BLOOMFIELD, Ky. — “There is no grand scheme,” said Linda Bruckheimer, who divides her time between a home in Beverly Hills, Calif., and Walnut Groves Farm on the outskirts of tiny Bloomfield, Ky., population 850, just 15 minutes northeast of Bardstown.

“I hadn’t planned to do all this,” she said.

But on a gray winter day in Nelson County, the soft-spoken, diminutive author of two semi-biographical novels — the best- selling “Dreaming Southern” and its 2004 sequel, “Southern Belles of Honeysuckle Way” — was seated in the foyer of her grand 1820 Greek Revival house set amid 1,200 picturesque acres.

Walnut Groves Farm is actually a compound rivaling the beauty of Shakertown at Pleasant Hill. Besides a new horse barn still under construction — dark charcoal with white cupolas, cedar horse stalls and color-coordinated horse blankets in an immaculate tack room — there’s another barn hiding the amateur hockey rink and Zamboni, a few grand guest cabins, a smokehouse turned billiard parlor, a washhouse, cannery, swimming pool and spa that looks like a stone-edged pond, a gazebo much like a round Grecian temple, a restored slave cabin alongside a lake and miles of white fence and dry stone walls. The mortar-less stacked stones have been perfectly restored, without a gap in sight.

Back a long driveway behind stone pillars and locked iron gates, just past the authentic cannon, is the antebellum main house — with white columns, of course. Bruckheimer has filled her Kentucky home with soft, sunny colors and American antiques. “I’ve always loved antiques.”

And there are large-scale oil paintings in the foyer, library and front parlor. A painting over the red Duncan Phyfe sofa in the library has an elaborately carved-and-gilded frame labeled “Marching Through Georgia,” 1815, Thomas Nast. The historic military scenes her husband loves.

He’s Jerry Bruckheimer, the mega-successful film and TV producer. Just a sampling of his films include “Top Gun,””Flashdance,””Beverly Hills Cop,””Black Hawk Down” and “Coyote Ugly.” Since 2000, he’s conquered the small screen with the hit TV series about forensics, “C.S.I.,” followed by many related series, plus “Without a Trace” and “Cold Case.” Bruckheimer’s foray into reality television sends couples around the globe in “The Amazing Race.”

Meanwhile, Mrs. Bruckheimer served six years as West Coast editor for Mirabella magazine and was writer-producer for two award- winning PBS specials.

She was born in 1945 and came of age in Louisville. Her first book, “Dreaming Southern” (Plume Printing, 1999), is a fictionalized account drawn from her own family’s late-1950s car trip from Kentucky to California. Her book’s characters may be Lila Mae Wooten and her four children crammed into a 1953 Packard-plus-trailer — but the ’50s references and description of the wild ride along Route 66 are so vivid, you know the author was along, likewise looking for the glamorous good life in Los Angeles.

After finding it, Bruckheimer felt that common tug to go back to her roots.

“The Southern Belles of Honeysuckle Way,” due out in paperback by the end of this month, put two of Lila Mae’s grown-up siblings and their teen-agers back on Route 66. They’re leaving California, headed for the fictional Blue Lick Springs, Ky., where they can see family and celebrate the good old days.

The novel’s villain, Horace Castle, happens to be a slick- talking developer aiming to bulldoze all the charm right out of the Commonwealth’s quaint village. Amid all the zaniness of relatives and small-town life, there’s romance and the belles’ determination to restore the town’s buildings.

That’s exactly what Linda Bruckheimer of Beverly Hills has done because her other passion, besides writing, is historic preservation. She’s a board member of the National Trust for Historic Preservation. In addition, the New York Times Magazine termed her “an advocate against overdevelopment in Kentucky who’s working with the University of Kentucky’s horticulture department to develop viable crops — like lavender, echinacea and Saint Johnswort — that will give new life to aging agricultural lands.

“Without new crops, land is worth little, and that leads to development,” Bruckheimer told the New York writer. To use a line from her “Southern Belles” book, developers swarm into depleted agricultural areas, turning the community into “a wasteland of fast- food restaurants, chain stores and neighborhoods with charming, woodsy names and Astro Turf lawns.”

Bloomfield, the real Kentucky village, is being transformed into a self-sufficient town and tourist destination by Bruckheimer and other residents enthusiastic about the tired town’s turnaround. Tourists may not visit the very private residence of Walnut Groves and its outbuildings; just the town, unless they’re among the Bruckheimers’ celebrity friends who visit for Derby weekend, or simply come to relax and envision another century in the deluxe, redesigned cabins or to join Jerry Bruckheimer’s Bad Boys hockey team — skating in the Walnut Groves Ice Garden — rustic on the outside, state-of-the-art inside. The famous film producer grew up in Michigan, which explains his favorite cold-weather sport.

The private estate began with Linda Bruckheimer’s purchase of the fine 1820 house, which she saved from old shag carpeting throughout. She kept the peacocks strolling about the grounds.

“I thought it was a mess when I first saw the house.” But with all the woodwork intact, she came to revise that opinion.

A cabin that once stood on the property by a rose garden was reduced to two stone chimneys, but Bruckheimer blended materials from two-and-one-half Kentucky cabins to make a fine guesthouse near the original cabin site. Then she got a call from Bloomfield, telling her about another cabin suitable for her acreage along the Lincoln Heritage Trail. This cabin had belonged to Nancy Hanks’ uncle, so the Richard Berry Jr. Cabin from Washington County was saved and erected at Walnut Groves Farm. A dogtrot cabin has joined that one. Then she agreed to restore a small slave cabin on behalf of Bloomfield citizens, buying it for $1 and setting it alongside a lake in view of cars coming and going from town.

A series of other interesting outbuildings are new but look old, such as the brick cannery with its wood-shake, conical roof and old cobblestone floor. Soft lights and a window or two illuminate the canning jars lined up on circular shelves. The jars are filled with vegetables from the large garden nearby; its perimeter a fence constructed of old tobacco stakes.

“This has all happened within the last 10 years, and I had no grand plan when I came here,” Bruckheimer said.

“I’m busier here in Kentucky (than in Los Angeles) — and all the buildings were done in record time. The dogtrot cabin was built in 38 days — from nothing on the ground to mints on the pillows.”

She said it has taken a lot of phone calls the past year and a half to organize the construction of the washhouse, cannery, storehouse and horse barn.

Along the way, she helped launch the renaissance of Bloomfield. She consulted the citizens first about what the town should be, could be like. She bought and restored the derelict 1899 Wells Building (on the National Register of Historic Places), then more buildings were restored until an entire Bruckheimer block of five was formed.

On one end, a narrow space is ready and waiting for some yet-to- be-found proprietor of an antique shop. It’s next to Amy’s Florist Shop, totally tasteful and uncrowded, all the better to see the well- polished, wide-plank floor underscoring the display of Valentine arrangements.

Jenny Wigginton of Olde Bloomfield Operations, LLC, and Bruckheimer’s assistant and spokesperson, gave a quick tour along this strip of red-brick sidewalk, its old herringbone pattern intact. A grant was written to restyle and give handicapped access to the bridge over Simpson Creek that flows through the center of town.

The charming copper-lantern streetlights were found and purchased by Bruckheimer, she said, after striking a deal with city hall that taxes would pay for their electrification and installation. First the copper fixtures had to be rescued from their coat of bright blue paint.

Further along the sidewalk is the Nettie Jarvis antique shop, fully operational after the raccoons were chased out and the back of the falling-down building restored. This fine shop at 111 Taylorsville Road is well worth a day-trip from Cincinnati. (Nettie Jarvis was Linda Bruckheimer’s great-grandmother.)

Open from 10 a.m. to 6 p.m. Tuesday through Saturday or by appointment, Nettie Jarvis is the real thing, a shop specializing in Kentucky antiques, though fine ones are scarce by now and expensive. The rest are American antiques, not mere collectibles, all neatly arranged in room settings with historical accuracy. There’s a fine silver display on the first floor in high wood-and-glass cases that seem to stretch forever. For more information, call (502) 252-9555.

For being so small, Bloomfield is remarkably self-sufficient, though its economy was no doubt hurt by Louisville malls 25 miles away. Wigginton reflected on the town’s past glory: “We used to have the tobacco market, and a train (depot) — .”

Now the town has a hardware store, pharmacy, food market, video source, antique stores, two florists — and other citizens have been inspired to restore the buildings they own. Bruckheimer restored a large building across the street from Nettie Jarvis as the Olde Bloomfield Meeting Hall, a family-friendly recreation place. It’s a delightful dip into the 1950s with a snack shop, ice cream parlor chairs, four bowling lanes, pool, pinball, a roller rink jazzed with neon lights and a Stereopticon gizmo on four legs. Just drop in a penny and visit the past. The walls of the roller rink are lined with black-and-white blowups of Linda Bruckheimer’s old family photos.

Due to her influential presence off and on, plus her preservation zeal, Bloomfield may be the only Kentucky town to boast both a Zamboni for her husband’s private ice rink and a perfumerie downtown. Her daughter, Alexandra Balahoutis, is not only a writer for Elle but also trained in the ancient perfume arts. The exotic shop is decorated with L.A. Confidential magazines, jars of dried lavender and rosebuds, plus oversize, antique perfume bottles from Guerlain and other Paris houses.

Bloomfield is definitely an entertaining trip back to the future.

Aging in males is accompanied by a steady decline of bioavailable testosterone levels, reaching, in 20-30% of men over 65 years old, levels below the reference range for young males. In the presence of signs and symptoms suggestive of androgen deficiency, subnormal levels of androgen may justify androgen supplementation.

The effects of this treatment are modest, characterized by an increase in lean body mass and decrease in fat mass (with little or no effects on muscle strength), a small increase in bone mineral density, increase in libido but little or no effect on erectile dysfunction, improvement of spatial cognition and verbal fluency, of mood and possibly of general well-being, the favorable effects being the more pronounced the lower the basal testosterone levels. The potential benefits of androgen supplementation in elderly men should, however, be weighed against the possible side-effects and risks, the most important concerning the prostate. Prostatic carcinoma is androgen-responsive and an absolute contraindication for androgen supplementation. Whether androgens might accelerate the transition of a subclinical carcinoma, highly prevalent in elderly men, to a clinical carcinoma is unclear for the moment, although the limited experience so far with androgen supplementation in elderly men is rather reassuring; androgens slightly increase levels of plasma prostate-specific antigen (PSA) and increase prostatic volume modestly.

As there is some evidence that estrogens, originating in males to a large extent from plasma testosterone, play a role in the development of benign prostatic hyperplasia, it has been suggested that non-aromatizable androgens might cause less prostate stimulation. Whereas 7α-methyl-19-nortestosterone (MENT) is just such a synthetic selective androgen receptor modulator (SARM), with less stimulating effects than testosterone on the prostate1,2, dihydrotestosterone (DHT) may be considered a natural selective androgen receptor modulator, as it cannot be aromatized. At first sight, it is surprising that DHT might have less prostate- stimulating effects than testosterone, as it is known that patients with congenital 5α-reductase 2 deficiency, and hence low DHT levels, have hypoplastic prostates. However, it seems that not plasma DHT but intratissular DHT, locally formed from testosterone, determines prostate growth. Due to the feed-back effect of DHT on pituitary secretion of luteinizing hormone (LH), plasma testosterone and estradiol levels decrease during DHT treatment3 and intraprostatic DHT may be decreased via decreased precursor testosterone levels.

Recently, Ly and colleagues4, as well as Kunelius and colleagues5, reported the effects of transdermal DHT treatment in placebo-controlled trials. Ly and colleagues4 administered DHT for 3 months at a dose of 70 mg/day as a 0.7% gel, whereas Kunelius and colleagues5 administered DHT 125-250 mg/day as a gel containing 2.596 of DHT. Based on the inclusion criteria (T

In the study of Ly and colleagues4, which did not require the presence of symptoms of partial androgen deficiency of aging male (PADAM) for inclusion, DHT levels increased to the normal concentration range of testosterone; levels of LH, follicle stimulating hormone (FSH), testosterone and free testosterone decreased as the consequence of the expected feed-back effect of DHT. Levels of total and low density lipoprotein cholesterol decreased without significant effect on the level of high density lipoprotein cholesterol. As to the clinical effects, lower limb muscle mass and strength increased, whereas fat mass decreased modestly, but no effects were seen in mobility tests, cognitive function or quality of life. However, Kunelius and colleagues5 included in their study men with clinical symptoms of androgen deficiency and, although using higher doses of DHT than Ly’s group, obtained lower DHT levels, and no tight correlation between dose and DHT was observed. Although the cumulated androgen levels, corresponding to the sum of testosterone and dihydrotestosterone, remained within the physiological range, there was a significant decrease in LH levels and a 50% decrease in estradiol levels. As to the clinical effects, the only statistically significant effect was an improvement in early morning erections and ability to maintain erections; effects on body composition were not studied, and no effects on well-being or vitality were observed. Prostate volume remained unchanged. It is interesting to mention that, in an earlier study, De Lignires6 had observed a modest decrease of prostate volume.

In so far as these short-term studies permit, it can be cautiously concluded that DHT treatment produces the expected androgen effects, whereas the absence of acute adverse effects may seem reassuring. The studies do not permit or even suggest that DHT treatment would have less effect on the prostate than testosterone. The studies do show, however, that the high concentrations of DHT do not have evident acute adverse effects on the prostate. The decrease in estrogen levels is not without concern, in view of the well- known role of estrogens in bone metabolism, as is evident in patients with estrogen resistance or aromatase deficiency who show significant osteopenia and delayed epiphyseal closure. Moreover, in elderly men, the correlation of bone mineral density is much stronger with estradiol than with testosterone, indicating a role for estradiol in maintaining bone mass. This was recently confirmed by a study by Meier and colleagues7 showing that chronic rhCG treatment (which increases estradiol levels), but not dihydrotestosterone, stimulates osteoblastic collagen synthesis in older men with partial androgen deficiency. Hence, it can be questioned whether treatment with the non-aromatizable DHT will maintain bone mass. As to the effect on the central nervous system, it seems that the effects of testosterone on cognitive functions are mediated via estradiol formed locally. Hence, whether DHT will have similar effects as testosterone on cognitive functions remains unknown. In conclusion, available data so far do not support the use of DHT in preference over testosterone in elderly men. Nevertheless, studies of longer duration, involving a large number of elderly men with subnormal androgen levels and clinical signs of androgen deficiency, comparing the effects of DHT to those of testosterone are certainly warranted in order to permit an answer to the question whether DHT has advantages over testosterone in the androgen replacement therapy of elderly men.

References

1. Cummings DE, Kuniar N, Bardin CW, Sundaram K, Brmner WJ. Prostate-sparing effects in primates of the potent androgen 7-alpha- methyl-19-nortestosterone: a potential alternative to testosterone for androgen replacement and male contraception. J CMn Endocrinol Metab 1998;83:4212-19

2. Anderson RA, Wallace AM, Sattar N, Kumar N, Sundaram K. Evidence for tissue selectivity of the synthetic androgen 7 alpha- methyl-19-nortestosterone in hypogonadal men. J CUn Endocrinol Metab 2003;88:2784-93

3. Wang C, Iranmanesh A, Berman N, et al. Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men. A clinical research center study. J Clin Endocrinol Metab 1998;83:2749-57

4. Ly LP, Jimenez M, Zhuang N, Celermajer DS, Conway J, Handelsman DJ. A double blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001;86:4078-88

5. Kunelius SP, Lukkarinen O, Haimuksela MI, Ikonen O, Tapanainen JS. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab 2002;87:1462-6

6. De Lignires B. Transdermal dihydrotestosterone treatment of andropause. Ann Med 1993;25:235-41

7. Ly LP, Jiminez M, Zhuang TN, et al. A double blind, placebo- controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility and quality of life in older men with partial androgen deficiency. J Clin Hudocniiol Metab 2001;86:4078-88

A. Vermeiden

Section of Endocrinology, Medical Clinic, University Hospital Gent, Belgium

Correspondence: Professor A. Vermeiden, section of Endocrinology, Department of Internal Medicine, University Hospital, De Pintelaan 185, 9000 Gent, Belgium

2004 Parthenon Publishing. A member of the Taylor & Francis Group

DOI: 10.1080/13685530400016672

Copyright CRC Press Dec 2004

[email protected]

With its slow motion movements, Tai Chi doesn’t look like a typical fast-paced form of martial arts.

But a martial art it is, said Tri-County YMCA Tai Chi instructor Vicki Elliott-Brown. “It’s a form of martial arts done very slowly,” Elliott-Brown said.

A year ago, the Tri-County YMCA started the Tai Chi for Arthritis & Health class, tailoring it for arthritis sufferers. Elliott-Brown said there are five forms of Tai Chi – Chen, Sun, Yang, Wu and Hao.

The Tai Chi for Arthritis & Health class teaches the Sun form, “Mainly because that has the least amount of extreme movement. This form is approved and supported by the Arthritis Foundation of America,” she said.

The Sun form of Tai Chi helps those with arthritis and fibromyalgia who have muscle and joint problems.

“There are a whole slew of benefits. It’s energetic, yet it relaxes. It relieves pain and stiffness, and it improves relaxation and concentration.”

Elliott-Brown said Tai Chi is an “internal” form of exercise that helps with balance and energy flow in the body.

“It focuses on breathing and is a mind-body form of exercise. It doesn’t necessarily mean that’s it’s easy to do, but this is designed to be very easy to do,” she said.

The Tai Chi for Arthritis and Health is a six-week class offered year round. Once students complete that class they can sign up for an intermediate Tai Chi class.

Elliott-Brown stressed that the Tai Chi class is beneficial for anyone, not just those with arthritis.

“We have people who don’t have arthritis taking the class. It’s for everyone, young and old.”

The Tai Chi movements are designed to be performed in a specific way. “It helps the body to relax and open up so that energy flows freely through the body,” Elliott-Brown said.

A Wisconsin native, Elliott-Brown started studying Tai Chi 11 years ago. “I actually studied Tae Kwon Do. I started practicing that and then learned about Tai Chi from an instructor where I lived. I went, and I loved it. I used to go at six o’clock in the morning,” she said.

Although a Tai Chi practitioner for more than a decade, Elliott- Brown said the martial art “takes a lifetime to master. And that’s the beauty of it. The goal is the journey of learning how to move efficiently and effectively and to free your mind.”

Elliott-Brown also teaches low-impact aerobics, Pilates and a “high-intensity sweatshop” class. She is also a personal trainer.

For more information about Tai Chi for Arthritis & Health or other Tri-County YMCA programs, call 757-0016.

Staff writer Ben Calwell can be reached via e-mail, or by calling 348-5188.

To THE EDITOR: Selective serotonin reuptake inhibitor (SSRI) antidepressants are considered effective, easy to use, and well tolerated. Because of their fairly benign side effect profile and low degree of interaction with the metabolism of other medications, SSRIs are also frequently used in the treatment of depressive symptoms in patients with various physical illnesses.

Gastrointestinal symptoms, such as nausea and diarrhea, are relatively common side effects of SSRIs (e.g., diarrhea with citalopram1). Carcinoid tumors of the gastrointestinal tract are also frequently associated with diarrhea. Serotonin may play a role in the pathophysiology of diarrhea associated with both SSRIs and carcinoid tumors.

We report a case of an elderly woman with a carcinoid tumor who developed serious profuse diarrhea after starting treatment of depression with citalopram.

case Report

Ms. A was a 75-year-old retired clerk who was evaluated by her primary care physician for vague gastrointestinal complaints, namely, softer stools but no abdominal pain. Her appetite was good, and her weight was stable. A finding of occult blood in the stool was followed by a colonoscopy. Because of poor visualization caused by numerous diverticula, the colonoscopy was incomplete. A barium enema revealed suspicious polyps in the ascending colon. An abdominal computerized tomography and ultrasound confirmed a mass in the ascending colon and possible metastases in the liver. After a right hemicolectomy, the pathology revealed a tubulovillous adenocarcinoma. In addition, the foci of the carcinoid tumor were found in pericolonic adipose tissue; however, the primary carcinoid tumor was not found. Subsequent chemotherapy with raltitrexed (not available in the United States) was well tolerated. Ms. A had loose stools twice a day without abdominal pain. She lost about 13 Ib in 6 months.

Because of a depressed mood and anxiety that developed after the seventh course of chemotherapy, she was given citalopram, 20 mg/ day. She reported profuse diarrhea after the first dose of citalopram, with loose stools up to 14 times/day. She became dehydrated and had to be hospitalized. Infection or recurrence of her adenocarcinoma were ruled out. Results of her laboratory tests (a CBC, liver enzyme measures, a urinalysis) were within normal limits. Ms. A was rehydrated and released to home care. Without citalopram, she began having loose stools twice a day. 5- Hydroxyindoleacetic acid (5-HIAA) in her urine was not increased 1 month after discharge (no 5-HIAA level was obtained during hospitalization). No diarrhea developed during subsequent treatment with mirtazapine, 15 mg at night.

Discussion

SSRIs block the reuptake of serotonin by neurons and thus increase the amount of serotonin at the synapse. As noted, SSRIs may be associated with diarrhea. Carcinoid tumors of the gastrointestinal tract produce large amounts of serotonin at times and are associated with diarrhea. Serotonin has been implicated in diarrhea associated with both SSRIs and carcinoid tumor. We postulate that the additive effect of elevated serotonin associated with both SSRIs and carcinoid tumors played a role in the pathophysiology of profuse, severe diarrhea in this patient.

Depression associated with carcinoid tumors is relatively rare;2 nevertheless, it could develop, especially in rare cases of severe comorbidity with other illnesses, as in our patient. Our case suggests that SSRIs should be avoided in patients with carcinoid tumors because a severe dehydrating diarrhea may develop.

References

1. Muldoon C:The safety and tolerability of citalopram. lnt Clin Psychopharmacol 1996; ll(suppl 1):35-40

2. Larsson G, Sjoden PO, Oberg K, Eriksson B, von Essen L: Health- related quality of life, anxiety and depression in patients with midgut carcinoid tumours. Acta Oncol 2001; 40:825-831

Zdenk Simbera, M.D.

Chocerady, Czech Republic

Richard Balon, M.D.

Dtroit, Mich.

Copyright American Psychiatric Press, Inc. Jan/Feb 2005

Researchers found progesterone therapy would block early labor in high-risk women

HealthDayNews — Using progesterone therapy to prevent preterm labor shows tremendous promise, at least among women at high risk for delivering prematurely, researchers report.

If all high-risk women had received the injections in 2002, it would have cut the nation’s preterm birth rate by 2 percent that year, according to a study reported in the February issue of Obstetrics and Gynecology.

“That translates to about 10,000 preterm births prevented, so we feel optimistic,” said study author Joann R. Petrini, director of the March of Dimes Perinatal Data Center.

The treatment involves receiving weekly injections of 17 alpha-hydroxyprogesterone caproate, a derivative of the hormone progesterone.

Researchers from the U.S. Centers for Disease Control and Prevention, the National Institute of Child Health and Human Development and others joined with the March of Dimes to assess the national impact of the progesterone derivative, known as 17P.

The new analysis is based on criteria from an earlier randomized controlled trial reported in the June 12, 2003, issue of the New England Journal of Medicine. That study showed a 33 percent reduction in preterm births among women with a history of spontaneous — meaning unexplained or unintended — preterm birth who got weekly injections of 17P.

Acknowledging the apparent benefits of the drug for high-risk women, the American College of Obstetricians and Gynecologists (ACOG) issued an opinion in October 2003 urging physicians to restrict progesterone use to pregnant women with a documented history of a previous spontaneous preterm birth. Further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, it said.

Preterm birth is a leading cause of infant mortality and long-term disability, according to the March of Dimes. In the United States, more than 480,000 births — or 12 percent of all live births each year– are preterm, meaning they occurred before 37 weeks of gestation. Between 1982 and 2002, the national rate of these births rose 27 percent.

Yet decades of research have yielded no intervention that is broadly effective in preventing preterm deliveries, the study authors said. From that perspective, 17P appears to be something of a breakthrough.

“That’s what the excitement is about: it’s the first drug that appears to help preterm labor,” said study co-author Dr. Nancy S. Green, medical director of the March of Dimes. There’s no other treatment on the horizon that promises to help prevent preterm labor, she added.

To estimate the national impact of 17P, researchers used 2002 birth certificate data augmented by vital statistics from two states. They included women who were pregnant with a single child, who had a documented history of spontaneous preterm birth and who began receiving prenatal care within the first four months of pregnancy. By estimating the number and rate of those births, they were able to predict the effect 17P might have.

In 2002, there were about 30,000 recurrent preterm births among women who fit the eligibility criteria for 17P, the authors estimate. That is based on 22 percent rate of recurrent spontaneous preterm births.

By administering 17P, the overall preterm birth rate would slip to 11.8 percent, preventing about 10,000 preterm births, they found.

“It’s not a panacea,” conceded study co-author Dr. Richard H. Schwarz, vice chairman of obstetrics and gynecology at Maimonides Medical Center in New York City. “The reason we’re keen on this is that this appears to be one area in which we do have something that seems to work.”

Doctors at Maimonides and across the country, in fact, are beginning to use it for patients who fit the high-risk profile, he added. One limitation: 17P is not commercially available; a physician must order it through a compounding pharmacy, which specializes in making special drug formulations.

Meantime, the potential of 17P among a broader population of women remains unknown. “More has to be done to know whether this drug, 17P, could be useful in other situations where there’s a risk of premature births,” including women pregnant with twins, Green said.

More information

U.S. Centers for Disease Control and Prevention

National Institute of Child Health and Human Development

American College of Obstetricians and Gynecologists (ACOG)

Check out the March of Dimes for more on preterm labor.

The essentials

* Some presentations of Parkinson’s diseasejriake diagnosis difficult.

* The underlying mechanism that ca uses PCHs un known._

* Bradykinesia, rigidity, tremor and postural instability are typical signs.

* Essential tremor is symmetrical and improves with alcohol.

* Parkinson plus syndromes are severe and have a poor prognosis.

1. History and epidemiology of Parkinson’s

Parkinson’s disease (PD) is a common progressive neurodegenerative condition, but patients present in a variety of ways, so sometimes the diagnosis can be difficult. Even the most experienced specialist in movement disorder is likely to misdiagnose up to a quarter of cases.

Accuracy is important, so that patients can be informed about what to expect, and to allow future planning. All patients should be referred to a specialist movement disorder clinic.

History of PD

James Parkinson first described PD in 1817, but the bradykinesia (slowness of movements) was mistaken for paralysis, and was termed ‘paralysis agitans’.

The first drug therapy, belladonna alkaloids, was used in the 186Os, but the next therapeutic advance was not made until anticholinergic drugs were introduced in the 194Os. Levodopa arrived in the 1960s, when PD patients were found to have neostriatal dopamine deficiency, after the finding that inhibition of peripheral decarboxylation of levodopa (using the decarboxylase inhibitors) improved cerebral levodopa delivery.

The first dopamine agonist (DA) bromocriptine was introduced in the 1970s. Further ergot-derived DAs were introduced in the 1980s, followed by non-ergot DAs in the 1990s. Enzyme inhibitors of monoamine oxidase B (selegiline) became available in the 1980s, and the catecholamine-O-methyltransferase inhibitor (entacapone) arrived in the 1990s.

Epidemiology

There are between four and 20 new cases of PD per 100,000 population per year. The incidence and prevalence increase with age, so a GP with a list size of 2,000 patients can expect to have about four patients.

The average age of onset of symptoms is 60 years. About 2 per cent of people over 65 years old have the condition, with men having a 1.5 times greater risk than women.

Racial differences

PD is most common in Caucasians, with the lowest rates in African races.

Patients with PD have a slightly reduced life expectancy, with a standardised mortality rate (the ratio of number of deaths in PD patients to controls) of 1.5. Parkinson’s disease is not a direct cause of death, and only half of death certificates for PD patients mention PD as an underlying contributory cause.

2. The range of possible causes

The specific cause of PD is unknown. There is loss of the pigmented dopaminergic neurones in the basal ganglia, but the underlying mechanism of this cell death remains a mystery.

What is clear is that there is a long pre-clinical phase, as symptoms only develop once there is significant depletion of striatal dopamine, and about a 50 per cent loss of pigmented neurons in the caudal substantia nigra. A delay in diagnosis is common. Many patients report symptoms well before the diagnosis is formalised.

The primary dopamine deficiency is not a simple depletion, as just replacing dopamine does not solve the problem. The basal ganglia consist of a complex network with positive and negative feedback loops involving several neurotransmitters, and the underlying pathophysiology is complex.

Genetic factors

The majority of PD cases are sporadic, but a few are inherited as a simple Mendelian trait. If an individual has a family history of PD, the risk of developing it is doubled, but still very low.

Twin studies have shown no increase in clinical PD in monozygotic twins, but functional imaging has shown reduced basal ganglia 18- fluorodopa uptake in monozygotic twins compared with dizygotic twins. This suggests that genetic factors may play a more important role than previously thought.

Environmental factors

Toxins can be involved, as demonstrated when a chemistry graduate in San Francisco manufactured a pethidine analogue for street sale that was contaminated with 1-methyl-4-phenyl-1,2,3,6- tertrahydropyridine (MPTP). Intravenous drug users injecting it developed severe parkinsonism, and active neuronal loss was found at autopsy.

Compounds structurally similar to MPTP are found in pesticides, and studies have shown a small increased risk of parkinsonism in rural areas and in those who drink contaminated well water. Heavy metals including manganese produce parkinsonism, but the clinical and pathological features are different from idiopathic PD. People drinking water containing manganese and aluminium have developed a parkinsonismdementia complex. Carbon monoxide poisoning can also induce parkinsonism.

Trauma and infection

Trauma resulting in head injury is sometimes cited as a cause of parkinsonism, but this is based on case-control cross-sectional studies, and has not been corroborated by a single prospective study.There is therefore the possibility that once Parkinson’s disease is diagnosed, patients may recall a head injury in the past (recall bias).

Early last century, post-encephalitic parkinsonism led to the suggestion of a possible viral aetiology, but the clinical and pathological features of post-encephalitic parkinsonism are different from those of the idiopathic disease.

Protective factors

Cigarette smoking imparts a reduced risk of PD, even after correcting for increased mortality in smokers. Explanations include a protective effect of nicotine, or personality factors. The loss of sense of smell in PD may contribute to stopping smoking in the early presymptomatic stages. Vitamin C has also been associated with PD.

3. The presentation of Parkinson’s

To make a diagnosis of PD using the UK Brain Bank criteria, there needs to be evidence of bradykinesia (slowness of movements), plus at least one of the following: muscular rigidity (resistance to passive movement), a tremor at rest with a frequency of 4-6Hz, and postural instability that has no other cause.

Bradykinesia

Bradykinesia is the only essential feature. Patients complain that they have slowed down, have difficulty with fine movements such as cutting food or managing buttons or zips, that their walking has deteriorated with a tendency to drag one leg and that their handwriting has become smaller.

They also have difficulty turning in bed at night. An early sign is loss of arm swing on one side.The family notice a loss of facial expression.

Generalised bradykinesia can be made from overall observations, and hand movements are examined by asking the patient to open and close the hands, to tap their index finger on the thumb (finger taps) or perform repeated wrist pronation/supination. In PD there is fatiguing of these movements with loss of amplitude, and with arrest of movement in later disease.

Leg movements are tested by asking the patient to tap the heel on the ground, lifting the foot by 5cm each time and watching for reduced amplitude and fatiguing.

Rigidity and tremor

Muscular rigidity is often described as muscle stiffness or sometimes as pain, leading to patients occasionally being misdiagnosed with an orthopaedic problem such as frozen shoulder.

Rigidity is present throughout the range of movement and can be described as ‘lead-pipe’ if smooth or ‘cog-wheel’ if tremor is superimposed. Mild rigidity can be detected by activation, that is by asking the patient to open and close the contralateral hand.

Although tremor is often the presenting feature of PD, it occurs in only 70 per cent of cases. It is typically asymmetrical, starting on one side but spreading to the other as the disease progresses. Tremor present at rest (pill-rolling) is classical of PD, but many patients also have postural tremor (demonstrated by asking patients to hold their arms outstretched and spread the fingers).This postural tremor is often latent and only emerges after a short delay, and tremors on action can also be present.

Postural instability

Postural instability develops as PD progresses, with patients complaining of poor balance and falling. It can often be detected clinically by the ‘pull test’, even early on.The patient stands with feet slightly apart and the clinician stands behind the patients and pulls sharply at both shoulders. The patient’s tendency to fall is observed, but the examiner needs to be ready to catch the patient if necessary.

The diagnosis of Parkinson’s disease remains largely clinical. Supporting features include persisting asymmetry of symptoms, a good therapy response, and the development of therapy-induced involuntary movements (dyskinesia). The diagnosis is supported by an abnormal result from presynaptic dopamine imaging.

4. Possible differential diagnoses

Essential tremor

Tremor is a common symptom, may be physiological, and can be enhanced by stress, certain drugs such as salbutamol, or diseases such as hyperthyroidism.

Management of tremor in primary care can be complex, and most difficulty lies in differentiating PD from essential tremor. In some cases functional imaging can help the diagnosis.

Essential tremor is usually present for months or years, is predominantly an action tremor, and is bilateral with symmetrical symptoms. There is of ten a positive family history, with no associated symptoms, and impr\oves with alcohol.

Treatment options

It is important to explain that it is not Parkinson’s disease, and does not affect life expectancy. Treatment may not be needed or wanted, but propranolol LA 80mg each morning can prove useful, although side-effects can outweigh the benefits. Primidone may also help but should only be used under supervision. Severe or doubtful cases should be referred.

Drug-induced parkinsonism

In epidemiological studies between a third and a half of parkinsonism is caused by medication and may be clinically indistinguishable from idiopathic PD, although a symmetrical presentation is commoner than in idiopathic PD. Neuroleptics are most commonly implicated, but the newer atypical neuroleptics are less likely to induce parkinsonism.

Anti-nausea agents such as prochlorperazine and cinnarizine are other culprits. Domperidone is the only anti-emetic which does not cross the blood-brain barrier and is often co-prescribed when initiating dopamine replacement therapy to reduce nausea, vomiting and postural hypotension. Sodium valproate, tetrabenazine, antidepressants and calcium antagonist are also reported to cause parkinsonism.

Drugs may be the sole cause of the parkinsonism, or may unmask underlying idiopathic PD. If purely drug induced, symptoms regress if the offending drug is stopped, but may persist for months or years. Sometimes it may be difficult to stop the medication or find a suitable alternative, when the severity of the symptoms and the Datient’s wishes should be taken into account.

Functional imaging can distinguish between drug-induced and idiopathic parkinsonism, and is increasingly available.

5. Other related syndromes

Vascular parkinsonism

Cerebrovascular disease can cause parkinsonism. Vascular parkinsonism has been described as classically of sudden onset, and involves the lower body, whereas idiopathic PD involves the arms more than the legs. A shuffling gait and small steps are therefore common. Structural imaging may confirm a multi-infarct state with infarction of the basal ganglia, or indicate small vessel disease that may influence the expression of parkinsonism.

However, cerebrovascular disease and idiopalhic PD may co-exisl and confuse the clinical picture. Functional imaging can then be useful to distinguish a purely vascular picture from neurodegenerative parkinsonism. This is important because neurodegenerative parkinsonism will respond to anti-parkinson therapy, but vascular parkinsonism responds poorly.

Parkinson plus syndromes

Parkinson plus syndromes represent a more widespread degenerative process of postsynaptic as well as presynaptic dopaminergic neurones, and so respond poorly to therapy. They are 10 times less common than idiopathic PD. Progression is faster, with decreased life expectancy.

Red flag signs that point to parkinson plus syndromes include axial rigidity, falls, loss of vertical gaze, dementia, and speech or swallowing problems that suggest a progressive supranuclear palsy. There may also be early autonomie features such as bladder instability and impotence, and cerebellar signs that suggest multiple system atrophy.

Parkinson plus syndromes are relatively rare but respond poorly to therapy and have a worse prognosis.

Many conditions cause parkinsonism. The diagnoses of Parkinson’s disease and parkinsonism are best confirmed by a healthcare professional with a special interest in movement disorders.

Further resources

Further reading

Movement Disorders in Clinical Practice edited by G Sawle, published by Isis Medical Media. Parkinson’s Disease in Practice by C Clarke, published by the Royal Society of Medicine Press.

Previously in Clinical Review

You can print an A4 copy of any Clinical Review published in the past year by logging on to GPonline.com. Recent issues have covered:

* secondary headaches (17 December)

* Primary headaches (10 December)

* Bladder dysfunction (3 December)

An extensive clinical review archive is available at www.GPonline.com

Parkinson’s disease is related to dopamine depletion in the basal ganglia, which have complex connections

Key points

* James Parkinson first described Parkinson’s disease in 1817.

* All patients should be referred to a specialist movement disorder clinic.

* An accurate diagnosis helps patients plan for the future.

* PD is nota direct cause of death, and reduces life expectancy only slightly.

Trauma to the head is not a confirmed cause of PD

Key points

* There is a long pre-clinical phase before Parkinson’s disease becomes evident.

* Genetic factors may play a more important role than previously thought.

* Toxins such as manganese and aluminium can cause a parkinsonism- dementia complex.

* Cigarette smoking imparts a reduced risk of PD, but the explanation is not clear.

Dopamine scans of the basal ganglia can be useful

Key points

* Bradykinesia is the only essential feature.

* Muscular rigidity is often described as muscle stiffness or sometimes pain.

* Tremor is only present in 70 per cent of cases.

* Patients may complain of poor balance and falling.

Thyroid scan: abnormal function can cause tremor

Key points

* Tremor may be physiological and can be enhanced by stress and certain drugs.

* Essential tremor may have a family history, and there are no associated symptoms.

* Reassure the patientthat an essential tremor isnotParkinson’s.

* Propranolol can prove useful, but side-effects can outweigh the benefits.

MRI can show small vessel disease in parkinsonism

Key points

* Vascular parkinsonism is classically of sudden onset.

* Confusion can occur if vascular parkinsonism and PD co-exist.

* Red flag signs suggest a parkinson plus syndrome.

* Parkinson plus syndromes respond poorly to therapy.

Contributed by Dr Katherine Grosset, GP and hospital practitioner, and Dr Donald Grosset, consultant neurologist, both at the neurology department, Southern General Hospital, Glasgow

Copyright Haymarket Business Publications Ltd. Jan 14, 2005

EARLY one dark and dreary January morning a year ago, Alison Vaughan, 36, a director of an art and design firm, dragged herself to the gym.

Joining the gym for the first time was her New Year resolution. Her gym instructor, Jeremy, had brown hair, a toned, lithe body and a cheeky smile.

And the fact that he was ten years younger than her, charming and devastatingly attractive certainly helped motivate Alison in her bid to get fit.

Before she knew it, he had not only talked her into agreeing to do three gym sessions a week, but also persuaded her to get up at 6am for a personal cardio workout.

Jeremy was extremely attentive and his compliments made Alison feel good.

She was proud of herself for finding the motivation to get fit.

At Pounds 25 an hour three times a week, it was an expensive hobby, but she reasoned that if it had worked for celebrities such as Kate Beckinsale, it would work for her.

She also knew how proud her husband Andrew, 42, a director at the same company, would be.

Though they had no children and Alison didn’t have the excuse of pregnancy weight gain, she had noticed that she was getting flabby around her waist and thighs. She wanted to make sure that Andrew still had eyes for her alone.

Within weeks, Jeremy offered to take sessions in her house as well as at the gym.

‘Soon, I started to look forward to the sessions perhaps a little more than I should,’ says Alison.

‘If I’d been honest with myself, the real reason for booking more and more gym sessions with Jeremy was that I enjoyed his company.

‘My husband worked long hours and I enjoyed the easy banter with my personal trainer. Without wanting to sound like a woman with a schoolgirl crush, I was enjoying the way he made me feel.’ The workouts became an escape from the boring outside world of meetings and hard work.

‘It was addictive. The fact that Jeremy made me feel attractive even when I was sweaty and not wearing makeup was hugely appealing.

‘He made me see the potential in myself to look sensational. I loved his company, the fact he was always complimentary and courteous, and treated me like a lady. After a few weeks, I found myself fantasising about wrapping my body around him.

‘I still loved my husband and had never been tempted to cheat on him before but the more I saw of Jeremy, the more I wanted to be with him.

‘I knew there was the potential for something to happen between us.

His physical fitness was a huge turnon.

The fact his skin would rub against mine as we were working out and I could smell his sweat was so exciting and intimate.’ Jeremy’s ability to make Alison feel as though she was the only woman in the world was an incredible aphrodisiac: suddenly, she was ready to walk into a trap which is proving a temptation for many women.

Plenty has been written about relationships between celebrities and gym instructors. Madonna’s personal trainer, Carlos Leon, fathered her first child, Lourdes. VANESSA Feltz found long-term solace in the arms of her trainer, Dennis Duhaney, after the break- up of her 16-year-old marriage.

And it’s not just famous people who are drawn to their gym instructors.

With more than 5,000 registered personal trainers in the UK, the number of ordinary women using their services is increasing.

And the number of wives finding themselves embroiled in locker room love affairs is growing, too.

The attraction is not purely physical. Cary Cooper, professor of psychology and health at Lancaster University, says that because of the intimate role personal trainers play in women’s lives, and the positive encouragement they offer, they can appear to have all the qualities of the perfect partner.

‘Busy women with equally busy partners crave the sort of attention that a personal trainer can give them,’ he says.

‘He takes the role of a confidant in much the same way as a hairdresser does, someone who sees you regularly and will listen to your problems and concerns.

‘Working one-on-one can be incredibly intimate, physically and emotionally. The personal trainer has a vested interest in your health and wellbeing, and is there to help you look and feel better. He is supportive and encouraging.

‘Moreover, he sees you at your worst, with no makeup and looking sweaty and unkempt. Yet for all that, he still accepts you for what you are.

‘Essentially, he is behaving in exactly the same way you would want your ideal partner to.’ However, like any affair, a relationship with a personal trainer is inextricably linked with lies and deceit.

In the case of Alison, she found herself acting entirely out of character and actively pursuing an extramarital affair.

‘I made the first move,’ she admits.

‘During one lunchtime session, Jeremy was adjusting some equipment I was working on and I spontaneously kissed his ear. As soon as I had done it, I felt mortified. Not because of my husband but in case Jeremy thought I was crazy. But he responded by telling me that he was extremely attracted to me.

‘Later that day, he called me on my mobile phone – he had my number to arrange our training sessions – and asked me to go out for a drink with him the following day.

‘I was so excited but my stomach was churning with guilt. He’d awakened feelings in me that I hadn’t experienced for many years.

‘I knew deep down where it was leading and over the next few weeks our drinks turned from flirty chats to a fullblown affair.

‘Once a week, I would tell my husband I was seeing girlfriends, when I was really having the best sex of my life. Sex had suddenly become forbidden, exciting and sensual, unlike with my husband, who was predictable in bed.’

Naturally, Alison’s affair started to dent her marriage as she found herself comparing her husband unfavourably with Jeremy. And while he continued to work long hours and so didn’t suspect anything, Alison was aware of an unspoken gulf growing between them.

She made the classic mistake of thinking she was the only client Jeremy was involved with and so was devastated to discover he was having a similar relationship with another woman.

‘When a gym client I was friendly with told me she, too, had been sleeping with Jeremy, I felt sick. I confronted him and he didn’t even try to deny it.

He just said he still fancied me but it was “just one of those things”.

‘At first, I was hurt, then angry and finally I was overcome with utter shame at what a fool I’d been.

‘Of course, a man as good looking as Jeremy was going to have lots of women throwing themselves at him. I couldn’t believe I’d put my marriage on the line over an affair; but for him, I was just another perk of the job.

‘I quickly changed gyms and although I still have a personal trainer, I made sure this time I chose a woman.

‘When I see other women in the gym flirting with their male instructors, I feel sorry for them. I know how easy it is to be conned by their flattery and hope they don’t make the same mistake I did.’ PAUL COOK, a 27-yearold personal trainer from Wimbledon, South- West London, says women throwing themselves at him is just part of the job.

‘Flirting with clients has always gone on, and most of the time it’s harmless.

The majority of the women aren’t my type anyway,’ he says.

‘It’s usually wealthy, married women in their late 30s with children who come on to me. It’s not that they’re bored housewives – most of them are intelligent career women with great jobs, who probably should know better, but can’t quite stop themselves.’ Dr Nick Neave, evolutionary psychologist at Northumbria University, says the attraction between a woman and her personal trainer is often inevitable purely in terms of how humans have developed.

‘Women prefer physical fitness in men because it indicates they are healthy.

They like broad shoulders, a narrow waist and guys who are hunky but not too muscular,’ he says.

‘During exercise, the body releases chemicals called endorphins, which make you feel relaxed, happy and can even dull pain. When women feel some of these emotions, they can be far more sexually receptive.

‘This natural high makes them feel sexy and, subconsciously, they start looking for a mate.

‘Also, exercise releases chemicals called pheromones from a man’s armpits, which increase his attractiveness to a woman. These chemicals can even change her perception of his face so she finds him more attractive.’ A potent combination of sexual evolution and the fact that many women use their relationships – sexual and non- sexual – as an escape from unhappy relationships and marriages reflects a deeper problem in modern society, where increasingly both partners work hard, leaving little time for intimacy.

This is certainly what happened to Susan Woods, a 30-year-old marketing executive from Jersey.

Deeply unhappy in her live-in relationship of three years, she found her head was turned by the obvious flirting when she started gym sessions with her personal trainer, David.

‘It was obvious he was a real ladies’ man and the more I saw him, the more the flirting escalated,’ she says. HE WAS extremely tactile.

Whenever he helped me use a new piece of equipment or do a new exercise, we would touch and I’d feel a spark between us.

‘Sometimes, he would just pat my shoulder or arm but at other times he’d put his hand on my stomach to check I was working my muscles properly or put nearly all his body weight on me to help me stretch, which felt incredibly sexy.

‘I had been confiding in him from the beginning about the rows with my boyfriend. At first, it was just like having a male friend to confide in. But then one day, a couple of months after we met, I broke down in tears in the gym after another row with my partner.

‘David took me by the hand, led me into another room, closed the door and kissed me full on the lips as I leant against the wall. It was late in the evening and no one else was around.

‘I was shocked when it happened – so much so, that I couldn’t speak. He smiled and suggested that we finish the workout.

It was surreal, but I wanted more. I felt terrible that I had kissed another man after all, I had never been unfaithful to my boyfriend before.

But I couldn’t stop thinking about David.

‘The next time I saw him was by coincidence.

The following day, I was walking back from work and he passed by on his bike. He stopped and asked if I wanted to go back to his place. I said ‘Yes’ – and that’s when our four-month affair began.

‘While I was seeing David in secret at his flat, I didn’t want sex with my boyfriend but he never even questioned it or asked if there was anything the matter.

‘This reinforced my decision to have an affair. If my boyfriend didn’t care about me, then why shouldn’t I find solace with someone else?

‘I knew my relationship with David would never go anywhere because I was just another conquest to him.

‘I suspected he was having other affairs while he was seeing me – he often used to go outside to speak on his mobile phone and was always flirting with other women in the gym. I never asked him because I didn’t need to.

‘Looking back, our relationship was based purely on sex. He was passionate in bed and taught me things I had only ever read about. Eventually, I was the one to end things when I moved to Kent to take up a new job.

‘Seeing David made me realise that my relationship with my boyfriend was all wrong – so I left him.

‘I ended my relationship with David around the same time because I wanted a clean start. He wasn’t upset when we split up: he wished me luck and accepted I had to move on. THE AFFAIR served its purpose and I eventually went on to meet someone who was not a ladies’ man. I don’t think all personal trainers are womanisers, though it would be easy to fall for one because most are charming and you spend so much time with them.

‘I wasn’t the first client David had an affair with and I’m sure I won’t be the last.’ But relationships with personal trainers don’t have to be sordid affairs. Fleur Rhiannon, 23, who is single and a personal assistant for an actor’s agency in Kensington, West London, dated her gym instructor for nine months.

She hired her trainer, Paul, to help her shed a stone in weight. But a feeling of closeness and camaraderie soon developed and they became friends outside the gym. One night, eight months after the training sessions began, they went for a drink in a bar together.

‘Trainers have a really bad reputation. I know a few people who have had a fling with theirs,’ says Fleur. ‘So I assumed Paul would have women falling at his feet and had no intention of being another conquest. But that drink was the start of a relationship that proved me wrong.

‘Even though we were dating, while we worked out at the gym he was totally professional and treated me like any other client.

‘One of the attractions was the physical element of our training together and the accidental physical contact.

‘I was worried that after spending the day with beautiful bodies, he’d come home and find fault in mine. But he never did. He wouldn’t even pass a comment if we went out for dinner and I ate fatty foods.

‘At the beginning of the affair, I asked him if he’d had a relationship with a client before, but he said I was the first. I still believe him.

‘He was friendly with the women he trained and I can see how easy it would be to misconstrue this for something more. I felt jealous of the more attractive ones he worked with. But I felt sorry for the women who made themselves embarrassingly available to him because they must have been lonely and misguided.

‘We split up after nine months because the relationship had run its course. I would never put anyone off going out with a personal trainer, but it isn’t the easiest relationship to have. The temptation for many gym instructors is too great.’ Of course, not all personal trainers take advantage of the situation. Kristoph Thompson, a 23-year-old gym instructor from Eastbourne, East Sussex, has faced women with a crush many times and has learned strategies to deal with it.

‘Almost all of my clients are women and about 75 per cent of them flirt with me. If a woman approaches me, I make it very clear that although I’m flattered, I don’t mix business with pleasure,’ he says.

‘I think it would be unprofessional but I know a lot of trainers who don’t think that and are more than happy to take advantage.

But they’re the ones who give this profession a bad name.’

With the shift to outpatient surgery and same-day admissions, as many as 90% of patients arrive at the facility on the day of their surgery. More complex surgery is being done in the outpatient setting, and even patients with fairly serious health problems are having surgery on a same-day basis.

This makes the preoperative process harder to coordinate, and it is more difficult for nurses and anesthesia providers to get the information they need about patients before surgery. There also is a wide variation in preoperative testing practices.

Seeing the need for a framework for this process, a consensus group at Johns Hopkins developed guidelines on preoperative evaluation, an effort led by anesthesiologist L. Reuven Pasternak, MD. Dr Pasternak also chaired the task force that developed the American Society of Anesthesiologists (ASA) Practice Advisory for Preanesthesia Evaluation.

The Johns Hopkins guidelines used an empirical approach because definitive studies are still lacking, he says. The guidelines rely on ASA physical status as well as a surgical procedure risk classification system developed by the Johns Hopkins group. Procedures are classified from Levels 1 to 5 according to risks independent of the patient’s underlying health status or type of anesthesia, such as blood loss and invasiveness. The ASA status plus the surgical risk are combined in a matrix to indicate whether patients should have a preoperative evaluation on the day of surgery or before the day of surgery by a primary care provider or by an anesthesia provider.

These tables are from the Johns Hopkins guidelines.

Conditions for which preoperative evaluation is recommended prior to the day of surgery

General

* Medical condition inhibiting the ability to engage in normal daily activity

* Medical conditions necessitating continual assistance or monitoring at home within the past 6 months

* Admission within the past 2 months for acute condition or exacerbation of chronic condition

Cardiocirculatory

* History of angina, coronary artery disease, myocardial infarction

* Symptomatic arrhythmias

* Poorly controlled hypertension (diastolic >110, systolic >160)

* History of congestive heart failure

Respiratory

* Asthma/chronic obstructive pulmonary disease requiring chronic medication or with acute exacerbation and progression within past 6 months

* History of major airway surgery or unusual airway anatomy

* Upper and / or lower airway tumor or obstruction

* History of chronic respiratory distress requiring home ventilatory assistance or monitoring

Endocrine

* Non-diet controlled diabetes (insulin or oral hypoglycemic agents)

* Adrenal disorders

* Active thyroid disease

Neuromuscular

* History of seizure disorder or other significant central nervous system disease (eg, multiple sclerosis)

* History of myopathy or other muscle disorders

Hepatic

* Any active hepatobiliary disease or compromise

Musculoskeletal

* Kyphosis and/or scoliosis causing functional compromise

* Temporomandibular joint disorder

* Cervical or thoracic spine surgery

Oncologic

* Patients receiving chemotherapy

* Other onocologic process with significant physiologic residual or compromise

Gastrointestinal

* Massive obesity (>140% ideal body weight)

* Hiatal hernia

* Symptomatic gastroesophageal reflux

Recommended laboratory testing

These tests are those required for administration of anesthesia and are not intended to limit those required by surgeons for issues specific to their surgical management.

Electrocardiogram

* Age 50 or older

* Hypertension

* Current or past significant cardiac disease

* Current or past circulatory disease

* Diabetes mellitus (age 40 or older)

* Renal, thyroid, or other metabolic disease

* Procedure Level 5

Chest x-ray

* Asthma or chronic obstructive pulmonary disease that is debilitating or with change of symptoms or acute episode within past 6 months

* Cardiothoracic procedure

* Procedure Level 5

Serum chemistries

* Renal disease

* Adrenal or thyroid disorders

* Diuretic therapy

* Chemotherapy

* Procedure Level 5

Urinalysis

* Diabetes mellitus

* Renal disease

* Genitourologic procedure

* Recent genitourinary infection

* Metabolic disorder involving renal function

* Procedure Level 5

Complete blood count

* Hematologic disorder

* Vascular procedure

* Chemotherapy

* Procedure Level 4

Coagulation studies

* Anticoagulation therapy

* Vascular procedure

* Procedure Level 5

Procedure Level 4

Highly invasive procedure with blood loss >1,500 cc; major risk to patient independent of anesthesia.

Includes: Major orthopedic-spinal reconstruction, major reconstruction of GI tract, major genitourinary surgery such as radical retropubic prostatectomy, major vascular repair without postoperative ICU stay.

Procedure Level 5

Highly invasive procedure with blood loss >1,500 cc; critical risk to patient independent of anesthesia; usual postoperative ICU stay with invasive monitoring.

Includes: Cardiothoracic procedure; major procedure on oropharynx; major vascular, skeletal, neurologic repair.

Source: Pasternak L R, Rosenfeld B A, Handelsman J C, et al. A consensus approach to preoperative evaluation using the Johns Hopkins risk classification system. Reprinted with permission.

A copy of the Johns Hopkins consensus guidelines, with the matrix and surgical risk classification, is available by e-mailing Dr Pasternak at [email protected]

Copyright O R Manager, Inc. Jan 2005

Abstract

Introduction: Although branchial cysts may present as asymptomatic swellings, about one-third present acutely due to inflammation. The use of fine-needle aspiration biopsy (FNAB) and computerized tomography (CT) is controversial. The treatment of inflamed cysts is also controversial.

Aims: To compare the findings of FNAB and CT between cases of branchial cysts presenting as an asymptomatic swelling, and those presenting acutely due to inflammation, and to examine the management of infected cysts.

Materials and methods: Retrospective review of the medical records of 39 adult patients with histologically proven branchial cysts treated by the senior author (C.V.T.) between 1994 and 2003.

Results: Twenty-eight patients presented with an asymptomatic swelling. Eleven presented acutely with inflammation. A higher incidence of indeterminate fine needle aspirates and atypical CT features were found in the inflamed group. Initial treatment in the infected group consisted of intravenous antibiotics, followed by aspiration or surgical exploration in non-resolving cases. Interval excision after six weeks was performed in all inflamed cases without complication.

Conclusions: FNAB is recommended in all cystic neck lumps to rule out malignancy, but may be inconclusive, especially in inflamed cysts. Inflamed cysts are best treated with intravenous antibiotics, with or without aspiration or incision and drainage, followed by interval excision.

Key words: Branchial, infection, aspiration

Introduction

Branchial anomalies may exist as a cyst, a sinus, or a fistula. They are due to persistence of vestigial remnants of a branchial cleft or pouch.1 The first recorded treatment of branchial cysts was by Langenbeck in 1855. He treated one by incision, and another by insertion of a seton.2

The majority present as asymptomatic neck swellings; however, around one third have been reported to present as rapidly enlarging masses due to inflammation.3 Investigations vary from solely clinical diagnosis,4 to the use of fine-needle aspiration biopsy (FNAB) and more involved radiology such as ultrasound and computed tomography (CT) scanning.5 The treatment of choice is surgical removal because of the natural history of increase in size and liability for infection.2 Most of the reported series have included a mixture of all branchial anomalies, with little information given regarding the usefulness of radiological investigations or FNAB. The management of inflamed branchial cysts is another area which is not well described in the literature.

The objectives of the present study were: firstly, to compare the findings of FNAB and CT scanning in cases of branchial cysts presenting as asymptomatic swellings with those presenting acutely due to inflammation; and secondly, to examine the management of inflamed branchial cysts, and the outcome of this management.

Materials and methods

The medical records of all adult patients with a diagnosis of branchial cleft cyst undergoing surgery under the care of the senior author (C.V.T.) at the Royal Victoria Eye and Ear Hospital and St. James’ Hospital, Dublin, Ireland, over a nine-year period between 1994 and 2003, were retrospectively reviewed. Patients were included only if they met the clinical criteria for diagnosis of a second arch branchial cleft cyst, and the diagnosis of branchial cyst was confirmed histologically.6 Patients with first arch branchial cleft cysts, or with cervical cysts in unusual locations, were thus excluded. Cases of cystic mtastases masquerading as branchial cysts were also excluded. Data was collected regarding patient demographics, clinical features, radiological findings, fine-needle aspiration cytology findings, and pathological findings, as well as treatment administered, complications, and recurrence rate.

TABLE I

DATA ON FINE NEEDLE ASPIRATION BIOPSIES

The patients were divided into those who presented with asymptomatic neck swellings, who were booked for elective surgery (non-inflamed group), and those who presented acutely with painful rapidly enlarging neck swellings, requiring emergency hospital admission (inflamed group). The radiological and pathological findings were examined with comparison of the two groups. In addition, the management of patients with inflamed branchial cysts, as well as the eventual outcome in these patients, was examined.

Results

Forty-one patients with a clinical diagnosis of branchial cyst were identified; of these two were considered to have first arch branchial anomalies, and were thus excluded, leaving 39 for analysis. Twenty-three (59 per cent) were female and 16 (41 per cent) were male. The patients’ ages ranged from 16 to 52 years, with a mean of 30.3 years, and a median of 26 years. Twenty-three (59 per cent) of the cysts were left-sided. Twenty-eight patients (71.8 per cent) presented with typical features of an asymptomatic lateral neck swelling gradually increasing in size over a period of time ranging from four weeks to 18 months. Eleven patients (28.2 per cent) presented acutely with a rapidly enlarging painful swelling over a period of time ranging from four days to six weeks and were admitted to hospital as emergencies.

TABLE II

RADIOLOGICAL DATA

FNAB was performed in 36 patients. Twenty-six of these were in the non-inflamed group, and 10 were in the inflamed group. Table I summarizes the FNAB findings in patients with inflamed and non- inflamed cysts. In six (60 per cent) of the patients with inflamed cysts, and in 19 (73 per cent) of the patients with non-inflamed cysts, the diagnosis of branchial cleft cyst was considered to be clearly supported by the finding of mature squames, with or without polymorphonuclear cells, and cholesterol crystals on FNAB. In one further patient in each group, the finding of cellular debris was considered to be consistent with a diagnosis of branchial cleft cyst. FNAB findings were reported as inconclusive in three (37.5 per cent) patients with inflamed cysts, and in five (19.2 per cent) patients with noninflamed cysts. FNAB was reported as showing squamous cell carcinoma in one patient with a noninflamed cyst; however this was subsequently found to represent a false-positive finding.

Microbiological culture of the aspirates of patients with inflamed cysts in every case failed to yield causative organisms.

Radiological studies were performed in nine patients with inflamed cysts, and in 13 patients with non-inflamed cysts. The radiological findings are summarized in Table II. Ultrasonography was performed in four patients (two with inflamed cysts, and two with non-inflamed cysts). Ultrasonography was not found to be helpful in making the diagnosis of branchial cleft cyst in any of these cases. CT scanning was performed in 18 patients (seven with inflamed cysts, and 11 with non-inflamed cysts). This demonstrated an abscess in five of the seven patients with inflamed cysts, and a necrotic mass in the other two. Among patients with non-inflamed cysts, CT scanning effectively demonstrated an anterior cystic neck swelling consistent with a diagnosis of branchial cyst in eight of eleven cases. Only two patients, both with non-inflamed cysts, underwent magnetic resonance imaging (MRI). In both cases, the presence of a cystic cervical swelling consistent with a diagnosis of branchial cleft cyst was effectively demonstrated.

All 28 patients with non-inflamed cysts underwent excision of the cyst as surgical treatment, and no complications were recorded. The initial treatment for the 11 patients with inflamed branchial cysts was hospitalization for intravenous antibiotics. With this treatment, resolution of the inflammatory process occurred in four patients. Four patients underwent aspiration of the contents of the inflamed cyst. In two patients, the inflammation subsequently resolved. The other two patients, along with the three others who failed to settle on antibiotics alone, proceeded to undergo surgical exploration of the mass. At surgery, the cysts were found to be adherent and impossible to resect completely without risking morbidity. Incision and drainage of the contents was thus performed, along with biopsy of the cyst wall. All 11 patients with infected cysts underwent interval excision at six weeks without complication (Figure 1).

Histopathological examination of the excised branchial cyst demonstrated squamous epithelium, with abundant lymphoid tissue in the cyst wall in 34 patients (87 per cent) and cholesterol crystals in four patients (10.25 per cent). None of the cases showed any evidence of malignancy, including the case in which FNAB had been reported as showing squamous cell carcinoma.

Discussion

The age distribution, and the laterality of the cysts in the present series are similar to those reported by others.2,7 However, although other authors have reported branchial cysts to be more common in men, most of the patients in the present series were women.2,8

FIG. I

Treatment of inflamed cysts.

Branchial cysts most commonly present as asymptomatic neck swellings; however, acute presentation with a rapidly enlarging painful neck mass due to inflammation may also occur. Fleming reported infection to be the presenting feature in nine of 26 (35 per cent) patients with branchial cysts.3 A similar incidence of acute presentation with inflammation (28 per cent) was found in the pre\sent series.

