Heart specialists at Johns Hopkins believe they have figured a way around a persistent barrier to successful adult stem cell therapy for millions of Americans who have survived a heart attack but remain at risk of dying from chronic heart failure.

Two clinical trials since 2002 using transplanted adult stem cells successfully led to tissue regrowth in damaged hearts, but 11 of 18 patients later developed potentially fatal heart rhythm disturbances, including one who required cardiac resuscitation. “It was a potential case of the cure being worse than the disease,” says senior researcher and cardiovascular physiologist Eduardo Marbán, M.D., Ph.D., professor and chief of cardiology at The Johns Hopkins University School of Medicine and its Heart Institute. “It was very discouraging to know that these patients developed arrhythmias, yet not know if it was the muscle stem cells at fault or simply a progression of the patients’ heart disease.”

Marbán is also editor in chief of the journal Circulation Research, in which the findings will be published online June 23.

Marbán’s team says it has discovered the source of the arrhythmias to be transplantation of myoblasts, which are adult stem cells taken from patients’ own healthy skeletal muscle. In patients, these myoblasts are injected directly into damaged heart muscle to regrow new tissue. In petri dish studies using these cells, the transplantation process caused an immediate disruption in heart muscle tissue’s regular electrical rhythm, or conductivity, which is necessary to stimulate a regular heart beat.

Moreover, the Hopkins group was able to minimize arrhythmias dramatically by using gene therapy to replace a key protein, called connexin 43, missing in heart muscle fibers that regrew as a result of the stem cell injections. Connexin 43 makes up the gap junctions between muscle cells, allowing cells to communicate with each other to regularly contract and expand.

“We believe that by combining gene therapy with adult stem cell transplantation, we can go a long way to prevent the development of potentially fatal arrhythmias in patients who will have these myoblast transplants,” says Marbán. According to the latest statistics from the American Heart Association, in 2002, there were an estimated 565,000 new cases of heart attack in the United States, plus an additional 300,000 cases of recurrent heart attack. More than 3 million Americans suffer from congestive heart failure, a common target of the myoblast stem cell therapy.

In the study, Marbán and his team created a simulation of stem cell transplantation using healthy muscle cells taken from rats’ hearts and mixing them with myoblasts from healthy human skeletal muscle. A liquid suspension kept both cell types alive, and their electrical interactions were mapped with a voltage-sensitive dye. The team found that mixing the two cell types slowed normal conduction rates among heart muscle cells by two-thirds. Computer printouts of the optical maps showed a spiral-wave pattern, the most common kind of arrhythmia.

Four different mixtures of muscle stem cells were used, with the highest concentrations of stem cells, 20 percent and 50 percent, producing spiral-wave electrical patterns in all cultured heart cells. Lower stem cell concentrations of 1 percent resulted in no arrhythmia, and a 10 percent concentration led to only half of the cultured heart cells showing signs of arrhythmia.

“Our results confirmed that myoblast transplantation was responsible for the arrhythmias and that higher doses of stem cells aggravate the problem,” says cardiologist M. Roselle Abraham, M.B.B.S., an assistant professor at Hopkins who led the study. “But we were not exactly sure how this was related to the subsequent cell regrowth occurring in the heart, or if it could be treated using gene therapy.”

Previous research from animal transplants showed that heart tissue regrowth produced a mix of skeletal and heart muscle, resulting in long strands of muscle fibers. In the Hopkins experiment, for example, muscle fibers ranged in length from 500 microns to 1.5 millimeters when viewed under the microscope.

Though otherwise healthy, these muscle fibers are known to lack gap junctions, or protein connections between cell membranes that allow neighboring cells to communicate with each other through the exchange of ions and other electrical signals, the researchers say.

In the gene therapy experiments, the Hopkins team increased production of connexin 43 by injecting a virus carrying the gene that codes for the gap-junction protein into the cultured cells. The researchers found that the addition of connexin 43 dramatically increased conductivity between cells to normal levels, with only two of nine cultures developing signs of arrhythmia. Meanwhile, a majority of cultures, 13 of 14, which did not receive connexin gene therapy, went on to develop irregular heart-cell signals.

“We think we can now explain some of the underlying problems associated with adult stem cell therapies for heart failure and show how combining them with ex vivo therapy can possibly be more effective,” says Marbán.

While their precise biological action is not known, adult stem cells are a special type of body cell found in skeletal muscle, heart, bone marrow and other tissues that gives rise to other types of specialized cells, including bone, cartilage, fat, and muscle, such as the heart. Because they can be extracted and reinjected into the same person, use of adult stem cells avoids the potiential for rejection by the body’s immune system.

Marbán is also the Michel Mirowski, M.D., Professor of Medicine at Hopkins and director of its Institute of Molecular Cardiobiology.

On the Internet:

Johns Hopkins Medical Institutions

Fox Valley Renegades founder and longtime coach Matt Schacht remembers attempting to change the bulbs atop the light poles at historic Jockey Field in East Dundee.

“The first year we were there, we found the belt they used to wrap around the pole to climb up there and the spur things for your shoes,” said Schacht. “I went up that pole and got up to where the foot pegs were and it started to creek. Dude, I got so scared I thought I was going to wet my pants.”

Those poles (much more on them later) and a variety of other quirks, stories and memories are the things that have made Jockey Field (located on Third Street in East Dundee) one of the most historic softball parks in Northern Illinois – sporting a legacy that dates back to the conclusion of World War II.

Schacht and the rest of the Renegades family have brought back the once-thriving field that boasted some of the best men’s fastpitch softball around from extended dormancy after the slow death of church leagues and men’s fastpitch and have transformed it into a modern, full-amenity youth facility that plays host to a plethora of girls fastpitch travel games each spring and summer.

Jockey Field will host the second annual Fox Valley Senior All- Star Game at 6 p.m. Monday. The game, featuring the top senior high school softball players in the Fox Valley area, is sponsored by the Fox Valley Renegades, the Northern Illinois Lightning, the Daily Herald and Cami Sports & More.

Schacht, a veteran youth sports coach in the Elgin area, started the renovations of the field after ceding from another travel softball organization and starting the Renegades 7 years ago.

“We kind of put the cart before the horse,” said Schacht. “We formed the Renegades really without a place to play. When I was growing up, my parents were members of the VFW in East Dundee. And parents would take their kids there and you’d go to Jockey. I hadn’t been there in years. I wondered what the place looked like. So we all decided to take a ride down there in the middle of winter. It had that immediate look of tradition with the old backstop and the old wooden lights. We asked each other if we thought we could revive it.”

And revive it they did. After getting permission from the property owner (Patricia Thompson, whose father, Woody, owned the property before her) to use the field, Schacht and the Renegades embarked on a refurbishment project that, through hard work and the help of players, parents and sponsors throughout the years, has turned the field into the envy of youth softball facilities (complete with sprinkler system, concession stand and indoor bathrooms).

“There’s no substitute for a vision and hard work,” said Schacht, also noting the tremendous success of Renegades’ teams on the field the past 7 years.

“It’s incredible what we’ve been able to do in seven years.”

But back in the day Jockey Field, originally constructed from funds raised from a pair of charity basketball games according to the Renegades’ Web site, was the place to be for men’s fastpitch softball.

“There was a lot of church league fastpitch and a lot of semi- pro ASA,” said Larry Freeman, a 1961 Dundee High School graduate who used to watch his father “Bull” Freeman play. Larry Freeman is a longtime area high school softball official and was a longtime member of the Jockey Club.

“When the church league was going big, you’d have the whole town going down there on any night of the week. There were a lot of great players.”

Carpentersville resident David Lueck, another longtime member of the Jockey Club, remembers plenty of close contests.

“You’d have teams coming all over from DeKalb and Genoa- Kingston,” said Lueck, a 1939 graduate of Dundee High School. “You’d have games that were 1-1 going 12-14 innings.”

As famous as the stories were about the players and the classic contests, there is equal lore about the field itself.

“The field was an old stockyard,” said East Dundee resident Milt Waschow, who coached the Jockey Club fastpitch team in its heyday and still coaches a women’s softball team in Cary each week. “I was a kid when they poured those light poles. They just dumped bags of cement in there. Those poles (sunk 12-15 feet in the ground) in those (55-gallon) drums have been sitting there since 1947.”

Schacht pointed out that a railroad bed runs underneath the surface through centerfield. Standard Oil, he said, used to have oil towers on the property that held fuel for surrounding homes. A peat moss bed also sits beneath the surface and Schacht says natural wells are below the ground as well. One of the field’s original tractors is still at the field.

