep your plastic surgeries straight. Restoration is a plus; augmentation is not.

– You will not be allowed to enter the B&T (That’s Bath and Tennis Club, silly) if you have a pierced eyebrow.

When your blood isn’t blue (and other minor scandals)

– A fine family lineage is important, but not mandatory. If you fake it, you’ll be found out. Which brings us to another point by social observer and writer Kit Reed: “Respect the existing hierarchy, the old-guard social order, no matter how arcane it may seem.”

And again, remember: Grace and style trump cash.

– If you aren’t what you say you are, or you mess up in other ways, you can rehabilitate yourself in Palm Beach.

If your wife catches you in bed with another woman or another man, you can make a comeback, if you are repentant and pay penance.

However, there is a double standard. Wives who are caught by their husbands usually have more trouble. “Men can get away with more here than women because there are fewer of them,” Reed says.

The top old-guard BALLS

Bal des Arts

Feb. 5, Norton Museum of Art, $1,000-$25,000, 227-1250

Cancer Ball

Feb. 4, The Breakers, $500, 655-3449

Discovery Ball

Dana-Farber Cancer Institute, Feb. 19, The Breakers, $650, 833- 2080

Heart Ball

Feb. 14, The Breakers, $750. This year is the 50th anniversary, 615-3888

International Red Cross Ball

Jan. 29, Mar-a-Lago Club, 650-9133

Preservation Foundation Gala

March 4, The Breakers. Sorry, this one is by invitation only.

Up-and-coming galas

Artists Ball

Jan. 8, Armory Art Center, $300, 832-1776

Guests wearing white serve as living canvases to be painted by artists

Diamond Constellation Ball for the South Florida Science Museum

Jan. 15, Mar-a-Lago Club, $550, 832-1988,

Ext. 236

Glitz 2004 for March of Dimes

Dec. 10, The Breakers, $300 adults,

$225 juniors, 684-0102

Florida Oxygen Ball

(Lung Association), March 13,

Mar-a-Lago Club, 659-7644

Night of Stars at The Kravis Center with Vanessa Williams

Dec. 16, $750, 651-4320

Sixty-five Roses Ball

Cystic Fibrosis Foundation, Jan. 8,

The Breakers, $500-up, 683-9965

Top charity events

– Andy Roddick Tennis Weekend featuring Anna Kournikova and other stars, Dec. 11-12, Polo Club in Boca Raton. Sold out. Maybe next year.

– Beautiful Table Settings: The Art of Fine Dining preview party,

March 3, Norton Museum of Art, $175, 832-5196

– Chris Evert/Bank of America Pro-Celebrity Tennis Classic & Gala, Dec. 3-5, Delray Beach Tennis Center and Boca Raton Resort and Club (gala), $500 gala, $20-$900 tournament. 394-2400

– Global Society Ball for Orbis International, Feb. 28, Flagler Museum, $350-$1,000. (Dina Merrill Hartley, honoree, music by Peter Duchin Orchestra). By invitation.

– Historical Society of Palm Beach County Archival Evening honoring Lilly Pulitzer, Dec. 2, Club Colette, $500, By invitation.

– Holiday Bazaar for New Hope Charities, Dec. 2, Sailfish Club, $150 or $200 at the door. 366-5093

Top charity events

– National Horse Show including Jumping Under the Stars, Nov. 30- Dec. 5, for dinner/dance 753-3389

– Studio 54 Party for Equestrian AIDS Foundation, Dec. 3, Palm Beach Equestrian Center, $2,500-$4,000 for the week

– “Spain in the Age of Exploration” Gala Premier for the Norton Museum of Art, Jan. 31, at the Norton, $5,000-$25,000

– Outback/Sidelines Equestrian Triathlon for Equestrian AIDS Foundation, Jan. 8, Palm Beach Equestrian Club in Wellington, $175 VIP seating, $10 general admission. (Competitors from polo, show jumping and dressage compete in all three disciplines.) 818-4502

– Palm Beach International Film Festival Grand Awards Gala, April 16,

Boca Raton Resort and Club, $1,000. 362-0003

– Palm Beach Opera Evening of Splendor with Placido Domingo, Feb. 27, Kravis Center, $1250 gala, concert $50-$125, 833-7888

– Red Cross Polo Luncheon, March 6, International Polo Club,

$200, 833-7711

– Swingtime Golf Tennis for the Tim & Tom Gullikson Foundation, Dec. 11-12, Ibis Golf & Country Club, Tennis $35-$55, Gala $200 ($150 if also buying tennis tickets) 394-9190

– Zegna Par-Tee and Jay Robert Lauer Golf Tournament for Hospice of the Palm Beaches, Dec. 10-11, The Breakers, $350 Par-Tee, $850 golf, Matt Lauer hosts, 642-6888

Me and My Health: Darcey Bussell

Darcey Bussell, 34, is a principal dancer with the Royal Ballet. She started dancing when she was five and joined the Royal Ballet School at 13. She lives in London with her husband and two children

Were you a healthy child?

I always had too much energy as a child so I suppose that that helps keep you healthy. I think I ate well – as a child I was a total cereal fanatic. Though equally I did live on tinned ravioli and fishfingers and mash, which are not really the healthiest of things.

Would you say that you are a healthy person?

I suppose I have been unconsciously healthy. I’ve never smoked and I don’t drink tea or coffee. I’ve also always eaten quite well – though there are of course horrible things like diet cola that that I sometimes feel I can’t live without.

Do you have to watch what you eat?

I haven’t a clue how many calories I eat a day. As a dancer, it is terribly important to eat a lot as you burn food off so quickly. People think that we’re so thin because we don’t eat, but it’s the exercise – a single performance can be three hours long. The only restriction on your eating is that you can’t eat too close to a show – being thrown around with a full stomach is not nice!

What raises your emotional blood pressure?

The only thing that really irritates me is people wasting time. When you have two children, you suddenly become very conscious that time is so precious.

How do you cope with stress?

On the night before a performance I will have a long hot bath with Epsom salts. Epsom salts are actually for constipation when you swallow them, but dancers bathe in them as they relax muscles brilliantly.

What are your favourite foods?

I love Italian food – so a really yummy bowl of Italian pasta, followed by a chocolate mousse is perfect for me. I do love chocolate!

Are you allowed to drink?

I do drink alcohol, though not in the week. I do love a glass of red – and I don’t think that is a bad thing. And I would never turn down a glass of champagne.

How did you cope with your pregnancy?

I performed for the first three months – I felt fine and they say if you feel all right just to go for it. After that I just took class, which is for an hour and a quarter every day. It was quite difficult going from such a hectic schedule to that. Luckily, when I was pregnant the second time we were doing up our house, so I was totally preoccupied with that. But I was at a bit of a loss.

Would you say that dancing is a healthy occupation?

No! I think it’s totally unnatural. The sort of lines that you must hold are extremely unnatural and ballet is very athletic and physical, so much more than it ever used to be. You are really pushing your body to the extreme. You will always have some ache or strain but because you put yourself through it so often you become a bit numb to it. Dancers actually have a very high pain threshold.

What’s in your medicine cabinet?

I have to say I am a fan of ibuprofen as it is an anti- inflammatory – though I would only really take it before I go to bed. I wouldn’t take it during the day as obviously it is a painkiller as well, so you can’t gauge what you are doing.

Do you use any alternative remedies?

I do believe in acupuncture and I always go to an osteopath. When I had an operation last year on my ankle to treat my bone spurs I used vitamin E oil to help the scarring.

Hottest 25 People of Orange County

Geoff Shively

These are heady times for computer Wunderkind Geoff Shively. At the tender age of 21, he has seen PivX Solutions – the company he founded in 1999 – become a prominent player in the field of software security. Its 2003 revenues surpassed $2 million, and its computer- protection services have been employed by business behemoths such as Microsoft, Boeing and Sony.

Further boosting the company’s cachet, Shively oversaw the late- summer launch of PivX’s first product, Qwik-Fix Pro, which earned positive reviews in computer publications.

And if that weren’t enough, he was one of a couple hundred high- tech experts in the U.S. invited to the National Cyber Security Summit, held at the end of last year in Santa Clara. The conference represented the first joint venture on software security between the government (the Department of Homeland Security) and the private sector. Shively, an amiable young man who grew up in Irvine and loves to surf, was tabbed to chair a 40-member subcommittee, whose recommendations for protection against cyber attacks were included in a report the conference participants submitted to President Bush in March.

All of this on the resume of a guy barely old enough to buy alcohol. “Sometimes I get caught up in it,” Shively admits with a chuckle. “I’m going out to lunch with congressmen, meeting with people running the country, billionaire businessmen, leaders from China.

“I have to put it all in perspective and say, ‘Wow, I’m 21. If I can accomplish this from 16 to 21, what am I going to do between 21 to 30?’ There’s the possibility that if I want to, I can make a difference.”

He’s always been someone who has stood out. The 6-foot-5 scientist could assemble a computer from parts at 13, was a rogue hacker as a teen-ager, and left Newport Harbor High School in his junior year to pursue his business goals.

Now he’s attaining them – with his dad, Rob Shively, as his corporate cohort. The older Shively is the CEO of PivX. Rob does the financials, Geoff does the science.

The precocious techie says he and the 35 employees of the Newport Beach company are intent on staunching the costly damage that malicious hackers create for businesses.

“Our goal -I almost want to call it a crusade – is to implement security measures that are long-lasting, and to create a technology that moves with the security needs (of companies with elaborate computer operations), because those needs will change. They change every day.”

-By Paul Sterman

RESIDENCE: Laguna Beach

WHAT HE DOES: Founder and chief scientist of PivX Solutions

FAMILY: Single

HOBBIES: Downhill skateboarding, photography

FAVORITE ENTERTAINER: Loves all genres of music – punk, rap, classical and blues

STEPHENE E. CARLEY

RESIDENCE: Los Angeles

WHAT HE DOES: CEO, El Polio Loco

FAMILY: Married, two boys

HOBBY: Fly-fishing

FAVORITE ENTERTAINER: Eric Clapton

Apparently, there is at least one more way to “do chicken right.” For Steve Carley, CEO of Irvine-based El Polio Loco, doing it right means more than just serving up good food. “El Polio Loco is successful because we have great people who are very passionate about what they do in the restaurants,” Carley says. “We also happen to have a fantastic product that has withstood the test of time and something that consumers continue to have indicated that they really, really appreciate.”

The head job at El Polio Loco came after many years of experience in the hospitality industry. During a 12-year stint at PepsiCo in the 1980s and ’90s, Carley rose to become vice president of development for Taco Bell. In 1996, Carley became the president and chief operating officer of Universal City Hollywood where he directed all components of the world’s No. 1 motion picture andTV- themed attraction. During his watch, Universal added the popular “Terminator 2,3-D” and the expansion of City walk.

Carley joined El Polio Loco in April 2001. In just three years under Carley, the chain has achieved record sales and is planning an aggressive expansion that includes 130 new restaurants in markets across the nation, including 10 in the Chicago area.

“When I came in, El Polio Loco had just been taken private after being the abused stepchild of the Denny’s Corp. I saw it as a great opportunity to take a fantastic brand with incredibly passionate people and bring discipline, planning, strategy and execution and take it across the country.

“From a consumer standpoint we know that we provide healthy food at a great value that our guests can customize to their own tastes in a clean environment with friendly people. The other secret about El Polio Loco is that it is a brand with tremendous attractiveness across ethnicities and demographics. We do as well in East LA. as we do in Santa Monica.

“We appeal to young people and yuppies, and we’re great with parents because our food provides their kids a guilt-free option. Surprisingly, we attract older folks who are not anywhere near the typical fast-food user.”

El Polio Loco’s format has fallen somewhere between the “fast” and “fast-casual” restaurant categories. Customers can order in the drive-thru or over the counter, where fresh food is delivered quickly. The stores also feature exhibition-style cooking, rare in either category. Carley calls it the “sweet spot.”

“The food is of a quality that is equal to or better than many sit-down competitors,” Carley says.

Exciting times await in the Windy City. “We’re taking a look at the research we’ve done in Chicago about the brand which indicates that people love the chicken. One of the reasons we know that is because we were at ‘A Taste of Chicago’ this year where we served thousands and thousands of people over the course of ten days.”

Why Chicago? Apparently it has nothing whatsoever to do with m the fact that Carley was born and raised on the city’s north side.

Carley’s formula for success is based on basic business principles. “I look at what’s happening with the consumer – with pricing and new products. Then I revert to operations -I like to look at competitive restaurants and see how they are doing. The third area is financial – the benchmarking areas.”

But even business principles are wrapped around the human factor. “It is a commitment to setting the highest standards of performance and attempting to achieve them.”

-By Steve Smith

Gregg Schwenk

If Gregg Schwenk were a screen hero, he’d be the Renaissance Man. Here’s a guy who’s an investment banker, an adjunct professor at Cal State Fullerton in the department of communications, and – in the role he’s best-known for – the executive director of the; Newport Beach Film Festival.

Actually, having the financial skills of an investment banker,can come in quite handy when you’re running a film festival, Such events don’t exactly generate rivers of revenue, and “the highly creative personality,” notes Schwenk, can sometimes view financial initiations as bothersome distractions.

Now in his sixth year of shepherding the festival, he has built solid foundation of financial supporters and sponsors, steadily the selection of films, raised the national profile and garnered growing media attention for the event.

This year more than 300 films from 40 countries were screened including some top-rate documentaries -and the 10-day festival drew more than 20,000 people. The opening night gala had all the excitement and glamour of a Hollywood premiere, including a red- carpet entrance with popping flashbulbs. In fact, a major Hollywood film did premiere before a packed theater draped in red velvet and filled with tuxedos and evening gowns. The film’s director and three of the stars were on hand to take bows.

The short-film format has become a particular area of interest for the festival. It screens more short films than any other feature- film festival in the U.S, according to Schenk, senior vice president at RSM EquiCo in Costa Mesa.

The fistival also spotlights Qrange County filmmakers, Southland film schools and OC filmmakers 18 and under. “One of our mandates is to make the arts accessible and open up the creative process to the greatest number of people.”

-By Paul Sterman

RESIDENCE; Newport Beach

WHAT HE DOES: Investment banker, professor and executive director of the Newport Beach Film Festival

FAMILY: Single

HOBBIES: Wine and travel

FAVORITE ENTERTAINERS: Frank Sinatra and Nora Jones

SHAUNA FLEMING

RESIDENCE: Orange

WHAT SHE DOES: High school student, troop support activist

FAMILY: Mother and father, Robbin and Mike; brother, Ryan, 10

HOBBIES: Basketball and theater

FAVORITE EMTERTAINER: MercyMe, a Christian band

When Shauna Fleming asked her father how many letters she should try to collect and send to the U.S. troops in Iraq, he playfully threw out a huge number: 1 million.

Well, dad has one determined daughter. Intent on meeting that goal, the 15-year-old has spearheaded a massive letter-writing campaign to American soldiers. And this month, about six months after she started the project, Shauna reached the mountaintop: The number of letters passed the 1 million mark.

“She worked really hard on this,” says Mike Fleming, who runs a skating rink and an entertainment center. “I never imagined anything to this extent… I’m just glad my daughter is someone who likes to take the initiative.”

Dubbing the project “A Million Thanks,” Shauna went to great lengths to get the word out, and she’s overseen a well-organized effort to gather and distribute the letters, which hav\e come in from all over the world. Her high school, Orange Lutheran in Orange, is her base of operations.

The letters she and others have written often have been the soldiers’ only lifeline to America. It’s been a much-valued outpouring of support and caring for the troops. Soldiers have e- mailed and called Shauna from Iraq to express their gratitude for the correspondence. And some write letters back, voicing those sentiments to Shauna.

“I get them a few times a week,” she says. “They’ll say, ‘You really have no idea what you’re doing for us – it makes such a difference. There’s so many times that if we lose a lot of men from our unit, it’s so hard to keep going, but if we read these letters, it boosts our morale.’ They feel that they’re fighting for the people writing these letters.”

Among the men who have established e-mail correspondence with Shauna is Everett Headley, a chaplain’s assistant serving in the Marine Corps, who was married just before he went to Iraq. In an e- mail message to OC METRO Magazine, the 21-year-old from Missoula, Mont., writes of the letters:

“It meant a lot for someone to take the time out of their day to remember us. It did impress me that someone as young as Shauna would take on something so big.”

To inform people about “A Million Thanks,” and let them know how they go about sending the letters, Shauna created a Website: aMillionThanks. org.

Sponsors, and donations included with letters sent to Shauna for distribution, have helped cover postage costs.

The letter-gathering effort continues, with the teen now urging people to send Christmas and holiday cards to the soldiers.

Shauna’s classmates (who showed up for Saturday mail-sorting parties), friends and family (including grandparents) all helped with the project.

But much of the operation’s success came down to her own dedication, which meant late nights working on the Web site, answering e-mails daily, setting up booths at summer fairs, figuring out logistical matters and doing as many media interviews – both local and national – as possible. On occasion, this meant rising at 4 a.m. to be interviewed on East Coast time for early-morning radio shows.

“It takes up a lot of time,” Shauna admits, “but the obstacles and problems can’t even compare to the rewards you get. That’s what you have to keep in mind when you start to feel tired.”

-By Paul Sterman

VAN TRAN

RESIDENCE: Garden Grove

WHAT HE DOES: Garden Grove city councilman, attorney, and candidate for the 68th district Assembly seat

FAMILY: Engaged to be married

HOBBY: Cigars

FAVORITE ENTERTAINER: John Wayne

It is, we are pleased to report, a story that is common in America: Immigrant lands in the United States with one foot nailed to the floor and one hand tied behind his back. Through hard work and the belief that this is indeed the land of opportunity, he makes good, establishing himself in a successful career before going into politics.

This year, Gov. Arnold Schwarzenegger is not the only immigrant to tell this tale. For voters and supporters in California’s 68th Assembly district, this is the year of Van Tran.

In the years leading up to the fall of Saigon in 1975, the city’s residents were sheltered from the tragedies of the war.

“We lived in a pretty insulated environment,” says Tran. “The war was somewhere else, not Saigon.” At the age of 10, Tran and his family fled, winding up in a refugee camp at Fort Chaffee, Ark. “I can confidently say [the Vietnamese refugees] are the newest pilgrims. My mom was a dentist in Saigon and we lost everything – we picked up and ran for our lives,” Tran says.

From Arkansas, the Trans moved to Grand Rapids, Mich., to be near their sponsors.

Arriving in America, Tran spoke only two words. “I knew OK’ and ‘Salem,’ which is GI slang for ‘everything is fine.'”

In 1980,Tran’s parents chose to move to California so his mother could resume her dental career in a state that had no restrictions on foreign practitioners who passed their mandated tests.

“My dad was a teacher in Michigan and we were living a middle- class life. One day they got all the kids together and said they were going to sell the house and move to California. It was a decision they made for mom. We sold our house in 10 days and drove to California in a rented U-Haul.”

Finally settled in America, Tran immersed himself in opportunities. “I was a poli sci major at UCI,” says Tran. “My friends were changing majors like they were changing socks but I stuck with political science. I didn’t see politics as a career but as a way to serve and contribute.”

A few years later, the political bug bit. “I worked for Bob Dornan from 1985-1987 in D.C. and in the district. I was 20 years old and that was my first paid political job. In 1988,1 worked for a year for Ed Royce.” In 2000, Tran won a seat on the Garden Grove City Council.

Tran now is running for the 68th district Assembly seat and is expected to win. The district is one of the state’s most diverse, with its 190,000 registered voters stretching from Anaheim to Balboa Island.

“The key issues in the district are transportation and affordable housing,” Tran says. “There should be a better infrastructure so roads and freeways are expanded to promote our productivity. Less time on the roads means more time working. This has an impact on our quality of life.

“There is a shortage of affordable housing for seniors. The baby boom generation is now the ‘gray generation’ and there is a desperate need for senior housing.”

Tran lives with both his Vietnamese roots and the unlimited possibilities of his adopted homeland. “I have no doubt that [through politics] I am giving back the fruits of what my family and I have received through the years.”

So would he support a Constitutional amendment to allow a foreign- born president? “I’ll leave that to Arnold. I don’t see myself as doing this forever. I want new challenges and want to explore myself professionally.”

-By Steve Smith

Alan E. ” Lanny” Ross

RESIDENCE: Irvine

WHAT HE DOES: President & CEO, Broadcom

FAMILY: Wife, Terri; four children and five granddaughters. Terri has two sons and one grandson.

HOBBIES: Target shooting, amateur radio call sign K7LAN, computing, golf and tennis.

For Lanny Ross, the decision to come out of semi-retirement to return to a full-time working position first as Broadcom’s COO, then its CEO, was not agonizing. “It is rare when I do not respond quickly to decision opportunities. I believe this decision was made in a board meeting and took around 30 seconds, because the need was obvious and I had the background to help out.”

At the time, Broadcom, once the shining star in the semiconductor universe, was hemorrhaging red ink: The company had lost more than $2.2 billion in 2002.

“There were no minuses in the decision, as I knew what had to be done and was aware of most of the dependencies,” he says.

It helped Ross that his wife, Terri, was not only from the semiconductor industry, but was supportive emotionally as well. At the time of his re-entry, Ross was battling a physical condition. “I was getting ready for a hip replacement one week before reporting. I have a world-class wife in Terri, who wanted me to follow my instincts with her total unconditional support, which is very mutual in our relationship.”

Ross makes it clear that while the company had financial challenges, they were not symptomatic of a basic failing in its operations. “It’s important to note that the $2.2 billion loss in 2002 was related to acquisition charges, and did not reflect the operational successes of Broadcom. That said, it was very clear that certain steps had to be taken to bring the company back to profitability.”

Ross’ actions proved successful and in March, the company posted its first profitable quarter in three years.