Cystic neck lumps may present a challenge to the head and neck surgeon. The commonest cause of a cystic neck lump is a branchial cyst; however, cystic metastases from squamous cell carcinoma of the head and neck, or from papillary carcinoma of the thyroid, may also occur, and may masquerade as a branchial cyst.9-13 Accurate diagnosis of cystic neck lumps is thus of significant importance. However, excision of a neck lump of unknown aetiology is generally considered to be contraindicated, as this practice has been shown to have an adverse impact on outcome in cases where the lump transpires to be metastatic.14

Fine needle aspiration biopsy (FNAB) is of proven utility in the diagnosis of solid neck lumps, and does not violate the neck.15 However, the efficacy of this procedure in the diagnosis of cystic neck masses is less clear. The cytological features of branchial cysts include mature squamous cells, cellular debris, lymphocytes and macrophages.16 Previous authors have reported the sensitivity of FNAB in the detection of malignancy in cervical cysts to be poor; however, the numbers of patients undergoing this procedure in these studies were small.10-13 A recent paper reported FNAB to have a sensitivity of 73 per cent in the diagnosis of any type of cystic cervical metastasis, and a sensitivity of 60 per cent in the diagnosis of cystic metastases masquerading as branchial cleft cysts.9 False-negative aspirations commonly arise due to hypocellular or insufficient aspirates,16 and arc reported to be less likely when part of the cyst wall is included in the aspirate.17 The use of flow cytometry to detect aneuploidy has also been suggested to improve sensitivity.18 False-positive aspirates may also occur, as was the case in one of our patients. This is commonly due to cytological atypia on account of inflammation and regeneration.17 In general, falsepositive findings are reported to be rare.16

In the present series, 25 of 36 patients had FNAB findings which were considered to be strongly supportive of a diagnosis of branchial cyst (mature squamous cells, polymorphonuclear cells, and cholesterol crystals), with two others having findings considered to be consistent with a diagnosis of branchial cleft cysts (cellular debris with no evidence of malignant cells). FNAB findings were inconclusive in eight patients. A higher incidence of inconclusive findings was found in patients with inflamed cysts. We believe, given the high false negative rate of FNAB in the diagnosis of cystic neck lumps, that a biopsy of the cyst wall should be sent for histological examination at the time of surgical incision and drainage in all cases. Finally, definitive exclusion of malignancy is possible only after interval excision of the cyst, therefore, if this is not to be undertaken, further investigations (repeat FNAB, endoscopy) should be considered.

FNAB was falsely positive for malignancy in one patient who presented with an asymptomatic neck swelling. This patient subsequently underwent endoscopy and surgery under frozen section control; however, histological examination of the resected cyst showed no evidence of malignancy, and the patient has remained well without appearance of head and neck cancer for over five years. However, it should be borne in mind that 10-24 per cent of patients presenting to the head and neck surgeon with a presumed diagnosis of branchial cyst transpire to have a cystic metastasis,9-13 and this proportion is higher in older patients.9,11,13 Fibre-optic examination of the upper aerodigestive tract as well as FNAB of the neck lump is mandatory before surgery in all cases of branchial cysts prior to surgery. In older patients, or where a clinical suspicion of malignancy exists, consideration should be given to performing endoscopy with directed biopsies / tonsillectomy prior to surgery, and to performing the operation under frozen section control, with consent for a radical neck dissection, even in cases where FNAB is negative.12,19

It has been reported that the use of CT scan and ultrasound may improve diagnostic accuracy and anatomic definition.7 In our experience, CT scanning is particularly useful in cases of infected branchial cysts, in order to exclude deep neck space infection. Only two patients in our series were evaluated with MRI, so we are unable to make any definitive statement regarding this imaging tool.

The management of inflamed branchial cysts has not been addressed in any of the previous literature. These cases may pose a significant dilemma to the surgeon. Such cases in the present series were generally treated initially with intravenous antibiotics. In those cases where the inflammation persisted, aspiration of the cyst contents was found to permit resolution of the inflammatory process with continuation of the use of intravenous antibiotics in many cases. Incision and drainage was thus reserved for cases where inflammation persisted in spite of maximum antibiotic treatment, with or without aspiration. In all cases, formal excision was undertaken after an interval of six weeks. This was performed in all cases without any complications or recurrence. It has been our experience that complete surgical excision of infected branchial cysts is technically difficult, owing to the difficulty in identifying tissue planes for dissection, and also because such dissection is associated with higher risk of incomplete excision. On the other hand, interval excision was safe and effective and without any additional morbidity.

Conclusions

FNAB is a useful investigation in patients presenting with cystic neck lumps; however, there is a higher incidence of inconclusive aspirates in patients presenting acutely due to inflammation. Acutely inflamed cysts are best treated with intravenous antibiotics with or without aspiration or incision and drainage followed by interval excision.

* Branchial cysts commonly present as asymptomatic swellings unless they are secondarily inflamed

* In this retrospective study the findings at fine needle aspiration and on CT scanning are presented in these two sub-groups

* Patients presenting with inflammation tended to have indeterminate findings on FNAB as well as atypical CT findings. This latter group was treated, as would be expected, with interval excision after antibiotics

References:

1 Work WP. Newer concepts of first branchial clefts defects. Laryngoscope 1972;82:1581

2 Maran AG, Buchanan DR. Branchial cysts, sinuses and fistulae. Clin Otolaryngol 1978;3:77-92

3 Fleming WB. Infection in branchial cysts. Auxt NZ J Surg 1988;58:481-483

4 Takimoto T, Itoh M, Furukawa M, Sakano K, Sakashita H, Iwawaki J, Uie T. Branchial cleft (pouch) anomalies: a review of 42 cases. Aims Nasus Larynx 1991 ;18:87-92

5 Coppens F, Peene P, Lemahieu SF. Diagnosis and differential diagnosis of branchial cleft cysts by CT scan. J Beige Radial 1990;73:189-196

6 Cunningham MJ. Congenital malformations of the head and neck. In: Cotton RT, Myers CM (eds). Practical Pediatric Otolaryngology. Philadelphia: Lippincott-Raven, 1999, pp 663-80

7 Agaton-Bonilla FC. Gay-Escoda C. Diagnosis and treatment of branchial cleft cysts and fistulae. A retrospective study of 183 patients. Int J Oral Maxillofac Surg 1996;25:449-452

8 Sukgi SC, and Zalzal GH. Branchial Anomalies: a review of 52 cases. Laryngoscope 1995;105:909-13

9 Sheahan P, O’Leary G, Lee G, Fitzgibbon J. Cystic cervical mtastases: incidence and diagnosis using fine needle aspiration biopsy. Otolaryngol Head Neck Surg 2002;127:294-8

10 Cinberg JZ, Silver CE, Molnar JJ, Vogl SE. Cervical cysts: cancer until proven otherwise? Laryngoscope 1982; 92:27-30

11 Gourin CG, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts. Laryngoscope 2000;110:1637-41

12 Flanagan PM, Roland NJ, Jones AS. Cervical node metastases presenting with features of branchial cysts. J Laryngol Otol 1994;108:1068-71

13 Granstrom G, Edstrom S. The relationship between cervical cysts and tonsillar carcinoma in adults. J Oral Maxillofac Surg 1989;47:16-20

14 McGuirt WF, McCabe BF. Significance of node biopsy before definitive treatment of cervical metastatic carcinoma. Laryngoscope 1978;88:594-7

15 Frable WJ, Frable MA. Thin-needle aspiration biopsy in the diagnosis of head and neck tumours. Laryngoscope 1974;84:1069-77

16 Frierson HF Jr. Cysts of the head and neck sampled by fine- needle aspiration: sources of diagnostic difficulty. Am J Clin Pathol. 1996;106:559-60

17 Orell SR. Pitfalls in fine needle aspiration cytology. Cytopathology 2003;14:173-82

18 Nordemar S, Hogmo A, Lindholm J, Tani E, Sjostrom B, Auer G, Munck-Wikland E. The clinical value of image cytometry DNA analysis in distinguishing branchial cleft cysts from cystic metastases of head and neck cancer. Laryngoscope 2002;112:1983-7

19 Andrews PJ, Giddings CE, Su AP. Management of lateral cystic swellings in the neck in the over 40s’ age group. J Laryngol Otol 2003;117:493-5

A. L. KADHIM, F.R.C.S.I., P. SHEAHAN, A.F.R.C.S.I., M. P. COLREAVY, F.R.C.S.I., C. V. TIMON, F.R.C.S.I., F.R.C.S.(ORL)

From the Department of Otolaryngology, Head & Neck Surgery, Trinity College, Dublin, Ireland.

Accepted for publication: 24 September 2004.

Address for correspondence:

Mr A.L. Kadhim, 2 Riverwood Copse, Castleknock, Dublin 15, Republic of Ireland.

Email: [email protected]

Mr A. L. Kadhim takes responsibility for the integrity of the content of the paper.

Competing interests: None declared

Copyright Royal Society of Medicine Press Ltd. Dec 2004

Lunasin is a novel, cancer-preventive peptide whose efficacy against chemical carcinogens and oncogenes has been demonstrated in mammalian cells and in a skin cancer mouse model. Isolated and characterized in soy, lunasin peptide is also documented in barley. Lunasin is found in all of the genotypes analyzed from the US soy germ plasm collection and in commercially available soy proteins. Pilot studies show that lunasin is bioavailable in mice and rats when orally ingested, opening the way for dietary administration in cancer prevention studies. Lunasin internalizes into mammalian cells within minutes of exogenous application, and localizes in the nucleus after 18 hours. It inhibits acetylation of core histones in mammalian cells. In spite of its cancer-preventive properties, lunasin does not affect the growth rate of normal and established cancer cell lines. An epigenetic mechanism of action is proposed whereby lunasin selectively kills cells being transformed or newly transformed by binding to deacetylated core histones exposed by the transformation event, disrupting the dynamics of histone acetylation- deacetylation and leading to cell death.

Key words: lunasin, soy, soybean, cancer, peptide

2005 International Life Sciences Institute

doi: 10.1301/nr.2004.janr.16-21

Introduction

The consumption of soybean products is associated with overall low mortality rates from cancers of the prostate, breast, colon, and others.1-2 Southeast Asians have a 4- to 10-fold lower incidence of and death from breast and prostate cancers. However, following emigration to the United States, the risk of these cancers rises rapidly in one generation to that equal to that of Americans.2-3 Differences in the diet are thought to account for a large part of this variation.4 The average intake of soy protein in Asia varies from 10 g/d in China to 30 to 50 g/d in Japan and Taiwan.5 In contrast, Americans eat less than 1 to 3 g/d. Two-thirds of the reported studies in the epidemiological literature associate soy intake with reduction of cancer risk.6 More recent epidemiological studies, animal experiments, and in vitro studies also show that soy products reduce cancer risk.7

A study of prostate cancer mortality in 42 countries showed that grains and cereals are protective against prostate cancer, and that soy products seem to be a major protector.8 Soy products are associated with decreased risk for prostate,9-11 breast,1 and endometrial cancers.12 Consumption of soy milk more than once a day is associated with a 70% reduction in prostate cancer risk compared with no soy milk intake.10 Candidate chemoprcventivc substances in soy include the Bowman-Birk protease inhibitor (BBI) and a BBI- enriched soy concentrate (BBIC), inositol hexaphosphate (phytic acid), -sitosterol, and isoflavones.13-14 BBIC and isoflavones are the most widely studied.15-16 BBIC, now in human clinical trials for oral cancer prevention, has been shown to be protective against a number of cancers in in vitro and in vivo models, including models of prostate cancer.15-19 BBIC evidently works by inhibiting proteases involved in initiation and promotion of carcinogenesis,19 but the molecular details remain to be established.

The administration of soy isoflavones in a soy protein matrix has raised the possibility of a contribution of other proteins to the observed preventive effects attributed to isoflavones. Lobund- Wistar rats fed a diet containing soy meal (50% protein) had a 30% incidence of prostate tumors compared with a 3% incidence in rats fed soy protein isolate (>90% protein), although both of these substances have approximately equal isoflavone content.20 Soy protein isolates with negligible isoflavones are more effective than isoflavone-enriched soy in reducing mammary tumors in rats,21-22 suggesting that the mechanism of the preventive effect of soy isolate is distinct from that of the isoflavones. These observations give special significance to the discovery of the cancerpreventive properties of lunasin and its presence in soy proteins.

Discovery of the Anti-Mitotic Effect of the Lunasin Gene

In a project to enhance the nutritional quality of soy protein through bioengineering, a gene coding for a soy albumin protein (GM2S-1) was cloned. GM2S-1 codes not only for the methionine-rich protein that was sought but for three other proteins: a signal peptide, lunasin, and a linker peptide.23 Lunasin is a 43-amino acid peptide that contains a poly-D carboxyl end with 9 D-residues (underlined), an -RGD- cell adhesion motif (bold), and a predicted, structurally conserved helix region (underlined italics):

SKWQHQQDSCRKQLQGVNLTPCEKHIMEKIQ GRGDDDDDDDDD.

Transformation of the lunasin cDNA into Escherichia coli leads to arrest of cell division manifested in non-septated filaments.24 The cells transformed with full lunasin fail to divide, while those transformed with the deletion mutant control without the poly-D divide normally. Subsequently, constitutive expression of lunasin tagged with green fluorescent protein in mammalian cells (murine hepatoma, human breast cancer cells, and murine fibroblast) leads to mitotic arrest and lysis of cells containing broken pieces of chromosomes to which the lunasin is attached.24 The lunasin evidently binds to the kinetochore of the centromere, a hypoacetylated region of the chromosome, and prevents attachment of the microtubule to the centromere, resulting in mitotic arrest. This is the first indication that lunasin, a highly negatively charged molecule, could bind specifically to the positively charged deacetylated histones in the hypoacetylated regions of the chromatin.25 Thus, the constitutive expression of the lunasin gene in mammalian cells leads to cell death, suggesting that it has a possible use in cancer therapy. However, since the lunasin gene affects both normal and cancer cells, a specific delivery system that targets cancer cells is needed.

The Cancer-Preventive Property of the Lunasin Peptide

Since people eat proteins and peptides in soy, the cancerpreventive property of lunasin peptide was next investigated. In contrast to the anti-mitotic effect of the constitutive expression of the lunasin gene, lunasin peptide added exogenously prevents transformation of mammalian cells caused by chemical carcinogens (DMBA and MCA) and viral oncogenes (E1A and ras).26,27 Using the foci formation assay, lunasin suppresses transformation by about 62% to 90% relative to the positive control (DMBA or MCA alone) at concentrations ranging from 10 nM to 10 M. On a molar basis, lunasin is more effective than BBIC, a known cancer- preventive agent from soy.26,27 Lunasin also suppresses transformation of NIH3T3 cells induced by E1A in a dose-dependent manner, with an effective dose as low as 20 nM. Interestingly, lunasin is effective even when added up to 15 days after transfection with E1A gene, suggesting its efficacy when applied even after the transformation event.27 How this translates into animal models in terms of lunasin administration relative to the time after application of the carcinogen remains to be shown.

In the first animal model, lunasin applied topically at 250 g/ week suppresses skin papilloma formation in SENCAR mice treated with DMBA and TPA by 70% compared with the untreated control.26 Tumor multiplicity (tumors/mouse) is also reduced, and the appearance of papilloma is delayed by 2 weeks in the mice treated with lunasin relative to the untreated control. This is consistent with a recent observation that lunasin slows down epidermal cell proliferation in mouse skin in the absence and presence of DMBA using a ^sup 2^H2O- labeling method to measure cell proliferation in vivo.28

Molecular Mechanism of Action

Interestingly, lunasin peptide added exogenously to mammalian cells internalizes within a few minutes and localizes in the nucleus in approximately 18 hours.27 There is also evidence that lunasin is found in hypoacetylated regions of the chromosome such as the telomere.26 For internalization, the -RGD-cell adhesion motif is required in one cell line (C3H), but is unnecessary in another line (NIH3T3), suggesting that the role of -RGD- is cell-line specific. How lunasin internalizes into the cell and ends up in the nucleus is an intriguing mechanism that remains to be elucidated.

Lunasin inhibits core (H3 and H4) histone acetylation in mammalian cells, both normal (C3H) and cancerous (MCF-7), in the presence of the deacetylase inhibitor sodium butyrate (Figure 1).26 This is supported by in vitro binding studies showing that lunasin binds specifically to deacetylated core histones but not to acetylated histones.26 The poly-D is required for binding, while the putative helical region enhances binding but is not required. This helical region is structurally conserved and has homology with a number of chromosome-binding proteins,26 suggesting that it might target lunasin to core histones.

A common property of cancer-preventive agents is their ability to slow down growth of cancer cells but not normal cells.29 In contrast, lunasin does not affect the growth of either normal or established cancer cell lines.27 Interestingly, BBIC does not affect growth of normal cells either.19 Lunasin is still effective when added 15 days after transfection with E1A, suggesting that it is \effective only within a certain window of the transformation event. A working mechanism based on the E1A-Rb-HDAC model is proposed27 (Figure 2). The mechanism shows that lunasin selectively kills cells that are being transformed or newly transformed by binding to deacetylated histone substrates exposed by the transformation event and by inhibiting histone acetylation catalyzed by histone acetyl transferases. This disrupts the dynamics of histone acetylationdeacetylation, which is perceived as abnormal by the cell and leads to cell death. In normal and established cancer cell lines, this window is absent because the deacetylated histones are not accessible functionally and/or physically. An analogy is that lunasin is a “watchdog” agent that sits in the nucleus and effectively does nothing when there is no transformation event. When a transformation event occurs, lunasin is triggered into action and binds to the deacetylated core histones exposed by the transformation event, leading to the selective killing of cells being transformed or newly transformed. It is likely that this model will evolve as the mechanism is better understood.

Figure 1. Lunasin inhibits acetylation of core histories H3 and H4 in mammalian cells in the presence of Na butyrate, a histone deacetylase inhibitor. C3H are normal (immortalized, nontumorigenic) cells and MCF-7 are human breast cancer cells. Acid-extracted proteins enriched for histones from the different treatment combinations are blotted onto nitrocellulose membranes and probed with antibodies against acetylated H3 and H4 histones.

Chromatin and cancer were linked when the tumor suppressors Rb and p53 were shown to recruit histone deacetylase (HDAC) to maintain core histones that interact with transcription factors in the hypoacetylated state to repress genes involved in carcinogenesis.30- 34 Specific viral oncoprotein sequences disrupt the interaction between Rb and HDACl and displace histone deacetylase activity from Rb.31-33 This is significant because viral oncogenes target and inactivate critical components of tumor suppressor proteins such as Rb and p53, which are mutated in 20% to 50% of advancedstage prostate cancers.34-35

To summarize, the two major tumor suppressor proteins, Rb and p53, utilize HDACs as co-repressors of transcription. This repression is lost when viral oncogenes such as E1A and HPV disrupt the interaction between HDACs and Rb and p53, leading to proliferation of transformed cells. Mutations in Rb and p53 have been associated with a number of human cancers.35-36 It is conceivable that lunasin, when introduced into the tissues, could act as a surrogate tumor suppressor by inhibiting histone acetylation. The fundamental nature of this epigenetic mechanism suggests that lunasin could be effective against different kinds of cancer where chromatin modification is involved in carcinogenesis. Clearly, demonstrating the efficacy of orally administered forms of lunasin against different cancers is a priority.

Lunasin in Soy and Other Seeds

We propose an intriguing role of lunasin in seed development. The three stages of angiosperm seed development are rapid cell division and differentiation, followed by cessation of cell division in the central parenchyma cells of the cotyledon or endosperm and enlargement of the cells accompanied by biosynthesis of storage forms of carbohydrates, proteins, lipids, and nucleic acids for the geminating seeds.37 In the last stage, the seed dehydrates. The second stage is considered unique to angiosperm seeds in which there is “endoreduplication” of DNA without cell division. Endoreduplication is a unique cell cycle wherein the G1- and S- phases occur without cell division, and thus DNA synthesis is uncoupled from cell division, allowing DNA accumulation for purposes of storage.38 We propose that lunasin is an effector molecule that allows arrest of cell division and initiates the second stage of seed development. Therefore, in theory, all angiosperm seeds should contain lunasin. Lunasin has been found and characterized in barley39 and has also been found in wheat (unpublished data). An initial screening using Western blot shows that it is not detected in the common bean. A more rigorous and systematic screening should be carried out, which could include different extraction procedures, testing different stages of seeds, and perhaps designing antibodies to recognize lunasin homologs.

Lunasin extracted from soy has been characterized.40 A recent screening of the US soybean germ plasm collection at the University of Illinois shows that lunasin is present in all genotypes in varying amounts, suggesting the possibility of selecting and breeding varieties of soy with higher lunasin content.41 The presence of lunasin in all commercially available soy protein samples analyzed41 suggests the presence of lunasin in most commercial soy products. Interestingly, lunasin is a very heat- stable peptide, retaining its bioactivity even after 5 minutes of boiling (unpublished data).

Figure 2. E1A-Rb-HDAC model to explain the ability of lunasin to suppress E1A-induced transformation without affecting growth of immortalized and established cancer cell lines. Rb controls G1/S transition by interacting with E2F promoter and recruiting HDAC to keep the core histones in the deaccetylated (repressed) state. Top diagram: Cells being transformed or newly transformed. In the presence of lunasin, E1A inactivates Rb and dissociates the Rb-HDAC complex, exposing the deacetylated core histones in the E2F promoter. Lunasin competes with histone aetyl transferases (HAT) in binding to the deacetylated core histones. Lunasin binds and turns off transcription, perceived as abnormal by cell and commits apoptosis. HAT binds and acetylates core histones, turning on E2F cell cycle transcription factors. Middle diagram: In immortalized, non-tumorgenic cells, the active Rb-HDAC complex keeps the core histones in E2F promoter deacetylated and inaccessible to added lunasin. Bottom diagram: In established cancer cell lines, transformation has occurred in the absence of lunasin. HAT has acetylated the core histones, turning on cell cycle transcription factors and keeping the acetylated core histones inaccessible and unable to react with added lunasin.

Oral Bioavailability of Lunasin

One of the properties of an ideal cancer-preventive agent is that it can be taken orally. A crucial question is whether lunasin, a peptide, survives digestion in the gastrointestinal tract when ingested orally. Pilot studies using 3H-labeled synthetic lunasin showed that about 35% of the oral dose is absorbed and ends up in the various tissues of mice and rats 6 hours after administration by gavage (unpublished data). Furthermore, lunasin from the blood and liver is intact and is bioactive by an in vitro assay. Bioavailability studies are continuing.

Future Work

The epigenetic mechanism of lunasin suggests that it could be effective against many different cancers where chromatin modification is involved in carcinogenesis. The preventive efficacy of lunasin administered in the diet and other routes should be tested against breast, prostate, colon, lung, oral, and cervical cancers. The proposed epigenetic mechanism should be further elucidated through genomics and proteomics. The intriguing mechanism of how lunasin enters the cells and localizes in the nucleus should also be investigated. Further oral bioavailability studies are being carried out.

Acknowledgments

The work described is partly supported by USDA NRICGP, DOD Congressionally Mandated Medical Research Program, University of California Biostar Program, and FilGen BioSciences, Inc. The author acknowledges the excellent contributions of the various authors in the lunasin publications without whose efforts this work would not be possible.

1. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control, 1998;9:553-557.

2. Moyad MA. Soy, disease prevention, and prostate cancer. Semin Ural Oncol. 1999;17:97-102.

3. Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer. 1991 ;63:963-966.

4. Dunn JE. Cancer epidemiology in populations of the US-with emphasis on Hawaii and California-and Japan. Cancer Res. 1975;35(11 part 2):3240-3245.

5. Shurtleff W, Aoyagi A. Green Vegetable Soybeans and Vegetable- Type Soybeans: Bibliography and Sourcebook, 3rd Century A.D. to 1994. Lafayette, CA: Soyfoods Center, 1994.

6. Messina M, Persky V, Setchell KD, Barnes S. Soy intake and cancer risk: a review of in vitro and in vivo data. Nutr Cancer. 1994;21:113-131.

7. Crowell JA, Jeffcoat R, Zeisel SH. Clinical phase 1 studies of isoflavones. Paper presented at: Third International Symposium on the Role of Soy in Preventing and Treating Chronic Disease; October 31November 3, 1999; Washington, DC.

8. Kennedy AR. The evidence for soybean products as cancer preventive agents. J Nutr. 1995;125(suppl 3):733S-743S.

9. Blumenfeld AJ, Fleshner N, Casselman B, Trachtenberg J. Nutritional aspects of prostate cancer: a review. Can J Urol. 2000;7:927-935.

10. Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, Hampl JS. Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J Natl Cancer Inst. 1998;90:1637- 1647.

11. Fournier DB, Erdman JW Jr, Gordon GB. Soy, its components, and cancer prevention: a review of the in vitro, animal, and human data. Cancer Epidemiol Biomarkers Prev. 1998;7:1055-1065.

12. Strom SS, Yamamura Y, Duphorne CM, et al. Phytoestrogen intake and prostate cancer: a case-control study using a new database. Nutr Cancer. 1999; 33:20-25.

13. Wu AH, Ziegler RG, Nomura AM, et al. Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nutr. 1998;\68(suppl 6):1437S1444S.

14. Goodman MT, Wilkens LR, Hankin JH, Lyu LC, Wu AH, Kolonel LN. Association of soy and fiber consumption with the risk of endometrial cancer. Am J Epidemiol. 1997;146:294-306.

15. Armstrong WB, Kennedy AR, Wan XS, Atiba J, McLaren CE, Meyskens FL Single-dose administration of Bowman-Birk inhibitor concentrate in patients with oral leukoplakia. Cancer Epidemiol Biomarkers Prev. 2000;9:43-47.

16. Kennedy AR. The Bowman Birk inhibitor from soybean as an anticarcinogenic agent. Amer J Clin Nutr. 1998;68(suppl 6):1406S- 1412S.

17. Kennedy AR, Wan XS. Effects of the Bowman-Birk inhibitor on growth, invasion, and clonogenic survival of human prostate epithelial cells and prostate cancer cells. Prostate. 2000;50:125- 133.

18. Wan XS, Ware JH, Zhang L, Newberne PM, Evans SM, Clark LC, Kennedy AR. Treatment with soybean-derived Bowman Birk inhibitor increases serum prostate-specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice. Prostate. 1999;41:243252.

19. Kennedy AR. Prevention of carcinogenesis by protease inhibitors. Cancer Res. 1994;54(suppl 7): 1999S-2005S.

20. Pollard M, Wolter W, Sun L. Prevention of induced prostate- related cancer by soy protein isolate/ isoflavone-supplemented diet in Lobund-Wistar rats. In Vivo. 2000;14:389-392.

21. Constantinou Al, Lucas LM, Lantvit D, et al. Soy protein isolate prevents chemically induced rat mammary tumors. Pharmaceutical Biology. 2002; 40:24-34.

22. Hakkak R, Korourian S, Hale K, et al. The effects of soy protein isolate containing negligible isoflavones and of casein on DMBA-induced mammary tumors in rats (abstract #4089). In: Proceedings of the 93rd Annual Meeting of the American Association for Cancer Research. San Francisco: American Association for Cancer Research; 2002:823-824.

23. Galvez AF, Revilleza MJ, de Lumen BO. A novel methionine- rich protein from soybean cotyledon: cloning and characterization of cDNA (Accession No. AF005030) (PGR #97-103). Plant Physiol. 1997; 114:1567.

24. Galvez AF, de Lumen BO. A soybean cDNA encoding a chromatin- binding peptide inhibits mitosis of mammalian cells. Nat Biotechnol. 1999;17:495-500.

25. Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 1998;12:599606.

26. Galvez AF, Chen N, Macasieb J, de Lumen BO. Chemopreventive property of a soybean peptide (lunasin) that binds to deacetylated histones and inhibits histone acetylation. Cancer Res. 2001;61: 7473- 7478.

27. Lam Y, Galvez AF, de Lumen BO. Lunasin suppresses E1A- mediated transformation of mammalian cells but does not inhibit growth of immortalized and established cancer cell lines. Nutr Cancer. 2003;47:88-94.

28. Hsieh E, Chai CM, de Lumen BO, Neese RA, Hellerstein MK. Dynamics of keratinocytes in vivo using HO labeling: a sensitive marker of epidermal proliferation state. J Invest Dermatol. 2004; 123:530-536.

29. Greenwald P, Clifford CK, Milner JA. Diet and cancer prevention. Eur J Cancer. 2002;37:948-965.

30. DePinho RA. Transcriptional repression: the cancer chromatin connection. Nature. 1998;391:533-536.

31. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature. 1998;391:597-601.

32. Magnaghi-Jaulin L, Groisman R, Naguibneva I, et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature. 1998;391: 601-605.

33. Luo RX, Postigo AA, Dean DC. Rb interacts with histone deacetylase to repress transcription. Cell. 1998;92:463-473.

34. Murphy M, Ahn J, Walker KK, et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 1999;13:2490-2501.

35. Kubota Y, Shuin T, Uemura H, et al.. Tumor suppressor gene p53 mutations in human prostate cancer. Prostate 1995;27:18-24.

36. Bookstein R. Tumor suppressor genes in prostate oncogenesis. J Cell Biochem Suppl. 1994;19:217223.

37. Spencer D, Higgins TJ. Molecular aspects of seed protein biosynthesis. In: Smith H, ed. Commentaries in Plant Science. Vol 2. New York: Pergamon Press; 1981:175-189.

38. Hellerstein MH. Antimitotic peptide characterized from soybean: role in protection from cancer? Nutr Rev. 1999:57:359-361.

39. Jeong HJ, Lam Y, de Lumen BO. Barley lunasin suppresses ras- induced colony formation and inhibits core histone acetylation in mammalian cells. J Agric Food Chem. 2002;50:5903-5908.

40. Jeong HJ, Park JH, Lam Y, de Lumen BO. Characterization of lunasin isolated from soybean. J Agric Food Chem. 2003;51:7901- 7906.

41. Gonzalez de Mejia E, Vasconez M, de Lumen BO, Nelson R. Lunasin concentration in soybean genotypes, commercial soy protein, and isoflavone products. J Agric Food Chem. 2004;52:5882-5887.

Ben O. de Lumen, PhD

Dr. de Lumen is with the Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.

Address for correspondence: Division of Nutritional Sciences and Toxicology, 231 Morgan Hall, Berkeley, CA 94720-3104; Phone: 215- 440-9300; Fax: 215-642-0535; E-mail: [email protected].

[Editor’s Note: The reader is referred to an article on lunasin previously published in Nutrition Reviews: de Mejia EG, Bradford T, Hasler C. The anticarcinogenic potential of soybean lectin and lunasin. Nutr Rev. 2003;61(7):239-246.]

Copyright International Life Sciences Institute and Nutrition Foundation Jan 2005

Summary: Bowenoid papulosis is a pre-malignant condition affecting the ano-genital area. Pathogenesis may be associated with high-risk human papillomavirus genotypes, and sexual transmission is the most likely mode of acquisition. Risk of progression to invasive disease is low. Treatment usually involves locally destructive or ablative therapies. We report well-tolerated, successful clearance of bowenoid papulosis of the penis in a 25-year-old male, using topical Aldara (imiquimod) cream 5%, once every other day for two months.

Keywords: bowenoid papulosis, penis, imiquimod, immunocompetent

Introduction

Bowenoid papulosis exhibits histological features of carcinoma in situ, with similarities to other genital dermatoses such as Bowen’s disease. It presents clinically with macular or papular lesions in the ano-genital area which are typically pink or flesh coloured, and may be mistaken for condyloma accuminata, seborrhoeic keratosis or other common dermatoses such as lichen planus. Human papillomavirus (HPV) types 16 and 18 have been associated with the disease and patients are often young and sexually active. Distribution shares similarities with condylomata accuminata. Histological confirmation of diagnosis is usually followed by appropriate treatment, for which invasive and non-invasive modalities are available.

We describe a case in a young White male who responded to treatment with the immune response modifier imiquimod.

Case history

A 25-year-old British male presented to a university dermatology department whilst on a backpacking holiday in Australia and Southeast Asia. He expressed concern about an intermittent, nonitchy penile rash which had been present for the previous 12 months. His general health was good, other than asthma and flexural eczema. He had no history of sexually transmitted infection (but never tested for HIV) and was a non-smoker. There had been several casual female partners during his travels but no unprotected sex. His current regular female partner of 12 months had no history of genital warts or abnormal cervical cytology. This was also true of his previous regular partners. The only treatment prior to presentation was over- thecounter Canesten (clotrimazole) cream with some improvement of the rash.

Clinical examination at the time of diagnosis (September 2003) revealed an erythematous macular eruption on the glans penis (uncircumcised), with no signs of general dermatoses and no inguinal lymphadenopathy (Figure 1). Differential diagnosis included lichen planus, seborrhoiec balanitis, and atypical warts. Penile biopsy and histology revealed parakeratosis, abnormal cellular atypia and hyperchromatism, which, combined with preservation of the dermo- epidermal junction were suggestive of carcinoma in situ changes (Figure 2), and consistent with the diagnosis of bowenoid papulosis. The patient was offered surgical excision of his disease but declined, preferring to wait until his return to the UK, upon which he was seen by a dermatologist and promptly referred to the sexual health clinic for management.

Various treatment options were discussed but he was concerned about destructive therapies such as laser and electrodessication. After a negative HIV test result, topical imiquimod cream 5% was initiated, once a day on alternative days for one month. Follow-up at the end of treatment revealed a 75% reduction in lesion area, with no adverse effects. After a further month of imiquimod, the lesion had completely cleared (Figure 3) and treatment was discontinued. One month later a penile biopsy showed absence of both disease (Figure 4) and high risk HPV DNA. To date the patient remains clear of his bowenoid papulosis.

Figure 1. Bowenoid papulosis on glans penis before treatment

Figure 2a. Histological changes of carcinoma in situ with cellular atypia and parakeratosis of epithelium

Figure 2b. Showing preservation of dermo-epidermal junction

Figure 3. After treatment showing clearance of lesion on glans

Figure 4. Normal histological appearance, with hyperkeratosis and absence of atypia

Discussion

This case illustrates the importance of considering a diagnosis of bowenoid papulosis in sexually active young persons presenting with atypical macular papular or warty lesions on the anogenital area. Similar appearance to other pre-malignant conditions such as Bowen’s disease means that clinical diagnosis should be confirmed by histology. HPV-16, 18 and other genotypes are frequently found in bowenoid papulosis1 and sexual transmission is thought to be the main mode of transmission2. There have also been reports of vertical transmission of HPV-16 and development of bowenoid papulosis in a child3. Although classified as a carcinoma in situ, the risk for progression to invasive disease is low4, though a more aggressive course is found in older and immunosuppressed5 patients.

Current treatment is by ablative or destructive therapies, including surgical excision, CO2 laser and cryotherapy. Since recurrence is common, there has been increased interest in non- invasive methods such as intralesional β-interferon, cidovofir and 5FU. However, none of these are specific for HPV infection6.

Imiquimod, licensed for the treatment of external condyloma accuminata, acts via stimulation of the innate and cell-mediated immune systems to eliminate virally infected cells and reduce HPV viral load7. Concomitant induction of memory lymphocytes potentially reduces disease recurrence7. Reports in the literature suggest that imiquimod may be a well-tolerated and useful adjunct to managing bowenoid papulosis8. Our results concur with this view, although long-term follow-up for signs of disease recurrence will be required and his sexual partner will also need regular cytological screening.

References

1 De-Villiers EM. Papillomavirus and HPV typing. Clin Derm 1997;15:199-206

2 Obacks S, Jadlonska S, Beaudenon S, Walzczak L, Orth G. Bowenoid papulosis of male and female genitalia: risk of cervical neoplasia. J Am Acad Dermatol 1985;3:104-13

3 Godfrey JC, Vaughan MC, Williams JV, et al. Successful treatment of bowenoid papulosis in a 9 year-old girl with vertically acquired HIV. Paediatrics 2003;112(1):73-6

4 De-Belilosky C, Lessana-Leibovitch M. Bowen’s disease and bowenoid papulosis, comparison of clinical viral and disease progression aspects. Contraception Fertilitie Sexualitie 1993;21:231- 6

5 Redondo P, Lionet P. Topical imiquimod for bowenoid papulosis in an HIV positive women. Acta Derm Venereal 2002;82:212-13

6 Zanoti KM, Belinson J. Update on the diagnosis and treatment of HPV infection. Cleveland Clinic J Med 2002;69:948-61

7 Stanley MA. Mechanism of action of imiquimod. Papillomavirus Report 1999;10:23-9

8 Wigbels B, Luger T, Metze D. Imiquimod – a new possible treatment for bowenoid papulosis? Hautarzt 2001;52:128-31

(Accepted 3 June 2004)

B P Goorney FRCP and R Polori DipGUM

Department of Genito-Urinary Medicine, Hope Hospital, Stott Lane, Manchester M6 8HD, UK

Correspondence to: Dr B P Goorney

E-mail: [email protected]

Copyright Royal Society of Medicine Press Ltd. Dec 2004

Serum amylase and lipase levels are markers of pancreatic inflammation and are standard tests to diagnose acute pancreatitis. Lipase level is a more specific and sensitive index of pancreatic disease than amylase level, but an elevation of lipase levels three or less times the normal range may be nonspecific and rarely may predict significant pancreatic pathology.1 Lipase activity may be measured using several methods, but considerable interassay discrepancies may be found.2

Lipase organ specificity for the pancreas is reduced in patients with renal insufficiency,3-7 diseases of the liver,8 alcohol abuse,9,10 and in various intra-abdominal11-15 or extra-abdominal nonpancreatic diseases.16-26

Thus, in patients with renal failure and no abdominal pain, hyperlipasemia has been found in as much as 80%.3 Elevations are not evident until creatinine clearance falls to

Among liver diseases, hyperlipasemia has been reported as a manifestation of chronic hepatitis C virus infection. A significant association between alanine transferase and lipase was observed. Interestingly, the normalization of high lipase levels has been reported only among responders to antiviral therapy.8

In asymptomatic alcoholics without acute pancreatitis, hyperlipasemia may be a common finding. Elevations of serum lipase levels have been found in 11 to 33% of these patients.9,10 Most of them have levels that are one to two times the normal level, and no patient usually exceeds three times the normal level.9 This background information is important in the interpretation of serum lipase levels in alcoholic patients with abdominal pain, because using an elevated serum lipase level to diagnose acute pancreatitis in an alcoholic patient with abdominal pain may not be appropriate.

GI disease may increase lipase values by two to three times the normal level. Thus, elevated serum lipase and amylase levels are observed in 14% of inflammatory bowel disease patients without clinical symptoms of a pancreatitis. Patients with Crohn disease have a slightly greater prevalence of hyperlipasemia than those of ulcerative colitis, although enzyme level increases are associated with more extensive and active inflammatory bowel disease.11-13 Interestingly, a significant increase (greater than twice the normal standard) has been shown more often in lipase levels than in amylase levels, but a specific pancreatitis is not considered in such cases.11 Although hyperlipasemia has been reported as an adverse event of therapy with some drugs (eg, azathioprine and salazosulfapyridine) that are commonly used to treat these patients,14,15 no influence of the use of medication on enzyme levels has been shown.12

Elevations in serum lipase levels also may result from macrolipasemia, which is a complex of lipase enzyme-linked Igs, in which hyperlipasemia results from the combination of lipase with IgG,16,17 IgAl-κ,18 or α^sub 2^-macroglobulin,19,20 rather than from pancreatitis. In rare instances, macrolipasemia also may be associated to macroamylasemia18,21 or even may be accompanied by Crohn disease,17 thus making a correct diagnosis difficult. In patients with anorexia nervosa or bulimia, increases in lipase levels have been described, but they have been unrelated to pancreatic disease.22 Hyperlipasemia has also been reported in 25% of patients with diabetic ketoacidosis with unremarkable findings on CT scans of the pancreas and no objective evidence of abdominal pain.23,24 In contrast to increases in amylase levels, the elevation of lipase levels has been found to be correlated with serum osmolality but not with pH in these patients.24 In approximately 7% of patients with altered states of consciousness due to head injury or stroke, hyperlipasemia of nonpancreatic origin has been found.25,26 As a result, a diagnosis of acute pancreatitis in all the above-mentioned clinical conditions based solely on elevated amylase or lipase levels, even to more than three times the normal level, is not justifiable. This knowledge may save these patients from invasive and costly examinations.

Elevated lipase levels from pancreatic origin other than pancreatitis can be seen in patients with blunt pancreatic trauma,27,28 malignancy,29,30 and, more rarely, sarcoidosis.31 As a result, these differential diagnoses need to be considered in patients presenting with hyperlipasemia.

In critically ill patients who are admitted to the ICU with diagnoses other than pancreatitis, increased lipase levels have been observed. Thus, in patients who have undergone cardiac surgery, the incidences of symptomatic hyperlipasemia and documented pancreatitis after surgery have been found to be 1.3% and 0.1%, respectively.32,33 However, there is little information about the incidence of these abnormalities among general ICU patients.

In this issue of CHEST (see page 246), Manjuck and colleagues have studied the incidence of hyperlipasemia of nonpancreatic origin among 245 critically ill patients on ICU admission. Because a major concern remains among critical care physicians when unsuspected hyperlipasemia is found in ICU patients, this is an interesting work that attempts to clarify the epidemiology of this subject. In their study population, a lipase level just above the upper limit of normal (ie, > 209 U/L) was arbitrarily considered as abnormal (group 2) by the authors. Obviously, this approach will have included some of the clinical conditions mentioned above, in which mildly increased lipase levels of extrapancreatic origin also can be seen.

Thus considered, Manjuck and colleagues found increased lipase levels in 40% of critically ill patients on ICU admission. Reasonably, renal insufficiency as a source of hyperlipasemia of extrapancreatic origin was a criterion to exclude patients from the study, but possibly group 2 may have selected patients with alcohol abuse or liver disease whose lipase levels could be raised at the baseline. Interestingly, there was no difference in the incidence of history of alcohol abuse between groups, but transaminase levels were found to be significantly increased in group 2.

In their study, Manjuck et al have identified hypotension, fever, low hemoglobin levels, elevated bilirubin levels, and the need for mechanical ventilation as determinants of higher lipase levels among critically ill patients at ICU admission. Because patients with mildly increased lipase plasma levels were pooled with others having much higher levels, including several cases of confirmed pancreatitis, perhaps multivariate logistic regression analysis may be of limited value in order to predict significant hyperlipasemia. However, good agreement is expected between these variables and abnormal values of lipase at any level.

In the report by Manjuck et al, imaging studies were performed in 50% of patients in group 2, possibly those with markedly increased lipase levels. CT scans or ultrasonographic imaging studies of the pancreas revealed positive findings in only 11 patients. However, these imaging methods may have some limitations in explaining mild increases in lipase levels that result from other conditions. More than 50% of cases of asymptomatic, mild elevations of serum lipase levels in the general population are found to be of pathoanatomic causes using magnetic resonance cholangiopancreatography (MRCP).34 Mechanical alterations of the bile duct or the pancreas can possibly be better seen using this method. The “gold standard” endoscopic retrograde cholangiopancreatography carries a risk of morbidity and mortality, and, although other imaging methods such as endoscopie ultrasound, small-bowel follow through, or hepatobiliary scanning are also available, MRCP may be the preferred method.28,34,35

Reported findings from MRCP in such cases are pancreas divisum, primary sclerosing cholangitis, chronic pancreatitis, healed pancreatic laceration, juxtapapillary duodenal diverticulum, papillary sclerosis, intraductal pancreatic lithiasis, and hemochromatosis.34 MRCP also has been used in clinical assessment after pancreatic trauma and provides useful information to guide management decisions.28,35

Thus, although in this report a minority of positive findings of imaging studies was found, other abnormalities possibly could have been detected by alternative methods in order to better explain the clinical significance of increased lipase levels on admission to the ICU. Although we agree with Manjuck and colleagues that common conditions in the critically ill, such as hypoperfnsion, major surgery, and others, can be responsible for pancreatic damage that would explain increased lipase levels on ICU admission, other diagnoses or comorbidities also may be related to the minor lipase derangements that are observent among these patients.

REFERENCES

1 Byrne MF, Mitchell RM, Stiffler H, et al. Extensive investigation of patients with mild elevations of serum amylase and/ or lipase is “low yield.” Can J Gastroenterol 2002; 16:84\9-854

2 Lessinger JM, Ferard G. Plasma pancreatic lipase activity: from analytical specificity to clinical efficiency for the diagnosis of acute pancreatitis. Eur J Clin Chem Clin Biochem 1994; 32:377-381

3 Lin XZ, Chen TW, Wang SS, et al. Pancreatic enzymes in uremic patients with or without dialysis. Clin Biochem 1988; 21:189-192

4 Collen MJ, Ansher AF, Chapman AB, et al. Serum amylase in patients with renal insufficiency and renal failure. Am J Gastroenterol 1990; 85:1377-1380

5 Seno T, Harada H, Ochi K, et al. Serum levels of six pancreatic enzymes as related to the degree of renal dysfunction. Am J Gastroenterol 1995; 90:2002-2005

6 Masoero G, Bruno M, Gallo L, et al. Increased serum pancreatic enzymes in uremia: relation with treatment modality and pancreatic involvement. Pancreas 1996; 13:350-355

7 Vaziri ND, Chang D, Malekpour A, et al. Pancreatic enzymes in patients with end-stage renal disease maintained on hemodialysis. Am J Gastroenterol 1988; 83:410-412

8 Yoffe B, Bagri AS, Tran T, et al. Hyperlipasemia associated with hepatitis C virus. Dig Dis Sci 2003; 48:1648-1653

9 Gumaste W, Sereny G, Dave P, et al. Serum lipase levels in chronic alcoholics. J Clin Gastroenterol 1991; 13:407-410

10 d’Emden MC, Wong L, Harris OD. Serum amylase, isoamylase and lipase in acute alcoholism. Aust N Z J Med 1984; 14:819-821

11 Bokemeyer B. Asymptomatic elevation of serum lipase and amylase in conjunction with Crohn’s disease and ulcerative colitis. Z Gastroenterol 2002; 40:5-10

12 Heikius B, Niemela S, Lehtola J, et al. Elevated pancreatic enzymes in inflammatory bowel disease are associated with extensive disease. Am J Gastroenterol 1999; 94:1062-1069

13 Tromin A, Holtmann B, Huppe D, et al. Hyperamylasemia, hyperlipasemia and acute pancreatitis in chronic inflammatory bowel diseases. Leber Magen Darm 1991; 21:15-22

14 Chiba M, Horie Y, Ishida H, et al. A case of salicylazosulfapyridine (Salazopyhn)-induced acute pancreatitis with positive lymphocyte stimulation test (LST). Gastroenterol Jpn 1987; 22:228-233

15 Ludwig D, Stance EF. Efficacy of azathioprine in the treatment of chronic active Crohn’s disease: prospective one-year follow-up study; German Imurek Study Group. Z Gastroenterol 1999; 37:1085- 1091

16 Keating JP, Lowe ME. Persistent hyperlipasemia caused by macrolipase in an adolescent. J Pediatr 2002; 141:129-131

17 Okumura Y, Tamba J, Shintani Y, et al. Macrolipasemia in Crohn’s disease. Pancreas 1998; 16:205-210

18 Goto H, Wakui H, Komatsuda A, et al. Simultaneous macroamylasemia and macrolipasemia in a patient with systemic lupus erythematosus in remission. Intern Med 200; 39: 1115-1118

19 Fujita K. Abnormal isoenzymes. Rinsho Byori 2001; 116(suppl): 7-15

20 Taes YE, Louagie H, Yvergneaux JP, et al. Prolonged hyperlipasemia attributable to a novel type of macrolipase. Clin Chem 2000; 46:2008-2013

21 Gullo L, Pezzilli H, Tomassetti P. Unusual association of macroamylasemia and hyperlipasemia: report of two cases. Am J Gastroenterol 1996; 91:2441-2442

22 Hempen I, Lehnert P, Fichter M, et al. Hyperamylasemia in anorexia nervosa and bulimia nervosa: indication of a pancreatic disease? Dtsch Med Wochenschr 1989; 114: 1913-1916

23 Nsien EE, Steinherg WM, Borum M, et al. Marked hyperlipasemia in diabetic ketoacidosis: a report of three cases. J Clin Gastroenterol 1992; 15:117-121

24 Yadav D, Nair S, Norkus EP, et al. Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol 2000; 95:3123-3128

25 Pezzilli R, Billi P, Barakat B, et al. Serum pancreatic enzymes in patients with coma due to head injury or acute stroke. Int J Clin Lab Res 1997; 27:244-246

26 Liu KJ, Atten MJ, Lichtor T, et al. Serum amylase and lipase elevation is associated with intracranial events. Am Surg 2001; 67:215-219

27 Ryan S, Sandler A, Trenhaile S, et al. Pancreatic enzyme elevations after blunt trauma. Surgery 1994; 116:622-627

28 Lin BC, Chen RJ, Fang JF, et al. Management of blunt major pancreatic injury. J Trauma 2004; 56:774-778

29 Thanigaraj S, Haibach H, Lott JA, et al. Marked hyperlipasemia after radiotherapy in a patient with prostate cancer. South Med J 1996; 89:1127-1128

30 Good AE, Schnitzer B, Kawanishi H, et al. Acinar pancreatic tumor with metastatic fat necrosis: report of a case and review of rheumatic manifestations. Am J Dig Dis 1976; 21:978-987

31 Duerksen DR, Tsang M, Parry DM. Chronic hyperlipasemia caused by sarcoidosis. Dig Dis Sci 2000; 45:1545-1548

32 Babineau TJ, Hernandez E, Forse RA, et al. Symptomatic hyperlipasemia after cardiopulmonary bypass: implications for enteral nutritional support. Nutrition 1993; 9:237-239

33 Rattner DW, Gu ZY, Vlahakes GJ, et al. Hyperamylasemia after cardiac surgery: incidence, significance, and management. Ann Surg 1989; 209:279-283

34 Mortele KJ, Wiesner W, Zou KH, et al. Asymptomatic nonspecific serum hyperamylasemia and hyperlipasemia: spectrum of MRGP findings and clinical implications. Abdom Imaging 2004; 29:109-114

35 Fulcher AS, Turner MA, Yelon JA, et al. Magnetic resonance cholangiopancreatography (MRCP) in the assessment of pancreatic duct trauma and its sequelae: preliminary findings. J Trauma 2000; 48:1001-1007

Nicols Serrano, MD, PhD, FCCP

Tenerife, Canary Islands, Spain

Dr. Serrano is Senior Staff ICU Specialist at Hospital Universitario de Canarias, and Assistant Professor of Critical Care Medicine, Universidad de La Laguna.

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

Correspondence to: Nicols Serrano, MD, PhD, FCCP, Critical Care Department, PO Box 273, Hospital Universitario de Canarias, 38320- La Laguna, Tenerife, Spain; e-mail: nserrano@ epicure.org

Copyright American College of Chest Physicians Jan 2005

EVEN if you don’t understand a skinking word of the Address To A Haggis, most of us can at least appreciate the spirit of the poem, which will again be recited at Burns Night suppers across Scotland and around the world on Tuesday. This national dish has both historical and nutritional value.

Warm-reekin’ haggis has been providing Scots with sustenance for so long, we can’t even remember where we got the recipe . . . the Vikings might have brought it over, but some say it was passed down from the ancient Greeks via the Romans.

“Haggis contains a good mix of proteins, iron and fibre from the meat and the oatmeal, ” confirms Dr Ann Payne, head of nutrition and dietetics at Glasgow Caledonian University. “It is high in animal fat, but when you have it with neeps and tatties, you’ve got quite a solid, healthy meal.”

Neeps, of course, only became a common field crop in the early 1700s. And, while the turnip has never been celebrated in verse, it was the first root vegetable, and the first vitamin C, made widely available to many Scots. Tatties became a vital staple shortly afterwards, saving the poorest Highlanders and islanders from economic ruin and fatal malnutrition before the Clearances and the potato blight took their toll. Throw these ingredients together with cullen skink, cranachan and oatcakes, and your Burns Night supper – most people’s most “Scottish” meal of the year – might also be your most well-balanced. Traditionallyspeaking, and as oxymoronic as it sounds, there is such a thing as a good Scottish diet.

“The unhealthy Scottish diet is in some ways a 20th century phenomenon, ” says Payne. “If you go back 200 years or so, Scots were living on a very healthy diet of local produce. Lots of oats, root vegetables, kale, dairy products, fish, a bit of meat, berries in the summer. And they were living to a good old age.”

Not Robert Burns, obviously, who died in 1796 at the age of 37. “True, ” says Payne, “but he was a strapping lad when he was alive, and it wasn’t his diet that killed him.”

In his day, besides his lyrical affection for haggis, Burns described porridge oats as “chief of Scotia’s food”. His English contemporary Dr Samuel Johnson – who was no particular fan of Scotland (“Though God made it, ” he once wrote, “God also made hell.”) – was prepared to concede the obvious benefits of the oat- heavy diet.

“Such food, ” he observed on one visit, “makes men strong like horses, and purges the brain of pedantry.”

In the mid-1980s, American scientists identified oatmeal as a kind of “miracle food”, containing soluble fibres which release slowly into the body, regulating the level of fats and sugars in the blood and reducing the risk of heart disease. That knowledge has gradually made porridge popular again, despite years of negative associations with prison-food. The slow energy-releasing properties of oats give them an ideal low score on the Glycemic Index – the “GI diet” being the fashionable health plan of the moment. And this week there was a rare positive dietary statistic to report in Scotland – porridge is now the UK’s second-favourite breakfast cereal. Around [pounds]79.6 million worth of oats are sold every year: a little less than Weetabix, a lot more than Corn Flakes. Admittedly, much of that is packaged into synthetic, microwaveable, snappy-titled brands like Oatso Simple.

“I’m very glad that more people seem to be eating porridge oats, ” says Maisie Steven, author of The Good Scots Diet. “They do terrible things to it these days, cooking it in the microwave and mixing it with sugar and tinned fruit, but it’s a good start. A great deal of money has been spent on providing schoolchildren with free fruit and that’s great, but it’s a bit ineffectual if the rest of their diet is pure junk. I would rather see them get a bowl of free porridge and milk in the mornings.”

Steven originally wrote The Good Scots Diet: Where Did It Go? as an academic report in 1985, when she was Payne’s distant predecessor as lecturer in nutrition and dietetics at Glasgow Caledonian (then The Queen’s College). It has only recently been re-edited and reprinted, without the despairing subtitle, for the modern healthbook market. As much a study of social history as nutrition, her book also identifies the late 18th century – after the dark days of endemic malnutrition, when many Highlanders had struggled to survive on nettles, grass, snails and cattle blood, but before the Clearances, the blight, and the industrial revolution – as the high point of Scottish eating habits. The Scots of circa 1800 were, says Steven, “exceptionally vigorous, with an infinitely healthier diet than we are used to today”.

Don’t go thinking it was a golden age.

“There was still an unacceptably small range of fruit and vegetables available, ” she says. “There was scurvy, and typhoid, and rhuematic fevers, which killed a lot of children. [Modern doctors have suggested that Robert Burns himself died of bacterial endocardtis, a heart-weakening after-effect of the rheumatic fever he suffered as a child. ] But the survivors tended to be incredibly hardy.”

Source materials bear this out. The statistical accounts taken by local clergymen and magistrates of the period record Perthshire farmers working 14-hour days without complaint at the age of 103.

“Generally speaking, we live longer now, ” says Steven, “but there are amazing stories from that time of millers and crofters still going strong at a remarkable old age.”

Steven has equated the Scots of that period to the Himalayan Hunza tribes studied by Sir Robert McCarrison in the 1930s – indigenous people living long, healthy lives on a similar and limited range of local wholegrain cereals, dairy products and small amounts of meat and fish.

“Obviously that traditional Scottish diet was still deficient in certain ways, and very boring. But with the immense choice and variety available today, think how much we could be improving on it.”

Any expert will tell you that diet is a complex issue. “And in Scotland, ” notes Payne, “it can be a particularly emotional subject.” Modern Scottish eating habits are creating palpable health problems – over 50per cent of the population is overweight, one in eight people admitted to Scottish hospitals is undernourished; and the Scottish Executive, the World Health Organisation, and independent researchers seem entirely disunited over root causes and solutions. But whether Scots eat too much salt, fat and sugar for behavioral, educational or economic reasons, the diet that has made so many “fat, toothless and constipated” (as Steven puts it in her book) isn’t Scottish at all. But for historical and political flux, we’d still be living on whatever produce we could grow or kill for ourselves.

“Scotland is like a lot of societies, where indigenous people could eat very well on local produce, ” says Dr David Morrison, an NHS consultant in public health medicine for Greater Glasgow. “Certainly we have the basis of a healthy diet with the food available to us – the root vegetables, game, fresh fish, oats and so on. And in some ways it’s the loss of those foods from our diet that has done us damage.”

Most agree with Steven that “the great downward spiral” began with the industrial revolution, when Scotland’s rural population was cleared out of the Highlands and packed into cities, living and working in poverty, consuming cheap factory products rich in refined flour and imported sugar.

“That’s basically when we forgot our traditional eating habits, ” says Payne, “and developed our taste for refined carbohydrates.”

“When conditions were that bad, ” explains Morrison, “and the working day often involved very heavy physical labour, people would eat any food that could get the calories in and the energy up. Nowadays, what we expect from our diet has completely changed – we’re living longer and we’re worried about chronic diseases, hence the concern over calorie intake.”

Morrison argues that any serious change in the Scottish diet will have to happen “with considerable difficulty, in a marketplace”.

But if porridge oats can make a profit for the modern food industry then there must be some hope. The increasing popularity of organic produce, home gardening and farmers’ markets are all small positive signs.

And last year the G1 Group – the corporate chain of Glasgow style bars and restaurants – opened their new venture The Bothy, with a menu full of basic, classic native dishes such as Scotch broth and barefit stovies.

“We open 10 restaurants a year, ” says executive chef Gary Maclean. “We were looking for something different. And believe it or not, a Scottish restaurant in Scotland was almost a novelty. But the turnover has been quite dramatic. I think you’ll be seeing more places like it, more people shouting about how good Scottish food can be. We’ve got some of the best stuff in the world.”

Maisie Steven, long since retired from academia to her Perthshire home, says a return to a good Scots diet is entirely possible – “the ingredients and the recipes haven’t really been forgotten”.

“The irony, ” she says, “is that we seem to eat best when we don’t really have a choice.

The two healthiest times for the Scots diet were before the industrial age, and straight after the second world war when sweets and flour were rationed. Now we have all this variety and we don’t seem to be able to make good use of it. ” So next Tuesday night let’s toast the menu as well as the man. May ye live braw and weel on traditional Scottish food, and langer than poor deed Rabbie.

The Good Scots Diet is available now from Argyll Press, (6.99)

FOR years health advisers have been telling us we should drink at least eight glasses of water a day.

But now scientists have discovered that taking a cold shower in the morning can help to reduce stress.

Researchers from Hull University found it increased mental toughness and the ability to face intense situations.

Water, or the Great Healer, as it is called by some alternative therapists, has been used to treat everything from headaches to high blood pressure.

Perhaps it’s not so surprising considering the human body is two- thirds water and every bodily function is regulated by it and depends on it to work properly.

Not convinced? Read our guide to what water can do for you.

DRINK

EVERY diet and healthy eating regime recommends we drink eight to 10 glasses of water a day.

A high level of water intake daily can enhance digestion, improve skin condition and help detoxify while improving every aspect of health.

Drinking enough H2O can cure headaches, back pain, arthritis, ulcers, asthma, hypertension, morning sickness and fatigue, while also boosting energy and curbing hunger pangs.

Scientists have also proved that drinking just five glasses a day decreases the risk of colon cancer by 49 per cent, breast cancer by 79 per cent and bladder cancer by up to 50 per cent.

EXERCISE

WORKING out in water has many benefits compared to hours in the gym or pounding the pavement.

Acting like a giant cushion it helps prevent bodily wear and tear, which is especially good for overweight people or those prone to injury, while also giving you a better work out as muscles have to work harder to combat the force of the water.

And exercising in water doesn’t just mean swimming.Water polo, aquarobics and even aqua chi are all good ways of getting fit underwater.

SALT WATER

MAYBE not in the Scots winter, but try to get down to the beach and into the sea as often as you can.

Sea water contains minerals which eliminate toxins and boost circulation.

Its high levels of magnesium, potassium, calcium sulphates and sodium also act like antiseptics, boosting the rate of cell renewal.

Many alternative therapies now make use of sea water, including Thalassotherapy, which involves sitting in a bath of warm salt water while your body is pummelled by water jets – fantastic for boosting circulation, easing arthritis and clearing up skinconditions. Another treatment is called WATSU and involves being stretched by a therapist while floating in a salt water pool.

As well as balancing body and mind it opens up muscle tissues, loosens joints and improves flexibility.

Aqua detox simply involves sitting with your feet in a basin of organic sea salt water while your toxins drain out – watch in amazement as the detoxifying water changes from clear to murky brown as it soaks up your body’s rubbish.

CLEANSING

WATER is also back as the best way to cleanse and moisturise your face.

Most top brands of cosmetics sell bars of soap or wash away cleansers to be used with water instead of cleansing milks.

Bottled water giant Evian have even created a range of skin care with water as its core ingredient.

COLONIC IRRIGATION

ONCE unmentionable in polite society, as soon as Princess Diana and Kim Basinger admitted it was an essential part of their health and beauty regimes, people were queuing up to have their intestinal tubes flushed out at salons.

The colon collects many of the body’s toxins, but once they are washed away with a

good old fashioned douche, colon hydrotherapy fans report vast improvements in skin condition, hair lustre and cellulite.

It can also help alleviate arthritis, psoriasis, food allergies and chronic fatigue.

DOGS

WATER isn’t just good for us, its miracle healing properties can help our canine pals as well.

Dogs with injuries, cancer and all kinds of other conditions benefit amazingly from swimming sessions in a warm pool, where limbs can move freely without weight bearing forces allowing sick animals to exercise with less pain.

It is also good for healthy dogs who just need to improve their levels of fitness.

DOUCHES

HAVING a jet of water directed at particular parts of the body can also help alleviate a range of conditions.

Knee douches, where the jet is drawn from the small toe up to the back of the knee on both legs helps headaches, low blood pressure, insomnia and varicose veins. Raising the stream higher to include the thigh helps ease muscular rheumatism andcoxarthritis. Including the lower trunk helps certain gallbladder and liver problems. An arm douche is good for treating nervous disorders, heart problems and paralysis. Including the chest helps asthma and doing the upper trunk as well can aid treatmentof vocal chord disorders. Back, neck and face douches can help with lung disease, depression and tinnitus.