“It’s been many things besides a boys and girls softball field,” said Schacht. “To understand the history behind it is cool.”

The famed wooden light poles remain in place to this day and have caused major headaches over the years due to them formerly being in the field of play.

“They put the fence up and the poles were inside the fence,” said Elgin resident Steve Gabler, who played at Jockey. “It was scary when you were chasing a fly ball sometimes. And then if you hit the pole, it was a ground rule double. It didn’t matter if you hit the top. Everybody complained. If you hit it that high up it probably would have rolled to the school (the old Dundee High School which is now the current Carpentersville Middle School). But I wouldn’t change anything. I miss playing there. It was a lot of fun.”

Gabler was one of many talented performers that passed through Jockey over the years. His cousin is Daily Herald Fox Valley sports editor John Radtke.

“He was an awesome pitcher,” said Radtke. “My dad used to take me to Jockey to see Gabe pitch when I was like 10 or something. He could throw a softball as fast as anyone I’ve ever seen.”

Dundee-Crown athletic director Dick Storm was also a talented fastpitch player during the Jockey heyday and remembers those poles vividly.

“Those polls being in play were dangerous,” said Storm, who lauded the efforts of the late Don Swanson and Jim Smith, who both helped with the upkeep of the field when it was dormant prior to the Renegades renovating it. “All they had was a tire around the poles. Someone chasing a fly ball full-boat, that wouldn’t stop anything.”

There were other “home field” advantages as well at Jockey.

“Certain parts of the season you could be carried away by mosquitoes,” said Gabler. “There were other times when the fog was so thick, you couldn’t see the outfielders.”

Even today there are factors that sway in favor of the home team.

“The moths came out the other night for 15 minutes,” said Schacht. “The other team will complain they got a bug in their mouth. Our girls just spit them out.”

Lueck can remember the original construction of the concession stand.

“It was a chicken coop,” said Lueck. “We pulled it across the street and paneled it and put a door on it and used it as a stand. In the original club house, my dad nailed his foot to the rafters. He put the nail right through the shoe and couldn’t move.”

Storm was part of a core group of Jockey Club players that included Steve Trebes, Dave Swanson, current Hampshire High School softball coach Mike Wendt, Jim Roesslein and Daryl Wells. Waschow was their coach.

“I really got hooked on fastpitch softball,” said Storm, whose father, Elmer, also played at Jockey. “It was a good run. We had a group of us that played at Immanuel Lutheran. We were probably responsible for killing off the church league. We were so good nobody could keep up with us. We’d play other churches that had players that were just starting out or had never played before. We had a couple of guys from the Jockey Club and we would just smoke teams.”

Storm didn’t just dabble in softball.

“We played games 37 days in a row once,” said Storm. “There were times where we’d play 100 games over the summer. I fell in love with the sport. My dad used to take me to see Immanuel play. It was like watching the pros. There was no fence at the time. It was like Field of Dreams with cars parked in the outfield and then they had to have rules if the ball bounced under a car. The allure to me was putting myself out there 10-20 years later. We had a good team, but not a great team. We just hung around together. That was our thing.”

Wendt grew up three blocks from the park.

“Oh boy, that was a lot of fun,” said Wendt, who played several years of fastpitch there in the late 60s and early 70s. “I played sandlot ball there from the time I was 10-years-old.”

So where exactly did the name of the field come from? There are varying stories, but all with plausible explanations.

“When the husbands were playing the wives would come along and be jockeying the umpires,” said Freeman.

“They’d razz the other teams when we would go to DeKalb and St. Charles,” said Lueck. “They would get on the other teams. The Jockey Club.”

Waschow had his take on the name as well.

“People would come by when they were working on the field and yell, ‘look at those jockstraps over there working on the field. They’re just a bunch of jockstraps,’ ” said Waschow, a 1952 Dundee High graduate. “There were the jockstraps making the swamps into a ball field.”

And there was an actual Jockey Club, complete with memberships, dues and age limitations.

“There were 35 members maximum and you had to be recommended to join,” said Waschow. “You had to be over 18 because they drank beer. They asked me when I was 19 or 20. Dues were 10 bucks a year.”

“We had quite a few members,” said Lueck. “Masi’s in downtown let us use a place.”

The other feature that distinguished the field was the community involvement.

“There was that old, local town mentality,” said Storm. “It was the place to go. It was the only thing in Dundee at the time. The neighbors were always so supportive. You never heard a complaint.”

“Everybody went over to watch softball,” said Waschow. “The war ended in 1945 and the field was built around 1946-1947. Town sports were big. Everybody sponsored a team. Sometimes it used to cost you 10 cents to get down that road. If you wanted to sit down and watch, they wanted a dime.”

Storm still goes by the field on occasion.

“Every now and then I ride my bike and stop by and watch and wonder how we avoided those polls when we played,” said Storm.

“Time marches on, but that doesn’t mean the memories don’t live on.”

Rockville, Md. ““ A person’s prior knowledge of the geometry of faces affects his or her ability to estimate distance and complete visually guided reaching tasks according to a study published in the June issue of Journal of Vision, an online, free access publication of the Association for Research in Vision and Ophthalmology (ARVO).

In a joint study by the University of Minnesota in Minneapolis, and the University of Giessen and the Max-Planck-Institute Tuebingen, both in Germany, researchers used the “hollow-face illusion” to test if the perceived shape of a face also affects participants’ reaches and verbal estimates of distance. “Hollow-face illusion,” in which a hollow mask viewed from a distance looks like a normal convex, occurs because prior knowledge of the shape of the face is sufficient to override the true depth indicated by other cues such as binocular disparity.

Study participants viewed concave and convex faces and made verbal and reach estimates that indicated their perceived shape of the face. In the verbal task, participants gave a verbal estimate of the distance from their viewing position to either the nose or the cheek of the faces.

In the reaching task, participants touched either the nose or cheek of the face within a certain period of time. The time limit was imposed to ensure the response time was similar to that of the verbal task. The study’s data show that the magnitude of the hollow-face illusion is similar for reaching tasks and verbal tasks.

Volker H. Franz, PhD, one of the study’s researchers says, “We show that prior knowledge about the general shape of faces can interact with the information the person acquires from vision at the time of the action. Without the knowledge that they are reaching to a face and what the typical shape of a face is, participants would perform the reaching movements differently. This stresses the importance of object recognition even for very simple motor tasks and shows that humans perform these actions in a more complex way than, for example, typical applications in robotics which do not take into account prior knowledge about objects.”

On the World Wide Web:

Association for Research in Vision and Ophthalmology

ABSTRACT

Perimenopause marks the transition from normal ovulation to anovulation and ultimately to permanent loss of ovarian function. Fecundity, the average monthly probability of conception, declines by half as early as the mid-forties, however women during the perimenopause still need effective contraception. Issues arising at this period such as menstrual cycle abnormalities, vasomotor instability, the need for osteoporosis and cardiovascular disease prevention, as well as the increased risk of gynecological cancer, should be taken into consideration before the initiation of a specific method of contraception. Various contraceptive options may be offered to perimenopausal women, including oral contraceptives, tubal ligation, intrauterine devices, barrier methods, hormonal injectables and implants. Recently, new methods of contraception have been introduced presenting high efficacy rates and minor side- effects, such as the monthly injectable system, the contraceptive vaginal ring and the transdermal contraceptive system. However, these new methods have to be further tested in perimenopausal women, and more definite data are required to confirm their advantages as effective contraceptive alternatives in this specific age group. The use of the various contraceptive methods during perimenopause holds special benefits and risks that should be carefully balanced, after a thorough consultation and according to each woman’s contraceptive needs.

KEY WORDS Perimenopause, Contraception, Oral contraceptives, IUDs, Tubal ligation, Barrier contraceptive methods, Hormonal injectables and implants

INTRODUCTION

Perimenopause is defined as the period before, during and after the menopause. The length of this period varies, but it is usually considered to last approximately 7 years, beginning with the decline in ovarian function in a woman’s forties and continuing until she has not had a menstrual period for 1 year. The average duration of the perimenopause is 5 years, with an average age of onset around the 46th year1. The most important hormonal change during the so- called menopausal transition is anovulation. Although fecundity, i.e. the average monthly probability of conception, declines by 50% at age 43, up to 80% of women between 40 and 43 are still able to conceive2,3. Thus, women in perimenopause need adequate counseling regarding their current contraceptive options.