To achieve the goals, Ross reduced operating expenses and increased revenue; the result was profitability and positive cash flow. “We restructured the organization into four groups, each headed by an empowered group vice president deeply experienced in the applicable markets and technology. Revenue for 2003 was up more than 50 percent with 500 fewer people than we had in November 2002.”

Ross calls himself “A macro manager who provides clear, achievable targets accompanied by delegation of authority to execute at the highest level.

“This works only in the instance of mutual trust and confidence among team members. Forty-five years of experience helps give me the insight necessary to respond quickly to situations as they arise. I also have a deeply developed instinct for people, who they are, what they are and their potential.”

Ross understands that, in any industry, it is the people within an organization that make the difference between success and failure. “People continue to be any business’ major asset, and Broadcom has the highest personnel quality of any organization I have ever seen. It is truly remarkable. Our hiring standards are as lofty as are our results, a not so insignificant correlation. Another is execution excellence, an attribute instilled by our founders, Dr. Henry Nicholas and Dr. Henry Samueli. Their early standards of excellence remain an attribute of our [corporate] culture today.”

Looking to the future, Ross sees more changes. “Diversification is necessary for major scaling, so look for our internal growth to be supplemented by acquisition of technologies and product lines adjacent to our present portfolio.”

And will he be at Broadcom to lead the charge? “I will retire again within 12 months.”

-By Steve Smith

Mickey Mouse

RESIDENCE: Anaheim

WHAT HE DOES: World famous cartoon character

FAMILY: Girlfriend, Minnie, dog Pluto

HOBBY: Magic

FAVORITE ENTERTAINER: Walt Disney

It is hard to believe that Mickey Mouse, who started life in 1929 as Steamboat Willie, has reached the ripe old age of 75. But what will really make your head spin is mulling over just how much merriment – and money – Mickey has produced over the \past three- quarters of a century.

The diminutive mouse has long been a pop-culture giant -adored by children all over the world. He makes adults smile, too. Walt Disney himsefl provided the original high, squeaky voice for Mickey, and the cheery character embodies many of the qualities that marked Walt’s personality, says Marty Sklar, who wrote for Walt for 10 years.

“Walt was so optimistic and hopeful,” says Sklar, who now heads up the Imagineering department, the division that devises the rides and attractions at the Disney theme parks.

“He believed things would be better in the future – and he created Disneyland.”

Mickey has been a meal sicker for the Magic Kingdom – a signature character at the theme parks, star of numerous films, inspiration for the hugely popular TV show “The Mickey Mouse Club.” And don’t forget the mountains of merchandise this mouse moves every year for the Walt Disney Co.

According to Forbes magazine, Mickey Mouse merchandise generated $4.7 billion in sales in 2002, the latest year for which such statistics are available.

Sklar’s longtime friend and Disney colleague, John Hench – who painted the first official portrait of Mickey Mouse – had an interesting theory as to why the benevolent, big-eared creature has such universal and enduring appeal.

“Joe always said that it’s because Mickey was drawn in circles,” Sklar recalls. “Circles aren’t threatening; they represent innocence and happiness.” -By Paul Sterman

Mike McGee

RESIDENCE: Santa Ana

WHAT HE DOES: Cal State Fullerton Gallery director and co- founder of Grand Central Art Center

FAMILY: Lives with his girlfriend, Andrea, and her 4-year-old son Alex

HOBBIES: Weightlifting, running and reading

FAVORITE ENTERTAINERS: David Byrne and Leonard Cohen

As an artist, Mike McGee has learned to solve problems creatively. In 1993, he faced a tough one as gallery director at Cal State Fullerton: The university was short on studio space. Where would his graduate arts students set up their easels? Ironically, the perfect solution was another problem, one owned by the city of Santa Ana: a rundown, nearly abandoned building built in 1924, off 2nd Street and Broadway, 10 miles from campus. Formerly known as the Central Market of Orange County, this boarded-up embarrassment was a blight on the landscape, overrun by dereliction and disrepair.

“It was a scary place,” recalls McGee. “Policemen would ask me, ‘What are you doing here? Are you crazy?'”

Guided by the vision of Don Cribb, a community activist who masterminded the surrounding area now known as the Artists Village, McGee saw its potential. Together, they convinced the university and the city of Santa Ana that refurbishing this building was in everyone’s best interests. They were right. In 1999, after the city invested $8 million to buy and reconstruct the facility, the Grand Central Art Center emerged as the jewel of Cribb’s celebrated redevelopment project. Today, this 45,000-square-foot phoenix is a vital link to the community, alive with art students who live and work there, and buzzing with commerce and purposefulness again.

Though partly subsidized by the city and the university, Grand Central nearly pays for itself. “We put together a plan that made the center an economic engine that was self-sustaining,” says McGee, who divides his time between his role as Grand Central’s project facilitator and his faculty obligations at CSUF.

McGee’s novel plan that generates about $350,000 a year to pay for the bulk of Grand Central’s day-to-day operations consists of several components: 27 apartments subleased to CSUF graduate art students ($600-$700 a month in rent includes a separate work studio); the Gypsy Den restaurant and a printmaking studio subleased to outside operators; and shared profits from a university-managed theater, and a sales and rental gallery. “It’s bringing a new economy to this area, a sense of pride.”

Best of all, it’s re-inventing a community. Lured by the “birds of a feather” concept, other creative businesses that share in the vision of an artist enclave have flocked nearby: DGWB advertising agency, post-production houses, a theater company, restaurants and Orange County High School of the Arts. “I think the Artists Village will continue to attract that kind of element,” says McGee.

He may be onto something. For the first time ever, arts and entertainment passed the tech sector as the major economic sector in California. Forget the “poor, starving artist” stereotype. Art has become a real moneymaker, and there’s a growing demand for it. “Santa Ana is really fortunate to catch this wave,” McGee says. He believes the surge in arts-related jobs is due in large part to the image-driven Internet and video-gaming industry.

McGee is particularly proud of the center’s well-attended art shows and exhibitions. The center also runs an artistic outreach program with Santa Ana High School that encourages kids to go to college.

“The connections between people and a sense of community aren’t something we put a lot of emphasis on,” says McGee. “I think this project does that in a real positive way.”

The city of Santa Ana agrees. It recently extended Grand Central’s 10-year contract an additional 20 years.

-By Lynn Armitage

KELLY MONAHAN

Under the leadership of Kelly Monahan, BNC Mortgage has enjoyed a dramatic upswing in its financial fortunes. Check out the numbers:

In the early summer of 2000, just before Monahan led a management buyout of BNC and became the president and CEO of the company, BNC was producing approximately $80 million in loans each month.

Today the monthly total is $1 billion.

Pre-buyout, there were 300 employees. Now there are 1,100 – 400 in the Irvine headquarters alone. And the company keeps surging forward.

“The goal is $15 billion a year,” Monhana says.

BNC originates, purchases and sells nonconforming residential mortgage loans. An operating subdidiary of Lehman Brothers, the company is one of the nation’s largest wholesale subprime lenders.

The subprime industry is extemely competitive and the biggest players are here in Orange County, including Argent and Option One. Monahan, however, doesn’t seem daunted by the work ahead. He says he thrives on challenges.

At BNC, says the 47-year-old former C.P.A., business is flourishing, staff turnover is low, and the company has a corporate culture that is upbeat and supportive.

“I have the best job in the world.”

-By Paul Sterman

RESIDENCE: Aliso Viejo

WHAT HE DOES: President and CEO of BNC Mortgage

FAMILY: Married to Melissa, with three daughters: Lauren, 14, Meghan, 10, Kaylie, 8

HOBBIES: Wakeboarding and soccer

FAVORITE ENTERTAINER: Jack Nicholson

RICK WARREN

RESIDENCE: Trabuco Canyon

WHAT HE DOES: Founding pastor of Saddleback Church in Lake Forest and author of the best-selling hardback, nonfiction book in history, “The Purpose Driven Life”

FAMILY: Wife, Kay; sons Matt and Josh; daughter Amy and granddaughter Kaylie.

HOBBIES: Guitar, gardening, golf and anything outdoors

FAVORITE ENTERTAINER: Mel Gibson

When Rick Warren talks, people listen. They also respond to his call, which W W is why the founding pastor of Saddleback Church in Lake Forest is often referred to as “the most influential spiritual leader in America.” Who else, after all, could get 9,000 volunteers from “The OC” to make time in their schedules to collect, sort and distribute three meals a day for 40 days in order to feed Orange County’s 35,000 homeless people? This is just a small part of his recent emphasis – “40 Days of Community.”

Warren’s influence, though, extends far beyond the borders of Orange County. The spiritual entrepreneur, who advises presidents and world leaders, has founded several of America’s largest and best known ministries: Saddleback Church, where 23,000 people attend service each weekend; the Purpose Driven Network, which consists of 139,000 churches worldwide; and Pastors.com, the largest Website for ministers. He is also the author of the fastest-selling book in history, “The Purpose Driven Life,” which has already sold more than 20 million copies.

“No one has been more astounded by the massive acceptance of the book than I am. I’ve received tens of thousands of notes from national leaders, academic leaders, generals, entertainers, billionaire CEOs and sports celebrities,” he says. “But I’ve also heard from prisoners and peasants and average people all over the world. The message is having a global impact.”

Warren’s previous book, “The Purpose Driven Church,” published in 1995, was also a hit. Translated into 25 languages, it won the Gold Medallion Award and was named one of the 100 Christian books that changed the 20th Century. More than 350,000 pastors and church leaders from 120 countries have attended Purpose-Driven training seminars to date.

But despite Warren’s international influence, the essence and values of Saddleback Church remain the same. It is a safe haven for people who need help, hope and spiritual strength for life. The casual worship services have a refreshing honesty and openness about admitting shortcomings – “the hurts, habits and hang-ups that all of us struggle with,” says Warren.

Warren and his wife Kay both were 25 when they moved to south Orange County in January 1980 to start Saddleback Church in their condo with one other family. Today, one out of every nine residents in south Orange County attend each weekend.

Located on a 120-acre site (about the size of South Coast Plaza), Saddleback has an annual budget of $20 million-plus, 300 paid staff, more than 3,000 neighborhood small groups and 9,000 volunteers in ministry. As Forbes magazine noted, “If Warren’s church was a business it would be compared with Dell, Google or Starbucks.”

“I learn from the Bible, from my friendships with many effective CEOs and leaders, from my lifelong mentor Peter Drucker, and from experience. But God also gifted me with the ability to organize and lead,” he says. “The Bible is fi\lled with great insights for strategic thinking, planning, organizing, evaluating and leading. It contains thousands of years of leadership examples. I learn from everybody and everything, including critics. All leaders are learners. The moment you stop learning, you stop leading. Growing organizations require growing leaders.”

-By Sandy Bennett

Donald P. Kennedy

RESIDENCE: Santa Ana

WHAT HE DOES: Chairman emeritus, The First American Corp., and chairman emeritus, Bowers Museum

FAMILY: Wife, Dorthy; son, Parker S. Kennedy; two daughters, Elizabeth Myers and Amy Healey; and six grandchildren.

HOBBY: Golf

FAVORITE ENTERTAINER: Dean Martin

Don’t consider for a second that Donald P. Kennedy, who across 53 years has helped Santa Ana-based The First American Corp. become a leader in business information, products and services, has slowed up. Company president in 1963, chairman of the board in 1993 and chairman emeritus since 2003, Kennedy has now turned his energy to the Bowers Museum, one of the world’s great small museums.

And thanks to Kennedy’s business acumen and fund-raising savvy, the Bowers soon won’t be so little. The museum’s chairman emeritus – he served three years as chairman – has taken charge of the approximately $10 million planned expansion of the Bowers which, by June 2006, will double exhibition space to 100,000 square feet. The June 2005 groundbreaking of the North Wing will be the beginning of a 30,000-square-foot structure to include a 350-seat auditorium for lectures and presentations.

Over the past several years, the Bowers has secured some of the world’s great exhibits, being the first or one of the first to show them outside their country of origin. These include “Dead Sea Scrolls” (October 2001-January 2002); “Secret World of the Forbidden City” (February 2000-September 2000); “Gems! The Art and Nature of Precious Stones” (February 2002-February 2004); “Tibet: Treasures from the Roof of the World” (October 2003-September 2004); and “Queen of Sheba” (opened Oct. 17 and continues to March 13, 2005).

“I really feel so strongly that Orange County should stand alone, and that everything we do should be the best: Have the best private university, the best law school, the best museum, the best repertory theater,” says Kennedy, 85. “And we’re pretty near there.”

Kennedy has been instrumental in the museum’s latest coup – an exclusive agreement with the British Museum. The Bowers is the first museum ever to sign a long-term joint venture with the world-famous institution. The immediate results are the “Queen of Sheba” and the upcoming “Mummies!” exhibit (opens April 17, 2005).

The Bowers’ blockbuster exhibits also reflect the long-term work of museum President and Director Peter Keller and key volunteers such as Anne Shih and Ruth Seigle. Keller, who shared those trips to London with Kennedy, saw how a business giant helps ink an artistic deal. “He’s been a real mentor and teacher for me,” says Keller. “He knows what has to be done … and he can make it happen.”

The expansion of the Bowers, Kennedy believes, will be “the springboard for something else … a future move.”

Kennedy has reached out countywide. He is a major benefactor to Chapman University School of Law, where the law school building, Kennedy Hall, is named after him.

“You have to support activities in the county,” he says. “I was on the board at Chapman for a long time…and active in South Coast Repertory. And I’m on 3 or 4 boards now, stuff that I’m interested in. One thing it does, it keeps you busy.”

-By Craig Reem

MARC TAKEMIYA

RESIDENCE: Huntington Beach

WHAT HE DOES: Comedian, winner of the “Funniest Person in Orange County” contest

FAMILY: Single

HOBBIES: Tennis, writing, surfing and short walks on the beach

FAVORITE ENTERTAINERS: Brian Regan, Eddie Murphy, Dan Tosh

Marc Takemiya personifies the phrase “up and coming.” He also happens to be the winner of this year’s Orange County’s Funniest Person contest. The 25-year-old San Clemente native has participated in host Bill Word’s contest annually since its inception. True, the contest is – at three years – still in its infancy, but the fact that Takemiya has been one of the top two finalists every time has to mean something … right?

Yes. It means he’s truly a funny guy. Not the contextual, self- aware funny that pervades so many cookie-cutter sitcoms; not prop- reliant funny like Gallagher and Carrot Top; just an accessible guy who happens to have a great stage presence and a penchant for comedy. He proved just that on Sept 11 in the finate of a three- round contest at Martini Blues in Huntington Beach, competing alongside eight of Orange County’s funniest comics for a $800 purse and, more importantly, the chance to showcase his tatent for the crowd.

“I’ve been doing comedy for about three years now,” says Takemiya, who regularly participates in open mic nights. “My passion is doing stand-up. I perform three-to-five nights a week and some mornings as well.” As for this style: “I just get out there and tackle the stage.” Currently without representation, Takiemiya has no iliusions of grandeur, at least in the immediate sense. “I still consider myself to be somewhat of a beginner for the reason that one can always be funnier. The fonger we do it, the funnier we get. Someday whers I’m 97, I should be freakin’ hilariousl”

-By Matt Susson

CALEB SIEMON

RESIDENCE: Laguna Beach

WHAT HE DOES: Glassblower, one of People magazine’s “50 Sexiest Men Alive”

FAMILY: Married to Carmen Salazar

HOBBIES: Surfing and gardening

FAVORITE ENTERTAINER: Loves all kinds of music

Even before People magazine named him one of the “50 Sexiest Men Alive” last December, Caleb Siemon was gaining an increasing amount of exposure. Over the past few years, the young Laguna Beach resident has established a reputation as one of the finest in his artistic field of glassblowing. He creates translucent pieces with simple, graceful shapes and bands of vivid colors at his studio in Santa Ana – bowls, cylinders, vases – that sell for as much as $2,000 (though small pieces can begin at $100). His line of products (www.calebsiemon.com) is featured in more than 100 stores across the country – including Barney’s in New York.

Oh, yes, and then there’s that People magazine thing. The modest 29-year-old feels a bit awkward talking about it.

“It was embarrassing,” he says sheepishly.

Maybe it was the romantic image of the passionate artist that captivated People’s editors: the intense glassblower in sweat- soaked shirt glowing from the firelight given off by the 2,000- degree furnace he stands in front of for up to eight hours a day.

Yes, Caleb is definitely a hot guy.

But there will be no groupies for this glassblower: Siemon is happily married to Carmen Salazar, 29. Her response to the “50 Sexiest Men” tag?

“She just laughed,” says the good-natured Siemon.

His buddies had fun ribbing him about the honor.

Siemon has garnered quite a bit of national media attention, with stories in Elle, Vogue Hommes International, the Los Angeles Times, and fashion and style magazine Metro Pop.

He’s won praise for his strong glassblowing technique and visual touches, and orders from stores keep piling up.

“It’s nonstop,” says Siemon, who has five assistants working with him. “We can’t make pieces fast enough.”

His studio is located in a four-acre complex that also houses his father’s large jewelry-making facility. Bob Siemon is a well-known designer of faith- and inspirational-themed jewelry and other products, and it was watching his father work while growing up that inspired Caleb to make art.

Now the son is a rising art star whose work is in galleries and museums, and the father couldn’t be prouder. Bob will tell you how Caleb studied as an apprentice to Italian glassblower Pino Signore, considered perhaps the greatest in the world. And about the time Caleb went off to a prestigious art summer camp as a teen-ager and, having been introduced to glassblowing, returned home transformed to tell his dad that he wanted to be a glassblower instead of a jeweler.

Bob’s response?

“Go for it, dude.”

With that kind of support, Caleb has flourished. His father got a son in the special People issue, but he enjoys it more when Caleb gets recognition for making a great vase rather than for having a great face.

-By Paul Sterman

ANDREW J. POLICANO

RESIDENCE: Irvine

WHAT HE DOES: Dean of UC Irvine’s Graduate School of Management

FAMILY: Married to Pam; they each have two children college age or older

HOBBIES: Golf, travel, reading

FAVORSTE ENTERTAINER: Billy Joel

Last month, South Coast Repertory premiered “Brooklyn Boy,” a semi-autobiographical play by Donald Margulies about an anguished writer whose visit to the borough where he was born sparks painful conflicts even as his career takes off.

Among those in the audience on opening night was Andrew J. Policano, the theater buff from Brooklyn who is the new dean of UC Irvine’s Graduate School of Management. He loved the production.

Unlike Marguiles’ troubled artist, this Brooklyn boy appears to be a very happy man who has embarked on a thrilling new adventure.

The journey began this summer. The former dean of the University of Wisconsin-Madison School of Business, Policano was married in July. He and his wife, Pam, moved to Irvine, where Policano took the helm at the Graduate School of Management. So far, he reports, he’s thoroughly impressed with what he’s seen at the Irvine business school.

“There are very high-quality people here, a lot of very passionate people,” he says. “There’s great leadership, very good faculty and terrific students.”

And how does the 55-year-old economist like Orange County?

“What’s not to like?” he responds with a chuckle. “My wife and I love it here. Every day it’s beautiful.”

Policano disproves the stereotype that economists are dry, dull numbers guys: A lover of opera and Impressionist paintings, he also goes to Elton John and Rod Stewart con\certs – and grooves to the sounds of Prince, as well, who is one of his wife’s favorite entertainers.

And exactly how many business-school deans do you know that practice the art of calligraphy? Policano even used his elegant handiwork to address the couple’s wedding invitations.

After growing up in New York and attending college in the state university system there, Policano earned his master’s and P.h.D. in economics from Brown University. He was dean of the UW-Madison School of Business for 10 years, stepping down from the post in 2001 after having doubled the number of companies recruiting the school’s graduates.

One reason he’s so excited about being at UCI, Policano notes, is because of the high-flying business scene in the surrounding areas, where booming high-tech and financial companies are at the fulcrum of entrepreneurial development in the United States.

“I’ve already been meeting with very influential people in the business community,” says the dean, who taught in the finance department at Wisconsin.

His hope is that UCI’s Graduate School of Management can capitalize on this hometown, real-world resource by having its students – as part of their curriculum – get training and work experience at some of these thriving firms. In return, the companies will receive help from smart, talented, business-oriented people at zero cost to them.

“Everyone would gain from the situation,” says Policano.

The grad school chief will certainly have his share of challenges at UCI. While the business school is consistently ranked among the Top 50 in the country, its endowment is relatively small and it doesn’t have a deep alumni network to help raise the school’s profile or serve as a resource for students.

Policano doesn’t view these limitations as negatives. Rather, he sees them as “terrific opportunities,” fertile ground for growth as opposed to well-established ground where he’s not really needed to make an impact.

UCI officials are confidant Policano will indeed have a significant impact on the Graduate School of Management. They note that during his tenure as dean at Wisconsin, the business school’s endowment rose from $6 million to more than $95 million. Orange County expects big things from this Brooklyn boy.

-By Paul Sterman

LEFT TO RIGHT: JULES SWIMMER MARC COHEN TERRY ROTHBARD MARK SINGER

MARC COHEN

RESIDENCE: Mission Viejo

WHAT HE DOES: Executive chef and partner, 230 Forest Avenue, Opah Restaurant & Bar and Agave Mexican Grill and Cantina

FAMILY: Wife, Michelle, and three children: Jacob, 7, Sydney, 5 and Emma, 4

HOBBY: Baseball

FAVORITE ENTERTAINER: I don’t know…I work

MARK SINGER

RESIDENCE: Laguna Beach

WHAT HE DOES: Partner, project architect and interior designer for company restaurants, and renowned residential architect

FAMILY: Wife, Miriam, and two children, Ryan and Jessica

HOBBY: Builds custom furniture

FAVORITE ENTERTAINERS: Sade and Astrid Gilberto

TERRY ROTHBARD

RESIDENCE: Laguna Beach

WHAT SHE DOES: Managing partner for 230 Forest Avenue, Opah Restaurant & Bar and Agave Mexican Grill and Cantina

FAMILY: Husband, Richard, a psychiatrist and wine consultant; three grown children and two grandkids

HOBBY: Scuba diving

JULES SWIMMER

RESIDENCE: Corona del Mar

WHAT HE DOES: Partner, new-site negotiator, and business development

FAMILY: Wife, Diane, and six kids; two golden labs and a eat

HOBBIES: Tennis, sailing, real estate development

FAVORITE ENTERTAINER: Ray Charles

What’s the sure-fire recipe for a winning restaurant? The right mix of concept, cuisine and kismet.