Aim. Extrinsic compression of the popliteal artery and absence of surrounding anatomical abnormalities characterize the functional popliteal artery entrapment syndrome (PAES). The diagnosis is confirmed to individuals who have typical symptoms of popliteal entrapment and occlusion or important stenosis of the popliteal artery with color duplex sonography (CDS), magnetic resonance imaging (MRI) or arteriography during active plantar flexion- extension maneuvers. However, variable result findings in normal asymptomatic subjects have raised doubts as to the validity of these tests. The purpose of this study was to compare the frequency of popliteal artery compression in 2 groups of asymptomatic subjects, athletes and non-athletes.

Methods. Forty-two individuals were studied. Twenty-one subjects were indoor soccer players, and 21 were sedentary individuals. Physical activity was evaluated through questionnaires, anthropometric measurements, and cardiopulmonary exercise test. Evaluation of popliteal artery compression was performed in lower limbs with CDS, ankle-brachial index (ABI) measurements and continuous wave Doppler of the posterior tibial artery.

Results. The athletes studied fulfilled the criteria of high level of physical activity whereas sedentary subjects met the criteria of low level of activity. Popliteal artery compression was observed with CDS in 6 (14.2%) studied subjects; 2 of whom (4.7%) were athletes and 4 (9.5%) were non-athletes. This difference was not statistically significant (p=0.21). Doppler of the tibial arteries and ABI measurements gave good specificity and sensibility in the identification of popliteal artery compression.

Conclusion. The frequency of popliteal artery compression during maneuvers in normal subjects was 14.2% irrespective of whether or not they performed regular physical activities. Both Doppler and ABI showed good agreement with CDS and should be considered in screening popliteal arteries in individuals suspected of PAES.

[Int Angiol 2004;23:218-29]

Key words: Popliteal artery – Functional entrapment syndrome, diagnosis – Ultrasonography, Doppler, color.

Popliteal artery entrapment syndrome (PAES) is a congenital disease characterized by extrinsic compression of this artery caused either by a deviation of its normal anatomical course or its compression by musculotendinous structures in the popliteal fossa. Different anatomical variations occur as a result of embryological anomalies of arterial or muscle development in this area. The most frequent alterations include: medial deviation of the popliteal artery in relation to the medial head of gastrocnemius muscle, which can have its normal origin in the medial femoral condyle or be laterally inserted in the femoral metaphysis; compressions by the popliteal muscle, plantar muscle or by surrounding fibrous bands.1

In general, symptoms appear in young adults. The repetitive trauma to the popliteal artery by surrounding structures, may result in initially reversible lesions, histologically identified as adventitial fibrosis. The persistence of the pathological factor may cause a lesion of the medial layer, rupture of the external elastic lamina and finally thrombosis due to intimai layer degeneration.2 Clinically, subjects have intermittent claudication and decreased distal pulses with active plantar flexion-extension maneuvers. Early diagnosis is fundamental as it restricts surgical treatment to the removal of elements that entrap the popliteal artery, without vascular reconstruction.

Patients suspected of having PAES initially have their posterior tibial artery evaluated with continuous-wave Doppler and their ankle- brachial index (ABI) measurements taken. The presence of alterations in the curve components, classically described as amplitude reduction, audible Doppler signal reduction or pressure values reduction during provocation maneuvers, are considered important signs for the diagnosis of popliteal entrapment.3,4 PAES is confirmed by the presence of occlusion or important stenosis of the popliteal artery in symptomatic subjects during provocation maneuvers, with (CDS) and/or arteriography.5, 6 Lately, MRI has improved the chances of identifying surrounding structures involved in the entrapment.7

Even more recently, a functional type of popliteal entrapment, which also occurs in young adults, particularly in athletes,8 has been studied. Differently from the anatomical type, there are no morphological alterations of the popliteal artery or surrounding muscles. Symptoms such as plantar paresthesia may occur, probably as a consequence of intermittent trauma to the neurovascular bundle during physical activities. In these cases, popliteal artery thrombosis is a rare but possible event.

In 1985, Rignauld et al.9 first described functional PAES in an individual with symptoms of intermittent claudication and continuous- wave Doppler and arteriography findings indicating extrinsic compression of the popliteal artery during active plantar flexion- extension maneuvers. Despite the suggestive diagnosis of PAES, surprisingly, anatomical alterations were not observed during surgery. Only hypertrophy of the gastrocnemius muscles was observed. In this case, the skin was sutured without closing the muscular fascia. As there was a complete remission of the symptoms in the postoperative period, the treatment was considered successful due to a change in the anatomical relationship of the popliteal artery to the surrounding muscles. In a parallel study, these authors evaluated the posterior tibial artery of asymptomatic subjects with continuous-wave Doppler and identified 30% positive results in militaries and 50% in athletes.

Some authors 8,10,11 have suggested that in the functional type, in subjects who practice sports regularly leg muscle hypertrophy could be responsible for the compression of the popliteal neurovascular bundle during muscle contractions. Others have suggested that the slightly lateralized insertion of the medial head of the gastrocnemius (which can be potentiated by muscular hypertrophy) would be responsible for this compression.12, 13

With the improvement of screening tests and the use of CDS and MRI, asymptomatic subjects started to be evaluated in order to identify possible occurrence of extrinsic compression of the popliteal artery during provocation maneuvers and to analyze the influence of sport activities. Erdoes et al.14 identified 53% positive results in 36 evaluated subjects (20 sedentary subjects and 16 athletes). Huffman et al.15 had 88% positive results in 42 subjects (18 athletes and 24 sedentary subjects). In both studies, there were no significant differences as to the frequency of alterations between athletes and sedentary subjects.

We proposed this study because of the disagreement in the literature as to the percentage of asymptomatic subjects who have extrinsic compression of the popliteal artery during active plantar flexion-extension maneuvers and whether regular physical activity is responsible for positive results. Our purpose was to evaluate the prevalence of this compression in asymptomatic subjects and to observe the influence of regular physical activity in the increase of positive results.

Materials and methods

The Research Ethics Committee of the Medical School of Botucatu – UNESP – approved the present study. The purpose of the study was explained for the volunteers. They freely decided to take part in it and signed the Informed Consent Form.

Healthy, non-smoking subjects (21 indoor-soccer players and 21 sedentary subjects) took part in this study. The subjects’ mean age and standard deviation were 204 years. In the first phase of the study, the groups were analyzed and classified as to their level of physical activity. They were then evaluated to identify extrinsic compression of the popliteal artery.

TABLE I.-Classification after physical activity evaluations.

Initially, the subjects answered the short version of the International Physical Activity Questionnaire (IPAQ)16 and were classified according to the answers given: very or regularly active subjects, performing intense or moderate physical activity, more than 5 times a week and for at least 30 minutes; irregularly active or inactive subjects performing physical activity less than 3 times a week and for less than 30 minutes a day. Direct questioning was also used to determine present and previous physical activity.

The following anthropometric measurements were taken: height, weight, body mass index (BMI) and perimetry in both inferior limbs, at the greatest circumference of the thigh and leg. Percent of body fat was also calculated using the techniques of skin fold fat measurement and bioimpedance.

The determination of percent of body fat using the technique of skin fold fat measurements was performed according to Pollock protocol. Based on these measurements, body density was determined as follows:17

Body density= 1.112-(0.00043499X)+0.00000055 (X2)-(0.0002882Y), for X = sum of skin fold fat measurements (at the triceps, axila, chest, subscapula, suprailium, abdomen and thigh); Y = age of evaluated subject. After that, percent of body fat was determined using the formula of Siri:18 % body fat = (4.95/body density)-4.5.

Weight and bioimpedan\ce were taken with a Tanita electronic scale. Subjects were positioned barefoot on the base of the scale wearing the least amount of clothing possible. Weight and height values previously taken were included and impedance was determined. The calculated data were entered into the scale computer program and percent of body fat was obtained according to the bioimpedance technique.

In order to evaluate functional capacity, both groups performed cardiopulmonary exercise tests. The test was administered in a treadmill without ramp, according to the protocol of variable speed.19 The test consisted of warming up, workload and recovery phases. Initially the subject remained 2 minutes at rest and then warmed up for 4 minutes at 6 km/h. The test started at 7 km/h and 1 km/h was incremented at every 2 minutes. The test ended when the subject reached the VO^sub 2^max, in the presence of clinical symptoms or when maximum effort was established according to Borgs scale 20 (linear scale, in which the subject classifies his/her effort form 0 to 10). The recovery phase lasted 4 minutes with controlled speeds of 7, 5, 4 and 3 km/h. During the exercise in the treadmill, arterial pressures were taken using the method of indirect auscultation. Heart frequency was monitored with a transmitter attached to the chest by an elastic band, which continuously sent information to the computer program. A facial polyethylene mask was used to analyze inhaled and exhaled gases. At regular intervals, a vacuum bomb withdrew samples from the mask reservoir bag to measure the exhaled oxygen fractions (EO^sub 2^) and exhaled carbon dioxide fractions (ECO^sub 2^F). The variables (respiratory frequency, current volume, pulmonary ventilation, oxygen consumption, carbon dioxide, respiratory coefficient, oxygen pulse, exhaled oxygen fractions and exhaled carbon dioxide fractions) were analyzed through a computerized microprocessor that controlled the (unctions of the gas analyzer, entered the data, and made the necessary calculations to determine oxygen consumption (VO^sub 2^). VO^sub 2^max was obtained when oxygen consumption was stabilized, despite the increments of workload. This happened when VO^sub 2^ values reached a plateau or when maximum oxygen consumption at the end of the exercise was observed. Before every test, the volume (by injecting a known gas volume in the mask) and the composition of the gases (by analyzing the pattern mixture with 16% of O2 and 5% of CO2) were calibrated.

Once the physical evaluations were finished, the obtained data were compared with the values on Table I 21-23 to analyze the characteristics of athlete and non-athlete groups.24

In the second phase of the study, evaluations of positional compression of the popliteal artery (extrinsic compression during provocation maneuvers) with CDS and continuous-wave Doppler of the posterior tibial artery were made. These tests were performed at the Vascular Service of the ‘Hospital das Clinicas” at the Medical School of UNESP in Botucatu City, So Paulo State, Brazil. The examination room temperature was kept at about 22C.

Figure 1.-Alterations identified with CDS in the posterior tibial artery (arrow indicates beginning of maneuvers): altered waveforms curve with monophase curve of low amplitude (A), identified using CDS in subjects with total popliteal artery occlusion; waveforms altered with irregularities at the peak of high systolic speed (B) or at the biphase curve of reduced amplitude (C). These alterations were found using CDS in individuals with partial compression of popliteal artery.25

Continuous-wave Doppler, CDS tests and ABI measurements were performed in the resting position and during active plantar flexion- extension maneuvers which were obtained by pushing the foot against the hand of the operator with voluntary and simultaneous contraction of the femoral quadriceps.

The same investigator performed the continuous-wave Doppler tests. The subject was positioned in horizontal dorsal decubitus with extended lower limbs. The probe was placed over the posterior tibial artery at the medial retromaleolar region, using an angle of 60 degrees. Three evaluations were repeated in each subject and the final result corresponded to the presence of, at least, 2 coincidental values.

Based on these tests, the results obtained with continuous wave Doppler of the posterior tibial artery were:

– Normal Doppler (ND): without curve alterations at rest and with active plantar flexion-extension maneuvers.

– Altered Doppler (AD): identification of alterations in continuous wave Doppler findings during provocation maneuvers (Figure 1).25

ABI measurements were taken in all subjects at horizontal dorsal decubitus, at rest and during provocation maneuvers. Each measurement was taken 3 times and the obtained mean values were calculated. Pressures were determined with continuous wave Doppler, by first taking the systolic pressure of the right brachial artery, then by taking the pressure at the ankle with a probe positioned at the posterior tibial artery. The ABI was calculated by dividing the systolic mean values of the posterior tibial artery by those of the right brachial artery. Based on the results, ABI was considered altered when values inferior to 1 were obtained and normal when values equal or superior to 126 were obtained.

CDS tests were made with the patient in horizontal ventral decubitus and feet in neutral position and during active plantar flexion-extension maneuvers.

Two vascular ultrasound operators performed CDS evaluations. The tests were recorded in a videocassette and reviewed by a 3rd investigator who was not aware of the reports and of the groups. The popliteal arteries of both inferior limbs were examined with CDS, using an angle of 60 degrees. The whole extension of the popliteal artery was evaluated using B mode in longitudinal and transverse cuts. The popliteal fossa was also studied to identify surrounding anatomical anomalies. The popliteal artery was visualized by CDS with color gain to observe turbulence or interruptions in the flow signal. It was possible to observe the curve characteristics and to measure the speed through the analysis of the Doppler curve. The popliteal artery was evaluated at rest and during active plantar flexion-extension provocation maneuvers.

Figure 2.-Normal CDS: example of normal examination; popliteal artery seen at rest (1) and during dorsifiexion of the foot (2).

Figure 3.-Occlusion: example of altered examination with total occlusion of the popliteal artery due to its extrinsic compression when foot was in forced active plantar flexion-extension maneuvers.

Figure 4.-CDS: stenosis. A) Popliteal artery is normal with feet in neutral position; B) during active plantar flexion-extension maneuvers, a reduction of the popliteal artery caliber can be observed. Using Doppler spectral curve, the speed in the proximal segment of the artery was 79 cm/s and in the stenotic segment was 270 cm/s (rare of 3.4 [b/a], which corresponded to a stenosis higher than 70%).27

Popliteal artery alterations identified with CDS are shown in Figures 2-4.27

According to popliteal artery alterations identified with CDS, the results were classified as follows:

– Normal (N): differences in the popliteal artery at rest or with maneuvers were not identified.

– Occlusion (O): total obstruction of the popliteal artery during maneuvers.

– Stenosis (E): identification of important stenosis in B mode and color Doppler. Velocity ratios higher than 2.5 obtained with Doppler spectral curve, which corresponded to a stenosis higher than 70%. This ratio was calculated by dividing the area’s systolic speed by the proximal segment speed.

In order to evaluate the accuracy, sensitivity and specificity of continuous-wave Doppler findings of the posterior tibial artery and ABI, a study comparing them to CDS findings, considered in this case as gold-standard,28 was carried out.

TABLE II.-Summary of the procedures and materials used.

In the statistical analysis, size of the sample was determined using percent values obtained in the literature, with 5% significance and 90% power test. The Student t-test was used to compare the groups, considering whether the populational observations were homogenous or not for each variable. In the evaluation of the quantitative variables, Fisher’s test was used. A significance level of 5% was used.

Details of the procedures, materials, and protocols used are described in Table II.

Results

Evaluation results of the physical fitness: age, history of physical activity, anthropometry, and maximum oxygen consumption are shown in Table III.

The International Physical Activity Questionnaire (IPAQ) showed that all subjects in the athlete group were very active. In the non- athlete group, 6 or 28.6% were inactive and 15 (71.4%) were irregularly active.

According to Tables I and III, it was observed that all subjects in the athlete group fulfilled the definition criteria compatible with high levels of physical fitness, whereas all subjects in the non-athlete group fulfilled the criteria of sedentary subjects.

Tables IV-VI show the results of CDS of the popliteal artery and Doppler evaluation of the posterior tibial artery.

Alterations in CDS findings were identified in 10 inferior limbs of 6 subjects (4 bilateral). Bilateral alterations in CDS findings occurred in 2 subjects of the athlete group and in 2 subjects of non- athlete group. In both groups, occlusion in inferior dominant limb and stenosis on the other limb were observed (Table V).

TABLE III.-Mean and deviation pattern of the variables referring to the physical fitness evaluation.

TABLE IV.-Distribution of absolute and relative frequencies in the CDS, continuous-wave Doppler and ABI tests in relation to studied inferior limbs and according to groups.

At rest, all subjects obtained ABI values higher than or equal to 1. Altered ABI during provocation maneuvers range\d from 0.33 to 0.8 (mean of 0.59).

According to the results obtained and having CDS as gold- standard to identify positional popliteal compression, sensitivity, specificity and accuracy of continuous wave doppler Doppler and of ABI were studied (Tables VII, VIII).

Discussion and conclusions

Occlusion or important stenosis of the popliteal artery during active plantar flexion-extension maneuvers was accepted as a diagnostic criterion of popliteal entrapment. In the presence of anatomical anomalies of the popliteal artery or surrounding structures, resulting from congenital anomalies, classical PAES would be defined, whereas in the absence of these anomalies functional PAES would be diagnosed.1 However, the presence of positional popliteal compression in asymptomatic subjects who did not have anatornical anomalies brought uncertainties regarding the validity of the tests used to diagnose PAES. Erdoes et al.14 evaluated 36 asymptomatic subjects with CDS and observed that positional popliteal artery occlusion occurred in 53% of the them. Huffman et al.15 identified occlusion of the popliteal artery in 88% of 42 asymptomatic subjects. Subjects who performed different levels of physical activities were compared based on the hypothesis that muscle hypertrophy of inferior limbs caused by exercises could determine popliteal artery compression and a consequent increase in positive results.8-10 However, no important differences between athletes and sedentary subjects were identified in both studies.

TABLE V.-Distribution of absolute and relative frequencies in CDS, Doppler and ABI tests in relation to studied inferior limbs and according to groups.

TABLE VI.-Summary of altered results.

These authors had the initiative of studying positional popliteal compression tests in the normal population using a sophisticated methodology of imaging diagnoses, therefore improving previous studies made by Rignault et al.9 and Dany et al.29 with Doppler. However, in these studies, there was not a discerning selection of the groups regarding physical activity (PA) to appropriately classify the subjects as athletes or non-athletes. In order to avoid this, PA of the subjects in this study was rigorously evaluated, which allowed an unequivocal characterization of the groups.

TABLE VII.-Comparison of continuous-wave Doppler to CDS.

To evaluate the PA questionnaires, physiological measurements determined by cardiopulmonary exercise tests and anthropornetrical analyses 30 were used. The questionnaires proved to be low-cost and easily hcindled instruments that allowed a thorough analysis of the physical activity performed. In the studied groups, present and previous physical activity results showed that daily physical activity, frequency as well as years of practice were greater in the athlete group than in the sedentary group. Cardio-respiratory fitness evaluated through cardiopulmonary exercise tests allowed a precise study of the subjects’ performances during the treadmill test as well as analyses of cardio-circulatory parameters and maximum oxygen consumption.31 In the subjects of the indoor soccer team of Botucatu City, maximum oxygen consumption values were compatible with those of champion teams mentioned by Dantas et al.21 and Suva.22 Whereas in the nonathlete group, the mean values were consonants to the low level of PA performed by these subjects. Body percent fat in athletes was inferior to the body fat percent in sedentary subjects, which represented the regular physical activity of soccer players. Based on these evaluations, it can be concluded that the subjects of the indoor soccer team showed well-defined characteristics of athletes whereas sedentary subjects, in fact, formed the non-athlete group.

The indoor soccer team was chosen as athlete group due to the large number of individuals who practice it in Brazil, which made recruiting volunteers easier. The Botucatu team, in particular, had an adequate and regular level of practice, which made its inclusion unquestionable as athletes of high performance. Besides that, it is interesting for the study of the popliteal artery compression the fact that this practice uses inferior limb muscles intensely. It is possible that the recruitment of athletes who practice other sports such as weight lifting, judo or Volleyball in which a greater muscle hypertrophy can be observed,32 could result in a higher frequency of positive results. Therefore, other studies to evaluate the influence of these sports in the frequency of positional popliteal compression are necessary.

The frequency of positive results in this study, identified in 14% of the subjects, were expressively lower when compared to the studies of Erdoes et al. 14 (53%) and Huffman et al. 15 (88%). This difference occurred despite the similarity of methods used: CDS was used to identify popliteal artery compression during provocation maneuvers of active flexion-extension of the foot; duplex scans were similar and the investigators were experienced. In Hoffman et al.15 study, in particular, active plantar flexion-extension maneuvers were performed against a commercially available resistance scale vertically positioned at the feet and that measured the force used by the subject during maneuvers. This technique was an improvement of the methodology, but it could not separately account for the high percentage of positional popliteal artery compression identified by these authors. Eventually, the participation in the study of athletes who performed different kinds of physical activity may have influenced higher frequency results, however, such fact would not explain the alterations in positional popliteal artery compression found in most sedentary subjects. A multi-centered study using large samples to disperse these frequency differences and to better define their true results is necessary.

The mean of skin fold values taken at the thigh and the right leg of athletes was smaller than that of non-athletes (p=0.01), which indicated a smaller quantity of local fat. As the perimetry evaluated in these extremities was similar in both groups, we could imagine muscle hypertrophy in the athletes. However, more accurate studies visualizing the transversal plane of the inferior limb with MRI or computerized tomography to identify more precisely muscle composition of these extremities should be made.33 There were no important differences between the groups studied (p=0.21) when positional popliteal artery compression was investigated with CDS. Therefore, regular physical activity and greater muscle hypertrophy of the inferior limbs in the athlete group in this study did not interfere in positive results.

In 1974, Darling et al.34 used continuous wave Doppler as initial eveiluation test of the posterior tibial artery in patients with suggestive symptoms of PAES. According to these authors, the presence of alterations in the pattern of the curve during Doppler examination, described as a reduction in the curve amplitude during maneuvers would indicate the suspicion of proximal popliteal stenosis. Based on this description, Doppler examinations started to be largely used in the postoperative control of patients with PAES as well as in the diagnosis of popliteal entrapment.3, 4, 6 In order to observe the correlation of these non-invasive diagnostic methods, this study evaluated sensitivity, specificity, and accuracy of continuous wave Doppler and of ABI, having the visualization of the popliteal compression with CDS as gold standard of evaluation. The results indicated good levels of correspondence between Doppler and ABI with positional popliteal compression detected with CDS. As these examinations have a lower cost compared to the other diagnostic methods, their use could be suggested in the initial screening of individuals suspected of having PAES. It should be emphasized that in this study all identified alterations in the Doppler curve were considered (amplitude reduction, irregularities in the peak of high systolic speed, monophase curve).22 However, technical difficulties in obtaining the flow signal at the posterior tibial artery due to probe deviation caused by muscular contraction during maneuvers, as well as false positive results caused by extrinsic compressions of the leg arteries which would occur bellow the soleus ring, could limit these evaluations.29,35

Arteriography and MRI are used to diagnose and select those requiring surgical treatment of PAES as they identify popliteal compression during provocation maneuvers as well as surrounding structures involved in the entrapment.3, 7, 14 With the arrival of CDS, a precise non-invasive cheaper evaluation in subjects suspected of having PAES was possible. Di Marzo et al.36 observed a good correlation between CDS, arteriography, and internal surgical results of individuals with popliteal entrapment. Erdoes et al. 14 verified that among positive CDS results in asymptomatic subjects, 60% were identified with MRI. The authors believed that, despite being precise in visualizing the artery’s surrounding structures, MRI showed limitations in identifying artery compression as the subject had to remain 6 minutes in continuous muscular contraction (during maneuvers), which produced artifacts in the visualization of the popliteal artery. This fact associated to the high cost of MRI would limit its use. It is possible that faster and modern MRI equipment does not have this technical limitation. Cormier et al.37 and Fermand et al.38 recommended the use of CDS as it is noninvasive and produces a detailed and dynamic study of the popliteal artery. As it became known, CDS started to be used in the diagnosis of patients suspected of having PAES as well as in studies of positional popliteal artery compression in a normal population. In this study, CDS evaluation in B mode produced good visualization of the popliteal artery and surrounding structures, which allowed th\e identification of important occlusion or stenosis of the artery during provocation maneuvers. Besides that, using color Doppler and curve spectral continuous-wave Doppler, it was possible to identify characteristics of the curves of proximal and distal arterial flow and the arterial stenosis, whirling, and alterations in their speed.

The present study shows that a large number of normal asymptomatic individuals may have examination findings compatible with positional occlusion of the popliteal artery.14,15 Rignault et al.9 described that these alterations would be similar to the compression of the subclavian vessels by scapular waist in the outlet syndrome. In both cases, the neurovascular bundle is intimately delimited by bone and surrounding tendinous-muscular structures in a relatively restricted space. Any deviation or hypertrophy of these structures could lead to arterial compressions. It is unknown, however, whether this compression would cause any pathological lesion. Tumipseed et al.10 reported, “No clinical evidence exists Lo support the concept that functional entrapment, in the absence of any clinical symptoms, requires a surgical intervention”. Porter,39 in 1999, wrote that the “positional popliteal artery occlusion is normal and should not be used to diagnose abnormal conditions”.

On the other hand, several authors 2,40 described histologie alterations of the popliteal artery in PAES and showed that they were similar to alterations in arteries that suffered repetitive extrinsic trauma of their wall, and that they could occur, therefore, in the anatomical or functional type of the disease. Levien et al.2 reported 3 cases of popliteal artery thrombosis due to chronic extrinsic trauma of the wall in subjects with functional PAES. Therefore, it can be assumed that the extrinsic compression of the popliteal artery, without anatomical alterations, may eventually indicate risk of lesion of the vascular wall and thrombosis.

The reason why some individuals with positional popliteal compression are symptomatic and others are not is unknown. However, it should be emphasized that the presence of symptoms is important in choosing the treatment of functional PAES. In the literature, all patients described with symptoms of functional entrapment practiced sports regularly as a common characteristic. Based on these facts, Melo et al.41 suggested that physical activity could be a determinant for the onset of symptoms. On the other hand, it is possible that some normal individuals with positional occlusion of the popliteal artery may be asymptomatic as their physical activity is insufficient for the onset of clinical complaints. However, they could have typical symptoms of functional PAES when practicing stronger physical activities. Therefore, although physical activity does not interfere with the frequency of positional compression of the popliteal artery, it could determine the onset of symptoms in these individuals.

In view of the results obtained in this study, the presence of extrinsic compression of the popliteal artery was demonstrated in 14% of the evaluated subjects during active plantar flexion- extension maneuvers. These subjects were asymptomatic and did not have anatomical alterations. In the diagnosis of this compression Doppler and ABI showed a good correlation with CDS and therefore could be used in screening examinations. Not only are they non- invasive, but also have a lower cost. It was also observed that indoor soccer practice did not interfere in the frequency of these alterations. Long-term consequences of the positional compression of the popliteal artery in these individuals remain uncertain. Observational studies and clinical follow-ups of these individuals are suggested to understand the real meaning of the positional compression of the popliteal artery in the future.

Acknowledgments.-We gratefully acknowledge Prof Dr Nathanael Ribeiro de MeIo, Dr Daniel Habberman, Vascular Ultrasonograph laboratory of School of Medicine of Botucatu and the Associao Atltica Botucatuense’s indoor soccer players.

The authors worked in the Non-invasive Vascular Laboratory, School of Medicine of Botucatu, “Estadual Paulista” University and the physical activity evaluations was done in Personal Med Clinic.

This original article was presented at:

– First Congress of the Latin American Chapter of the International Union of Angiology. Third Latin American Venous Forum. Brazil. April 9-12, 2003. Belo Horizonte, Brazil.

– First Meeting “So Paulo” of Vascular Surgery. April 4-5, 2003. So Paulo, Brazil.

This original article was partially financed by the Surgery and Orthopedics Department, School of Medicine of Botucatu – UNESP, Botucatu, Brazil.

Received January 14, 2004, Accepted for publication February 19, 2004.

References

1. Castiglia V. Sindrome do aprisionamento da artria poplitea. Reviso de literatura. In: Maffei FHA, Lastoria S, Yoshida WB, Rollo HA, editors. Doenas vasculares perifricas, Vol. 2. 3a ed. Rio de Janeiro: Medsi editora; 2002.p.1305-16.

2. Levien LJ, Veller MG. Popliteal artery entrapment syndrome: more common than previously recognized. J Vasc Surgi 999;30:587-98.

3. McDonald PT, Easterbrook JA, Rich NM, Collins GJ Jr, Kozloff L, Clagetl GP et al. Popliteal artery entrapment syndrome. Clinical, noninvasive and angiographie diagnosis. Am J Surg 1980; 139:318-25.

4. Greenwood LH, Yrizarry JM, Hallet Jr JW. Popliteal artery entrapment: importance of the stress runoff for diagnosis. Cardiovase Intervent Radiol 1986, 9: 93-9.

5. di Marzo L, Cavallaro A, Sciacca V, Lepidi S, Marmorale A, Tamburelli A et al. Diagnosis of popliteal artery entrapment syndrome: the role of duplex scanning. J Vase Surg 1991:13:434-8.

6. Akkersdijk WL, Uikelboom BC. Color Doppler ultrasonographic imaging in the diagnosis of the popliteal artery entrapment syndrome. Br J Surg 1995:82: 134-9.

7. Atilla S, Akpek ET, Yucel C, Tali ET, Isik S. MR imaging and MR angiography in popliteal artery entrapment syndrome. Eur Radiol 1998;8:1025-9.

8. Kloostcr NJ, Kitslaar P, Janevsky BK. Popliteal artery entrapment syndrome. Fortsch Ronlgenstr 1988;148:624-6.

9. Rignault DP, Pailler JL, Lunel F. The “functional” popliteal entrapment syndrome. Int Angiol 1985;4: 341-3.

10. Turnipseed WD, Pozniak M. Popliteal entrapment as a result of neurovascular compression by the soleus and plantaris muscles. J Vasc Surg 1992; 15:285-94.

11. Chernoff DM, Walker AT, Khorasani R, Polak JF, Jolesz FA. Asymptomatic functional popliteal artery entrapment: demonstration at MR imaging. Radiology 1995;195:176-80.

12. Araujo JD, Araujo Filho JD, Ciorlin E, Oliveira AP, Sanchez Manrique GE, Pereira AD. Aprisionamento de vasos popliteos: diagnostico e lratamcnto e o coneeito do aprisionamento funcional. J Vase Br 2002;1: 22-31.

13. Sperryn CW, Bcningfield SJ, Immelman EJ. Functional entrapment of the popliteal artery. Australas Radiol 2000;44:121-4.

14. Erdoes LS, Devine JJ, Bernhard VM, Baker MR, Berman SS, Hunter GC. Popliteal vascular compression in a normal population. J Vasc Surg 1994;20:978-86.

15. Hoffmann U, Vetter J, Rainoni L. Popliteal artery compression and force of active plantar flexion in a young healthy volunteers. J Vase Surg 1997;26:281-7.

16. Matsudo SM, Arajo T, Matsudo V. Questionrio International de Atividade Fisica (IPAQ): estudo de validade e reprodutibilidade no Brasil. Rev Bras Atividade Fisica Saude 2001;6:5-18.

17. Jackson A, Pollock M, Ward A. Generalized equations lor predicting body density for men. Br J Nutr 1978;40:497-504.

18. Siri WE. Body composition from fluid spaces and density. In: Brozek J, Henschel A, editors. Techniques for measuring body composition. Washington, D. C.: National Academy of Science; 1961 .p.223-44.

19. Tebexreni AS, Lima EV, Barros Neto TL. Protocoles tradicionais em ergometria, suas aplicaes prticas versus protocolos de rampa. Rev Soc Cardiol Estado de So Paulo 2001;11:519-26.

20. Borg G. Perceived exertion as an indicator of somatic stress. Scan J Rehabil Med 1970;2:92-6.

21. Dantas MS, Badini ST, dos Anjos MAB. Avaliao de somatotipo, aptido fsica e dermatoglia da equipe do Vasco da Gama de Futsal adulta masculina, campe da Liga National 2000: Um diagnstico de previso e prescrio. XXII Simposio International de Cincias do Esporte. Summary 2000;1-133.p.109.

22. Silva L. Perfil morfofuncional de atletas de Futsal. XXII Simpsio International de Cincias do Esporte. Summary 2000;1-133.p. 109.

23. Pollock ML, Schmidt DH, Jackson AS. Measurement of cardio- respiratory fitness and body composition in the clinical setting. Compr Ther 1980;6:12-27.

24. Silva PR, Romano A, Yasbek Jnior P. Ergoespirometria computadorizada ou calorimetria indireta: um mtodo no invasivo de crescente valorizao na avaliao carcliorrespiratria ao exercicio. Rev Bras Med Esporte 1998;4:147-58.

25. Van Bellen B. Dopplcr ultra-som, ndice de Presso e prova de Esforo na Avaliao das Doenas Arteriais. In: Maifei FHA, editor. Doenas vasculares perifricas, Vol. 2. 3a ed. Rio de Janeiro: Medsi ditera; 2002.p.319-27.

26. Gale SS, Scissons RP, Salles Cunha SX. Lower extremity arterial evaluation: are segmental arterial blood pressures worthwhile? J Vasc Surg 1998;27:831-9.

27. Giannini M. Mapeamento Duplex das artrias dos membros inferiores. In: Maffei FHS, editor. Doenas vasculares perifricas, Vol. 1. 3a ed. Rio de Janeiro: Medsi editora;2002.p.341-5.

28. Campana AC. Investigao cientfica na rea mdica. In: Pesquisa Clnica. So Paulo: Editera Manole; 2001 .p. 145-9.

29. Dany F, Laskar M, Legaron C et al. Artres poplites pieges. Incidence, pidmiologie, consideration thrapeutiques. Arch Mal Coeur Vaiss 1985;78: 1511-8.

30. Matsudo VK, Matsudo SM, Araujo T. Tcnicas de medicla da atividade fisica. Rev mbito Medicina Desportiva 1998;2:3-8.

31. Santos Silva PR, Romano A, Visconti AM. Avaliao funcional multivariada ern jogadores de futebol profissional: uma \metanlise. Rev Bras Med Esporle 1998;4:182-94.

32. Petroski LE, Santos AP, Cardoso TA. O estudo somatotipolgico dos atletas da modalidade de atletismo de Santa Catarina. Revista Bras Cincias do Esporte 1982;3:93-8.

33. Seidell JC, Bakker CJ, van der Kooy K. Imaging techniques for measuring adipose-tissue distribution: a comparison between computed tomography and 1.5-T magnetic resonance. Am J Clin Nutr 1990;51:953- 7.

34. Darling RC, Buckley CJ, Abbott WM, Raines JK. Intermittent claudication in young athletes: popliteal artery entrapment syndrome. J Trauma 1974; 14:543-52.

35. Mailis A, Lossing A, Ashby P. Intermittent claudication caused by compression of tibial vessels as a result of calf muscle hypertrophy: case report. J Vasc Surg 1992; 16:116-20.

36. Marzo L, Cavallaro A, Mingoli A, Sapienza P, Tedesco M, Slipa S. Popliteal artery entrapment syndrome: the role of early diagnosis and treatment. Surgery 1997; 122: 26-31.

37. Cormier JM, Laurian CL, Fichelle JM et al. Artre poplite piege. Apport de exploration ultrasonographique. Presse Med 1985;14:183-5.

38. Fermamd M, Houlle D, Vayssairat M et al. Tomodensitometrie et imagerie par rsonance magntique dans le diagnostic des artre poplites pieges. Press Med 1989;18:983.

39. Porter JM, editor. 1999. Yearbook of vascular surgery. St Louis: Mosby; 1999.p.203-7.

40. Ikeda M, Iwase T, Ashicla K, Tankawa H. Popliteal artery entrapment syndrome. Report of a case and study of 18 cases in Japan. Am J Surg 1981 ; 141:726-30.

41. Melo NR, Hafner L, Fabron C et al. Smdrome do aprisionamento da artria popltea. XXXII Congresso Brasileiro de Angiologia e Cirurgia Vascular. Summary 1997;1-351.

M. J. DE ALMEIDA 1, W. BONETTI YOSHIDA 1, D. HABBERMAN 2, E. M. MEDEIROS 3 M. GIANNINI 1, N. RIBEIRO DE MELO 4

1 Department of Surgery and Orthopedics, Medical School of Botucatu, UNESP, Botucatu, Brazil

2 Personal Med Clinic, Botucatu, Brazil

3 Ultra-Rad Clinic, Manila, SP, Brazil

4 Department of Surgery at FAMEMA, Medical School of Manila, SP, Brazil

Address reprint requests to: M. J. de Almeida, Rua Professor Francisco Morato 135, CEP17501-020, Marlia, Brazil. E-mail: [email protected]

Copyright Edizioni Minerva Medica Sep 2004

N OEL Edmonds has been “utterly humiliated” by the revelation that his wife had an affair with her fitness instructor, close friends revealed yesterday.

Ex-House Party host Edmonds, 56, and Helen, 41, who now plan a quickie divorce, have been separated for two years and had always said there was no one else involved.

But Helen’s torrid affair with Pilates instructor Stuart Lord, also 41, is far from unique, according to personal fitness instructor Tony Maxwell.

The 30-year-old, from north London, has lost count of the number of bored housewives who’ve tried their luck with him – and, quite often, he simply couldn’t resist them.

Here, he lifts the lid on the sexually charged sessions he claims are commonplace in his line of work…

I’VE been a freelance instructor for five years, covering cardiovascular, weights, body toning, nutrition, circuit training and general fitness.

But I soon found there is another element to this job – casual sex.

Since I started this work, I’ve had sex with dozens of women and I don’t think anyone’s been hurt – unless one of their husbands found out about it.

When women contact me it’s because they’re usually unhappy with their body and want to improve it.

So I’m there to get them fitter and build up their confidence. This means that there’s a lot of intimacy.

I spend several hours a week in close contact with my clients, either in their homes or on a jogging track, building up their trust and encouraging them.

Naturally, many of them open up and tell you about their life and relationships. I’m their trainer, their friend and, for many, their sexual fantasy.

But I wouldn’t try it on with them. She has to give me some obvious signals that she wants to have fun. Within two months of starting my job, I had a situation with Ruth, a married brunette in her mid-30s.

You’d think that these women would be fat and unattractive but many of them, like Ruth, look really great and are striving for perfection.

She had a stunning figure and wanted me to work on her general fitness and help her develop a six-pack belly.

I was in her home getting her to do an exercise I call the cat lick, which is a press-up with a circular motion, like a cat licking its paws.

I was behind her, holding her stomach to correct her form, and I noticed she kept moving closer to me. I decided I must be imagining it, because Ruth was a married woman.

But I soon realised she was deliberately flirting with me, allowing our bodies to touch at every opportunity and sticking her bottom up in the air.

After we’d finished the workout, she started telling me that her husband was not fulfilling her and it was obvious she wanted a piece of me.

Let’s just say that it was a very, very nice day – the first of many.

Ruth did get her six-pack in the end but it might have been more to do with our athletic sex sessions than the cat licks. I didn’t feel guilty because I was single and it’s up to her if she wanted to get it on with me.

I thought that would be a one-off experience but it was the first of many and, now I knew the signs, I felt more confident about reacting to attention.

I was taking another married woman, Sarah, to the local jogging track one day and I got the impression she was trying to impress me with more than her athletic abilities.

She wore a tight Lycra leotard-like outfit that was cut so low her breasts were practically popping out.

I couldn’t help staring and she asked me if I liked them.

I told her I did and she smiled.

The next session, she wore tiny hot pants and it was too much – I had to grab that butt.

I was worried she might scream but she told me it was nice.

We started a relationship but she broke it off because she was confused about her feelings.

In the end, I lost her as a client but the best was yet to come…

There were other brief flings and there was an unforgettable experience the following year with a woman named Amy, who was blonde, 5ft 10in, with a good figure.

Amy made it clear from the first that she liked me a lot. I’m a man and if I see an attractive woman is flirting with me, I’ll play the game. She had a boyfriend but was very forward with me and we’d become good friends.

One day, she was doing sit-ups and I was holding out my arm to show her where she should move to. Her breasts were pushing against me as she sat up and we smiled because we were both enjoying it.

Later, I had Amy doing kicks and I touched her legs, then moved my hand up. When she didn’t give a damn, I knew her barriers were down.

Amy told me her relationship with her boyfriend was bad and, joking, I asked: “What if we were to get together?” That was it. We were all over each other and had some great sessions.

She kept calling me but I only wanted to have fun – if they got serious I didn’t want to know. So in the end, I tried to put it in perspective for her by asking: “Do you want to have a threesome, to spice it up a bit?”

I thought she was joking when she told me that she did indeed have a friend who could train with us.

It was too good to be true and I thought it was just her way of trying to keep me interested. But, sure enough, a week later she came over with Carmena, a Spanish brunette, armed with tequila and wine.

They both drank a lot but I don’t really drink. Then, when Amy left the room for a minute, I started cuddling Carmena.

When Amy came back she began fooling around with Carmena in front of me – and you can imagine the rest…

It was another experience I can cross off my list and would have loved to do it on a regular basis. Unfortunately, Carmena regretted it when she’d sobered up the next day and I’ve never seen her since.

They were great times but those days of casual sex are over now because I have a long-term girlfriend and wouldn’t dream of cheating on her.

I know some people may take a dim view of my exploits but I don’t feel bad about it, especially because I was single at the time.

It’s the women who should feel guilty for cheating on their partners.

Finally, I suppose my story should serve as a warning to all the husbands out there with bad marriages. If your wife books someone like me, just make sure you know what kind of workout they’re being given.

Names have been changed.

CELEBRITY FITNESS FLINGS

VANESSA FELTZ

ROLY-POLY TV star Vanessa met her boyfriend Dennis Duhaney when she hired him as her personal fitness trainer four years ago… after her surgeon husband, Michael Kurer, gave her an ultimatum to lose weight.

DEMI MOORE

THE Hollywood star, 42, had a three-year relationship with fitness trainer and martial arts instructor Oliver Whitcomb, who romanced her after she threw out unfaithful ex-husband Bruce Willis.

DANIEL DAY-LEWIS

ACTOR Daniel had a fling with his personal fitness trainer, Deya Pichardo, in the mid 90s. But it ended after 12 months, when she discovered he had secretly wed Rebecca Miller, the daughter of playwright Arthur Miller.

MADONNA

THE singing legend has an eight-year-old daughter, Lourdes, by former lover Carlos Leon, a fitness trainer she met while jogging in Central Park in 1995.

SHARRON DAVIES

THE former Olympic swimmer-turned-TV host married fitness instructor/gym boss John Crisp but later divorced him after he had an affair.

TRUDE MOSTUE

THE two-timing Norwegian telly vet, 36, married personal fitness trainer Howard Thomas in 2001, after cheating on her ex, Danish model Brian Povlsen.

Growth hormone is a protein hormone (not a steroid hormone) produced and secreted by the pituitary gland in the brain. After age 30, growth hormone secretion declines by approximately 14 percent per decade. By age 60, the average person secretes 75 percent less growth hormone than a 20-year-old. The dramatic decline in growth hormone secretion as we age is directly associated with many aspects of aging. Growth hormone is primarily released in pulses that occur during the beginning phases of sleep, which in turn stimulates the release of IGF-I from the liver. As growth hormone secretions decline with aging, so do blood levels of IGF-I.

The decline in IGF-I blood levels as we age has been shown to contribute to many aspects of aging, including thinning of our skin, more rapid wrinkling, brittle hair, and nails, grayed or dulled hair color, reduced energy, loss of muscle and bone mass, decreased libido and sexual performance ability, increased body fat, and other common signs and symptoms of aging. Conversely, growth hormone injections and/or supplementation with natural agents that stimulate the release of growth hormone have been shown to boost IGF-I blood levels back to more youthful levels and reverse many age-related changes in the body. Studies have shown that boosting IGF-I blood levels back to more youthful levels leads to a multitude of anti- aging benefits, including:

* improved immune function;

* increased sexual potency and function;

* increased muscle strength, muscle mass and energy;

* decreased body fat;

* elevated mood;

* improved sleep patterns;

* improved memory;

* improved skin thickness, texture, and reduced wrinkle lines;

* restoration of hair color; and

* improved vision.

The most pronounced anti-aging effects have been seen in patients whose IGF-I blood levels were returned to a level at or greater than 350ng/ml, which certain anti-aging doctors claim can single- handedly reverse aging by up to 20 years in older subjects. To achieve blood levels in this range, regular injections of growth hormone are required by a physician trained in anti-aging medicine.

However, growth hormone injections have been shown to cause side- effects, especially in subjects whose IGF-I returned to levels approaching 400ng/ ml. The most common side-effects include swelling of the feet, fluid retention, joint pains, carpal tunnel syndrome, and more rarely, allergic responses.

I am concerned about boosting IGF-I blood levels above 290-300ng/ ml, as a number of research papers have correlated higher IGF-I levels with an increased risk for breast and prostate cancer. This doesn’t necessarily mean that IGF-I causes cancer, but it does imply that more research is required before we can state with certainty that growth hormone injections are a completely safe anti-aging intervention.

Growth Hormone secretagogue Supplements: A Safer, Natural Alternative

A number of studies have revealed that a combination of certain amino acids, ingested orally as a supplement at specific dosages, can stimulate the pituitary gland to release greater quantities of growth hormone after the age of 40, elevating our IGF-I blood levels to match those we experienced up to our mid-30s. Studies show that supplementation with these amino acid combinations, collectively known as growth-hormone secretagogues, can raise IGF-I blood levels up to 275ng/ml, which may be a safer level than 350-400ng/ml.

In a three-month study involving a proven growth hormone secretagogue supplement, blood levels of IGF-I increased by 30% on average by the end of the 12th week, and patient self-assessment scores indicated that, of the 36 participants, 58% noted improvement in muscular strength; 42% reported an increase in muscle size; 68% reported body fat reduction; 74% noted an increase in energy; 47% reported improvements in skin texture; 32% reported improved skin thickness; 37% reported reduction in wrinkles (disappearance or reversal); 21% reported improvement in general healing capacity; 37% reported improvement in joint and back flexibility; 47% felt their immune system was stronger; 32% reported improved sexual potency; 44% of men reported better sexual stamina (penile erection); 66% of men reported less frequent nighttime urination; 53% reported improved mental energy and clarity; 37% reported improved attitude and mood elevation; and 47% reported improvement in memory. In male subjects, there was a reduction in PSA blood levels (prostate- specific antigen), signifying that this intervention did not trigger prostate malignancy or enlargement. As well, blood sugar levels in diabetic subjects were shown to improve, and there was also improvement in both cardiac (heart) and pulmonary (lungs) tests during the course of the three-month trial.

The author of the study, D.M. Ladley, MD, also noted that blood pressure was better controlled and improvement in menopausal symptoms was reported among affected women in this age group. Dr. Ladley, an authority on the use of growth hormone secretagogues, elaborated that improved energy, endurance, muscle mass and strength, and reduced body fat, were among the most frequently reported benefits in the first four weeks of supplementation. New hair growth, restoration of hair color, thickening of the skin, and disappearance of skin discoloration generally occurred between the eighth and 12th weeks, with continued improvement beyond the 12- week term. There were no side-effects reported from the use of the growth hormone secretagogue by any of the participants in this study. (Growth hormone secretagogues are generally well- tolerated and no consistent reports of adverse side-effects have been reported.)

In the study, initial blood levels of IGF-I ranged from 21-276ng/ ml. Subjects with lower values appeared to have experienced the largest increases in IGF-I blood levels with secretagogue supplementation. As a rule, growth hormone secretagogue supplementation cannot elevate blood levels of IGF-I beyond 275ng/ ml. Thus, before beginning a supplementation program with a growth hormone secretagogue, you should first have your blood levels of IGF- I evaluated.

What Supplements Qualify?

Unfortunately, the growth hormone secretagogue industry is filled with unproven, ineffective and/or scam products that are not worth spending your money on. Individuals can assemble their own growth hormone secretagogue by stacking several amino acids together and taking them at once, one hour before bedtime. Growth-hormone and antiaging specialist Vincent Giampapa, MD (medical director of the Longevity Institute International in Montclair, N.J.), suggests a starter amino-acid stack program consisting of:

* Arginine – 2 grams

* Ornithine – 2 grams

* Lysine – 1 gram

* Glutamine – 1 gram

After an initial course of one month, increase all of the amino acids in the stack by 2 grams each. Growth hormone secretagogue supplements are usually taken for five consecutive days, followed by two days with no supplementation, and then five days on again, repeating this sequence.

It is advisable to have your IGF-I levels checked after three months of growth hormone secretagogue supplementation, in order to see how much of an increase has occurred in this hormone, and to gauge the extent of its anabolic and other anti-aging effects.

This article is available online at www.chiroweb.com/columnist/ meschino. You may also leave a comment or ask a question at his “Talk Back” forum at the same location.

Resources

1. Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)- dencient adults bef ore and after GH replacement therapy at low doses. Journal of Clinical Endocrinology and Metabolism 1993;77:1671- 1676.

2. Bengtsson BA, Eden S, Lonn L, et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. Journal of Clinical Endocrinology and Metabolism 1993;76;309-317.

3. Bengtsson BA. The consequences of growth hormone deficiency in adults. Acta Endocrinologica 1993;128(Suppl 2):2-5.

4. Cummings DE, et al. Age-related changes in growth hormone secretion: should the somatopause be treated? Sem Reproductive Endo 1999;17(4):311-326.

5. Cuneo RC, Salomon F, Wiles CM, et al. Growth hormone treatment in growth hormone deficient adults. II. Effects on exercise performance. Journal of Applied Physiology 1991;70:695-700.

6. Fuh VL, Bach MA. Growth hormone secretagogues: mechanism of action and use in aging. 1998 Merck Research Laboratories. Growth Horn IGF Res 1998 Feb; 8ml: 13-20.

7. JamiesonJ and Dorman L.E. The Role of Somatotroph-Specific Peptides and IGF-I Intermediates as an Alternative to HGHInjections. Presented for the American College for Advancement in Medicine, Oct. 30, 1997.

8. Jamieson J, Dorman L. Growth Hormone: Reversing Human Aging Naturally. Longevity News Network 1997.

9. Johnston DG, Bengtsson BA. Workshop report: the effects of growth hormone and growth hormone deficiency on lipids and the cardiovascular system. Acta Endocrinologica 1993; 128 (Suppl 2):69- 70.

10. Klatz R. Grow Young With HGH. Harper Perennial, 1998.

11. Ladley D.M. The Role of Oral Growth Hormone secretagogues in Anti- Aging Therapy. Presented at the European International Conferences on Quality of Life and Longevity Medicine (Sept. 28-30, 1998).

12. McGauley GA, Cuneo RC, Salomon F, et al. Psychological well- being before and after growth hormo\ne treatment in adults with growth hormone deficiency. Hormone Research 1990;33(suppl 4):52-54.

13. O’Halloran DJ, Tsatsoulis A, Whitehouse RW , et al. Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency. Journal of Clinical Endocrinology and Metabolism 1993;76:1344-1348.

14. Rudman D, et al. Effects of human growth hormone in men over 60 years old. NEnglfMed 1990;323(l):l-6.

15. Salomon F, Cuneo RC, Hesp R, et al. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. New England Journal of Medicine 1989;321:1797-1803.

16. Stanford University Medical Center Many effects of aging can now be reversed, bring about dramatic rejuvenating results in older people. PsychoNeuro Endocrinology 1992;17(4).

17. Veldhuis JD. Endocrinology of aging. Medscape Diabetes and Endocrinology 2000;2(1).

James Meschino, DC, MS. Previous articles, a “Talk Back” forum and a brief biography of the author are available online at www.chiroweb. com/columnist/ meschino.

James Meschino, DC, MS

Toronto, Ontario

Canada

www.renaisante.com

Copyright Dynamic Chiropractic Jan 15, 2005

OME adult cancer patients are turning to breast milk to help them beat the illness, it emerged yesterday.

They believe it can boost their immune system and ease the side- effects of chemotherapy.

For four years a milk bank in San Jose, California, has been supplying donated breast milk meant for low-weight and premature babies to 28 adult patients who have a doctor’s prescription.

Howard Cohen, who has twice weekly ‘smoothies’ made from the milk, believes it has helped put his prostate cancer into remission and enabled him to avoid invasive surgery.

The Californian software consultant started taking the milk after his wife learned of Swedish research which suggested that breast milk could kill cancer cells in a test tube.

Mr Cohen said his levels of Prostate Specific Antigen (PSA), an enzyme in the blood which can be a warning sign for prostate cancer- dropped back to normal after taking the milk. His doctor has told him that as some prostate cancers grow so slowly, the breast milk may have made little difference.

However he is convinced it has, saying that when he stopped taking the milk temporarily, his PSA levels went up.

Last night UK doctors warned there was no real evidence of any benefit to cancer patients from breast milk. Dr Lesley Walker, of Cancer Research UK, said: ‘I think by and large it might not do any harm, although it would be crucial to make sure it was tested for any viruses. But the chances of it having any major effect are very low.

‘The problem with anecdotal evidence is that it is simply not possible to evaluate the efficacy of something in this way.’

David Kerr, professor of clinical pharmacology and cancer therapeutics at Oxford University, said he understood why patients wanted to leave no stone unturned in their quest for a cure.

But he added: ‘This is quite bizarre, completely anecdotal and probably complete bunkum. It probably won’t do any harm but it is unlikely to do any good either.’

New mothers are strongly urged to breast feed their babies.

Research has shown breast milk boosts the immune system and babies who are breastfed have lower blood pressure and are less likely to be obese in later life. In 1995 researchers from Lund University in Sweden found that a protein in breast milk appeared to destroy cancer cells in the laboratory.

Last year another study by the same university found a different compound in breast milk appeared to destroy skin warts triggered by the human papilloma virus (HPV).

Writing in the New England Journal of Medicine, the authors said the discovery could have implications for preventing or treating other HPV-related cancers, such cervical cancer.

Acute lung injury can be a complication of hemorrhagic shock. Mechanisms of injury include neutrophil-derived inflammatory products that induce necrosis within the lung. Recent data has shown apoptosis, in addition to necrosis, as a pathway leading toward acute lung injury in shock models. This study quantitates apoptotic and necrotic cells in the lung after hemorrhagic shock. Mongrel pigs (20-30 kg) under general anesthesia (with pancuronium and pentobarbital) underwent instrumentation with placement of carotid and external jugular catheters. The animals were randomized to sham hemorrhage (n = 6) and to hemorrhagic shock (n = 7). The hemorrhagic shock group then underwent hemorrhage (40-45% blood volume) to a systolic blood pressure of 40-50 mm Hg for 1 hour. The animals were then resuscitated with shed blood plus crystalloid to normalization of heart rate and blood pressure. The animals were observed under general anesthesia for 6 hours after resuscitation, then sacrificed, and lungs were harvested. Lung injury parameters including histology (H&E stain), apoptosis [terminal deoxynucleotidy] transferase- mediated dUTP biotin nick end labeling (TUNEL)], and myeloperioxidase activity (spectrophotometric assay) were assessed. Hemorrhagic shock induced marked loss of lung architecture, neutrophil infiltration, alveolar septal thickening, hemorrhage, and edema in H&E staining. Furthermore, MPO activity, a marker for neutrophil infiltration and activation, was more than doubled as compared to controls (44.0 vs 20.0 Grisham units activity/g). Apoptosis (cell shrinkage, membrane blebbing, apoptotic bodies) and necrosis (cellular swelling, membrane lysis) in neutrophils, macrophages, as well as in alveolar cells was demonstrated and quantified by H&E staining use. Apoptosis was confirmed and further quantified by positive TUNEL signaling via digital semiquantitative analysis, which revealed a significant increase in apoptotic cells (16.0 vs 2.5 cells/hpf, shock vs control, respectively) and necrotic cells (16.0 vs 2.0 cells/hpf, shock vs control, respectively). Acute lung injury is a complex pathophysiologic process. Apoptosis in cells (neutrophils, macrophages, alveolar cells) is induced within the lung after hemorrhagic shock. The role of apoptosis in pulmonary dysfunction after hemorrhagic shock has yet to be determined.

PULMONARY DYSFUNCTION is a is common complication after hemorrhagic shock and causes significant morbidity and mortality in trauma patients. The etiology of acute lung injury is multifactorial and includes multiple organ ischemia and reperfusion injury after resuscitation. Central to this theme is the intestinal ischemia associated with hemorrhagic shock followed by reperfusion after resuscitation.1,2 This is associated with priming of the airway endothelial cells secondary to free oxygen radical release and the activation of neutrophils and subsequent migration into lung tissue.3-5 This event results in the pulmonary accumulation of neutrophils and secondary damage to the lung tissue due to the release of neutrophilassociated inflammatory products, namely reactive oxygen species, proteolytic enzymes, and multiple eicosanoids. This acute lung injury is characterized by alveolar capillary endothelial cell injury, increased capillary permeability, and hypoxia. In worst-case scenarios, these events lead to acute respiratory distress syndrome, or ARDS.

Numerous strategies have been developed to treat or prevent acute lung injury after hemorrhagic, as well as other forms of shock. These strategies include different resuscitation modalities, the use of anti-inflammatory agents,6-10 antioxidants,5,11 and antiadhesion molecule agents.12 However, with each of these different strategies, the lung injury in some cases is improved, but not to the point where pulmonary function is restored.

The process of programmed cell death, or apoptosis, in recent studies has been shown as a potential pathway leading toward acute lung injury in various shock models.13-15 Typical cellular death after shock or trauma is due to necrosis-a fundamental modality of cellular death, by which the cell membrane is damaged and the cellular content is released, therefore aggravating the inflammatory response after hemorrhagic shock. Apoptosis is different from necrosis. Apoptosis is characterized by cellular shrinkage, condensation of nuclear content and chromatin, apoptotic body formation, and noninflammatory phagocytosis by tissue macrophages.16- 18 Neutrophil apoptosis is believed to play a major role through which the duration of the inflammatory process is regulated. In addition, alveolar cell apoptosis is believed to play a role in the hypoxia associated with acute lung injury.

The purpose of this study is to demonstrate and quantitate the presence of apoptosis and necrosis in lung tissue in a clinically relevant model of hemorrhagic shock. In addition, the possible roles of apoptosis and the significance of apoptosis in alveolar cells and neutrophiis in lung tissue will be addressed.

Materials and Methods

Mongrel pigs weighing 20 to 40 kg were used and acclimated for 7 days in the Animal Care Facility at the University of Tennessee Health Science Center prior to surgical procedures. The experiment was approved by the Animal Care and Utilization Committee of the University of Tennessee Health Science Center. All care complied with the Principles of Laboratory Animal Care and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD).

Animals underwent induction of anesthesia with intramuscular injections of ketamine and xylazine, and general anesthesia was maintained with continuous intravenous pentobarbital infusion. Right carotid artery and right external jugular vein catheters were inserted. The animals were monitored continuously during surgery with ECG, pulse oximetry, and continuous arterial blood pressure measurements.

The experiments were designed to mimic the clinical scenario of exsanguinating hemorrhagic shock followed by resuscitation. After instrumentation, the animals were randomized to sham hemorrhage (n = 6) and to hemorrhagic shock (n = 7). The hemorrhagic shock group underwent hemorrhage (44% to 55% blood volume) to a systolic blood pressure of 40 to 50 mm Hg and were maintained at that pressure with incremental blood loss for 1 hour. The animals were then resuscitated with shed blood plus crystalloid (normal saline) to normalization of heart rate and blood pressure. The animals were then observed under general anesthesia for 6 hours after resuscitation. After the 6-hour observation period, the animals then underwent bilateral thorocatomies, lungs were inspected grossly, and then harvested. The animals were then sacrificed with lethal injections of potassium chloride, pentobarbital, and pancuronium.

Tissue was then randomly biopsied from the harvested lungs and either immediately rinsed and placed in 10 per cent buffered formalin solution or frozen at -70C. The specimens were allowed to fix for 7 days. Sections were made and embedded in paraffin and cut into 6-μm sections for slides. All tissue slides underwent hematoxylin and eosin (H&E) staining. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick- end labeling (TUNEL) method (Roche Diagnostic TUNEL apoptosis kit). In addition, neutrophil presence and activation was detected by myeloperoxidase activity from frozen tissue samples by a spectrophotometer assay at 665-nm wavelength. H&E slides and TUNEL slides were then digitally analyzed. Cells undergoing apoptosis and necrosis were identified and quantitated per highpowered field.

Results

A total of 13 animals were randomized: 6 to the sham hemorrhage group, 7 to the hemorrhagic group. One animal died in the hemorrhagic group due to shock unresponsive to resuscitation.

In the hemorrhagic shock group, all animals had appropriate responses to hemorrhagic shock with profound hypotension and tachycardia. Resuscitation with shed blood plus crystalloid restored the animal’s vital signs to near baseline levels within a couple of hours after the hemorrhage. As expected, the sham hemorrhage group had no changes in blood pressure or heart rate during the 6-hour observation period (Fig. 1).

Myeloperoxidase Activity

Myeloperoxidase is an enzyme associated with the presence of activated neutrophils, The presence of elevated myeloperoxidase activity in tissue is therefore associated with tissue injury with subsequent migration of activated neutrophils into the tissue and release of myeloperoxidase and free oxygen radicals. In the sham hemorrhage group, myeloperoxidase activity was measured at 20 Grisham units activity per gram of lung tissue (Gu/g). This compares to the hemorrhagic shock group myeloperoxidase activity of 44 Gu/g (P

FIG. 1. Resuscitation endpoints. The control group maintained baseline heart rate and blood pressure during observation. After hemorrhage, the shock group was resuscitated to near baseline heart rate and blood pressure during the observation period.

FIG. 2. Hematoxylin an\d eosin staining of control group: normal- appearing lung parenchyma.

FIG. 3. Hematoxylin and eosin staining of hemorrhagic shock group: marked loss of lung architecture, neutrophil infiltration, alveolar septal thickening, and edema.

H&E Staining

Standard H&E staining of biopsied lung tissue was performed. Examination of slides of the sham hemorrhage group revealed normal- appearing lung parenchyma with open alveoli and thin-walled alveoli septi (Fig. 2). Examination of slides of the hemorrhagic shock group revealed marked loss of lung architecture, neutrophil infiltration, alveolar septal thickening, hemorrhage, and edema (Fig. 3).