HORMONAL CHANGES IN PERIMENOPAUSE

Data suggest that during perimenopause ovarian follicles undergo an accelerated rate of loss until they are finally depleted4. It seems that aging follicles lose their productive quality. As a sequence, secretion of inhibin is reduced and the negative feedback influence over follicle-stimulating hormone (FSH) secretion by the pituitary gland is lost. As inhibin A and inhibin B levels decrease with aging, FSH levels rise5,6. In contrast, levels of estradiol and luteinizing hormone remain in the normal range, and start to decline almost 1 year before menopause7,8. All the above lead to chronic anovulation, which explains the low fecundity rates in this age group. Occasionally, ovulation takes place and the risk of an unplanned and unwanted pregnancy is always present. Even with high levels of FSH ( > 20 IU/l), occasional resumption of ovarian function has been demonstrated8,9. Therefore, the need for contraception until the postmenopausal state has been established is recommended, especially in sexually active women.

PERIMENOPAUSE: THE SYMPTOMS

The majority of women during their mid-forties experience unique changes. The most common complaint is abnormal uterine bleeding, which occurs in more than half of all women during the menopausal transition10. The perimenopausal bleeding patterns encountered are sudden amenorrhea (12%), oligomenorrhea or hypomenorrhea (70%) and menorrhagia, metrorrhagia and hypermenorrhea (18%)11. Vasomotor disturbances (hot flushes and cold sweats) are common perimenopausal symptoms. It has been estimated that almost 50% of those women complain of hot flushes12. Finally, atrophic genital changes, including vaginal dryness, itching and dyspareunia, may contribute to sexual dysfunction13.

RISKS OF PREGNANCY DURING PERIMENOPAUSE

It has been estimated that the induced abortion rate of unintended pregnancies among women above 40 is nearly 60%14. These figures clearly demonstrate that a pregnancy in this age group is usually considered an unwanted pregnancy. On the other hand, pregnancy in women over 35 years of age carries increased risks for both the mother and the fetus. In particular, there is an increased frequency of gestational diabetes, placenta previa, breech presentation, postpartum hemorrhage, operative vaginal delivery, emergency or elective Caesarean section, premature delivery, low birthweight and stillbirth15. Women aged > 40 years had even higher risk for the same complications. Also, increased maternal age has been directly related to fetal aneuploidy16, and to increased spontaneous abortion rates17.

CONTRACEPTION OPTIONS FOR THE PERIMENOPAUSAL WOMAN

The above information leads to the certain conclusion that contraception during perimenopause is of paramount importance. An unplanned pregnancy during the perimenopausal years leads to high induced or spontaneous abortion rates. In addition, the age-related increased maternal morbidity and mortality have to be taken into consideration, as well as the perinatal mortality under those circumstances. Also, contraception may offer improved sexual relationships and therefore, a higher quality of living. Therefore, health-care providers have to be familiar with today’s contraceptive methods and capable of proper counseling, regarding the benefits and risks of each one.

Periodic abstinence

As mentioned above, the menstrual cycles of perimenopausal women are grossly irregular, shorter or longer than normal. The menstrual period is also abnormal, either heavier or lighter. Intermenstrual bleeding is common as well. Therefore, ovulation prediction may be difficult, and probably unreliable.

Female sterilization

Female sterilization is currently the most common method of contraception used by perimenopausal women in the United States , and probably in many other developed countries. Contrary to general belief, it is not more effective than other methods. However, female sterilization remains a very effective contraceptive method for the perimenopausal woman, with a reported failure rate from 0.75 to 3.65%, according to the method used19. Currently, modern laparoscopic sterilization takes place as a 1-day surgical procedure, with operative risks directly related to laparoscopy and anesthesia. Female sterilization seems to protect from ovarian cancer probably because of reduced ‘carcinogen transmission’ through the closed tubes20. Tubal ligation afforded a risk reduction even 20 or more years after the surgery21. On the other hand, it does not seem to affect the menstrual cycle22. A major disadvantage of the method is the lack of protection against sexually transmitted diseases. Sterilization regret and reversal request, although common in younger women, are not of major concern in older women23.

Barrier methods

Perimenopausal women, especially those with infrequent sexual intercourse, may find barrier methods extremely suitable. Female condoms, cervical caps and vaginal diaphragms have not gained wide acceptance, whereas male condoms are much easier to use, and therefore remain widely accepted both in developing and developed countries. Efficacy rates are estimated to be around 86-88%24. Barrier methods, especially condoms and diaphragms, present the advantage of decreasing sexually transmitted diseases25, cervical intraepithelial neoplasia and invasive cervical cancer26, without major side-effects. On the other hand, they must be used during each sexual intercourse and more important, they do not reduce menstrual irregularities and perimenopausal symptoms, such as hot flushes and cold sweats.

Injectable hormonal contraceptives

Depomedroxyprogesterone acetate (DMPA), in the form of an intramuscular injection every 3 months, is a highly efficient contraceptive method27. On the other hand, its use is associated with common side-effects, such as depression, headache and weight gain. Furthermore, DMPA causes abnormal spotting and irregular bleeding, which are unacceptable for the perimenopausal woman. In addition, there is evidence that medroxyprogesterone increases bone lose and osteoporosis, both of which are also unacceptable28. Another available injectable combination, recently approved in the United States, called Lunelle, consists of 25 mg DMPA plus 5 mg estradiol cyprionate. Given once a month, this combination produces excellent contraceptive effects29. It does not cause abnormal bleeding, and because of the estrogen it contains it may relieve climacteric symptoms and prevent osteoporosis. Up to now, it has not been adequately studied in perimenopausal women.

Implants

Currently, contraceptive implant technology has been used by millions of women throughout the world, however there are not sufficient data regarding its use by women in perimenopause. The three marketed implant systems today are levonorgestrel-releasing implants (Norplant and Jadelle), and a single etonogestrel- releasing implant \(Implanon)30. The subcutaneous hormonal contraceptive systems present high efficacy rates as well as safety, long duration of action (3-5 years) and reversibility30-32. Unfortunately, they cause common side-effects such as abnormal bleeding, headache and depression. Additionally, a health-care provider is needed to insert and remove them. For these reasons, they have not gained wide acceptance among perimenopausal women.

Intrauterine devices

lntrauterine devices (IUDs) seem to be very appealing for contraception during the perimenopause. Both the copper-containing IUD and the 20 g/day levonorgestrel intrauterine system (Mirena), especially the latter, show remarkably low pregnancy rates33,34. The method requires insertion by a health-care provider, but no other effort thereafter. Standard risks include pelvic inflammatory disease (PID), usually within 20 days after insertion, and uterine perforation during the procedure. As far as ectopic pregnancy is concerned, intrauterine devices reduce the risk by 80-90%35. The copper IUD may increase menstrual bleeding and dysmenorrhea, an unwanted side-effect during perimenopause. The levonorgestrel IUD produces atrophic endometrium, and reduces menstrual flow and dysmenorrhea. It also increases the risk of amenorrhea, which actually could be a benefit instead of a risk for many women36. Recently, a new 14-g/day levonorgestrel-releasing IUD has been tested in peri- and postmenopausal women. It has shown excellent compliance along with contraceptive efficacy37. Since the effectiveness of all the above systems lasts for 5-10 years, both can offer adequate contraception during the perimenopause.

Oral contraceptives

Without doubt, the oral contraceptive pill (OC) is one of the most effective contraceptive methods available. The reported efficacy rates are about 99% with perfect use38. Unfortunately, only a minority of women during perimenopause uses the OCs, mainly because of major fears regarding the relationship between the OCs and breast cancer, or cardiovascular events in this age group. Only 11% of women aged 40-44 years and 4% of women aged 45-50 are using oral contraceptives39. The reduction of the estrogen and progestogen concentrations in modem OCs during the last decades, especially the reduction of estrogen to less than 50 g, has led to a corresponding reduction in the incidence of the above health risks. As far as breast cancer is concerned, data show a small increase during OC use, which begins to decline shortly after stopping and which disappears 10 years after discontinuation40. In addition, many studies suggest that long-term use of OCs possibly increases the risk of cervical cancer, and the relative risk increases with increasing duration of use41-43. In normotensive and nonsmoking perimenopausal women, without other risk factors, there is no additional risk for myocardial infarction or stroke44-48. Finally, there is only a small risk associated with venous thromboembolism in OC users, actually half the risk observed during pregnancy48,49. The highest risk of venous thromboembolism is observed with preparations containing third-generation progestogens (desogestrel or gestodene)48.