Twelve years ago, Terry Rothbard, a resident of Laguna Beach, was in Washington D.C. for a medical convention with her husband, Richard. The Rothbards owned a psychiatric hospital. They had dinner at the Blue Point Grill in nearby Alexandria, Va … and that meal changed their lives forever.

“The food was incredible,” remembers Rothbard, who right then and there had an epiphany to open a restaurant back in Laguna with Blue Point Grill’s impressive chef (and perfect stranger), Marc Cohen, the youngest executive chef in the Washington D.C. area. Rothbard contacted her friend, Mark Singer, an architect who knows Laguna Beach intimately, and asked if he knew of any locations that could be converted into a restaurant.

Here’s the kismet part. “Mark said, ‘Terry, you’re not going to believe this, but I just got a restaurant site approved by the City Council. The lease is with Jules Swimmer. All we need is a chef and a managing partner.'” Terry is still awestruck by the quirk of fate that jump-started the foursome’s first restaurant venture, 230 Forest Avenue, in Laguna Beach.

“My only stipulation was that if I could prove that 230 Forest Avenue would do well after about two years, then I’d like to work on a conceptual restaurant that could be reproduced in Orange County,” says Cohen, who has frequently been named one of OC’s great chefs.

Over a decade and many daily specials later, this dynamic duo times two has made good on that original deal and now own four other hot restaurants in Orange County: Opah Restaurant & Bar in Aliso Viejo, Rancho Santa Margarita and Irvine; and Agave Mexican Grill and Cantina in Rancho Santa Margarita – their newest concept restaurant launched this past July.

Dining establishments come and go, but this team has found a formula that sticks: creative, trendy food at reasonable prices in the heart of suburbia. Location has been the key.

Their first concept restaurant was Opah in Aliso Viejo, named after a 400-pound Hawaiian moonfish. “In Hawaii, Opah was once given away as a gesture of goodwill to people in the community,” Cohen says. By sharing the big fish, the fisherman ensured continued good luck with other catches. It has certainly worked that way for the four partners, who have opened two other, successful Opah restaurants in the past few years.

“Our goal with Opah is to bring more exotic ingredients to neighborhoods…mahi mahi, shitake mushrooms and dayboat scallops – which I’ll bet you can’t find anywhere else in Aliso Viejo,” asserts Cohen.

“We demand excellent work, from the cooks down to the servers (330 employees total), and Marc monitors every piece of fish that comes into the restaurant,” explains Rothbard.

Cohen whips up his specialties at all five restaurants each day, about 50 miles back and forth. He starts work at 6:30 a.m. and doesn’t stop hustling until midnight, seven days a week.

“And we’re all still married!” Rothbard jokes.

There’s talk of opening even more restaurants within a year. “We’d rather be running a million miles a minute than slowing down.”

-By Lynn Armitage

MISTY MAY

THE ORANGE COUNTY OLYMPIANS

Imagine that. Had Orange County been a country, it would have ranked 11th in total medals (29) in the world, with 23 of 41 athletes connected to OC coming home with gold, silver or bronze.

While swimmers and water polo players dominated local lists, there was no more embraceable pair than the gold medallists in beach Volleyball, Kerri Walsh and Costa Mesa’s Misty May (On the cover and above). And there may not have been a better team at the Athens Games than the American softball team, which won gold, thanks in part to four county residents. And there was no team with a more storied history than the women’s gold-medal soccer team that included Julie Foudy of Mission Viejo and Joy Fawcett of Foothill Ranch. Here is a breakdown of awards and the cities to which the local athletes are connected:

Swimming: Amanda Beard, Irvine, gold in the 200 breaststroke and silver in the 200 IM and the 4×100 medley relay.

Aaron Peirsol, Irvine, gold in the 100 backstroke, 200 backstroke and 4×100 medley relay.

Larsen Jensen, Mission Viejo, silver in the 1,500 freestyle.

Lenny Krayzelburg, Irvine, gold in the 4×100 medley relay.

Colleen Lanne, Aliso Viejo, silver in the 4×100 freestyle relay.

Jason Lezak, Irvine, gold in the 4×100 medley relay and bronze in the 100 freestyle.

Kaitlin Sandeno, Irvine, gold in 4×200 freestyle relay, silver in 400 IM, and bronze in 400 freestyle.

Gabe Woodward, Aliso Viejo, bronze in 4×100 freestyle relay.

Water Polo: The bronze to the women who included Robin Beauregard of Huntington Beach, Jackie Frank of Seal Beach, Natalie Golda of Fullerton, Heather Moody of Anaheim, Amber Stachowski of Rancho Santa Margarita, and Nicolle Payne of Seal Beach.

Softball: The gold to the women who included Amanda Freed of Cypress, Lori Harrigan of Anaheim, Lovieanne Jung of Fountain Valley, and Natasha Watley of Irvine.

Beach Volleyball: Misty May, Costa Mesa, gold. Elaine Youngs, Lake Forest, bronze.

Cycling: Erin Mirabella, La Habra, bronze.

Soccer: The gold to the women who included Joy Fawcett of Foothill Ranch and Julie Foudy of Mission Viejo.

-By Craig Reem

SERRAGLIO

RESIDENCE: Irvine

WHAT HE DOES: Director of sales and marketing for high-rise condo builder Bosa Development

FAMILY: Married to Michelle; two children: Jeremy, 14, and Stephanie, 8

HOBBIES: Squash, golf, cooking

FAVORITE ENTERTAINER: Larry David (“Curb Your Enthusiasm”)

Dennis Serraglio is the marketing man who helped sell homebuyers on the high-rise.

Not that he needed to do much persuading.

Vancouver-based Bosa Development, for whom Serraglio is director of sales and marketing, is building two 18-story towers of luxury condominiums in Irvine – one of the first high-rise residential projects in Orange County. County residents – and, in particular, danizens of Irvine, the quintessential planned community – have never seen the likes of such soaring homes. Before now, going vertical in OC has seemed verboten.

But while some dread such development in Irvine, any notion that prospective condo buyers would stay away from the Bosa project has been proven resoundingly wrong.

St was back in June when Bosa broke ground on the towers – called Marquee at Park Place, near the intersection of the 405 freeway and Jamboree Road – and by She end of September all 232 “condominium suites” were so\ld, reports Serraglio.

The sell-out of Park Place is just one more sign of a nationwide homesales boom. Residential builders have more work than they know what to do with, as peoples clamor for new homes in OC. The trouble is, the county is running out of available land.

There is nowhere to go but up, as Bosa is well aware. Thus, the two towers.

“The market is very deep,” Serraglio says of the demand for housing in this area. “We could sell up two more towers very quickly.”

And these are not cheap places we’re talking about here. The announced prices in the summer for Park Place unite ranged from an approximate starting price of $525,000 for a two-bedroom, 1,275- square-foot unit to $735,000 for a two-level, two-bedroom unit with a den, to $1.48 million for a penthouse unit And Serraglio says the prices have gone up “10 to 15 percent” since then.

He maintains lifestyle choices were a key reason why people bought the Irvine condos. “The demographics just demand that sort of project – nice, big, viable units. “The project is fully amenitized; it’s got a 24-hour concierge, pools, a spa, a weight room, everything people are looking for.”

-By Paul Sterman

Diedrich Coffee

There is something instructive about the choices that Diedrich Coffee, Inc. executives make when they order at one of their own coffeehouses. CEO Roger “Rocky” Laverty picks a medium Toffee Crunch, a cool, summery specialty drink that works on this dry Newport Beach day. Founder and namesake Martin Diedrich chooses a small drip-roast Kenya.

The Orange County-raised and-based company has made a remarkable financial recovery in the past year, moving into the black for the first time in several years after a bold expansion fizzled and the company limped back to its roots. In the fiscal year that ended June 2004, the publicly traded company earned $266,000 on revenue of $54.625 million. That is nothing to retire on, but it is a huge improvement from a net loss of $1.223 million for fiscal year 2003. The biggest part of the turnaround occurred in fourth quarter 2004, with net income of $92,000 compared to a net loss of $1.7 million for the same quarter in 2003.

The company has 482 retail outlets worldwide, including 23 Diedrich locations (19 in Orange County). The remaining stores are divided between Diedrich’s Gloria Jean’s and Coffee People brands. Diedrich is the No. 2 specialty coffeehouse company, behind -far behind – industry behemoth Starbucks, which has 8,000 coffeehouses in more than 30 countries.

During the past year, Diedrich has turned this seeming disadvantage into an advantage, making fun of itself while also saluting its business model with this clever ad pitch: “Diedrich, not so big.”

“We believe that we have an opportunity to develop and grow a specialty coffee concept that is unique – that has higher-quality products and local customer service with a community atmosphere,” Laverty says. “We have no intention to become a worldwide brand.”

But there is room, he believes, in the Southern California market to add numerous Diedrich coffeehouses. “There is a real advantage to not being huge like Starbucks, both in terms of developing a consistent culture among our employees and customers, and in being able to ensure the consistency of our product.” During the next year, the company plans to open five Diedrich stores in Orange County; 25 Gloria Jean’s domestically; and about 100 Gloria Jean’s worldwide.

Says Laverty: “The bigger and more successful Starbucks gets, the greater the opportunity for us to really grab hold of the solid No. 2 position.”

Both executives are appreciative of the Starbucks influence, which prompts people to drink specialty coffee. “Every advertising dollar they spend,” says Diedrich, “grows the pie for everybody else. They bring consumers … to a more refined approach to coffee.”

That, too, is the Diedrich model, with brands from across the world splashed inside every store: Columbia, Costa Rica, Ethiopia – a Brazil estate exclusive has been a big hit in the past several months. The company pushes its motto of “selling the world’s highest quality coffees.”

Laverty, a former Smart & Final CEO hired in April 2003, gets credit for refocusing the company and earning the profit that has recycled into the renovation of 17 Diedrich stores in the past year. But the rebound is more than new chairs and counters. Even in the dark days, the product was always first-rate, he says. So the company rebuilt its structure without ever having to recast its coffee.

DIEDRICH CEO ROGER “ROCKY” LAVERTY

The company has a fascinating history. Martin Diedrich’s grandmother, Charlotte, inherited a coffee plantation in 1916 in Costa Rica. Her son, Carl, German-born, joined the business in 1946 by studying the art and craft of roasting. He and his wife, Inga, purchased a coffee plantation in Antigua, Guatemala in 1966. By 1972 they were selling their beans in Orange County. In 1983, Martin Diedrich founded the company; the first coffeehouse still stands in Costa Mesa.

-By Craig Reem

VIVIAN M. DICKERSON MD.

RESIDENCE: Orange

WHAT SHE DOES: Medical doctor, professor and president of the American College of Obstetricians and Gynecologists

FAMILY: Single; 24-year-old son working on Ph.D. in neuroscience

HOBBIES: Hiking, skiing and scuba diving

FAVORITE ENTERTAINER: Judy Garland

A long-time champion of women’s health issues, Dr. Vivian Dickerson is in the right place at the right time to impact the state of women’s health in this country. In May of this year she was sworn in, in front of thousands of her peers, as the 55th president of the American College of Obstetricians and Gynecologists (ACOG), based in Washington, D.C.

Dickerson, a resident of Orange, is an associate professor of obstetrics and gynecology at UC Irvine and director of the division of general obstetrics and gynecology at the UCI Medical Center. With all her accomplishments, Dickerson still considers herself a late bloomer.

“Most kids in medical school knew they wanted to go into medicine since they were young,” Dickerson says. Not young Vivian. “As a response to the horrible stuff that went on in the Vietnam war, I joined the Peace Corps and was sent to Africa. I started working with women, many of whom were pregnant, and discovered this was what I wanted to do.”

A political science and music major in college, Dickerson returned to school to prepare for the new direction her life had taken. Interestingly, it was a comment during her medical school interview that may have predicted her future. “At age 29,” Dickerson recalls, “I was asked, ‘Why should we accept you over some young buck when you’ll be positively menopausal by the time you graduate?'” Now, a specialist in menopause, she is director of UCI’s Post Reproductive Women’s Integrative Health Center and a nationally known expert on the subject.

In her role as president of ACOG, Dickerson has presented her 10- point Women’s Bill of Rights. Among them: Freedom from discrimination based on gender, age, race, or ethnicity. “I’ve always felt it was important for women to be represented. At that time [during her med school interview], there were almost no women in obstetrics and gynecology.” Now, she says, women are the majority of those in residency, but gender disparity is clear in the top ranks. Dickerson is just the third female president of ACOG and the American Medical Association has had only one female at the helm.

A true torchbearer for women’s health issues, Dickerson says, “I’ve had a lifelong love of advocating for people not adequately represented.” As she leads the charge in her new role, more women surely will benefit.

-By Kimberly Porrazzo

Linda Spilker

RESIDENCE: Monrovia

WHAT SHE DOES: Cassini (Saturn exploration vehicle) deputy project scientist

FAMILY: Married with two daughters and one stepdaughter, all in college

HOBBIES: Hiking and traveling, especially to New Zealand

FAVORITE ENTERTAINERS: Tom Hanks and Billy Joel

It all started with Santa Claus. Had he not delivered a telescope to a curious, nine-year-old girl from Yorba Linda in 1964, planet like Saturn might still be just a galactic mystery. Linda Spilker has always set her sights high: on the stars, you might say. The little girl with the telescope is now known as the ringmaster, an expert on the majestic rings that surround Saturn and an integral part of NASA’s team. As deputy project scientist for the Cassini project, the U.S. mission to Saturn, Spilker is part of the team that successfully placed a spacecraft into Saturn’s orbit last June.

Spilker remembers reading the “Golden Book of Astronomy” as a child and being fascinated with the planets and the solar system.

“When I was in first grade and the Mercury astronauts were in space, they stopped what we were doing in the classroom so we could listen to the news coverage” she says. That was the spark that ignited Spilker’s passion for the cosmos and launched visions of becoming an astronaut, “I was interested in space because of time I grew up in”, she says. “I was totally fascinated with Neil Armstrong walking on the moon in 1969 when I was 14 years old.”

Though she excelled in her advanced math and science courses in high school, her guidance counselor discouraged her from pursuing her passion, saying that she was heading into a field that not many women choose. “It was a very nontraditional field for women at that time,” Spilker admits, but she adds that both her parents and her teahers were very supportive. As an undergraduate at Cal State Fullerton, she earned her degree in physics, began to research meteorites and was soon hired to work on the Voyager mission. For 13 years she studied data sent back to Earth from Saturn, Uranus and Neptune, reveling in conducting the research she loved so much. Realizing that in order to pursue her own research she’d need an advanced degree, she earned a Ph.D. in geophysics and space physics at UCLA.

Spilker’s work helped pa\ved the way for the exciting strides that are being made in space travel today, with launches like the recent SpacShipOne, which will – accroding to its project leaders – enable civilians to soon enjoy space travel. And she’s not done yet.

“NASA’s long-range goals are to find earth-size planets around neighboring stars.” That may be 10 to 20 years away, but Spilker doesn’t mind the wait. “I like the feeling of exploration and discovery,” she says.

-By Kimberly Porrazzo

Jacqueline Chattopadhyay

RESIDENCE: Irvine

WHAT SHE DOES: Fourth-year student at UC Irvine recently named one of Glamour magazine’s Top 10 College Women of the Year

FAMILY: Single

HOBBY: Dance

FAVORITE ENTERTASNER: Conan O’Brien

As Jacqueline Chattopadhyay thumbed through an issue of Glamour magazine when she was 14 years old, she was inspired by the young women who were highlighted for their leadership, work in community service and academic success. Today, the fourth-year UC Irvine student serves as an inspiration to others. This month, she was one of Glamour’s Top 10 College Women of the Year, chosen out of 500 applicants from across the country.

The 21-year-old, who holds honors majors in both political science and economics, was recognized for founding Students- Mentoring-Students at UCI. The outreach program helps disadvantaged high school students at Estancia High School in Costa Mesa to become competitive college applicants.

“I’ve always been interested in the topic of racial and ethnic minorities being able to have equal access to college,” she says. “I guess that partly comes from the fact that my parents come from two different cultures. I grew up very tuned in to the idea that one’s background does in many cases shape your opportunities and your social interactions.”

Chattopadhyay, whose says that “college has been the most important thing” in her life, works with a team of 12 UCI undergraduate students. Together, they assist students who have been identified as good college applicants, but who are unlikely to attend because of a number of barriers, such as language, finances and legal issues. Though workshops, such as one on how to write a personal statement, the team’s goal is to guide the students through the process.

“During my own time in high school, I found out that a lot of people were taking SAT prep courses or hiring private college counselors to usher them through the entire process, from standardized tests to applications, personal statements and so forth,” Chattopadhyay says. “And I really didn’t like the fact that these kinds of programs were almost making college admission a pay- for-place system. I think that admission should be based on merit, not how much you can pay to boost your SAT score.”

Earlier this year, Chattopadhyay won a Donald A. Strauss Scholarship to continue expanding the program. She also has received the prestigious Harry S. Truman Scholarship, which recognizes individuals who are interested in bringing change to the community.

The Irvine resident, who will graduate in June, plans on pursing her education by attending graduate or law school. After that, she says, “I think I’d love to work as a speechwriter for a politician or work in a think tank. At some point, I might like to run for elected office, probably starting at the city council level, maybe going to state Assembly.”

-By Sandy Bennett

GEORGE KURTZ

RESIDENCE:

DIET & SLIMMING: Face Facts.. How Kate Looks Great ; BODYWORKS

GLOWING with health and slimmer than ever, Kate Winslet has mastered a healthy approach to the post-pregnancy shape-up.

The actress once famed for her curvy size 16 figure dropped four stone after first child Mia’s arrival, and just 10 months after giving birth to son Joe, she’s a svelte size 10.

Her trim figure is down to a special Facial Analysis detox diet created by nutritionist Elizabeth Gibaud. The diet is based on eating the right food types for the shape of your face.

Here Elizabeth – who has also treated Cherie Blair, former Spice Girl Mel C and TV presenter Emma Forbes – shows how to follow the eating plan.

“I look for colours, lines and textures in the face that indicate what foods might be causing problems and which vitamins and minerals are lacking in the diet,” says Elizabeth. “Paleness, puffiness or markings on the face can reveal the state of your internal organs. But I can’t do anything with a person who’s had botox – a lot of information comes from expressions and lines in the face.”

A trained naturopath, Elizabeth’s method is based on ancient Oriental traditions as well as her own experience over 30 years. She says: “If you don’t water a plant it goes very many colours before it dies – yellow, brown and then black. And it’s the same with our bodies when they lack the fluid and minerals they need to be healthy.

“I recommend people try to get all their nutrients through a diet of fresh organic food, but if you live in a city you should take supplements because a lot of the goodness in food is destroyed by pollution.”

WHAT THE DIET DOES

ELIZABETH’S diet plans are individually tailored to her patients’ needs and face types, but all start with a strict two-day detox plan where all alcohol and processed foods are avoided. This is followed by the two-week core diet to cleanse the body. Based on the slimmer’s face type, the plan eliminates “irritating” foods and replaces them with “soothing” alternatives. Elizabeth then prescribes daily supplements. Here is a brief description of the six face types and sample foods to cut out:

TYPE A: Ruled by the thyroid gland. Dry skin, shiny nose, dull, fluffy hair, bulging eyes, cold hands and feet.

Foods to avoid: Yeast products, chocolate, red wine, white flour, mango.

Foods to eat: Apples, aspar-agus, oats, potatoes, cucumber.

TYPE B: Ruled by the liver. Yellow hue to skin, especially around the mouth, blue-ish or reddish nose, thick, furry tongue, red ears. Sufferers experience lack of motivation and concentration, and nausea.

Avoid: Alcohol, coffee, bananas, curry, oranges.

Eat: Apricots, garlic, potatoes, limes, cherries.

TYPE C: Suffers water retention. Bloated face, puffiness beneath the eyes, vertical line or groove under tip of nose, swollen ankles or fingers, lack of concentration.

Avoid: Canned fruit, cheese, peanuts, red meat, soy sauce.

Eat: Broccoli, fresh fish, onions, pineapples, spinach.

TYPE D: Prone to inflammation. Greasy forehead, nose and chin, large, open pores or very tight pores, sagging cheeks, horizontal lines across the forehead, smelly feet.

Avoid: Alcohol, mayonnaise, pastry, shellfish, rice.

Eat: Asparagus, turnips, berries, carrots, millet.

TYPE E: Prone to skin complaints.

Avoid: Beer, eggs, raisins, strawberries, watermelon.

Eat: Butter, cabbage, parsley, apples, oats.

TYPE F: This type only applies to men and is ruled by the prostate. Red forehead and top of ear, dark rings under the eyes, horizontal crease above the top lip, furred tongue.

Avoid: Aubergine, blue cheese, red wine, vinegar, sweet potato.

Eat: Courgette, lentils, peach, watercress, grapefruit.

THE TOP TIPS

-ALWAYS choose brown over white when it comes to pasta, rice or bread. Elizabeth says: “Pasta is just white flour and water – the stuff we used to make glue in school. Brown or buckwheat versions are always more nutritious.”

-TRY to stick to traditional British staples like oats and potatoes if you are prone to bloating. “Rice and pasta are recent additions to our diet and some people have trouble digesting them.”

-CHOOSE unsalted butter over margarine or other low-fat spreads and opt for jam sweetened in its own juice. “Butter is a fresh and natural product while other spreads contain all sorts of dyes and additives. Many sugar-free jams also contain artificial sweeteners which pollute the body.”