Apoplosis and Necrosis Quantification

Apoptotic cells, described as those cells with cellular shrinkage, membrane blebbing, and the presence of apoptotic bodies, were identified on H&E staining. Necrotic cells, described as those cells with cellular swelling, nuclear and cellular membrane lysing, were also identified on H&E staining. Consecutive section slides were then stained for apoptosis presence by the TUNEL technique. The two consecutive slides (H&E and the corresponding TUNEL slide) were then digitalized for cellular identification and quantification. Those cells that were identified as undergoing apoptosis on H&E were confirmed by positive TUNEL staining in the digital analysis. Cells were then quantified per high-powered field (hpf) over five different sections of each of the four different animal lobes and then averaged. In the sham hemorrhage group, lung tissue averaged 2 necrotic cells per hpf and 2.2 apoptotic cells per hpf. This compares to 15 necrotic cells per hpf and 16 apoptotic cells per hpf in the hemorrhagic shock group. Comparing the sham hemorrhage group to the hemorrhagic shock group, there was a significant difference between the apoptotic (P

Discussion

In 1972, Kerr et al. first published an article describing the process of apoptosis.19 He described this novel physiological process of cells undergoing apoptotic cellular suicide, rapid energy- dependent cell shrinkage, and loss of their normal intercellular framework. Subsequently, those cells then exhibited chromatin condensation, nuclear fragmentation, cytoplasmic blebbing and fragmentation into small apoptotic bodies. Because no cytosolic contents are exposed during this process, noninflammatory phagocytosis of these apoptotic bodies occurs. Apoptosis maintains a homeostatic balance between cellular proliferation and death and varies from tissue to tissue. Apoptosis is important in developmental biology and in remodeling of tissues during repair. Dysregulation of apoptosis is associated with pathogenesis of numerous diseases including cancer, autoimmunity, heart and neurodegenerative diseases, and prolonged inflammatory processes. In some diseases, there is promotion of apoptosis leading to such diseases as organ dysplasia and neurodegeneration. In other diseases, there is inhibition of apoptosis leading to cellular proliferation dysfunction such as cancers and several inflammatory diseases.

Acute lung injury after hemorrhagic shock as well as other forms of shock was long attributed to the effects of neutrophils and neutrophil-derived inflammatory products. Initial strategies for alleviating this inflammatory injury, besides better resuscitation, were with anti-inflammatory agents such as steroids, different NSAIDS such as indocin, and the newer COX-2 inhibitors, and different immunomodulators such as adenosine. All of these agents have shown some improvement in diminishing the inflammatory process and somewhat improving pulmonary function.6-11 However, the body seemed to circumvent these inflammatory inhibitors and still cause significant pulmonary dysfunction.

The role of apoptosis in acute lung injury after shock is believed to bimodal.20,21 The “neutrophillic hypothesis” suggests that during acute lung injury, the release of various cytokines and hormones such as granulocyte colony stimulating factor and granulocyte/ macrophage colony stimulating factor prolong the survival of neutrophils by inhibiting apoptosis and thus prolonging the neutrophil life span. This continued presence of neutrophils and their inflammatory prodnets is further accentuated by the arrival of macrophages and their inflammatory by-products such as the cytokines TNF-alpha and IL-1. These products further enhance the inflammatory process and inhibit neutrophil apoptosis. Recent work has suggested the role of MAP kinases in neutrophil apoptosis. NF Kappa beta released from macrophages causes inhibition of neutrophil MAP kinases and thus inhibits apoptosis in neutrophils.22 The potential importance of apoptosis in the regulation of inflammation suggests therapeutic modalities may be used to alter the complex cascade of apoptosis to enhance neutrophil apoptosis in cases of acute lung injury after shock.22

The second hypothesis is the “epithelial hypothesis” of acute lung injury after shock. Epithelial cells such as alveolar cells type I and II are injured during shock and die by either necrosis due to irreversible damage or apoptosis. Alveolar cells that are not initially killed by the acute inflammatory process are stressed and either undergo repair and regain their function in oxygen absorption or undergo apoptosis. Stressed alveolar cells can sometimes undergo membrane changes causing Fas, which is a cell surface membrane protein normally located on the cytosolic side of the cellular membrane, to be transported to the extracellular side of the cellular membrane. Soluble Fas ligand is released from inflammatory cells, namely cytotoxic T cells, and binds to Fas, causing initiation of apoptosis. In addition, in a similar fashion, TNF released from macrophages during inflammation binds to a cell surface protein called TNF-receptor 1, causing apoptosis in alveolar cells. The end result of the initiation of apoptosis is the activation of the caspase pathway cascade and subsequent DNA fragmentation and cell death.3 The potential importance of apoptosis in the regulation of alveolar cell death is the theory that by inhibiting alveolar cell apoptosis, the cell will then repair itself and regain cellular function of oxygen absorption and carbon dioxide release. The use of surfactant protein A, nitrous oxide, and N- acetylcysteine in recent studies has shown promising results in increasing the survival of alveolar cells type I and II by inhibiting alveolar cell apoptosis.23-27

Acute lung injury is a typical response to a host of different pulmonary and systemic insults. The initial inflammatory response to the insult may well be adaptive and protective in nature with neutrophil recruitment to fight infection. At some point in time, the inflammatory process becomes excessive or dysregulated and becomes injurious to the tissues. The regulation of neutrophils is important in stopping the inflammatory process. Through combination therapies used to inhibit the inflammatory process as well as promote neutrophil apoptosis, the extent of neutrophil-induced damage might be controlled. In addition, to regain pulmonary function, alveolar cells must be protected by regulating the bombardment of inflammatory products, as well as inhibiting alveolar cell apoptosis. By doing so, alveolar cells might repair themselves and regain their function in oxygen transport.

The results of this study indicate that apoptosis does have a role in acute lung injury after hemorrhagic shock. Further studies will be needed to determine how modulating apoptosis of different cell lines, namely neutrophils and alveolar cells, will affect pulmonary function and recovery from acute lung injury.

REFERENCES

1. Adams CA Jr, Magnotti LJ, Xu DZ, et al. Acute lung injury after hemorrhagic shock is dependent on gut injury and sex. Am Surg 2000;66:905-12.

2. Magnotti LJ, Upperman JS, Xu DZ, et al. Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock. Ann Surg 1998;228:518-27.

3. Lee WL, Downey GP. Neutrophil activation and acute lung injury. Curr Opin Crit Care 2001;7:1-7.

4. Kuzu MA, Cuneyt K, Isinsu K, et al. Role of integrins and intracellular adhesion molecule-1 in lung injury after intestinal ischemia-reperfusion. Am J Surg 2002; 183:70-4.

5. Zimmerman BJ, Grisham MB, Granger DN. Role of oxidants in ischemia/reperfusion-induced granulocyte infiltration. Am J Physiol 1990;258:G185-90.

6. Davis KA, Fabian TC, Croce MA, et al. Prostanoids: early mediators in the secondary injury that develops after unilateral pulmonary contusion. J Trauma 1999;46:824-31.

7. Davis KA, Fabian TC, Ragsdale DN, et al. Combination therapy that targets secondary pulmonary change after abdominal trauma. Shock 2001; 15:479-84.

8. Davis KA, Fabian TC, Ragsdale DN, et al. Endogenous adenosine and secondary injury after chest trauma. J Trauma 2000; 49:892-8.

9. Desselle WJ, Greenhaw JJ, Trenthem LL, et al. Macrophage cyclooxygenase expression, immunosuppression, and cardiopulmonary dysfunction after blunt chest trauma. J Trauma 2001;51: 239-51.

10. Kelly ME, Miller PR, Greenhaw JJ, et al. Novel resuscitation strategy for pulmonary contusion after severe chest trauma. J Trauma 2003;55:94-105.

11. Maxwell RA, Gibson JB, Fabian TC, et al. Effects of a novel antioxidant during resuscitation from severe blunt chest trauma. Shock 2000; 14:646-51.

12. Tasaki O, Goodwin C, Mozingo D, et al. Selectin blockade worsened lipopolysaccharide-induced lung injury in a swine model. J Trauma 1999;46:1089-95.

13. Hiramatsu M, Hotchkiss RS, Karl IE, et al. Cecal ligation and puncture (CLP) induces apoptosis in thymus, spleen, lung, and gut by an endotoxin and TNF-independent pathway. Shock 1997; 7:247-53.

14. Hotchkiss RS, Swanson PE, Freeman BD, \et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999;27:1230-51.

15. Guan J, Jin D, Jin L, et al. Apoptosis in organs of rats in early stage after polytrauma combined with shock. J Trauma 2002; 52:104-11.

16. Israels L, Israels E. Apoptosis. Stem Cells. 1999;17: 306- 13.

17. Alien RT, Hunter WJ, Agrawal DK. Morphological and biochemical characterization and analysis of apoptosis. JPM 1997;37:215-28.

18. Hetts SW. To die or not to die: an overview of apoptosis and its role in disease. JAMA 1998;279:300-7.

19. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biologic phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972:26:239-57.

20. Martin TR, Nakamura M, Matute-Bello G. The role of apoptosis in acute lung injury. Crit Care Med 2003;31:S184-8.

21. Matute-Bello G, Martin TR. Science review: apoptosis in acute lung injury. Crit Care 2003;7:355-8.

22. Abraham E. Neutrophils and acute lung injury. Crit Care Med 2003;31:8195-9.

23. Sutherland LM, Edwards YS, Murray AW. Alveolar type II cell apoptosis. Comp Biochem Physio A Mol Integr Physiol 2001; 129:267- 85.

24. Reidy MF, Wright JR. Surfactant protein A enhances apoptotic cell uptake and TGF-betal release by inflammatory alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2003;285: L854-61.

25. White MK, Strayer DS. Survival signaling in type II pneumocytes activated by surfactant protein A. Exp Cell Res 2002;280: 270-9.

26. Rudkowski JC, Barreiro E, Harfouche R, et al. Role of inducible and neuronal nitric oxide synthases in sepsis-induced pulmonary apoptosis. Am J Physiol Lung Cell Mol Physiol 2003;286:793- 800.

27. Ozdulger A, Cinel I, Koksel O, et al. The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. Shock 2003; 19:366-72.

T. WRIGHT JERNIGAN, M.D., MARTIN A. CROCE, M.D., TIMOTHY C. FABIAN, M.D.

From the Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee

Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Atlanta, GA January 31-February 3, 2004.

Address correspondence and reprint requests to Timothy C. Fabian, M.D., Harwell Wilson Alumni Professor & Chairman, Department of Surgery, University of Tennessee Health Science Center, 956 Court Avenue, Suite G228, Memphis, TN 38163.

Copyright The Southeastern Surgical Congress Dec 2004

Background: The National Kidney Foundation has advocated the use of the abbreviated Modification of Diet in Renal Disease (MDRD) equation to estimate glomerular filtration rate (GFR) from serum creatinine measurements in clinical laboratories. However, healthy persons were not included in the development of the MDRD equation.

Objectives: To assess the accuracy of the MDRD equation in patients with chronic kidney disease compared with healthy persons and to develop a new equation that uses both patients with chronic kidney disease and healthy persons.

Design: Cross-sectional study.

Setting: The Mayo Clinic, a tertiary-care medical center.

Participants: Consecutive patients (n = 320) who had an iothalamate clearance test specifically for chronic kidney disease evaluation and consecutive healthy persons (n = 580) who had an iothalamate clearance test specifically for kidney donor evaluation.

Measurements: Serum creatinine levels, GFR, demographic characteristics, and clinical characteristics were abstracted from the medical record.

Results: The MDRD equation underestimated GFR by 6.2% in patients with chronic kidney disease and by 29% in healthy persons. Re- estimated coefficients for serum creatinine and sex were similar to the original MDRD equation in the chronic kidney disease series but not in the healthy series. At the same serum creatinine level, age, and sex, GFR was on average 26% higher in healthy persons than in patients with chronic kidney disease (P

Limitations: The new equation was not developed in a general population sample. Elderly and African-American persons were underrepresented.

Conclusion: The MDRD equation systematically underestimates GFR in healthy persons. A new equation developed with patients who have chronic kidney disease and healthy persons may be a step toward accurately estimating GFR when the diagnosis of chronic kidney disease is unknown.

Ann Intern Med. 2004;141:929-937. www.annals.org

Recently, the National Kidney Foundation endorsed a series of guidelines to assess patients with chronic kidney disease. These guidelines highlighted problems associated with using creatinine clearance to measure glomerular filtration rate (GFR). They instead recommended estimation of GFR by using prediction equations based on serum creatinine determinations (1, 2). The abbreviated Modification of Diet in Renal Disease (MDRD) equation (3, 4) was advocated because it correlated well with GFR measured by iothalamate clearance (2, 5). It also performed as well as a more complicated MDRD equation that required serum urea nitrogen and albumin determinations (3).

The abbreviated MDRD equation has also been used to estimate the prevalence of chronic kidney disease in the U.S. population with serum creatinine determinations adjusted for calibration bias (6, 7). However, this equation was developed by using persons with chronic kidney disease and did not include healthy persons (3, 4). Thus, the MDRD equation may not be appropriate for determining the prevalence of chronic kidney disease. Previous studies have raised the concern that MDRD equations may underestimate GFR in healthier populations (8-12). Furthermore, in a population-based study, the relationship between cardiovascular risk factors and GFR differed when the abbreviated MDRD equation was used instead of creatinine clearance (13).

The primary objective of the current study was to determine whether estimated GFR with the MDRD equation was accurate in healthy persons compared to patients with chronic kidney disease. The secondary objective was to develop a new GFR prediction equation based on both healthy persons and patients with chronic kidney disease.

METHODS

Healthy and Chronic Kidney Disease Series

Records of all potential living donors for kidney transplantation at the Mayo Clinic from 1996 to 2002 were reviewed, with institutional review board approval; this review was an expansion of a previously reported series (9). Originally, potential kidney recipients had identified the potential donors and had perceived them to be healthy enough to be evaluated for kidney donation. Most donors (71%) were related to the potential kidney recipient (9). A total of 599 potential donors had an iothalamate clearance test to measure GFR, which was routinely obtained before a clinic visit with a nephrologist (Figure 1). After exclusions for missing serum creatinine determinations or for age younger than 17 years, the healthy series consisted of 580 potential donors.

Records of 501 consecutive patients who had an iothalamate clearance test for any reason between October 1999 and March 2000 were also reviewed, with institutional review board approval (Figure 1). A nephrologist abstracted these records for a cystatin C study (14). Of these patients, 353 had an iothalamate clearance test to measure GFR as part of an evaluation for known or suspected chronic kidney disease. Iothalamate clearance was routinely and primarily ordered by nephrologists at the Mayo Clinic during outpatient referrals. An elevated serum creatinine level, proteinuria, abnormal urinary sediment, history of kidney disease, or kidney transplantation recipient status were typical indications for the iothalamate clearance test. Thus, chronic kidney disease was defined by clinical presentation and not by a GFR cutoff. In recipients of a nonkidney solid organ transplant, iothalamate clearance for routine monitoring only was not considered an evaluation for chronic kidney disease. After exclusions for missing serum creatinine determinations or for age younger than 17 years, the chronic kidney disease series consisted of 320 patients.

Figure 1. Sampling process for healthy series and chronic kidney disease series.

Iothalamate Clearance and Serum Creatinine Assays

Measurement of GFR with the renal clearance of nonradiolabeled iothalamate has previously been described (15). This test involved the subcutaneous injection of nonradiolabeled iothalamate after oral hydration with 4 to 6 glasses of water. After 2 hours, GFR was determined by the clearance equation (UV/P) using the average of 2 serum samples and 1 urine sample assayed for iothalamate concentration via capillary electrophoresis. Glomerular filtration rate was expressed per 1.73 m by multiplying the measured value by 1.73 and dividing by body surface area. Nonradiolabeled iothalamate clearance correlates well with radiolabeled iothalamate clearance (r = 0.998) (15) and provides a normal value range similar to that of other GFR measurement techniques (9, 16). Interassay coefficient of variation for nonradiolabeled iothalamate clearance was reported as 5%.

Serum creatinine levels were all assayed with the rate-Jaffe reaction on a Hitachi 747 autoanalyzer (Roche Diagnostics Corp., Indianapolis, Indiana). This assay was calibrated daily with a Cfas calibrator (Roche Diagnostics Corp.) by using the uncompensated method during the study period. The interassay coefficient of variation for serum creatinine determinations was reported as 3.1% at 1.3 mg/dL (115 mol/L) and 1.5% at 6.1 mg/dL (539 mol/L) with stability during the study period. The 2.5th to 97.5th percentile of serum creatinine by this assay was 0.7 to 1.2 mg/dL (62 to 106 mol/ L) in normal white women and 0.9 to 1.4 mg/dL (80 to 124 mol/L) in normal white men. Estimated GFR was calculated by using the abbreviated MDRD equation (Table 1, equation 1).

Statistical Analysis

We compared the baseline characteristics of patients in the healthy and chronic kidney disease series by using the chi-square test (nominal factors), Wilcoxon rank-sum, or Student t-test. We defined bias as the mean of estimated GFR minus measured GFR. We defined percentage bias as the mean of individual ([estimated GFR – measured GFR]/measured GFR) 100%. P30% was defined as the percentage of estimated GFR within 30% of measured GFR. We compared estimated GFR and measured GFR in the healthy and chronic kidney disease series by using bias, percentage bias, R (coefficient of determination), and P30%. Similar analyses were done with the Cockcroft-Gault equation (17), adjusted for body surface area (mL/ min per 1.73 m^sup 2^) and adjusted to predict GFR instead of creatinine clearance (3).

The log-linear form of the abbreviated MDRD equation was refit for new coefficients by using multiple linear regression in the healthy and chronic kidney disease series independently. A log- linear form of the abbreviated MDRD equation was also refit in a combined series (n = 900) with an indicator variable for healthy versus kidney disease status. Each coefficient was compared with the original MDRD study coefficient (4).

To develop a new equation for use when the diagnosis of chronic kidney disease is unknown, we used an approach similar to that used to develop the MDRD equations (3, 4). The natural logarithmic (ln) transformed measured GFR was regressed on age, sex, and serum creatinine in the combined series. Because the relationship of ln GFR with ln serum creatin\ine was nonlinear, the following terms were considered: linear, quadratic, and cubic reciprocal serum creatinine. Linear, quadratic, and logarithmic age terms were also considered. In addition, we examined pairwise interactions between the 3 factors. Because of the large sample size, terms that were statistically significant often added little to the predictive ability of the model. In the interest of parsimony, an increase in R^sup 2^ of 0.02 or more was arbitrarily required to consider a more complicated model (18). The new equation was internally validated by using bootstrapping (500 replications) to estimate its performance (R^sup 2^ adjusted for optimism) on independent data sets (19).

Table 1. Prediction Equations for Glomerular Filtration Rate*

All statistical analyses were performed with JMP, version 5.1 (SAS Institute, Inc., Cary, North Carolina), except for bootstrapping, which was done with SAS, version 8.2.

Role of the Funding Source

The study was funded by a National Research Service Award and grants from the Division of Nephrology, Mayo Clinic, Rochester, Minnesota. The funding sources had no role in the collection, analysis, or interpretation of data or in the decision to submit the manuscript for publication.

RESULTS

Comparison of Healthy and Chronic Kidney Disease Series

Table 2 shows the characteristics of the patient samples. Information on race was not available in 14% of the patients. The number of African-American patients was inadequate to analyze the race component in either series. In the chronic kidney disease series, 53% of patients had native kidney disease alone, 16% of patients had a nonkidney solid organ transplant with or without a kidney transplant, and 31% of patients had a kidney transplant alone. In the patients with native kidney disease alone, 36% had hypertension or kidney disease of unknown cause, 24% had glomerulopathy, 13% had diabetes mellitus, and the remaining 27% had miscellaneous causes. Serum creatinine levels were normal (≤1.4 mg/dL [≤124 mol/L] in men and ≤1.2 mg/dL [≤106 mol/L] in women) in 93 (29%) of the chronic kidney disease series.

Table 2. Clinical Characteristics in the Healthy Series and Chronic Kidney Disease Series*

Figure 2 displays estimated GFR (abbreviated MDRD equation) plotted against measured GFR (iothalamate clearance). Estimated GFR predicted measured GFR well in the chronic kidney disease series, but measured GFR was higher than estimated GFR in the healthy series. Table 3 shows the accuracy and precision of estimated GFR calculated by using the original MDRD equation. The MDRD equation was less accurate in the healthy series than in the chronic kidney disease series. With the Cockcroft-Gault equation, percentage bias was -5.9% 1.7% in the chronic kidney disease series, -9.6% 3.9% in the chronic kidney disease series with an estimated GFR of 60 mL/ min per 1.73 m^sup 2^ or greater (n = 61), and – 27% 1% in the healthy series. Thus, the Cockcroft-Gault equation was also less accurate in the healthy series than in the chronic kidney disease series.

The top panel of Figure 3 displays the reciprocal of serum creatinine plotted against logarithmic measured GFR. At any serum creatinine level, patients in the healthy series had a higher average GFR than did patients in the chronic kidney disease series. Patients with chronic kidney disease who had transplants were similar to patients with chronic kidney disease who did not have transplants.

The refit MDRD equations derived in this study were compared with the original MDRD equation (equation 1). In the chronic kidney disease series (equation 2), the coefficients (SE) were similar to the original MDRD equation for serum creatinine (-1.290 0.039 vs. – 1.154), age (-0.290 0.050 vs. 0.203), and female sex (0.767 [exp(- 0.265 -0.032)] vs. 0.742 [exp(-0.298)]). Adding a transplant status variable was not statistically significant (P > 0.2) and did not change the serum creatinine, age, or sex coefficients substantively. In the healthy series (equation 3), the age coefficient was also similar to the original MDRD equation (-0.192 0.021 vs. 0.203). However, the coefficients were very different from the original MDRD equation for serum creatinine (-0.490 0.052 vs. -1.154) and for female sex (0.923 [exp (-0.080 0.016)] vs. 0.742 [exp(-0.298)]). At the same serum creatinine level, women had 77% the GFR of men in the chronic kidney disease series but 92% the GFR of men in the healthy series.

When health status was added as a separate variable in a refit MDRD equation (equation 4), healthy persons had a 26% higher GFR on average than did patients with chronic kidney disease (P

Development and Validation of a New Equation

In clinical practice, it may be unknown whether a patient is healthy or has chronic kidney disease. Thus, a new equation was developed on the basis of a combined sample of healthy persons and patients with chronic kidney disease. The best model was the quadratic GFR equation with the following covariates: 1/SCr, 1/ SCr^sup 2^, age, and sex (where SCr = serum creatinine) to predict ln measured GFR (equation 5). Serum creatinine values less than 0.8 mg/dL (71 mol/L) were set to 0.8 in the development of this equation. Inclusion of all pairwise interactions increased the R^sup 2^ value by only 0.007. The quadratic GFR equation (R^sup 2^ = 0.863, equation 5) fit the combined series better than the original MDRD equation (R^sup 2^ = 0.830, equation 1) and a refit MDRD equation derived by using the combined series (R^sup 2^ = 0.841, equation not shown). The bootstrap corrected R^sup 2^ for the quadratic model was 0.862 compared with 0.863 uncorrected. The bottom panel of Figure 3 compares the quadratic GFR equation with the original MDRD equation. The quadratic GFR equation had a higher estimated GFR in the normal serum creatinine range.

Figure 2. Relationship between estimated glomerular filtration rate (GFR) (abbreviated Modification of Diet in Renal Disease equation) and measured GFR (iothalamate clearance) in 900 patients on a logarithmic scale.

DISCUSSION

These analyses indicate that although the abbreviated MDRD equation was reasonably accurate in patients with chronic kidney disease, it significantly underestimated GFR in healthy persons. This was probably due to the exclusion of healthy persons from the study participants used to develop this equation. At the same serum creatinine level, age, and sex, GFR was on average 26% higher in healthy persons than in patients with chronic kidney disease. A new quadratic GFR equation may be more accurate than the MDRD equation in estimating GFR when kidney disease status is unknown. This study highlights the importance of selection bias in the target population used to develop GFR prediction equations. Thus, the application of the MDRD equation to the general population (7) may have overestimated the prevalence of chronic kidney disease (when defined by a reduced GFR).

A concern with GFR prediction equations has been bias from a lack of standard calibration in serum creatinine assays across laboratories (20). One study found that the MDRD study laboratory had serum creatinine values 0.23 mg/dL (20 mol/L) lower than values measured at another laboratory. The implication was that a constant calibration bias caused greater inaccuracies in estimated GFR for persons with a normal serum creatinine level than for persons with an elevated serum creatinine level (6). Calibration bias is being addressed by the Laboratory Working Group of the National Kidney Disease Education Program (21). Correction of this calibration bias, however, does not rectify a selection bias present in the original MDRD equation. After subtracting 0.23 mg/dL (20 mol/L) from all serum creatinine values (6), GFR (with multivariable adjustment [serum creatinine level, age, and sex]) was still 26% higher in healthy persons than in patients with chronic kidney disease.

To further investigate the potential effect of calibration, serum samples assayed for creatinine (n = 180) were reassayed at Loyola University Medical Center on a rate-Jaffe Beckman LX20 autoanalyzer (Beckman Coulter, Inc., Fullerton, California). A rate-Jaffe Beckman CX3 autoanalyzer (older model) was used for deriving the original MDRD equation (6). A calibration equation (SCr^sub Loyola^ = – 0.18 + 1.14 X SCr^sub Mayo^) was derived to adjust the serum creatinine values. This adjustment slightly improved bias with the MDRD equation in the healthy series (-29% before calibration, -26% after calibration) but led to more bias in the chronic kidney disease series (-6.2% before calibration, -9.5% after calibration). However, GFR (with multivariable adjustment) was still 26% higher in healthy persons than in patients with chronic kidney disease.

The additive effects of calibration bias and selection bias may explain why 12% of the middle-aged healthy serie\s had an estimated GFR less than 60 mL/min per 1.73 m^sup 2^ with the MDRD equation, diagnostic criteria for chronic kidney disease (2). For example, if a 50-year-old woman presented to donate a kidney and had a Mayo Clinic serum creatinine level of 1.1 mg/dL (97 mol/L), she would have an estimated GFR of 90 mL/min per 1.73 m^sup 2^ (equation 3). If instead an equation derived with the Mayo Clinic chronic kidney disease sample were used (equation 2), her estimated GFR would be 65 mL/min per 1.73 m^sup 2^. But if an equation derived with the MDRD study chronic kidney disease sample were used (equation 1), her estimated GFR would be 56 mL/min per 1.73 m^sup 2^.

Table 3. Accuracy and Precision of the Abbreviated Modification of Diet in Renal Disease Equation in the Chronic Kidney Disease Series and Healthy Series*

One possible explanation for a selection bias in the MDRD equation is that healthy persons may have more muscle mass and more protein intake than patients with chronic kidney disease who are chronically ill and have protein-restricted diets. Substantial muscle atrophy has been shown to occur in patients receiving dialysis compared with healthy controls (22). In patients who develop kidney disease, the increase in serum creatinine level caused by GFR reduction may be attenuated by muscle atrophy and decreased dietary protein. A decrease in serum creatinine level was evident in a comparison of a healthy person to a patient with kidney disease who had the same GFR, age, and sex. For example, consider a 60-year-old man with a GFR of 83 mL/min per 1.73 m^sup 2^. If healthy, a serum creatinine level of 1.4 mg/dL (124 mol/L) would be required to estimate this GFR (equation 3). But if he had kidney disease, a lower serum creatinine level of 1.07 mg/dL (95 mol/L) would be required to estimate this GFR (equation 2).

The physiology for serum creatinine variability may also differ in patients with chronic kidney disease compared with healthy persons. Consistent with this hypothesis, the serum creatinine coefficients calculated in kidney disease samples for this study (- 1.290) and the MDRD study (-1.154) (4) were much stronger than those calculated in healthy samples for this study (-0.490) and by other investigators (-0.113) (8). The difference in coefficients may be explained through the relationship between serum creatinine and GFR as expressed in the following clearance equation: S^sub Cr^ = U^sub Cr^V/GFR. In healthy persons, muscle mass and dietary protein intake (U^sub Cr^V) (23, 24) may have the dominant effect on serum creatinine variability, consistent with a weak coefficient in predicting GFR. For example, a 50% higher serum creatinine level in the healthy series was associated with an 18% lower GFR. In patients with kidney disease, GFR may have the dominant effect on serum creatinine variability, consistent with a strong coefficient in predicting GFR. For example, a 50% higher serum creatinine level in the chronic kidney disease series was associated with a 41% lower GFR. This was stronger than an inverse association, possibly reflecting the increasing role of tubular secretion as GFR declines (23).

Figure 3. Relationship between the reciprocal of serum creatinine and the natural logarithm of measured glomerular filtration rate (GFR) in 900 patients.

The quadratic GFR equation (equation 5) was developed by using a combined healthy and chronic kidney disease sample as a step toward improving the estimation of GFR when kidney disease status is unknown. Only 1 person (0.2%) in the healthy series had an estimated GFR less than 60 mL/min per 1.73 m^sup 2^ with the quadratic GFR equation. However, this equation has several limitations. The quadratic GFR equation assumes that persons with a normal serum creatinine level can be represented by a population in which 14% of patients had chronic kidney disease and 86% were potential kidney donors. The potential kidney donors may be “super healthy” compared with the general population. However, they were not without co- morbid conditions: 29% had a high blood pressure (systolic ≥ 140 mm Hg or diastolic ≥ 90 mm Hg) and 33% had hyperlipidemia (low-density lipoprotein cholesterol level > 130 mg/dL [>3.4 mmol/ L]). A GFR prediction equation developed in a population-based sample would be more accurate for general population studies. Also, the sample used to derive the quadratic GFR equation lacks adequate representation of elderly patients and nonwhite racial groups.

Several additional limitations in this study should be noted. Serum creatinine and GFR determinations were not always assayed the same day, and this occurred more often in the chronic kidney disease series. Only 51 persons in the healthy series had GFR determinations during the same time frame as the chronic kidney disease series. However, when indicator variables for these factors were considered in multivariable models, none of these factors changed the other coefficients substantively. There was less precision with the original MDRD equation applied to patients with chronic kidney disease for this study (R^sup 2^ = 0.786) compared with the MDRD study (R^sup 2^ = 0.892). The MDRD study had a larger sample size and used the average of 4 serum and 4 urine samples for measuring GFR with iothalamate clearance (25).

In summary, inaccurate estimates of GFR can occur if a serum creatinine-based equation is developed in a sample that is systematically different from the application population. This limits the generalizability of the abbreviated MDRD and Cockcroft- Gault equations, both developed in chronic kidney disease samples. The quadratic GFR equation is an improvement, but an equation developed from a general population sample is still needed. Future equations with alternative serum analytes, such as cystatin C (26), may ultimately be more accurate in predicting GFR across different populations.

From Mayo Clinic, Rochester, Minnesota.

Acknowledgments: The authors thank Timothy Uphoff, PhD, and Mary Burritt, PhD, for technical support on laboratory measurements.

Grant Support: By a National Research Service Award (T32 DK07013) and grants from the Division of Nephrology, Mayo Clinic, Rochester, Minnesota.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Fernando G. Cosio, MD, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; e-mail, [email protected].

Current author addresses and author contributions are available at www.annals.org.

Context

Experts increasingly use the Modification of Diet in Renal Disease (MDRD) equation to estimate glomerular filtration rate (GFR).

Contribution

This cross-sectional study compared GFR estimated by the MDRD equation with GFR measured by iothalamate clearance in 320 patients with chronic kidney disease and 580 healthy kidney donor candidates. The MDRD equation underestimated GFR by 6% in patients with kidney disease and by 29% in healthy persons. The authors also derived a quadratic equation that better estimated GFR in the healthy people than did the MDRD equation.

Implications

The MDRD equation systematically underestimates GFR and may erroneously categorize some healthy persons as having kidney disease.

-The Editors

References

1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1l-266. [PMID: 11904577]

2. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139:137-47. [PMID: 12859163]

3. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-70. [PMID: 10075613]

4. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine [Abstract]. J Am Soc Nephrol. 2000;11:A0828.

5. Manjunath G, Sarnak MJ, Levey AS. Prediction equations to estimate glomerular filtration rate: an update. Curr Opin Nephrol Hypertens. 2001;10:785-92. [PMID: 11706306]

6. Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis. 2002;39:920-9. [PMID: 11979335]

7. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41: 1-12. [PMID: 12500213]

8. Lin J, Knight EL, Hogan ML, Singh AK. A comparison of prediction equations for estimating glomerular filtration rare in adults without kidney disease. J Am Soc Nephrol. 2003;14:2573-80. [PMID: 14514734]

9. Rule AD, Gussak HM, Pond GR, Bergstralh EJ, Stegall MD, Cosio FG, et al. Measured and estimated GFR in healthy potential kidney donors. Am J Kidney Dis. 2004;43:112-9. [PMID: 14712434]

10. Bertolatus JA, Goddard L. Evaluation of renal function in potential living kidney donors. Transplantation. 2001;71:256-60. [PMID: 11213070]

11. Vervoort G, Willems HL, Wetzels JF. Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new (MDRD) prediction equation. Nephrol Dial Transplant. 2002;17:1909-13. [PMID: 12401845]

12. Pierrat A, Gravier E, Saunders C, Caira MV, At-Djafer Z, Legras B, et al. Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz, and modification of diet in renal disease formulas. Kidney Int. 2003;64:1425-36. [PMID: 12969162]

13. Verhave JC, Gansevoort RT, Hillege HL, De Zeeuw D, Curhan GC, De Jong PE. Drawbacks of the use of indirec\t estimates of renal function to evaluate the effect of risk factors on renal function. J Am Soc Nephrol. 2004;15:1316-22. [PMID: 15100372]

14. Buehrig CK, Larson TS, Bergert JH, Pond GR, Bergstralh EJ. Cystatin C is superior to serum creatinine for the assessment of renal function [Abstract]. J Am Soc Nephrol. 2001;12:A1005.

15. Wilson DM, Bergert JH, Larson TS, Liedtke RR. GFR determined by nonradiolabeled iothalamate using capillary electrophoresis. Am J Kidney Dis. 1997;30:646-52. [PMID: 9370179]

16. Slack TK, Wilson DM. Normal renal function: CIN and CPAH in healthy donors before and after nephrectomy. Mayo Clin Proc. 1976;51:296-300. [PMID: 1263599]

17. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. [PMID: 1244564]

18. Hand DJ. Scientific method and statistics. In: Armitage P, Colton T, eds. Encyclopedia of Biostatistics. Vol. 5. Chichester, United Kingdom: J Wiley; 1998:3967-71.

19. Harrell FE. Regression Modelling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analyses. New York: Springer-Verlag; 2001.

20. Hsu CY, Chertow GM, Curhan GC. Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int. 2002;61:1567-76. [PMID: 11967006]

21. Suggestions for Laboratories. National Kidney Disease Education Program. Accessed at www.nkdep.nih.gov/educresources/ nkdep_labreporting_factsheet.htm. on 2 August 2004.

22. Johansen KL, Shubert T, Doyle J, Soher B, Sakkas GK, Kent- Braun JA. Muscle atrophy in patients receiving hemodialysis: effects on muscle strength, muscle quality, and physical function. Kidney Int. 2003;63:291-7. [PMID: 12472795]

23. Schuster VL, Seidin DW. Renal clearance. In: Seldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology, 2nd ed. New York: Raven Pr; 1992:943-76.

24. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38:1933-53. [PMID: 1394976]

25. Beck GJ, Berg RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluchter MD, et al. Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group. Control Clin Trials. 1991;12:566- 86. [PMID: 1664792]

26. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta- analysis. Am J Kidney Dis. 2002;40:221-6. [PMID: 12148093]

Andrew D. Rule, MD; Timothy S. Larson, MD; Erik J. Bergstralh, MSc; Jeff M. Slezak, MSc; Steven J. Jacobsen, MD, PhD; and Fernando G. Cosio, MD

Copyright American College of Physicians Dec 21, 2004

THE flu season is upon us and it’s going to get nasty. “This is an unpleasant, type-A flu virus, which is considered worse than the type-B virus,” says Professor John Oxford, a top virologist based at the London Queen Mary School of Medicine.

It originated in China’s Fujian province and has already proved itself a force to be reckoned with. “This strain showed it had some punch when several young children died after catching it last winter,” Professor Oxford says.

“The good news is that this year the Fujian strain, along with the Shanghai and New Caledonia strains of influenza, is included in the flu vaccine, so vaccination will afford a more direct form of protection than the jab offered last year.”

So how do you protect yourself – and if you catch it, what do you do?

Is it too late to be immunised?

No. It takes about 10 days for your body to start producing the antibodies to the flu vaccine (possibly even less, advises Professor Oxford, if you have been immunised before) so you will have protection within a fortnight of immunisation.

If you are over 65 or in one of the “at risk” groups, which includes those suffering from asthma, kidney disease, diabetes, auto- immune conditions and heart disease (the jab can be given to babies over six months in the “at risk” groups), you qualify for free immunisation, which should be done through your GP.

The chief medical officer has also recommended, this year, that healthcare workers should be immunised – because they are more likely to come into contact with the disease than others.

For anyone outside these groups, private doctors and health clinics are still offering flu jabs for around Pounds 30 (try Samedaydoctor, W1, on 020 7935 0113 or Doctor Today, NW3, on 020 7433 1444).

Boots no longer offers flu jabs.

Is it really worth bothering with a flu jab?

While flu can lead to complications (such as bronchitis or secondary bacterial pneumonia) which can result in death for people in the “at risk” groups, it is unpleasant but not usually lifethreatening for anyone in normal health.

It may well be worth having the jab, however: in years like this where there is a good match between the vaccine and the strain of flu in circulation, flu jabs are 70-80 per cent effective, and if you do catch flu after the jab, it is likely to be much milder than if you hadn’t had the injection.

How else can I avoid catching flu?

It’s not easy, once other people around you have caught it. The flu virus is highly contagious and is easily passed on by breathing in tiny droplets of moisture from the breath of infected people.

Flu takes two or three days to incubate, and a sufferer can pass the virus on the day before their symptoms appear.

“Personal hygiene is very important in stopping the spread of flu,” says Professor Oxford. “People are very slapdash about hygiene. Cover your nose or mouth when you sneeze or cough and wash your hands frequently.”

Keep your immune system strong and you’ll stand a better chance of beating off bugs. Eat properly, as poor nutrition is the main cause of a weakened immune system. Have plenty of fruit containing vitamin C (blueberries and kiwi fruit are good choices) both to boost immunity and help you recover if you fall ill, as the body’s levels of vitamin C tumble when you have a virus.

There are also additional steps that can be taken to help defend yourself against flu.

Cold showers: Scientific studies have now backed up what naturopaths have been saying for years – that taking a cold shower every day can greatly improve your immunity to viruses. The theory goes that the shock of the cold water stimulates the body into warming itself up and raising its core temperature – which destroys cold and flu viruses. If you are suffering from flu, taking a cold shower may seem like purgatory but the same study concluded that it can shorten the duration of an infection, too.

Acupuncture: This can improve the body’s ability to resist infection and works best if done regularly. The treatment works through the nervous system and energy channels of the body and has been shown to cause the brain to release endorphins and enkephalins (natural pain killers) as well as boosting the immune system.

Zinc: Eat foods containing zinc – it is the main nutrient protecting the immune system, and helps white blood cells resist infection. Foods which contain zinc include eggs, wholegrain bread and cereals, nuts, seafood, meat and oysters.

Hemp seed: This appears to have a role in preventing upper- respiratory-tract infections; Finnish researchers found that people who took two tablespoons of hemp seed oil a day for dry skin had also suffered less from flu and colds.

Good Oil, a hemp seed oil, can be found at Waitrose for Pounds 6.99 a bottle.

What about the new anti-flu drugs?

There has been an increasing focus on antiviral drugs such as oseltamivir (Tamiflu) and zanamivir (Relenza) which are known as NIs or neuraminidase inhibitors (neuraminidase is the mushroom spike that sits on the outside of the flu virus, and these drugs block its function). They can be used both therapeutically (to help cure flu) or prophylactically (to prevent the disease developing).

The drugs are only available through GPs for people in the “at risk” groups.

Also, they need to be taken within 36 hours of the symptoms of flu developing, so if you think you may need them, move fast at the first signs.

What else can I do if I get flu?

Flu is a virus, so it will have to run its course and there is little you can do to make your body deal with it more swiftly.

However, the symptoms can be treated.

Painkillers: Over-the-counter medicines containing paracetamol (or, for adults, aspirin) will help to relieve symptoms.

Decongestants: Pseudoephedrine is one of the most effective decongestant ingredients available in over-the-counter medicines and usually comes in a ” nondrowsy” version. For something which is easy to take, try Boots Direct Dose cold-and-flu granules (Pounds 4.15 for 10 sachets).

For pregnant women who are avoiding drug treatments, seawater- based nasal sprays such as Sterimar can relieve blocked and stuffy noses (Pounds 5.99 at Boots).

Water: Drinking lots is vital, as keeping your body hydrated helps it to deal with illness better by removing the toxins and byproducts of the viruses. If you are suffering from a high fever which is making you sweat, it is important to keep drinking. If plain cold water is unappealing, try ginger tea or herb teas sweetened with honey; as a treat for ill children, try offering hot, well-diluted Ribena.

Garlic: This has strong antiviral properties thanks to an ingredient called allicin; if you don’t fancy eating garlic as it is, try Health Perception Allimax supplement which contains rapidly absorbed allicin powder (which means it shouldn’t make you smell strongly of garlic). Pounds 6.99 for 30 capsules; call 01252 861454 to order.

Steam inhalers: These cost about Pounds 10 at chemists and can relieve congestion in the head and sinuses.

Honey: It has been long feted in folkmedicine for its curative properties, and Active Manuka Honey from New Zealand is laboratory- tested to ensure a particularly high antibacterial action. It costs Pounds 13.99 for a 500g jar (plus Pounds 2 pp) from Nature’s Nectar, 01252 330 850.

Make it into a natural cough medicine by boiling a lemon for 10 minutes and extracting the juice. Put the juice in a glass with two tablespoonfuls of glycerine, and fill the glass up with honey.

Take a teaspoonful at a time.

Essential-oil patches. The Naturopatch is a new idea: a three- inch-diameter, stickon patch impregnated with a blend of essential oils, which is applied to the body for 48 hours, where it releases its healing vapours; for colds and flu try Eucalyptus, Pounds 14.95 for a tin of 15 patches; call 01737 819 883 to order.

FACTS ABOUT THE VIRUS

How can I tell the difference between flu and a cold?

Many people confuse the symptoms of flu with those of a bad cold. It’s an old joke that women catch colds and men get flu, but as anyone who has ever had flu can tell you, it is far worse than a bad cold.

As well as having a sore throat, a runny nose and possibly a cough, flu will make you feel achey and shivery, while running a high fever.

The symptoms may also come on alarmingly fast, while a cold tends to creep up on you. As a general guide, if you have a cold, you will feel under the weather for a week. If you have flu, you will feel knocked out for a week and your body will take up to three weeks to recover.

Why do we get flu in winter, rather than summer?

“We don’t really know,” says Professor Oxford. “Flu is a curious and unique virus; at any time of the year, it is striking somewhere in the globe. During our summer, it is striking in Australia, though in some equatorial countries it strikes all year round.

Many respiratory viruses are seasonal, and winterrelated – perhaps in part due to our social habits.

We spend more time indoors in winter, close to other people. But flu doesn’t disappear in the summer. It trickles along all year round, but there is certainly a great deal more of it in the winter.”

Cheryl Cummings Stegbauer, CFNP, PhD

Clinical Case Report Editor

AZ, a 19-year-old obese female, presented to her primary care provider complaining that her menses was longer than usual. She described a prolonged, heavy menstrual flow with increased cramping over the past 8 days. This was unlike her normal menses, which were regular in the past.

Menorrhagia is a common complaint. Approximately 5% of females seek medical attention for this condition.1 Menorrhagia is defined as cyclic menstrual bleeding producing more than 80 mL of blood and/ or bleeding for more than 7 consecutive days.1-5 Most individuals cannot accurately quantify the amount of menstrual bleeding in mL.6 Therefore, it is often helpful to ask the patient how the menses is disrupting her lifestyle.7

Most women have a consistent pattern of menstrual bleeding from month to month. When there is an excessive amount of bleeding during the expected menstrual cycle, an underlying organic or hematologic etiology must be considered.3

Since the definition of heavy menstrual bleeding varies, it is important to have guidelines for menstrual bleeding. A normal menstrual pattern occurs every 21 to 35 days8 and lasts from 2 to 7 days. The average woman loses approximately 30 to 40 cc of blood each cycle, which represents eight soaked pads or tampons per menses.2

* Obtaining Patient History

It is most important to obtain a detailed obstetric and gynecologic history. By comparing how the patient’s current menstrual cycle differs from her normal menstrual cycles in relation to duration, frequency, and intensity, the nurse practitioner (NP) can gain insight into the severity of bleeding.9-11

Further details should be obtained if the patient reports any of the following situations: menses lasting 3 or more days longer than usual; bleeding between each cycle; decreased intervals between the menses by 4 or more days; sudden increase of two or more sanitary pads or tampons per day; the interval between each menses is less than 21 days; each menses lasts longer than 7 days; passage of significant clots or flooding.10,12 The patient’s sexual history, use of birth control, possible pregnancy, and prior gynecologic surgeries must also be noted.

Nurse practitioners should explore the patient’s past medical history. It is important to know if the patient has a known bleeding or clotting disorder, thyroid disorder, chronic liver disease, or renal disease.11,13 The identification of renal disease is significant because patients with chronic renal disease frequently have excessive heavy menses.14 The NP should also ask about any over- the-counter medications, prescription drugs, or herbal remedies.

AZ had a medical history of obesity, migraine headaches, asthma, depression, and dyslipidemia. Her history was negative for thyroid disease, liver abnormalities, chronic renal disease, and bleeding or clotting disorders. There was no significant past surgical history. Her medications included: norethindrone/ ethinyl estradiol (Ortho- Novum 7/7/7), ibuprofen 800 mg tid prn or naproxen prn, fluticasone bid, and albuterol prn.

AZ reached menarche at age 12, and reported a regular menses approximately every 28 days, which usually lasted 7 days. During her most recent menstrual cycle however, she described a heavy menses; she changed a saturated pad every hour for 12 consecutive days. She had never been pregnant.

AZ believed that because she was taking norethindrone/ethinyl estradiol consistently, she did not need to use condoms. She had been sexually active with her current partner for 4 years. She had no history of a sexually transmitted infection and her Papanicolaou smear 6 months prior was normal.

The patient’s family history should be explored in detail as well. AZ’s family history revealed that her sister also experienced heavy, prolonged menstrual bleeding. She also had lupus. Oral contraceptive pills controlled her sister’s menses.

AZ’s mother, who was in the end stages of metastatic cancer, had a long history of heavy menses with clotting. Her mother’s heavy menses was never evaluated. AZ also reported that her maternal grandmother had a history of heavy menses. Although this family history was significant, there were no reports of any specific hmatologie disorders.

* Review of Systems

To determine if the patient is hemodynamically stable, ask about shortness of breath, fatigue, lightheadeddness, dizziness, presyncopal or syncopal events,>5 nausea, vomiting, or fever.

A thorough bleeding history should also be taken, particularly mucocutaneous bleeding. This includes prolonged epistaxis, easy bruising, gingival bleeding, or heavy menses.11 Severe abnormal bleeding (e.g., development of iron deficiency anemia requiring a blood transfusion; hemoglobin less than 10gm/dL) that is recurrent or that affects different anatomical sites are strong possibilities for an underlying systemic coagulopathy.16,17 Heavy bleeding associated with tooth extraction, surgery, postpartum, prolonged bleeding with superficial cuts, or reports of a heavy prolonged menses since menarche are also highly predictive of a bleeding disorder18 but the history may be subtle.

Heavy menstrual bleeding may be the only clinical manifestation of an inherited bleeding disorder.1,16,17,19,20 Finally, the NP should ask about any dyspareunia, vaginal discharge, or dysuria.

Upon questioning, AZ reported intermittent epistaxis and bruising easily as a teenager. She denied any gum bleeding or other sources of bleeding.

There was no history of shortness of breath, dizziness, fatigue, or presyncopal or syncopal events. AZ reported no significant history of nausea or vomiting, and no vaginal or urinary complaints.

* The Physical Examination

The patient’s hemodynamic status must be evaluated. In examining the patient’s skin, note petechiae and ecchymosis, which may be indicative of a hematologic disorder.10,21

In addition, it is important to check for any virilization including hirsutism,11 striae, or acanthosis nigricans. Next, the NP should examine for thyromegaly and abdominal tenderness, rigidity, or masses. A thorough gynecological and bimanual exam is needed to verify the bleeding site. Foreign bodies and discharge, as well as uterine or adnexal tenderness or masses, should be assessed.10 Inspection of the urethra, vagina, cervix, and rectum, including a Hemoccult test, is imperative to determine the source of bleeding.9

AZ was 5’6” and weighed 262 pounds, with a body mass index of 42. Her vital signs were as follows: left arm blood pressure (BP) was 128/90 (sitting) and right arm BP (sitting) was 128/88; pulse at 76 per minute; temperature 99.8 orally. There were no orthostatic changes with position change.

She exhibited no striae or acanthosis nigricans. Ecchymosis and petechiae were not observed. Her thyroid was not palpable. Her heart had normal S^sub 1^ S^sub 2^ heart sounds without murmur. Her abdomen was tender throughout with no masses, splenomegaly, rebound, or rigidity.

Her genital exam was normal, showing no external or internal lesions. She had an active bloody discharge per the cervical os. There was no foreign body detected, nor was there presence of any abnormal discharge. The bimanual exam was normal without any cervical motion, uterine, or adnexal tenderness. There were no masses palpated. The rectal exam was normal and the hemoccult test was negative.

* Laboratory Data

Initial laboratory work included a beta human chorionic gonadotropin, complete blood count with differential, platelet count, reticulocyte count, and cultures for chlamydia and Neisseria gonorrhoeae. If a bleeding disorder is suspected, obtain a prothrombin time, partial prothrombin time (PTT), and bleeding time.5,19

AZ’s beta human chorionic gonadotropin quantitative was negative, her white blood cell count was normal, hemoglobin and hematocrit were slightly down at 13.7 and 38.3 respectively.

Her platelet count was normal and prothrombin time was normal. The PTT and reticulocyte count were elevated at 33.6 seconds (normal 20.8 to 32.8) and 2.9 respectively. Additionally, AZ recently had a normal thyroid-stimulating hormone, blood urea nitrogen, creatinine, fasting blood sugar, iron profile, and urinalysis.

* The Initial Management Plan

The initial management plan was to increase AZ’s norethindrone/ ethinylestradiol dosage to twice a day until the bleeding stopped, and then resume a once-daily dosing. She was also given an antiemetic to use every 12 hours as needed and was told to return to the clinic in 3 days.

Iron supplements to treat anemia and antiprostaglandin medications such as ibuprofen or naproxen are also often recommended. To prevent heavy bleeding, combination oral contraceptives are recommended. If the patient cannot take oral contraceptives due to contraindication, progesterone can be given for 10 days starting on either day 11 or 14 of the menstrual cycle.22

One considerable concern is the risk for a venous thromboembolism, which is often related to an inherited defect such as factor V Leiden mutation.22 This mutation interferes with protein C-protein S anticoagulant pathway and is a risk with the increased oral contraceptive dose.8

* The Diagnosis

In AZ’s case, a coagulation disorder was suspected due to her heavy cyclic menstrual bleed,history of easy bruising and epistaxis, the prolonged PTT, and her significant family history of heavy menses.

Consequently, the PTT, hemoglobin, and hematocrit were repeated, and a von Willebrand (vWD) panel and bleeding time were obtained. A pelvic ultrasound was also ordered to rule out any fibroids, tumors, or cysts.

The vWD panel usually includes a factor VIII complex activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), and a ristocetin cofactor activity (vWF:RCo). In mild cases of vWD, the FVIILC is usually normal or slightly reduced. Nevertheless, in severe vWD, the FVIII:C may be less than 5% to 10% of normal. In severe cases, hemarthrosis and hematomas are noted secondarily to markedly low concentrations of factor VIII.16,17,23,24

Patients with mild forms of vWD usually have approximately 30% to 50% of normal vWF:Ag.16,17,23 The vWF:RCo measures how well the vWF is functioning. In Type 1 vWD, the vWF:Ag and vWF:RCo are usually reduced.23

Abbreviations

The bleeding time can be normal with a congenital bleeding disorder. The accuracy and reliability of the bleeding time is decreased in mild cases of vWD. However, it has been useful in demonstrating the bleeding tendency in severe cases of vWD.25 Overall, test results can vary depending on the administration technique. Moreover, cutaneous scarring can occur on the tested individual.18

AZ’s results revealed a mild drop in the hemoglobin and hemotocrit of 13.2 and 36.4 respectively. The PTT remained elevated at 33.6 seconds, the bleeding time was normal at 6.30 minutes, and the FVIII:C was normal at 71%. The vWF:Ag (normal = 43% to 150%) and the vWF:RCo (normal = 47% to 150%) were depressed at 28% and 31% respectively. Her pelvic ultrasound was normal. After these results were obtained, a hematologist ordered further testing, including vWF multimers. The vWF multimers are a qualitative measure of the structure of the vWF molecule and are only necessary if the vWF:Ag and vWF:RCo are abnormal. Conversely, it is not necessary if Type 3 vWD is known.26

Adolescents with menorrhagia are at a higher risk of having a bleeding disorder, especially once pregnancy and a pelvic pathology have been ruled out.4,5,27 Von Willebrand disease should be suspected in women with menorrhagia, other mucosal bleeding, excessive bruising without petechiae, heavy bleeding with tooth extraction, surgery, or postpartum. It should also be suspected in women who have a family history of heavy bleeding with menses or surgical procedures.8,13

The vWF can be falsely elevated if the patient is pregnant or experiencing other hormonal fluctuations, under a lot of stress, in a postoperative period, has an infection, or an inflammatory response. This can result in a normal laboratory value.28 In order to help prevent an inaccurate result due to hormonal fluctuations, it is recommended that testing for vWD be done on days 1 through 3 of the menstrual cycle.19 If there is a strong history suggestive of vWD, repeat testing may be necessary.16,17,29

The patient’s blood type affects results.16,17 If a patient is type O, generally the person will have lower vWF:Ag levels (36 to 160 u/dL). Types A, B, and AB have higher levels.13,19

AZ’s menorrhagia was secondary to vWD Type 1. Von Willebrand disease is the most common, autosomal dominant, congenital bleeding disorder affecting 0.5% to 1% of the general population.13,18,30,31 Menorrhagia is often the first symptom in women with vWD.32 This disease stems from the decreased production of vWF, a plasma protein necessary for normal blood clotting.18 When blood vessels are injured, platelets do not adhere properly. As a result, it takes longer for the bleeding to stop.

Once a patient is diagnosed, it is important to consider other family members. Recall that AZ’s sister had lupus and a history of heavy menses, and she responded favorably with oral contraceptive therapy. It is possible that acquired vWD can present in females with systemic lupus erythematosus, with the production of anti-von Willebrand factor antibody.33 Therefore, a response to hormonal therapy should not prevent a further diagnostic workup for a bleeding disorder.34 In this case, AZ’s sister should also be tested for vWD.

Acquired vWD may be found in patients with no family history, as well as in association with another disorder, such as leukemia, systemic lupus erythematosus, lymphoma, congenital heart disease, and hypothyroidism.35

However, this deficiency may appear when neither parent has the abnormality. In that case, it would be a new mutation and vWD could be passed on to future children.

* Treatment

For AZ, desmopressin acetate (DDAVP) nasal spray (Stimate) was chosen to help control her menorrhagia. Desmopressin acetate is the treatment of choice for vWD Type I.13,36 Desmopressin maybe given intravenously or intranasally, however, the intranasal spray is equally efficacious and more convenient.36

Patients should also use desmopressin acetate prophylactically before minor outpatient gynecological surgeries, as well as for other mucosal or dental procedures. Desmopressin acetate promotes the release of normal functioning vWF from the blood vessel’s endothelial cell lining.13,18,30 It strengthens hemostasis by decreasing the bleeding time, and increasing levels of factor VIII and the vWF.31,37,38

The NP must watch the patient’s sodium levels, since desmopressin acetate can cause hyponatremia.2031 To prevent this from occurring, the patient is instructed to limit fluid intake 18 hours after taking desmopressin acetate.30,39

Other side effects include mild tachycardia, headache, and flushing, which are related to the vasomotor effects of the medication. These symptoms are usually mild and transient.31,36,40 Lastly, desmopressin acetate is usually contraindicated with vWD Type 2B, due to the possibility of worsening effects of bleeding diathesis and thrombocytopenia.18,38 If the patient has less than 10% of the vWF:Ag, then desmopressin acetate will be ineffective.13,18,31,41

* Education

After AZ’s condition was diagnosed, her NP made sure she was thoroughly educated about vWD. She was instructed to report any breakthrough bleeding or irregular menses. Women with vWD have heavier menses. If menstrual bleeding occurs at other times, then another source must be ruled out.

AZ was instructed to report headaches, muscle weakness, nausea, vomiting, and seizures, because these can be signs of hyponatremia.36,42 The patient must avoid aspirin as well as nonsteroidal anti-inflammatory drugs, due to the risk of further defects in platelet function. AZ was instructed to inform all providers of her new diagnosis of vWD, especially before surgical procedures to the mucous membranes (mouth, nose, throat, gastrointestinal, gynecological, and urinary tract).

Additionally, AZ was advised about potential pregnancies. In patients with vWD Type 1, the vWF: Ag, and FVIII:C increase during pregnancy. Hence, bleeding during pregnancy is relatively uncommon.16,17,30,31,43 in addition, sex hormones increase during pregnancy and prevent postpartum hemorrhage.39 Bleeding during pregnancy is noted for patients with severe disease, such as those with undetectable levels of vWF.43

New precautions for traveling were also discussed. AZ was instructed to carry an identification bracelet that indicates she has vWD Type 1 and is using desmopressin acetate.

Since the definition of heavy menstrual bleeding varies, it is important to have guidelines for menstrual bleeding.

Differential Diagnosis of Menorrhagia

Pregnancy/ectopic pregnancy/ trophoblastic disease/spontaneous or incomplete abortion

Infection: chlamydia/gonorrhea/ trichomonas

Trauma/sexual abuse

Foreign body

Medication induced: medroxyprogesterone acetate, oral contraceptive, acetylsalicylic acid, anticoagulants, nonsteroidal antiinflammatory drugs, steroids, major tranquilizers, tricyclic antidepressants

Other gynecological pathology or structural anomaly

Endocrine disorders: hyperthyroidism, hypothyroidism, polycystic ovarian syndrome

Underlying systemic disorders: von Willebrand disease, liver disease, thrombocytopenia, idiopathic thrombocytopenic purpura, severe sepsis, leukemia, aplastic anemia, hypersplenism

Dysfunctional uterine bleeding

The patient’s sexual history, use of birth control, possible pregnancy, and prior gynecologic surgeries must be noted.

Heavy menstrual bleeding may be the only clinical manifestation of an inherited bleeding disorder.

The vWF can be falsely elevated if the patient is pregnant or experiencing other hormonal fluctuations.

REFERENCES

1. Kadir RA, Aledort LM: Obstetrical and gynaecological bleeding: A common presenting symptom. Clin Lab Haematol 2000;22(l):12-6.

2. Emans SJ, Laufer MR, Goldstein DE, eds: Delayed puberty and menstrual irregularities. In: Pediatric and Adolescent Gynecology. 4th ed., Philadelphia: Lippincott-Raven, 1998.

3. Goldfien A: Ovaries. In: Basic and Clinical Endocrinology. Greenspan FS, Gardner DG, eds. New York: Lange/McGraw-Hill, 2001, p.473.

4. Kadir RA, Economides DL, Sabin CA et al: Frequency of inherited bleeding disorders in women with menorrhagia. The Lancet 1998; 351:485-9.

5. Soler ME, Todd CS, Dobs AS: Menstrual disorders and other disorders of female reproductive endocrinology. In: Principles of Ambulatory Medicine. Barker LR, Burton JR, Zieve PD, eds. Philadelphia: Williams & Wilkins, 2003,1575-90.

6. Roy SN, Bhattacharya S: Benefits and risks of pharmacological agents used for the treatment of menorrhagia. Drug Safety 2004;27(2):75-90.

7. Noble J, Green HL, Levinson W et al, eds.: Abnormal menstruation. In: Primary Care Medicine. Sondheimer S, ed. 3rd ed, St. Louis: Mosby, 2001.

8. Munro MG: Dysfunctional uterine bleeding: advances in diagnosis and treatment. Current Opin Obstet Gynecol 2001; 13, (5):475-89.

9. Fauci AS, Braunwald E, Isselbacher KJ, et al, eds: Gynecologic complaints in women. In: Harrison’s Principles of Internal Medic\ine. 14th ed., New York: McGraw-Hill, 1998.

10. Goroll AH, May LA, Mulley AG, Jr., eds: Approach to the woman with abnormal vaginal bleeding. In: Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 3rd ed., Philadelphia: J.B. Lippincott Company, 1995.

11. Templeman C, Hertweck SP, Muram D et al: Vaginal bleeding in childhood and menstrual disorders in adolescence. In: Pediatric and Adolescent Gynecology. Sanfilippo JS, Muram D, DeWhurst J et al, eds.Philadelphia: W.B. Saunders, 2001,237-47.

12. Brenner PF: Differential diagnosis of abnormal uterine bleeding.Am J Obstet Gynecol 1996;175(3): 766-9.

13. Lusher IM: Screening and diagnosis of coagulation disorders. Am J Obstet Gynecol 1996;175(3): 778-83.

14. Cochrane R, Regan L: Undetected gynaecological disorders in women with renal disease. Human Reproduction 1997;12(4): 667-70.

15. Strasburger VC, Brown RT: Menstrual disorders. In: Adolescent Medicine: A Practical Guide. 2nd. ed., Philadelphia: Lippincott- Raven, 1998.

16. Shwayder JM: Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin N Am 2000;27:219-34.

17. Ewenstein BM: The pathophysiology of bleeding disorders presenting as abnormal uterine bleeding. Am I Obstet Gyneco 1996;175(3): 77077.

18. Hambleton J: Diagnosis and incidence of inherited von willebrand disease. Curr Opin Hematol 2001;8(5): 306-11.

19. Budde U, Drewke E, Mainusch K et al: Laboratory diagnosis of congenital von willebrand disease. Sem Thromb Hemostas 2002; 28(2): 173-89.

20. Pier, M.M. “Drug Therapy: Treatment of Von Willebrand’s Disease.” New England Journal of Medicine 351, no. 7 (2004): 683- 94.

21. Harman, S.M., and M.R. Blackman. “Common Problems in Reproductive Endocrinology.” In Principles of Ambulatory Medicine, edited by L.R. Barker, J.R. Burton and P.D. Zieve, Baltimore: Williams & Wilkins, 1995, 1132-34.

22. Burkman, R.T., J.A. Collins, L.P. Shulman, and J.K. Williams. “Current Perspectives on Oral Contraceptive Use.” American Journal of Obstetrics & Gynecology 185, no. 2 (2001): s4-s!2.