On the other hand, OCs demonstrate major health benefits beyond the female reproductive system. The best-established health benefit is the reduction of ovarian cancer risk, with suppression of ovulation being the mechanism responsible50. A series of reports and meta-analyses in the last 15 years, clearly support a risk reduction for ovarian cancer with OC use. Women taking OCs for 10 or more years, showed the greatest risk reduction, around 80%51. The protection against ovarian cancer seems to last up to 15 years after discontinuation and is independent of the contraceptive formulation taken52. There is no definite information regarding the new OCs containing 20 g of ethinylestradiol, and there is no definite answer whether carriers of the BRCA1 and BRCA42 mutations are protected as well53,54. The incidence of endometrial cancer and colorectal cancer increases particularly during the perimenopausal years. The risk for a woman who has ever used an OC, of endometrial cancer is reduced by 50-80% in comparison to that for a nonuser, depending on duration of use55,56. The protective effect is independent of the formulation or dose and lasts for at least 15-20 years after discontinuation56,57. The protective mechanism seems to be the antimitotic effect of the OC progestogen on the proliferative endometrium and the reduction of estrogen-associated endometrial hyperplasia. Information regarding the relation between OCs and colorectal cancer is less clear. Recent data however, suggest a significant reduction in the incidence of colorectal cancer among OC users58.

PID is one of the commonest benign disorders of the female reproductive tract, responsible for serious complications such as infertility and pelvic pain. The risk of PID is reduced by 50% among OC users in comparison to nonusers59,60. It is believed that the OCs act by thickening the cervical mucus, decreasing retrograde menstruation and reducing menstrual now. Both high-dose and low- dose OCs cause a marked reduction in both functional cysts and corpus luteum cysts61,62. Studies have also demonstrated a reduction in breast fibroadenomas and chronic breast cysts63. Recent data suggest that OCs may decrease the risk of osteoporosis and postmenopausal hip fracture by 30% in perimenopausal women64. OC use has been proved to decrease both the incidence and progression of rheumatoid arthritis65. Finally, OCs relieve dysmenorrhea, reduce the amount and duration of the menstrual period and thus deal with perimenopausal dysfunctional bleeding66,67.

Contraceptive vaginal ring

A new contraceptive vaginal ring containing ethinylestradiol and etonogestrel, traded as Nuvaring, has become available in the United States and in Europe recently. The ring delivers the hormonal combination for 3 weeks on a monthly basis, like modern OC regimens. Data suggest high efficacy rates, high compliance rates and minor side-effects68. It seems that the contraceptive vaginal ring, having as a major advantage its easy method of use, might represent a promising contraceptive method during perimenopause. It has not been tested in that specific age group, so more definite data are required.

Transdermal contraceptive system

The first transdermal contraceptive patch has been recently approved in the USA and many European countries, called Ortho Evra. It delivers ethinylestradiol and norelgestromin (17- deacetylnorgestimate), over a 3-week period, like the OCs and the contraceptive vaginal ring. The reported failure rate is about 0.70 pregnancies per 100 woman-years for perfect use, except individuals weighing over 90 kg, in whom use is associated with lower efficacy rates69. The above regimen offers cycle control similar to that offered by the OCs, with a similar side-effect profile70. The main advantage of the method, compared to the OC, is the higher compliance rates, making it very attractive both for nonmenopausal and menopausal women. Like the contraceptive vaginal ring, more studies are needed to confirm these preliminary suggestions.

CONCLUSIONS

Women during the perimenopausal years, have to be aware of the risks of an unwanted pregnancy and the variety of the contraceptive methods offered. There is no contraceptive method that is contraindicated merely by age, consequently a variety of contraceptive methods are suggested for perimenopausal women, including female sterilization, barrier methods, IUDs, injectables, implants and OCs. Clearly, the ideal contraceptive method has not yet been found, and each one presents certain advantages and disadvantages. Modern OCs, compared to other common methods of contraception such as female sterilization, barrier methods, and the levonorgestrel-releasing IUDs, demonstrate high contraceptive efficacy together with significant noncontraceptive benefits for the perimenopausal woman. Moreover, based on accumulating data over the last few years, there is a clear shift from OC-related risks to health benefits, and for that reason OCs probably represent the first choice during the perimenopause. Nevertheless, new preparations, like the monthly injection, the vaginal contraceptive ring, and the transdermal contraceptive system, seem to be promising as well. That remains however to be proved by further large studies specifically in women in perimenopause.

REFERENCES

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2. Toner JP, Flood JT. Fertility after the age of 40. Obstet Gynecol Clin North Am 1993;20:261-72.

3. Schmidt-Sarosi C. Infertility in the older woman. Clin Obstet Gynecol 1998;41:940-50.

4. Richardson SJ, Senicas V, Nelson JF. Follicular depletion during the menopausal transition – evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231-7.

5. Klein NA, Illingworth PJ, Groome NP, et al. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab 1996;81:2742-5.

6. Welt CK, McNicholl DJ, Taylor AE, et al. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999;84:105-11.

7. MacNaughton J, Bangah M, McCloud P, et al. Age-related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and imimmoreactive inhibin in women of reproductive age. Clin Endocrinol 1992;36:339.

8. Burger HG, Dudley EC, Robertson DM, et al. Hormonal changes in the menopause transition. Recent Pros Horm Res 2002;57:257-75.

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28. Berenson AB, Radecki CM, Grady JJ, et al. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol 2001;98:576-82.

29. Kaunitz AM. Lunelle monthly injectable contraception: an effective, safe, and convenient new birth control option. Arch Gynecol Obstet 2001;265:119-23.

30. Brache V, Faundes A, Alvarez F. Risk-benefit effects of implantable contraceptives in women. Expert Opin Drug Saf 2003;2:321- 32.

31. Darney PD. Hormonal implants: contraception for a new century. Am J Obstet Gynecol 1994;170:1536-43.

32. Davies GC, Li XF, Newton JR, et al. Release characteristics, ovarian activity and menstrual bleeding pattern with a single contraceptive implant releasing 3 Keto desogestrel. Contraception 1993;47:251-61.

33. Pakarinen P, Toivonen J, Luukkainen T. Randomized comparison of levonorgestrel- and copper-releasing intrauterine systems immediately after abortion, with 5 years’ follow-up. Contraception 2003;68:31-4

34. Sivin I, Stem J, Coutinho E. Prolonged intrauterine contraception: a seven-year Contraception 1991;44:473-80.

35. Sivin I, Stern J. Health during prolonged use of levonogestrel 20 micrograms/d and the copper Tcu 380A intrauterine contraceptive devices: a multicenter study. Fertil Steril 1994;61:70- 7.

36. Onyeka BA. Levonorgestrel-releasing (20mcg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives. Br J Obstet Gynecol 2001;108:770-1.

37. Wildemeersch D, Schacht E, Wildemeersch P. Performance and acceptability of intrauterine release of levonorgestrel with a miniature delivery system for hormonal substitution therapy, contraception and treatment in peri and postmenopausal women. Maturitas 2003;44:237-45.

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39. Ortho-McNeil P. Ortho Annual Birth Control Study 1999. Raritan, NJ: Ortho-McNeil Pharmaceutical, 2000.

40. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives:collaborative reanalysis of individual data on 53,297 with breast cancer and 100,239 women without breast cancer from 54 epidimiological studies. Lancet 1996;347:1713-27.

41. Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives : a systematic review. Lancet 2003;361:1159-67.

42. Beral V, Hermon C, Kay C, et al. Mortality associated with oral contraceptive use: 25 year follow-up of cohort of 46000 women from Royal College of General Practitioners’ oral contraceptive study. BMJ 1999;318(7176):96-100.

43. Moreno V, Bosch FX, Munoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002;359:1085-92.

44. Lewis MA, Heinemann LAJ, Spitzer WO, et al. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women: results from the transnational study on oral contraceptives and the health of young women. Contraception 1997;56:129-40.

45. WHO Scientific Group. Cardiovascular disease and steroid contraception: report of a WHO scientific group. Technical Report 877. Geneva: World Health Organisation, 1998.

46. Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low-dose contraceptives. N Engl J Med 1996;335:8-15.

47. Sidney S, Petitti DB, Quesenberry CP. Myocardial infarction in user of low-dose oral contraceptives. Obstet Gynecol 1996;88:939- 44.

48. Consensus conference on combination oral contraceptives and cardiovascular disease. Fertil Steril 1999;71(suppl. 3):1S-6S.

49. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynecol 1995;15:195-200.

50. Purdie DM, Bain CJ, Siskind V, et al. Ovulation and risk of epithelial ovarian cancer. Int J Cancer 2003;20:104:228-32.

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52. Siskind V, Green A, Bain C, et al. Beyond ovulation: oral contraceptives and epithelial ovarian cancer. Epidemiology 2000;11:106-10.

53. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424-8.