-DRINK plenty of water throughout the day. “If you’re thirsty, you’re already dehydrated and your body can’t function properly.”

-TAKE a break. Get plenty of fresh air by getting out into the parks or countryside and don’t take on more than you can handle. “Health is the most important thing we have and it has to be our priority.”

-DON’T drink any alcohol and stay off caffeine during the plan – both tea and coffee can cause headaches, water retention, anxiety and insomnia while alcohol contributes to dehydration.

For more information on Facial Analysis and your face type, see The Facial Analysis Diet by Elizabeth Gibaud, pounds 6.99 (Random House). Or contact her clinic on 020 7486 3486. Mineral salt supplements available from www.nutricentre.com.

DIET & SLIMMING: Face Facts.. How Kate Looks Great ; BODYWORKS

GLOWING with health and slimmer than ever, Kate Winslet has mastered a healthy approach to the post-pregnancy shape-up.

The actress once famed for her curvy size 16 figure dropped four stone after first child Mia’s arrival, and just 10 months after giving birth to son Joe, she’s a svelte size 10.

Her trim figure is down to a special Facial Analysis detox diet created by nutritionist Elizabeth Gibaud. The diet is based on eating the right food types for the shape of your face.

Here Elizabeth – who has also treated Cherie Blair, former Spice Girl Mel C and TV presenter Emma Forbes – shows how to follow the eating plan.

“I look for colours, lines and textures in the face that indicate what foods might be causing problems and which vitamins and minerals are lacking in the diet,” says Elizabeth. “Paleness, puffiness or markings on the face can reveal the state of your internal organs. But I can’t do anything with a person who’s had botox – a lot of information comes from expressions and lines in the face.”

A trained naturopath, Elizabeth’s method is based on ancient Oriental traditions as well as her own experience over 30 years. She says: “If you don’t water a plant it goes very many colours before it dies – yellow, brown and then black. And it’s the same with our bodies when they lack the fluid and minerals they need to be healthy.

“I recommend people try to get all their nutrients through a diet of fresh organic food, but if you live in a city you should take supplements because a lot of the goodness in food is destroyed by pollution.”

WHAT THE DIET DOES

ELIZABETH’S diet plans are individually tailored to her patients’ needs and face types, but all start with a strict two-day detox plan where all alcohol and processed foods are avoided. This is followed by the two-week core diet to cleanse the body. Based on the slimmer’s face type, the plan eliminates “irritating” foods and replaces them with “soothing” alternatives. Elizabeth then prescribes daily supplements. Here is a brief description of the six face types and sample foods to cut out:

TYPE A: Ruled by the thyroid gland. Dry skin, shiny nose, dull, fluffy hair, bulging eyes, cold hands and feet.

Foods to avoid: Yeast products, chocolate, red wine, white flour, mango.

Foods to eat: Apples, aspar-agus, oats, potatoes, cucumber.

TYPE B: Ruled by the liver. Yellow hue to skin, especially around the mouth, blue-ish or reddish nose, thick, furry tongue, red ears. Sufferers experience lack of motivation and concentration, and nausea.

Avoid: Alcohol, coffee, bananas, curry, oranges.

Eat: Apricots, garlic, potatoes, limes, cherries.

TYPE C: Suffers water retention. Bloated face, puffiness beneath the eyes, vertical line or groove under tip of nose, swollen ankles or fingers, lack of concentration.

Avoid: Canned fruit, cheese, peanuts, red meat, soy sauce.

Eat: Broccoli, fresh fish, onions, pineapples, spinach.

TYPE D: Prone to inflammation. Greasy forehead, nose and chin, large, open pores or very tight pores, sagging cheeks, horizontal lines across the forehead, smelly feet.

Avoid: Alcohol, mayonnaise, pastry, shellfish, rice.

Eat: Asparagus, turnips, berries, carrots, millet.

TYPE E: Prone to skin complaints.

Avoid: Beer, eggs, raisins, strawberries, watermelon.

Eat: Butter, cabbage, parsley, apples, oats.

TYPE F: This type only applies to men and is ruled by the prostate. Red forehead and top of ear, dark rings under the eyes, horizontal crease above the top lip, furred tongue.

Avoid: Aubergine, blue cheese, red wine, vinegar, sweet potato.

Eat: Courgette, lentils, peach, watercress, grapefruit.

THE TOP TIPS

-ALWAYS choose brown over white when it comes to pasta, rice or bread. Elizabeth says: “Pasta is just white flour and water – the stuff we used to make glue in school. Brown or buckwheat versions are always more nutritious.”

-TRY to stick to traditional British staples like oats and potatoes if you are prone to bloating. “Rice and pasta are recent additions to our diet and some people have trouble digesting them.”

-CHOOSE unsalted butter over margarine or other low-fat spreads and opt for jam sweetened in its own juice. “Butter is a fresh and natural product while other spreads contain all sorts of dyes and additives. Many sugar-free jams also contain artificial sweeteners which pollute the body.”

-DRINK plenty of water throughout the day. “If you’re thirsty, you’re already dehydrated and your body can’t function properly.”

-TAKE a break. Get plenty of fresh air by getting out into the parks or countryside and don’t take on more than you can handle. “Health is the most important thing we have and it has to be our priority.”

-DON’T drink any alcohol and stay off caffeine during the plan – both tea and coffee can cause headaches, water retention, anxiety and insomnia while alcohol contributes to dehydration.

For more information on Facial Analysis and your face type, see The Facial Analysis Diet by Elizabeth Gibaud, pounds 6.99 (Random House). Or contact her clinic on 020 7486 3486. Mineral salt supplements available from www.nutricentre.com.

Compounding for Sports Medicine

To the sore itself a compress, anointed with white cerate, will be sufficient, for if a piece of flesh or nerve [tendon?] become black, it will fall off . . .

Hippocrates

On Fractures, Part 27: The Treatment of Sores; 400 BC.

The potential for injury is embedded in athletic competition. Today’s amateur and professional athletes, however, are pampered in comparison to competitors in many ancient sports. Underhanded tactics in the early Olympics were often considered part of the game. In boxing matches, gouging with all fingers was permitted. Boxers wrapped their hands with leather thongs that caused painful wheals to develop on opponents struck during competition. In competitive pankration, a violent combination of boxing and wrestling, kicking and strangling were allowed, and breaking an opponent’s fingers was a common first move.1

Treating sports-related injuries has challenged physicians since antiquity, but today’s compounding pharmacists offer new therapies that can minimize tissue damage and ensure a rapid return to fitness. Some formulations can be used before exercise or competition to ready the body for increased physical stress. Other preparations can be applied shortly after injury to enhance healing.

Sports trainers, physicians and compounding pharmacists have unique perspectives on sports injuries but a common goal: healing the injured athlete. Danny Poole, MEd, ATC, is the director of sports medicine and head athletic trainer at Clemson University in Clemson, South Carolina. Austin Gore, PharmD, and William Wills, RPh, are compounding pharmacists whose specialties include sports medicine preparations. Patrick Knost, MD, is a physician skilled in the treatment of sports injuries, including those sustained in extreme-sports competition. In this article, these experts explain their use of compounds in treating amateur and professional athletes- and weekend warriors as well.

The Trainer’s Perspective

A staff member of the Clemson athletic department for more than 20 years, Danny Poole now oversees 18 intercollegiate sports programs for men and women, including football, volleyball, basketball, swimming, soccer, baseball, golf, tennis and track. Approximately 550 students who range in age from 18 to 22 years participate in Clemson sports.

As a certified athletic trainer, Poole has a three-fold responsibility: first, to prevent injuries from occurring; then, if they do occur, to intervene with immediate first aid to prevent injury-related complications; and, finally, to rehabilitate the athlete to pre-injury fitness level and a quick return to competition. Poole works closely with coaches and an onsite team physician who prescribes either compounded or commercially prepared medications and oversees therapy as healing progresses. “Many factors are involved in preventing and treating sports injuries,” Poole said. “We handle almost all the medical needs of our student athletes. We ensure that protective sports equipment fits correctly and that the athlete has the proper equipment before competition begins. For example, the correct type of brace can prevent injury to the knees or ankles during practice. We try to cover all the bases, literally; the practice area must be carefully surveyed before use. Holes in a football field must be filled and devices like sprinkler heads must be removed before practice or a game. Accidents do occur, though, and treating sports injuries is a big part of the professional life of every athletic trainer.”

Sports medicine staff are often the first responders to medical emergencies that occur during competition, and prompt treatment is essential. “We see two types of sports injuries,” said Poole. “Chronic overuse injuries are caused by repetitive stress and/or improper style. Acute injuries are caused by traumatic contact during competition. The type of injury varies with the sport. Swimmers and baseball players most often sustain overuse injuries such as tendinitis or muscle inflammation, or they experience pain caused by mechanically improper style. Acute injuries like sprains, strains or fractures are common in those who participate in a contact-collision sport like football; they can injure anything from their head to their toes. Muscle strain and tendinitis often occur in athletes who participate in track. Soft-tissue injuries are very common in all sports, and skin problems like cuts, rashes or abrasions can afflict any athlete.”

Over the years, Poole has found that certain compounded topicals applied immediately after injury are especially effective in minimizing soft-tissue damage. “Nothing available over the counter comes close to the effectiveness of compounds,” he said. “They are prescription-based medications prepared specifically for the injured patient.” About half the medications he uses to treat sports injuries are compounded, and he keeps a supply of various preparations on hand. Because a compound must be used within a specified period of time, he always verifies that each medication has not expired before it is applied. “We often use a topical compound as a second-line treatment for chronic injury when therapy with ice, muscle stimulation, ultrasound or moist-heat packs has failed. If an injury is severe, we might follow up with iontophoresis or phonophoresis to convey a compounded anti- inflammatory drug, acetic acid (which reduces scar tissue) or lidocaine in a special cream or gel base to injured tissue.”

The Medicine Chest

Poole keeps the following compounds handy to treat injured Clemson athletes. The schedule for application and the duration of treatment vary from patient to patient.

* Ketoprofen 10%, 15% or 20% in Pluronic lecithin organogel (PLO) to treat sprains, strains and inflammation. A pea-sized amount of the PLO gel is rubbed with a moist fingertip into the skin three to four times daily. An aqueous solution of that drug can also be administered by iontophoresis, or the medication can be prepared as an ultrasound gel for use in phonophoresis.

* Dexamethasone 0.4% in an aqueous solution for iontophoresis to treat sprains, strains and inflammation. That concentration of dexamethasone can also be prepared in PLO for application immediately after a sports-related injury to minimize inflammation. In those cases, a pea-sized amount of the gel is rubbed with a moist fingertip into the skin.

* Acetic acid 2% or 4% in an aqueous solution administered by iontophoresis to reduce scar tissue.

* A combination of baclofen 5%, lidocaine 10% and guaifenesin 10% or 20% in PLO to prevent muscle cramps.

* Lidocaine 4%, epinephrine (adrenalin) 0.05% and tetracaine 0.5% (LAT) in a spray or hydroxyethylcellulose gel to treat cuts and abrasions. This preparation is applied immediately after injury.

* Muscle relaxants such as guaifenesin (usually 10% or 20%) in PLO or cyclobenzaprine 0.5%, 1% or 2% in PLO. The mechanism of action of those drugs determines which is selected to treat muscle strain. Cyclobenzaprine in PLO is administered topically or by ultrasound, and guaifenesin in PLO is applied topically three to four times daily until relief is noted.

“Compounds definitely have a place in the treatment of the injured college athlete,” said Poole. “The customized topicals that we use for sports injuries are not commercially available. Athletic trainers should work with a compounding pharmacist and a physician to devise treatments for the injuries their athletes usually sustain. They should also keep an adequate supply of those medications on hand for immediate use or long-term therapy. It is our goal to put athletes back into their field of play as safely and quickly as possible, and compounding pharmacists can often help. They can provide us with therapeutic tools to restore the injured athlete to pre-injury fitness.”

The Compounded Viewpoint

Austin Gore, PharmD, CGP, is a certified geriatrics pharmacist, a clinical pharmacist and the owner of Clinical Specialties Compounding Pharmacy in Augusta, Georgia. He is also the compounder who provides most of the customized topicals for injured Clemson athletes. “Clinical Specialties is a compounding-only pharmacy with a wide range of services,” said Gore. “Our patients range in age from 8 weeks to 98 years, and among them are Danny Poole’s students. But many of the injuries that occur during sports competition (sprains, muscle inflammation, contusions) also afflict nonathletes.

“Sports medicine today has a broad definition. It’s not just about athletes any more; it’s also about the average individual, the patient in rehabilitation and the weekend warrior. For example, the gels and creams used to treat sports injuries can be used by podiatric or orthopedic patients, people undergoing physical therapy, individuals who have everyday aches and pains and arthritis sufferers.” Gore always works with a physician who provides a prescription for the compounds prepared. “My goal is to enhance the practice of sports medicine by the trainer, the physician or the physical therapist to improve outcome. Compounding often provides more and better treatment options for doing so.”

Gore’s most often requested sports medications are topical gels that are not available commercially. “Topical medications convey the drug directly to the site of injury and produce minimal adverse effects,” he said. “Some of the most effective topicals we prepare contain combinations of various a\nti-inflammatories or corticosteroids such as ketoprofen, dexamethasone, diclofenac, indomethacin, naproxen sodium, lidocaine or magnesium sulfate plus methylsulfonylmethane (MSM) in PLO or Lipoderm. Many of these preparations are very effective as a pregame rub and are popular remedies for the weekend warrior’s anticipated overuse injuries.

“LAT gel, which can be used to minimize bleeding from scrapes and cuts, is frequently requested. When the cuts begin to heal, we prepare our ‘special blend’ (a cream that accelerates the healing process) for our patients.” Gore has applied for a patent on that preparation, which is very promising as a wound-care treatment.

Also popular is an electrolyte-balancing preparation that contains a combination of potassium chloride, sodium chloride, magnesium and calcium carbonate. It is available in capsules or as a powder that must be mixed with a liquid, and the formulation can be adjusted to meet athletes’ specific rehydration needs. Unlike some commercially available electrolyte products and supplements that may be unregulated in content, the concentration of ingredients in the compound is carefully monitored by the compounding pharmacist. “We also prepare capsules of magnesium glycinate, which reduces postgame stiffness and soreness and promotes restful sleep,” said Gore. “The compounds requested most frequently for sports-related trauma, though, are those used to treat soft-tissue injuries: dexamethasone 0.4% or ketoprofen 10% in cither PLO or in an aqueous solution for use in iontophoresis, ketoprofen 10% or 20% solid anhydrous, diclofenac 10% solid anhydrous or indomethacin 10% or 20% solid anhydrous. To treat calcifications, we prepare an aqueous solution of acetic acid 4% for administration by iontophoresis.”

Gore is now researching the half-life of various nonsteroidal anti-inflammatory drugs (NSAIDs) to determine whether better, safer topical formulations could reduce the number of doses administered daily. “I like to think outside the box,” he said. “For example, topical ketoprofen is often applied three or four times daily by student athletes or patients, but oral NSAlDs like oxaprozin can be compounded in a PLO gel for once-daily topical use. That preparation is not commercially available but could be very effective and safe in treating soft-tissue injuries.

“We’re also investigating the stability and efficacy of naproxen sodium for use in iontophoresis,” Gore said. “The space left in the vial containing naproxen sodium must be blanketed with sterile nitrogen gas. Because I don’t have access to sterile nitrogen gas, we have dispensed that medication in unit-dose packages that contain no dead space.”

Gore has been very successful in building the sports-medicine component of his compounding practice. He has done so by creating relationships with his clients and with local physicians, athletic trainers and physical therapists. “If you want to market the sports medicine component of your practice,” he said, “identify and contact the doctors who treat high school or college athletes. Local colleges or universities usually have a variety of athletic programs, and the athletic trainers there can often use your help. Contact local orthopedic and family practice physicians, and get to know your patients.

“Remember that sports medicine preparations can also be helpful to the nonathlete. Patients who are recovering from knee replacement or are undergoing rehabilitation can, in my opinion, recover faster when a compounded topical medication is applied to the surgical site. Almost every patient that pharmacists see has some aches and pains that would respond to a customized sports preparation. Your intervention can prepare the way for your visit to those patients’ healthcare professionals to share information about other useful compounds.”

Patrick M. Knost, MD, is a family medicine physician with expertise in diverse specialties: sports medicine, wilderness medicine, travel medicine and the treatment of andropause. In solo private practice in Placerville, California, he is also a nationally renowned lecturer on men’s health and bioidentical hormone replacement. Dr. Knost has long been a participant in extreme sports and martial arts competitions and provides medical care for athletes in a variety of national and international sports events. He has also served as a medical committee member of the USA National Karate- do Federation (USA-NKF) and as an attending physician at the international 2000 TreK competition. Sports medicine remains his special interest. “I enjoy working with people who want to recover,” he said, “and most injured athletes are highly motivated to return to their pre-injury functional level.” Suturing, taping and gluing are often required onsite for more severe competition-related injuries such as open nasal fractures and transient paralysis. Common lesser trauma includes sprains, muscle inflammation and abrasions.

Dr. Knost has found that topical compounds can be very effective in the treatment of sports-related soft-tissue injuries. “I often use a compound of aloe vera, lidocaine and bupivacaine to treat abrasions,” he said. “The lidocaine and bupivacaine are regional infiltrative anesthetics. The aloe, which has antibiotic properties, also acts as an antiprostaglandin to reduce inflammation, soothe injured tissue, and promote healing.”

Knost’s prescription of choice for treating the scrapes and soft- tissue injuries sustained during competition is ketoprofen 20% in penetration-enhancing vehicles. “In sports medicine, compounded ketoprofen cream is incredibly effective,” he said. “It provides immediate relief, and it’s very safe-I don’t know what I’d do without it. It’s an excellent treatment for contusions, sprains (especially twisted knees), strains, insect bites and crush injuries. I often give my injured patients a 10-mL syringe filled with the cream for later application. I’ve also prescribed it for patients who have trochanteric bursitis, which often afflicts weekend warriors or those who have just started an exercise program. It provides relief from tennis elbow in 10 minutes, and it’s a great treatment for osteoarthritis of the fingers. Compounds like this cream provide my patients with effective treatments that aren’t available commercially.”

For additional information on the treatment of sprains, strains and abrasions, contact Patrick M. Knost, MD, 1106 Corker Street, Placerville, CA 95667. E-mail: [email protected]

William R. Wills is the owner of Grandpa’s Compounding Pharmacy in Placerville, California. He prepares ketoprofen 20% cream and other formulations for Dr. Patrick Knost and a host of other physicians who treat sports- and work-related injuries. “Compounds provide practitioners with a greater variety of treatment options,” said Wills. “Every sports medicine chest should be equipped with a compounded topical anti-inflammatory like ketoprofen 20% cream for use as a pregame rub or a treatment for sprains and strains. Guaifenesin 20%, a muscle relaxant, can be added to the ketoprofen cream or used as the sole ingredient in a cream base to relieve muscle tightness in seconds. Bruises, scrapes, cuts, abrasions and other injuries (including open wounds) can be treated with a topical preparation containing vitamins B5 and B6 in PLO. That preparation has anti-infective properties, inhibits bleeding, provides analgesia without anesthesia and promotes rapid healing. It causes the worst bruises to resolve within 4 days and heals blisters very rapidly.

“Athletes do have health problems other than injuries,” Wills notes. “For refractory athlete’s foot, we can compound an anti- fungal, antibacterial ‘foot bomb’ containing a customized combination of ketoconazole, miconazole, clotrimazole, terbinafine, ibuprofen, nystatin and/or tea tree oil in Dermabase.

“Because they convey prescribed drugs immediately to targeted tissues, topical compounds are very effective in treating injuries and chronic pain. Most of those medications are not available commercially. There are no contraindications to their use, and they produce no adverse effects. We can use them to treat and resolve many sports-related injuries without causing more problems for our patients.”

For additional information on the treatment of sprains, strains and abrasions, contact William R. Wills, HPh, Grandpa’s Compounding Pharmacy, 7563 Green Valley Road, Placerville, CA 95667-3917. E- mail: [email protected]

Reference

1. Kuntz T. The guy who ate a cow and other Olympic stars. New York Times. [New York Times Website.] July 14, 1996. Available at: http://www.nytimes.com/specials/olympics/cntdown/ 0714oly- review.html. Accessed April 26, 2004.

Jane Vail

St. Louis, Missouri

Address correspondence to: Danny Poole, MEd, ATC, PO Box 31, Clemson, SC 29633. E-mail: [email protected]; or Austin Gore, PharmD, Clinical Specialties Compounding Pharmacy, 3708-A Executive Center Drive, Augusta, GA 30907. E-mail: [email protected]; Website: www.clinicalrx.net

Copyright International Journal of Pharmaceutical Compounding Nov/ Dec 2004

Body Talk: Boy or Girl? Tell-Tale Signs That Reveal a Baby’s Sex

OK, so a scan’s the most foolproof method of finding out the sex of your unborn baby. But there are plenty of other signs that can indicate whether you’re likely to have a girl or a boy.

And we’re not talking about old wives’ tales here. Modern scientific research has unearthed some surprising clues as to who might be hiding under that bump.

IT’S (PROBABLY) A BOY IF…

You have an assertive, aggressive,

bold or dominant personality

Research by Dr Valerie Grant at Auckland University in New Zealand reveals that women who see themselves as having “masculine” traits are more likely to have boys.

This may be because their levels of testosterone are higher than those in other women, which in turn might make the environment of the womb more receptive to implantation of male embryos than female ones.

Want to know your personality profile? Visit www.sexratio.com and take Dr Grant’s test to find out.

You’re always hungry

Women expecting boys eat about 10 per cent more than those expecting girls, according to recent research from Harvard School of Public Health.