23. Fauci, A.S., E. Braunwald, K.J. Isselbacher, J.D. Wilson, J.B. Martin, D.L. Kasper, S.L. Hauser, and D.L. Longo, eds. Harrison’s Principles of Internal Medicine. 14ed.317-320 vols, Oncology and Hematology. New York: McGraw-Hill, 1998.

24. Rick, M. E. Clinical Presentation and Diagnosis of Von Willebrand Disease UpToDate, April 28, 2003 2003 [cited July 29 2003].

25. Ingerslev, J., and T. Gursel. “Diagnosis of Von WiIlabrand Disease.” Haemophilia 5, no. 2 (1999): 5056.

26. Favaloro, E.J. “Von Willebrand Factor CollagenBinding (Activity) Assay in the Diagnosis of Von Willebrand Disease: A 15- Year Journey.” Seminars in Thrombosis and Hemostasis 28, no. 2 (2002): 191-202.

27. Long, C.A. “Evaluation of Patients with Abnormal Uterine Bleeding.” American Journal of Obstetrics & Gynecology 175, no. 3 (1996): 784-86.

28. Kirtava, A., S. Crudder, A. Dilley, C. Lally, and B. Evatt. “Trends in Clinical Management of Women with Von Willebrand Disease: A Survey of 75 Women Enrolled in Haemophilia Treatment Centres in the United States.” Haemophilia 10, no. 2(2004):158-61.

29. Handin, R.I. “Bleeding and Thrombosis.” In Harrison’s Principles of Internal Medicine, edited by E. Braunwald, A.S. Fauci, K.J. Isselbacher, D.L. Kasper, S.L. Hauser, D.L. Longo and J.L. Jameson, New York: McGraw-Hill, 2002.

30. Chuong, C. J., and P. R Brenner. “Management of Abnormal Uterine Bleeding.” American Journal of Obstetrics & Gynecology. 175, no. 3 Pt 2 (1996): 787-92.

31. Federici, A.B., and Pier Mannuccio Mannucci. “Advances in the Genetics and Treatment of Von Willebrand Disease.” Current Opinion in Pediatrics 14, no. 1 (2002): 23-33.

32. Ragni, M.V., F.A. Bontempo, and A.C. Hassett. “Von Willebrand Disease and Bleeding in Women.” Haemophilia 5 (1999): 313-17.

33. Soff, G.A., and D. Green. “Autoantibody to Von Willabrand Factor in Systemic Lupus Erthematosus.” Journal of Laboratory and Clinical Medicine 121 (1993): 424.

34. Bevan, J.A., K.W. Maloney, C.A. Hillery, JC. Gill, R.R. Montgomery, and J.R. Scott. “Bleeding Disorders: A Common Cause of Menorrhagia in Adolescents.” The Journal of Pediatrics 138, no. 6 (2001): 856-61.

35. Rick, M. E. Classification and Pathophysiology of Von Willebrand Disease UpToDate, April 16, 2003 2003 [cited July 29 2003).

36. Gill, J. C., M. Ottum, and B. Schwartz. “Evaluation of High Concentration Intranasal and Intravenous Desmopressin in Pediatric Patients with Mild Hemophilia a or Mild-to-Moderate Type l Von Willebrand Disease.” The Journal of Pediatrics 140, no. 5 (2002): 595-99.

37. Bevan, J. A., K. W. Maloney, C. A. Hillery, J. C. Gill, R. R. Montgomery, and J. P. Scott. “Bleeding Disorders: A Common Cause of Menorrhagia in Adolescents.” Journal of Pediatrics. 138, no. 6 (2001): 856-61.

38. Revel-Vilk, S., M. Schmugge, M.D. Carcao, P. Blanchette, M.L. Rand, and VS. Blanchett. “Desmopressin (Ddavp) Responsiveness in Children with Von Willebrand Disease.” Journal of Pediatric Hematology/Oncology 25, no. 11 (2003): 874-79.

39. Weiss, R.M. “case Presentation: A Patient with Von Willabrand Disease and Menorrhagia.” American Journal of Obstetrics & Gynecology 175, no. 3 (1996): 763-65.

40. Nolan, B., B. White, J. Smith, C. O’Reily, C. McMahon, B. Fitzpatrick, and O.P. Smith. “Desmopressin: Therapeutic Limitations in Children and Adults with Inherited Coagulation Disorders.” British Journal of Haematology 109, no. 4-II (2000): 865-69.

41. Mannucci, Pier Mannuccio. “Desmopressin (Ddavp) in the Treatment of Bleeding Disorders: The First 20 years.” Blood 90, no. 7 (1997): 251521.

42. Dunn, A.L., J.R. Powers, MJ. Ribeiro, F.R. Rickles, and T.C. Abshire. “Adverse Events During Use of Intranasal Desmopressin Acetate for Haemophilia a and Von Willebrand Disease: A Case Report and Review of 40 Patients.” Haemophilia 6 (2000): 11-14.

43. Lee, C.A. “Women and Von Willebrand Disease.” Haemophilia 5, no. Suppl. 2 (1999): 38-45.

ACKNOWLEDGEMENTS

The author would like to thank Jennifer Cironi, APRN and Ivy Alexander, APRN, Yale University, for their thorough review of this article.

Karen A. Stemler, MS, RN, APRN, FNP

ABOUT THE AUTHOR

Karen Stemler holds a joint appointment as a Program Instructor at Yale University School of Nursing and as a Family Nurse Practitioner in an internal medicine practice in New Haven, Conn.

Copyright Springhouse Corporation Dec 2004

AYOUNG pregnant woman lies huddled on a bed in a dank flat in North London, petrified at the prospect of what is about to happen. This is 1950s Britain and, like everyone else, she has heard all the horror stories about back-street abortions.

She expects the abortionist to be a tough, contemptuous woman who will treat her in the most brutal fashion in return for her two guineas.

Instead, she gets Vera Drake – a frail-looking, middle-aged lady who wouldn’t dream of taking her money but just wants to do a good turn.

Nor does Vera produce knitting needles, crochet hooks, a pickle spoon or any of the other assorted apparatus that was the staple of some of the illegal abortionists operating during that time. Instead, Vera uses a rubber syringe to fill the girl’s womb with soapy water. Afterwards, she gives her a kindly look, tells her to wait a couple of days and everything will be all right.

Vera, played by actress Imelda Staunton, carries out several such abortions in Mike Leigh’s acclaimed new film before one girl on whom she operates is rushed to hospital in agony. The girl survives – just.

This is, though, a disastrous exception in Vera’s 20-year philanthropic mission to ‘help’ young women who have ‘got themselves into trouble’.

Vera Drake, which opens in Britain tonight, has already earned its director, Mike Leigh, acclaim around the world, while its star, Staunton, has been nominated for a Golden Globe award. She is also tipped for an Oscar.

Much has been made by Leigh of the painstaking research done before filming to ensure accuracy. Yet according to Jennifer Worth, who was a midwife in the Fifties and Sixties, before abortion was legalised in 1967, Vera Drake is a fanciful character who does not come close to portraying accurately the grim brutality and danger of what really happened in those days of back-street abortion.

What’s more, Jennifer Worth says, this portrayal is downright dangerous.

‘Women who were abortionists were tough to the point of brutality, and I never once heard of anyone doing it for philanthropic reasons,’ she says.

‘Basically, they were in it for the money. If a woman died after an illegal termination, the abortionist would be charged with manslaughter. It was a very risky business, and no one would risk that “just to help out”.

‘It was also a very dangerous procedure, which could lead to infection and, in some cases, even death. When I was a ward sister in the East End in the 1950s, you would have between four and eight women in at any one time with severe complications caused by abortion.

‘I think it’s rather implausible to suggest that Vera had such a high success rate.

‘I’m also concerned that a young woman today, who has got herself pregnant and is afraid of going to a doctor, might decide, literally, to try to abort her baby at home because it looks relatively straightforward.’ While the film is presented as a morally neutral but highly accurate portrayal, the truth is very different.

If abortionists were to be portrayed accurately, the audience might come away with a totally different opinion.

‘Social conditions were very different then,’ says Jennifer, 69. ‘People had too many children and inadequate housing. You’d get a family with six children living in a two-room tenement flat.

‘There were women who simply could not cope with or afford another child.

A lot of men would refuse to wear condoms, so there were all these unwanted pregnancies.

‘Then there were the single girls, working-class and middle- class, who’d got themselves in trouble.

There was a terrible stigma attached to illegitimacy then.

‘A lot of women who fell pregnant were put into mental asylums by their families – and remained there for the rest of their lives. There were also a lot of suicides by so- called “fallen women”. The desperation that drove these women can not be underestimated.’ Pregnant women would often, says Mrs Worth, take various concoctions, such as quinine or a lead-based liquid, in the vain hope that it would bring about a miscarriage. Others took scalding hot baths and consumed vast quantities of gin.

Only when all this failed would they seek out the back-street abortionist – as portrayed by homely Vera Drake.

It was a gruesome procedure and would have been carried out in a perfunctory fashion. None of Mrs Drake’s comforting words about putting the kettle on for a nice cup of tea.

‘The abortion would be performed on the kitchen table in the woman’s flat,’ says Mrs Worth, a mother-of-two and a grandmother, who now lives in Hemel Hempstead, Hertfordshire, and is married to a retired schoolmaster-turned-painter.

‘It was done without anaesthetic by someone who wasn’t medically trained. It was so excruciatingly painful that the girl would have to be physically held down – usually by her mother or an aunt.

‘It was a very difficult operation to perform. The whole of nature is directed towards the propagation of the species, and when a woman becomes pregnant the body does everything it can to protect the foetus.

The cervix will clamp tight for the protection of the foetus.

‘Most abortionists somehow managed to get hold of obsolete surgical instruments, but some would use knitting needles or crochet hooks. A pickle spoon might be used, or a curette, which had a long handle and a slightly bulbous tip, like a small spoon.There would be blood everywhere.

‘Once the foetus was removed, it would be wrapped up in newspaper and put in the fire. But often bits would be left behind in the womb – bits of a mangled foetus or bits of mangled placenta – which would putrefy and cause severe infection.’ ‘ In the film, there is none of this.

There is a little discomfort during the procedure, and then nice Mrs Drake waves a cheery goodbye. She does this day in, day out, out of the goodness of her heart, risking a manslaughter charge every time.

In real life, the trauma suffered by the pregnant girl would be compounded if she then developed an infection or complication and had to be admitted to hospital.

While working as ward sister at Elizabeth Garrett Anderson Women’s Hospital in London from 1960 to 1965, Mrs Worth, who left nursing in 1973 to become a professional singer (she is now a writer and music teacher), witnessed some harrowing scenes.

‘These poor souls would come in with massive injuries to their reproductive tract. Some would have a torn cervix or a punctured uterus, or a punctured rectum or bladder.

Once, we had a girl with total renal failure. How she survived, I don’t know.

‘When a woman came to us with complications, we never asked what had happened, because if a doctor found out he would have a legal obligation to inform the police. We were not social workers or police informers: we were there to give medical assistance.’ (In the film, by contrast, the doctor does inform the police.) Most of these women would have been left infertile. Many others died.

‘When I had just begun my career at a hospital in Reading, one woman, a 35-year- old mother-of-five, came in with a punctured uterus,’ recalls Mrs Worth. ‘She developed a terrible infection and deteriorated for several weeks before she finally died.

‘I will never forget her children, all aged under ten, being brought in to say goodbye to her. It was heartbreaking.’ Some deaths, no doubt, would have been brought about by Vera Drake’s soapand-water method. One woman who underwent an abortion this way was Lucy, who recalled her experience for Voices For Choice, a publication by Marie Stopes International and the National Abortion Campaign, now called Abortion Rights.

‘They were two biddies from Stepney,’ Lucy said. ‘They used that awful pink soap, Lifebuoy, and hot water. It didn’t work first time round, so they had to come over and do it again.

Seven hours later, the labour pains started and I went and sat on the loo.

‘The worst thing was that I had no idea it was going to look like a baby.

This was extremely devastating for me. It still is. It was a tiny baby – but a baby nevertheless. Afterwards, I was losing so much blood that I had to go to hospital.’ Peter Bowen-Simpkins, a gynaecologist and spokesman for the Royal College of Obstetricians and Gynaecologists, says the method – portrayed as so straightforward in Vera Drake – placed a woman at risk from infection and other complications.

‘If the water was not sterilised, there would be an extreme risk of infection,’ he says. ‘And if water entered the bloodstream, an air embolus – bubbles in the blood – could occur and result in death.’ It was the poorer women who suffered the most. Those who were well off enough to part with around 150 guineas – as opposed to the two guineas charged for an illegal operation – could have an abortion at a private clinic.

Legally, all they had to do was persuade a psychiatrist that they were mentally unstable.

Among them was Deborah Ainger, now 62. ‘I had a steady boyfriend and we were responsible and used condoms, but one time the condom split and I got pregnant. I had absolutely no intention of having the baby. My boyfriend was from overseas and was preparing to go back, and I did not want to uproot my whole life.

‘I was very lucky in that I had supportive parents who agreed to pay for me to go to a private clinic. But the first psychiatrist I saw said I didn’t seem upset enough and refused to authorise an abortion. I had to put on a terrible act with the second, smoking like a chimney and the like. Today, I feel very strongly that abortion should be available on request.’ Ms Ainger was one of the lucky ones. Thousands more suffered injuries – physical and mental – that they never fully recovered from.

The first reference to abortion in English law appeared in the 13th century, when the law followed Church teaching that abortion was acceptable until ‘quickening’. This, it was believed, was when the soul entered the foetus at around 13 weeks.

The legal situation remained like this until the 19th century, when a series of laws were passed severely restricting abortion, which was at one time punishable by death. By the fictional Vera Drake’s day, in 1950, a woman undergoing an illegal abortion and the abortionist would be liable to prosecution.

In today’s high-tech world, we have a far greater knowledge of the development of the foetus because of extraordinary pictures of babies in the womb – such as those captured last year by Professor Stuart Campbell, former head of obstetrics at King’s College Hospital and St George’s Hospital, London, using a new 3D scanning process.

There were babies at 12 weeks’ development ‘jumping off the womb like a trampoline’; at 18 weeks, opening their eyes; at 22 weeks even appearing to smile.

Enormous advances have also been made in medical science – to the point where it is possible for an emergency Caesarean to save the life of a baby at 24 weeks of gestation.

What concerns many people today is how late into a pregnancy it is possible to have a termination. Mrs Worth, who has written a book on her experiences of midwifery, entitled Call The Midwife, says she was shocked at the 28-week limit for abortion. (It has since been reduced to 24 weeks.) ‘I was profoundly shocked by that. All babies born prematurely at 28 weeks are capable of surviving, and nowadays, with all the modern equipment we have, you get babies born prematurely at 24 weeks who survive.’ Mrs Worth, who was a midwife until the early 1970s, says that for all the modern debate over the law, there was ‘ enormous relief’ among the medical profession when abortion was legalised.

Until then, there were upwards of 250,000 illegal abortions a year.

Thousands of women are believed to have died, and sometimes children were born with mental or physical impairment following a failed abortion.

‘When abortion was legalised, it immediately brought an end to terrible suffering and often death,’ says Mrs Worth. ‘The situation had been such that some women felt they had no choice but to go to a backstreet abortionist. I think that was terribly sad.’ With his film, Mike Leigh has succeeded in reminding us of that terrible time for women, which no sensible person would ever wish to return to.

Yet his homely portrayal of the abortionist is ultimately misleading. It was, in fact, a nasty, brutal business – and the Vera Drakes were at the heart of it.

SAN DIEGO, Jan. 10 /PRNewswire/ — One of the nation’s leading naturopathic medical doctors and a holistic pharmacist with more than 30 years experience have joined forces to create Life Solutions Natural Products. The company will produce an extensive line of liquid nutritional supplements that absorb quicker than vitamin capsules or tablets and unlike many other supplements available in stores — will be of pharmaceutical quality.

After years of treating patients with lesser quality products, tablets and capsules, Dr. Mark Stengler, N.M.D., author/co-author of 18 natural health books, teamed with pharmacist Michael Lenzner to develop professional strength liquid supplements that could be used with patients and also made available to consumers. The result is Life Solutions Natural Products — a line of supplements made up of well-known, time-tested ingredients Stengler has relied on for years to treat patients. The product line contains ingredients such as vitamins A, B, C, lutein, lycopene, glucosamine and black cohosh — all in a liquid form that absorbs more reliably than capsules or tablets.

“Many common health problems can be aided through natural remedies,” said Stengler. “I’m excited to create a product line that so directly and effectively provides these vital nutrients.”

“This premium product line is a breakthrough,” said Lenzner. “In addition to providing accelerated absorption and easier ingestion than vitamin capsules and tablets, Life Solutions products can be adjusted to address specific problems — fatigue, sleeplessness, stomach aches or ailments related to menopause — as well as the many symptoms of stress.”

The extensive product line developed by Stengler and Lenzner includes liquid multivitamins for adults and children, and a wide range of nutrients including calcium, magnesium, E, C, lutein and others. Life Solutions’ line also includes antioxidant blends and remedies such as Liquid Natural Sleep, Liquid Natural Digestive Formula, Liquid Natural Menopause, Liquid Anti-Stress Plus Adrenal Support and Liquid Natural Libido Enhancer.

The increased therapeutic potency of Life Solutions supplements means less product needs to be taken compared to capsules.

Additional benefits of liquid supplements include:

* Accelerated absorption rate versus capsules or tablets.

* Liquid is more readily digestible than capsules or tablets, ensuring

greater therapeutic benefits.

* Liquid is easy to swallow for children and seniors.

* The amount of supplement taken can easily be changed for individual

patient needs.

Life Solutions Natural Products will be available for purchase at health food stores nationwide.

Stengler, co-author of the new bestseller “Prescription for Natural Cures” (Wiley, 2004), is among the country’s most well known naturopathic doctors and one of California’s first naturopathic medical doctors. He has served on a medical advisory committee for Yale University Complementary Medicine Outcomes Research Project. An associate clinical professor at the National College of Naturopathic Medicine, Stengler is vice-president and medical director for Life Solutions Inc.

Lenzner, R. Ph., is president and CEO of Life Solutions Inc. He has over 30 years experience as a registered pharmacist and entrepreneur. A graduate of Wayne State University School of Pharmacy in Detroit, Michigan, Lenzner has special expertise in compounding natural remedies and pharmaceuticals for the individual needs of his patients. He has served as CEO of several multimillion dollar corporations and is the driving force behind Life Solutions’ management.

Life Solutions Natural Products

Life Solutions Natural Products was formed in 2004 by Dr. Mark Stengler and pharmacist Michael Lenzner. Based in San Diego County, Life Solutions Natural Products is a nutritional supplement company that provides a natural means for healthy living through high quality liquid nutritional supplements that absorb more rapidly than traditional vitamin tablets and, unlike many other supplements, are pharmaceutical quality. All Life Solutions products are manufactured in a state-of-the-art GMP certified facility for liquid nutritional supplements.

Life Solutions Natural Products

CONTACT: Karen Korr, cell, +1-619-944-0650, [email protected], or MiaTaylor, cell, +1-858-752-0172, [email protected], both of BerkmanCommunications, +1-619-231-9977, for Life Solutions Natural Products

Rejuvenon Corporation, a privately held pharmaceutical company developing therapeutics for cancer and metabolic disorders, has received US Food and Drug Administration (FDA) “fast track” designation for its investigational compound, RC-1291, a small-molecule ghrelin mimetic, for the treatment of cachexia (loss of body weight) and anorexia (loss of appetite) in cancer patients. The anorexia/cachexia syndrome is a common, life-threatening complication of underlying malignancies.

“There is a significant unmet need for a pharmaceutical treatment in cancer cachexia,” said Gary C. Cupit, PharmD, president and chief executive officer of Rejuvenon. “Unexpected weight loss is an all-too-common and devastating consequence of cancer. Currently, effective treatments are lacking and the patient population in need of an effective treatment is substantial. Clinicians and patients are seeking a product that offers the potential we see in Rejuvenon’s lead candidate, RC-1291.”

The fast-track programs of the FDA are designed to facilitate the development and expedite the review of new drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. In its letter to Rejuvenon, the FDA stated that based on preclinical and early clinical data, RC-1291 shows potential as a treatment for cancer anorexia/cachexia. This syndrome frequently accompanies malignant disease states and often results in the death of the patient. In these patients, weight loss is an independent risk factor for poor survival, and cachectic patients also suffer increased complications from surgery, radiotherapy, and chemotherapy. To date, there are no effective treatments approved for this indication.

“Preclinical and clinical data have demonstrated the potent appetite-stimulating effects of RC-1291,” said William J. Polvino, MD, Rejuvenon’s senior vice president of development. “In addition, RC-1291 has potential anabolic attributes that we expect to reduce or eliminate the ongoing loss of body weight and/or muscle mass. No other agent provides the dual actions of potent appetite stimulation and anabolic activity. Consequently RC-1291 represents an important therapeutic prospect in the treatment of cancer anorexia/cachexia. We expect intervention with RC-1291 to improve appetite and food intake and attenuate or reverse ongoing weight loss. Additional benefits may include improvements in quality of life and functional performance.”

About Ghrelin and RC-1291

The recent discovery of ghrelin-mediated effects on appetite opens a new avenue for pharmaceutical treatment. Ghrelin is a small endogenous protein that acts on the Growth Hormone Secretagogue Receptor (GHSR), a G-Protein Coupled Receptor recognized as a key control point in the growth hormone signaling pathway. The GHSR is a target for treatment of several metabolic disorders including those related to maintenance of ideal body weight and composition. Agonists for this receptor have been identified as drug candidates for treatment of wasting and body fat redistribution syndromes associated with a range of diseases, such as cancer and AIDS. However, potential clinical use of ghrelin itself for wasting disorders is limited, because it must be administered by injection.

RC-1291 is a synthetic, small-molecule ghrelin mimetic that binds to, and stimulates, the GHSR. Unlike ghrelin, RC-1291 can be delivered by mouth. This highly potent, orally available compound is intended to be administered as a convenient once-daily treatment for patients with cancer anorexia/cachexia. The compound has been studied in a series of seven completed or ongoing clinical studies in human volunteers, including a double-blind placebo-controlled study in which, compared to placebo, RC-1291 significantly increased appetite and spontaneous food intake. Under the FDA fast-track designation, Rejuvenon plans to conduct Phase II trials later this year.

In addition to the known stimulation of appetite and food intake via central orexigenic pathways, additional mechanisms of action of RC-1291 may be relevant in treating cancer anorexia/cachexia. Loss of appetite and body weight associated with cancer is somewhat driven by circulating inflammatory cytokines such as TNF-alpha (originally named “cachectin”) and IL-6. Recent studies have shown that activation of the ghrelin receptor may play a direct role in reducing the production and circulating levels of inflammatory cytokines such as TNF-alpha. Ghrelin and RC-1291 are both highly potent agonists at the same receptor, thus experimental data generated with ghrelin help to validate use of RC-1291 in cancer anorexia/cachexia.

Dr. Cupit added, “Our lead program is a superb example of the dynamic synergy of Rejuvenon’s big pharma/biotech partnering strategy. We are delighted that the development team has reached this milestone so rapidly from a preclinical candidate into Phase II. We are equally pleased with the consensus between Rejuvenon and the FDA in recognizing cancer anorexia/cachexia as an important unmet medical need. Our efforts are now focused on speeding the development of RC-1291 by generating the data needed to bring the product to market. Believing that this represents the first of many potential opportunities, we will continue to leverage the skills of our expanding development team through additional product acquisitions.”

About Rejuvenon

Rejuvenon, founded in 2000 by Dr. Roy G. Smith of the Baylor College of Medicine, is a private pharmaceutical development company whose strategy is to in-license and develop promising drug candidates that are ready for preclinical or clinical testing. The company is developing small molecule drugs to treat metabolic and oncologic diseases for which existing therapies are limited or marginally effective. Rejuvenon’s first portfolio of drug candidates were in-licensed as preclinical compounds from Novo Nordisk in May 2001. RC-1291 is the furthest advanced of this series of orally-deliverable compounds for treatment of cancer-related weight loss. The company is moving several additional molecules through preclinical development. As development proceeds on these compounds, Rejuvenon is actively seeking other preclinical in-licensing candidates to fill the development pipeline.

ST. LOUIS, Jan. 10 /PRNewswire-FirstCall/ — KV Pharmaceutical Company announced today that it has entered into agreements with Representaciones E Investigaciones Medicas, S.A. de C.V. (RIMSA) for the granting of licensing rights in Mexico for KV’s two single dose prescription vaginal cream products, U.S. market leader Gynazole-1(R) and the recently FDA-approved Clindesse(TM). KV will receive licensing fees and manufacturing revenues under the terms of the agreement with RIMSA for both products.

The products will be marketed in Mexico by RIMSA through its outstanding sales force of more than 200 which focuses on women’s healthcare products. KV anticipates that Gynazole-1(R) will be ready for introduction in Mexico late in KV’s fiscal year ending March 2006, with Clindesse(TM) to follow. Mexico’s prescription marketplace for vaginal anti-infective products is estimated to be approximately $25 million, according to IMS.

Marc S. Hermelin, Vice Chairman of the Board and Chief Executive Officer of KV stated, “These new agreements reinforce the growing stature of our Ther-Rx subsidiary’s branded women’s health franchise. Gynazole-1(R) has generated substantial interest throughout the world, with over 50 nations licensed and two markets already successfully launched. And now, with the approval of Clindesse(TM) we offer international partners like RIMSA a powerful package to market to their clientele. We look forward to working with our new partners to launch these two innovative and patient-friendly products into the Mexican marketplace.”

Gynazole-1(R) is a rapidly growing branded prescription vaginal antifungal product indicated for the local treatment of vulvovaginal candidiasis in the United States, having 30% of the branded prescription cream segment. Prescriptions for Gynazole-1(R) filled in the most recently completed quarter ending September 2004, were up 13% sequentially over the previous quarter representing the highest quarterly growth rate for the product in over three years. KV has license agreements in place for Gynazole-1(R) in over 50 markets worldwide.

Clindesse(TM) (clindamycin phosphate) Vaginal Cream 2% is the first approved single-dose therapy for non-pregnant patients with bacterial vaginosis (“BV”), the most common form of vaginitis. The product was demonstrated in clinical trials to effectively treat BV and its symptoms with results equivalent to 7 days of Cleoncin(R) vaginal cream. Currently, other approved BV treatments require a course of 3-10 doses. Clindesse(TM) recently won approval for marketing in the U.S. from the Food and Drug Administration.

Additional Safety Information about Gynazole-1(R) and Clindesse(TM):

Gynazole-1(R) (butoconazole nitrate) Vaginal Cream, 2%

Gynazole-1(R) is indicated for the local treatment of vulvovaginal candidasis. The diagnosis should be confirmed by KOH smears and/or cultures. Gynazole-1(R) is safe and effective in non-pregnant women; however, the safety and effectiveness in pregnant women has not been established.

Gynazole-1(R) is contraindicated in patients with a history of hypersensitivity to any of the components in the product.

Gynazole-1(R) contains mineral oil, which may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms; therefore, use of such products within 72 hours following treatment with Gynazole-1(R) is not recommended. Recurrent vaginal yeast infections, especially those that are difficult to eradicate, can be an early sign of infection with the human immunodeficiency virus (HIV) in women who are considered at risk for HIV infection. If clinical symptoms persist, tests should be repeated to rule out other pathogens, to conform original diagnosis, and to rule out other conditions that may predispose a patient to recurrent vaginal fungal infections.

Clindesse(TM) (clindamycin phosphate) Vaginal Cream, 2%

Clindesse(TM) is contraindicated in individuals with a history of hypersensitivity to clindamycin, lincomycin, or any of the components of this vaginal cream, and in individuals with a history of regional enteritis, ulcerative colitis, or a history of “antibiotic-associated” colitis. There are no adequate and well controlled studies of Clindesse(TM) in pregnant women.

Clindesse(TM) contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, the use of such barrier contraceptives is not recommended concurrently or for 5 days following treatment with Clindesse(TM). During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV or other sexually transmitted diseases.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin. Orally and parenterally administered clindamycin has been associated with severe colitis. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of clindamycin, even though there is minimal systemic absorption of clindamycin from the vagina with administration of Clindesse(TM) cream.

In clinical trials totaling 368 women associated with a single dose of Clindesse, 1.6% of the patients discontinued therapy due to adverse events. The most frequently reported adverse events were vaginosis fungal (14.1%), vulvovaginal pruritus (3.3%), and headache (2.7%).

About RIMSA

RIMSA, was founded 31 years ago and manufactures and promotes the sale of prescription and over-the-counter pharmaceutical products including tablets, capsules, syrups, suspensions and injectable products.

About KV Pharmaceutical Company

KV Pharmaceutical Company is a fully integrated specialty pharmaceutical company that develops and markets technology-distinguished branded and generic/non-branded prescription pharmaceutical products. The Company markets its technology distinguished products through ETHEX Corporation, a national leader in pharmaceuticals that compete with branded products, and Ther-Rx Corporation, its emerging branded drug subsidiary. KV has consistently ranked as one of America’s fastest growing small companies, most recently by Forbes in its November 2004 issue.

For further information about KV Pharmaceutical Company, please visit the Company’s corporate website at http://www.kvpharmaceutical.com/.

Safe Harbor and Product Risk Factors

The information in this release may contain various forward-looking statements within the meaning of the United States Private Securities Litigation reform Act of 1995 (“PSLRA”) and which may be based on or include assumptions, concerning KV’s operations, future results and prospects. Such statements may be identified by the use of words like “plans,””expect,””aim,””believe,””projects,””anticipate,””commit,””intend,””estimate,””will,””should,””could,” and other expressions that indicate future events and trends.

All statements that address expectations or projections about the future, including without limitation, statements about the Company’s strategy for growth, product development, regulatory approvals, market position, expenditures and financial results, are forward-looking statements.

All forward-looking statements are based on current expectations and are subject to risk and uncertainties. In connection with the “safe harbor” provisions, KV provides the following cautionary statements identifying important economic, political and technology factors which, among others, could cause the actual results or events to differ materially from those set forth or implied by the forward-looking statements and related assumptions.

Such factors include (but are not limited to) the following: (1) changes in the current and future business environment, including interest rates and capital and consumer spending; (2) the difficulty of predicting local regulatory approvals including the timing,; (3) acceptance and demand for new pharmaceutical products; (4) the impact of competitive products and pricing; (5) new product development and launch including but limited to the possibility that any product launch may be delayed or that product acceptance may be less than anticipated; (6) reliance on key strategic alliances; (7) the availability of raw materials; (8) the regulatory environment; (9) the risk that market size estimates may be more or less than estimated; 10) fluctuations in operating results; (11) the difficulty of predicting the pattern of inventory movements by the Company’s customers; (12) the impact of competitive response to the Company’s sales, marketing and strategic efforts; (13) risks that the company may not ultimately prevail in its litigation; and (14) the risks detailed from time to time in the Company’s filings with the Securities and Exchange Commission.

This discussion is by no means exhaustive, but is designed to highlight important factors that may impact the Company’s outlook.

KV Pharmaceutical Company

CONTACT: Catherine M. Biffignani, Vice President, Investor Relations ofKV Pharmaceutical Company, +1-314-645-6600

Web site: http://www.kvpharmaceutical.com/

Last month, GP and the Kings Fund asked for your views on what makes a good doctor in the 21st century

…accurate and informed medical practice

A good doctor is still one who listens to the patients and helps them make sense of their experiences. The acknowledgement of where the patient is coming from and where the patient hopes to get to, and realistically can reach, is intrinsic to good medical practice.

The focus is entirely individualistic, and the values in play are only those of the doctor and the patient.

The basic duty of the doctor is to understand the patient’s values, without condoning criminal behaviour or immorality. The values of society are not present except insofar as they are brought in by either doctor or patient. The values of society in any case are multifaceted, largely unknown and variable, and so there are no yardsticks by which to measure an individual consultation.

Unjustified interference

The interaction between doctor and patient is based on duty, not utility, and so is only valid for that doctor and that patient. Interference from the outside world in the consultation is actually an unjustified intrusion.

There is no intrinsic demand that a consultation should serve any greater good for the community, only that it should help the individual.

The system exists to support the consultation-not the other way round. The fact that the current system is inadequate is regrettable. Both doctors and patients live in permanent disappointment over this situation, which benefits neither party.

Too many people want to be in the consulting room who have no right to be there. If ‘modern professionalism’ means accommodating them, then I do not want it.

I know what I should be doing in alliance with, and on behalf of, my patients. This is not paternalism; this is accurate and informed medicine practised to the benefit of my patients, with their negotiated concordance and consent.

For all the changes in medical regulation the fundamentals of good medical practice remain unchanged. These are listening to the patient, respecting the patient, diagnosing accurately, and doing no harm and some good with the treatment.

As a doctor I know what I should be doing. The challenge is for the politicians to understand where my duty lies and make it easier for me to deliver good medical care to my patients, who are also their voters. The interests of patients and doctors are as one here.

* Dr Peter Davies is a GP in Halifax, West Yorkshire. He has been invited to take part in a King’s Fund debate on medical professionalism

…continuing development and keeping up with NHS change

Trust, approachability and reliable, high-quality care are still key. However, these now need to be supported with a developing foundation of personal learning and development, encompassing evidence-based medicine, clinical governance and the need for change.

Modernisation challenge

Today’s politicised NHS is in a continuous state of change and modernisation. A good modern doctor needs to be informed and involved if they are to improve both the care they offer to patients and their own personal sense of achievement.

Modern medicine evolves at a furious and unrelenting pace, clinically and non-clinically. Today’s doctor needs to ensure that they can keep up with information on such changes from sources like the NICE guidelines, NSFs, evidence-based guidelines and local delivery plans.

They also need the skills to scrutinise this information for relevant details that can be introduced into daily practice.

This time pressure will only be acceptable if the modern doctor can welcome and support a wider group of healthcare providers with extending roles, such as nurses and pharmacists, while ensuring a level of governance and quality.

The future of healthcare is interwoven with good-quality IT. As a result, the GP must gain a clear understanding of clinical systems and the development programme for IT within the NHS.

However, the modern GP needs to remember that their work is not just about evidence-based, politically cultivated, financially rewarding care. We are the face of the NHS to most of the population, the first port of call when trouble presents, trusted and approachable.

Whatever else makes a good doctor in today’s society, these must still be core features.

* Dr Richard Jenkins is a GP in Chase Terrace, Staffordshire

…an ability to balance patients with politics

High standards are expected of today’s GP and, in order to deliver them, he or she will need to embrace the new situations thrust upon them in the face of changing healthcare.

GPs today are in a powerful position to become leaders within the NHS and to shape the future of general practice.

In order to attain the status of ‘good doctor’, GPs are developing certain attributes. The patient must remain at the centre of general practice and delivering high-quality care requires continual development and a meticulous attention to clinical practice and guidelines.

While doing this the doctor must still be able to elicit and address the concerns, whether physical, social or psychological, of their patients.

However, this is not the entirety of the GP’s role. With the advent of changes such as the new GMS contract and practice-based commissioning, GPs can play an important role within primary care organisations, advising them on what is important to their patients and in delivering community care.

The GP cannot shy away from the political agenda, but must face it and ensure the GP voice is heard.

The GP needs to be able to evaluate new ideas and ways of working and, if appropriate, explain and recommend them to colleagues in order for general practice to develop in pace with other areas of healthcare.

The GP is part of a team. The primary healthcare team is taking on an ever increasing importance under new GMS, while increasingly GPs must also forge links with other healthcare providers.

Within all this, in order to be effective, the GP must care for themselves, their own families and the welfare of their colleagues. Juggling work and family commitments is an increasing issue, and the ability to do this and derive support from others is essential for all GPs in today’s NHS.

* Dr Rachel Cooper is a GP in Benwell, Newcastle-upon-Tyne. She has been invited to take part in a King’s Fund debate on medical professionalism

…adaptability to change for better or worse

Today’s doctors have to please many different groups with varied agendas such as primary care organisations, government, patients, colleagues, employees and lawyers, to name but a few. The ability to reconcile these, at times, conflicting interests is one of the most difficult challenges.

Professional competence is clearly key. The advent of appraisal and accreditation has, in my view, established a clear means of demonstrating core competence and is not to be feared by the profession.

A caring attitude is vital and outcomes must matter. Good medicine today involves balancing patients’ wants and needs against resources, and a doctor must sometimes be prepared to disappoint patients and at other times to champion the individual.

Professional honesty is vital, to inform and protect patients and increasingly to protect one-self. Account must be taken of patients’ views and doctors must be honest about any mistakes.

A good doctor needs to be responsive to change, for better or worse. Responsible demeanour, personal and professional probity and moderation will continue to serve us well.

Good doctors are also made by good government, good leadership, reasonable working conditions and fair treatment by employers, patients, the law and the media.

* Dr John Inmonger is a GP in Blackpool, Lancashire

…a long-term, solution-focused approach

GP education needs to shift from being problem orientated to solution focused.

Giving advice or pills is not the way forward. Instead patients need to be empowered to develop their own physical and mental health. Ailments presented in the surgery are in general the result of stress.

Solution-focused brief therapy techniques, motivational interviewing techniques, building self-esteem and life coaching principles, on the other hand, are more helpful.

Through these the doctor helps to mobilise the resources of the patient and make the patient independent of the doctor.

A medicalised approach with pills will do the opposite. It encourages the patient to be dependent and to continue to frequent the surgery. Working in a solution-focused way is also more rewarding for the GP.

Such changes will benefit both patients and doctors.

* Dr Wouter Having a is a GP in Randwick, Gloucestershire

Have your say

GP still wants to hear your views on this issue. Write to [email protected], marking your response ‘King’s Fund’.

Dr Peter Davies: ‘The fundamentals of good practice remain unchanged’

A good doctor is still one who listens to the patients and helps them make sense of their experiences

Dr Peter Davies

GPs cannot shy away from the political agenda but must ensure their voices are heard

Dr Rachel Cooper

Dr Rachel Cooper: ‘The GP needs to be able to evaluate new ideas’

Good doctors are made by good government, good leadership, reasonable working conditions and \fair treatment

Dr John Inmonger

Acupuncture is one of the many therapies now available that may help patients find a solution to stress

Copyright Haymarket Business Publications Ltd. Dec 17, 2004

For cellulitis that does not respond to conventional antimicrobial treatment, clinicians should consider, among other explanations, several noninfectious disorders that might masquerade as infectious cellulitis. Diseases that commonly masquerade as this condition include thrombophlebitis, contact dermatitis, insect stings, drug reactions, eosinophilic cellulitis (the Wells syndrome), gouty arthritis, carcinoma erysipelatoides, familial Mediterranean fever, and foreign-body reactions. Diseases that uncommonly masquerade as infectious cellulitis include urticaria, lymphedema, lupus erythematosus, sarcoidosis, lymphoma, leukemia, Paget disease, and panniculitis. Clinicians should do an initial diagnostic work-up directed by the findings from a detailed history and complete physical examination. In many cases, skin biopsy is the only tool that helps identify the correct diagnosis. Special tests may also be needed.

Ann Intern Med. 2005;142:47-55. www.annals.org

Cellulitis, an inflammatory disease that involves the skin and subcutaneous tissues, frequently leads to office visits and hospital admissions. The term erysipelas, a distinct type of inflammatory disease more superficial than cellulitis, is reserved for cutaneous infection mainly due to Streptococcus pyogenes. Most cases of cellulitis can be attributed to an infectious cause. However, physicians may be challenged by cases that do not respond to the initial antimicrobial regimen. In addition to considering inappropriate empirical antimicrobial treatment, poor patient adherence, antibiotic resistance, underlying deep-seated infection, foreign body-related infection, and depressed immune status, physicians should also consider a broad spectrum of noninfectious causes that masquerade as infectious cellulitis. They should take into account several vascular, primary dermatologie, rheumatic, immunologic-idiopathic, malignant, familial, and other diseases that commonly (Table 1) or uncommonly (Table 2) masquerade as infectious cellulitis. The literature lacks data about the relative frequency of infectious cellulitis compared with non-infectious masqueraders. We review the diseases that mimic infectious cellulitis and may present a diagnostic challenge to physicians.

METHODS

We identified data by searching PubMed (from 1950 until April 2004), Current Contents, and references from relevant articles. The main search terms were cellulitis, erysipelas, non-infectious, thrombophlebitis, contact dermatitis, Wells syndrome, Sweet syndrome, familial mediterranean fever, foreign-body reaction, lymphoma, leukemia, panniculitis, and Paget disease. We reviewed English-language papers.

DISEASES THAT COMMONLY MASQUERADE AS INFECTIOUS CELLULITIS

Superficial Thrombophlebitis

Superficial thrombophlebitis, which is often caused by the presence of an intravenous needle or catheter, frequently presents as a red, indurated area (1). A tender cord palpable along the course of the affected superficial vein can help differentiate this disorder from infectious cellulitis. Extension of the inflammation beyond the vein might suggest an infectious process. Superficial thrombophlebitis is treated with anti-inflammatory medications, compression therapy (2, 3), and removal of the intravenous catheter. This condition may be complicated by an infection in which the signs of inflammation persist despite treatment of symptoms. In such cases, antibiotic use is appropriate.

Superficial migrating thrombophlebitis presents as successive episodes of thrombophlebitis involving different veins in different body areas (Trousseau phenomenon). This clinical syndrome may resemble recurrent infectious cellulitis and should prompt a search for underlying diseases, such as thromboangiitis obliterans, malignant tumors (4), and hypercoagulable states.

Deep Venous Thrombosis

Deep venous thrombosis presents as unilateral leg edema, warmth, or erythema, all of which may be confused with infection (5-7). Tenderness along the involved veins and engorgement of superficial veins are other presenting features that might help in the differential diagnosis of infectious cellulitis. Rarely, a palpable clot may suggest the correct diagnosis. In addition, patients with deep venous thrombosis can have fever due to a systemic inflammatory response; however, body temperature rarely exceeds 38.3 C. Although leukocytosis suggests infectious cellulitis, this laboratory finding may also occur in patients with deep venous thrombosis. The presence of risk factors such as a hypercoagulable state suggests deep venous thrombosis. However, history and physical examination are of limited value, and an imaging study is frequently needed. Duplex ultrasonography is the initial diagnostic study of choice (8, 9), and heparin is the favored treatment. To prevent recurrences, a 3- to 12-month course of oral anticoagulant therapy should follow heparin treatment (10).

Table 1. Diseases That Commonly Masquerade as Infectious Cellulitis

Table 2. Diseases That Uncommonly Masquerade as Infectious Cellulitis

Contact Dermatitis

Contact dermatitis, especially in the acute form, may masquerade as cellulitis (11, 12). In toxic or irritant (non-allergic) contact dermatitis, the lesion is sharply demarcated and constricted to the area of exposure. Allergic contact dermatitis is a delayed hypersensitivity reaction and may spread beyond the site of initial contact. Commonly implicated agents include detergents, solvents, disinfectants, metals, and dyes, as well as poison ivy and poison oak.

History of exposure to an irritating agent and the associated pruritus help differentiate contact dermatitis from infectious cellulitis. Skin biopsy and patch testing may confirm the diagnosis (13). Nonetheless, patch testing should be deferred until active lesions have subsided. Avoidance of exposure is the cornerstone of treatment. Once contact dermatitis has developed, topical corticosteroid preparations are usually effective. Systemic corticosteroids are indicated for severe cases (14, 15). Clinicians should remember that secondary infection may complicate skin barrier disruption elicited by dermatitis (16). In such cases, reemergence of signs of inflammation is evident and antibiotic therapy should be instituted.

Insect Stings or Bites and Other Envenomations

Allergic reactions to insect stings range from mild local erythema to anaphylaxis (17). An extensive local reaction presents as swelling that extends over a large area, peaks within 48 hours, and lasts up to 7 days (18). Such a lesion may resemble infectious cellulitis, which, in fact, infrequently develops after an insect sting. The presence of ascending lymphangitis and lymphadenopathy suggests infection. A common mistake after an insect sting is to treat an infection rather than an allergic reaction. The usual medical treatment for insect stings is antihistamines and acetylsalicylic acid, if necessary. Systemic steroids should be administered for an extensive lesion.

In insect bites, a disturbing local inflammation usually develops but resolves within a few hours. Systemic reactions are extremely rare. The presence of pruritus distinguishes this lesion from infectious cellulitis. Systemic anti-histamines are the treatment of choice (19). Other contact reactions, such as caterpillar dermatitis and beetle vesications, can manifest as a cellulitis-like reaction. Envenomations by marine animals, including stonefish, can cause similar symptoms. Corral and sea urchin spicule foreign bodies can cause noninfectious reactions, although an infectious component may be concomitant.

Drug Reactions

Rashes are common adverse drug reactions. A fixed drug eruption presents as a well-demarcated plaque that recurs at the same site each time the offending drug is administered (20, 21). The associated itching or burning sensation also helps differentiate this entity from infectious cellulitis. The most commonly affected areas are the lips and the genitalia. Characteristically, the lesions do not spread as rapidly as infectious cellulitis. Healing is usually associated with residual hyperpigmentation. This residual hyperpigmentation indicates site recognition. Medications that are usually implicated include antibiotics (trimethoprim- sulfamethoxazole is the leading agent) and anti-inflammatory drugs. An oral challenge test or topical provocation with drug preparations are reliable diagnostic tools (22, 23). Withholding the offending agent and using topical corticosteroids are the treatment of choice.

Eosinophilic Cellulitis

Eosinophilic cellulitis (the Wells syndrome) is characterized by acute pruritic dermatitis (24, 25). Patients typically present with one or a few erythematous plaques, which may resemble infectious cellulitis. The lesions evolve over 2 to 3 days and resolve completely without scarring in 2 to 8 weeks. The disease usually recurs. Peripheral eosinophilia, manifested during the acute phase, and dermal eosinophilic infiltration help differentiate this entity from infectious cellulitis. The Wells syndrome may be idiopathic or associated with conditions such as myeloproliferative, immunologie, and infectious disorders and with medications (26-28). Most cases respond favorably to oral corticosteroid treatment (29).

The Sweet Syndrome

The Sweet syndrome (acu\te febrile neutrophilic dermatosis) is characterized by papules that coalesce to form inflammatory plaques (30-32). These lesions are erythematous and tender; they most commonly occur on the upper extremities, face, and neck. Associated findings include fever, conjunctivitis or iridocyclitis, oral aphthae, and arthralgia or arthritis. Patients also have moderate neutrophilia and dermal infiltration by polymorphonuclear leukocytes. Sometimes the syndrome is mistaken for infectious cellulitis (33-35). Ten percent of patients with the syndrome also have an associated malignant condition, usually acute myelogenous leukemia. Immunologic disorders, such as rheumatoid arthritis and inflammatory bowel disease, have also been implicated. Corticosteroids remain the mainstay of treatment (36).

Gouty Arthritis

In acute gouty arthritis, the affected joint is inflamed with prominent overlying erythema and warmth (37). The cutaneous erythema may extend in areas beyond the joint and resemble cellulitis. In addition, gout may affect periarticular structures and lead to tendonitis and bursitis. Chills, a low-grade fever, and an elevated leukocyte count may occur, mimicking an infection. In differentiating this entity from a skin infection, clinicians should not under-estimate the inflammation of the joint. Gouty arthritis is typically monoarticular and predominantly affects the lower extremity, usually the first metatarsophalangeal joint or knee. The condition is diagnosed by presence of urate crystals in aspirates of joint fluid (38). Colchicine and non-steroidal anti-inflammatory drugs are used to treat acute attacks (39). Corticosteroids can also be used as an alternative.

Erythromelalgia

Erythromelalgia is a rare disease entity characterized by episodic burning pain, increased skin temperature, and bilateral redness of the extremities (40). It usually affects the feet and, to a lesser extent, the hands. Increased ambient temperature, fever, or exercise may induce symptoms. A dependent position may aggravate the disease. No symptoms or signs are present between attacks. Skin biopsy specimens show nonspecific changes and should not be routinely used. The paroxysmal nature of the disease, its aggravating factors, and the location of lesions may help differentiate erythromelalgia from cellulitis. Erythromelalgia may be primary or secondary. Myeloproliferative disorders have been particularly associated with the disease (41, 42). Several medications have been tried, with varying success. Some patients do not respond even to aspirin, which was once thought to be helpful in most cases (43). In cases of secondary erythromelalgia, treatment of the underlying disease may alleviate the symptoms.

Relapsing Polychondritis

Relapsing polychondritis is an uncommon disease that affects cartilaginous structures (44). Auricular chondritis is the most common manifestation, and it usually affects both ears. The acute inflammation may resemble cellulitis (45-47). However, a bacterial infection is usually unilateral and is associated with regional lymphadenopathy. In addition, relapsing polychondritis spares the ear lobe because this structure is not cartilaginous (48). Recurrent inflammation may result in auricular or saddle-nose deformity. Associated features include peripheral, nonerosive polyarthritis; episcleritis; keratitis or uveitis; and aortic valve insufficiency. These features support the diagnosis of relapsing polychondritis, which is primarily based on clinical criteria. Biopsy is indicated if the diagnosis is uncertain. Corticosteroids are usually effective, but immunosuppressive agents may be used in severe cases (49).

Carcinoma Erysipelatoides

Carcinoma erysipelatoides, also known as inflammatory carcinoma, is an uncommon form of skin metastasis. It develops when cancer cells invade the cutaneous lymph vessels (50, 51). It most commonly originates from breast carcinoma. Inflammatory breast cancer appears as an erythematous plaque on an enlarged breast. The absence of fever and leukocytosis should raise suspicion of a noninfectious process. Thus, if a suspected breast infection does not resolve with antibiotics, mammography and tissue biopsy should be done to rule out breast carcinoma. Because carcinoma erysipelatoides is a form of advanced cancer, treatment is based on managing the underlying malignancy.

Familial Mediterranean Fever and Familial Hibernian Fever

Familial Mediterranean fever is an autosomal recessive disease that primarily affects Jewish and Arab persons from the Mediterranean basin. It presents as acute self-limited episodes of fever accompanied by peritonitis, pleuritis, pericarditis, or synovitis (52, 53). Typically, the initial attack ensues in childhood or early adolescence. Erysipelaslike erythema is considered the most characteristic cutaneous manifestation of the disease. It consists of tender, erythematous, well-demarcated, warm, swollen areas with a diameter of 10 to 15 cm (54). These lesions usually occur below the knee, on the anterior leg or dorsum of the foot (unilaterally or symmetrically). The erythema subsides spontaneously within 24 to 48 hours as the acute attack resolves. The recurrent nature of the disease, a positive family history, and the coincidence of erythema with the acute attack help differentiate this entity from erysipelas. Nonetheless, skin lesions may sometimes occur without abdominal or chest pain. Colchicine is the drug of choice (55, 56).

Familial Hibernian fever is a rare distinct clinical entity that affects individuals of Irish ancestry (57). The characteristic erysipelas-like lesion may occur anywhere on the body, although the most common site is on a limb. It begins proximally and migrates distally during the course of the attack. The lesion (approximately 1 5 cm in diameter) is well-demarcated, erythematous, warm, and painful. Lesions do not respond to colchicine. Corticosteroids are usually effective, although symptoms may persist (58).

Foreign-Body Reaction

Some rare cases of adverse reactions to metallic implants have been described (59). Newer devices are associated with a lower rate of hypersensitivity reaction. Orthopedic implants, such as hip and knee prostheses, may cause noninfectious cellulitis-like erythema on the overlying skin. Sensitizing materials include nickel, chromium, and cobalt. Patch testing aids in the diagnosis. While a positive metal patch result is not definitive for an implant allergy, a negative result is more reliable for ruling out an implant allergy. If oral corticosteroids are ineffective, the prosthesis must be removed.

Meshes of different types are now used in the surgical repair of abdominal and inguinal hernias. In patients intolerant of foreign material, the mesh induces a local reaction that presents as an erythematous area on the overlying skin. This noninfectious reaction may be mistaken for cellulitis (60, 61).

DISEASES THAT UNCOMMONLY MASQUERADE AS INFECTIOUS CELLULITIS

Urticaria and Angioedema

The pruritic lesions of urticaria vary in size. Uniform red giant urticaria lesions may masquerade as cellulitis. Angioedema consists of thicker plaques that result from massive transudation of fluid. If on the skin, angioedema lesions may also resemble infection (62). The transient character of the lesion, the associated pruritus, and a history of exposure to a precipitating factor aid in the differential diagnosis. Prevention of exposure to implicated agents and use of mast cell-stabilizing agents, such as ketotifen, are of paramount importance. For active lesions, oral antihistamines are used. Doxepin, a tricyclic antidepressant with H^sub 1^- blocking properties, is useful for chronic urticaria (63).

Follicular Occlusion Triad

Hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp constitute the follicular occlusion triad (64). These entities may rarely present simultaneously in the same patient and may resemble cellulitis. Dissecting cellulitis of the scalp can occur independently of the triad. This condition, also called perifolliculitis capitis abscedens et suffodiens, is characterized by recurrent, painful, fluctuant dermal and subcutaneous nodules; scarring; and alopecia (65). It is clearly an inflammatory process that can be treated with retinoids, although antibiotics and corticosteroids have also been used successfully (66, 67).

Lymphedema

Lymphedema is characterized by nonpitting edema of an extremity (68). If it also appears with concomitant erythema and induration, it could masquerade as infectious cellulitis. The absence of fever or absence of response to antibiotics helps differentiate this condition from infectious disorders. Nonetheless, lymphedema itself may often be complicated by infection, even recurrently. Lymphangioscintigraphy will clarify the diagnosis in uncertain cases (69). Treatment includes low-stretch compression garments and other mechanical means of reducing interstitial fluid accumulation (70). Antibiotics are used in cases of superinfection. Surgical treatment is reserved for severe cases, although its effectiveness is often questionable.

Postsurgical lymphedema of the breast has been used after mastectomy, excisional biopsy, or axillary lymph node excision (71, 72). Skin biopsy is occasionally required to rule out malignancy because the condition may also masquerade as carcinoma erysipelatoides. No specific treatment is required, and the condition frequently subsides spontaneously.

Lupus Erythematosus

Cutaneous lupus erythematosus can be classified into 3 forms: acute, subacute, and chronic or discoid lupus (73, 74). Lupus lesions are characteristically photosensitive. Dermatologie manifestations are also evident in most patients with systemic lupus erythematosus. Acute cutaneous lupus erythematosus is manifested by papular, pruritic lesions on sun-exposed areas that range in color from erythematous to violaceous. These lesions may someti\mes lead to an erroneous diagnosis of infectious cellulitis. Acute cutaneous lupus erythematosus may involve fine scaling but not atrophy. Disease activity may wax and wane in parallel with underlying systemic lupus activity. Skin biopsy leads to the correct diagnosis. In subacute cutaneous lupus erythematosus, the appearance of the lesions ranges from that of the acute butterfly rash to that of chronic discoid lesions. Lesions are hyperkeratotic with adherent scaling and thus more closely resemble psoriasis.

Avoidance of sun exposure and use of sunscreens are important measures for preventing the disease. Treatment involves topical corticosteroids (75). Antimalarial agents should be used for nonresponding lesions (76). Systemic corticosteroids and immunosuppressants are reserved for severe bullous lesions (77).

Sarcoidosis

The dermatologic manifestations of sarcoidosis include the characteristic granulomas, as well as nonspecific lesions such as erythema nodosum (78). Some atypical lesions may resemble cellulitis because they manifest as indurated erythematous plaques associated with edema and pain (79). The associated systemic findings, such as pulmonary involvement, lymphadenopathy, and uveitis, help establish the correct diagnosis. Serum angiotensin-converting enzyme levels are useful, although not specific. Another helpful clue is the presence of skin lesions in the site of old scars. Skin biopsy remains the primary diagnostic tool. Pharmacologie treatment is usually reserved for severe systemic disease and not for isolated skin manifestations. Nonetheless, chronic cutaneous lesions, which may lead to scarring, or widespread skin involvement should be treated with corticosteroids (80).

Polyarteritis Nodosa

Polyarteritis nodosa is a multisystemic, necrotizing form of vasculitis (81). Subcutaneous, inflammatory, bright red to bluish nodules (

Erythema Nodosum

Erythema nodosum is the most common form of panniculitis. It usually consists of raised, painful, bilateral, tender lesions that are frequently located over both shins but may also occur on the knees, thighs, or arms (86). Sometimes, erythema nodosum may present as a large solitary erythematous lesion. In addition, the typical erythema nodosum lesions may coalesce and thereby resemble infectious cellulitis. The lesions resolve spontaneously in 4 to 6 weeks but may recur depending on the underlying illness. Skin biopsy reveals septal panniculitis. Erythema nodosum can be caused by several systemic disorders (87), such as sarcoidosis, inflammatory bowel disease, and the Behet syndrome. It has also been attributed to medication use and several infectious diseases (88, 89). Nonsteroidal antiinflammatory agents in full doses are usually effective. Corticosteroids can be used for severe cases if not contraindicated by an underlying disease (90).

Lipodermatosclerosis

Lipodermatosclerosis, a form of panniculitis, was formerly called chronic indurated cellulitis and hypodermitis sclerodermaformis. It usually affects middle-aged women and is associated with venous insufficiency (91). The acute form of the disease may masquerade as cellulitis. It presents as a painful, erythematous, indurated, somewhat edematous area in the medial aspect of the leg. It may extend to the ankles and pretibial areas. The condition usually lasts a few months but can persist for more than a year. Superimposed infectious cellulitis may occur and aggravate the clinical manifestations of lipodermatosclerosis (92). Compression thetapy, which reduces venous hypertension and fluid extravasation, is useful (93). In addition, the lesions respond favorably to stanozolol (94).

Morphea

Morphea, also known as localized scleroderma, is a type of localized cutaneous sclerosis. These plaques are initially violaceous and then become ivory-colored (95). If rapid in onset, the plaques may be erythematous. However, the evolving changes and the associated induration help to differentiate these lesions from infectious cellulitis. Treatment with intralesional steroids or D- penicillamine may be effective (96). The differential diagnosis should also include eosinophilic fasciitis and the eosinophilia- myalgia syndrome, which may also masquerade as infectious cellulitis.

Other Forms of Panniculitis

Several physical agents, such as cold, blunt trauma, and chemical materials injected subcutaneously (97), may elicit panniculitis. Postirradiation pseudosclerodermatous panniculitis is an unusual variant that results from megavoltage radiation therapy (98, 99). The differential diagnosis, which includes metastatic disease, infectious cellulitis, or connective tissue disease, should be based on pathologic findings.

Pancreatic disease, either inflammatory or neoplastic, may lead to panniculitis presenting as tender, erythematous nodules. The lesions are located on the pretibial regions, thighs, or buttocks and occasionally discharge a yellowish oily substance. Treatment is directed at the underlying pancreatic disorder (100).

Lupus panniculitis consists of firm, well-demarcated plaques or nodules most commonly located on the face and upper extremities (101). Their diameter ranges from 1 to several centimeters. Results of the antinuclear antibody test are usually positive, although other signs of systemic lupus may be misleadingly absent. Patients should avoid sun exposure. Antimalarial agents or corticosteroids are usually effective. Immunosuppressive agents are used for resistant cases (102).

α^sub 1^-Antitrypsin deficiency may present as cellulitis- like areas or red, tender nodules on the trunk and proximal extremities, often precipitated by trauma. Other signs of the disease, such as panacinar emphysema, noninfectious hepatitis, and cirrhosis, should suggest the diagnosis (103). Protein electrophoresis reveals low levels of α^sub 1^-antitrypsin. Some patients respond to dapsone or α^sub 1^-protease inhibitor concentrate (104).

Other forms of panniculitis, such us Weber-Christian disease, cytophagic histiocytic panniculitis, post-steroid panniculitis, and nodular panniculitis, may also uncommonly be confused with infectious cellulitis. For all the causes of panniculitis mentioned, biopsy can confirm the diagnosis. Because the inflammation occurs in the subcutaneous tissue, a deep excisional biopsy to the fascia rather than punch biopsy should be performed.

Lymphoma

Non-Hodgkin lymphomas and, to a lesser degree, Hodgkin disease can present with skin manifestations (105, 106). In rare cases lymphoma presents as cellulitis, usually diagnosed after failure of conventional antimicrobial therapy (107). Persisting fever or generalized lymphadenopathy may suggest the diagnosis. The Szary syndrome is a form of cutaneous lymphoma characterized by generalized erythroderma (108). Extranodal natural killer/ T-cell lymphoma, nasal type, causes the syndrome of midline granuloma, which may resemble facial cellulitis (109). Diagnosis of lymphoma always requires histologic confirmation. Localized disease should be treated with x-ray or electron-beam therapy (110). For extracutaneous disease, various chemotherapeutic agents have been used.

Leukemia

T-cell prolymphocytic leukemia is a rare chronic lymphoproliferative disease characterized by an aggressive clinical course. The principal disease characteristics are organomegaly, an elevated lymphocyte count, and dermatologic manifestations (diffuse erythema, infiltration localized to the face and ears, and skin nodules) (111). The condition sometimes mimics cellulitis (112). Other forms of leukemia may present with various skin lesions (including erythroderma) but are rarely misdiagnosed as cellulitis. Skin biopsy confirms the clinical suspicion. Cytotoxic chemotherapy is used to treat the disease.

Paget Disease

Paget disease of the breast constitutes the cutaneous manifestation of an underlying breast ductal carcinoma (113, 114). The disease consists of a rather sharply demarcated, unilateral eczematoid lesion affecting the nipple or areola. It is also associated with edema and hyperemia, thus mimicking infection. Eczematous dermatitis of the nipples, which is much more common, almost invariably appears bilaterally and responds to topical corticosteroids. Breastconserving surgery followed by radiation therapy has excellent results in patients with limited underlying malignancy (115).

Extramammary Paget disease is a rare cutaneous adenocarcinoma that primarily affects the anogenital area. The disease appears as an erythematous, eczematoid plaque, often associated with scaling. It is clinically and histologically similar to Paget disease of the breast. It may also be misdiagnosed as infectious cellulitis. The disease may be associated with a synchronous malignancy of the breast, lower gastrointestinal tract, urinary tract, or female genital tract (116). Surgical resection is recommended (117).

Glucagonoma

Glucagonoma, a tumor of the pancreas that is almost always malignant, presents with diabetes mellitus, diarrhea, and weight loss. It also causes characteristic necrolytic migratory erythema. The rash begins as an erythematous area and gradually spreads; after central cr\usting occurs, the lesions heal. At the site of the initial erythema, hyperpigmented lesions remain. It usually affects intertriginous, perioral, and perigenital areas. The erythema may be the only presenting sign of the underlying malignancy (118). The rash responds poorly to therapy. Zinc supplementation and infusion of amino acids and essential fatty acids diminish its severity (119). Glucagonoma is treated by surgical resection in patients without widespread hepatic metastasis (120).