54. Modan B, Hartge P, Hirsch-Yechezkel G, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001;26:345:235-40.

55. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Combination. Oral contraceptive use and the risk of endometrial cancer. JAMA 1987;257:796-800.

56. Weiderpass E, Adami HO, Baron JA, et al. Use of oral contraceptives and endometrial cancer risk (Sweden). Cancer Causes Control 1999;10:277-84.

57. Schlesselman JJ. Oral contraceptives and neoplasia of the uterine corpus. Contraception 1991;43:557-79.

58. Fernandez E, LaVecchia C, Balducci A, et al. Oral contraceptives and colorectal cancer risk: a meta-analysis. Br J Cancer 2001;84:72-727.

59. Rubin GL, Ory HW, Layde PM. Oral contraceptives and pelvic inflammatory disease. Am J Obstet Gynecot 1982;144:630-5.

60. Wolner-Hanssen F, Eschenbach DA, Paavonen J, et al. Decreased risk of symptomatic chlamydial pelvic inflammatory disease associated with oral contraceptives. JAMA 1990;263:54-9.

61. Vessey M, Metcalfe A, Wells C, et al. Ovarian neoplasms, functional ovarian cysts, and oral contraceptives. BMJ 1987;294:1518- 20.

62. Lanes SF, Birmann B, Walker AM, et al. Oral contraceptive type and functional ovarian cysts. Am J Obstet Gynecol 1992;166:956- 61.

63. Brinton LA, Vessey MP, Flavel R, et al. Risk factors for benign breast disease. Am J Epidemiol 1981;113:203-14.

64. Michaelsson K, Baron JA, Farahmand BY, et al. Oral contraceptive use and the risk of hip fracture:a case-control study. Lancet 1999;353:1481-4.

65. Jorgensen C, Picot MO, Bologna C, et al. Oral contraception, parity, breastfeeding, and severity of rheumatoid arthritis. Ann Rheum Dis 1996;55:94-8.

66. Apgar BS. Dysmenorrhea and dysfunctional uterine bleeding. Prim Care 1997;24:161-78.

67. Larsson G, Milsoni I, Lindstedt G, et al. The influence of a low-dose combined oral contraceptive on menstrual blood loss and iron status. Contraception 1992;46:327-34.

68. Mulders TM, Dieben TO. Use of the novel combined cotraceptive vaginal ring (Nuvaring) for ovulation inhibition. Fcrtil Steril 2001;75:865-70.

69. Smallwood GH, Meador ML, Lenihan JP, et al. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol 2001;98:799-805.

70. Burkman RT. The transdermal contraceptive patch:a new approach to hormonal contraception. Int J Fertil Womens Med 2002;47:69-76.

N. A. Kailas, S. Sifakis and E. Koumantakis

Department of Obstetrics and Gynecology, University of Crete, Heraklion, Greece

Correspondence: Dr E. Koumantakis, Department of Obstetrics and Gynecology, University of Crete, Heraklion, Crete

2005 European Society of Contraception

DOI: 10.1080/13625180400020861

MS 312

Received 24-10-04

Accepted 5-06-04

Copyright CRC Press Mar 2005

WEST LAFAYETTE, Ind. ““ Purdue University researchers may have isolated the substance most responsible for the tissue damage that follows initial spinal cord injury, a discovery that could also improve treatments for a host of other neurodegenerative conditions.

A research team led by Riyi Shi (REE-yee SHEE) has found that a chemical called acrolein, a known carcinogen, is present at high levels in spinal tissue for several days after a traumatic injury. Although acrolein is produced by the body and is non-toxic at normally occurring low levels, it becomes hazardous when its concentration increases, as it often does in tissue that experiences stresses such as exposure to smoke or pesticides. That list of stresses now includes physical damage, and in the case of spinal injury, acrolein’s hazard may be the key in causing debilitating paralysis that sets in after the initial trauma.

“When a spinal cord ruptures, not only are the traumatized cells at increased risk of damage from free radicals that oxidize the tissue, but the cells also spill chemicals that actually help the free radicals to launch repeated attacks,” said Shi, who is an associate professor of neuroscience and biomedical engineering in Purdue’s School of Veterinary Medicine and Weldon School of Biomedical Engineering. “Our latest research indicates that acrolein may be the primary culprit that enables this vicious cycle. Because acrolein has already been implicated in cancer and neurological diseases, drugs that detoxify it could become important for treating not only spinal cord damage but a host of other conditions as well.”

The research, which Shi carried out with his student Jian Luo and Koji Uchida of Japan’s Nagoya University, appears in the (still forthcoming) March 2005 issue of the scientific journal Neurochemical Research.

Free radical molecules are well-known enemies of bodily health, and for years, physicians have recommended a diet rich in antioxidants ““ such as vitamins C and E ““ which are able to attach themselves to free radicals, detoxifying them. While there is nothing inherently wrong with this approach, Shi said, it might not be getting at the root of some health problems.

“Antioxidants are good scavengers of free radicals, and it’s certainly wise to have plenty of them circulating in your bloodstream,” he said. “The trouble is that when free radicals start attacking tissue, it happens in a tiny fraction of a second, after which they are gone. But the acrolein that these attacks release survives in our bodies much longer, for several days at least, and its toxicity is well documented.”

For example, acrolein has long been known to cause cancer when its concentration in the body rises, and not much is needed to be dangerous. When a person inhales smog or tobacco smoke, for example, the fluids lining the respiratory tract show an acrolein concentration of about a millimole ““ not much by measuring-cup standards, but still over 1,000 times more than usual.

“If you took a single grain of salt from a shaker and dissolved it in a liter jug, the water wouldn’t taste very salty,” Shi said. “But even that would be more than a millimole, and that’s much more acrolein than the body can handle at once.”

Because a high concentration of acrolein also has been linked to neurodegenerative conditions such as Parkinson’s, Huntington’s and Alzheimer’s diseases ““ all of which progress slowly and resist treatment ““ Shi’s team decided to see if the chemical was present in another slow-developing, seemingly untreatable condition: the degeneration of the spinal cord after initial traumatic injury.

“Unlike most other parts of the body, spinal cord tissue does not heal after injury,” Shi said. “After the initial shock, it actually gets worse. Science has long been aware that some chemicals the damaged cells release are part of the problem, but no one has ever been sure which chemicals are responsible.”

When a spine is damaged, the change in its ability to function follows a well-defined pattern. In response to the initial shock, the spine immediately becomes completely nonfunctional but then starts to recover quickly. Over the course of the next few days, in response to the secondary damage, the spine’s function again begins to drop, and within about three days it has leveled off at a point of near non-functionality.

“What our group did was measure the levels of acrolein in the injured spines of 25 guinea pigs for several days following an injury,” Shi said. “We found that levels of acrolein peak 24 hours afterward, and they remain high for at least a week. Because acrolein has such a long lifespan and is so toxic, we theorize that it is primarily responsible for the secondary damage that keeps injured spines from healing.”

Acrolein’s involvement with other conditions suggests that it could be the key to fighting a number of diseases, Shi said.

“When the brain suffers a stroke, for example, it is deprived of oxygen, which is often thought to be the cause of brain damage. But, in fact, you can starve the nervous tissue of oxygen for up to an hour without harm if only you control the acrolein levels,” Shi said. “This paper suggests that the body is generally pretty resilient but that acrolein may be something it can’t handle.”

Shi said that some drugs already under development for other conditions could be used to treat neurodegenerative diseases as well.

“Hypertension drugs, which bind to acrolein and detoxify it, are already under study for their added potential to promote liver health,” Shi said. “We would like to see whether they also could be modified to treat the conditions we are interested in.”

Further research will be necessary to determine how great a role acrolein actually plays in the process of secondary spinal cord damage, but Shi said that once this role is clarified, drugs that counter acrolein’s effects could join the other approaches to treating spinal cord injury under development at Purdue’s Center for Paralysis Research.

“My colleague Richard Borgens and I have already had our hands in developing PEG, a substance that coats damaged spinal cells so that their membranes can heal and also oscillating field stimulator implants that encourage the tissue to regenerate,” Shi said. “We are hopeful that detoxifying acrolein will allow doctors to stop the chemical attack cycle as well, adding to the number of treatment methods available.”

The center was established in 1987 both to develop and to test promising methods of treatment for spinal cord injuries. The center uses its close affiliation with the Department of Veterinary Clinical Sciences in the College of Veterinary Medicine to move basic laboratory methods into clinically meaningful veterinary testing.

This research was funded in part by the National Institutes of Health and the State of Indiana.

On the Web:

Purdue University

Dear Dr. Gott: For the past five years, from time-to-time, my feet peel. The situation isn’t uncomfortable, but it’s annoying. What causes such enormous amounts of skin to peel from my feet?