The study’s author, Dimitrios Trichopoulos, believes it’s because boys tend to weigh more than girls when they are born so the mother’s appetite naturally adapts to help them take on more fuel.

You ate lots of bananas before you conceived

If your diet is rich in high-potassium food such as bananas or pears you are more likely to conceive a boy.

A study in the International Journal Of Obstetrics And Gynaecology reveals that the body becomes more alkaline if you eat this way.

And some experts claim this is a better environment for sperm that is carrying the male Y chromosomes, increasing the chance that one of these will reach the egg first.

You have a tricky labour

OK, it’s leaving it a little late and when you’re in labour the last thing you’d be looking for are any clues as to what colour to paint the nursery. But there is still an interesting link between boy babies and tough births.

Irish researcher Dr Maeve Eogan found that women who had boys at the National Maternity Hospital in Dublin were more likely to have had a longer labour or to need help such as forceps or a caesarean – mainly because boys have bigger heads.

IT’S (PROBABLY) A GIRL IF…

You’re dreaming it is

Sleep on this one… Dr Janet DiPietro at the Johns Hopkins School of Public Health in Baltimore found that 75 per cent of mums correctly predicted the sex of their unborn baby in their dreams.

Your asthma is as bad as ever

Dr Peter Gibson, from the John Hunter Hospital in Newcastle, Australia, found that 60 per cent of asthmatics carrying boys were symptom-free during pregnancy, compared to only 28 per cent carrying girls.

“We don’t know why, but it’s possible that baby girls produce a substance that somehow worsens inflammation in the airways,” says Dr Gibson.

You got pregnant between

March and May

This is the peak conception time for girls – boys are more commonly conceived from September to November. The seasonal difference might be because girls are hardier babies and can survive the winter better, says Dr Angelo Cagnacci from the Policlinico of Modena, Italy.

You or your partner smoke

Smokers are 20 per cent more likely to have girls than boys.

“Sperm cells carrying the Y chromosome are more sensitive to unfavourable changes caused by smoking, so are less likely to fertilise and implant an egg,” says Professor Anne Grete Byskov from the Laboratory of Reproductive Biology in Copenhagen.

Your partner is older than you

Couples where the woman is younger have more girls than those where she’s older. Why isn’t known.

You’ve gained weight on

your hips and thighs

Dr DiPietro found no evidence to support the old theory that “boy” bumps look like basketballs and “girl” bumps are more spread across the tummy, but she did find a difference in where you put on weight.

Carrying a girl causes a mum-to-be to put more weight on her hips and thighs. This may be because oestrogen levels in the body are raised and this promotes fat storage in these particular areas.

Collaboration and Independent Practice: Ongoing Issues for Nursing

Inter-professional collaboration and independent practice: Why these issues are important

During the twentieth century, the nursing profession has undergone immense change. Nursing has progressed from an occupation to a fully licensed profession, with members that provide a broad range of services independently, and in a variety of professional relationships with other providers. This evolution has changed how nurses are educated, clinically prepared, and how they perceive their role. Starting with turn-of-the-century debates concerning the appropriateness of professional nursing practice, registered nurses began assessing not only their licensure status, but their roles related to other professionals.(1, 2)

In the early years of the nursing profession, it was generally believed that nurses served and cared for their patients by assisting physicians. However, the perception of nursing often varied dramatically from its practice. During wars and times of crises, nurses worked with and beside physicians conducting surgical procedures, diagnosing care, and prescribing treatments and drugs. These practices were documented as occurring in the U.S. as early as the Civil War. The role of the public health nurse, as it developed earlier in this century, was often independent, with nurses working with families of patients with tuberculosis or other highly contagious diseases and providing a broad range of interventions, both health- and socially-focused.

Intrinsic to nursing is the collaborative process: nurses and physicians working together and independently assessing, diagnosing, and caring for consumers by preparing patient histories, conducting physical and psychosocial assessments, and reviewing and discussing their cases with other health professionals to determine the hanging health status of each client. Yet the products of these fruitful relationships and work structures were discounted due to state regulation of health care and the additional need to define relationships and responsibilities in statute.

Nurses and physicians have understood the importance of this overlap in scopes, practices, and patient care, yet there is little literature and virtually no legislation that clearly provides a balanced accounting of the benefits of this working relationship. This article describes the regulatory and professional history of collaboration and nursing practice and explains the distinctions in state law related to collaborative practice. This article also provides a historical basis for review of collaboration and incorporates a survey on case law and collaborative practice.

DISCUSSION

History of Collaboration

As noted by Safriet (1992) and Hadley (1989), early nurse practice acts were generally constructed around their medical counterparts and were written to avoid conflict in professional practice. In the context of professional regulation, nursing scopes were structured to include narrowly defined independent functions and to mandate a dependent or complementary role for nurses.(3) Physicians, as the first category of health care providers to gain licensure, attempted to incorporate all aspects of diagnosis and treatment into the definition of medical practice.(4) Nurses, recognizing the limitations created by early medical practice acts, attempted to write around the physician-imposed limitations to create a nursing scope of practice. At that time, the medical profession was virtually all male and nursing almost all female; divisions and attitudes toward and between the two professions often reflected these gender differences. The debate about regulation was limited to elected officials and regulators who, at that time, were almost exclusively male, and who brought a male perspective to regulation. Nursing continued its thoughtful and deliberative studies and discussions on regulation and licensure, but their ideas and recommendations were then interpreted by male legislators and lawyers when incorporated into statute. Not fully understanding the concerns of nurses, legislators and regulators continued to perpetuate a model of health regulation that confined nurses to a largely complementary role in providing health services.(5) Although nurses made diagnoses and recommended care, and often noted inappropriate diagnosis or medication errors, the role of the nurse as an equal partner in the assessment and evaluation process was neither emphasized nor acknowledged outside of the clinical setting.

With the evolution of nursing practice and the expansion of professional certification and specialty practice, the nursing profession tried to expand and redefine nursing practice to reflect actual practice, and not the restrictive regulatory model. Both professionals and regulators attempted to reshape and restructure the basic premises of nursing practice. However, regulators often felt that a distinct disadvantage existed in the regulatory process, which was compounded by the limited authority generally delegated by the legislature to Boards of Nursing (BON). Some BONs did not even have the authority to issue declaratory opinions interpreting the nurse practice act. Thus, any interpretations offered by the boards were considered advisory and given limited weight within the administrative regulatory process. It was feared that should another board question the advisory interpretation and conduct full administrative adjudicatory hearings on the issues and render a decision, courts might find the second opinions more instructive on nursing practice than the advisory opinion of the BON. For these reasons, nurses in emerging specialty practice often did not challenge their legal scopes and roles, but instead worked in the practice setting to establish new professional boundaries and roles.

Collaboration and Advanced Practice

During the 1960s, nurses revisited the issue of collaboration with the evolution of advanced nursing practice. Once again, the evolution of the profession exceeded the bounds of the legislated nursing scope of practice. Although Advanced Practice Nurses (APNs) were trained to practice independently and to diagnose drugs, therapies, and devices, few nurse practice acts created an independent scope of nursing practice. In states where the practice act did create an independent scope of nursing practice, regulators were fearful of moving toward independent authorization of APNs. When questions arose about the scope of nursing practice, physicians and others often used the language incorporated in nursing or medical practice acts to limit the evolution of nursing practice.(6) Referring to medical practice acts or other licensing language that uses the terms “medical diagnosis” or “delegated medical acts,” Boards of Medicine (BOM) often intimated that nurses might be practicing medicine without a license. Many state BONs, as well as BOMs, often believed that much of the requisite authority needed for advanced practice could only be derived by physician delegation of medical practices.

Instead of directly challenging this interpretation of regulatory policy, nurses used the existing dichotomy in professional and regulated practices to emphasize the expansion of the role and responsibility of the nurse in the professional setting. When legislation was introduced, APNs testified about their actual practice setting structure, the responsibilities given to them by supervising physicians, and their ability to provide care independently, often in under-served areas. Emphasizing the realities of nursing roles, education, and how nurses collaborate with physicians and other professionals, nurses began to see an emerging legislative trend involving the incorporation of collaboration into statutory definitions of practice. To a large extent, this trend reflected a compromise that emerged in the face of organized physician opposition to the expansion of nursing practice. However, inasmuch as it also reflected current practice arrangements for many nurses, it was often a compromise that nurses were willing to accept if it included official recognition of their expanding roles. As different legislation was enacted in one state, and then another, each state developed its own approach to collaborative practice.

Concerns about Statutory Requirements for Collaboration

Nurses have always practiced in collaboration with other professionals-with physicians, pharmacists, other nurses, social workers, and a wide variety of health care practitioners. Arguably more than any other category of health care professional, nurses have understood that good patient care depends on the contributions and interactions of various providers. Moreover, in the late 1990s, health care is increasingly being provided in large, complex systems of care in which no provider works in isolation. Even physicians, who have served as the very model of independent practice, rarely practice alone. Increasingly, physicians are practicing as members of practice groups-often large, multi specialty groups-or as employees or contractors of large health systems. Even physicians who maintain private practices refer to and consult with specialists, or use other practitioners for emergency back-up.

If collaboration is the norm in professional practice, why should nurses object to it as a requirement for advanced practice, prescriptive authority, or for reimbursement? There are a number of reasons. Many nurses object to the practic\e of legislating their practice patterns. Determining what kind of relationship is needed with other professionals, when it is needed, and what form it should take are questions of professional judgment and norms. Not only are legislative and regulatory requirements unable to substitute for professional judgment, such requirements are unlikely to provide the flexibility needed to fit the wide variety of clinical situations and physician-nurse interactions necessary to be effective in the first place. (One can only imagine what the reaction of organized medicine would be if a state legislature attempted to delineate when and how internist physicians should refer patients to a specialist.) Further, because “collaboration” is rarely defined (at least in any agreed upon way) and is often used as a euphemism for “supervision,” many nurses chafe at the notion of prescribing into law an antiquated, dependent view of nursing practice.

In its testimony before the Physician Payment Review Commission (PPRC) in 1993, the American Nurses Association (ANA) explained its concerns about statutory requirements for “collaboration:”

Advanced practice nurses are, as are all registered nurses, independently licensed and accountable for their actions. [They are].able to deliver.services independent of their relationship with physicians or other health care providers. Collaborating with and referring to other health providers is a matter of good professional practice . Regardless of practice setting or supervision requirements, advanced practice nurses, like most health professionals, generally maintain a network for referral to and collaboration with other professionals and maintain a means to access emergency back-up.

In short, few could object to “collaboration” as a goal and as a means of effective professional practice. What proves more problematic is the use of this concept to enforce a dependent and hierarchical relationship between independent professions-a relationship away from which nursing has already largely evolved.

The Crazy Quilt Continues

To better understand the concept of collaboration, we must understand the differences in state practice acts. There are twenty- seven states with joint regulation of advanced practice (ANA, 1997). Likewise, there are forty-eight states with some form of statute or regulation authorizing nurse prescriptive authority.(7) Yet virtually every statute is different, in part because medical societies have intervened to limit nursing practice. In some states, collaboration is not defined, but implicit to the relationship articulated in the practice act, while in other states collaboration is presumed to occur in the development of practice agreements, collaborative agreements, or protocols. Some states define collaboration in a manner akin to supervision, while others instead define and compel supervised practice arrangements. And, in some states, the law requires one level of collaboration for advanced practice designation and another level of collaboration for prescribing drugs and devices (Pearson 1998). Some states even make distinctions in the level of collaboration or supervision required by setting. (8) Although every state’s legislative structure cannot be discussed, analysis and evaluation of some may be helpful in understanding why collaboration is not an easily defined legislative concept.

Alaska, which has one of the most flexible statutes in the country, does not include a definition of collaboration in its statute. Instead, state law requires APNs to develop a consultation and referral plan that outlines procedures for consultation with other health care professionals.

Alternatively, Alabama and Mississippi have joint regulation of advanced practice. Alabama has a joint committee (BON/BOM) for writing the rules and regulations related to collaborative practice; Mississippi’s joint committee is responsible for writing rules on acts of medical diagnosis, prescription writing, or other corrective measures. Alabama’s definition of collaboration does not require “direct, on-site supervision, but does require professional oversight and directions as may be required.” Mississippi defines the role of the APN as a “collaborative, consultative relationship” with a physician whose practice is compatible with the Nurse Practitioner (NP).

Nebraska and Arkansas have different levels of collaboration for APNs. Nebraska has joint regulation of advanced practice and Arkansas does not. Nebraska requires physician-supervised practice for APNs without a master’s degree. APNs with a master’s degree practice with consultation, collaboration, and with the consent of a physician. Also, Nebraska waives the requirement for collaboration, supervision, or practice agreement if APNs can show they have made a diligent effort to obtain an integrated practice agreement and will practice in a geographic area where there is a shortage of health services.

Like Nebraska, Arkansas requires physician direction/protocol for NPs who were originally authorized by the state, and the statute provides second licensure for APNs who are nationally certified.

Arkansas, as well as a number of other states, creates a separate level of collaboration for nurses who prescribe. Thus, APNs in Arkansas can practice independently if they do not prescribe (with the exception of nurse midwives, who must have a consulting physician), but if the APN prescribes, he or she must enter into a collaborative practice and use protocols to prescribe.(9) There is also a move by states to impose an overall collaboration/ supervision requirement on new NPs.(10) Thus, it is quite obvious that statutory collaboration does not follow any general format and ranges in flexibility and application under state law.

Other Definitions of Collaboration

Federal law defines “collaboration” as it applies to advanced nursing practice. For example, Section 1861(s)(K)(2), which refers to Medicare Part B reimbursement of professional services provided by nurse practitioners and clinical nurse specialists, requires that such services be delivered “in collaboration with a physician” to be eligible for payment. Section 1866 provides this definition of “collaboration:”

A process in which a nurse practitioner [or clinical nurse specialist] works with a physician to deliver health care services within the scope of the nurse practitioner’s [or clinical nurse specialist’s] professional expertise, with medical direction and appropriate supervision as provided for in jointly developed guidelines or other mechanisms as defined by the law of the State in which services are performed.

This definition is a broad one, allowing some flexibility as to the form and substance of a collaborative agreement between nurse and physician. It is the same definition that has applied since 1990 to NPs and Clinical Nursing Specialists (CNSs) practicing in rural areas and who seek Medicare reimbursement, which became available as a result of the Omnibus Budget Reconciliation Act of 1990 (OBRA ’90). As of January 1, 1998, as a result of the Balanced Budget Act of 1997, NPs and CNSs in all geographic areas are eligible for Medicare Part B reimbursement when providing Medicare-eligible services. With broadened availability of Medicare reimbursement-and thus a broader applicability of the “collaboration” requirement for NPs and CNSs seeking reimbursement-it remains to be seen what, if any, problems are posed by this requirement. The Health Care Financing Administration (HCFA), the federal agency that administers the Medicare and Medicaid programs, has not provided any specific guidance in interpreting this statutory definition. HCFA’s instructions to Medicare carriers and intermediaries (private Contractors who administer Medicare in each state) regarding NP and CNS reimbursement under OBRA ’90 essentially repeat the statutory language. A more recent communication to carriers and intermediaries regarding the Balanced Budget Act provisions on NP/CNS reimbursement provides no further discussion or expansion of this subject.

The issue of collaboration also became a point of concern during the national discussion on comprehensive federal health care reform during 1992-94. Nurses pushed for broader use of registered nurses and APNs as a critical resource in expanding access to affordable, quality health care services. Nurses won a largely sympathetic ear from the Clinton Administration, which recognized the role that nurses could play in a reformed health care system, particularly in expanding access. The President’s Health Security Act ultimately included provisions to expand reimbursement for NP and CNS services and pre-empt state laws that unduly restrict the practice of nurses and physician assistants.

Such bold stances, however, earned the enmity of organized medicine, particularly the American Medical Association, for which the Clinton plan’s pro-nurse provisions provided one (of many) sources of uneasiness with the Health Security Act. The American Medical Association (AMA) continued to assert its opposition to direct reimbursement for advanced practice nursing services and its conviction that APNs must act only under physician “supervision.”

Leaders of AMA and ANA met during 1993 and 1994 in an effort to reach agreement on the dimensions of nurse-physician professional relationships, and specifically to establish a mutually agreeable definition of “collaboration.” After lengthy discussion and negotiation, a joint AMA-ANA task force arrived at the following definition:

Collaboration is the process whereby physicians and nurses plan and practice together as colleagues, working interdependently within the boundaries of their scopes of practice with shared values and mutual acknowledgment and respect for each other’s contribution to care for individuals, their families, and their communities.

Members of this task force took the definition back to their respe\ctive organizations. The ANA Board of Directors adopted it in 1994. The AMA, however, has never adopted it, nor have further formal discussions on the issue of “collaboration” taken place since.

Case Law Related to Collaboration

Under the early nurse practice acts, all nurses worked under the supervision of physicians. Along with regulation and growth in the profession, registered nurses developed an independent scope of nursing practice. Although each registered nurse sued may not necessarily be independently responsible for her practice, more registered nurses are being held legally accountable using independent nursing judgement and expertise. (American Jurisprudence 1997) This independent accountability has provided an important foundation for the development of independent nursing practice. However, with continued use of collaborative arrangements, combined with inconsistent definitions of collaboration and other factors, the case precedent has become blurred.

Physician groups often imply that medical supervision of advanced nursing practice is necessary, because they believe nurses always function as agents or employees of physicians, and as such, do not practice independently. This is untrue, especially when there is clarity about the regulation of the APN. APNs have been held to a standard of care independent of physician supervision in malpractice suits. In the case of Fein v. Permanents Medical Group 38 Cal. 3d 137, aff’d 414 U.S. 892 (1985), the lead case defining the standard of care for NPs, the California Supreme Court went directly to the state nurse practice act and acknowledged the legislative intent “to recognize the existence of overlapping functions between nurses and physicians and to permit additional sharing of functions within organized health systems which provide collaboration between physicians, and registered nurses.” Thus, the court noted that: …the ‘examination’ or ‘diagnosis’ of a patient cannot in all circumstances be said-as a matter of low-to be a function reserved to physicians, rather than registered nurses or nurse practitioners.

The court expanded the standard of care for NPs to require them to meet “the standard of care of a reasonably prudent nurse practitioner in conducting the examination and prescribing treatment.” Fein, ibid.

This standard has been applied to other cases as well. In the matter of Kennedy v. U.S. 750 F.Supp 206 (1990), the court was asked to determine malpractice in a cancer misdiagnosis that involved a NP and two physicians acting independently. In this matter, the court did not directly address the NP’s malpractice. However, in stating the standard of care utilized in this case, the court noted that “Medical testimony unequivocally establishes that the standard of care relevant to the diagnosis and treatment of breast lumps is uniform.” Thus, a uniform standard was applied to all health care professionals in this case, including the NP, in determining malpractice.

Likewise, the Supreme Court of Ohio held nurse practitioners to the standard of conduct for licensed nurse practitioners applicable to the community engaged in that occupation, even though nurse practitioners are presently authorized by statute to provide care only under supervision in selected sites within the state. See Berdyck v. Shinde 613 N.B. 2d 1014 (1993).

In another case addressing the activities of a nurse anesthetist who worked under a protocol and scope of practice agreement, the court held that neither the physician she worked with nor his corporation were responsible for her negligence:

The record shows that the nurse anesthetist who administered anesthesia. was acting independently and not under the direct supervision of a physician within the statute. Accordingly, no physician-shareholder could have been held liable for a nurse anesthetist’s negligence. (See Gersheeny v. Martin McFall Messenger Anesthesia Professional Association 539 So.2d 1131 [1989])

There has been only one case where physicians have been held accountable for an APN’s malpractice. In that case the physician was held accountable because Missouri, the state where the suit occurred, had enacted similar legislation to mandate physician responsibility for patient care. The case was Callahan v. Cardinal Glennon Hospital and St. Louis University, and it held the physician liable for inappropriate NP practice. Subsequently the law was changed in Missouri to recognize and authorize independent advanced nursing practice

CONCLUSION

To provide effective and comprehensive care, nurses, physicians and other health care professionals must collaborate with each other. No group can claim total authority over the other. Each profession exhibits different areas of professional competence that, when combined together, provide a continuum of care that the consumer has come to expect. The definitions of collaboration have not been structured to reflect true practice. Instead, at best, they reflect compromise, and at worst are conditioned and tailored to limit competition.

The issue of if, when, why, and how collaborative interprofessional relationships are to be written into state and federal law and regulation may continue to confront the nursing profession for some time to come. The issue is not just one of recognizing the parameters of nursing practice (and its evolution), but the impact of unnecessarily restrictive requirements on access to health care and the cost of health care services. These are issues that policy makers will need to revisit and confront as nurses, including APNs, continue to work to meet the expanding health care needs of individuals, families, and communities across the nation.

ENDNOTES

1. In 1903, North Carolina enacted the first nursing registration law.

2. New York enacted the first mandatory nursing licensure law and three other states (New York, New Jersey and Virginia) passed registration acts in the same year. By 1923, all the states then existing as well as the District of Columbia and Hawaii had enacted nurse licensure laws, modeled upon New York law.

3. When the New York statute was enacted in 1903, it included the one of the first legislative provisions which clearly distinguished between the practice of nursing and the practice of medicine and prohibited nurses from the practice of medicine without a license.

4. Safriet, B. J. (1992) and Hadley, E.A. (1989) touched on the concept that organized medicine attempted to confine nurses to a largely complementary and supervised role through the development of “all-inclusive medical scopes of practice.”

5. Hadley, ibid.

6. Although the 1903 New York nurse practice act did not include a scope, the language prohibiting nurses from practicing medicine was incorporated into the nurse practice act.

7. Pearson, L., (1998). V.

8. Delaware still retains setting distinctions.

9. Other states with the independent practice/prescriptive authority collaboration distinctions include: Colorado, Minnesota, Nevada and Oregon.