Calciphylaxis

Calciphylaxis primarily affects diabetic patients with end-stage renal disease and hyperparathyroidism who are receiving renal replacement therapy. Its pathophysiologic basis is widespread metastatic calcification leading to small-vessel vasculoparhy. At an early stage, it presents with nonulcerating plaques in the calves and is easily confused with cellulitis (121). The lesions eventually become necrotic and painful ulcers develop. A history of renal disease and the evolution of the lesions help diagnose Calciphylaxis, which is managed by treatment of the renal failure and debridement of any necrotic tissue (122). Subtotal parathyroidectomy may be helpful (123).

Compartment Syndrome

Acute compartment syndrome is caused by increased pressure in an enclosed osseofascial space (124). It usually affects the anterior tibial compartment. Common causes include open or closed fractures, soft-tissue injury, extrinsic compression, reperfusion injury, and strenuous exercise. Pain out of proportion to the sustained injury is a cardinal feature. Cutaneous manifestations are occasionally present and include dusky redness of the skin overlying the compartment. Rarely, the lesions may resemble cellulitis. Cases of compartment syndrome unrelated to an obvious injury may challenge the clinician (125). The condition is diagnosed by measuring the compartment pressure. Full-blown cases of the syndrome necessitate emergency fasciotomy (126).

CONCLUSION

Physicians challenged by a case of cellulitis that does not respond to conventional antimicrobial agents should promptly consider a noninfectious cause of cellulitis. A thorough history and a complete physical examination are the major tools in a productive differential diagnosis. Chronic lesions suggest the possibility of a noninfectious cause; in contrast, acute lesions are usually caused by an infectious agent.

Routine and special laboratory tests may be done to confirm the postulated diagnosis. In many cases, cutaneous biopsy specimens examined by an experienced pathologist may be needed to identify the correct diagnosis. Skin biopsy may be performed at an earlier stage before advanced diagnostic tests are done. An appropriate biopsy specimen should be obtained. Special stains are sometimes required to rule out lymphomatous disease. In addition, mycobacterial and fungal stains may be used to exclude an atypical infectious agent. Cultures for common bacteria, mycobacteria, and fungi should also be obtained.

References

1. Tagalakis V, Kahn SR, Libman M, Blostein M. The epidemiology of peripheral vein infusion thrombophlebitis: a critical review. Am J Med. 2002;113:146-51. [PMID: 12133753]

2. Ascher E, Hanson JN, Salles-Cunha S, Hingorani A. Lesser saphenous vein thrombophlebitis: its natural history and implications for management. Vasc Endovascular Surg. 2003;37:421-7. [PMID: 14671697]

3. Raake W, Binder M. [Treatment of superficial thrombophlebitis]. Hamostaseologie. 2002;22:149-53. [PMID: 12540973]

4. Siegelman ES, Needleman L. Venous thrombosis and cancer [Letter]. N Engl J Med. 1993;328:885; author reply 886-7. [PMID: 8373456]

5. Kennedy D, Setnik G, Li J. Physical examination findings in deep venous thrombosis. Emerg Med Clin North Am. 2001;19:869-76. [PMID: 11762276]

6. Baker WF Jr. Diagnosis of deep venous thrombosis and pulmonary embolism. Med Clin North Am. 1998;82:459-76. [PMID: 9646774]

7. Frazee BW, Snoey ER. Diagnostic role of ED ultrasound in deep venous thrombosis and pulmonary embolism. Am J Emerg Med. 1999;17:271-8. [PMID: 10337888]

8. Baker WF Jr. Diagnosis of deep venous thrombosis and pulmonary embolism. Med Clin North Am. 1998;82:459-76. [PMID: 9646774]

9. Frazee BW, Snoey ER. Diagnostic role of ED ultrasound in deep venous thrombosis and pulmonary embolism. Am J Emerg Med. 1999;17:271-8. [PMID: 10337888]

10. Rainzi DW, Leeper KV. DVT and pulmonary embolism: Part II. Treatment and prevention. Am Fam Physician. 2004;69:2841-8. [PMID: 15222649]

11. Erdmann SM, Merk HF. [Contact sensitization to external agents]. Hautarzt. 2003;54:331-7. [PMID: 12669204]

12. Antezana M, Parker F. Occupational contact dermatitis. Immunol Allergy Clin North Am. 2003;23:269-90, vii. [PMID: 12803363]

13. Fonacier L, Charlesworth EN. Parch testing for allergic contact dermatitis in the allergist office. Curr Allergy Asthma Rep. 2003;3:283-90. [PMID: 12791205]

14. Levin C, Maibach HI. An overview of the efficacy of topical corticosteroids in experimental human nickel contact dermaritis. Contact Dermatitis. 2000;43: 317-21. [PMID: 11140380]

15. Martin BG. Contact dermatitis: evaluation and treatment. J Am Osteopath Assoc. 1999;99:511-4. [PMID: 10217916]

16. Brook I. Secondaiy bacterial infections complicating skin lesions. J Med Microbiol. 2002;51:808-12. [PMID: 12435058]

17. Reisman RE. Insect stings. N Engl J Med. 1994;331:523-7. [PMID: 8041420]

18. Green AW, Reisman RE, Arbesman CE. Clinical and immunologic studies of patients with large local reactions following insect stings. J Allergy Clin Immunol. 1980;66:186-9. [PMID: 7410742]

19. Stawiski MA. Insect bites and stings. Emerg Med Clin North Am. 1985;3: 785-808. [PMID: 2414093]

20. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-8. [PMID: 9865869]

21. Ozkaya-Bayazit E. Specific site involvement in fixed drug eruption. J Am Acad Dermatol. 2003;49:1003-7. [PMID: 14639376]

22. Ozkaya-Bayazit E, Bayazit H, Ozarmagan G. Topical provocation in 27 cases of cotrimoxazole-induced fixed drug eruption. Contact Dermatitis. 1999; 41:185-9. [PMID: 10515095]

23. Alanko K. Topical provocation of fixed drug eruption. A study of 30 patients. Contact Dermatitis. 1994;31:25-7. [PMID: 7924289]

24. Moossavi M, Mehregan DR. Wells’ syndrome: a clinical and histopathologic review of seven cases. Int J Dermatol. 2003;42:62- 7. [PMID: 12581147]

25. Weiss G, Shemer A, Confino Y, Kaplan B, Trau H. Wells’ syndrome: report of a case and review of the literature. Int J Dermatol. 2001;40:148-52. [PMID: 11328401]

26. Bogenrieder T, Griese DP, Schififner R, Bttner R, Riegger GA, Hohenleutner U, et al. Wells’ syndrome associated with idiopathic hypereosinophilic syndrome. Br J Dermatol. 1997;137:978-82. [PMID: 9470919]

27. Ludwig RJ, Grundmann-Kollmann M, Holtmeier W, Woher M, Glas J, Podda M, et al. Herpes simplex virus type 2-associated eosinophilic cellulitis (Wells’ syndrome). J Am Acad Dermatol. 2003;48:560-1. [PMID: 12734477]

28. Sekin D, Demirhan B. Drugs and Wells’ syndrome: a possible causal relationship? Int J Dermatol. 2001;40:138-40. [PMID: 11328398]

29. Weiss G, Shemer A, Confino Y, Kaplan B, Trau H. Wells’ syndrome: report of a case and review of the literature. Int J Dermatol. 2001;40:148-52. [PMID: 11328401]

30. Burrall B. Sweet’s syndrome (acute febrile neutrophilic dermatosis). Dermatol Online J. 1999;5:8. [PMID: 10673451]

31. Cohen PR, Kurzrock R. Sweet’s syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42:761-78. [PMID: 14521689]

32. Cohen PR, Kurzrock R. Sweet’s syndrome: a review of current treatment options. Am J Clin Dermatol. 2002;3:117-31. [PMID: 11893223]

33. Dompmartin A, Troussard X, Lorier E, Jacobs F, Reman O, Leroy D, et al. Sweet syndrome associated with acute myelogenous leukemia. Atypical form simulating facial erysipelas. Int J Dermatol. 1991;30:644-7. [PMID: 1938078]

34. Crum NF, Higginbottom PA, Fehl FC, Graham BS. Sweet’s syndrome masquerading as facial cellulitis. Cutis. 2003;71:469-72. [PMID: 12839258]

35. Tercedor J, Rdenas JM, Henraz MT, Garca-Mellado V, Gutierrez- Salmern MT, Naranjo R. Facial cellulitis-like Sweet’s syndrome in acute myelogenous leukemia [Letter]. Int J Dermatol. 1992;31:598-9. [PMID: 1428459]

36. Cohen JB. Cutaneous involvement of dermatomyositis can respond to Dapsone therapy. Int J Dermatol. 2002;41:182-4. [PMID: 12010348]

37. Siva C, Velazquez C, Mody A, Brasington R. Diagnosing acute monoarthritis in adults: a practical approach for the family physician. Am Fam Physician. 2003;68:83-90. [PMlD: 12887114]

38. Swan A, Amer H, Dieppe P. The value of synovial fluid assays in the diagnosis of joint disease: a literature survey. Ann Rheum Dis. 2002;61:493-8. [PMID: 12006320]

39. Terkeltaub RA. Clinical practice. Gout. N Engl J Med. 2003;349:1647-55. [PMID: 14573737]

40. Kurzrock R, Cohen PR. Erythromelalgia: review of clinical characteristics and pathophysiology. Am J Med. 1991;91:416-22. [PMID: 1951386]

41. Michiels JJ. Etythromelalgia and vascular complications in polycythemia vera. Semin Thromb Hemost. 1997;23:441-54. [PMID: 9387203]

42. McCarthy L, Eichelberger L, Skipworth E, Danielson C. Erythromelalgia due to essential thrombocythemia. Transfusion. 2002;42:1245. [PMID: 12423504]

43. Davis MD, O’Fallon WM, Rogers RS 3rd, Rooke TW. Natural history of erythromelalgia: presentation and outcome in 168 patients. Arch Dermatol. 2000;136:330-6. [PMID: 10724194]

44. Letko E, Zafiralds P, Baltatzis S, Voudouri A, Livir- Rallatos C, Foster CS. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum. 2002;31:384-95. [PMID: 12077711]

45. Coppola M, Yealy DM. Relapsing polychondritis: an unusual cause of painful auricular swelling. Ann Emerg Med. 1992;21:81-5. [PMID: 1539895]

46. Khan AJ, Lynfield Y, Baldwin H. Relapsing polychondritis: case report and review of the literature. Cutis. 1994;54:98-100. [PMID: 7956342]

47. Soto-Romero I, Fustes-Morales AJ, De Leon-Bojorge B, Contreras-Ruiz \J, Ruiz-Maldonado R. Relapsing polychondritis: a pediatric case. Pediatr Dermatol. 2002;19:60-3. [PMID: 11860574]

48. Khan JH, Ahmed I. A case of relapsing polychondritis involving the tragal and the conchal bowl areas with sparing of the helix and the antihelix. J Am Acad Dermatol. 1999;41:299-302. [PMID: 10426914]

49. Khan AJ, Lynfield Y, Baldwin H. Relapsing polychondritis: case report and review of the literature. Cutis. 1994;54:98-100. [PMID: 7956342]

50. Copeman PW, Farthing CF, Leader M. Cutaneous metastasis (cancer en cuirasse and carcinoma erysipelatoides): a non-invasive search for the primary cancer using microscopical techniques on urine and skin. J R Soc Med. 1985;78 Suppl 11:43-5. [PMID: 3005564]

51. Hazelrigg DE, Rudolph AH. Inflammatory metastic carcinoma. Carcinoma erysipelatoides. Arch Dermatol. 1977;113:69-70. [PMID: 831626]

52. Langevitz P, Livneh A, Padeh S, Zalts N, Shinar Y, Zemer D, et al. Familial Mediterranean fever: new aspects and prospects at the end of the millenium. Isr Med Assoc J. 1999;1:31-6. [PMID: 11370119]

53. Majeed HA, Quabazard Z, Hijazi Z, Farwana S, Harshani F. The cutaneous manifestations in children with familial Mediterranean fever (recurrent hereditary polyserositis). A six-year study. Q J Med. 1990;75:607-16. [PMID: 2217666]

54. Barzilai A, Langevitz P, Goldberg I, Kopolovic J, Livneh A, Pras M, et al. Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic correlation. J Am Acad Dermatol. 2000;42:791-5. [PMID: 10775856]

55. Dinarello CA, Wolff SM, Goldfinger SE, Dale DC, Ailing DW. Colchicine therapy for familial mediterranean fever. A double-blind trial. N Engl J Med. 1974;291:934-7. [PMID: 4606353]

56. Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, et al. A controlled trial of colchicine in preventing attacks of familial mediterranean fever. N Engl J Med. 1974;291:932-4. [PMID: 4606109]

57. Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ. Familial Hibernian fever. Q J Med. 1982;51:469-80. [PMID: 7156325]

58. McDermott EM, Smillie DM, Powell RJ. Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin Proc. 1997;72:806-17. [PMID: 9294526]

59. Vigan M, Girardin P, Adessi B, Laurent R. [Cutaneous reactions to orthopedic implants]. Ann Dermatol Venereol. 1996;123:686-90. [PMID: 9615136]

60. Falagas ME, Kasiakou SK. [Mesh-related infections after hernia repair surgery.] Clinical Microbiology and Infection. [In press].

61. Klosterhalfen B, Hermanns B, Rosch R, Junge K. [Biological response to mesh.]. European Surgery. 2003;35:16-20.

62. Fitzpatrick BT. Urticaria and angioedema. In: Fitzpatrick BT, Johnson RA, Wolff K, Suurmond D, eds. Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases. 4th ed. New York: McGraw-Hill; 2000.

63. Ledo A, Harto A, Sendagorta E. Doxepin in the treatment of chronic urticaria [Letter]. J Am Acad Dermatol. 1985;13:1058-9. [PMID: 4078098]

64. Chicarilli ZN. Follicular occlusion triad: hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp. Ann Plast Surg. 1987;18:230-7. [PMID: 2954503]

65. Scheinfeld NS. A case of dissecting cellulitis and a review of the literature. Dermatol Online J. 2003;9:8. [PMID: 12639466]

66. Schewach-Millet M, Ziv R, Shapira D. Perifolliculitis capitis abscedens et suffodiens treated with isotretinoin (13-cis-retinoic acid) [Letter]. J Am Acad Dermatol. 1986;15:1291-2. [PMID: 3468134]

67. Shaffer N, Billick RC, Srolovitz H. Perifolliculitis capitis abscedens et suffodiens. Resolution with combination therapy. Arch Dermatol. 1992;128:1329-31. [PMID: 1417019]

68. Szuba A, Rockson SG. Lymphedema: classification, diagnosis and therapy. Vasc Med. 1998;3:145-56. [PMID: 9796078]

69. Witte CL, Witte MH, Unger EC, Williams WH, Bernas MJ, McNeill GC, et al. Advances in imaging of lymph flow disorders. Radiographies. 2000;20: 1697-719. [PMID: 11112825]

70. The diagnosis and treatment of peripheral lymphedema. Consensus document of the International Society of Lymphology. Lymphology. 2003;36:84-91. [PMID: 12926833]s

71. Loprinzi CL, Okuno Sh, Pisansky TM, Sterioff S, Gaffey TA, Morton RF. Postsurgical changes of the breast that mimic inflammatory breast carcinoma. Mayo Clin Proc. 1996;71:552-5. [PMID: 8642883]

72. King R, Duncan L, Shupp DL, Googe PB. Postsurgical dermal lymphedema clinically mimicking inflammatory breast carcinoma [Letter]. Arch Dermatol. 2001;137:969-70. [PMID: 11453830]

73. Fabbri P, Cardinali C, Giomi B, Caproni M. Cutaneous lupus erythematosus: diagnosis and management. Am J Clin Dermatol. 2003;4:449-65. [PMID: 12814335]

74. Patel P, Werth V. Cutaneous lupus erythematosus: a review. Dermatol Clin. 2002;20:373-85, v. [PMID: 12170873]

75. Callen JP. Management of skin disease in patients with lupus erythematosus. Best Pract Res Clin Rheumatol. 2002;16:245-64. [PMID: 12041952]

76. Wozniacka A, Carter A, McCauliffe DP. Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit. Lupus. 2002;11:71-81. [PMID: 11958581]

77. Fabbri P, Cardinali C, Giomi B, Caproni M. Cutaneous lupus erythematosus: diagnosis and management. Am J Clin Dermatol. 2003;4:449-65. [PMID: 12814335]

78. Young RJ 3rd, Gilson RT, Yanase D, Elston DM. Cutaneous sarcoidosis. Int J Dermatol. 2001;40:249-53. [PMID: 11454079]

79. Katta R. Cutaneous sarcoidosis: a dermatologic masquerader. Am Fam Physician. 2002;65:1581-4. [PMID: 11989634]

80. Russo G, Millikan LE. Cutaneous sarcoidosis: diagnosis and treatment. Compr Ther. 1994;20:418-21. [PMID: 7924231]

81. Hughes LB, Bridges SL Jr. Polyarteritis nodosa and microscopic polyangiitis: etiologic and diagnostic considerations. Curr Rheumatol Rep. 2002;4:75-82. [PMID: 11798986]

82. Gushi A, Hashiguchi T, Fukumaru K, Usuki K, Kanekura T, Kanzaki T. Three cases of polyarteritis nodosa cutanea and a review of the literature. J Dermatol. 2000;27:778-81. [PMID: 11211794]

83. Chen KR. Cutaneous polyarteritis nodosa: a clinical and histopathological study of 20 cases. J Dermatol. 1989;16:429-42. [PMID: 2576427]

84. Guillevin L, Lhote F. Treatment of polyatteritis nodosa and microscopic polyangiitis. Arthritis Rheum. 1998;41:2100-5. [PMID: 9870866]

85. Erhardt A, Sagir A, Guillevin L, Neuen-Jacob E, Hussinger D. Successful treatment of hepatitis B virus associated polyarteritis nodosa with a combination of prednisolone, alpha-interferon and lamivudine. J Hepatol. 2000;33:677-83. [PMID: 11059878]

86. Requena L, Requena C. Erythema nodosum. Dermatol Online J. 2002;8:4. [PMID: 12165214]

87. Psychos DN, Voulgari PV, Skopouli FN, Drosos AA, Moutsopoulos HM. Erythema nodosum: the underlying conditions. Clin Rheumatol. 2000;19:212-6. [PMID: 10870657]

88. O’Neill JH Jr. The differential diagnosis of erythema nodosum. Del Med J. 1991;63:683-9. [PMID: 1786841]

89. Hassink RI, Pasquinelli-Egli CE, Jacomella V, Laux-End R, Bianchetti MG. Conditions currently associated with erythema nodosum in Swiss children. Eur J Pediatr. 1997;156:851-3. [PMID: 9392398]

90. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R. Eiythema nodosum: an experience of 10 years. Scand J Infect Dis. 2004;36:424-7. [PMID: 15307561]

91. Kirsner RS, Pardes JB, Eaglstein WH, Falanga V. The clinical spectrum of lipodermatosclerosis. J Am Acad Dermatol. 1993;28:623- 7. [PMID: 8463465]

92. Naschitz JE, Yeshurun D, Schwartz H, Croitoru S, Shajrawi I, Misselevich I, et al. Pathogenesis of lipodermatosclerosis of venous disease: the lesson learned from eosinophilic fasditis. Cardiovasc Surg. 1993;1:524-9. [PMID: 8076090]

93. Gniadecka M, Karlsmark T, Bertram A. Removal of dermal edema with class 1 and II compression stockings in patients with lipodermatosclerosis. J Am Acad Dermatol. 1998;39:966-70. [PMID: 9843010]

94. Brace AJ, Bennett DD, Lohse CM, Rooke TW, Davis MD. Lipodermatosclerosis: review of cases evaluated at Mayo Clinic. J Am Acad Dermatol. 2002; 46:187-92. [PMID: 11807428]

95. Sehgal VN, Srivastava G, Aggarwal AK, BeH PN, Choudhaiy M, Bajaj P. Localized scleroderma/morphea. Int J Dermatol. 2002;41:467- 75. [PMID: 12207760]

96. Falanga V, Medsger TA Jr. D-penicillamine in the treatment of localized scleroderma. Arch Dermatol. 1990;126:609-12. [PMID: 2334179]

97. Falagas ME, Christopoulou M, Rosmarakis ES, Vlastou C. Munchausen’s syndrome presenting as severe panniculitis. Int J Clin Pract. 2004;58:720-2. [PMID: 15311731]

98. Carrasco L, Moreno C, Pastor MA, Izquierdo MJ, Faria C, Martn L, et al. Postirradiation pseudosclerodermatous panniculitis. Am J Dermatopathol. 2001;23:283-7. [PMID: 11481517]

99. Winkelmann RK, Grado GL, Quimby SR, Connolly SM. Pseudosclerodermatous panniculitis after irradiation: an unusual complication of megavoltage treatment of breast carcinoma. Mayo Clin Proc. 1993;68:122-7. [PMID: 8423691]

100. Preiss JC, Faiss S, Loddenkemper C, Zeitz M, Duchmann R. Pancreatic panniculitis in an 88-year-old man with neuroendocrine carcinoma. Digestion. 2002;66:193-6. [PMID: 12481166]

101. Peters MS, Su WP. Lupus erythematosus panniculitis. Med Clin North Am. 1989;73:1113-26. [PMID: 2671535]

102. Martens PB, Moder KG, Ahmed I. Lupus panniculitis: clinical perspectives from a case series. J Rheumatol. 1999;26:68-72. [PMID: 9918242]

103. McBean J, Sable A, Maude J, Robinson-Bostom L. Alpha 1- antitrypsin deficiency panniculitis. Cutis. 2003;71:205-9. [PMID: 12661748]

104. Kjus T, Ltzow-Holm C, Christensen OB. Treatment of panniculitis associated with alpha- 1-antitrypsin deficiency with alpha-1-protease inhibitor [Letter]. Acta Derm Venereol. 2003;83:462- 3. [PMID: 14690345]

105. Watabe H, Kawakami T, Sonia Y, Baba T, Mizoguchi M. Primary cutaneous T-cell-rich B-cell lymphoma in a zosteriform distribution associated with Epstein-Barr virus infection. J Dermatol. 2002;29:748-53. [PMID: 12484440]

106. Cavalli F. Rare syndromes in Hodgkin’s disease. Ann Oncol. 1998;9 Suppl 5:5109-13. [PMID: 9926248]

107. \Baddour LM, Haden KH, Alien JW. Primary skeletal muscle lymphoma presenting as refractory cellulitis. Cutis. 2001;68:223-6. [PMID: 11579790]

108. Russell-Jones R, Whittaker S. Szary syndrome: diagnostic criteria and therapeutic options. Semin Cutan Med Surg. 2000;19:100- 8. [PMID: 10892711]

109. Sheahan P, Donnelly M, O’Reilly S, Murphy M. T/NK cell non- Hodgkin’s lymphoma of the sinonasal tract. J Laryngol Otol. 2001;115:1032-5. [PMID: 11779343]

110. Kacinski BM, Flick M. Apoptosis and cutaneous T cell lymphoma. Ann N Y Acad Sci. 2001;941:194-9. [PMID: 11594573]

111. Mallett RB, Maintes E, Catovsky D, Maclennan K, Mortimer PS, Holden CA. Cutaneous infiltration in T-cell prolymphocytic leukaemia. Br J Dermatol. 1995;132:263-6. [PMID: 7888364]

112. Serra A, Estrach MT, Marti R, Villamor N, Rafel M, Montserrat E. Cutaneous involvement as the first manifestation in a case of T-cell prolymphocytic leukaemia. Acta Derm Venereol. 1998;78:198-200. [PMID: 9602226]

113. Yim JH, Wick MR, Philpott GW, Norton JA, Doherty GM. Underlying pathology in mammary Pager’s disease. Ann Surg Oncol. 1997;4:287-92. [PMID: 9181226]

114. Fu W, Mittel VK, Young SC. Paget disease of the breast: analysis of 41 patients. Am J Clin Oncol. 2001;24:397-400. [PMID: 11474272]

115. Marshall JK, Griffith KA, Haffty BG, Solin LJ, Vicini FA, McCormick B, et al. Conservative management of Paget disease of the breast with radiotherapy: 10- and 15-year results. Cancer. 2003;97:2142-9. [PMID: 12712465]

116. Fanning J, Lambert HC, Hale TM, Morris PC, Schuerch C. Paget’s disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget’s disease, and recurrence after surgical excision. Am J Obstet Gynecol. 1999;180:24-7. [PMID: 9914572]

117. Curtin JP, Rubin SC, Jones WB, Hoskins WJ, Lewis JL Jr. Paget’s disease of the vulva. Gynecol Oncol. 1990;39:374-7. [PMID: 2175288]

118. Johnson SM, Smoller BR, Lamps LW, Horn TD. Necrolytic migratory eryrhema as the only presenting sign of a glucagonoma. J Am Acad Dermatol. 2003;49:325-8. [PMID: 12894090]

119. Alexander EK, Robinson M, Staniec M, Dluhy RG. Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome. Clin Endocrinol (Oxf). 2002;57:827-31. [PMID: 12460334]

120. Matthews BD, Smith TI, Kercher ICW, Holder WD Jr, Heniford BT. Surgical experience with functioning pancreatic neuroendocrine rumors. Am Surg. 2002;68:660-5; discussion 665-6. [PMID: 12206598]

121. Fine A, Zacharias J. Calciphylaxis is usually non- ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61:2210-7. [PMID: 12028462]

122. Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15:172-86. [PMID: 12100455]

123. Arch-Ferrer JE, Beenken SW, Rue LW, Bland KI, Diethelm AG. Therapy for Calciphylaxis: an outcome analysis. Surgery. 2003;134:941-4; discussion 944-5. [PMID: 14668726]

124. Tiwari A, Haq AI, Myint F, Hamilton G. Acute compartment syndromes. Br J Surg. 2002;89:397-412. [PMID: 11952578]

125. Petit A, Sigal M, Merat R, Pepin E, Couffinhal JC. Pseudoerysipelas resulting from acute anterior tibial compartment syndrome. J Am Acad Dermatol. 1996;34:521-2. [PMID: 8609275]

126. Hope MJ, McQueen MM. Acute compartment syndrome in the absence of fracture. J Orthop Trauma. 2004;18:220-4. [PMID: 15087965]

Matthew E. Falagas, MD, MSc, and Paschalis I. Vergidis, MD

From Alfa HealthCare, Athens, Greece, and Tufts University School of Medicine, Boston, Massachusetts.

Acknowledgment: The authors thank Dr. Sofia K. Kasiakou for critical review of the manuscript.

Requests for Single Reprints: Matthew E. Falagas, MD, MSc, Alfa HealthCare, 9 Neapoleos Street, 151 23 Marousi, Athens, Greece; e- mail, [email protected].

Current author addresses are available at www.annals.org.

Copyright American College of Physicians Jan 4, 2005

Seventeenth-century philospher Rene Descartes conceptualized the distinction between the mind and the body. He viewed the ‘mind’ as completely separable from the ‘body’ (or ‘matter’ in general). The mind was seen as the concern of organized religion, whereas the body was seen as the concern of physicians. This partitioning ushered in a separation between the so-called ‘mental’ and ‘physical’ health. This dualism has influenced the thinking of health professionals as well as lay people for a long time. However, the twentieth century has witnessed remarkable advances in the understanding of mental disorders and the brain, and there is realization of the centrality of mental health to overall health and well being. The focus has shifted in the last decade to holistic medicine.

In Ayurveda, an ancient Indian system of medicine, symptoms and diseases that could be categorized as mental thoughts or feelings are just as important as symptoms and diseases of the physical body. There can be no mental health without physical health and vice versa. The mind and the body not only influence each other – they are each other. The whole life and life style must be in harmony before one can enjoy well being.

Recent research provides evidence that stresses that affect the brain can hurt the body at the cellular and molecular level and diminish a person’s health and quality of life. Psychoneuroimmunology seeks to understand the complex communications among the brain and the immune system, and their implications for health. New molecular techniques have allowed scientists to detail links between stress and disease immunity, pinpointing changes in hormone flow and immune system cells. Recent work has demonstrated that hormones and neurotransmitters released under stress can change immune cell behaviour.

Co-occuring physical, psychological and psychiatric disorders

There is now sufficient evidence on. co-morbidity of mental and physical disorders. Several psychological factors can take a toll on cardiac health, although each factor may act at different stages through different mechanisms. Psychological risk factors for coronary disease1 can be classified in to three categories: chronic, episodic and acute based on their duration and closeness in time to coronary syndromes. Chronic psychological factors that are associated with increased risk of first heart attack include long- term stable characteristics like a hostile personality, type A behavior, or low socio-economic status. These chronic factors play an important role in early disease stages when the build up of arteryblocking plaque is beginning. Fat deposits, inflammation of the arteries and higher white blood cell counts are known to result from these psychological traits by way of the nervous system. For instance, low socio-economic status correlates with increased exposure to bacteria and viruses, to higher levels of cytokines and to elevated C-reactive protein, a marker for inflammation1.

The same pattern holds true for episodic risk factors like depression and exhaustion. Episodic mental health conditions may lead to unstable plaques. Depression with elements of immune system, like increased cytokines, lymphocytes and white blood cells, strengthens the association between depression and inflammatory markers. Acting in the short term, acute psychological risk factors can directly trigger heart attacks once disease has reached advanced stages. Outbursts of anger increase the risk of heart attack by reducing adequate blood supply to the heart plaque.

A study on association between emotional upset and cardiac arrhythmia2 showed that negative emotion was associated with increased arrhythmia. Additionally, greater negative emotion was significantly associated with increased arrhythmia among participants in a lower left ventricular ejection fraction group (LVEF). However, this relationship between negative emotion and arrhythmia was not observed among higher LVEF participants. This can be seen as contributing to a larger body of evidence suggesting that negative moods may exacerbate cardiac conditions.

A great deal of research has investigated the relationship between stress and physical health. Posttraumatic stress disorder (PTSD) and other clinically significant distress reactions are a key step in triggering the processes through which exposure affects health. These processes involve psychological , biological, behavioural mechanisms that interact to strain the body’s ability to adapt, thereby increasing the likelihood of illness. A study3 on primary care patients showed that individuals with PTSD were more likely to have a number of specific medical problems including anaemia, arthritis, asthma, back pain, diabetes, eczema, kidney disease, lung disease and ulcer.

Generalized anxiety disorder is associated with increased risk of peptic ulcer disease, odds ratio ranging from 1.3 – 5.7 with evidence of a doseresponse relationship4. Neuroticism is also associated with significantly increased risk of self reported peptic ulcer disease, odds ratio ranging from 1.03 to 2.45. The mechanism of this association remains unknown and requires further research.

There is a strong association between panic attacks and self- reported respiratory diseases such as asthma, chronic bronchitis, or emphysema and other self-reported lung diseases have also been found to associate with a significantly increased odds of panic attacks, odds ratio ranging from 1.2 to 4.2(6).

A longitudinal study among children7 showed that poor physical health predicted future depression, independent of previous depression and demographic characteristics. Similarly major depression predicted future poor physical health, independent of previous physical health and demographic characteristics. Significant relationships among specific disorders reported in the longitudinal data were limited to major depression for mental disorders and immunologically related physical disorders such as allergies and asthma.

Role of cortisol

Elevated cortisol in a subset of depressed patients is a consistent finding. A recent review8 suggests that a subset of depressed patients have subtle evidence of physical effects similar to those in patients with Cushing’s syndrome or the metabolic syndrome. Cushing’s disease is an illness associated with cortisol elevations secondary to adrenocorticotropic hormonesecreting pituitary tumours. However, the cortisol elevations in patients with major depressive disorder (MDD) may be associated with clinically significant health effects despite the absence of obvious Cushingoid features. The metabolic syndrome is a common symptom cluster that includes dysregulated insulin and glucose metabolism, abdominal obesity, hyperlipidaemia and hypertension. The metabolic syndrome is a risk factor for the development of type 2 diabetes and cardiovascular disease. This review further shows that strong data evidence exists for a relationship between elevated cortisol and depression, hippocampal atrophy, cognitive impairment, abdominal obesity, and loss of bone density. Some evidence suggests an association between depression and hypertension, peptic ulcers, and diabetes. The mechanism by which corticosteroids may exert adverse effects on the body may be different for each condition. Alterations in serotonin levels, enhanced glutamate release, or inhibition of neurogenesis may be important factors in the central nervous system (CNS) effects of corticosteroids. The corticosteroidinduced decrease in bone mineral metabolism could in part be responsible for association of depression with loss of bone density. Elevated levels of catecholamines that appear to be associated with elevated cortisol levels in depressed patients could result in hypertension. As corticosteroids have potent anti-inflammatory and immunosuppressant effects, alterations in the immune system could also play a role in some disease processes. Cortisol seems to have a complex interaction with measures of immune functioning in depressed patients, which can include cytokine-induced activation of the hypothalamuspituitary-adrenal (HPA) axis and association between cytokine and cortisol levels.

Management of co-morbidity

When physical disorders become chronic in nature, there are often psychiatric sequelae associated with them. A study of chronic childhood illness, disability, and mental and social well being revealed that children with both chronic illness and associated disability were at greater than three-fold risk for psychiatric disorders and considerable risk for social adjustment problems9. Children with chronic medical conditions, but no disability had about two-fold increase in psychiatric disorders but little increased risk for social adjustment problems. The findings suggest that physicians in the community who care for children with chronic health problems should become skilled in the recognition of existing or incipient mental health and social problems and familiar with preventive and treatment approaches that may lessen the excessive burden of psychosocial problems among those with chronic ill health. On the other side, the psychotic patients may be unable to comprehend or describe their physical symptoms adequately. Physical disorders of psychotic patients may be overlooked if clinicians are not vigilant and thorough in assessing the patient’s complaints, especially if suc\h complaints sound delusional or bizarre. There is an obvious need for further research to better understand how to manage the co-morbidity of physical and mental disorders.

In past, the mental health field often focused principally on mental illness in order to serve individuals who were most severely affected. Now there is a need to respond to intensifying interest and concerns about disease prevention and health promotion. Mental health, like the broader field of health, has to be rooted in a population-based public health model, characterized by concern for the health of a population in its entirety and by awareness of the linkage between health and physical and psychosocial environment.

References

1. Kop WJ. The integration of cardiovascular behavioral medicine and psychoncuroimmunology : New developments based on converging research fields. Brain Behav Immun 2003; 17: 233-7.

2. Carels RA, Cacciapaglia H, Perez-Benitez CI, Douglass O, Christie S, O’Brien WH. The association between emotional upset and cardiac arrhythmia during daily life. J Consult Clin Psychol 2003; 71 : 613-8.

3. Weisberg RB, Bruce SE, Machan JT, Kessler, RC, Culpepper L, Keller, MB. Nonpsychiatric illness among primary care patients with trauma histories and post-traumatic stress disorder. Psychiatr Serv 2002; 53 : 848-54.

4. Goodwill RD, Stein MB. Generalized anxiety disorder and peptic ulcer disease among adults in the United States. Psychosom Med 2002; 64 : 862-6.

5. Goodwin RD, Stein MB. Peptic ulcer disease and neuroticism in the United Slates adult population. Psychother Psychosom 2003; 72: 10-5.

6. Goodwin RD, Pine DS. Respiratory disease and panic attacks among adults in the United States. Chest 2002; 122 : 645-50.

7. Cohen P, Pine DS, Must A, Kasen S, Brook J. Prospective associations between somatic illness and mental illness from childhood to adulthood. Am J Epidemiol 1998;147:232-9.

8. Brown ES, Varghese FP, McEwen BS. Association of depression with medical illness : does cortisol play a role ? Biol Psychiatry 2004; 55: 1-9.

9. Cadman D, Boyle M, Szatmari P, Offord DR. Chronic illness, disability and mental and social well-being: findings of the Ontario Child Health Study. Pediatrics 1987: 79 : 805-13.

Narender Kumar

Division of Non-Communiable Diseases

ICMR Headquarters

New Delhi 110029, India

e-mail : [email protected]

Copyright Indian Council of Medical Research Nov 2004

Seventeenth-century philospher Rene Descartes conceptualized the distinction between the mind and the body. He viewed the ‘mind’ as completely separable from the ‘body’ (or ‘matter’ in general). The mind was seen as the concern of organized religion, whereas the body was seen as the concern of physicians. This partitioning ushered in a separation between the so-called ‘mental’ and ‘physical’ health. This dualism has influenced the thinking of health professionals as well as lay people for a long time. However, the twentieth century has witnessed remarkable advances in the understanding of mental disorders and the brain, and there is realization of the centrality of mental health to overall health and well being. The focus has shifted in the last decade to holistic medicine.

In Ayurveda, an ancient Indian system of medicine, symptoms and diseases that could be categorized as mental thoughts or feelings are just as important as symptoms and diseases of the physical body. There can be no mental health without physical health and vice versa. The mind and the body not only influence each other – they are each other. The whole life and life style must be in harmony before one can enjoy well being.

Recent research provides evidence that stresses that affect the brain can hurt the body at the cellular and molecular level and diminish a person’s health and quality of life. Psychoneuroimmunology seeks to understand the complex communications among the brain and the immune system, and their implications for health. New molecular techniques have allowed scientists to detail links between stress and disease immunity, pinpointing changes in hormone flow and immune system cells. Recent work has demonstrated that hormones and neurotransmitters released under stress can change immune cell behaviour.

Co-occuring physical, psychological and psychiatric disorders

There is now sufficient evidence on. co-morbidity of mental and physical disorders. Several psychological factors can take a toll on cardiac health, although each factor may act at different stages through different mechanisms. Psychological risk factors for coronary disease1 can be classified in to three categories: chronic, episodic and acute based on their duration and closeness in time to coronary syndromes. Chronic psychological factors that are associated with increased risk of first heart attack include long- term stable characteristics like a hostile personality, type A behavior, or low socio-economic status. These chronic factors play an important role in early disease stages when the build up of arteryblocking plaque is beginning. Fat deposits, inflammation of the arteries and higher white blood cell counts are known to result from these psychological traits by way of the nervous system. For instance, low socio-economic status correlates with increased exposure to bacteria and viruses, to higher levels of cytokines and to elevated C-reactive protein, a marker for inflammation1.

The same pattern holds true for episodic risk factors like depression and exhaustion. Episodic mental health conditions may lead to unstable plaques. Depression with elements of immune system, like increased cytokines, lymphocytes and white blood cells, strengthens the association between depression and inflammatory markers. Acting in the short term, acute psychological risk factors can directly trigger heart attacks once disease has reached advanced stages. Outbursts of anger increase the risk of heart attack by reducing adequate blood supply to the heart plaque.

A study on association between emotional upset and cardiac arrhythmia2 showed that negative emotion was associated with increased arrhythmia. Additionally, greater negative emotion was significantly associated with increased arrhythmia among participants in a lower left ventricular ejection fraction group (LVEF). However, this relationship between negative emotion and arrhythmia was not observed among higher LVEF participants. This can be seen as contributing to a larger body of evidence suggesting that negative moods may exacerbate cardiac conditions.

A great deal of research has investigated the relationship between stress and physical health. Posttraumatic stress disorder (PTSD) and other clinically significant distress reactions are a key step in triggering the processes through which exposure affects health. These processes involve psychological , biological, behavioural mechanisms that interact to strain the body’s ability to adapt, thereby increasing the likelihood of illness. A study3 on primary care patients showed that individuals with PTSD were more likely to have a number of specific medical problems including anaemia, arthritis, asthma, back pain, diabetes, eczema, kidney disease, lung disease and ulcer.

Generalized anxiety disorder is associated with increased risk of peptic ulcer disease, odds ratio ranging from 1.3 – 5.7 with evidence of a doseresponse relationship4. Neuroticism is also associated with significantly increased risk of self reported peptic ulcer disease, odds ratio ranging from 1.03 to 2.45. The mechanism of this association remains unknown and requires further research.

There is a strong association between panic attacks and self- reported respiratory diseases such as asthma, chronic bronchitis, or emphysema and other self-reported lung diseases have also been found to associate with a significantly increased odds of panic attacks, odds ratio ranging from 1.2 to 4.2(6).

A longitudinal study among children7 showed that poor physical health predicted future depression, independent of previous depression and demographic characteristics. Similarly major depression predicted future poor physical health, independent of previous physical health and demographic characteristics. Significant relationships among specific disorders reported in the longitudinal data were limited to major depression for mental disorders and immunologically related physical disorders such as allergies and asthma.

Role of cortisol

Elevated cortisol in a subset of depressed patients is a consistent finding. A recent review8 suggests that a subset of depressed patients have subtle evidence of physical effects similar to those in patients with Cushing’s syndrome or the metabolic syndrome. Cushing’s disease is an illness associated with cortisol elevations secondary to adrenocorticotropic hormonesecreting pituitary tumours. However, the cortisol elevations in patients with major depressive disorder (MDD) may be associated with clinically significant health effects despite the absence of obvious Cushingoid features. The metabolic syndrome is a common symptom cluster that includes dysregulated insulin and glucose metabolism, abdominal obesity, hyperlipidaemia and hypertension. The metabolic syndrome is a risk factor for the development of type 2 diabetes and cardiovascular disease. This review further shows that strong data evidence exists for a relationship between elevated cortisol and depression, hippocampal atrophy, cognitive impairment, abdominal obesity, and loss of bone density. Some evidence suggests an association between depression and hypertension, peptic ulcers, and diabetes. The mechanism by which corticosteroids may exert adverse effects on the body may be different for each condition. Alterations in serotonin levels, enhanced glutamate release, or inhibition of neurogenesis may be important factors in the central nervous system (CNS) effects of corticosteroids. The corticosteroidinduced decrease in bone mineral metabolism could in part be responsible for association of depression with loss of bone density. Elevated levels of catecholamines that appear to be associated with elevated cortisol levels in depressed patients could result in hypertension. As corticosteroids have potent anti-inflammatory and immunosuppressant effects, alterations in the immune system could also play a role in some disease processes. Cortisol seems to have a complex interaction with measures of immune functioning in depressed patients, which can include cytokine-induced activation of the hypothalamuspituitary-adrenal (HPA) axis and association between cytokine and cortisol levels.

Management of co-morbidity

When physical disorders become chronic in nature, there are often psychiatric sequelae associated with them. A study of chronic childhood illness, disability, and mental and social well being revealed that children with both chronic illness and associated disability were at greater than three-fold risk for psychiatric disorders and considerable risk for social adjustment problems9. Children with chronic medical conditions, but no disability had about two-fold increase in psychiatric disorders but little increased risk for social adjustment problems. The findings suggest that physicians in the community who care for children with chronic health problems should become skilled in the recognition of existing or incipient mental health and social problems and familiar with preventive and treatment approaches that may lessen the excessive burden of psychosocial problems among those with chronic ill health. On the other side, the psychotic patients may be unable to comprehend or describe their physical symptoms adequately. Physical disorders of psychotic patients may be overlooked if clinicians are not vigilant and thorough in assessing the patient’s complaints, especially if suc\h complaints sound delusional or bizarre. There is an obvious need for further research to better understand how to manage the co-morbidity of physical and mental disorders.

In past, the mental health field often focused principally on mental illness in order to serve individuals who were most severely affected. Now there is a need to respond to intensifying interest and concerns about disease prevention and health promotion. Mental health, like the broader field of health, has to be rooted in a population-based public health model, characterized by concern for the health of a population in its entirety and by awareness of the linkage between health and physical and psychosocial environment.

References

1. Kop WJ. The integration of cardiovascular behavioral medicine and psychoncuroimmunology : New developments based on converging research fields. Brain Behav Immun 2003; 17: 233-7.

2. Carels RA, Cacciapaglia H, Perez-Benitez CI, Douglass O, Christie S, O’Brien WH. The association between emotional upset and cardiac arrhythmia during daily life. J Consult Clin Psychol 2003; 71 : 613-8.

3. Weisberg RB, Bruce SE, Machan JT, Kessler, RC, Culpepper L, Keller, MB. Nonpsychiatric illness among primary care patients with trauma histories and post-traumatic stress disorder. Psychiatr Serv 2002; 53 : 848-54.

4. Goodwill RD, Stein MB. Generalized anxiety disorder and peptic ulcer disease among adults in the United States. Psychosom Med 2002; 64 : 862-6.

5. Goodwin RD, Stein MB. Peptic ulcer disease and neuroticism in the United Slates adult population. Psychother Psychosom 2003; 72: 10-5.

6. Goodwin RD, Pine DS. Respiratory disease and panic attacks among adults in the United States. Chest 2002; 122 : 645-50.

7. Cohen P, Pine DS, Must A, Kasen S, Brook J. Prospective associations between somatic illness and mental illness from childhood to adulthood. Am J Epidemiol 1998;147:232-9.

8. Brown ES, Varghese FP, McEwen BS. Association of depression with medical illness : does cortisol play a role ? Biol Psychiatry 2004; 55: 1-9.

9. Cadman D, Boyle M, Szatmari P, Offord DR. Chronic illness, disability and mental and social well-being: findings of the Ontario Child Health Study. Pediatrics 1987: 79 : 805-13.

Narender Kumar

Division of Non-Communiable Diseases

ICMR Headquarters

New Delhi 110029, India

e-mail : [email protected]

Copyright Indian Council of Medical Research Nov 2004

TRYING too hard to balance home, family and work life has led to an epidemic of “Hurried Woman Syndrome” among British women.

More than three-quarters of 10,000 women questioned by the UK women’s magazine Prima showed signs of the condition, which is caused by trying to do too much at once.

Hurried Woman Syndrome, which causes sufferers to become overweight, tired and have a low sex drive was first identified by a Texan doctor, Brent Bost.

The first UK study discovered that 74 per cent of women questioned are suffering from at least five symptoms of the condition, which lowers serotonin in the brain and can lead to clinical depression.

Ruth Tierney, the features editor of Prima, said: “The results were shocking, with three-quarters of British women admitting to suffering from the condition.

“Many of the women we interviewed instantly identified with the vicious circle of symptoms, which often begins with tiredness, leading to an increase in appetite, weight gain, and a loss of interest in sex and exercise.

“These changes kick-start a cycle of emotional symptoms including a lack of self-esteem, irritability, feelings of guilt and worthlessness, and a drop in motivation.

“As women’s hectic schedules increase in pace, so too do their stress levels. This is a uniquely female condition, because women today have the pressure of looking after the day-to-day running of the household, while many also have the pressure of going out to work.

“It seems the answer to this very modern condition is to go back to basics, and to stop trying to be the perfect wife, mother and employee.”

Dr Bost urges women to exercise, get enough sleep and to set realistic limits about what they can achieve.

Dr Bost said: “Do the things granny would have told you to do. Basically, slow down and smell the roses, set priorities and realise you have limits.”

By R.J. Ignelzi

Copley News Service

While some employees meet up for a midday pizza or burger, Qualcomm legal secretary Kim Carey has a regular lunch date with the company treadmill.

Instead of downing a brew after work, Solar Turbines engineer Scott Thompson is more likely to be doing the Downward Dog in his on-site yoga class.

And, as many Sempra Energy workers grab a coffee or smoke during their break, others try to grab their toes in the twice-a-day staff stretching session.

From sweating it out in the corporate fitness center to learning to kayak on weekends with colleagues, an increasing number of employees are exercising company health and fitness perks and finding that workplace workouts work.

“Workplace health and fitness programs benefit the company as much as the employee,” said Vicki Wilson, Solar Turbines’ health and fitness coordinator. “Fit and healthy employees mean higher productivity, lower absenteeism and lower health care claims.”

If that’s not enough, studies say employers’ efforts pay off in better employee attitude.

“Our surveys show that if there’s evidence of an employer’s concern about the health and well being of employees, it improves employee morale,” said LuAnn Heinen, director of the Institute on the Costs and Health Effects of Obesity, part from the Washington, D.C.-based National Business Group on Health. “A healthy employee is a happy employee.”

Soaring insurance costs – medical benefits costs have nearly doubled for many companies in the past five years – and a broader awareness of the health costs associated with obesity, smoking, stress and other lifestyle issues have helped to fuel the push to get employees moving.

Heinen’s group found that of 84 U.S. companies surveyed, 77 percent have an on-site fitness center, 69 percent have on-site fitness programs and 38 percent have Web-based tools that offer online health appraisals and guidance in weight loss, stress management and disease prevention.

Since so many people spend so much time on the job, it makes sense to incorporate a health and fitness program into the workday or make it available on the work site.

“The convenience factor is huge. The No. 1 barrier to people exercising is the perception that they don’t have time,” said exercise physiologist Richard Cotton, spokesman for the American Council on Exercise and founder of myexerciseplan.com.

“Workplace fitness programs let employees exercise before work, during lunch or after work. It’s not a big additional commute, and they fit it right into their schedule.”

Different companies are approaching wellness in different ways.

Some large workplaces like the Pfizer Lab in San Diego, Qualcomm and Solar Turbines offer employees fitness centers that rival first-class health clubs.

Pfizer’s luxurious, full-service fitness center, which cost $250,000 to build and charges employees $24 per month to use, is staffed by three full-time fitness specialists who offer exercise guidance, personal training, health and fitness assessments and group exercise classes. Company grounds include a jogging track that’s spawned an active running club.

Pfizer workouts seem to be doing the job for research associate Amy LaPaglia. She lost 35 pounds this past year, thanks in part to the company fitness program. Three or four afternoons a week, about the time of day she’s yearning for a candy bar, she heads down to the fitness center.

“It’s right here, so I have no excuses not to use it. Plus, I feel so good afterward,” said the 28-year-old who does a mix of strength training and cardiovascular exercises.

Other employers such as Sempra Energy don’t offer workers an on-site facility but sponsor discounted off-site gym memberships. A few have walking and running clubs, finding that group movement is motivating.

Sempra encourages desk-bound employees to use their 15-minute breaks to get outside, stretch their legs and rev up their heart rate. One-mile, 15-minute power walks are led a couple times a day. At lunchtime, there’s a longer three-mile, 40-minute walk.

Sempra executive assistant Debbie Sheets has logged over 1,535 miles in the last nine months on lunchtime walks.

“The walks are great. Just being away from the desk and getting some fresh air helps me feel more energetic and gets me through the afternoon,” she said.

Companies of all sizes are offering employees healthier cafeteria fare with salad bars, fresh fruit and a variety of bottled water, juices and teas. While sodas, chips and doughnuts are still available, most workplaces offer some kind of nutritious alternative.

“Our cafeteria offers something to fit into every diet,” said Allen Carrier, Pfizer spokesman. “There are choices for the Atkins diet, South Beach Diet, low-fat diet and vegetarians.”

Companies such as Solar Turbines and Qualcomm have moved fitness beyond the gym and traditional sweaty workout. Although both offer 24/7 fitness centers, with the latest equipment and a variety of group exercise classes, they also try to attract the exercise-shy.

One of the most popular fitness programs at Qualcomm is “exercise-light,” a concept designed to “simply get people out of their chairs and moving,” said David Beadle, manager of Qualcomm’s human resources and an exercise physiologist.

“We’re looking for those who don’t exercise regularly and may be too intimidated to even walk in the door of a fitness center.”

With minimal sweating, exercise-light participants don’t even have to change into workout clothes for the classes, which are both indoors and outdoors and offer a workout mix of flexibility, strength training and a little cardio.

Both Qualcomm and Solar have tried to put the fun into their fitness programs, engaging employees in activities they enjoy instead of ones that are simply good for them.

“We found that when people are passionate about something, that’s a good thing for their health because they usually figure out a way to get more of it,” Beadle said.

In addition to offering an outdoor recreation complex for the court sports fan, Solar also provides a networking opportunity for the sports enthusiast. Solar Employees Recreation Association is 25 to 30 activity groups ranging from the bowling club to the triathlon club, which meet and workout together at their sport.

Qualcomm wanted to give employees the chance to not only engage in their favorite activities, but also to experience things they’d never done before. The company offers 30 to 40 “learn to” classes, including scuba diving, kayaking, tennis, volleyball, swimming, sailing and golf. Held after work and on weekends, all of the classes are open to employee family members and are paid for by the employee. The company simply facilitates the process and brings them together.

The recreational classes have enabled Qualcomm patent attorney David Kordich to expand his exercise repertoire. In addition to using the corporate gym, he also takes advantage of the classes and tries out new sports, including hiking, scuba diving, surfing and golfing.

“I’ve always exercised,” said 49-year-old Kordich. “But, now with these classes I’m able to get in my exercise but also do fun stuff.”

SIDEBAR

Fit things your boss can do

Copley News Service

Is your workplace health and fitness program a bit flabby? The following suggestions may help you and your employer tone it up.

– Ask employer to subsidize employee memberships to off-site health clubs.

– Encourage employer to hold annual health and fitness fairs or once-a-year health screening to monitor employee blood pressure, body fat and cholesterol and to offer healthy living tips.

– Ask employer to sponsor walkers or runners in local charity walks and runs. Not only is it good corporate exposure, it also prods employees to get in shape for the competition.

– Encourage employer to host health and fitness speakers. Groups such as the American Heart Association, the American Lung Association and the American Cancer Society often have a free speakers bureau and can offer employees important health information and materials.

– Ask your employer to offer a salad bar in the cafeteria and replace some of the vending machine chips and pastries with healthier fare.

– Ask employer to offer online health and fitness coaching programs for the employees.

– So more employees might be encouraged to ride bikes to work, ask employer to provide secure storage for bikes.

– As a favor to all employees, ask your employer to install showers in the men’s and women’s rooms.

SIDEBAR

Employer no help? Take charge

Copley News Service

If workplace health and fitness is left up to you, the following tips can help you and your colleagues shape up.

– Ask a nearby fitness center for a corporate group discount. Many health clubs will offer 15 percent to 30 percent off fees if groups of six or more join.

– Organize after-work or weekend group activity lessons with fellow employees. Follow up with group outings such as ski trips, scuba dives or golf tournaments.

– Form a lunchtime or after-work running or walking club with fellow employees. Exercising with others can be a great motivating force.

– Organize a video/CD-led exercise class. All you need is an empty conference room or auditorium, a VCR or DVD player, a couple of good instructional exercise tapes and some willing participants.

– Hire an exercise instructor to come to the work site once or twice a week to teach a yoga or strength-training class. (Many personal trainers do off-site group exercise instruction.) Participants can split the instructor’s fee.

– Once every couple of weeks hold a healthful picnic lunch with fellow workers. Everyone bring a nutritious dish to share along with copies of the recipe to expand healthful menu repertoire.

Visit Copley News Service at www.copleynews.com.

Jan. 2–Nine-year-old Kaitlyn Langstaff of Saratoga died 20 months after taking Children’s Motrin. Sabrina Brierton Johnson of Los Angeles went blind two months after the 7-year-old took the same drug. Three-year-old Heather Rose Kiss of New Jersey died a week after taking a few doses of Children’s Advil.

All three girls developed a rare, excruciatingly painful disease after an apparent allergic reaction to ibuprofen. And the parents of all three said they never dreamed that an over-the-counter pain reliever sold everywhere from supermarkets to the corner 7-Eleven could kill or disable their children.

The U.S. Food and Drug Administration has not required the makers of ibuprofen to include the life-threatening disease or its symptoms on non-prescription labels, even though warnings are required on prescription-strength ibuprofen and other prescription drugs that can cause the same reactions. The FDA and a spokesman for the maker of Children’s Advil told the Mercury News that no warning is needed because the disease is so rare.

But after the third lawsuit in two years was filed this week against the makers of Children’s Motrin — health care giant Johnson & Johnson and its subsidiary, McNeil Consumer & Specialty Pharmaceuticals — a spokeswoman said McNeil will look into the case.

“As the makers of Children’s Motrin products, we are deeply concerned by all matters relating to our products and we are investigating the situation,” said Bonnie Jacobs, spokeswoman for the Fort Washington, Pa.-based McNeil.

Fran Sullivan, spokesman for Wyeth Consumer Health Care, the maker of Children’s Advil, told the Mercury News he had no personal knowledge of Heather Rose’s death, but added: “If it turns out this child died after taking Children’s Advil, we would look into it as well. We want to get the information so we can investigate it.”

In the suit filed Tuesday, (12-28), Sabrina and her parents allege that Motrin’s makers knew the product could cause the rare and sometimes deadly allergic reactions called Stevens Johnson Syndrome and toxic epidermal necrolysis — and that they failed to warn consumers.

The family is seeking monetary damages, but also wants the drug maker to take Children’s Motrin off the market until it carries a warning about the syndrome and its symptoms. They said parents and doctors need to know that they should stop giving children ibuprofen at the first sign of a rash to prevent the disease from advancing to the more serious toxic epidermal necrolysis, which has about a 30 percent mortality rate. Symptoms also include blisters on the ears, nose and genital area and sores on the inside of the mouth.

Kaitlyn’s parents received a confidential settlement in a similar suit in November and said they can no longer discuss the case. McNeil also settled in November with the parents of a young Texas girl.

Prior to the settlement, Kerry Langstaff, Kaitlyn’s mother, said the family hoped to educate the medical community and parents about this over-the-counter drug causing this disease.

“We can’t tell you how many doctors and nurses have said to us, ‘I didn’t know,'” Langstaff said.

After a 20-month struggle to overcome the disease, which left her unable to see, speak, breathe on her own or eat without a tube in her stomach, Kaitlyn died just before Christmas a year ago.

Stories in the Mercury News about her fight to remain a normal kid prompted thousands of offers of help and inspired a local rock promoter to have a poem she wrote set to music and recorded on a CD.

Dr. Roy Levin, who said he was unaware of the association between Children’s Motrin and Stevens Johnson Syndrome until he treated Kaitlyn Langstaff, said of the drug companies: “They have to warn people who think it’s as safe as getting M&Ms.”

And Darlene Kiss, Heather’s mother, said she believes parents have the right to know that medicines used routinely for children have the potential for such catastrophic consequences.

“Even if it’s a verbal warning from the doctor, it would make you think,” said Kiss, who named her baby daughter Heidi Rose in honor of Heather Rose, who died March 17, 2003. Kiss has hired an attorney but has not filed suit.

A number of other drugs can cause Stevens Johnson Syndrome, and some of them — including prescription-strength ibuprofen — carry warnings about the risk of the severe skin reactions. Though the FDA has acknowledged that ibuprofen can cause the syndrome, the government has not ordered pharmaceutical companies to mention the disease that killed Heather Rose and Kaitlyn on over-the-counter ibuprofen labeling, saying the risk of harm is too low.

Space on drug labels should be devoted to more common adverse reactions, such as gastrointestinal bleeding and kidney problems, the agency says.

“There is only so much you can put on a label,” the FDA said in a statement to the Mercury News. “We already know that the longer the labels, the less someone is going to read them.”

There are an estimated one to six cases of Stevens Johnson Syndrome per million people in the United States each year, due to drug reactions as well as other causes. The FDA told the Mercury News it has received about 150 reports of the syndrome in patients who had used ibuprofen over the years. The agency would not say how common a side effect needs to be to trigger a specific warning on the label.

However, Pfizer announced last month that it will add a “black-box” warning — the strongest a drug can carry — to the label of its prescription painkiller Bextra after 87 people taking the drug developed severe skin reactions, including Stevens Johnson Syndrome and toxic epidermal necrolysis, and four died. Bextra is part of the same broad class of drugs — known as non-steroidal anti-inflammatory drugs or NSAIDs — as ibuprofen.

The FDA has been under fire for months over its handling of safety concerns about other drugs, including Vioxx, a top-selling prescription NSAID used to treat arthritis pain. Vioxx was removed from shelves around the world in September after it was linked to an increased risk for heart attacks.

An FDA advisory committee in February will consider risks of Vioxx, Bextra and other NSAIDs “to determine whether additional regulatory action is needed,” the agency said in a statement last week.(12/23) It was not known whether the committee would address ibuprofen or Stevens Johnson Syndrome.

Stevens Johnson Syndrome and its various forms can afflict people of all ages. But the Stevens Johnson Syndrome Foundation has seen a jump in the number of cases involving children and ibuprofen reported to it in the past year.

“We’re getting about one or two reports of new cases each month,” said Jean McCawley, director and founder of the Westminster, Colo.-based foundation. “The only thing that’s rare about SJS is that it’s not mandatory to report it to the FDA.”

These days Sabrina is back at home, but her eyes are so sensitive to light that she must wear a hat pulled down over her face all the time, and she has numerous other medical problems from the disease.

“Johnson & Johnson’s failure to warn has cost Sabrina her sight and has cost other innocent children their lives,” said her mother. “It’s time for the truth to be told, and it’s time for Johnson & Johnson to do the responsible thing and put proper warnings and instructions on Children’s Motrin.”

—–

To see more of the San Jose Mercury News, or to subscribe to the newspaper, go to http://www.mercurynews.com.

(c) 2005, San Jose Mercury News, Calif. Distributed by Knight Ridder/Tribune Business News. For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

SE, IYCOY, 8264, JNJ, WYE,

Background: Although intravenous immunoglobulin G (IVIG) therapy has been reported in hyperbilirubinemia of Rh hemolytic disease, its use in ABO hemolytic disease has been reported in only a few studies. In our institute we have observed that almost 30% of babies with hyperbilirubinemia due to ABO hemolytic disease required exchange transfusion.

Objective: To determine whether administration of IVIG to newborns with significant hyperbilirubinemia due to ABO hemolytic disease would reduce the need for exchange transfusion as a primary goal in these babies.

Design: This was a prospective study involving all newborns with significant hyperbilirubinemia due to direct Coombs-positive ABO hemolytic disease.

Methods: All healthy term babies with ABO hemolytic disease with positive direct Coombs test in the period between 2000 and 2002 were identified. Significant hyperbilirubinemia was defined as hyperbilirubinemia requiring phototherapy and/or rising by 8.5 mol/ l per h (0.5 mg/dl per h) or more to require exchange transfusion. Babies were randomly assigned into two groups: group 1 (study group) received phototherapy plus IVIG (500 mg/kg); and group 2 (control group) received phototherapy alone. Exchange transfusion was carried out in any group if at any time the bilirubin level reached 340 mol/ l (20 mg/dl) or more, or rose by 8.5 mol/l per h (0.5 mg/dl per h) in group 2.

Results: A total of 112 babies were enrolled over 2 years, 56 in each group. Exchange transfusion was carried out in four babies in the study group, while 16 babies in the control group required exchange. Late anemia was not of concern in either group. No adverse effects related to IVIG administration were recorded.