Dear Reader: Peeling feet often reflect the presence of a fungus infection, resembling athlete’s foot, in the skin. The yeast disrupts the integrity of the skin, causing portions of dead skin (callus) to peel away.

This condition can easily be diagnosed by your family doctor, using skin scrapings that are specially treated and examined in the laboratory.

If a fungus is identified, treatment with antifungal creams, such as Nizoral, should cure the condition.

If no fungus is present in the skin sample, you should be referred to a dermatologist, because skin diseases, such as eczema and psoriasis, can also cause peeling feet and should be treated with other prescription medications.

Dear Dr. Gott: I use cornstarch as a dusting powder and have been very pleased with the results. Now I am concerned about whether inhalation of pure cornstarch can cause an accumulation in the lungs like coal dust or asbestos particles. Since it is corn-based, can it be absorbed by the body and disposed of as waste?

Dear Reader: Cornstarch is a digestible substance, unlike asbestos, silica and talc. Therefore, it will not cause lung damage or respiratory disorders when used appropriately as a dusting powder.

Obviously, as with any inhaled vapor or dust, you should minimize your exposure (by not breathing in excessive quantities of cornstarch). However, when used prudently, this product is safe and, as you’ve discovered, quite effective.

Dear Dr. Gott: I have a problem with my fingernails splitting and peeling. I’ve been told that folic acid might help. Since I’m in my 70s and there’s no chance of my getting pregnant, I wonder if this is a possible remedy.

Dear Reader: Splitting of the nails commonly accompanies old age. The condition is annoying and difficult to treat. Traditionally, protein supplements (such as gelatin) have been used to strengthen the nails.

I am not aware that folic acid, a necessary nutrient for normal cell metabolism, helps cure split nails. Generally speaking, folic acid deficiency causes anemia and malnutrition during pregnancy. The Recommended Daily Allowance is 400 milligrams per day for adults.

The substance is completely safe and is routinely prescribed for expectant mothers; toxicity from folic acid has not been reported to occur when taken according to the recommended dose.

If readers would like to contact Dr. Gott, they may write him through your newspaper or send their mail directly to Dr. Gott c/o United Media, 200 Madison Ave., 4th fl., New York, NY 10016. However, if readers want to request a newsletter, they should write to the Ohio address.

THREE months after that most glamorous of operations bunion removal I found myself with a shapelier foot but a considerably less svelte body.

All that enforced rest had left me half a stone heavier and with all the energy of a slug, so the offer to spend a week at the renowned Le Saint Geran Hotel in Mauritius following their ‘slimming desire’ programme which includes a four-handed massage was irresistible.

First day..

GREETED by a squad of hotel staff I’m ushered into the Givenchy spa, where I am weighed and pinched with metal forceps by my personal trainer, Maggie. She gives my upper body and legs the OK but looks shocked by my ample middle and seems surprised that I have only two children. Tomorrow we start in earnest in the pool.

After a jetlag-busting massage, I have the ‘slimming desire’ dinner, which includes a delicious pineapple tart. I wonder how this can possibly be slimming but am assured by the charming waiter that it is ‘all in the molecules’.

Friday..

MY first session in the pool with Maggie is a revelation. Feel rather smug because she thinks my front crawl is slick but then she makes me propel myself through the water in a cycling motion while holding aquatic dumbbells.

Fiendishly difficult and makes me feel rather like Alice in Wonderland, working very hard to keep still.

Workout in the pool is followed by a session in a bubbling hydrotherapy bath which, while not exactly unpleasant, is the closest I hope I will ever get to being in the spin cycle of a washing machine.

Lunch is a munificent three portions: cold celery soup, fillet of beef and another pineapple tart. Feel very virtuous as I push the beef around on my plate, decline the bread and look away as they bring petit fours with my citronella tea.

After lying on the beach trying to spot the breasts that have been surgically enhanced, it’s off for a session in the gym with the gorgeous Ludovic who, for me, puts the desire into this ‘slimming desire’ programme.

Am mortified when he puts me on the ‘senior exercise programme’and insist on doing more than he recommends to prove how young and fit I really am.

Saturday…

THE laid-back Maggie has been replaced by Prakash, who shows no mercy. He keeps asking me how often I go to the gym at home and, when I mumble something about going whenever I have time, he orders me to do another four lengths of underwater bicycling.

After lunch decide to go on an undersea walk, which looks quite charmingly Jules Verne-ish and not strenuous at all.

Indescribable sensation walking, wearing a plastic astronaut helmet connected to the mother ship by a plastic tube, through shoals of fish. Am quite disconcerted, though, when the guide gives me a black phallic object to hold a sea cucumber and then takes my picture, his leer clearly visible through his visor.

Adjourn to the beachside bar to watch the sunset, drinking citronella tea rather than one of the sensational cocktails that

everyone else is having.

Feeling a little desolate about spending the evening alone, I have a four-handed massage with ylangylang oil. This involves a man and a woman massaging every inch of my body with scented unguents and is probably the closest I am ever going to get to a threesome!

It was recommended to me by a French friend who said it was the only massage where they really got to grips with her bottom.

Afterwards, stagger to the dining room where I am served with another delicious meal of smoked marlin, grilled tuna and strawberry ice-cream. Find it hard to believe that so much utterly delicious food can really be slimming but the chef swears it is all about portion control.

Am also allowed a glass of wine, which again I find hard to believe, but the truth will out when I get weighed on Wednesday.

Back in my room, attempt to watch Minority Report but Tom Cruise is no match for the luscious fatigue that overwhelms me. For the first time in many weeks I sleep without waking up at four in the morning in an existential panic.

Sunday…

OVERSLEEP and gulp down the poached egg and kiwi fruit that makes up my ‘slimming desire’ breakfast. The butler looks rather hurt when I don’t receive the complimentary rose with due ceremony.

Hurtle down the corridor to the pool, where I am instantly brought to my senses by front-crawl sprints. Achieve a best time of 19 seconds, which Ludovic tells me isn’t bad for a woman of my age.

I instantly decide to take up marathon running and ask Ludovic if he thinks I could run one this time next year. He laughs for quite a long time then says kindly I might be able to manage a 10k.

Venture afterwards to the local market at Flacq, which bristles with bindis, gorgeous jangling bracelets, pashminas and saris. Am persuaded into buying two saris after the stallholder drapes one around me and tells me how tall and elegant it makes me look. As I have only a hand mirror to look in, I can’t tell if he is telling the truth or whether I really look like Cherie Blair going to an Asian fundraiser.

Very few other tourists in the market.

Maybe they have all gone to the ubiquitously advertised Rude clothing store. Am keen to pay a visit there myself but have to get back to the Givenchy spa for something called the No Complex massage.

This is advertised by a picture of a model, wearing a pink wisp of material, who clearly has no complex at all about her perfect bottom, tummy and thighs. Having always been a little sceptical about anti-cellulite creams, I find it hard to believe there is no gain without pain. But, as my stomach has lately been looking not so much dimpled as cratered with cellulite like the inside of an Aero bar, I decide I have nothing to lose.

Except my complexes, of course, as the treatment consists of Menek, a beautiful Mauritian man, twiddling the flesh on my bum, thighs, tummy and, yes, breasts to break down the fat deposits with special site-specific creams. He says I need at least four treatments to see an effect but, as I stand under the cruel light of my bathroom mirror that night, I swear that my hips and tummy look a little less lunar-like.

Monday…

BAD news have just heard that a dear friend has been diagnosed with inoperable cancer. Feel horribly dislocated lying on a perfect, white, sandy beach, being waited on hand and foot, while he is going through so much pain.

Maggie, my trainer, is briskly sympathetic and tells me I will feel better after a workout, which strangely enough I do. Endorphins are wonderful things. Resolve to keep up this level of activity when I get home.

In completely irrational moment decide to learn how to waterski.

Given that I am probably the most uncoordinated person on the planet, who failed her driving test 13 times, who singularly failed to learn how to play tennis and who was never picked for any sports team, learning to waterski is a tall order. But, then again, so is dealing with cancer.

The waterski instructors are tough but patient. We spend about 30 minutes on deck learning how to stand up in the skis. Finally, I get into the water and spend an hour just trying to get up without success. My legs feel like they are being ripped apart. But slowly and surely I make progress and after three hours in the water, I finally stand up, knees bent, arms straight, head up.

Manage an almost complete circuit of the lagoon but spoil it all by falling off just as I reach the boathouse. However, I get a round of applause from the instructor, who tells me: ‘You stuck with it, madame. I am the best teacher and I have to tell you I was worried but you did it.’ Feel convinced that if I can learn to waterski, my friend can beat his cancer.