10. Maine incorporated such into the 1993 revisions to the nurse practice act, which incorporated independent practice for the established nurse practitioner.

(this article originally appeared in the Online Journal of Issues in Nursing (need issue/volume info) – Reprinted with permission)

REFERENCES

1. ANA. Testimony to the Physician Practice Review Commission, November, 1993.

2. ANA. Statement on Physician Supervision of Allied Health Professional Before the Practicing Physicians Advisory Council, Health Care Financing Administration, March 16, 1998.

3. ANA. Joint Regulation of Advanced Nursing Practice, 1997.

4. 40 American Jurisprudence 2d Hospital and Asylums, sec. 43 provides extensive discussion of case law on registered nurse and physician collaboration to provide care and make patient medical records.

5. Department of Health and Human Services. HCFA Medicare Carriers Manual, Part 3-Claims Process, May 1992.

6. HCFA Transmittal No. AB-98-15, April 1998.

7. Campbell-Heider, N., R.M. Kleinpell, and W.L. Holzemer. Commentary about Marchione and Gardland’s “An Emerging Profession? The Case of the Nurse Practitioner,” 1997.

8. Marchione, Joan, and T. Neal Garland. “Image: A Journal of Nursing Scholarship,” 29(4): 338-339.

9. Eubanks, P. “RN clears path for nurse-MD collaboration.” Hospitals 64(19): 68, 1990.

10. Eubanks, P. “Quality improvement key to changing nurse-MD relationship.” Hospitals 65(8): 26-30, 1991.

11. Eubanks, P. “Restructuring care: patient focus is key to innovation; Chicago’s Mercy meets patients’ needs rather than system’s routine.” Hospitals 65(15): 26-27, 1991.

12. Goldman, D.A., S.M. Andrews, S. Paternack, D.G. Nathan, and RH. Lovejoy. “A service chief model for general pediatric inpatient care and residence training.” Pediatrics 89:601-607, 1992.

13. Hadley, E.A. “Nurses and prescriptive authority: a legal and economic analysis.” American Journal of Law and Medicine 15:245- 299, 1989.

14. Hagland, M.M. “Restructuring care: patient focus is key to innovation; Penobscot Bay integrates acute, long-term, home care.” Hospitals 65(15): 28-29, 1991.

15. Knudsen, J.A., J.R. Rasch, T. Capriotti, P.W. Irvine, R. Matz, A. Zuger, D.E. Rubin, J.M. Bloom, and J.P. Kassirer. “Nurse Practitioners in Primary Care.” New England Journal of Medicine 330:1537-1540, 1994.

16. Pearson, L. “Annual -Update of How Each State Stands on Legislative Issues Affecting Advanced Nursing Practice.” Nurse Practitioner 23(1): 14-66, 1998.

17. Safriet, B.J. “Health care dollars and regulatory sense: the role of advanced practice nursing.” Yale Journal of Regulation 9:417- 488, 1992.

18. Sharer, J.L. “Putting patients first; hospital work to define patient-centered care.” Hospitals 67(3): 14-18, 1993.

19. Stein, J.I., D.T. Watts, and T. Howell. “The doctor-nurse revisited.” New England Journal of Medicine 322:546-549, 1990

20. Stone, E. L. “Pediatric Practice: How to survive and thrive in the changing health ca\re system.” Pediatrics 96 (Suppl): 844- 851, 1995.

Copyright Nevada Nurses Association Nov 2004

Seduction Theory and the Recovery of Feminine Aesthetics: Implications for Rhetorical Criticism

This essay addresses applications of rhetorical criticism to seduction theory. Recently recovered and articulated by post-modern and neo-sophistic theorists, critics judge seductive aesthetics both liberating and subversive insofar as they lessen woman’s dependency upon the patriarchal scripts of logocentric rhetorics. Seductive stratagems include affective appeals, teasing, withdrawing, and a demeanor mirroring charm, allure, and enchantment. This essay addresses issues relative to rhetorical criticism and the interpretative value of seduction theory as a critical lens. Specifically, we explicate seduction theory and its critical bearing. We analyze, by way of illustration, Hillary Rodham Clinton’s use of seductive appeals as an “undecided” candidate for the United States Senate. The First Lady’s forestalled candidacy, listening tour, and identity management, we posit, reveal rhetorical choices constituted in seduction theory.

KEY CONCEPTS feminine style, seduction, criticism, Hillary Rodham Clinton

“The world is driven…by seduction….Seduction is destiny.” Jean Baudrillard, (1990, pp. 174; 180)

Seduction is notorious as a site of flirtatious, frequently erotic, relational performances (Villadsen, 2000). Early French and British novelists, poets, and dramatists, for example, routinely fictionalized the exploits and subsequent undoing of seductresses (Armstrong, 1990). Chroniclers of the eighteenth-century typically identified seduction with coquetry, fin-de-siede culture, salon life, and sexual adventurism (Dijkstra, 1990). Social critics and conduct manuals likewise clucked over the seductress’s threat to masculine privilege, societal norms, and essentialist notions of female decorum (Poovey, 1984). Specifically, both men and women of status disavowed women who used seduction to acquire position. While powerful men viewed seduction as a threat to patriarchic order and domination, female liberationists considered it a subversive male fantasy intended to tarnish woman’s intellect or familial significance (Wollstonecraft, 1792). However, seduction more accurately represented an “expression of ‘managed desire,’ a display of female power as well as an arena of freedom built on a dialectic of consent and refusal” (Kaye, 1996, p. v). Seduction, therefore, was a site of empowerment primarily “exploited by women to create and re-create [themselves] in society’s eyes” (Owens, 1996).

Contemporary theories of seduction bear little resemblance to coquetry and its libertine emphasis on “male predation and/or female folly” (Richards, 1998, p. 239; Ballif, 2001; Baudrillard, 1990; Carotenuto, 2002; Crowley, 1989; Perniola, 1984; Wick, 1992). Today, theorists promote seduction’s liberationist potential to reduce woman’s dependency upon the patriarchal scripts of gender objectification and commodification. Accordingly, the oppressive operations of western rationalism resist, even discipline, its expression. Rationalism’s dismissal of seductive appeals is a poignant reminder of how the “repressed feminine haunts rhetorical theorizing and criticism” (Campbell, 2002, p. 49). Indeed, throughout history patriarchy has influenced rhetorical theory’s ideological frames. Although Gorgias viewed seduction as a form of rhetorical “logic” (Bell, 1997, p. 22), Plato scandalized it as artless flattery and apate (illusion, deception, and semblance) (Erickson, 1979). Dismissed as a feminine mirage of truth-a threat to logic and ontology – seduction was subsequently uprooted from its sophistic heritage and repudiated by rationalists (Sutton, 1992). In the absence of its sophistic relationship to sublimity, seduction’s latter-day association with body artifice, relational thralldom, and playful representations of woman’s true being regrettably tarnished its appeal for women.

Recovering the seductive arts as a means of addressing women’s issues is an ideologically bold proposition. Baudrillard (1990), though, urges women to appropriate seduction as a means of exercising political power. He offers the hypothesis that “seduction represents mastery over the symbolic universe” (p. 8). Baudrillard maintains that for feminists to ignore or reject seduction theory outright would constitute a misguided ideological move. Why? Because seduction theory flaunts modernity and its subscription to absolute values, “a social world that produces moral [women] by framing, wrapping, and protecting them” (Moallem, 1993, p. 328). Ballif (2001) agrees, contending that seduction is the only “tactic left to us that has any chance of subverting modernism’s logic and its will to produce and represent” (p. 193). Even if this claim is only fractionally the case, prudence dictates that critical tools be devised that are capable of assessing and interpreting seduction theory’s assertions, as well as its rhetorical practices. What follows then is an analysis of seduction theory and its implications for rhetorical criticism. Specifically, we propose a critical lens sensitive to seduction theory. Such perspective taking privileges feminine aesthetics and style, which represents a fundamental departure from “traditional rhetorical theory [that] is inherently hostile to the discourse of women…and is unsuited to its analysis” (Campbell, 2002, p. 51). Specifically, this project demonstrates the potential interpretive power of seduction theory by analyzing Hillary Rodham Clinton’s [HRC] seductive appeals and performatives prior to her campaign for the U.S. Senate. We judge this project significant insofar as seduction theory’s critical perspective claims to locate and recover discourse styles suppressed by patriarchy, rationalism, and cultural norms. We proceed by assessing issues of the seductive arts, including an analysis of both theory and praxis. Implications for the rhetorical critic are woven throughout the essay.

CRITIQUING THE SEDUCTIVE ARTS

Seduction Theory: Foundational Issues

Seduction theory acts to destabilize and free woman’s dependency upon rationalism’s “falsely naturalized logic” (Jarratt, 1991, p. 76). It seeks to empower women by valorizing a feminine aesthetic and style, a project that constitutes fresh “‘cognitive mapping,’ a new political art” (Jameson, 1984, p. 92). Seduction theory does not romanticize neo-sophistic rhetoric nor does it advance a binary logic of male versus female. Rather, it heartily envisions a “universe where the feminine is not what opposes the masculine, but what seduces the masculine” (Baudrillard, 1990, p. 7). Seduction is not a strategy of conquest, though, nor is it revolutionary in its exposure and detachment from logos as the rhetor appropriates all the available means of persuasion. Seduction theory subsequently adopts an antistrophic [“sister art”] posture toward rationalism, thereby empowering it as “more subtle, more ingenious, more critical, and more ironic”(Ballif, 2001, p. 193). The circumspect seductive rhetor, for example, recognizes that certain exigencies may call for traditional applications of rhetoric but that “good arguments” may also excite aesthetic pleasure (terpsis) (Foss, Griffin, & Foss, 1997; Foss, Foss, & Griffin, 1999). Accordingly, seduction theory envisions little political utility in practicing a purely binary style (masculine or feminine), thus avoiding what Irigary labels the “labor of the negative” (Irigary, 1984, p. 120).

The western tradition of rhetoric is an operation of production, a guarantor of subjectivity. Seduction theory, though, offers “no possibility of ‘real-ising’ the subject,” that is, making it “subject to the demands of ‘truth'” (Ballif, 2001, p. 21). The rhetorical critic should subsequently read seductive appeals as a means of rebelling against gender commodification and objectification. Performed at the intersection of feminine and masculine sites of rhetorical practice, therefore, seduction theory stands in sharp relief to rationalism. Nonetheless, seduction does not operate as a dialectical opposition insofar as it is indeterminate and “unrepresentable” by rationalism’s standards of productivity and representation (Ballif, 2001, p. 21). Paul de Man (1979), for example, would likely have viewed seduction as holding in abeyance western culture’s ideological dependence on logos by “suspending] logic and openfing] up vertiginous possibilities of referential aberration” (p. 10). Vitanza’s (1991) aggressive reading of seduction theory interprets it as the “‘art’ of resisting and disrupting….” (p. 133). However, seductive rhetors subtly defy and/ or challenge oppressive institutions, power structures, and/or sites of authority. Subjects are likely to be enchanted by a seductive rhetor’s captivating charm, inductive subjectivity, and prudent appeals to the passions. As such, a seductive rhetor’s appropriation of affect inducing aesthetics counters or displaces patriarchal language codes that both “produce” women and suffocate their voice (Mattingly & Royster, 2000, p. 104).

Critically, a significant measure of a seductive rhetor’s impact is whether aesthetic appeals and overtures sway a subject. Assessing the influence of seductive performatives is difficult given that seduction operates in spaces of the sublime. Seduction, for example, does not \suppress, sublimate, or “mask, but tempts the ‘autonomy’ of desire” (Baudrillard, 1990, p. T). However, a critic should not assume that seduction tricks or fools subjects into following a wayward path. Such a perspective presumes a “realm of truth,” a reason-based trajectory that subjects would have chosen had they not been weak (Perniola, 1984). Subjects react freely to seductive rhetors; they actively participate in the rhetorical exchange as the seductive rhetor shuns the appearance of possessing an unchanging or “overbearing will” (Bell, 1997, p. 23). A rhetorical critic, therefore, may elect to evaluate a rhetor’s prudence and decorum as judged against “aesthetic propriety, the rhetorical practice of image management that stimulates the spectator’s aesthetic responses (emotions such as pleasure, joy, awe, wonderment)” (Hariman, 1995, p. 140). Appraising rhetorical performances that stimulate desire and longing, incite the imagination, and aesthetically enthrall others, therefore, requires a critical appreciation of sublimity. Non-felicitous performances (inconstant articulation of the substantive, blatant displays of self-importance, and honeyed sycophancy), by contrast, may readily signal a rhetor’s imprudent, manipulative intentions.

Seductive rhetors can stimulate desire and longing in subjects by teasing and withdrawal stratagems, and by finessing time and the kairotic moment (Villadsen, 2000, p. 39). Kaye (1996), in fact, contends that seduction finds its rhetorical “identity in the manipulation of time” (p. 12). A critic must subsequently take into account that kairos, as managed by seductive rhetors, is more than a propitious moment when one strikes for rhetorical advantage. Rather, seduction uses temporal playfulness to acknowledge subjects as agents. Seductive rhetors are, as a consequence, comparatively taciturn relative to prolix advocates and agitators whose opinions generously populate the public forum. Seductive rhetors recognize that to seduce is to “produce language that enjoys, language that takes pleasure in having ‘no more to say'” (Felman, 1983, p. 28). Indeed, seduction theory suggests that “power means not having to act, more accurately, the capacity to be more…casual about any single performance” (Scott, 1990, p. 29). The seductive rhetor’s patient style, therefore, stands in relief to urgent calls for action and compliance – an appearance of passivity easily misjudged by logocentric critical frames as ineffectual or non-persuasive. Nevertheless, non-aggressiveness is what provides seduction its strength. In like manner, seductive rhetors do not signal the conceit that they possess universal knowledge nor do they flaunt the apparatuses of power. They are nevertheless keenly attentive to subjects, and display themselves as constituting the full measure of a desired or hoped for gift (Joseph, 1987). What could be more seductive than HRC’s “gift” to the electorate that promised: “I’ll stay with you; I’ll fight for you; I’ll stick with you” (Harpaz, 2001, p. 13). Not surprisingly, many “courted” New Yorkers perceived themselves to be the principle focus of the First Lady’s regard. By contrast, many voters bristled at the patriarchal articulation of authority, privilege, and power vocalized by HRC’s male opponents (Nagourney, 1999a). Deconstructing seductive appeals, therefore, generates critical insight regarding its nontransparent power and rhetorical operations.

Conducting a motive-based critique of seductive appeals is problematic given the reluctance of rhetor’s to bestow an impression of having taken the initiative in the seduction process (as such acts would be equivalent to an awkward affront). An astute critic nevertheless will be sensitive to aesthetic performatives that serve to court subjects seductively. Specifically, a critic will likely recover evidence of a rhetor who teasingly approaches and prudently retreats from view (Burke, 1945/1969). Essentially, advancement and withdrawal seductively suspend or prolong the kairotic moment, thereby keeping the subject in a state of anticipation. Withholding behaviors, for example, create a condition of relational indetermination as the potential of unfulfilled desire remains. Flirtatious indecision, therefore, constitutes a “saboteur of the cherished vocabulary of commitment” (Phillips, 1994, p. xvii). A critic must be aware, therefore, that the arousal of desire “always occurs in response to a representation and promise and operates in the enlarged field of anticipation” (Wallace, 1998, p. 491). As such, evaluating a rhetor’s formal texts is unlikely to yield evidence of specific promises or offers of relief. This action would cause the seductive rhetor to relinquish a psychological hold on subjects. Instead, these rhetors tantalize subjects with the possibility of alliance, psychological release, and fulfilled desire.

Seductive teasing signals the appearance of flirting insofar as the outcome of a longed-for decision or anticipated course of action remains in question (e.g., “Will she or won’t she declare her candidacy?”). In HRCs case, a critic would likely argue that teasing and withdrawal stratagems enhanced her desirability because she was “built up in [the subjects’] imagination” (Greene, 2001, p. 74). The seductive tease becomes in one’s imagined relationship, present – perceived as sharing one’s future insofar as teasing holds out potential outcomes, and acknowledges a positive future. The experience of being captivated is an ecstatic state of wonderment, exhilaration, and joy. The enabling tension between absence and presence, desire and fulfillment, as well as anticipation and closure helps negotiate a seductive rhetor’s attractiveness. Rather than logical compliance or agreement, the seductive rhetor “sweeps the listener off his or her feet and fosters abandon and celebration of the moment” (Baudrillard, 1990, p. 112). A major feature of seduction “is to be-there/not-there, and thereby produce a sort of flickering, a hypnotic mechanism that crystallizes attention outside all concern with meaning” (Baudrillard, 1990, p. 85). As a critical lens, therefore, seduction theory may render knowable the sublime dynamics of a liminal, seductive moment. By contrast, rationalist explanations of aesthetic phenomena pale as interpretative schemas.

The rhetorical critic should avoid a rationalist bias when assessing seductive performatives, in particular the supposition that somehow a sinister or deceptive veil was cast over subjects. Upon close inspection, seductive teasing clearly lends pleasure to a subject’s instability, stimulating “the contingency of lives by turning doubt-or ambiguity -into suspense” (Phillips, 1994, xxiii). Awaiting or anticipating the seductive rhetor’s attention is a joyous indulgence, not a futile fantasy. Why? Because the seductive rhetor’s attentiveness, claims Felman (1983), creates in subjects a sense of desirability. Numerous organizations and groups, for example, had publicly voiced their hope that HRC would declare her candidacy in their presence. The question that consumed many citizens, therefore, was not if but to whom HRC would announce her candidacy-a “Who does she like the most?” guessing game created by rhetorical teasing. At the conclusion of the campaign scores of petitioners believed they had contributed to HRC’s decision to declare, and they felt politically fulfilled for having done so (Bennett, 2000). As one bemused critic observes, “once our vanity is at stake, we succumb” (Greene, 2001, p. 74).

Seduction Theory: Rhetorical Applications

Performed at the social and cultural borders of the sublime, seductive performatives are challenging to critique given seduction’s aptitude for operating “instantaneously, in a single moment” (Baudrillard, 1990, p. 81). Its enigmatic nature and the cultural frame of subjects resist formulaic scripting or instrumental strategies. Seduction theory nevertheless implies prudential mastery of aesthetic materials, a foundational issue for the rhetorical critic. A competent rhetor, for example, will likely assess an audience’s aesthetic pulse regarding propriety and form in order to render strategic motives scarcely detectable. Seduction does not violently jar a subject’s cultural expectations or performative vocabulary. The rhetor appropriates appeals and stratagems that mute, temper, or elide detection, thus felicitously minimizing notice as invasive compliance-gaining stratagems. Obviously, a rhetor would be foolish to signal overtly “I intend to seduce you!” The rhetor’s subtlety ingeniously eludes the stigma that seduction’s value resides in appearances or deception. Rather, seductive rhetors charm and enchant by aesthetically framing contested issues to the “fragments of the public’s alienated aspirations” (Luke, 1989, p. 135). Interacting with subjects at the boundaries of normative rhetorical and aesthetic conventions enables the seductive rhetor to minimize detection as agent. Consequently, a critic must skillfully excavate sublime aesthetics insofar as seduction is unquestionably a “form of indirect power that brilliantly disguises its own power” (Greene, 2001, p. 75).

A palpable performance is key to appreciating the rhetor’s seductive efficacy. Seduction, for example, “constantly negotiates a balance between sincerity and clich” (Villadsen, 2000, p. 25). As such, a seductive style establishes a stasis that intercedes the “dialectical tension of a private identity functioning in marked tension with a public persona” (Kaye, 1996, p. 89). Ideally, the seductive rhetor achieves aesthetic balance by imaging a persona that signals sincerity and authenticity, thereby creating a wonder- inducing ethos that materializes in the contingent space of a subject’s fantasized desire. Such desire arises, according to Ferguson, from the “attempt to totalize one’s subjectivity, to fill the lacuna that inevitably threaten theposited comprehensiveness of the self” (Ferguson, 1999, p. 82). For many voters HRC’s persona clearly resonated as an authentic expression of self. This point echoes in the excitement of an enamored New York nun: “It’s not fake. She’s really not a politician” (DaIy, 1999, p. A4). A rhetor’s seductiveness, therefore, rests not in some mystical link to eras or rhetorical banter but in the ability to stimulate desire via aesthetic performances that enfold the subject. Seductive rhetors accordingly organize the social geometry of their relationships by conflating the bicameral role of agent and subject. Seduction theory extends, not unlike Foss and Griffin’s (1995) invitational rhetoric, “an invitation to pleasurable interaction, not a threat of dominance or a challenge to [one’s] worldview” (Villadsen, 2000, p. 267). Envisioned as such, seduction is a collaborative effort between the rhetor and subject, which for the rhetorical critic renders questions of culpability irrelevant.

In addition, the seductive rhetor may simultaneously signal approachability and aloofness, thereby trapping individuals emotionally. As alluded to earlier, the rhetorical jolt of seductive rhetors lies not only in the “tease and temptation but in the subsequent step-back, the emotional withdrawal” (Carotenuto, 2002, p. 195). HRC, for example, practiced withdrawal by avoiding position stands and, from time-to-time, absenting herself from the campaign (e.g., duties as First Lady). By doing so, she kept both the media and public off-balance, surprised, and captivated. HRC’s physical withdrawals had the impact of intensifying political drama, effecting mystery, heightening suspense, diverting attention, and magnifying her attraction. As Carotenuto (2002) observes, attraction “increases with distance, with the eternal oscillation between presence and absence” (p. 200). A seductive rhetor’s absence confirms the magnitude of our longing as its power lies in the “evocation and revocation of the other, with a slowness and suspense that are poetic” (Baudrillard, 1990, p. 84). In addition, withdrawal psychologically exploits a subject’s bewilderment by deferring closure. Withdrawal also suspends time by establishing necessary pauses that allow for introspection and surveillance. Prudent withdrawal is a way, therefore, of cultivating time. Pain nevertheless accompanies a rhetor’s withdrawal; absence prompts subjects to question their worthiness as “partaking of so sublime an experience produces the torment of doubt” (Carotenuto, 2002, p. 195). Doubt, as a construct of the seduced, affords the critic a lens through which to comprehend a subject’s psychological attachment to a seductive rhetor.