Conclusion: Administration of IVIG to newborns with significant hyperbilirubinemia due to ABO hemolytic disease with positive direct Coomb’s test reduces the need for exchange transfusion without producing immediate adverse effects.

Key words: ABO HEMOLYTIC DISEASE OF THE NEWBORN; INTRAVENOUS IMMUNOGLOBULIN

INTRODUCTION

Intravenous immunoglobulin G (IVIG) has been used in immunological neonatal disorders including alloimmune and autoimmune neonatal thrombocytopaenia1. IVIG is also used as an adjuvant therapy in neonatal sepsis2. Its use in neonatal Rh hemolytic disease has stemmed from its antenatal administration to pregnant women to salvage fetuses with severe Rh isoimmunization3 in addition to its indication in other neonatal immunological disorders. The trials describing the administration of IVIG in hemolytic disease of the newborn have involved mostly babies with Rh hemolytic disease and very few babies with ABO hemolytic disease4-8. Hyperbilirubinemia due to ABO hemolytic disease is the major indicator for exchange transfusion in our institute. Against this background we set out to investigate whether IVIG administration to babies with significant hyperbilirubinemia due to ARO hemolytic disease would reduce the need for exchange transfusion.

PATIENTS AND METHODS

During the period from 2000 to 2002, 112 babies were diagnosed as having significant hyperbilirubinemia due to ABO hemolytic disease confirmed by a positive direct Coombs test. Phototherapy was commenced if the level of serum bilirubin was rising by 8.5 mol/l per h (0.5 mg/dl per h) or if the total bilirubin level exceeded 170 mol/l per h (10 mg/dl per h), 204 mol/l per h (12 mg/dl per h) or 238 mol/l per h (H mg/dl per h) at

The demographic data of both groups are shown in Table 1. There were no differences between the groups in relation to gestational age, birth weight or sex. All babies had been delivered at term and were healthy at the beginning of treatment. Babies were excluded from the trial if they were of low birth weight, had Rh hemolytic disease or other hemolytic anemias, or were sick from other causes such as perinatal asphyxia, or had severe congenital malfomiations.

All babies had 4-hourly serum bilirubin estimation and daily estimation of hemoglobin, red blood cell count, reticulocyte count, white blood cell count and platelet count. Babies were followed in the high-risk clinic at the age of 6 and 12 weeks to check their hemoglobin and red cell count and reticulocyte count for development of late anemia.

Exchange transfusion was performed if at any time the serum bilirubin level was found to be 340/itnol/1 (20 mg/dl) or more, in any of the two groups, or if it was rising by 8.5 mol/l per h (0.5 mg/dl per h) or more in group 2 babies.

Table 1 Demographic data for both groups

Late anemia was considered to be present if the hemoglobin level fell below 120 gl1 on follow-up. Severe late anemia requiring top- up red blood cell transfusion was defined as a hemoglobin level below 70 g/l10.

Any possible adverse effects related to IVIG administration, umbilical venous catheterization or blood transfusion were recorded.

Results are expressed as mean and standard deviation. Statistical significance was set at p

RESULTS

There were no statistically significant differences between the two groups with respect to mode of delivery, Apgar score or the initial values of serum bilirubin, hemoglobin and reticulocyte count.

There were a total of 76 babies with blood group A and 36 babies with blood group B, distributed between the two groups (Table 2). All the mothers were of the O Rh-positive group. Four babies in the study group (group 1) required exchange transfusions compared to 16 babies in the control group (group 2). This was statistically significant (p = 0.007; Table 3).

When comparing the number of babies who had exchange transfusion according to their blood groups, it could be seen that for babies in group 1, only one baby of blood group A was exchanged whereas three babies of blood group B required exchange (Fisher exact test 14, not significant; Table 2). However, for babies in group 2, five of blood group A and 11 of blood group B were exchanged (χ^sup 2^ = 17.23, p

The hospital stay for both groups did not differ significantly (mean of 7.05 days for group 1 versus 7.46 for group 2, p = 0.63). However, in both groups the length of stay was affected by development of clinical or culture-positive sepsis which necessitated a prolonged course of antibiotics.

When followed for late anemia, none of the babies in either group required top-up blood transfusion, because the hemoglobin level remained above 100 g/l.

The times at which IVIG was given varied between 2 h and 72 h with 68% of the babies receiving IVIG before or at the age of 24 h and 94.6% receiving IVIG by the age of 48 h (Table 4) The four babies who were exchanged in the IVIG group all underwent exchange before the age of 24 h.

No immediate adverse effects related to IVIG were noted, including fever, allergic reactions, volume overload or hemolysis.

The duration of phototherapy for both groups showed that group 1 babies had phototherapy for 2-7 days (average 3.848 days) while group 2 babies had phototherapy for 2-9 days (average 4-402 days). This was statistically significant (p = 0.036; Table 5).

Table 2 Exchange transfusion according to blood group

Table 3 Babies requiring or not requiring exchange transfusions (total 112)

Table 4 Age of administration of IVIG

Table 5 Duration of phototherapy (days)

DISCUSSION

The clinical significance of hyperbilirubinemia in newborn infants lies in its historical association with kernicterus, where significant unconjugated bilirubin appears to produce an encephalopathy with a specific clinical neurological syndrome”.

One of the most important causes of hyperbilirubinemia in the newborn is immune hemolytic anemia due to antibodies acquired from the mother transplacentally. With the wide use of anti-D to prevent Rh hemolytic disease, other blood group incompatibilities now assume a major role in the causation of neonatal hyperbilirubinemia which may require exchange transfusion.

Initial reports describing the use of IVIG for Rh isoimmunization in pregnant women in the third trimester have indicated a reduction in maternal antibody titers and severity of fetal hemolysis, and hence a reduction in severity of neonatal Rh isoimmune disease’. The mechanism by which IVIG is thought to reduce the degree of hemolysis is by blocking the reticuloendothelial Fc receptor sites and hence preventing the extravascular destruction of neonatal red blood cells by transplacentally acquired maternal isoantibodies12,13. This competitive action of IVIG with isoantibodies has led to the suggestion that, in order for IVIG to be ef\fective, it must be administered as soon as the diagnosis of isoimmune hemolytic anemia is made4,14.

Our study has shown that ABO hemolytic disease is an important cause of significant hyperbilirubinemia, which may necessitate exchange transfusion, and that IVIG administration significantly reduces the need for exchange transfusion. Although advocates of IVIG suggest administering it early4,14, we were able to show that IVIG administration can still be effective if given as late as the age of 72 h of life. Although the majority of babies in our study were of blood group A, rather than blood group B (76 vs. 36), more babies with blood group B tended to require exchange transfusion than babies with blood group A. This was significant in babies who did not receive IVIG, indicating that ABO hemolytic disease tends to be severe in our babies with blood group B. Our study suggests that administering IVIG has resulted in significantly fewer babies of blood group B needing exchange transfusion compared to babies who received phototherapy alone (Table 2). Therefore, it is justifiable to suggest that a family history of a previous baby of blood group B requiring exchange transfusion for significant hyperbilirubinemia due to ABO hemolytic disease should be treated with IVIG as soon as the diagnosis is made. All babies who were given IVIG received one dose; in our opinion, this will be effective without the need for a repeat dose.

Exchange transfusion is not without risks. In fact, ten of the babies who had exchange, from both groups, had to be treated for blood culture-positive or clinical sepsis, needing to extend their length of stay to complete the antibiotic course. This was the main reason why the length of stay in our babies who received IVIG was not significantly shortened in comparison with other studies, which reported significant reduction in the length of hospital stay when IVIG was administered6. Given the risks of exchange transfusion, we found that IVIG treatment was effective and non-invasive. Although the length of stay for both groups was not significantly different, we were able to show that the duration of phototherapy was significantly shortened in the IVIG group compared with the control group. In our opinion, this difference reflects the continuing effect of IVIG in controlling the hemolytic process and hence the need for longer use of phototherapy.

Transfusions for late anemia have been reported to be increased in babies who received IVIG4,6,7. This is explained by the fact that antibody-sensitized neonatal erythrocytes will bind to the Fc sites on the surface of the reticuloendothelial cells which have become free after the effect of IVIG had faded, causing late hemolysis. In our patients, severe late anemia requiring blood transfusion was not encountered. This may be related to the sparse distribution of A and B sites on the red cells of the newborn, leading to a minimal effect on the erythrocyte life span, in ABO hemolytic disease. This is in contradistinction to Rh hemolytic disease, where the surface of the red cell becomes coated with antibodies, leading to its rapid destruction and marked shortening of its life span.

Mild adverse effects related to IVIG include fever, allergic reactions, hemolysis and fluid overload. Serious adverse effects are rare and include anaphylaxis and possible transmission of infections. We did not encounter any of the mild adverse effects in our babies. With improvements in the processing of IVIG the serious adverse effects will be avoided. We conclude that IVIG is a safe and effective therapy for reducing the need for exchange transfusion in significant hyperbilirubinemia of ABO hemolytic disease.

Acknowledgements

We are especially grateful to the medical and nursing staff in the neonatal intensive care unit at Security Forces Hospital who helped us to finish this study. We thank Mrs Bing Borromeo for typing this manuscript and for secretarial support.

REFERENCE

1. Ouwehond WH, Smith G, Ranosinghe E. Management of severe alloimmune thrombocytopenia in the newborn. Arch Ois Child Fetal Neonatal Ed 2000;82:F173-5

2. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev 2000;2:CD001239

3. Voto LS, Mathet ER, Zapoterio JL, et al. High dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs). A new alternative for the treatment of severe fetal hemolytic disease. J Perinat Med 1997;25:85-8

4. Rubo J, Albrecht K, Lasch P, et al. High dose intravenous immunoglobulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 1992;121:93-7

5. Voto LS, Sexer H, Ferreiro G, et al. Neonatal administration of high-dose intravenous immunoglobulin in rhesus hemolytic disease. J Perinat Med 1995;23:443-51

6. Alpoy F, Sorici SU, Okuton V, et al. High-dose intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice. Acta Paediatr 1999;88:216-9

7. Gottstein R, Cooke RWI. Systematic review of intravenous immunoglobulin in hemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003;88:F6-10

8. Steven M. Peterec: management of neonatal Rh disease. Clin Perinatal 1995;22:561

9. Osborn LM, Lenarsky C, Oakes RC, et al. Phototherapy in full- term infants with hemolytic disease secondary to ABO incompatibility. Pediatrics 1984;74:371

10. Fraser ID, Oppe TE, Tovey GH, et al. Post-exchange anaemia in Rh hemolytic disease. Lancet 1964;2:1309

11. Hansen TWR. Mechanism of bilirubin toxidty: clinical implications. Clin Perinatal 2002;29:765

12. Berlin G, Selbing A, Ryden G. Rhesus hemolytic disease treated with high-dose intravenous immunoglobulin. Lancet 1985;1:1153

13. Besalduch J, Forteza A, Duran MA, et al. Rh hemolytic disease of the newborn treated with high-dose intravenous immunoglobulin and plasmapheresis. Transfusion 1991;31:380

14. Rubo J, Wahn V. High-dose intravenous gammaglobulin in rhesus- hemolytic disease. Lancet 1991;337:914

A. M. Miqdad, O. B. Abdelbasit, M. M. Shaheed, M. Z. Seidahmed, A. M. Abomelha and O. P. Arcala

Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia

Correspondence: Dr O. B. Abdelbasit, Department of Pediatrics, Security Forces Hospital, P. O. Box 3643, Riyadh 1 1 481, Kingdom of Saudi Arabia

2004 Parthenon Publishing. A member of the Taylor & Francis Group

DOI: 10.1080/14767050400009873

Received 23-12-03 Revised 20-04-04 Accepted 21-04-04

Copyright CRC Press Sep 2004

This essay explores the banal as a contemporary photographic aesthetic, examining banality in relation to notions of boredom and ennui. The “perceptual boredom” of the banal image-its resistance to emotional and critical engagement-is considered in relation to its content, style, and spatial structure.

In her classic text On Photography, Susan Sontag claims that photographic seeing has to be “constantly renewed with new shocks, whether of subject matter or technique, so as to produce the impression of violating ordinary vision” (31). For Sontag, photography represents a kind of “extraordinary vision,” a perception that continues to inform a great deal of photographic criticism. The past decade, however, has seen the emergence of a different kind of photographic aesthetic. In the words of Neville Wakefield:

Bad photography now reigns. [… ] It makes for good art at a time when good photography witnesses only the flow of technical virtuosity into addictive banality. With the demise of photographic authority, the former province of “photography” with its silver gelatin bureaucrats and legislative decrees has become something much more like a republic of photographic practice. […] Artists deliberately flout photographic convention to […] practice without a license. (239)

The work I will be examining here reflects a more prosaic approach to photographic seeing-a fascination with the everyday, a preoccupation with the vernacular, an “ordinary,” rather than an “extraordinary” vision. Rather than simply dismissing this as “bad photography,” however, I would like to examine the banal as an aesthetic category, as a motif and a mode of reception, and to look critically at the embodiment of the ordinary that lies at its heart.

Photography’s fascination with the ordinary is nothing new, but the crystallization of this fascination into a curatorial and editorial aesthetic is a relatively recent development. Such recent exhibitions as Reality Check at the Photographer’s Gallery and Cruel and Tender at the Tate Modern introduce to a larger public a number of aesthetic preoccupations that have been visible in exhibition practice for the past decade. Grounded in the allied motifs of boredom, repetition, and inertia, these concerns are also evident in current critical writing on photography. “Banality” and “the banal” show up frequently in accounts of the work of Thomas Ruff, Martin Parr, Richard Billingham, and others; they also feature thematically in the retrospective attention paid to photographers like Robert Adams, William Eggleston, and Stephen Shore. Fashion and advertising have been quick to take up the mass appeal of the banal image (it surfaces in the “snapshot aesthethic” of photographers like Terry Richardson and Jeurgen Teller), and to push its boundaries; arguably, heroin chic was born out of the morbid allure of drug culture as seen through the eyes of photographers like Corrine Day, Davide Sorrenti, and Nan Goldin.

“Banality” and “the banal” are not easy terms to pin down with precision, and it is unlikely that there is any advantage to be gained in doing so. Although the term banal can be used to categorize a broad selection of work, it is not intended here as a totalizing description, nor as a pretext for eliding other important concerns-political, aesthetic, or otherwise-in the work of individual photographers. As Meaghan Morris points out, however, banality is part of the modern history of taste, and generally indicates a negative value judgement (12). Banality, she claims, is a sensibility intrinsic to modernity; certainly the history of photography is littered with comments on the banality of photographic images, most of them intended in a pejorative sense. As an aesthetic category, however, and as a means of challenging the prejudicial bias that still characterizes the term, banality, as I understand it, suggests something more specific to postmodernity and to contemporary photographic practice.

In common parlance, an aesthetic is frequently used to indicate a theme or motif uniting a group of works. Though this definition lacks theoretical precision, it is a useful starting point for unpacking the notion of the banal on the level of signification. Banality is a problem of late capitalism, a creation of macroeconomics, and an effect of material culture. Closely bound up with notions of boredom and ennui, the banal is a kind of shorthand for those routines and value systems of high capitalism that are as annoying and trivial as they are obligatory. As a photographic aesthetic or style, banality could be described as a kind of postindustrial realism, a turn away from the spectacular and an often pitiless focus on its antithesis. It pans out in images as an obsession with the mundane facts of life under Western capitalism and the bland, omnipresent world of commodity culture. This is no dream world infused with myth, however, where the trivial becomes an object of reverence, but a world of unrelenting monotony, where the everyday is rarely allowed to rise above its own insignificance. Banality, as Goldstein remarks, is “the antithesis of originality” (82); as a photographic aesthetic, it is less about the transformation of the everyday into the fantastic than it is about its ordinary re-presentation.

This ordinariness is part of the way that the banal is manifested on the level of reception. Banality is linked, as I will show, to the conventions of vernacular photography-the throwaway aesthetic of the snapshot, the bland familiarity of the photo-booth portrait or the passport photograph-and to the “visual economy of repetition” (Petro 83) that characterizes these types of images. Here, as I will argue, our cultural overfamiliarity with certain kinds of images acts as a deterrent to critical engagement, and banality, as a mode of response, takes on the shadings of indifference and frustrated desire. Banality, according to Petro, is “about both too much and too little, sensory overload and sensory deprivation, anxieties of excess as well as anxieties of loss” (81). All of these extremes are actualized in the banal image, in its resistance to engagement, and in its insistent presence as an ordinary thing, a piece of consumer ephemera.

As a philosophical category, aesthetics was originally conceived as a way of dealing with the domain of sensuous experience, that unstable mediatory category between the corporeal realm of the body and the abstract domain of the mind. Aesthetics is a matter not simply of content but of presentation, and, as such, it has more complex phciiomciiological connotations. The final sections of this paper will focus on the specifics of the event of seeing and on the nature of viewer’s encounter with the image. When judging an image in terms of our experience of it, “banal” and “banality” usually indicate work that is in some way unengaging. Taking this refusal as a starting point, I will examine banality as a particular attitude towards a photographic image, a type of aesthetic effect.

The affinity for the superficial that marks the banal image on the level of content is reduplicated on the level of experience, in the refusal of the image to acknowledge the mobility of the viewer’s gaze. This frustration of the look can be understood in phenomenological terms as a kind of “perceptual boredom.” The latter is an effect specific to the perspectival image, the consequence of a particular use or manipulation of photographic space. The static, “depthless” space of the banal image assumes a viewing body bereft of sensual pleasure, and acts to suppress the affective-and potentially political-dimensions of the viewer’s encounter with the image.

As a literary theme, boredom dates back to Greek and Roman times, but its recent history is intricately bound up with that of the modern subject. In the West, boredom entered the popular imagination in the latter years of the nineteenth century, the new-found affliction of a burgeoning middle class that found itself with too much spare time on its hands. In nineteenth-century discourse, boredom referred to the “unbearable experience of being in the everyday.” By the early twentieth century, psychoanalytic discourse had allied boredom with depression, anger, and the possibility of clinical release from these symptoms, while critical theory understood it “in relation to leisure, and also to waiting, to an expectation or future orientation of subjectivity devoid of anxiety or alienation” (Petro 81). In both cases, boredom (or dsoeuvrement) is a temporal concern; a forced inactivity of mind; a temporary slowdown of the normal flow of perception. Wc experience this kind of boredom standing in a queue, waiting for a train, dealing with the tedious imperatives of modern life. Boredom of this nature is an effect of external circumstances, and normally goes away when these circumstances change.

Ennui, on the other hand, is a more complex existential condition. The term stems from the Latin odium, to hate, but from the early middle ages, ennui has had two essentially contradictory meanings. On the one hand, as Kuhn relates, “it designated something, often of a petty nature, that proved vexatious and irritating. […] On the other hand [… ] the word ‘enui’ is used to designate a profound sorrow”(5-6). Ennui combines trifling irritation with deeper spiritual distress, and, unlike boredom, it is not necessarily linked to external circumstance. It is an ongoing, chronic condition, attacking body and soul; it is the “stare of emptiness that the soul feels when it is deprived of interest in action, life, and the world […]” (Kuhn 13).

Time moves slowly for those in the grip of boredom or ennui, and this torpor is part of the vocabulary of the banal. In the work of Sarah Jones and Hannah Starkey, apathetic teenagers, usually girls, languish, slack-limbed and expressionless, in dimlylit cafs, nondescript interiors, and anonymous shopping malls. The cheerless Department of Health and Social security (DHSS) waiting rooms depicted in Paul Graham’s Beyond Caring series (1985) present boredom as the inevitable consequence of a hopelessly overextended social welfare system, while Corinne Day’s Diary (2000) frames ennui as both the incentive and the effect of alternative lifestyle choices. In these images and others like them, individuals stand apart from the world, separated from it by a screen of indifference. It is not that they actively refuse to invest in their surroundings; they simply do not have the energy. There is nothing decisive about the moments shown in these images. Instead, they capture indecisive moments, identical in their monotony to those that came before and those that will likely follow. Here, the photograph functions not as a register of the extraordinary, but as the index of a chronic and invariant condition.

It is clear that there is a good deal of room for semantic slippage between “boredom,””ennui,” and “banality,” and it will be difficult to avoid reproducing this imprecision at some points in the following discussion. All three terms are historically specific, however, and there are important distinctions between them. Boredom and ennui are emblems of early modernity, born out of shifting labour patterns and the novelty of unfilled time. Banality proper is a creature of late- and postmodernity, a feature of a late capitalist culture where empty moments are no longer a novelty, but a void to be filled. Banality and the banal are descriptive of the ways we fill this time, and of the objects with which we fill it. To borrow Rick Poynor’s fluent idiom, boredom is the “existential corollary of excess” (22). It engulfs the subject in a world that has lost its meaning, and this loss is both a spiritual and a phenomenological one. If boredom and ennui represent the exhaustion of the soul, a private concern, then banality is the tangible, communal substrate of this exhaustion: where ennui is about too much time, banality is about too much stuff.

As a cultural condition, banality is bound up with the material processes of commodity production. Home appliances, commuting, frozen dinners: necessities of modern life, these things also embody a kind of vacancy in the phenomenological register. Banal objects lack anima. Most of the time, we do not even register them; they hold our attention only when their presence or absence becomes vexatious. These sorts of mundane objects show up again and again in recent photography-in images by David Bate (his Zone series, 2002), Nigel Shafran (his Washing Up, series, 2000), John R. Taylor, Wolfgang Tillmans, and many others-and our relation to them is one of habit. It is tempting to think of the banal along the same lines as kitsch. Like Greenberg’s nemesis, the banal is “mechanical and operates by formula”; it is the “epitome of all that is spurious in the life of our times”. Unlike kitsch, however, the banal does not aspire to the status of “ersatz culture” (Greenberg 10). Lacking the ambition and the brazen, seedy sensuality of kitsch, the banal does not even register on the cultural scale. It is embedded in material culture, but its proper domain is that of the unconsidered. Banality goes hand in hand with superabundance and mindless consumption, with things and obligations so fixed in necessity that their presence has become anaesthetic. Numbing the senses and paralyzing the imagination, banality is the cut-price plastic materialization of the “crisis in perception” that marked modernity.

1. John Taylor, Bold 3, 1989 (courtesy of John Taylor).

Though banality is grounded in material culture, it cannot be reduced to objects per se. It is more useful to think of it as a feature of postmodern life, a consequence of all the rituals and transactions that have grown up around stuff-locating it, paying for it, moving it around, showing it off, breaking it, getting rid of it. The archetypes of banality, as Goldstein points out, are forged in the “disposable venues” of postindustrial culture (81); they are born in shopping malls, dollar stores, and mail-order catalogues, and feed on an endless cycle of unfulfilled and unfulfillable desire.

In images, banality is often signified as a marriage of material excess and spiritual destitution. It is epitomized in the work of Martin Parr. His images speak not of the heroism of daily life, but of its banality, the “boredom of plenty.” They are filled with nameless, ubiquitous reminders of consumer excess-“synthetic, garish, glutinous, purulent, obscene”-and peopled with the casualties of advanced capitalism (Poynor 18-20). Adrift in a sea of abundance, Parr’s subjects play out their various routines and obligations with a pliant indolence that often borders on desperation (see Plate 9 in colour section). Hannah Starkey’s work is filled with a similar ambience: in one image (Untitled, October 1998), a young woman regards herself spiritlessly in a changing- room mirror, wearied by the uniformity of the garment she is trying, or by the empty ritual of purchasing it, or maybe both. Bored with life, bored with things, these subjects hold on tightly to “the pretence of aesthetic experience [… ] [living] an artificially extended existence that has lost its dignity” (Masterson 57). In Lesley Shearer’s Women and Men series (1998), intimate relationships take on the quotidien status of the environments in which they are set; here, even human emotions disappear below the horizon of the commonplace.

Of course, this is not the first time that photography has engaged the domain of the everyday: Paul Strand, Edward Steichen, and Edward Weston are among those who shared photographic modernism’s fascination with mass produced objects. Pop art’s fascination with the banal was equally sanguine and ostensibly more accessible; more recently, artists like Jeff Koons have adopted banality as leitmotif of post-modernily. There is an upbeat excitement in Pop that is missing in the postmillennial banal, though, and it generally lacks the satirical edge of Koons, who eulogizes banality in such elaborate fashion that it no longer warrants the label.

Parr’s work has been criticized as “gratuitous and cruel,” and he has been condemned for his tendency to collapse the everyday into the abject: “Where a photographer like Cartier-Bresson instinctively sought the good in people, producing dignified, celebratory images of everyday life, Parr rubs the viewer’s nose in squalor, tackiness, affectation and monotony” (Poynor 17). There is an undeniable cynicism in Parr’s vision, an inclination to frame the banality of everyday life as a combination of boredom and powerlessness. A similar sensibility, coloured with the pathos of disappointed longing, pervades Rineke Dijkstra’s portraits of young clubbers (Buzz Club, Liverpool, 1995), and images like Bertien van Manen’s Dancing Couples, Grooves’ Bar, Shanghai, 2001. Here, banality transcends its customary demographic, the middle aged suburbanite, and shows itself as an affliction of urban youth culture as well. These images foreground the totalitarian quality and sense of oppression that characterize late capitalist culture; they show a civilization in a state of economic and spiritual decline, and a newly underemployed middle class who are “not only earning less than their parents, but having less of a good time.” (Masterson 57).

Despite this, there is a kind of comfort in the banal, a strange serenity in the denial of individuality that it connotes: “When objects radiate-or when people project-banality, we can feel reassured. It’s some sort of sublime comfort to lull in the divestiture of distinction they provide” (Goldstein 81). Rather than a threat to the subject, banality acts as a shield; it mitigates against the trauma of everyday life. Like neurasthenia, it brings about a “disintegration of the capacity for experience” (Buck-Morss 19). Here, however, this dysfunction is not simply a reaction, a compensatory response to sensory overstimulation, but an imperceptible degeneration, a painless slide into a state of “luminescent emptiness,” a way of making tolerable the soul- destroying uniformity of life under late capitalism. Particularly in Day’s work, ennui is worn like an emblem of rebellion, and the daily round of life consists of little more than the replacement of one form of mental inertia with another (Ted at Home [1995]; Tim and Tara at Home, Stoke Newington [1999]). Oblivious and untouchable, Day’s subjects advocate a politics of glassy-eyed refusal; here, anti-capitalist insurrection takes the paralytic form of doing nothing at all.

Banality, argues Richard Goldstein, has its aesthetic roots in advertising (77). For the most part, however, the banal image lacks the spectacularity, or at least the aspirations to spectacularity, that distinguishes conventional advertising imagery. Though it may be responsible for popularizing this aesthetic, I would suggest that the roots of the banal sensibility lie less with advertising than they do with vernacular photography.

Vernacular images, broadly speaking, are those that “preoccupy home and heart but rarely the museum or the academy” (Batchen, “Vernacular Photographies” 262). Craig Owens has suggested that vernacu\lar photographies (the plural is intentional; there are many different genera within this classification) constitute art photography’s parergon-that category of images which determines what art photography is not (in Batchen, “Responses to a Questionnaire” 262). Taken most often, but not exclusively, by amateur photographers, vernacular photographs are not generally intended for public display. Rather, they are produced and consumed as part of a prescribed set of social activities, and come with their own set of aesthetic standards. In part, these standards are grounded in the legibility of the image. Keeping still, holding the camera straight, keeping one’s finger away from the lens, photographing in adequate lighting conditions, etc.-all of these “encompass an aesthetic which must be recognized and admitted so that transgression of its imperative appears as a failure” (Bourdieu 165).

Social function also plays a role in defining what Bourdieu characterizes as the “mass aesthetic” of vernacular imagery. In many cases, the full significance of such images is limited to those who understand their context. Personal photographs, for example, “expect to be understood within an interpretive community, a group of users who share the same understandings of pictures which record and confirm valued rites of passage and culturally significant moments” (Holland 153). Other types of vernacular imagery, such as passport photographs, serve a more civic function. Both roles presuppose a more or less uncritical acceptance of the photograph as a “message without a code,” and both types of images share a kind of manifest explicitness. Concerned primarily with re-presenting what was seen, as it was seen, the vast bulk of vernacular imagery deliberately avoids formal experimentation or aesthetic novelty. Instead, it objectifies what Petro has termed a “visual economy of repetition” (83)-the perceptual boredom of the already seen.

Thomas Ruff’s portraits mimic the deadpan style of the passport image or mug shot. Taken in a studio setting, they conform to the same invariant formula: subjects are posed from the shoulders up, against a neutral background, looking directly and expressionlessly into the camera. This stripped-down style has been widely adopted by other photographers, though they may include coloured backgrounds (Marie-Jo Lafontaine’s Pandemonium series, 1998), or pose the subject in the street (Jitka Hanzlov’s Brixton series, 2002; Tillmans’s Annie, Marylebone Flyover, 1993) or in their home (Tillmans’s Alex in Her Room, 1993; Julia, 1991). Even in the latter two strategies, however, the subject’s surroundings seldom succeed in transcending the anonymity of the studio background, and one gets the impression that they are not meant to. A subtly different visual economy of repetition is at work in the “snapshot” aesthetic, in the apparently ingenuous vision of photographers like Goldin, Day, Teller, and Billingham. Technically undistinguished, their work situates itself in the domain of the vernacular by assuming the mediocrity, and the ersatz neutrality, of the underachieved image. Here, the banal manifests itself as an “aesthetics of disappointment” (Wakefield 244); it is embodied in the very unremarkableness of these images, and in the fact that they fail, for the most part, to fulfill the social functions they suggest. Ruff’s images may look like passport photos, but they deliberately reveal very little about the sitter’s identity. Billingham, Day, and Goldin invite the viewer into their world not as a participant, but as a voyeur; there is a stubborn opacity to their images that even the seeming intimacy of first-name titles like Day’s Tara at Home, 1994, or Goldin’s Gina at Bruce’s Dinner Party, 1991, cannot overcome (see Plate 10 in colour section).

Banality is characterized by “an enigmatic surface, a willed simplicity that generates contemplation of emptiness” (Goldstein 81)- a kind of ennui of vision. Certainly, the calculated informality of the vernacular style seems to willfully resist critical engagement or closure. This fondness for the vacuous has also been evident in recent design and advertising as a trend for visually impoverished images “which [appear] to lack any semblance of an interior life” (Poynor 79). For Gavin Murphy, this unwillingness or inability to stimulate critical thought cuts right to the heart of the aesthetics of the banal (3). In some cases, this refusal is quite deliberate: Ruff, for instance, goes to considerable lengths to assure that his portraits have as little psychological depth as possible. Teller submerges his celebrity subjects in willfully mundane environments and situations (Stephanie in Playroom, Connecticut, 1999, and OJ. Simpson, Miami, 2000); other images are filled with stock poses and amateurish mistakes (Teller’s Lola and Snow White, Disneyland, 2000; Day’s Canned Beach, 1994). Whether it is articulated through shoddiness of technique or in the studied superficiality of subject matter, this refusal often translates into a tendency of the surface of the image to preside over its content in a kind of self- obsession that discourages the viewer from moving beyond the glossy skin of the print. In the case of Reality Check, this shallowness became the subject of the exhibition itself. Though it claimed to assert “the potency of the world as a subject for photography while simultaneously exploring the medium’s potential” (Bush 4), Reality Check seldom moved beyond the narcissism of the self-consciously “photographic.”

At its inception and throughout its early years, photography was understood as an instrument of transformation, a democratizing tool that conferred notability on whatever it recorded, transfiguring substance into image. This is not the case in the work discussed here, which seems, perversely, to work against photography’s transformative potential. Rather than raising the status of the objects they depict, the images themselves aspire to the status of objects. Batchen points out that vernacular photography depends upon the presence of the image as an artifact; as something that has “volume, opacity, tactility and a physical presence in the world” (“Vernacular Photographies” 263). Here, however, this tendency is pushed to its logical limit. Refusing the transcendency of the pure image, the banal photograph instead embraces its position as an undifferentiated consumer object. Without the gallery wall to support it, the banal image risks disappearing into the ranks of the same commodities whose very mundanity it mocks.

The fact that the banal image points towards its own status as object suggests that the aesthetics of the banal be approached not just in terms of what we read in the image, but of how we read it. The following section will re-examine the theme of superficiality, but here, my concern will shift from the question of representation to the act of reading itself-to the nature of the aesthetic encounter, the way that the image operates, and the kind of affective response it produces in the viewer.

Affective response is difficult to describe or quantify. In part, it refers to the variety of emotions that are stirred up when we experience an artwork, emotions which are not always easy to put into words. This inarticulacy or “muteness,” and the possibility of finding the means to describe it with language, is the motivation behind Peter De Bella’s investigation of affect in his Art Matters. Brian Massumi is equally fascinated by the difficulty of finding a cultural-theoretical vocabulary specific to affect, defining the latter in terms of the subject’s transitional power, its potential to exceed or “perform its way out of” pre-existing cultural codes. This potential, he argues, is grounded in the body, and contingent upon the extra-discursive or unassimilable character of affective response (3).

Both of these approaches, nonetheless, suggest that the affective dimension of an aesthetic encounter is, in part, a function of an individual’s material encounter with an object, and it is the mutuality or reflexivity of this exchange that interests me here. More specifically, I am concerned with the kind of look that the banal image anticipates-its presence and presentation as something “to be looked at”-and with the lexicon of feeling that this opens up. In the case of the banal image, this lexicon would appear to be a fairly limited one. This limitation arises not because we lack the means to describe the experience, but quite simply because we do not feel compelled to do so, and this reluctance is something that the banal image seems to call for. Faced with banality, we are asked to do nothing. The perceptual boredom of the “already seen” is played out on the level of the encounter with the image, and here it is a function of a specific treatment of photographic space.

The vernacular dimension of banality suggests a specific, and highly conventionalized, way of understanding the space of the photographic image. Pierre Bourdieu has suggested that the protocols of linear perspective function as a sort of “canonical aesthetic” within vernacular photography (163). A Renaissance “discovery” that has attained paradigmatic status in Western culture, linear perspective continues to shape thought and perception, remaining “resolutely unembarrassed [… ] by being declared obsolete” (Damisch xx). Charged with the illusory qualities of truth and objectivity, our predisposition to read photographic images according to this system has granted linear perspective the status of a “social definition of an objective vision of the world” (Bourdieu 164).

Reading a perspectival image nonetheless involves a certain investment of the self in its virtual space. Using the example of history painting, Louis Marin shows how iconic propositions in the image are converted into narrative ones as a result of specific operations involved in the contem\plative process. The archetypal narratives communicated in history painting are of course nothing like the more open-ended themes in the images presently under discussion. Although historical paintings and contemporary photographs involve different kinds of competence in deciphering their meaning, I would like to suggest that both entail a similar kind of “performance” on a structural level. The “act of reading” involves more than just unpacking an image semiotically in order to identify its content. It is also an embodied encounter, and as such it comprises particular effects-affective responses or intensities- that language cannot properly describe. Intensity or affect is embodied not in conscious thought, but in autonomie reactions, “outside expectation and adaptation, as disconnected from meaningful sequencing [and] narration as it is from vital function” (Massumi 24- 5).

Though it is commonly held that images constructed in perspective assume a static, monocular gaze, such images are in fact designed for an active look. The narrative propositions of an image are staged within its illusory three-dimensional space. It is here that the temporal diachronic sequences of the story are displaced onto the synchronie “atemporal” order of representation, distributed around a “central represented moment” which it is the viewer’s task to unpack. The latter displacement is, as Marin remarks, a structural one, involving the “lateralization” of the dimension of pictorial depth: the perspectival structure of the image enables the conversion of the image’s iconic propositions into narrative ones by inviting the eye to move sequentially “into” the image from foreground to horizon. The perspectival image opens up a “path of reading” for the subject, and in this sense, it functions as “a metaphor of the formal apparatus of enunciation” (Marin 313). As Hubert Damisch claims, the “formal apparatus put in place by the perspective paradigm is equivalent to that of the sentence, in that it assigns the subject a place within a previously established network that gives it meaning, while at the same time opening up the possibility of something like a statement.” (xxi). In order to read a perspectival image, in other words, the subject must invest in it both spatially and temporally. Rather than just a two-dimensional surface, the image is encountered in depth, as a field of potential action, and it is this potentiality that forms the basis of affective response.

David Bate has described perceptual boredom as “a question of what one does with space.” In circumstances where there is “nothing to see,” he argues, “it is not that there is not anything to see, rather that the subject cannot see it. Vision is colonized, inhabited by boredom” (6). This colonization is both a spatial and a temporal concern, and it shows up in literary works as well, where ennui is actualized in the time and space of the narrative and in the themes of enclosure and confinement (Kuhn 5). Using the example of Proust’s Remembrance of Things Past, Kuhn shows how ennui warps not just the subject’s sense of time, but their sense of space as well, distorting the normal apprehension of distances and proportions (266). Faced with a banal image, the effect on the viewer/reader is similar: a kind of perceptual stasis, a frustration of the act of reading not simply on a semantic or a semiotic plane but on a structural one. This frustration is played out as a kind of “lack of depth,” an obstacle in the path of reading.

It is this occlusion of space and time that lends many of Robert Adams’s images their peculiarly lifeless quality. In What We Bought: The New World (1970-74), the stifling, characterless interiors of suburban tract homes quash the activity of the eye, leaving it to slide aimlessly across bare white walls or terminate pointlessly in empty corners. Shot in the Denver metropolitan area, the landscapes in this series invoke the same kind of perceptual inertia: rather than acting as an enticement to the look, the horizon serves only to separate a bland, undifferentiated ground plane from a similarly featureless sky. Adams pictures the American West as a field of manufactured desires, where ideals of freedom are lived out in cookie-cutter fashion in endless rows of tract housing. The two- dimensionality of the American dream is actualized in the images themselves, in the way that they confine the gaze within a narrow wedge of space and time. Lynne Cohen’s interiors are equally dense in structure. Almost without exception, the images in her 1987 book Occupied Territory hold the eye captive in empty and indifferent institutional settings. The eerie silence of these images gives the environments the feeling of archaeological relics rather than living- or livable-spaces.

Institutional architecture lends itself well to the theme of inertia. Ori Gersht’s The Knowledge Factory (1999-2001) depicts school buildings from the 1950s and 60s, dropped like cinderblocks into the center of the frame. Positioned purposely in the middle ground of the image, they partition the space like a wall, dividing it into two volumes-a shallow frontal space, and an expanse beyond that is left unavailable to the eye. Instead of a deep space, the viewer encounters a slippery surface, or, at best, a sort of a shadow-box. Rather than inviting the viewer to enter the virtual space and time of the image, these photographs strand them in the hopelessly truncated here and now of their encounter with the image.

This perceptual stasis is characteristic of banal space, and at times it takes on a specifically political dimension. The images in Tom Hunter’s Holly Street Tower Block Project series (1997-98) confine the gaze within the cramped interiors of an East London council block (see Illus. 2). Made in collaboration with tenants in the months prior to the demolition of the building, these images speak simultaneously to the institutional uniformity of the interiors and to the personalities of their occupants. It was the latter that attracted Hunter, and this series was intended, in part, to comment on the determination of the tenants to create homes out of the bleak dwellings they have been allocated by a moribund social housing system. It is easy, nonetheless, to misread images like these, to see the restricted space of the image as the setting for similarly inert and overdetermined lives. Other projects tread a similarly fine line between individuality and conformity. John R. Taylor’s Ideal Home (1989) details the minutiae of suburban life in a series of beautifully detailed yet stiflingly claustrophobic black and white images. Magda Segal’s London at Home (1993) and Southampton’s Women (2000) series deal with similar subject matter. For the latter project, Segal photographed the inside of her subject’s homes, and of their refrigerators as well (see Illus. 3). Sparse or cluttered, squalid or spotless, both interiors speak volumes about the occupant’s lives. Intentional or not, all of these projects share an ambiguity of purpose: a combined sense of intimacy, respect, and melancholia that is part of their complexity and their appeal.

2. Tom Hunter, No. VIII from the Holly Street Tower Block Projects Series: Residents in Cedar Court, 1997 (courtesy of Jay Jopling/White Cube [London]).

In these images, late capitalist culture is set in an environment that consists of little more than depthless interiors and profoundly mundane landscapes. In all of them, photographic space is used as a way of arresting the gaze. Rather than opening up the space of the image as a field of potential action, it becomes an enclosure, a trap for the eye, a perceptual void. Georg Lukacs distinguished between “description” and “narration” in representation, and the insistence on closing down narrative pathways in the image may, as Emma Dexter argues, simply reduce it to the function of quiet description; banal images, for her, are those that simply speak “undemonstratively, not drawing attention to themselves” (16). Lucaks also claimed, however, that narrative alone was capable of encouraging empathy, and the lack of diegetic movement in these images means that their effect is profoundly anaesthetic: suppressing affective response, they threaten to lock the viewer into a specific, and ideologically expedient, way of relating to images.

Aesthetic discourse is thoroughly bound up with ideology; it is concerned with “texturing, packaging, fetishizing, and libidinalizing” social reality, and with naturalizing or concealing the operations of power (Eagleton, “Capitalism” 93). Though it may come packaged as nothing more ominous than “bad” photography, banality as an aesthetic is born out of specific institutional processes, ideological preferences, and vested interests, and is itself implicated in the production and reproduction of ascendant discourses. Ideology, in turn, becomes aestheticized when it presents itself in the form of habit, sentiment, or affection-when dominant ideals are lived out as custom or common sense, in seeming harmony with the body’s spontaneous impulses. Living out the aesthetics of the banal on the level of habit means, in other words, inscribing the body with a “subtly oppressive law” (Eagleton, Ideology, 21).

3. Magda Segal, Fridge, from the series, “Southampton’s Women,” 2000 (courtesy of Magda Segal).

These images frame “ordinary” vision as bored, debilitated, and depthless. They make themselves available to an exhausted and superficial gaze, a viewer for whom looking has become little more than another consumer habit. Like any aesthetic discourse, banality is a means of habituating viewers to a particular kind of encounter with an image. On the one hand, the candor of the banal might be understood as a leveling of the playing field, a way of democratizing visual experience: Koons works the banal on this plane. On the other hand, institutionally sanctioned banality \naturalizes fleeting and contentless encounters with images. This is the banal as it is embodied in the world of advertising, and it represents the commodification of culture at its most cynical. It also sanctions the sort of “love ’em and leave ’em” encounters with art that we find in the museum, where visitors are apt to spend as much time drinking coffee and contemplating prices in the gift shop as they are looking at the artworks. Disinclined to pass judgment on what they see, audiences, for their part, learn to leave such tasks to those more qualified-writers, curators, and other cultural pundits. When the temporary distraction of the active look starts to shift towards this more permanent kind of paralysis, perceptual boredom risks turning into perceptual ennui. Commenting on the sublime banality of photography in the age of video, David Campany remarks that “in its apparent finitude and muteness, [the photograph] can leave us in permanent limbo, obliterating even the need for analysis and bolstering a kind of liberal melancholy that shuns political explanation like a vampire shuns garlic” (132). Photographic seeing is given over to the consumption of corporate kitsch, and the democratization of viewing here amounts to little more than a surrender of individual critical agency.

At the same time, however, the banal aesthetic confronts us with our own reluctance to spend time with images, and with the superficiality of our customary relationships to them. Given this, maybe the museum is not such a bad place for this sort of work. Presented in a context that traditionally requires the viewer to take a bit of time, banal images ask the viewer to redirect their focus, to think of the photographic process as well as the product. The value of bad photography, argues Wakefield, surfaces when the image itself is framed as “a way of seeing rendered as strategy rather than goal” (244; emph. mine). This goes some way to explaining the frustration of looking at an exhibition like Reality Check, which failed, for the most part, to engage with the performative dimensions of image making. The visually uninspiring portraits that comprise Shizuka Yokomizo’s Stranger series (1999- 2001), for example, take on an entirely new dimension once the process behind them is foregrounded. Yokomizo wrote anonymous letters to the inhabitants of ground floor flats in a number of cities, asking them to stand in their front room at a specified time so that she could photograph them through the window. Participants were given a copy of their photograph for their efforts, but never met the photographer. Not everyone responded to her request, and the resulting images become all the more poignant when we know that their subjects represent the minority who were willing to relinquish their privacy and put their trust in the hands of an unseen stranger with a camera.

Banality can also be understood as a form of resistance to the institutionalization of photographic vision. Both Kracauer and Benjamin saw the “cultural negativity” of film and photography as means of “subverting the bourgeois cult of art and its aesthetic of illusionist absorption” (Petro 85); similarly, none of the photographers discussed here seek legitimization within the formal traditions of photography. As such, claims Wakefield, they stand a chance of retaining “a share in the public culture of [their] time” (246) and, perhaps, of engaging with the transformational power of the banal.

The emblems of banality speak volumes about the longings and desires of the postmodern subject. Disputing the politically inert critical strategies of parody and irony that characterized postmodern photographic practice, Goldstein argues for the need to confront our desires rather than ignoring them, sneering at them, or disengaging from them (81). Pop art engaged with banality in a transformative way; part of Claes Oldenberg’s project, as Dick Hebdige understands it, was to “make hostile objects human.” As I have argued above, the art institution can still provide the possibility for this sort of critical encounter with banality, and for the transformation of perception that it enables. Consciousness opens up alongside changes in perception, argues Goldstein, thus “banality means one thing when it is embedded in Family Ties and quite another when it surfaces in art. Then the sensibility of “capitalist realism” can become transcendence-which is why banality is so potentially useful as a style” (81). Aesthetic engagement with the banal, in other words, has the capacity to open up a different kind of vision, an attention to the material circumstances of looking, which might then be transformed into ethical and political action. Understood in terms of such transformational possibilities, the aesthetics of the banal has the potential to add up to more than the sum of its parts.

WORKS CITED

Batchen, Geoffrey. “Vernacular Photographies.” History of Photography 24.3 (Autumn 2000): 262-271.

_____ . “Vernacular Photographies: Responses to a Questionnaire.” History of Photography 24.3 (Autumn 2000): 229-231.

Bate, David. “Boredom and Baroque Space.” Boredom. CD-ROM. Cambridge, UK: Cambridge Darkroom, 1997.

Bourdieu, Pierre. “The Social Definition of Photography.” 1965. Visual Culture: The Reader. Eds. Jessica Evans and Stuart Hall. Thousand Oaks, CA: Sage Publications, 1999. 162-180.

Buck-Morss, Susan. “Aesthetics and Anaesthetics: Walter Benjamin’s Artwork Essay Reconsidered.” October 62 (Fall 1992): 3- 41.

Bush, Kate. “Reality Check: Recent Developments in British Photography and Video.” Reality Check, [exhibition catalogue] Photographer’s Gallery/British Council, 2002. 4-10.

Campany, David. “Safety in Numbness.” Where is the Photograph? Ed. David Green. Manchester, UK: Photoworks/PhotoforuM, 2003. 123- 132.

Damisch, Hubert. The Origin of Perspective. Trans. John Goodman. Cambridge, MA: MIT Press, 1995.

De Bolla, Peter. Art Matters. Cambridge, MA: Harvard UP, 2001.

Dexter, Emma. “Photography Itself.” Cruel and Tender [exhibition catalogue]. Eds. Emma Dexter and Thomas Weski. London: Tate Publishing, 2003. 15-21.

Eagleton, Terry. “Capitalism, Modernism, and Postmodernism.” Art in Modern Culture: An Anthology of Critical Texts. Eds. Francis Frascina and Charles Harrison. London: Phaidon, 1992. 91-100.

_____ . The Ideology of the Aesthetic. Cambridge, MA: Blackwell, 1990.

Goldstein, Richard. “Just Say Noh: The Esthetics of Banality.” Artforum (USA) 26.6 (Jan 1988): 77-82.

Greenberg, Clement. “Avant-Garde and Kitsch.” 1961. Art and Culture: Critical Essays. Boston: Beacon Press, 1989. 3-21.

Hebdige, Dick. “Fabulous Confusion! Pop Before Pop?” Visual Culture. Ed. Chris Jencks. London: Routledge, 1995. 96-119.

Holland, Patricia. “Sweet it is to Scan…: Personal Photographs and Popular Photography.” Photography: A Critical Introduction. 2nd ed. Ed. Liz Wells. London: Routledge, 2000. 117-164.

Kuhn, Reinhard. The Demon of Noontide: Ennui in Western Literature. Princeton, NJ: Princeton UP, 1976.

Marin, Louis. “Towards a Theory of Reading in the Visual Arts: Poussin’s The Arcadian Shepherds’.’ The Reader in the Text, Essays on Audience and Interpretation. Eds. Susan R. Suleiman and Inge Crosman. Princeton, NJ: Princeton UP, 1980. 293-324.

Massumi, Brian. Parables for the Virtual: Movement, Affect, Sensation. Durham, NC: Duke UP, 2002.

Masterson, Piers. “Anatomy of Boredom: Hannah Starkey.” Portfolio 29 (June 1999): 56-7.

Morris, Meaghan. “Banality in Cultural Studies.” Block 14 (1998): (10 Feb 2002).

Murphy, Gavin. “An Aesthetic of the Banal.” Source (10 Feb 2002).

Petro, Patrice. “After Shock/Between Boredom and History.” Discourse 16.2 (Winter 1993-94; special issue on Expanded Photography): 77-99.

Poynor, Rick. Obey the Giant: Life In the Image World. London: August Media, 2001.

Sontag, Susan. On Photography. Middlesex, UK: Penguin, 1977.

Wakefield, Neville. “second-hand Daylight: An Aesthetics of Disappointment.” Veronica’s Revenge: Contemporary Perspectives on Photography. Ed. Elizabeth Janus. Zurich: LAC Press, 1998. 238-247.

EUGNIE SHINKLE is a photographie artist and lecturer in Photographic Theory and Criticism at the University of Westminster, London, England. She has exhibited her photographic work in North America, Asia, and Europe, and has published articles in the fields of photography and digital culture.

Copyright MOSAIC Dec 2004

Abstract

Autoimmune inner ear disease is a well described entity. We report a case of sudden-onset sensorineural hearing loss in association with psoriatic arthritis, which has not been reported in the literature. The case satisfies the criteria for the presumptive diagnosis of autoimmune hearing loss. A high index of suspicion, with early diagnosis and aggressive treatment with steroids and/or immunosuppressive agents, is essential to prevent irreversible hearing loss. The condition of psoriatic arthritis must be added to the pantheon of autoimmune diseases that can lead to sensorineural hearing loss.

Key words: Autoimmune Disease; Hearing Loss, Sudden; Arthritis, Psoriatic

Introduction

McCabe first described the association of sensorineural hearing loss with autoimmune disorders in 1979.1 There have since been several reports in the literature of sensorineural hearing loss (SNHL) with autoimmune diseases like ulcerative colitis, rheumatoid arthritis, Wegener’s granulomatosis and giant cell arteritis.2-5 We report a case of sudden-onset SNHL with psoriatic arthritis, another autoimmune disease, but one whose association with SNHL has not been previously reported. The literature is reviewed, and we recommend the acceptance of criteria to help identify autoimmune hearing loss.6 Early diagnosis is essential in this treatable condition before hearing loss becomes irreversible.

Case report

A 62-year-old man presented with sudden-onset, right-sided hearing loss with poor speech discrimination and tinnitus. He had no vertigo. There was no preceding upper respiratory tract infection or head injury. He suffered from psoriatic arthritis, which had been diagnosed many years previously, and was well controlled with methotrexate. At presentation he was receiving methotrexate.

Clinical examination revealed normal tympanic membranes and a positive Rinne test in both the ears with the Weber lateralized to the left ear. Cranial nerve and neuro-otological examinations were normal. Pure tone audiometry (Figure 1) showed hearing thresholds of 50 dB. in the right ear (average thresholds at 0.5, 1, 2 kHz.) with normal hearing in the left ear.

Impedance audiometry showed normal compliance. Serum electrophoresis showed increased gamma globulins, and concentrations of C3 and C4 components of the complement system were raised, as was the erythroctye sedimentation rate (ESR) (73 mm/hr). The rheumatoid factor, antinuclear antibodies and ANCA tests were negative, as was the Otoblot test (antibodies to 68-kDa inner ear heat shock protein). A magnetic resonance imaging (MRI) scan of internal auditory meati, brain and cerebellopontine angle was normal.

The patient was treated with oral prednisolone (60 mg daily) for 3 weeks before tapering off and completion of treatment in the fourth week. At the end of the 4 weeks his hearing thresholds were nearly normal (Figure 2) and tinnitus had completely resolved. Three months later, the patient had not suffered any recurrence of hearing loss.

Discussion

The association between psoriatic arthritis and sensorineural hearing loss has not been described, although reports exist in the literature of toxic inner ear damage as a result of topical treatment of psoriatic arthritis with salicylates.7 Our patient did not receive such treatment. Autoimmune inner ear disease is a recently recognized entity. It usually presents as bilateral sensorineural hearing loss occurring over weeks to months. It is also associated in some instances with balance disturbance and tinnitus and is more common among middle-aged women. It is seen to occur in association with autoimmune diseases. Early recognition and treatment with steroids and/or immunosuppressive agents leads to recovery of hearing loss, at least in part,8 particularly in patients with mild hearing loss (

The inner ear is an immunoresponsive organ. These responses could be mediated via the immunocompetent cells recruited from either the endolymphatic sac or the systemic circulation. IgG is the predominant immunoglobulin found in the perilymph, with lesser amounts of IgM and IgA.9 Following an inflammatory injury there is entry of leucocytes from the circulation into the cochlea. The accumulation of leucocytes and local production of immunoglobulins incites an inflammatory reaction, resulting in degeneration of the organ of corti, stria vascularis and spiral ganglion, with resultant sensorineural hearing loss.10 A postulated mechanism for autoimmune inner ear disease is reversible damage to cellular components of the organ of Corti.6 Several other mechanisms have also been proposed. These include damage resulting from immune complex deposition and vasculitis, cross-reacting antibodies, T lymphocyte-mediated cytotoxicity, and low-grade tissue injury due to circulating pro- inflammatory cytokines in inflammatory bowel disease.3,11-13

FIG. 1

Pre-treatment pure tone audiogram.

FIG. 2

Post-treatment audiogram showing hearing improvement in right ear.

The complement system is activated, either through the classic or alternate pathway. It has been suggested that activation of the complement system is part of the systemic inflammatory reaction in which the inner ear demonstrates the only clinical dysfunction.10 This could explain the raised IgG, C3, C4 and ESR in our patient while also accounting for the absence of other systemic symptoms and negative immune markers.

It is interesting to note that laboratory diagnoses for autoimmune hearing loss are still inconclusive and nonspecific. Serological markers for active and inactive immune processes include antinuclear antibodies, ANCA, RA factors, antibody against type II collagen, and other auto-antibodies, including non-specific haematological tests like ESR and CRP. However, none of these are specific to immune disorders, unlike the serological marker for allergy, which is readily identified by a raised titre of total and specific IgE. A recent study demonstrated that there is no correlation between autoimmune sensorineural hearing loss and heat shock protein (HSP) 70 (antibodies to KHRI-3 cochlear protein [68 kDa]).14 This is unfortunate as this is the only test available for clinical use. Of course, HSP 70 is only one of many proteins cross- reacting against the inner ear in suspected immune-mediated hearing loss. Heat shock proteins can also be induced by a variety of stimuli, e.g. stress, ischaemia, free radicals and acoustic overstimulation.10 Measurement of these proteins would only support the diagnosis of immune-mediated hearing loss if occurring in association with systemic autoimmune diseases. Various immunological studies have tried to identify various antibodies that specifically cross-react with inner ear antigens,15-17 but this approach remains experimental at present. Unfortunately, as in the case described, the negative ANCA and HSP 70 (antibody to 68 kDa) tests do not preclude autoimmune mechanisms.

Studies have shown that hearing loss can be the only initial manifestation of autoimmune disease, as noted in polyarteritis nodosa.9 It can also occur in disease remission, as seen in ulcerative colitis.2 Furthermore, studies have shown that in systemic autoimmune diseases such as ulcerative colitis, systemic lupus erythematosus and rheumatoid arthritis, there is no correlation between sensorineural hearing loss, age, sex, disease duration or activity, articular and extra-articular manifestations and presence of auto-antibodies.9

The diagnosis of autoimmune inner ear disease is still largely presumptive. However, recent papers have proposed a diagnostic profile for immune-mediated sensorineural hearing loss.6 Major criteria proposed are: bilateral hearing loss, systemic autoimmune disease, raised titres of antinuclear or other antibodies, and complete recovery of hearing with steroid treatment. The minor criteria are: unilateral hearing loss, serum reactivity to HSP 70 and partial recovery of hearing with steroid treatment. The presence of three major criteria or two major and two minor criteria would support the diagnosis of immunemediated hearing loss.The patient we report had two major criteria, with evidence of raised immune function (elevated IgG levels, ESR and complement) and the presence of psoriatic arthritis, a well known systemic immune disease. In addition, the presence of two minor criteria in our patient (partial hearing recovery, affected unilaterally) would fit the diagnosis of autoimmune hearing loss.

A recent review of autoimmune hearing loss by the senior author (BNK)9 listed a variety of systemic diseases, including rheumatoid arthritis, but there is no mention in the literature of hearing loss with psoriatic arthritis. This case report illustrates the association of sensorineural hearing loss with psoriatic arthritis and this should be borne in mind by the otolaryngologist, as early and aggressive treatment with steroids may result in recovery of hearing.

* Case report of a patient with psoriatic arthropathy who developed sudden-onset mild-to-moderate sensorineural hearing loss

* The patient recovered on steroids

* The diagnosis is presumptive but based on existing criteria for immune-mediated sensorineural hearing loss

* Patients with psoriatic arthropathy may be prone to sudden or rapidly progressive sensorineural deafness; the prevalence of this is unknown

Referenc\es

1 McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1979;88:585-9

2 Kumar BN, Walsh RM, Wilson PS, Carlin WV. Sensorineural hearing loss and ulcerative colitis. J Laryngol Otol 1997;11:277-8

3 Weber RS, Jenkins HA, Coker NJ. Sensorineural hearing loss associated with ulcerative colitis. Arch Otolaryngol 1984;110:810- 12

4 Luqmani R, Jubb R, Reid A, Adu D. Inner ear deafness in Wegener’s granulomatosis. J Rheumatol 1991;18:766-8

5 Jacob A, Ledingham JG, Kerr AIG, Ford MJ. Ulcerative colitis and giant cell arteritis associated with sensorincrual deafness. J Laryngol Otol 1990;104:889-90

6 Garca Berrocal JR, Ramrez Camacho R, Milln I, Grriz C, Trinidad A, Arellano B, et al. Sudden presentation of immune-mediated inner ear disease: characterization and acceptance of a cochleovestibular dysfunction. J Laryngol Otol 2003;117:775-9

7 Maune S, Frese KA, Mrowietz U, Reker U. Toxic inner ear damage in topical treatment of psoriasis with salicylates. Laryngorhinootologic 1997;76:368-70

8 Summers RW, Harker L. Ulceralive colitis and sensorineural hearing loss: is there a relationship? J Clin Gastroenterol 1982;4:251-2

9 Mathews J, Kumar BN. Autoimmune sensorineural hearing loss. Clin Otolaryngol 2003;28:479-88

10 Garca Berrocal JR, Ramrez-Camacho, R. Sudden sensorineural hearing loss: supporting the immunological theory. Ann Otol Rhinol Laryngol 2002;111:989-97

11 Kumar BN, Smith MSH, Walsh RM, Green JR. Sensorineural hearing loss in ulcerative colitis. Clin Otolaryngol 2000;25:143-5

12 Kanzaki J, O-Uchi T Circulating immune complexes in steroid- responsive sensorineural hearing loss and the long term observation. Acta Otolaryngol Suppl Stockh 1983; 393:77-84

13 Brookes GB. Immune complex deafness: preliminary communication. J Roy Soc Med 1985;78:47-55

14 Yeom K, Gray J, Nair TS, Arts HA.Tellian AS, Disher MJ, et al. Antibodies to HSP-70 in normal donors and autoimmune hearing loss patients. Laryngoscope 2003; 113:1770-6

15 Mathews J, Rao S, Kumar BN. Autoimmune sensorineural hearing loss: is it still a clinical diagnosis. J Laryngol Otol 2003;117:212- 4

16 Harris JP, Sharp PA. Inner ear autoantibodies in patients with rapidly progressive hearing loss. Laryngoscope 1990; 100:516-24

17 Kastanioudakis I, Skevas A, Danielidis V, Tsiakou E, Drosos AA, Moustopoulos MH. Inner ear involvement in rhematoid arthritis: a prospective clinical study. J Laryngol Otol 1995;109:213-18

S. SRIKUMAR, D.L.O., M.R.C.S, M. K. DEEPAK, M.S., S. BASU, D.L.O., M.R.C.S, B. N. KUMAR, M.PHIL., F.R.C.S. (O.R.L.-H.N.S.)

From the Department of Otolaryngology, Royal Albert Edward Infirmary, Wrightington Wigan & Leigh NHS Trust, Wigan, UK.

Accepted for publication: 26 June 2004.

Address for correspondence:

B.N. Kumar,

Department of Otolaryngology,

Royal Albert Edward Infirmary,

Wigan Lane,

Wigan WN1 2NN, UK.

E-mail: [email protected]

Mr B. N. Kumar takes responsibility for the integrity of the content of the paper.

Competing interests: None declared

Copyright Royal Society of Medicine Press Ltd. Nov 2004

DAILY MAIL STAFF

The West Virginia Board of Medicine revoked the license of a former Raleigh General Hospital cardiologist because he performed scans he was not privileged to do.

Further, in a recent ruling, board members said Dr. Steven B. Hefter misrepresented to the hospital and to patients that he was “performing only those medical procedures that he had been given the authorization or privilege to do.”

Instead, he was performing peripheral angiographies during cardiac catheterizations.

The medical board said Hefter also failed to get consent from the majority of patients on whom he performed the catheterizations and failed to keep written records justifying treatment.

Hefter, whose current address with the board is Birmingham, Ala., also worked as a cardiologist at Greenbrier Valley Medical Center and at Summersville Memorial, Pocahontas Memorial and Summers County hospitals.

In other recent Board of Medicine business, the board:

* Set a disciplinary hearing for March 16 to 18, 2005, in a matter involving Dr. Iraj Derakhshan, a Charleston neurologist. The board investigated Derakhshan after Charleston Area Medical Center placed certain conditions on his privileges. Also, the board received complaints from two of Derakhshan’s patients regarding the use of Oxycontin.