After my waterski triumph, I can’t face another evening eating alone and Sally, the charming rep with ITC Classics, which has arranged my holiday, takes pity on me and invites me to the most beguiling restaurant in Grande Baie called Il Pescatore.

Waiter brings me what looks like a fruit juice but, after gulping it down, I realise it is laced with rum.

This is definitely not part of the ‘slimming desire’ programme but it encourages Sally to spill the beans about all the celebrities who come to Mauritius. Naturally, I am too discreet to name names but Harry Potter fans should start booking now.

Tuesday…

MAGGIE makes me work extra hard when I confess about the cocktail. Makes me swim three lengths underwater and then I have to run six lengths forwards and backwards in the pool with those dumbbells. Very hard work but brilliant apparently for toning all those wobbly bits and for getting the heart rate up.

It is certainly a lot more strenuous than my sporadic trips to my local pool where I plod up and down for 20 minutes and by the end of it just feel wet. Maggie also shows me how to swim back-crawl in a straight line it’s all a question of keeping the arms straight.

She encourages me to concentrate on front and back crawl and keep breast stroke to the minimum because it puts so much strain on the knees. By end of session am moving effortlessly through the water, making me wish I had paid more attention to swimming lessons at school.

In the afternoon I have an appointment with world-famous pedicurist Bastien Gonzalez. Three months after major foot surgery, my feet look like they could have been in the trenches but, after an hour in the salon, they are pink, polished and perfect. I had read a lot of hype about the Bastien Gonzalez pedicure and, sadly for my bank balance, it is all true.

At dinner that night tuna carpaccio, soya-infused chicken with steamed vegetables and oranges in ginger amuse myself by playing the guess the nationality game.

Brits are instantly recognisable by their sunburn, Russians by the perfection of the women and the fact that the men all have two cell phones.

French women are easy to spot because their sarongs are always tied just so and they always look just a little bit bored.

Final day…

PICK at my breakfast because I know the weigh-in is at noon. Work extra hard in the pool and try not to drink anything. At last Maggie leads me discreetly into the ladies’ changing room, where I step on to the scales. Have lost 5lb and more than an inch from my waist pretty good going for a week.

Maggie says sternly that this is only the beginning and I have a lot more work to do when I get home.

She would like me to lose at least a stone more. To that end she has given me a series of workouts to practise at home.

Make a pact with myself to keep at it or forfeit the right to come back here again.

And come back I definitely shall, especially when my butler, the lovely Rajiv, packs my suitcase for me, with tissue paper. That’s what I call service.

Head for home thinner, fitter and, I hope, more able to cope with all the challenges that lie ahead. I never thought that a holiday so apparently self-indulgent would teach me so much about my own capabilities. I went to lose weight but I lost something more important my fear of the future.

As one of the waiters said to me when I was crying in a corner: ‘Every day has its own pain.’

Getting there

Seven nights in a junior suite at Le Saint Geran Hotel cost from Pounds 3,400 per person.This includes return flights with British Airways, full board and private transfers plus the Rejuvenation Package which comprises a tailor-made programme including a one- hour gym session daily, various body scrubs,massages and other treatments.Call ITC Classics (01244 355527,www.itcclassics.co.uk).

Asthma and chronic obstructive pulmonary disease (COPD) involve chronic inflammation and constriction of the bronchioles. Optimal therapy for many patients requires control of both pathologic mechanisms through the use of inhaled bronchodilators and corticosteroids. Bronchodilator and corticosteroid inhalers eject a fine mist of medication which works directly on the bronchiole mucosa and smooth muscle when used properly. These inhaled medications are intended to exert localized, sitespecific therapeutic effects on the bronchioles (Skrepnek & Skrepnek, 2004).

Bronchiole smooth muscle is innervated by both sympathetic (beta- 2 adrenergic) and parasympathetic (cholinergic) autonomie nerves, which exert opposite effects on the airways. Stimulation of beta-2 adrenergic nerve fibers causes relaxation of bronchiole smooth muscle, leading to bronchodilation. Conversely, stimulation of the parasympathetic or cholinergic nerve fibers causes contraction of bronchiole smooth muscle, leading to bronchoconstriction (McPhee, Lingappa, Ganong, & Lange, 2000). Bronchospasm, a major component of asthma and COPD, limits airflow and can be relieved by bronchodilator inhaler medication. To exert bronchodilation, medications work by stimulating beta-2 adrenergic nerve receptors or blocking the cholinergic nerve receptors in bronchiole smooth muscle. Bronchodilator inhalers, therefore, are either beta-2 adrenergic agonists or anti-cholinergic medications (Skrepnek & Skrepnek, 2004).

Differences between the pathologic mechanisms of asthma and COPD dictate the implementation of distinctively different treatment methods. Asthma is primarily a chronic inflammatory disease involving episodes of reversible bronchoconstriction. Because inflammation is the main pathologic mechanism, anti- inflammatory agents (specifically inhaled corticosteroids) are first-line therapy in asthma. To prevent and counteract reversible episodes of bronchospasm, beta-2 adrenergic inhalers directly dilate the bronchioles. In contrast, bronchoconstriction in COPD is progressive, largely cholinergic mediated, and only partially reversible. Because bronchoconstriction is a major pathologic mechanism in COPD, bronchodilators (specifically anticholinergic inhalers) are first-line pharmacologic therapy (Doherty, 2004).

Therapeutic effects of inhalers are exhibited mainly by improving the patient’s pulmonary function test parameters: FEVl, PEFR, and PIF. FEVl is the forced expiratory volume in the first second of exhalation. PIF is the peak inspiratory now, and the PEFR indicates peak expiratory flow rate. Inhaled bronchodilator and corticosteroid medications directly ease the patient’s bronchiole resistance to air flow by widening the diameter of the airways and diminishing inflammation, thus increasing FEVl, PIF, and PEFR (Skrepnek & Skrepnek, 2004).

Mechanisms of “Rescue” vs. “Maintenance” Inhalers

Inhalers also are categorized as containing short-acting or long- acting medications. Short-acting bronchodilators are used as rescue medications for immediate relief of acute bronchospasm in asthma or COPD. These beta-2 adrenergic agonists exert a rapid bronchodilator effect and have a short duration. Long-acting beta-2 adrenergic bronchodilators are used as maintenance medications taken daily on a scheduled basis to prevent acute bronchospastic events. Long-acting adrenergic bronchodilators act within hours and have a prolonged duration of therapeutic effect (see Table 1) (Skrepnek & Skrepnek, 2004).

Anticholinergic bronchodilator inhalers, also used as maintenance therapy, are first-line medications in managing COPD (National Institutes of Health/National Heart, Lung, and Blood Institute/ World Health Organization [NIH/NHLBI/ WHO] Workshop Report, 2003). These inhalers block cholinergic stimulation of the bronchioles, thereby inhibiting bronchoconstriction. Anticholinergic inhalers are used on a scheduled, daily basis for preventing bronchoconstriction, not for acute episodes of bronchospasm (see Table 1).

Inhaled corticosteroids are long-acting maintenance medications taken daily for asthma. They have not been shown consistently to improve airway resistance in COPD, and their use is controversial in this disease group (Calverly & Barnes, 2000; Highland, Strange, & Heffner, 2003). They are to be taken on a scheduled, daily basis, not for acute bronchospasm. Corticosteroids are often found in combination with long-acting beta-2 adrenergic bronchodilators in inhaler devices (see Table 1).

Table 1.

Current Types of Rescue and Maintenance Inhalers Available

A common therapeutic regimen for a patient with persistent asthma or COPD consists of scheduled daily use of maintenance inhaler medications with rescue inhaler use as needed. In persistent asthma, this regimen consists of a daily inhaled long-acting bronchodilator and corticosteroid, with a short-acting bronchodilator (rescue) inhaler used as needed for acute bronchospastic episodes. Another combination maintenance inhaler consists of an anticholinergic medication and a short-acting beta-2 adrenergic agonist. These have proven beneficial in COPD due to the synergistic effect of anticholinergic inhibition of bronchoconstriction and the beta-2 adrenergic agonist stimulation of bronchodilation (American Thoracic Society, 1995; National Asthma Education and Prevention Program, 1997, 2003; NIH/NHLBI/WHO Workshop Report, 2003) (see Table 1).