Seduction theory ruptures traditional patriarchal covenants by reversing or placing on hold politics-as-usual. Hopkins (1997), applauding such institutional table turning, suggests that seduction “retains a potential for challenge and shock [because it] opposes the production of repression” (p. 17). Seduction theory’s opponents, however, view it as representing a disregard for cultural norms, a stance that disrupts traditional order, calibrated commitments, and ritual expectations. As such seduction theory borders on an act of defiance that repudiates the ontological “fixities” of our political culture (Butler, 1997b). The rhetorical critic, therefore, seeks to verify or disconfirm these claims, and to articulate the implications of aesthetic stratagems operating in contradistinction to rationalism. Champions of seduction theory likewise argue that it negates patriarchy’s well-established practices of political exclusion, control, and dominance. Hence, the critic must be sensitive to discourses that echo the suppressed transcripts of marginalized publics “hidden and ripened in the nooks and crannies of the social order” (Scott, 1990, p. 223). How, in fact, does the rhetor seductively empower such voices to speak out? HRC, for one, encouraged the articulation of suppressed voices by conducting a “listening tour” that performatively signaled her commitment to all New Yorkers. Flattered subjects frequently discharged their political privation with sublime responses, including pride, delight, and exhilaration, fueled it seemed by a sense of legitimization and political inclusion (Foer, 1999; Nagourney, 1999a).

Rhetorical critics should likewise assess patriarchal and dominant elite responses to the seductive rhetor’s overtures. They may, for example, blindly dismiss seductive performatives as rhetorical play, dismissing them as “disorderly, innovative, egalitarian, improvised, and/or disrespectful of authority” (Boissevain, 1992, p. 3). Kennedy (1999), however, notes that sophistic “playfulness” more accurately reflects dissatisfaction with an impervious political establishment that “refuses to question traditional values and practices” (p. 37). Not surprisingly, then, the power elite may perceive seduction as an affront to cultural or political stability insofar as it “nourishes itself on the back and forth movement from the real and ludic [trans.]” (Joseph, 1987, p. 224). Indeed, seduction’s mercurial nature will likely be bothersome to well-established patriarchic schemas and devices of control. Many journalists, accordingly, felt an authorial obligation to discipline HRC’s disruptive practices as she declined to walk lockstep to her masculine counterpart’s political tunes with respect to declaring her candidacy (Ingraham, 2003).

Finally, the rhetorical critic must assess those cultural barriers that limit seductive appeals and render stratagems gender specific. Gendered terms such as “tease” and “flirt,” for example, hint at beguiling, not-to-be-taken-seriously “feminine wiles,” strategies infrequently suited to masculine rhetors. Mario Cuomo, George H. Bush, Ross Perot, and Colin Powell, for example, experienced the ridicule and snipes of patriarchal journalists for their displays of “femininity.” Bill Clinton was accused of being “squishy,” (Klein, 1992, p. 39), and an “old maid in britches,” (King, 1993, p. 72). Regrettably, male candidates too frequently resort to gratuitous applications of a feminine style to patronize women, or worse, objectify them as accommodated “others.” Bill Clinton’s consolation, “J feel your pain,” still resonates with political comics. By contrast, HRC’s feminine style was perceived by women as an authentic voice, a point that emerges in the following analysis of HRC’s pre-candidacy “campaign” for the United States Senate.

HILLARY RODHAM CLINTON’S SEDUCTION OF NEW YORK

Hillary Rodham Clinton’s pre-candidacy “campaign” for the United States Senate (November, 1998 through February, 2000) captivated New Yorkers as well as the nation. Critics hotly debated the question, “Will she or will she not run?” Media mavens and talk show hosts expressed both enthusiasm and shock at the prospect of HRC’s candidacy, including an indignant Peggy Noonan: “Clinton’s candidacy is an act of mad narcissism” (Kennedy, 1999, p. A2). Similarly, Democratic Party leaders, pollsters, and assorted Washington insiders busied themselves assessing the viability of the First Lady’s potential candidacy. HRC, however, initially distanced herself from talk of a formal campaign. Political analysts parsed her intentions largely from the remarks of close acquaintances. Press secretary Marsha Berry, for example, brushed aside inquiries regarding the First Lady’s political aspirations, indicating only that it was HRC’s intention not to foreclose any option. President Clinton, though, chirped that she “would [make] a terrific senator” (Bennett, 1999, p. Bl), and Senator Robert Torricelli startled NBCs Meet the Press by declaring that HRC would run (Dao, 1999, p. B5). Harlem’s Al Sharpton joined the chorus of supporters by declaring that the Democratic nomination was hers for the asking because “You can always promise no primary to an 800 pound gorilla” (Hitchens, 2002, p. 302). By September 1999, however, an impatient Charles Rangel likened her seeming indecision to “being half-pregnant – either you’re in or out” (Hardt & Birmbaum, 1992, p. A2). The First Lady remained circumspect throughout (“I will give careful thought to a potential candidacy” [Ratnessar, Brannegan, & Carney, 1999, p. 3O]), coy (“If I decide to do this crazy thing” [Conason, 1999, p. A2]) and, later, flirtatious (“If I were leaning any further, I’d fall over” [Perez-Pena, 1999, p. A12]).

The following critique of HRC’s senate race relies primarily upon media accounts and the First Lady’s seductive performatives. HRC’s public statements were framed by the media as teasing, as opposed to “testing the waters.” Interestingly, four years after the race she candidly disclosed that “I had no plans to drop out of the [primary] race [emphasis added]” (Clinton, 2003, p. 510). Thus, the press correctly assessed as strategic her reluctance to declare. Clearly, then, her teasing performatives were not about floating “trial balloons.” Moreover, HRC’s role as First Lady appears to have had meager influence on her decision to declare. Neither HRC’s personal account of the campaign nor those of her advisors suggest that she perceived the senate race as being in conflict with her role as First Lady.

HRC’s disarmingly seductive performatives sparked the public’s imagination, generated substantial media interest, and positioned her center-stage politically. Her strategy of slow reveal, in time, proved highly effective although it was initially sneered at as a “highly-coordinated informational strip tease” (Cannon, 1999, p. 20). Uncharitable critics voiced the opinion that HRC’s playful courtship with New Yorkers clashed with her feminist resolve and “blond ambition” (Bazinet & Kennedy, 1999, p. A4). HRC likewise startled critics by revealing a feminine persona that portrayed her as a traditional, hard-working, family-oriented woman. Tomasky expressed it succintly: “It was infuriat\ing. It took a lot of gall. And in the end, it was kind of brilliant” (Tomasky, 2001, p. 289). As such, her political intentions remained elusive despite the fact she had staff in-place, campaign headquarters rented, and a “listening tour” underway. HRC did not formally announce her candidacy until February 6, 2000 – nearly fourteen months after columnists first broached the prospect of her candidacy. Two engaging questions emerge, therefore: “How did the First Lady seductively tease the electorate?” and “How did she appropriate a feminine style?”

A critique of HRC’s seductive campaign style “requires that one uncover what is in full view” (Hariman, 1992, p. 132). Few things are so visible yet hidden from direct gaze as the seductiveness of someone in whom we believe in or follow. HRC’s rhetorical stratagems, for example, seductively heightened public awareness, stimulated media coverage, baffled opponents, and distanced her from the rhetorical pitfalls of the public forum. Seductive performances likewise enabled her to hold in suspense unresolved political tensions and to rupture conventional venues of power. HRC’s critics nevertheless carped that her teasing transgressed political customs – actions postmodernists claim blur “the distinction between the symbolic and the real”(Villa, 1993, p. 227). Although HRC’s perceived indecisiveness and egalitarian monitoring of the electorate’s views raised eyebrows, faithful supporters stood by her. They pronounced her charming, approachable, and family centered, applauded her willingness to listen, weathered her periodic withdrawals, and professed tolerance regarding her reluctance to declare (DaIy, 1999). In what follows, we analyze HRC’s arousal, issue, and identity management strategies.

Arousal management. HRC barnstormed tirelessly before formally declaring her candidacy. “I want everybody in the state to know that I have made an effort to get to the different regions of the state before I, you know, 1 announce any final decision” (Herszenhorn, 1999, p. Al). She toured sixty-two counties and made approximately 115 public appearances (Grunwald, 2001). Although the press soon tired of asking the question, at nearly every stop someone asked or begged her to declare. She repeatedly said, to the groans of the press, “Some might think I have an announcement to make, but I don’t” (Marks, 1999, p. 3). An example of seductive teasing occurred during a nationally aired interview with CNN foreign correspondent Christiane Amanpour. HRC “turned coy. She giggled, she ducked, she dodged,” and when pressed on the subject of her candidacy, hinted, “Well, summer is not that far away” (Cottle, 1999, p. 24). Summer, however, came and went without a formal announcement. What, then, had begun as a hinted at candidacy turned into a daily tease. Media attention soon “rose to a clamorous din and then to a round-the- clock media roar” (Ratnesar, Branegan, & Carney, 1999, p. 30). Time and Newsweek, for example, featured her on their covers. The more HRC demurred, the more the media sought her out. HRC’s seductive teasing pandered to the media’s investigative instincts, and they responded by posing such questions as: “Will she run?””When will she declare?””Will she make it official?” HRC’s seductive tease soon became a story in countless media outlets. The national attention that her seductive actions generated framed her pre- campaign “candidacy.” The media obliged HRC’s rhetorical “priming” because the story was politically intriguing, had a national following, and contained the dramatistic elements of character, suspense, and mystery (Burke, 1945/1969).

Seductive teasing and withdrawal stratagems enabled HRC to gather essential endorsements and spike the public’s interest. Time was her rhetorical ally. As weeks and months passed, suspense built. HRC’s supporters eagerly awaited her decision. Numerous organizations, service agencies, unions, and loosely affiliated groups scrambled to extend a speaking invitation to the First Lady. She was the “hottest ticket” in town insofar as people believed she would formally announce her candidacy shortly. Moreover, the press was obliged to follow her every step for fear that she would declare in their absence. Time also helped her to flush out opponents and their issue stands. Significantly, time enabled her to get to know New Yorkers, and vice versa. HRC addressed dairy farmers and Hasidic Jews, marched in gay and Irish parades, attended athletic events, ribbon cuttings, and cultural activities, and symbolically addressed the needs of children in schools, hospitals, and homeless centers. However, by November the press no longer found the “Big Tease” amusing or particularly newsworthy (Harpaz, 2001). Criticism and pressure to announce mounted. Republican fed rumors speculated that HRC no longer had the stomach for politics. Teasing became wearisome and “old news,” labeled by some as a selfish indulgence unbecoming a serious candidate. Pressed to respond, HRC unexpectedly announced her intent to declare in late November. Members of the teacher’s union to whom she had been speaking exploded with joy, and the press rushed to cover the story (Tomasky, 2001, p. 84). On February 6,2000, in Purchase, New York, HRC formally declared herself a candidate for the U.S. Senate (Nagourney, 2000, p. Al). One of the most intriguing political teases and seductive performances in American political history concluded. Evidence, therefore, is compelling that HRC seductively teased and withheld her decision to seek public office.

Issue management. HRC initiated a “listening tour” of New York that empowered citizens to express their needs and concerns. Listening to the political needs of others proved to be an extraordinarily seductive gesture. Spanning several weeks, her tour converged on sites throughout the state. The campaign strategy was elegantly simple. New Yorkers would publicly air their issues while HRC listened. Her listening performatives constituted an unspoken pledge to resolve in future-time the issues discussed. Listening also reinforced HRC’s credibility. Courtly performances as auditor and lightning rod seductively commanded attention as they signaled her interest in others. HRC clearly recognized that strategic listening and silence deflect conflict, criticism, and unwelcome interrogatives. At nearly every stop, she positioned herself center- stage, notebook and pencil in hand, and recorded observations. HRC’s speech-making efforts consisted largely of ritualized greetings and perfunctory remarks (Nagourney, 1999b). As such, HRC’s listening performatives served as a site of personal discovery as well as a means of signaling consubstantiality with Town Hall attendees.

HRC’s listening performatives signaled dependence on and concern for others, as well as a seductively symbolic withdrawal from the role of knowledgeable elite – a label attached to her as First Lady. HRC’s listening tour maximized use of seductive appearances by isolating publics, emphasizing the personal, and displaying interest in the well-being of subjects. By listening rather than speaking, HRC claimed “authority based on…an intersubjectivity that [sought] to experience another’s life as though it were one’s own” (Goodrich, 1991, p. 21). As HRC reflected, “Now take a deep breath and think, there but for the grace of God go I” (Bennett, 1999b, p. 23). HRC’s listening forums accordingly facilitated for New Yorkers conversational intimacy, contextual relevance, and an opportunity to articulate private concerns. The performative act of listening may well have established an emotional bond between herself and those who spoke. It likely secured interpersonal attachments in an emotional and equitable manner more likely to endure than that obtained by “imposition or privilege” (Ttreault, 2000, p. 282). In any event, the First Lady’s listening performatives overshadowed her lack of issue stands. However, it exasperated some journalists who found themselves with little to weigh-in on or report. Consider one chagrined journalist’s high dudgeon polemic: “It was not so long ago that politicians talked at us incessantly. Now it’s worse, much worse. Now they listen” (Ferguson, 1999, p. 8). Such journalists failed to recognize, however, that HRC effected a relational transaction in which she seductively enhanced the public’s “ability to feel competent and powerful” (Goodrich, 1991, p. 20). HRC’s listening tour gave ear to citizen voices, a role reversal of the rhetor/auditor relationship, Foucault’s “orders of discourse” (Therborn 1980), and Farrell and Frentz’s (1979) “encounter rules.”

HRC’s framing of the political arena as an egalitarian reciprocity provided an opportunity for private transcripts to emerge that had the potential to negotiate terms of governance. Issues emerging from the public forum reflected community concerns as well as subaltern ideologies. A seemingly appreciative public openly welcomed HRC to their districts. Citizens applauded the First Lady’s appearances as an attempt to capture, appreciate, and attend to their interests -a soothing reinforcement of the cultural totem that democracy serves the public. HRC’s listening tour clearly gave voice to and encouraged the articulation of many varied political opinions. She did not confront, correct, reject, or object to the concerns expressed. Even HRC’s harshest critics agreed “that there was about her not the slightest hint of threat or superiority” (Tomasky, 2001, p. 53). Moreover, she clearly appreciated the rhetorical significance of nomos (narratives), having noted that “for women, the personal is political” (Mundy, 1999, p. W07). She observed, for example, that “my prospective constituents seemed genuinely comfortable sharing their stories and worries with me” (Clinton, 2003, pp. 510-511). HRC correspondingly signaled empathetic concern for the lives of others, an extraordinarily seduc\tive and captivating message. “I’ve been stunned to see how much passion I have unleashed,” she said. “It is quite validating [as otherwise] I’d be irrelevant” (Leonard, 2000, p. A11).

HRC’s critics scoffed that audiences who convened to watch the First Lady listen were often there “by invitation only” as “none of the listening tours were completely open to the public” (Harpaz, 2002, p. 40). They remonstrated that event coordinators controlled the theme of each listening session as the “issues turned out to be the ones that mattered most to Mrs. Clinton” (A. Ferguson, 1999, p. 8). HRC no doubt learned, however, “to name things anew, to become alert to exclusion and to forgotten aspects in a people’s history, to overhear what is usually drowned out by the predominant values, to rethink what is ordinarily taken for granted” (Nealon, 1998, p. xiii). This turn to political inclusiveness positioned citizens as subjects with social texts. HRC’s seductive listening performances likely educated her as well to the public’s political concerns even though she withheld her position regarding major issues. HRC’s reversal of the public sphere, consequently, helped to position her as an altruistic and sympathetic people’s candidate. This seductive posture projected a persona that bolstered her political attractiveness as someone “enormously positive [and] indisputable,” giving credence to the political value of just “showing up” because “that which appears is good” (Debord, 1991, para. 4).

Identity management. As an undeclared candidate, the First Lady surprised longtime supporters by practicing a pronounced feminine style. Heretofore, observes Campbell, she had demonstrated only a limited ability to perform femininity. As a public advocate HRC had spoken “forcefully and effectively” but she did so “with few of the discursive markers that signal femininity” (Campbell, 1998, p. 6). Harsh critics found her earlier style abrasive and unbecoming a First Lady. For loathing conservatives HRC represented a “convenient symbol,” a “stick to beat feminism” (Templin, 1999, p. 32). HRC no doubt smarted at the public’s reluctance to embrace her assertive style. She subsequently re-invented her image by adopting (unsuccessfully) a Madonna trope. Anderson (2002), though, speculates “there are undoubtedly other suggestive metaphors for tapping the mythic resources of change” (p. 22). The term “seduction” arguably captures the aesthetic style HRC used prior to declaring herself a candidate. As practiced by HRC, seduction came to symbolize rhetorical emancipation insofar as it created “space for a new perspective in which femininity and feminism [were] no longer cast as antithetical” (Anderson, 2002, p. 20). At play was the bonding of female autonomy and social normativity such that the category “woman” became the public site of the electorate’s “affective identification” (Burgett, 1998, p. 110).

HRC emphasized her interest as a caring, concerned citizen in the issues of health care, education, gun control, and full employment. HRC clearly signaled that she was self-reliant, hardworking, morally compassed, and a “family feminist” (Ingraham, 2003, p. 164) -a soothing term that conveys a felicitous balance of old-fashion and progressive values. In keeping with decorum and prudence, HRC avoided a roughshod assault on normative codes governing gender, political, and rhetorical roles. HRC underplayed her role as First Lady (Tomasky, 2001). Her charming demeanor avoided the appearance of elitism, privilege, or power. Even though HRC turned New York’s political order upside-down, she dodged charges of “being phony” or acting high-handed. Without question HRC’s enchanting demeanor struck an assuasive chord among voters, especially females who would later overwhelmingly support the First Lady in the New York Senate race. “That vote,” HRC said, “was a very powerful statement about what women voters care about, which is what I care about” (Bumiller, 2000, p. A5).

HRC’s charming demeanor and refusal to engage opponents confounded her adversaries. Although excoriated as an out-of-state “carpetbagger,” neither Rick Lazio’s jibe that “I’ve never needed an exploratory committee to decide where I want to live” nor Al D’Amato’s ad hominem crack: “Bring her on! If the bitch wants to establish residency in New York, she can stay at my place,” piqued HRC’s public ire (Monty, 1999). She demurely dismissed residency issues by donning a Yankee’s baseball cap, claiming “New York, my kind of town,” and declaring “What you’re for is more important than where you’re from” (Morrow, Grose, & Lord, 1999, p. 12). HRC’s newly discovered feminine voice, it appeared, precluded “not very lady- like” insult exchanges or vituperative mudslinging. HRC put it thusly: “They can launch anti-Hillary Web sites. They can use their limitless war chest to run negative television ads. But they can never stop me from standing up for what I believe” (Simendinger, 2000, p. 177). HRC’s seductive demeanor signaled authoritative calm as opposed to her counterpart’s chest thumping. “I am not going to comment on someone else’s campaign tactics. I will only speak for myself,” replied the First Lady (Nagourney, 1999c, p. A41).

HRC’s political style and advocacy of feminist causes as a first term First Lady created distance between herself and conservative women. By adopting a feminine demeanor during her pre-candidacy “campaign,” however, HRC found that some no longer perceived her as the “scheming harridan of their imaginations” (Grunwald, 2001, p. 50). “I come from the school of smaller steps now,” she said (Bennet, 1999b, p. 23). HRC’s feminine aesthetic shattered her previous image as an asexual, cold-hearted, political machine: “People tell me how down to earth I am….” (Bennet, 1999b, p. 23). She clearly recognized that people respond positively to a seductive feminine style. “I am not as bad as they thought,” she ventured (qtd. by Leonard, 2000, p. 11). Her newly exhibited feminine style was reflected in her family life, including a spirited defense of the President, house hunting excursions, and trips abroad with her daughter. These actions signaled spousal loyalty, domesticity, and nurturance, which had the effect of focusing the electorate’s attention on HRC’s femininity. Moreover, many female voters perceived HRC as having been betrayed by adultery. “Women felt she now had come down to their level… [as] one of the girls” (Emery, 1999, p. 18). HRC’s feminine style so convincingly re-framed her image that little negative notice was taken of her as she posed, “smiling serenely [in red satin] on the cover of Vogue” (“Run, Hillary, Run”, 1999, p. 9). It was as though performing femininity induced in “Hillary haters” a state of political amnesia. Emery marvels that even men re-evaluated “Hillary the woman,” especially when they paused to consider her marital loyalty and tolerance, suggesting that “their own wives should be this forgiving” (Emery, 1999, p. 18).

HRC’s articulation of a feminine grammar did not constitute an erasure of feminism, a turn to corporeal politics, or a rejection of either traditional or contemporary values. HRC’s displays of femininity held in balance her feminist idealism. HRC’s gender performance teased a feminine persona as it temporarily withheld/ suspended her feminist identity. As she put it, “It’s important when you’re in a campaign to always remember that this is not about you” (Tomasky, 2003, p. 39). Significantly, HRC’s appropriation of a feminine style had an immediate impact on her popularity. Her approval ratings skyrocketed. Many women saw her as a “fellow survivor; her victory [was] their redemption” (Noonan, 2000, p. xviii). Feminists saw her as challenging all odds. All this prompted the hypothesis that “If Mother Teresa rose from the dead and ran for the Democrats, she would still have ‘second-choice’ written all over her” (Anderson, 1999, p. 4).