* Set a hearing for Feb. 1 and 2 to determine whether the board should take disciplinary action against the license of Dr. Katherine Anne Hoover of Lost Creek.

* Set a hearing for April 6 regarding the license of Dr. Bradley Jess Richardson of Huntington, an internal medicine specialist, on a complaint that he videotaped a patient without her consent.

* Publicly reprimanded Dr. Christopher E. Ervin, an emergency medicine specialist whose address is Washington, D.C. The board said there were problems with notations of child support arrearage amounts on his license application.

* Put Dr. Douglas P. Bosack on probation for three years after his Ohio license was revoked, then reinstated, after he underwent treatment for alcohol dependency.

* Placed certain restrictions on the license of Dr. Susanne Choby for two years, including abstaining completely from the use of alcohol. Choby practices medicine in Morgantown.

* Publicly reprimanded Dr. Charles W. Snyder, Parkersburg psychiatrist, for failing to accurately report his continuing medical education to the board.

Contact writer Therese Smith at [email protected] or 348- 4874.

Benign primary bone tumors, including osteochondromas, rarely occur in the clavicle. We report an atypical case in which an osteochondroma developed in the medial part of the clavicle and caused thoracic outlet syndrome with primary subclavian vein thrombosis (Paget-Schroetter syndrome), brachial plexus paresthesias, and mechanical sternoclavicular pain in an otherwise healthy young man. To our knowledge, we are the first to report a case of thoracic outlet syndrome that was caused by an osteochondroma of the medial part of the clavicle. The two other medial clavicular tumors that have been reported in the literature were asymptomatic1,2. We present the natural history of this lesion and report the outcome after local excision through a clavicular osteotomy followed by internal fixation. We also discuss clavicular embryology and speculate on the pathoanatomic origin of a medial clavicular osteochondroma. The patient and his family were informed that data concerning this case would be submitted for publication.

Case Report

A sixteen-year-old male high-school student who worked part-time as a butcher presented to a vascular surgeon with a six-week history of insidious swelling in the left, nondominant arm. The patient also complained of diffuse brachial plexus paresthesias. He smoked one pack of cigarettes per year but was otherwise healthy. A laboratory evaluation for thrombophilia revealed normal findings. The family history was negative for hereditary bone tumors and thromboembolism. A venogram revealed complete occlusion of the left subclavian vein along with adjacent partial obstruction of the axillary vein. Increased collateral venous drainage was present, suggesting external compression. This finding was consistent with a primary subclavian thrombosis resulting from thoracic outlet syndrome, also known as Paget-Schroetter syndrome. Routine radiographs of the chest were initially interpreted as normal, although a later retrospective review ultimately revealed the lesion. Magnetic resonance images of the shoulder revealed no obvious extrinsic masses compressing the lateral aspects of the subclavian vessels or brachial plexus, although the medial aspects of these structures were not scanned. However, possible anterior scalene hypertrophy was noted, suggesting a specific type of thoracic outlet syndrome, namely, scalenus anticus syndrome. Thoracic outlet exploration was considered but was not performed given the absence of a definite extrinsic compression etiology. Interventional thrombolysis of the subclavian vein failed because of a technical inability to access the occluded vein. Anticoagulation therapy with Coumadin (warfarin) was instituted for one year, without any change in symptoms; it was stopped thereafter because of its inconvenience to the patient.

Three years after the onset of thrombosis, the patient was working full-time as a butcher and presented to his chiropractor because of new sternoclavicular pain and popping, which worsened with butchering duties that required ballistic overhead movements and heavy lifting. A radiograph of the shoulder revealed a conspicuous sessile osteolytic bone lesion on the medial part of the clavicle, adjacent to the sternoclavicular joint (Fig. 1). A retrospective review of an initial chest radiograph that had been made three years earlier also revealed this same lesion. There had been no obvious radiographic changes during the three-year interval. The patient was referred to the orthopaedic tumor service for further evaluation.

Physical examination revealed engorged veins throughout the proximal aspect of the arm. The range of motion of the shoulder was full. The sternoclavicular joint was tender, without a palpable mass. Forward flexion of the shoulder and adduction of the arm generated an audible and palpable pop over the sternoclavicular joint. The patient had full motor strength, a bounding radial pulse, and diffuse altered sensation throughout the hand and forearm. Adson’s test was positive.

A computerized tomographic scan demonstrated an osseous tumor that was located

Fig. 1

Radiograph showing a central osteolytic bone lesion on the medial aspect of the left clavicle.

The patient elected surgical decompression. An oblique clavicular osteotomy was performed distal and lateral to the lesion. Elevation of the medial clavicular fragment revealed a large, irregularly shaped osseous tumor compressing the neurovascular structures. After elevation of adherent soft tissues, the tumor was excised from the posterior aspect of the clavicle with an oscillating saw. The clavicular osteotomy site was reduced and was secured with lag screw- and-plate fixation (Fig. 3). The tumor measured 3.3 1.6 1.6 cm. The cartilage cap was small and without evidence of malignant transformation. The pathologic diagnosis was benign osteochondroma (Fig. 4).

Soon after surgery, the brachial plexus paresthesias resolved but the subclavian vein thrombosis with postphlebitic syndrome was clinically unchanged. Dilated and tortuous collateral veins persisted over the shoulder.

After three months of shoulder-strengthening rehabilitation, the patient had full range of motion of the glenohumeral and sternoclavicular joints. He no longer had crepitus or sternoclavicular popping. The clavicular osteotomy site was painless and had healed radiographically by three months after surgery, without complications (Fig. 3). The patient resumed light work and activities. Eight months postoperatively, a repeat venogram revealed the persistence of subclavian and axillary vein thrombosis, but with only partial obstructions, indicating some degree of recanalization. As we do not know the precise time when the partial recanalization of the subclavian vein occlusion occurred, we can only surmise that it may have occurred sometime after surgery as a result of the thoracic outlet decompression.

Discussion

We have described a rare case of thoracic outlet syndrome, with axillary-subclavian vein thrombosis and brachial plexus compression, secondary to an atypical medial clavicular osteochondroma. The axillary-subclavian vein has a unique position in the thoracic outlet at the junction of three major anatomic structures: the neck, the shoulder girdle, and the thorax. Our patient’s strenuous overhead work as a butcher probably exacerbated the thoracic outlet compression, causing depression of the shoulder girdle and scissoring the subclavian vein between the clavicular tumor and the first rib3. An extrinsic anatomic compression mechanism is present in most cases of effort-induced subclavian thrombosis, or Paget- Schroetter syndrome4,5. Anatomic sources of this extrinsic compression include congenital clavicular pseudarthrosis, cervical ribs, clavicular nonunion, clavicular malunion, hypertrophy of the scalenus anterior, hypertrophy of the subclavius, a prevenous phrenic nerve, abnormal insertion of the pectoralis minor muscle, clavicular tumors, and an abnormally small space between the clavicle and the first rib6-8.

Fig. 2

Sagittal computerized tomographic scan of the medial part of the left side of the chest, demonstrating an osseous lesion projecting posteriorly from the medial aspect of the clavicle and confirming cortical and medullary continuity between the lesion and the host clavicle.

Fig. 3

Radiograph, made three months after surgery, showing union with stable fixation at the site of the clavicular osteotomy.

According to the Mayo Clinic registry, only 0.5% of about 750 reported solitary osteochondromas were located in the clavicle9. Of the nine solitary clavicular osteochondromas that have been reported in the English-language literature, two developed in the medial third of the clavicle, one developed in the middle third, and six developed in the lateral third1,2,7,10-12. In contrast to the lesion in our patient, both of the other medial clavicular tumors reported in the literature were asymptomatic1,2. However, most lateral clavicular osteochondromas are symptomatic because of either extrinsic mechanical irritation of the rotator cuff or other mechanical alteration of shoulder girdle function1,11,12. Filis et al. reported the case of a patient with thoracic outlet syndrome resulting from a lateral clavicular osteochondroma who was managed with extensive decompression, including tumor excision and anterior scalenectomy7. We believe that primary bone tumors of the clavicle, albeit rare, should be added to the differential diagnosis ofsternoclavicular pain and thoracic outlet syndrome. Our main conclusion based on this rare case is that effective imaging with radiographs, magnetic resonance images, and computerized tomographic scans of the thoracic outlet and the medial part of the clavicle must be performed when there is any doubt about the cause of thoracic outlet syndrome. In the case of our patient, there also could have been a diagnostic role for contrast-enhanced computerized tomographic imaging, which could have been used to directly visualize the osteochondroma that was compressing adjacent contrast- enhanced vessels.

Fig. 4

Photomicrograph revealing some orderly organization of cartilage cells undergoing endochondral ossification (above), with an expected transition to trabecular bone (below). The cartilage cap was typical, small, and without evidence of malignant transformation (hematoxylin and eosin, 4).

Osteochondromas are thought to arise from either trauma or a deficiency in the perichondral ossification groove of Ranvier. Since this tumor arises in association with physeal growth, bones developing by means of intramembranous ossification, such as the skull, clavicle, and spine, are rarely involved13. In humans, the clavicle represents a remnant of an ancestral dermal exoskeleton and serves to stabilize the shoulder girdle14. Histologic studies of human embryos have indicated that the clavicular mesenchymal anlage ossifies primarily through two intramembranous primary ossification centers, appearing at six weeks and fusing at seven weeks15. Both the sternal and acromial ends of the clavicle have articular cartilage, but, after birth, a secondary ossification center develops in the cartilaginous sternal end only16. This medial (sternal) secondary ossification center and physis contribute almost 80% of the clavicle’s longitudinal growth, whereas the primary ossification centers contribute little to the increase in clavicular length15. This secondary ossification center unites with the rest of the clavicle by or before the twenty-fifth year17. It seems plausible that an osteochondroma of the medial part of the clavicle develops from the physis associated with this secondary ossification center.

References

1. Smith J, Yuppa F, Watson RC. Primary tumors and tumor-like lesions of the clavicle. Skeletal Radiol. 1988;17:235-46.

2. Alman BA, Goldberg MJ. Solitary osteochonctroma of the clavicle. J Pediatr Orthop. 1991;11:181-3.

3. Roos DB. Congenital anomalies associated with thoracic outlet syndrome. Anatomy, symptoms, diagnosis, and treatment. Am J Surg. 1976;132:771-8.

4. Adams JT, DeWeese JA. “Effort” thrombosis of the axillary and subclavian veins. J Trauma. 1971;11:923-30.

5. Urschel HC Jr, Razzuk MA. Improved management of the Paget- Schroetter syndrome secondary to thoracic outlet compression. Ann Thorac Surg. 1991; 52:1217-21.

6. Donayre CE, White GH, Mehringer SM, Wilson SE. Pathogenesis determines late morbidity of axillosubdavian vein thrombosis. Am J Surg. 1986;152:179-84.

7. Filis KA, Nguyen TQ, Olcott C 4th. Subclavian vein thrombosis caused by an unusual congenital clavicular anomaly in an atypical anatomic position. J Vase Surg. 2002;36:629-31.

8. Lim EV, Day U. Subclavian vein thrombosis following fracture of the clavicle. A case report. Orthopedics. 1987;10:349-51.

9. Unni KK. Dahlin’s bone tumors: general aspects and data on 11,087 cases. 5th ed. Philadelphia: Lippincott-Raven; 1996. Osteochondroma (osteocartilaginous exostosis): p 11-23.

10. Gerscovich EO, Greenspan A, Szabo RM. Benign clavicular lesions that may mimic malignancy. Skeletal Radiol. 1991;20:173-80.

11. Ogawa K, Yoshida A, Ui M. Symptomatic osteochondroma of the clavicle. A report of two cases. J Bone Joint Surg Am. 1999;81:404- 8.

12. Reichmister J, Reeder JD, Gold DL. Osteochondroma of the distal clavicle: an unusual cause of rotator cuff impingement. Am J Orthop. 2000; 29:807-9.

13. Milgram JW. The origins of osteochondromas and enchondromas. A histopathologic study. Clin Orthop. 1983;174:264-84.

14. Hall BK. Development of the clavicles in birds and mammals. J Exp Zool. 2001;289:153-61.

15. Ogata S, Uhthoff HK. The early development and ossification of the human clavicle-an embryologie study. Acta Orthop Scand. 1990;61:330-4.

16. Gardner E. The embryology of the clavicle. Clin Orthop. 1968;58:9-16.

17. Camp J, Cilley E. Diagrammatic chart showing time of appearance of the various centers of ossification and period of union. AJR Am J Roentgenol. 1931;26:905.

BY ANTHONY V. MOLLANO, MD, MARK L. HAGY, MD, KEVIN B. JONES, MD, AND JOSEPH A. BUCKWALTER, MD

Investigation performed at the University of Iowa, Iowa City, Iowa

Anthony V. Mollano, MD

Mark L. Hagy, MD

Kevin B. Jones, MD

Joseph A. Buckwalter, MD

Department of Orthopaedics and Rehabilitation, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242. E-mail address for A.V. Mollano: [email protected]

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Copyright Journal of Bone and Joint Surgery, Inc. Dec 2004

Criticism of a girl or woman’s body by those whom she trusts most, with whom she is most intimate, and to whom she is most vulnerable is not only one of many ways girls and women are abused, it is one of the most common. As Dorothy Taber, a rehabilitation counselor working with persons with psychological and physiological disabilities, has commented, “Over the many years that I have worked as a counselor of women, every female client I have worked with over a period of time, of months, regarding partner abuse, has commented about the trauma caused by negative remarks concerning their body by their abusers, adding to the basic shame that most women apparently have about their bodies. One would expect for persons with disfiguring conditions to have negative bodily images. But this isn’t necessarily so. Many people with average, healthy, ‘normal,’ and often beautiful physicality believe they are ugly, homely, and misshapen.”1 The criticism can be couched in any number of ways, and whether it is presented “lovingly” as “for your own good” or brutally as “you deserve to be punished for what you have done to yourself or “what you have become,” it is always painful for the fat woman to experience and it never feels like love. Whether the words come from a husband, a domestic partner, a lover, a parent, a sibling, or a friend, they always wound.

The earlier the criticism begins in the life of a person, the more permanent and long-term the damage can be. And when the criticism begins after or in conjunction with some highly stressful event (and a stressful event can be a welcome event, such as pregnancy or child-birth as well as a catastrophe, such as illness or the loss of a loved one), the person being criticized is even more vulnerable than at other times. Wounding remarks about a person’s natural appearance delivered by those who are supposed to love you are toxic. Being told you are too anything-too fat, too thin, too tall, too short, under-developed, over-developed, too dark- not only is a blow to one’s self-esteem and one’s natural sense of being at one with one’s own body, but it undermines one’s ability to trust in the safety of anyone’s love.

In heterosexual marriages, abusive husbands frequently try to control their wives’ appearances as if their wives were pieces of furniture, possessed by the men and vulnerable to reupholstering. It isn’t clear whether the men are really dissatisfied with their wives’ bodies at a personal level or if they are just desperate to have their wives conform to current beauty ideals because their wives’ appearances reflect on them. No doubt the men couldn’t make the distinction between their own personal preferences and their career ambitions themselves.

Fat girls often experience emotional and sometimes physical abuse, bullying, intimidation, and humiliation from their peers in public settings such as school or playgrounds. There is seldom interference in this bullying by adults for all that reasons that we know: adults rarely interfere in the torturing of children by each other. Perhaps the most significant reason they don’t interfere in the case of fat children is their conviction that the abuse is deserved.

The catalogue of abusive behaviors by parents of many fat girls and fat young women is increasingly familiar to children as the unwarranted hysteria about the so-called “obesity epidemic” reaches truly pandemic proportions. Children perceived to have “too much body” are put through a common routine of shaming, blaming, depriving, and distancing by parents with means and determination to govern the bodies of their fat youngsters for their own good:2 Children as young as three months are put on diets. Food restriction and withholding is a common memory for adults who grew up as fat children. Children whose parents have means are sent to “fat camps” that are run like institutions designed to punish; some are even sent to twelve-month “fat schools” to be schooled in self-hatred, self-deprivation, and self-surrender.

Our society has a general penchant for abusing the powerless and the weak and punishing the different; it makes perfect sense that people with fat bodies will be abused. And, since appearances are markers of such significance in determining social value in our culture, it makes perfect sense that abusers will attack those bodies in every way possible, including physically, sexually, verbally, medically, and financially.3

In fact, it often doesn’t matter if a woman is really fat; if she lives in a fat-fearing, fat-hating culture and she is in an intimate relationship with an abuser, she will be told, scolded for, punished because she is fat. Even if she isn’t. This abuse is perhaps only the most literal expression of the punishment our culture imposes on bodies that dare to transgress from the socially prescribed norms.

In the world at large, the abuse of fat women and girls remains a secret, surrounded by fear, shame, and self-blame. And, like abused women in general, many fat women are likely to go on suffering in silence unless and until the larger truths are told, and blame is placed where is belongs-on the abusers, and on the culture that produces them.

Although heterosexual women, and men, both fat men and those men called “fat admirers,”4 have participated in the founding, development, and maintenance of the fat acceptance movement on many fronts, the most radical literature about fat oppression and fat liberation has come from the lesbian feminist fat liberation movement. The literature of fat liberation (or size acceptance, or the fat civil rights movement) is a bravura literature ranging in tenor from pugnacious to lyrical, ironic to heartbroken, furious to comical. It includes the genres anticipated in such a literature: moving memoirs, heart-breaking confessions, declarations of love and alliance for those like the writer, white-jawed rants, murderous tirades, well-reasoned arguments, angry manifestos, three point sermons-and poetry that reflects all of these sentiments and more. As a body of literature, it is relatively new, seeming to begin with writing by the Fat Liberation Underground in 1974.

After these early publications, there has been a steadily increasing river of books and articles and periodicals addressing women and fatness. That more and more of these publications were feminist and represent something truly new in literature, that is, the voice of the fat woman herself, the fat woman as agent rallier than object, is a consequence of many factors.

During these three decades, fat people have begun to find our authentic literary voices and used them to portray and protest our outsider role in society, to question the science used to condemn us, and to assert our determination to define ourselves and live on our own terms. During the same period of years, eating disorders, including anorexia, bulimia, exercise addiction, binge eating, and compulsive overeating, seem to occur with greater frequency and the attention focused on these conditions has increased.

Whether a woman is a radical fat liberationist, fat, proud, defiant, and bound and determined to claim her rightful share of joy, to have her say, to take up space on the dance floors of life, to look you in the eye and say, Fat! So?5 or a size acceptance advocate who believes passionately in the all-rightness, the normalcy, the beauty of women of all shapes and sizes, or a woman who is stil in hiding, still wearing that black raincoat in summer, who hasn’t been swimming in decades, who spends her days and nights waiting for her life to begin once she “does something about herself- all of these women are telling their stories, writing poems and essays and manifestos and novels and short stories that say, “this is how it is for ME!”

I am grateful for their stones.

This piece appeared, in slightly different form, in The Strange History of Suzanne LaFleshe and Other Stories of Women and Fatness; edited and with an introduction and afterword by Susan Koppelman, preface by Alix Kates Shulman, published in December 2003 by the Feminist Press at the City University of New York (Order: 212-817- 7920 or www.feministpress.org).

The abuse of fat women and girls remains a secret, surrounded by fear, shame, and self-blame.

“The most radical literature about fat oppression and fat liberation has come from the lesbian feminist fat liberation movement.”

1 Personal communication, September 15, 2003.

2 An exploration of the overlap between disability issues and fat issues is beyond the scope of this essay but I do want to mention here one particularly poignant characteristic in the childhood histories of people born with disabilities or chronic illnesses, those who become disabled or chronically ill as children, and fat children: namely, they tend to be anomalous, “others,” in their families of origin. The grown-ups in the world of these children, parents and professionals alike, who do not share the condition of these children, whatever it is, are the ones who set the standards, establish the goals, and make the determinations about “what is to be done” for the “poor” child. The similarities between the experiences of childhood recorded in the autobiographies and memoirs of fat children and disabled or chronically ill children are unmistakable.

3 Dieting industry “will be worth 64bn.””The market in diet food and drink products \is expected to increase to 64 billion over the next four years, new research shows.” The complete article is available at: www.ananova.com/news/ story/sm_599092.html?menu=

4 Another term for men who prefer fat partners is “chubby chasers.” This term is disrespectful of both parties to the relationships, while “fat admirers” is an attempt to simply name in a neutral manner a group of people whose only similarity is a particular kind of preference in their choice of romantic or sexual partner. The most interesting thing to notice about these terms is the absence of similar terms for those who prefer very slender partners. There are terms for heterosexual men whose sexual preferences reveal fixations on particular female body parts, such as “leg men,””butt men,” and “breast men” (and yes, these terms refer to sexual preferences rather than culinary preferences!), but there simply are no terms for men whose preferences are for women whose bodies approach the current cultural ideal-except, maybe, “trophy wife.”

5 FAT!SO? is the title of both the periodical and the book published by Marilyn Wann. The full title is FAT!SO? Because you DON’T have to APOLOGIZE for your SIZE!, Ten SpeedPress, Berkeley, Ca., 1998.

Copyright Off Our Backs, Inc. Nov/Dec 2004

Lung transplantation is a viable therapeutic option for patients with end-stage lung disease. The focus of interest has shifted from advances in surgical techniques to improved quality of life for the transplant recipient. A prospective longitudinal repeated measures design was used to determine the impact of lung transplantation on quality of life and life satisfaction. Using 4 measurement points (before transplantation, after 8 weeks, and after 6 and 12 months), 61 patients were followed from before to 1 year after successful lung transplantation. Quality of life was measured using 2 generic (SF-36, Quality of Life Profile for Chronic Diseases) and 1 lung- specific (Saint George’s Respiratory Questionnaire) questionnaires. All dimensions of the health-related scores improved significantly after transplantation, except bodily pain. Patients reported the most significant improvements until 6 months after transplantation. Lung transplantation had no influence on social functioning or role emotional. The Saint George’s Respiratory Questionnaire ratings showed similar significantly better scores for transplant recipients at 6 months, and stagnations for most dimensions afterward. (Progress in Transplantation. 2004;14:331-336)

Health-related quality of life (QOL) has increasingly been accepted as a supplementary outcome measure for patients after lung transplantation. The focus of interest in clinical investigations regarding lung transplantation has changed from surgical technical advances to improved QOL for the individual. In preliminary studies, different approaches to measure these advances in QOL have been used to identify predictors of QOL and adjustment after lung transplantation. Previous studies that focused on these changes in QOL after lung transplantation generally report improvements in patients’ perceptions of QOL and life satisfaction.1-10 The results of clinical studies measuring QOL after lung transplantation are limited by small sample sizes,1-4,6,11 retrospective study designs with only 1 measurement point,5,6,12,13 and little or no information about the progress after transplantation for the individual.5,12,13 Studies on the QOL of lung transplant candidates and recipients generally report improvements in QOL following lung transplantation.1,7,8,14 However, comparisons between the studies and published results are difficult because of different study designs, patient populations, and measurement instruments used.2,5,9,10,15-18

From a methodological perspective, the best way to focus on improvements of QOL after lung transplantation is to follow patients by using a prospective longitudinal design with different measurement points, including initiation data before transplantation. Craven et al13 and Lanuza et al1 followed patients prospectively from candidacy on the waiting list until 6 months after transplantation, using 3 measurement points. In both studies, authors concluded that patients experience improved physical and psychological strengths, and that patients report a better global health satisfaction. Ten Vergert and colleagues7 administered the same set of questionnaires to patients from before to 19 months after successful lung transplantation. Improvements occurred about 4 months after transplantation in regards to mobility, energy, sleep, and activities of daily living dependency, and were maintained in the following 15 months.

QOL is multidimensional. Health-related QOL can be divided into a physical, psychological, and a social component of health. These 3 components are interrelated; each dimension can be assessed in 2 ways: (1) objective assessment of overall functioning (eg, 6-minute walk test for physical abilities) and (2) subjective assessment of patients’ perceptions regarding QOL-related scoring. Therefore, tools measuring patients’ perceptions of QOL should address all of these 3 dimensions adequately.5,8,10,12,14

To determine the impact of lung transplantation on QOL and life satisfaction, the same patient group was followed from before transplantation to 1 year after successful transplantation. Patients’ beliefs in their ability to improve their QOL were assessed to identify hypothetical barriers for improvement in individuals.

Methods

A prospective, longitudinal repeated measures design was used. Each part of the study was approved by the Ethics Committee at the Hanover Medical School. Data were collected before transplantation, 8 weeks after surgery (single or bilateral), and 6 and 12 months after transplantation. Lung transplant recipients (N = 61) were recruited exclusively as candidates on the waiting list during outpatient visits or during pretransplant hospital stays. Demographic data and diagnoses are shown in Tables 1 and 2. After written informed consent was obtained, patients completed a battery of questionnaires (Quality of Life Profile for Chronic Diseases [PLC], SF-36, and Saint George’s Respiratory Questionnaire [SGRQ]) measuring QOL and life satisfaction. In addition, a half-structured interview focused on patients’ beliefs that potentially influence QOL was conducted. For each patient, the second measurement point was 8 weeks after successful lung transplantation, followed by examinations at 6 and 12 months after transplantation. Patients were asked to complete the same set of questionnaires at each time point. Datasets from patients who died after transplantation or withdrew informed consent were excluded from this analysis: 2 patients withdrew their informed consent because of moves and follow-ups in other transplant centers, 4 patients died after transplant surgery (22-67 days), and 1 person died (after 157 days) between measurement points 2 and 3.

Quality of Life Profile for Chronic Diseases

The PLC19 is a German self-rating questionnaire and contains 40 Likert-scale questions, consisting of the following 3 components: (1) physical component of QOL-scale of physical functioning; (2) psychological components of QOL, (a) scale of negative moods, (b) scale of positive moods, and (c) scale of psychological functioning; and (3) social components of QOL, (a) scale of social well being and (b) scale of social functioning. The data are presented for the 3 components on a scale from 0 to 4, with higher scores indicating a higher perceived health-related QOL. The scale of negative moods needs to be repolarized, with higher scores indicating less negative moods. Validity and reliability for this instrument have been assessed for 8 clinical studies in chronic patient populations, and for a representative normative sample (n = 2047),20 showing that the internal consistency and the discrimination of the instrument were satisfactory.20,21

Table 1 Demographic data

Table 2 Diagnoses of lung transplant candidates

Internal consistency values measured with Cronbach α range between .72 and .89 for all subscales.21 For testing the construct validity, the level of significance was set at .01. Intercorrelation matrices showed moderate and strong correlation coefficients between .45 and .72 (all P = .0001).21 The scales of the PLC questionnaire showed close correlations to the similar scales of the SF-36 questionnaire (r between .6 and .8; P = .0001).

SF-36

The Medical Outcomes SF-36 is a general health status survey18,21- 23 and contains 36 Likert-scale questions; it assesses 8 dimensions of health: physical functioning, role limitations caused by physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations caused by emotional problems, and mental health. The SF-36 has been extensively validated for use in healthy groups, as well as in populations with acute and chronic diseases. Each dimension is scored separately, and scores are transformed to a 0 to 100 scale, with higher scores indicating a more satisfactory health status. The instrument has previously been validated in patients with chronic obstructive pulmonary disease,17,18 and has been used in the lung transplant population.2,6,8,10,14,24

Saint George’s Respiratory Questionnaire

The SGRQ is a lung-specific questionnaire capturing aspects of health-related QOL that are more specific for patients with respiratory problems.6,25,26 SGRQ contains 50 items with 76 weighted responses. The questionnaire consists of 3 components: (1) symptoms, measuring distress due to respiratory symptoms, related to the frequency of symptoms; (2) activities, effects of disturbance to mobility and physical activity; and (3) impacts, assessing the psychosocial impact of the disease. In addition, a total score is calculated by summing all positive responses in the 3 components and expressing the result as a percentage of weights for all items in the questionnaire. Each response has a unique empirically derived “weight” on a 0 to 100 scale, and the maximum possible weights that could be obtained represent the worst possible state by the patient. The SGRQ was validated for use in the lung transplant population with acceptable reliability scores.6,25,26

Interviews

The half-structured interviews were based on the Illness Beliefs Model,27 which focuses on illness beliefs and perceptions of self- efficacy by patients and their relatives that influence outcome and prognosis of chronic diseases.

Statistical Parameters

Descriptive statistical parameters suc\h as means and standard deviations were obtained for all continuous variables, and percentages were calculated for nominal variables for the study sample as a whole. Correlations were tested by calculating Kendall tau rank correlation coefficients for ordinal data. To detect statistically significant differences between the measurement points, paired t tests for related groups were used. All calculations have been realized by the SPSS 11.0 (Statistical Package for Social Sciences, SPSS Inc, Chicago, Ill) software. The level of significance was set at .05.28

Figure 1 The progression of perceived quality of life after lung transplantation using the Quality of Life Profile for Chronic Diseases. Datapoints are mean values.

Results

The questionnaires and interviews were completed by 61 eligible patients, age 20 to 63 years (mean 47, median 49 years). Fifty- three patients (87%) received a bilateral lung transplant, and 8 patients ( 13%) received a single lung transplant. The majority of the sample received social support from family (66%) and friends (74%).

As shown in Figures 1 and 2, patients rated their general QOL levels very low on all subscales (PLC and SF-36) during their candidacy for lung transplantation on the waiting list. The reported capabilities (PLC and SF-36) improved significantly from before transplantation to 6 months after transplantation (P = .0001), but stagnated afterward for most dimensions of QOL. Following the physical components of QOL (PLC) patients perceived statistically significant improvements for measurement points at 8 weeks, 6 months, and 12 months (P = .010, P = .003, and P = .042, respectively). Negative moods were reduced at 12 months after transplantation (P = .006), whereas the positive moods increased with the highest peak at 8 weeks after transplantation (P = .0001). Social components of QOL using the PLC were showing significant changes 6 months (P = .040) and 12 months after transplantation (P = .005).

Figure 2 The progression of perceived quality of life after lung transplantation using the SF-36. Datapoints are mean values.

These results were validated by significant improvements regarding the SF-36 subscales physical functioning (P = .028) and role physical (P = .049) at 6 months after transplantation. These 2 scales were scored close to 0 before transplantation. The scale for general health (SF-36) shows significant improvements reported by the patients for all measurement points following transplantation (P = .01). The SF-36 subscales for role physical and emotional, general, and for mental health perceptions stagnated or decreased between months 6 and 12 after transplantation. The progress with 4 measurement points for perceived QOL after lung transplantation is shown in Figures 1 and 2. The results shown in Figure 3 show statistically significant decreases in all SGRQ dimensions: symptoms (P = .005), impacts (P = .012), activities (P = .0001), and the total score (P = .0001) at month 6 following lung transplantation.

Patients’ perceptions of improvement of QOL after lung transplantation are supported by the interview results. Patients described their central concept of suffering before lung transplantation as increasing dyspnea and the related anxiety of dying before an organ is available. Consistent with the patients’ perceptions, dyspnea is largely responsible for the decrease in physical abilities and contact capabilities before transplantation. Patients with higher perceptions of internal self-efficacy reported better levels of QOL (P = .001). Patients with higher scores on health-related life satisfaction indicated that 3 interrelated factors influenced positive outcome and survival: medicine, family support, and themselves.

Conclusion

Patients on the waiting list for lung transplantation report dramatic restrictions in all dimensions of QOL, with lowest scoring in the physical subscales. These findings occur consistently within general (PLC, SF-36) and lung-specific (SGRQ) questionnaires. We found that successful lung transplantation has a large impact on QOL and its health-related dimensions. Lung transplantation significantly improves the subjects’ overall function and satisfaction regarding QOL, and has evolved to a viable treatment option for patients with end-stage lung diseases. Although lung transplant recipients report better general, physical, and psychological functioning, individuals’ self-estimations of these parameters differ greatly. Positive beliefs concerning abilities to influence the course of their therapy correlate with higher scores in perceived QOL.

Significant changes occur between all measurement points and for all dimensions (physical, psychological, and social), except the SF- 36 subscales social functioning and role emotional. Both subscales intercorrelate significantly (P = .003) at all measurement points (Table 3).

Figure 3 The progression of perceived quality of life after lung transplantation using the Saint George Respiratory Questionnaire. Datapoints are mean values.

Table 3 Changes in quality of life for all subscales between the measurement points-t test for paired samples*

These results do not correspond with other study results.2,6,10,14 A possible explanation could relate to the interview findings; patients reported changes regarding role definitions between the core family members (eg, changes of role definitions within the partnership) occurring within the time frame between 6 and 12 months after lung transplantation. Perceived improvements regarding physical functioning correspond with the patients’ activities to reintegrate themselves into social systems such as the family system. Successful adaptations from the patients’ point of view are related to higher scoring in regards to social and emotional QOL as well as life satisfaction.

These findings are consistent with earlier reports on QOL outcomes of lung transplant recipients.2,5,6,10 Mac Naughton et al2 report similar results as shown above and compare their data with estimations of a normative sample. They conclude that regardless of the overall improvements following transplantation, lung transplant recipients range one third under the normative population regarding overall QOL. These conclusions have also been confirmed by a research group from Norway.6

Further research should focus on the development of interventional nursing strategies to improve QOL after successful lung transplantation and identify potential barriers for improvement. Researchers need to identify which behaviors and characteristics are shared by lung transplant recipients who have successful clinical and QOL outcomes after transplantation.

References

1. Lanuza DM, Lefaiver C, McCabe M, et al. Prospective study of functional status and quality of life before and after lung transplantation. Chest. 2000;118:115-122.

2. MacNaughton KL, Rodrigue JR, Cicale M, et al. Health related quality of life and symptom frequency before and after lung transplantation. Clin Transplant. 1998;12:320-323.

3. Vermeulen KM, Ouwens JP, van der Bij W, et al. Long-term quality of life in patients surviving at least 55 months after lung transplantation. Gen Hosp Psychiatr. 2003;25:95-102.

4. Busschbach JJ, Horik PE, van den Bosch JM, et al. Measuring quality of life before and after bilateral lung transplantation in patients with cystic fibrosis. Chest. 1994;105:911-917.

5. Woodman CL, Geist LJ, Vance S, et al. Psychiatric disorders and survival after lung transplantation. Psychosomatics. 1999;40:293- 297.

6. Stavem K, Oystein B, Lund MB, et al. Health-related quality of life in lung transplant candidates and recipients. Respiration. 2000;67:159-165.

7. TenVergert EM, Essink-Bot ML, Geertsma A, et al. The effect of lung transplantation on health-related quality of life. Chest. 1998;113:358-364.

8. Littlefield C, Abbey S, Fiducia D. Quality of life following transplantation of the heart, liver, and lungs. Gen Hosp Psychiatr. 1996;8:36-47.

9. Cohen L, Littlefield C, Kelly J, et al. Predictors of quality of life and adjustment after lung transplantation. Chest. 1998;113:633-644.

10. Wright Pinson C, Feurer ID, Payne JL, et al. Health-related quality of life after different types of solid organ transplantation. Ann Surg. 2000;232:597-607.

11. Manzetti JD, Hoffman LA, Sereika SM, et al. Exercise, education, and quality of life in lung transplant candidates. J Heart Lung Transplant. 1994;13:297-305.

12. Craven JL, Bright J, Dear CL. Psychiatric, psychosocial, and rehabilitative aspects of lung transplantation. Clin Chest Med. 1990;11:247-258.

13. Burker EJ, Carels RA, Thomson LF. Quality of life in patients awaiting lung transplant: cystic fibrosis versus other end-stage lung diseases. Pediatr Pulmonol. 2000;30:453-460.

14. Limbos MM, Joyce DP, Chan CKN, et al. Psychological functioning and quality of life in lung transplant candidates and recipients. Chest. 2000;118:408-416.

15. Ramsey SD, Patrick DL, Albert RK, et al. The cost- effectiveness of lung transplantation. A pilot study. Chest. 1995;108:1594-1601.

16. Squir HC, Patrick DL, Lewis S, et al. Quality of well-being predicts survival in lung transplant candidates. Am J Respir Crit Care Med. 1995;152:2032-2036.

17. Prigatano GP, Wright EC, Levin D. Quality of life and its predictors in patients with mild hypoxemia and chronic obstructive pulmonary disease. Arch Intern Med. 1984;144:1613-1589.

18. Mahler DA, Mackowiack JI. Evaluation of the short form 36- item questionnaire to measure health- related quality of life in patients with COPD. Chest. 1995;107:1585-1589.

19. Siegrist J, Broer M, Junge A. PLC-Profil der Lebensqualitt Chronisch Kranker. Manual. Gttingen, Germany: Beltz-Test; 1996.

20. Laubach W, Schroeder CH, Siegrist J. et al. Standardization of the questionnaire “Quality of Life with Chronic Disease” on a representative german sample. Z Differentielle Diagnostische Psychol. 2001;22:100-110.

21. Ware JE. The SF-36 Health S\urvey. In: Spilker B, ed. Quality of Life and Pharmaeconomics in Clinical Trials. Philadelphia, Pa: Lippincott-Raven; 1996: 337-346.

22. Bullinger M, Kirchberger I. SF-36 Fragebogen zum Gesundheitszustand. Handanweisung. Gttingen, Germany: Hogrefe- Verlag; 1998.

23. McHorney CA, Ware JE Jr, Lu JF, et al. SF-36 Health Survey. Manual and Interpretation Guide. Boston, Mass: The Health Institute, New England Medical Center; 1993.

24. Napolitano MA, Babyak MA, Palmer S, et al. Effects of a telephone-based psychosocial intervention for patients awaiting lung transplantation. Chest. 2002;122:1176-1184.

25. Jones PW, Quirk FH, Baveystock CM. The St. George’s Respiratory Questionnaire. Respir Med. 1991;85(suppl B):25-31.

26. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self- complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145:1321-1327.

27. Wright LM, Watson WL, Bell JM. Beliefs. The Heart of Healing in Families and Illness. New York, NY: Basic Books; 1996.

28. Polit DF, Hungler BP. Nursing Research. Principles and Methods. 6th ed. Philadelphia, Pa: Lippincott; 1999.

Christiane Kugler, RN, MSN, Martin Strueber, MD, Uwe Tegtbur, MD, Jost Niedermeyer, MD, Axel Haverich, MD, PhD

Hanover Medical School, Hanover, Germany

To purchase electronic or print reprints, contact:

The InnoVision Group

101 Columbia, Aliso Viejo, CA 92656

Phone (800) 809-2273 (ext 532) or (949) 448-7370 (ext 532)

Fax (949) 362-2049

E-mail [email protected]

Copyright North American Transplant Coordinators Organization Dec 2004

Deep venous thrombosis (DVT) tops the differential diagnosis list for unilateral lower extremity edema, but another entity could imitate or even cause a DVT. May-Thurner syndrome is caused by compression of the left common iliac vein by the overlying right iliac artery, resulting in impeded venous blood flow from the left lower extremity. The left leg becomes edematous, causing discomfort and concern. Early recognition of May-Thurner could prevent a DVT and provide symptomatic relief.

Introduction

The aorta travels left of the inferior vena cava as it descends through the abdomen, such that when it bifurcates, the right common iliac artery must cross over the left common iliac vein, near the bifurcation of each central vessel (Fig. 1).1 Because an artery has a much thicker wall and is under much greater pressure than a vein, when pushed together the vein becomes the compressed vessel. If the vein is sufficiently compressed against the pelvic rim, the increased pressure can cause edema in the left lower extremity.2 Virchow’s Triad describes an increased risk of venous thrombosis with stasis, hypercoagulability, and vessel intimai injury, the first of which is present with any venous obstruction.3 There is evidence that intimai injury may also take place in the form of a spur when the compression occurs over time. Despite many collateral vessels throughout the pelvis, significant compression can produce symptomatic edema.

Because the etiology of May-Thurner is left common iliac vein compression by the overlying right common iliac artery, the diagnosis should only be entertained when the edematous leg is on the left. There is a female predominance, and in 1965, Cockett and Thomas4 generally found it in young women between the second and fourth decades. Surgery, pregnancy, and prolonged bed rest have all been mentioned as possible acute precipitating factors. Based on autopsies, May and Thurner found a 22% prevalence of a spur, the name they gave to the intravenous endothelial changes seen at the point of compression near the mouth of the left common iliac vein.5 May-Thurner patients may present only after a deep venous thrombosis (DVT) has formed, well past the primary prevention stage. Because iliac vein DVT are found more than twice as often on the left than the right, May-Thurner compression could be responsible for many of these cases.6

In one case, a 27-year-old active duty Hispanic woman presented with 4 months of left lower extremity swelling and ankle discomfort when running. The patient had no other symptoms, including chest pain, respiratory difficulty, or calf tenderness. The patient had a negative medical history, including surgery, trauma, pregnancy, oral contraception, current medication use, smoking, allergies, abnormal bleeding, or family history of coagulopathy. The patient was not obese, weighing 113 pounds and a height of 61 inches. Physical examination revealed 2+ pitting edema to the left knee, but a negative Roman’s sign. There was no inguinal lymphadenopathy or other abnormality on physical examination. The differences in circumference of the ankle and calf from the left to the right were 2 and 1.5 cm, respectively, with only trace difference at the knee (Fig. 2). An ultrasound was done that showed no evidence of DVT. Ultrasonography demonstrated a patent deep venous system from the popliteal to the left common iliac vein. However, during pelvic venogram via micropuncture catheter access of the left femoral vein, significant extrinsic compression of the left common iliac vein was noted under the crossing right common iliac artery (Figs. 3 and 4).

Diagnosis

The patient with symptomatic chronic left common iliac compression will typically present with symptoms, many of which are similar to those found in patients with a DVT. Swelling, pain in the distal lower extremity, engorged varicose veins, and even venous stasis skin changes can all be seen. An inability to wear a tight fitting shoe may be the initial complaint. Difficulty in performing physical exercise such as running can be seen in athletes or active duty military members secondary to the discomfort of having one leg swollen compared with the unaffected right side. Unlike a DVT, whose onset is generally acute, MayThurner would be expected to present in a more chronic fashion. However, a patient may fail to notice significant swelling until an event such as the wearing of a new shoe forces recognition of the difference. A precipitating event, such as the rapid anatomical change that accompanies the weight gain of pregnancy, is present in some cases.

When a patient presents with unilateral lower extremity edema, the clinician should attempt to rule in or out DVT. Most commonly, a compression/Doppler ultrasound is used because of its relative simplicity and noninvasiveness. Impedence plethysmoography is not used as often as ultrasound, but appears to have most of the same benefits and limitations as ultrasound in finding a DVT. Magnetic resonance imaging can also show thrombosis in the pelvis, but has not been shown to be superior to other, less expensive, choices. Venography is the gold standard for ruling in or out DVT and May- Thurner syndrome, but is invasive and painful.7 Intravascular ultrasonography is a relatively new test performed by placing a transducer in a large vessel using the Seldinger technique at an entry location in the groin.8 It can be used to detect a DVT or measure cross-sectional areas of vessels. In some studies, it has shown promising iliac vein results, but may be less widely available than more conventional tests.9

Fig. 1. Diagram showing right common iliac artery crossing over left common iliac vein.

Fig. 2. Case patient with left lower extremity edema.

When a patient presents with unilateral lower extremity edema, the clinician must consider the possibility of a DVT because of its potential for pulmonary embolism (PE). If the ultrasound shows a DVT, although prevention of PE is the top priority, May-Thurner might still be considered as a possible etiology of the DVT. If no DVT is seen on Doppler/compression ultrasound, given its 97% sensitivity, the clinician must run the differential diagnosis list while acknowledging the inherent 3% false-negative rate.10 The history and physical should include questions about personal and family bleeding disorders, respiratory symptoms, trauma, infection, and travel. The physical examination should document size difference between the extremities and the presence or absence of Homan’s sign, in which ankle dorsiflexion provokes calf pain.11 If the person has spent time in the East Indies or Africa, one could consider the possibility of lymphedema secondary to filariasis. Cancer metastatic to the lymph system can also cause secondary lymphedema. A tumor, such as a thigh lipoma, or a psoas or gluteal abscess could cause swelling in the proximal part of the lower extremity. Warmth, fever, erythema, and localized pain could indicate infection. Acute arthritis, a popliteal artery aneurysm, or ruptured Baker’s cyst could all cause unilateral leg swelling in the absence of trauma.12 Gout is a common cause of swelling and pain of the distal lower extremity, but does not normally cause measurable differences in calf diameter. If the history, physical, and ultrasound provide no evidence of DVT in a young woman with left lower extremity edema, May-Thurner syndrome should be considered.

Treatment

A literature search using OVID/MEDLINE and MDConsult revealed no widely accepted recommendations for patients suffering from May- Thurner syndrome who have not yet experienced a DVT. However, because stasis is one of the three pillars of Virchow’s Triad, such patients could be at increased risk. There are several options in DVT prevention. Decompression of the left common iliac vein via vascular surgery or interventional radiology can diminish the stasis. If an invasive procedure is not chosen, anticoagulation may be appropriate. If a patient has suffered a first DVT, anticoagulant treatment is indicated for a minimum of 3 to 6 months in patients in whom it is not contraindicated. With a second DVT and no treatable cause, anticoagulation is generally used indefinitely.13 In the case above, aspirin was chosen for DVT prophylaxis, at least until a more permanent treatment is undertaken. Aspirin is generally contraindicated for those with a history of one recent or multiple DVT because other anticoagulants are more effective, but no evidence is readily available for DVT prophylaxis in those with May-Thurner syndrome and no history of DVT.14 Aspirin was shown in the PE Prevention trial to prevent DVT compared with placebo in hip fracture patients.15 Although study has shown aspirin to be safe during the second and third trimester of pregnancy, the risks of taking aspirin during the first trimester are not known and aspirin is listed as a Class D medication in pregnancy, and counseling in such cases is appropriate if the patient is contemplating pregnancy.16

If DVT risk is significant, such as in the case of a patient with a history of DVT, the use of oral warfarin (Coumadin), a vitamin K antagonist, or an injectable low molecular weight heparin, an antithrombin III protagonist such as enoxaparin (Lovenox), is indicated. For those who are athletes, travelers to remote places where blood transfusion might be risky, or military members who \must pass stringent physical fitness testing to be ready for deployment to remote places, warfarin may not be an acceptable choice because of the frequent laboratory monitoring required. Enoxaparin requires daily or twice daily injections that have been shown to reduce DVT risk to a level equal to or better than warfarin in many postsurgical situations, but may have a slightly increased risk of major bleeding compared with warfarin.17 None of these situations can be directly compared with the iliac vein compression found in May-Thurner syndrome. In terms of cost, warfarin and low molecular weight heparin have been shown to be similar when the laboratory costs associated with warfarin are included, although both are much more expensive than aspirin. Several authors have suggested a possible link between air travel with limited limb movement and DVT, and many experts recommend some light exercise during air travel. However, no studies have definitively shown a reduction in DVT through regular cardiovascular exercise involving the legs, such as running. In fact, running may actually be more difficult when one extremity is edematous.

Fig. 3. Case patient’s venogram showing left common iliac vein compression. Note catheter just medial to left femoral head, dark left common iliac vein, and lighter area between vein and inferior vena cava at site of compression by right common iliac artery.

Fig. 4. Case patient’s venogram (oblique) showing left common iliac vein compression. Note light groove between dark left common iliac vein and inferior vena cava.

There is no definitive treatment for May-Thurner syndrome, although there are several promising treatments. Multiple journal articles report small numbers of successful venous stent placement, usually involving a Wallenstent. Immediate and short-term results are quite good, with 71% primary patency at 2 years.18 However, there are no long-term patency rates. A vascular surgical option can also be undertaken. Transection, movement, and reanastomosis of the right common iliac artery have been successful in a few cases.19 Another procedure involves bypassing the vein, which has also shown promising results in a few cases.20 Because of the relative rarity of this diagnosis, there are no long-term head-to-head studies comparing vascular surgery versus stent placement, therefore, no specific algorithm recommendation can be made after a review of the literature. In the case above, the consulting surgeon recommended no treatment, although referral for stent placement was offered.

Conservative management simply involves pain control with or without DVT prophylaxis. Because there is no known spontaneous resolution of May-Thurner, this could be a difficult decision for a competitive athlete or active duty military member who experiences discomfort during strenuous exercise.

Conclusion

The top of the differential diagnosis list for unilateral left lower extremity edema should be a DVT, but with or without sonographic evidence of DVT, another possibility is that stasis from May-Thurner could be the etiology of the symptoms. As treatment options improve, these patients may soon have more definitive choices, impacting the decision to continue a successful military career.

References

1. Gray H: Anatomy of the Human Body, Ed 20. Philadelphia, PA, Lea & Febiger, 1918 (obtained from www.bartleby.com/107/154.html).

2. Baron HC, Shams J, Wayne M: Iliac vein compression syndrome: a new method of treatment. Am Surg 2000; 66: 653-5.

3. Goldman L, Bennett JC: Cecil Textbook of Medicine, Ed 21. Philadelphia, PA, W.B. Saunders Co., 2000.

4. Patel NH, Stookey KR, Ketchum DB, Cragg AH: Endovascular management of acute extensive iliofemoral deep venous thrombosis caused by May-Thurner syndrome. J Vase Interv Radiol 2000; 11: 1297- 1302.

5. May R, Thurner J: The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins. Angiology 1957; 8: 419- 26.

6. Ouriel K, Green RM, Greenberg RK, Clair DG: The anatomy of deep venous thrombosis of the lower extremity. J Vasc Surg 2000; 31: 895-900.

7. Fauci AS, Braunwald E, Isselbacher KJ, et al: Harrison’s Principles of Internal Medicine, Ed 14. New York, McGraw-Hill, 1998.

8. Oppat WF, Chiou AC, Matsumura JS: Intravascular ultrasound- guided vena cava filter placement. J Endovasc Surg 1999; 6: 285-7.

9. Ahmed HK, Hagspiel KD: Intravascular ultrasonographic findings in May-Thurner syndrome (iliac vein compression syndrome). J Ultrasound Med 2001; 20: 251-6.

10. Frazee BW, Snoey ER: Diagnostic role of ED ultrasound in deep venous thrombosis and pulmonary embolism. Am J Emerg Med 1999: 17: 271.

11. Abeloff MD, Armilage JO, Lichter AS, Niederhuber JE: Clinical Oncology, Ed 2. New York, Churchill Livingstone, 2000.

12. Maksimovic Z, Cvetkovic S, Markovic M, Perisic M, Colic M, Putnik S: Diferencijaina Dijagnostika Tromboze Dubokih Vena [Differential Diagnosis of Deep Vein Thrombosis], Srpski Arhiv za Celokupno Lekarstvo. 2001; 129: 7-13.

13. Bick RL, Haas SK: Current concepts of thrombosis: prevalent trends for diagnosis and management. International consensus recommendations: summary statement and additional suggested guidelines. Med Clin North Am 1998; 82: 622-6.

14. Heit JA: Thromboembolic disease and anticoagulation in the elderly. Clin Geriatr Med 2001; 17: 1.

15. Kaboli P, Henderson MC, White RH: DVf prophylaxis and anticoagulalion in the surgical patient. Med Clin North Am 2003, 87: 77-110.

16. Ginsberg JS, Greer I, Hirsh J: Use of antithrombolic agents during pregnancy. Chest 2001; 119: 1.

17. Hirsh J, Warkentin TE, Shaughnessy SG, et al: Heparin and low- molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119: 64S-94S.

18. Raju S, Owen S, Neglen P: The clinical impact of iliac venous stents In the management of chronic venous insufficiency. J Vasc Surg 2002; 35: 8-15.

19. Simon C, Alvarex J, Becker GJ, et al: May-Thumer syndrome in an adolescent: persistence despite operative management. J Vasc Surg 1999; 30: 950-3.

20. Alimi YS, DiMauro P, Fabre D, Juhan C: Iliac vein reconstructions to treat acute and chronic venous occlusive disease. J Vasc Surg 1997; 25: 673-81.

Guarantor: LCDR David A. Boyd, MC USN

Contributor: LCDR David A. Boyd, MC USN

Department of Family Practice, Naval Hospital Jacksonville NAS, Jacksonville, FL 32214.

This manuscript was received for review in May 2003. The revised manuscript was accepted for publication in January 2004.

Reprint & Copyright by Association of Military Surgeons of U.S., 2004.

Copyright Association of Military Surgeons of the United States Dec 2004

A pill that helps patients kick their addiction to prescription painkillers is gaining interest from thousands of doctors nationwide.

But no Spokane doctors prescribe Suboxone because none has taken the eight-hour course required by federal law.

That leaves Spokane patients traveling as far as Yakima to find a doctor who can prescribe it.

Suboxone can change lives, according to doctors and patients. With abuse of painkillers such as OxyContin and hydrocodone on the rise nationally and locally, Suboxone offers hope.

“I can pop those pills in my mouth in the morning, and today, I know I’m going to be clean,” said Jerry Littlemore Jr. of Spokane, who got hooked on painkillers after he was injured in an accident. “I can’t get high because those receptors are blocked. It’s freedom. I don’t have to deal with that battle in my head.”

Only six doctors within reasonable driving distance of Spokane are prescribing Suboxone. Those doctors are in Moses Lake, Ephrata, Yakima, Post Falls, Coeur d’Alene and Sandpoint.

In contrast, 41 doctors west of the Cascades are prescribing Suboxone.

Littlemore travels to Moses Lake to see Dr. David Curnel, who prescribes his Suboxone.

People familiar with the situation say doctors may be avoiding Suboxone because they don’t want to acquire a reputation as Spokane’s addiction doctor. They may think patients who come to them for Suboxone may drive away their other patients.

Spokane doctors contacted for this story either had not heard of Suboxone or speculated that the hassle of taking a class and dealing with federal regulations has prevented some of their colleagues from signing up.

Meanwhile, there’s no shortage of people who could benefit from the treatment.

Spokane’s methadone clinic is overwhelmed with painkiller addicts, who now outnumber heroin addicts in the program 2-to-1. Spokane County is seeing a small but growing number of arrests involving prescription drugs.

The Spokane County Sheriff’s Department made 44 arrests involving prescription drugs in 2003, up from nine in 1996. The number underestimates the problem because addicts get their pills from doctors, from friends with prescriptions or by faking pain in emergency rooms – methods that don’t attract the attention of law enforcement.

But when there is an overdose, law enforcement gets involved.

“I have seen many deaths where OxyContin, hydrocodone and now, most recently, methadone, are a factor,” said Sgt. Brad Maskell, a detective with the Kootenai County Sheriff’s Department. He’s worked on death investigations eight years and started noticing prescription drug deaths four years ago. In September, he investigated three separate deaths involving teenagers overdosing on methadone.

Nationally, drug abuse-related emergency room visits involving prescription painkillers rose 153 percent from 1995 to 2002, according to the federal government’s Drug Abuse Warning Network. An estimated 4.7 million Americans are current abusers of prescription painkillers, according to the Office of National Drug Control Policy.

The people who run the Spokane methadone program want local doctors to start prescribing Suboxone.

“It would definitely help us immensely. We wouldn’t have to turn anybody away,” said Gary Kissel-Nielsen, program manager of the Spokane Regional Health District’s methadone program, which can handle up to 250 patients.

“There are a lot of stereotypes of what an addict looks like. In truth, most look like everyone else,” Kissel-Nielsen said. “We are seeing a lot more patients that have become addicted through prescription drug use. They were taking their prescriptions as prescribed for a legitimate reason, became addicted, were cut off by their doctor and now are addressing a dependency problem.”

Suboxone is regulated under a 4-year-old federal law. The Drug Addiction Treatment Act was written to set rules for office-based treatment using buprenorphine, the active ingredient in Suboxone, which at the time was not yet approved by the U.S. Food and Drug Administration.

The law limits each prescribing doctor to 30 patients at one time. With only six doctors nearby, there are 180 slots in the Inland Northwest for people who want to try Suboxone. Most of those are full.

‘THEY’RE DESPERATE’

J.L.R. spent more than 25 years scamming hospital emergency rooms to get the narcotics that fed her addiction. Now 47 years old, the Spokane woman lost her children and husband due to her habit. She asked that only her initials be used in this story to protect her family from embarrassment

In 2003, J.L.R. was among Washington state’s top abusers of hospital emergency rooms on a list compiled by the state’s Medicaid office. She visited ERs 119 times that year and the state paid $18,154 for her painkillers and other drugs.

When she decided she wanted help quitting narcotics, she considered the methadone clinic. But the 76 slots for Medicaid clients were full. In June, she learned from a social worker about Suboxone. Along with mental health therapy, Suboxone has helped her get off addictive painkillers.

“For the first time in my life, I am happy. I go to bed at night looking forward to getting up in the morning,” she said. “This Christmas, I’m getting a tree and decorating it. I don’t ever remember feeling this good.”

J.L.R. travels from Spokane to Post Falls to see Dr. Michael Carraher, who prescribes Suboxone. Her husband – they separated, but never divorced – wants to help and drives her to appointment.

“By the time (addicted patients) come in, some have lost everything, so they’re desperate,” Carraher said. About half the patients he’s started on Suboxone have stayed clean, a rate he says is good. The drug costs between $85 and $640 per month, depending on dosage.

Suboxone and an alternative formulation called Subutex were approved by the U.S. Food and Drug Administration in 2002. They are the only drugs approved for treatment of opiate dependence that can be prescribed out of a doctor’s office. (Methadone pills can be prescribed by doctors, but only for pain relief.)

Suboxone and Subutex are manufactured by Reckitt Benckiser Pharmaceuticals Inc. The company, based in Richmond, Va., is a subsidiary of Reckitt Benckiser PLC, a publicly traded British firm that sells household products such as Lysol. Suboxone and Subutex are manufactured in Hull, England.

Suboxone was developed, first as a painkiller, then as an alternative to methadone, which because of its potential for abuse and overdose, must be dispensed by federally approved clinics. Addicts must visit the methadone clinic every day to get their dose of the pink liquid.

In contrast, Suboxone offers more confidentiality because it is prescribed out of a doctor’s office and dispensed by a pharmacy.

“With Suboxone, the patients have the convenience and ease of coming into a confidential setting in the physician’s office,” said Dr. Kent Vye, the prescriber in Yakima. Vye has had three patients from Spokane come to him for the drug.

“To see somebody whose marriage and employment is on the edge get into recovery, get clean and sober, and get their job and their relationship back, that is gratifying,” he said.

HOW IT WORKS

Suboxone and methadone work in similar ways. They both attach to the same brain receptors as heroin and other opiates. Because they occupy the same chemical parking spaces in the brain, they satisfy the craving caused by addiction, stave off withdrawal symptoms and allow an addict to start rebuilding a life.

Because of its chemical properties, Suboxone is harder to abuse than methadone and less likely to cause a deadly overdose. It also doesn’t cause as much of a euphoric high as methadone.

Both Suboxone and methadone create physical dependence and use must be tapered gradually to avoid withdrawal symptoms.

Experts differentiate between addiction and physical dependence.

“Addiction is compulsive use despite negative consequences; physical dependence is needing a drug to function,” said Maia Szalavitz, co-author of “Recovery Options: The Complete Guide.”

“We’re all physically dependent on air and water, but not addicted to them. Maintenance replaces addiction and its negative consequences with simple physical dependence, which many people have on antidepressants and blood pressure meds, but that doesn’t make them addicts.”

People with experience taking Suboxone are posting messages about it on an Internet discussion board ( www.heroin-detox.com).

Much of the conversation is about withdrawal from Suboxone. People describe trouble sleeping, restless legs, intestinal problems, fatigue and feeling lousy as they taper off the drug.

A sample:

— “I don’t know that I could have quit hydrocodone use on my own. The Suboxone is a very quick-acting replacement that helped me move from one drug to the other. Now the trick will be to taper from it to no opioids.”

— “My doctor tried to start me way too high on sub (Suboxone). He wanted me to take 24 to 32 mgs the first few days. I had read a lot about sub before I started taking it and ‘started myself’ at 8 mgs a day and was fine. As others have said, ‘less is more’ with sub. Also, I wish I had only stayed on sub for a couple of weeks instead of a couple of months. By the time I got off sub I was addicted to it and have had a very rough time detoxing.”

— “My daughter used heroin off and on for about four years. For her, Suboxone was a miracle drug. She was on it for about 10 weeks and had absolutely no withdrawals when she stopped taking it. As far as I know, she is still clean.”

Methadone will always have its place, addiction experts say.

“People are trying to say that (Suboxone) could replace methadone, but that’s like saying Zoloft could replace Prozac. There will always be people for whom certain drugs are better for reasons we don’t know yet,” said author and recovery expert Szalavitz.

“I was instantly transformed into my old self. It’s been a complete miracle for me,” said Chris, an Eastern Washington electrician who is using Suboxone to kick a five-year addiction to OxyContin, originally prescribed for pain from a back injury. “My memory is coming back. My energy level is back. I’m a happy person again.”

3

SIDEBARS:1. FAST FACTSPAINKILLER ADDICTION Spokane’s methadone clinic is overwhelmed with painkiller addicts, who outnumber heroin addicts in the program 2-to-1. Spokane County is seeing a small but growing number of arrests involving prescription drugs. An estimated 4.7 million Americans are current abusers of prescription painkillers, according to the Office of National Drug Control Policy.2. IDAHO’S MEDICAID OFFERS MORE LEEWAYDr. Kent Vye and other doctors who prescribe Suboxone would like to see Washington state’s Medicaid program pay for one year of treatment instead of only six months, the current time limit for patients. Idaho’s Medicaid program gives doctors greater leeway in how long they can keep prescribing Suboxone and get reimbursed through Medicaid. One prescription can be refilled for up to a year, if that’s the way the doctor writes it. After a year, the doctor could write a new prescription. Idaho Medicaid limits patients to 16 mg a day of Suboxone. Washington has no such limit on daily dosage, but requires Medicaid clients to be in a state-approved drug treatment program in conjunction with Suboxone therapy. Washington state also requires a clean urine test every two weeks for a patient to continue on Suboxone. Idaho’s Medicaid program paid for 15 patients to take Suboxone during 2004. Washington’s Medicaid program paid for 61 people to use Suboxone in the first six months of this year.3. TO LEARN MORERESOURCES To locate a treatment facility or a doctor who prescribes Suboxone, go to http://buprenorphine.sam hsa.gov/ bwns_locator/. To reach the methadone program at the Spokane Regional Health District, call (509) 324-1420. Doctors can take an online class to qualify to prescribe Suboxone. Find the class at www.aaap.org and click on “buprenorphine.” An in-person training session for doctors is scheduled for March 5 in Seattle. See www.docoptin.com.

Carla K. Johnson can be reached at (509) 459-5148, or by e-mail at [email protected].