Once HRC formally declared her candidacy for the United States Senate, she abandoned the seductive strategies of teasing and withdrawing. Political support assured, HRC emerged full-throated, decisive, and agenda-driven. To assure there would be no mistaking her identification with the feminist movement, she also dropped the subordinating name “Clinton” and replaced it with “Hillary.” She retained her seductive demeanor as a charming and enchanting campaigner, however. HRC’s prudent mastery of seductive appeals and strategies clearly helped shape her feminine image and election to the U.S. Senate. Put simply, HRC discovered her feminine voice and image in a rhetorical style that aesthetically enchanted, charmed, and seduced voters. She overcame her image as an out-of-state interloper and “radical feminist” to win the affection and respect of New Yorkers. Her strong election day showing, therefore, “was a sweet rebuke indeed -not just to the Hillary-haters…but to anyone who said [her political style] wouldn’t succeed” (Harpaz, 2002, p. 249). It emerged as a stinging rejection of the dislocation and suppression of women’s political voices, and aided HRC’s escape from the social tyranny of political forms that typically discipline the feminine.

OBSERVATIONS AND CONCLUSION

Seduction theory claims to establish agency for females by valorizing the liberating process of rejecting the feminine “ideal” of woman as a politically powerless “other.” Rhetorical critics, therefore, should not pre-judge seduction theory as dclass, notorious, or indefensible. Simply put, seduction theory boldly re- frames the means by which women can exert rhetorical influence -a style less encumbered by logocentrism’s censure of aesthetics, charm, allure, and enchantment. Contemporary theorists, as such, envision it lessening woman’s dependency on rationalism and its relentless “production” of woman. Rhetorical critics are encouraged, therefore, to think of seduction theory as an empowerment vehi\cle for women. Moreover, the critic must remain mindful that seduction theory is not intended to “contradict the broader agenda of feminism but rather reinforce it” (Goshorn, 1994, p. 287). Accordingly, critics should weigh with due caution patriarchal admonitions denouncing seductive rhetors as merely “narcissistic tease[s] who persuade by means of attraction and resistance, not by orderly discourse”(Gallop, 1982, p. 37; Bernstein, 1989; Hartman, 1992). HRCs campaign, for example, was neither narcissistic nor was it devoid of orderly discourse. Obviously, HRC used rationalist appeals to reify her authoritative ethos. Nevertheless, a critical assessment of only those appeals would merely satisfy “the hegemonic logic of reason” (Baudrillard, 1990, p. 46).

The rhetorical critic should not reduce seduction theory to essentialist or idealistic frames. Circumspect critics will no doubt detect significant variability in the creation and impact of seductive acts and appeals. A rhetor’s infelicitous performance, for example, may fail to stimulate interest or desire in subjects. The public may likewise grow weary of a seductive rhetor, their patience tested by strategies such as teasing and withdrawing. In addition, a subject’s attraction to seductive appeals will likely be context, issue, and personality sensitive. Seductive appeals and performatives may, for example, simply ill-suit certain agents or their desired image. An imprudent use of seductive appeals may likewise ignite unanticipated emotional responses from those who perceive non-rationalist appeals or performatives as violating normative social or cultural customs. An interpretive assessment of such “violations,” therefore, may yield insight regarding the rhetor’s sensitivity, prudence, or sense of decorum. Critics must be mindful as well that seductive performatives are subject to misinterpretation as play, whimsy, or irresponsible defiance. Similarly, seduction lives in the moment, which suggests that the rhetor “must continually perform to maintain the glance of partners [trans.]” (Handke, 1982, p. 224). Thus, a critic should analyze a rhetor’s spontaneous performatives as well as the multiple “fragments” that reflect a sustained use of seduction. Locating the “text” of HRC’s seductiveness, for example, is found primarily in her performatives, passing remarks, and charm (as opposed to formally articulated position stands or speeches). With the aforementioned in mind, therefore, we encourage rhetorical critics to be mindful of five foundational observations.

First, a seductive rhetor’s clat may aesthetically stimulate in subjects a state of adoration or sublimity, a “sudden shock of awe, wonder, euphoria [which] transport [s] an audience beyond a traditional standpoint” (White, 1987, p. 32). Lyotard (1992) describes the sublime sensation as the soul being “seized with admiration, veneration, respect immobilized” (pp. 99-100). A rhetorical critic, therefore, may elect to evaluate the rhetorical and political implications of an enamored electorate. The potential for abuse, claim seduction theory’s adversaries, may be ripe if it is true that we feel more alive when swept up by a seductive rhetor. Lyotard contends that it is in this euphoric state that seducers are capable of striking citizens “dumb,” their stunned silence unable or unwilling to bring the seductive rhetor back into perspective (Boyne, 1998). Thus, critics may wish to address psychological as well as aesthetic issues relative to a seduced state.

Second, seduction has the potential to render indistinguishable affective and rational appeals. Plato, for example, disdained seduction’s seeming indifference to ontology and rationalism, and its subsequent valorization of appearances and the passions (Ballif, 2001, p. 46). Those who charge seductive rhetors with practicing false appearances or artifice, however, must not assume that behind all rationalist rhetoric resides the real, the non-illusional – a stance we take to be untenable (Kaufmann, 1986). The critic may nevertheless assess the impact of affect-driven seductions that rupture the public’s epistemological foundations. Prompted by patriarchal concerns, the following issues arise: Will seductive rhetoric and its seeming indifference to western rationalism create a cultural rift? Will seductive rhetoric force rational decision- making to take a back seat to the passions and appetites, those emotional states that minimize the “need for the inconvenient particularities of argument and inference” (Farrell, 1989, p. 161)? These questions are significant because they address how a seductive rhetor may discursively engage or performatively elide rationalist arguments and disputes.

Third, seductive performatives may mystify position stands, rupture political conventions, or obfuscate political realities. Seduction theory’s opponents contend, for example, that seduction may “blind” those unaccustomed to aesthetic performances that promote “gesture over accomplishment and appearance over fact” (Miroff, 1988, p. 289). The impact of stylized performatives on the electorate’s perceptions of political reality, they argue, may cloud the relations that mark democracy by lulling citizens into a state of awe and suspended engagement. Logocentrists might contend that seduction theory deprives citizens of a true public sphere, which subsequently relegates them to “gigantic spaces of circulation, ventilation, and ephemeral connections” (Goodnight, 1987, p. 429). A critic should assess, therefore, the impact a rhetor has on the public sphere. How, for example does the strategic use of ambiguity and indecisive position stands potentially jeopardize the public’s perceptions of relevant issues? Do seductive gestures emerge as substitutes for informed discourse?

Fourth, seduction theory requires that a critic be sensitive to feminine aesthetics and human relationships. Seductive performatives typically signal regard, warmth, and wellbeing for others, rather than strategic intentions designed to dominate. A seductive rhetor is likely as well to incorporate inductive reasoning, affect appeals, and nonthreatening, non-dominating, non-invasive aesthetic performatives. A rhetorical critic, therefore, assesses whether such seductive strategies evoke endearment, respect, or awe, as opposed to compliance by imposition, possession, or rational quiescence. Furthermore, a critic may judge the extent to which a rhetor’s seductive practices reflect a lessened dependency on objectifying language, rationalism, and suppressive discourse conventions. The seductive arts, for example, should not be inspected or critiqued as a “strategy of conquest -pre-formed, prepared, and implemented by stages” insofar as rhetor and subject frequently interact in the kairotic “instant, in one fell swoop….” (Baudrillard, 1990, p. 112).

Fifth, seduction theory has power and ideological implications. Rhetorical critics, therefore, are encouraged to look to seduction theory when issues of objectification, suppression dominance, and control are at play. Critical objectivity demands, though, that critics set aside bias-laden interpretative standards, models influenced by patriarchy, rationalism, and/or ideological positioning. Thus, the ideological implications of seduction theory extend well beyond message construction, artfulness, and aesthetics. Moreover, seduction theory as a critical lens does not privilege issues such as the presence or absence of rationalist “good reasons.” Likewise, issues regarding power and the ethical implications of seduction theory to the goals of feminism are unresolved tensions. For example, Bernstein’s (1989) antagonist position sees seductive aesthetics as the “operation of dominance and submission” rather than cooperative goals or pleasurable intentions (p. 204). A cynical or ideologically biased critic, therefore, may judge a seducer as repressing or exerting dominance over the seduced, or worse, breeding disillusionment among misled or deceived “victims.” By contrast, an empowerment reading envisions seduction theory liberating, rhetorically, both the seducer and seduced.

To conclude, seduction is an imaginable aesthetic style even though it escapes formalization and the taxonomies of artistic expression. Regrettably, rhetorical theory’s patriarchal forefathers saw fit to reject seduction, subsequently labeling it flattery and feminine illusionism. Its rhetorical implications, interpretive value, and heuristic merit are, therefore, largely unexplored. Thus, we urge the feminist community’s forbearance regarding seduction theory. Critical analysis may greatly illumine seduction theory’s interpretive ingenuity as well as the civic applications of aesthete politics to oppressed classes. Indeed, its principles and practices may facilitate fresh sites of interpretation, access to institutions of political knowledge, and afford critics “an unanticipated political future for deconstructive thinking” (Butler, 1997a, p. 118). Moreover, a critical lens respectful of the seductive arts will likely recover the persuasive force of feminine aesthetics.

REFERENCES

Anderson, A. (1999, June 6). Top adviser says first lady will form exploratory committee next month. The Chicago Tribune, p. A4.

Anderson, K. V. (2002). Hillary Rodham Clinton as “Madonna”: The role of metaphor and oxymoron in image restoration. Women’s Studies in Communication, 25, 1-24.

Armstrong, N. (1987). Desire and domestic fiction. A political history of the novel. New York: Oxford University Press.

Ballif, M. (2001). Seduction, sophistry, and the woman with the rhetorical figure. Carbondale, IL: Southern Illinois University Press.

Baudrillard, J. (1990). Seduction. (B. Singer, Trans.). New York: St. Martin’s Press.

Bazinet, K. R., & Kennedy, H. B. (1999, June 24). Critics want Hillary Clinton to repay cost of flights to New York. The New York Daily News, p. A4.

Bell, D. F. (\1997). Stendhal’s legacy: Jean Baudrillard on seduction. In D. Fisher & L. R. Scheher, (Eds.), Articulations of difference: Gender studies and writing in French (pp. 18-33). Stanford, CA: Stanford University Press.

Bennett, J. (1999a, Feb. 16). President says Hillary would be a “terrific senator.” The New York Times, p. B1.

Bennett, J. (1999b, May 30). The next Clinton. The New York Times, p. F23.

Bennett, J. (2000, June 18). The guru of small things. The New York Times Magazine, pp. 60-65.

Bernstein, S. D. (1989). Confessing Lacan. In D. Hunter (Ed.), Seduction and theory: Readings of gender, representation, and rhetoric (pp. 195-213). Urbana, IL: University of Illinois Press.

Boissevain, J. (Ed.). (1992). Revitalizing European rituals. London: Routledge.

Boyne, R. (1998). Post-modernism, the sublime and ethics. In J. Good & I. Velody (Eds.), The politics of postmodernity (pp. 210- 226). Cambridge: Cambridge University Press.

Bumiller, E. (2000, Nov. 12). How gender helped elect Hillary Clinton. The New York Times, p. A5.

Burgett, B. (1998). Sentimental bodies. Sex, gender, and citizenship in the early republic. Princeton, NJ: Princeton University Press.

Burke, K. (1945/1969). A grammar of motives. New York: Prentice- Hall.

Butler, J. (1997a). “Excitable speech”: A politics of the performative. New York: Routledge.

Butler, J. (1997b). The psychic life of power: Theories in subjection. Stanford, CA: Stanford University Press.

Campbell, K. K. (1998). The discursive performance of femininity: Hating Hillary Rodham Clinton. Rhetoric and Public Affairs, 1, 1- 20.

Campbell, K. K. (2002). Consciousness-raising: Linking theory, criticism, and practice. Rhetoric Society Quarterly, 32, 45-64.

Cannon, A. (1999, July 12). New York state of mind. U.S. News & World Report, 727, p. 20.

Carotenuto, A. (2002). Rites QMJ myths of seduction. (J. Tambureno, Trans.) Wilmette, IL: Chiron Publications.

Clinton, H. R. (2003). Living history. New York: Simon & Schuster.

Conason, J. (1999, June 18-25). Eleanor Roosevelt rides again. Worchester Phoenix, p. A2.

Cottle, M. (1999, June 7). The wrong race. We) Republic, p. 24.

Crowley, S. (1989). A plea for the revival of sophistry. Rhetoric Society Quarterly, 7, 318-334.

Daly, M. (1999, June 21). Mayor Rudy faces challenges in die- hard Hillary fans. The Ne; York Times, p. A4.

Dao, J. (1999, Feb. 13). Torricelli steps up effort to get Hillary Clinton to run for U.S. Senate. The New York Times, p. B5.

Debord, G. (1994). The society of the spectacle. (M. lmrie, Trans). New York: Zone Books,

de Man, Paul. (1979). Allegories of reading: Figurai language in Rousse, Nietzsche, Rilke, and Proust. New Haven, CT: Yale University Press.

Dijkstra, B. (1986). Idols of perversity: Fantasies of feminine evil in fin-de-sicle cuff re. New York: Oxford University Press.

Emery, N. (1999, Nov. 30). Hillary’s meltdown. National Review, p.18.

Erickson, K. V. (Ed.). (1979). Plato: True and sophistic rhetoric. Amsterdam: Editions Rodopi, N.V.

Farrell, T. B. (1989). Media rhetoric as social drama: The winter Olympics. Critical Studies in Mass Communication, 6, 156-182.

Farrell, T. B., & Frentz, T. S. (1979). Communication and meaning: A language-action synthesis. Philosophy and Rhetoric, 22, 215-255.

Felman, S. (1983). The literary speech act. Don Juan with }. L. Austin, or seduction in (wo languages. (C. Porter, Trans.). Cornell, NY: Cornell University Press.

Ferguson, A. (1999, Aug. 3). Now they’re all ears. Time, 254, p. 8.

Ferguson, K. (1999). The politics of judgment: Aesthetics, identity, and political theory Lanham, MD: Lexington Books.

Foer, F. (1999, July 12). Hillary’s big gamble. U.S. News θ World Report, 727, pp. 28-30.

Foss, K. A., Foss, S. K., & Griffin, C. L. (1999). Fern/nisi rhetorical theories. Thousand Oaks, CA: Sage.

Foss, S. K., Griffin, C. L., & Foss, K. A. (1997). Transforming rhetoric through feminist reconstruction: A response to the gender diversity perspective. Western Journal of Communication, 20, 117- 135.

Foss, S. K., & Griffin, C. L. (1995). Beyond persuasion: A proposal for an invitational rhetoric. Rhetoric Society Quarterly, 62, 2-18.

Gallop, J. (1982). The daughter’s seduction: Feminism and psychoanalysis. Ithaca, NY: Cornell University Press.

Goodnight, G. T. (1987). Public discourse. Critical Studies in Mass Communication, 4, 428-432.

Goodrich, T. J. (Ed.). (1991). Women and power Perspectives for family therapy. New York: Norton.

Goshorn, A. K. (1994). Valorizing “the feminine” while rejecting feminism? – Baudrillard’s feminist provocations. In D. Kellner (Ed.), Baudrillard: A critical reader (pp. 257-291). Oxford: Blackwell.

Greene, R. (2001). The art of seduction. New York: Viking, 2001.

Grunwald, M. (2001, April 9). The figure in the carpetbag. New Republic, pp. 50-52.

Handke, P. (1982). Lent retour. Gallimard: Paris.

Hardt, R., Jr., & Birmbaum, G. (1999, Sept. 23). First lady’s in no hurry to be first one in race. New York Posf, p. A2.

Hariman, R. (1992). Decorum, power, and the courtly style. Quarterly Journal of Speech, 78, 149172.

Hariman, R. (1995). Political style: The artistry of power. Chicago, IL: University of Chicago.

Harpaz, B. ( 2001). The girls in the van: Covering Hillary. New York: St. Martin’s Press.

Hartman, S. (1999). Seduction and the ruse of power. In C. Kaplan, N. Alacon, & M. Moallem (Eds.), Between women and nation: Nationalisms, transnationalisms, and the state (pp. 111-114). Durham, NC: Duke University.

Herszenhorn, D. M. (1999, Sept. 23). First lady steadily inches closer to making candidacy official. The New York Times, p. Al.

Hitchens, C. (2000). Twin Souls. In S. K. Fly

Revelation CHoppers Owners Revving Up

Revelation Choppers is turbo-charging the custom motorcycle craze, and the company’s two sculptors are pounding out their metal masterpieces from a garage in Clendenin.

Jason Barnhouse and Rob Parsons, both of Clendenin, are what happens when bikers become businessmen. Between the two of them, they have eight tattoos. Parsons answers to the name “Bear” more than his actual first name. And the guys aren’t afraid to throw around words like “radically designed” and “old school craftsmanship.”

But Barnhouse is just as comfortable in a conference room as he is in a garage. He knows how to market his product and manage a business. Parsons is the artist. He has an eye for color and a passion for detail. Combined, the two men are the brains and brawn behind Revelation Choppers.

“We’re total partners in this, from a bike’s design to the very last bolt,” Barnhouse said.

America’s love affair with bikers has been growing since the Orange County Choppers hit primetime in 2002 with the custom build show “American Choppers” on the Discovery Channel.

Motorcycle sales are expected to hit an all-time high this year.

And Barnhouse and Parsons are geared up to take the high octane industry by storm.

Revelation Choppers specializes in custom-crafted theme bikes and currently is constructing a one of a kind motorcycle for Marshall University. The bike is in the design phase, but likely will feature autographs by former Marshall athletes who now play in the NFL. Football Coach Bob Pruett is even welding a piece or two of the metal. The motorcycle will be raffled off next year to raise money for the school’s Quarterback Club and give a little extra exposure to a business that is gaining national acclaim.

In the Beginning

Barnhouse, 33, built his first bike in 1996. After waiting more than a year for a custom-ordered Harley-Davidson, he decided he could build his own. Barnhouse found the parts he wanted and pieced together his first custom-built bike. He called on his good friend Bear Parsons for a fresh coat of paint. The two decided bike building might just be for them, but the timing was all wrong.

Parsons, 42, is a boilermaker by trade. Barnhouse is a parts and service sales representative for Walker Machinery. The guys waited seven years before finding the right time to resurrect their bike- building dreams. Revelation Choppers was officially incorporated in November 2003.

Their approach to bike building is a little different than what it used to be. Today, Barnhouse and Parsons build it all.

“From every aspect, it’s all handcrafted – from beating the raw, sheet metal out and putting the gas tank together,” Barnhouse said. “Right down to the paint scheme on the rear fender, it’s all us.”

To start the business, the men decided to build two different bikes. The first one would be a pro-street motorcycle. The second would be a chopper.

“The chopper has a more rigid frame, which just means it has no suspension. They’re traditionally higher in the front and have those long front ends,” Barnhouse said. “The pro-street bike is the more traditional bike with a curvier, more sleeker and sexier look.”

Time is at Hand

In just 49 days, the partners crafted their first chopper. Oddly enough, heavy equipment manufacturer Caterpillar Inc. was their muse.

“My dad has turned wrenches for Cat for years. My brother has been with Cat for 16 years, and I’ve been selling the machinery for quite a few years,” Barnhouse said. “Caterpillar has been feeding me since I was a kid, so I figured it was perfect for our first corporate-themed bike.”

When the men take the bike on tour, they also bring toy versions of Caterpillar equipment to illustrate their inspiration. Barnhouse can point out a bulldozer blade on the toy version and then show where a replica of the blade appears on the bike.

The bike has generated so much interest that officials at Caterpillar Inc. have considered buying it, and Barnhouse said it’s for sale.

Revelation Choppers’ second bike is called the Metal Messiah. The bike features handmade metal weaponry and is adorned with genuine rubies and black onyx. Both bikes are generating a buzz in the industry. Last month, Revelation Choppers won second place at the All-Star Chopper Show in Maryland, beating out some of the best in the business, including Orange County Choppers.

“It was great for us because of the respect we got from other builders,” Parsons said. “It’s nice when your friends and family tell you what a great job you’ve done, but when other builders acknowledge all your time and effort, it’s just an amazing feeling.”

Barnhouse said the show’s top builder even marveled at the detail on their bikes.

“We were so proud, we walked around like bullfrogs on steroids,” Barnhouse said.

Do Unto Them

A few weeks ago, the two men got another confidence booster when they were called on for a little help. An Orange County Choppers bike was on tour in West Virginia. When the crew tried to fire it up for a crowd at AirGas in Charleston, the $1.2 million bike wouldn’t start. Parsons just happened to be there.

“I called Jason and said, ‘You’re not going to believe this. They want us to fix their bike,’ ” Parsons said.

The guys from Revelation Choppers obliged, but their repairs came at a price – they got to film themselves fixing the bike.

Motorcycle enthusiasts all across the country are hearing about Revelation Choppers. Next month, the Confederation of Clubs, a peacekeeping group for all the nation’s biker clubs, will descend on Charleston for the first time ever. Revelation Choppers will be the feature builders.

It’s been a whirlwind year for the two men from Clendenin. When they’re not touring with their bikes or laboring at their day jobs, the men behind Revelation Choppers are planning the company’s future. A clothing line is in the works. And they plan to start selling their bike parts at Biker’s Haven in Kanawha County But their main focus will continue to be hammering out one-of-a-kind masterpieces.

“The elite bikes are high-end works and will probably sell for somewhere between $65,000 and $100,000,” Barnhouse said. “When we build these bikes for a specific person, we’ll measure their arms and legs. If a person has a bad left shoulder, we’ll compensate for that in the build to make sure it fits like a tailor-made suit. These bikes are strictly one of a kind.”

Information about the company is available online at www.rcidelaware.com.

Copyright State Journal Corporation Oct 22, 2004