Cromolyn, a unique anti-inflammatory medication, is used for long- term management and prevention of acute bronchospastic episodes. Cromolyn stabilizes bronchiole mast cells and inhibits release of inflammatory mediators. Used as maintenance treatment, cromolyn can inhibit bronchospasm incited by exercise, aspirin, cold air, sulfur dioxide, toluene diisocyanate, and environmental pollutants. It also should be used shortly before anticipated exposure to bronchospasm- inciting factors such as exercise (Randolph, 2000) (see Table 1).

Both persistent asthma and COPD are chronic inflammatory conditions with potential for acute bronchospastic episodes. The overall therapeutic goal is to avert acute bronchospastic attacks with the use of daily maintenance inhaler medications. Preventing acute bronchospastic episodes is crucial because research has shown that each acute attack leads to detrimental long-term remodeling of the airways (Chetta et al., 1997; Elias, Zhu, Chupp, & Homer, 1999).

In summary, inhaler pulmonary medications may be categorized as follows:

Rescue inhaler treatment

* Short-acting beta-2 adrenergic bronchodilators

Maintenance inhaler treatment

* Long-acting beta-2 adrenergic bronchodilators

* Anticholinergic bronchodilators

* Corticosteroid inhalers

Combination inhaler treatment

* Corticosteroid plus short-acting beta-2 adrenergic bronchodilator

* Anticholinergic bronchodilator plus short-acting beta-2 adrenergic bronchodilator

Cromolyn inhaler treatment

Environmental Need for a Change in Inhaler Devices

In the past, chlorofluorocarbons (CFCs) were the primary substances used as propellants in aerosols. Since 1978, the use of CFCemitting products in the United States has been curtailed sharply because they were deteriorating the ozone layer (the earth’s protective screen against the harmful rays of the sun). Because CFCs were the propellants used in pulmonary inhalers, they were considered “essential-use” CFCs and exempt from a government- mandated ban under the Clean Air Act (Food & Drug Administration [FDA], 1997). The Clean Air Act allowed the pharmaceutical industry to develop alternative non-CFC propellant inhalers and introduce these gradually to the public by 2005 (FDA, 1997). This transition to non-CFC aerosol delivery systems is apparent in new pulmonary inhaler devices such as hydro-fluoroalkane-pressurized metered dose inhalers (HFA p MDIs) and dry powder inhalers (DPIs).

Current Types of Inhaler Devices

Pressurized metered-dose inhalers (pMDIs) use a chemical propellant to eject aerosolized medication. Chlorofluorocarbons (CFCs), chemical propellants used in the past, are now being phased out. Hydrofluoroalkanes (HFAs) are the new environmentally friendly chemical propellants replacing CFCs in pMDIs. Patients should be advised that the new HFA inhaler may have a different taste and inhalation sensation than CFC-propelled inhalers. However, HFA propellants deliver medication via inhalers in the same way as CFCs.

Pressurized MDIs are either squeeze-and-breathe inhalers or breath-activated inhalers. Squeezeand-breathe pMDIs are pressurized canisters with measured doses of medication activated by squeezing the top of the canister releasing a fine microcrystalline suspension of medication. Patients must use the proper inhalation method to obtain the optimal benefit of pMDIs. First, the canister should be shaken 3 to 4 times. The patient then needs to exhale fully. Next, the patient should place the lips around the mouthpiece, inhale slowly through the mouth, and simultaneously squeeze the canister top. The canister should be removed from the mouth and the medication should be held in the lungs for approximately 10 seconds before the patient exhales. After 30 seconds, this method can be repeated if additional inhalations are advised (Medical Economics, 2005).

The other type of pMDI is a breath-activated inhaler which automatically releases medication when the patient inhales. An HFA propellant mechanism, activated by inhalation, triggers the pressurizedmetered dose inhaler to release medication. The patient does not have to coordinate squeezing of the canister with inhalation. As with all breath-activated inhaler devices, the release of medication is influenced significantly by the patient’s strength of inspiration (3M Pharmaceuticals, 2000; Medical Economics, 2005).

DPIs are all breath-activated and do not use a chemical propellant to eject medication. Each device contains medication in the form of powder which is dispersed into particles by inspiration. DPIs require the patient to place the lips around a mouthpiece and inhale rapidly. Examples of DPI devices are the Serevent Diskus and Advair Diskus. These diskhalers consist of a series of foil pouches on a disk. The patient loads the diskhaler with a medication disk of numbered foil pouches. Activation of the device punctures a pouch to release powder into the disk, and the drug is inhaled through a mouthpiece. The patient places the mouthpiece between the teeth and lips. After each inhalation, the patient slides the next powder pouch into place for the next dose (Asthma Society of Canada, 2004; GlaxoSmithKline, 2004a, 2004b).

The Pulmicort Turbuhaler is another DPI device which requires loading of medication in the form of a pellet. When the body of the turbuhaler is rotated, a prescribed amount of drug is ground off the pellet. The ground pellet powder is then inhaled through a fluted aperture on the top of the device. The patient must inhale forcefully with lips on the device mouthpiece (AstraZeneca, 2002).

The Spiriva Handihaler is a DPI device which includes a spherical covered plastic chamber and foil blister card of Spiriva capsules. Each capsule contains the dry powder medication, which the patient loads into the device. The patient then presses a button to pierce the capsule, and inhales deeply and slowly until all the capsule powder is inhaled (Medical Economics, 2005).

Rescue Inhalers: Short-Acting Beta-2 Adrenergic Bronchodilator Inhalers

Albuterol. Short-acting bronchodilators are indicated for acute bronchospasm when immediate rescue medication is necessary. A prototypical, short-acting bronchodilator is albuterol (also called salbutamol), a selective beta-2 adrenergic agonist which relaxes bronchiole smooth muscle. The albuterol inhaler (Ventolin HFA) is a pressurized MDI. The recommended dose is two inhalations every 4 to 6 hours in patients 4 years of age and older. The peak effect is reached within an average of 5 to 7 minutes and remains in the bloodstream for 4 to 6 hours (Medical Economics, 2005).

Metaproterenol (Alupent Inhalation Aerosol) is another selective beta-2 adrenergic agonist bronchodilator. This inhaler is supplied as 75 mg metaproterenol contained in a 100-inhalation canister, or as 150 mg of metaproterenol in a 200-inhalation canister. The recommended dose is 2 to 3 inhalations every 3 to 4 hours for patients over age 12 (Medical Economics, 2005).

Pirbuterol (Maxair Autohaler) is a short-acting selective beta-2 adrenergic agonist. This is a breathactivated inhaler which delivers medication automatically with inspiration and does not require the patient to coordinate inhalation with squeezing of the canister. Each 14 g canister contains 400 inhalations. After inhalation, bronchodilation occurs within 5 minutes, with maximum improvement in 1 to 2 hours and duration of effect for 5 hours. As with all breath- activated devices, the autohaler device is dependent on the strength of the patient’s inhalation force. Most patients are advised to take 1 to 2 inhalations every 4 to 6 hours as needed during episodes of acute bronchospasm (3M Pharmaceuticals, 2000; Medical Economics, 2005).

Maintenance Inhalers: Long-Acting Adrenergic Bronchodilator Inhalers

Salmeterol is a long-acting selective beta-2 adrenergic bronchodilator supplied as a DPI. This delivery system contains a double foil blister strip of 50 meg of powdered salmeterol in 12.5 mg of lactose. Salmeterol is available alone as the Serevent Diskus and Serevent Inhalation Aerosol, and in combination with flucatisone in the Advair Diskus. This is a long-acting medication; a 50 meg dose of salmeterol produces maximal bronchodilation within 2 hours and a continual therapeutic effect for 12 hours. The recommended dosage is two inhalations twice daily (once in the morning and evening) for patients age 4 and older. Salmeterol is used for maintenance therapy in persistent asthma and COPD, not as a rescue medication for acute bronchospasm. It is also used for prevention of exercise-induced asthma (GlaxoSmithKline, 2004a, 2004b; Medical Economics, 2005).

Formoterol (Foradil Aerolizer) is another long-acting selective beta-2 adrenergic bronchodilator supplied as a DPI. The DPI requires insertion of one formoterol capsule with each use. Each capsule contains 12 meg of formoterol; the patient inhales the contents of each capsule with activation of the aerolizer device. For adults and children older than 5 years of age, the recommended dosage is inhalation of the 12 meg capsule contents once every 12 hours, not to exceed 24 meg total daily (Medical Economics, 2005).

Maintenance Inhalers: Anticholinergic Bronchodilators in COPD

Ipratropium (Atrovent Inhalation Aerosol), a CFC-propelled pMDI, is indicated for maintenance treatment of bronchospasm associated with COPD. After inhalation, peak therapeutic effects occur in 1 to 2 hours and persist for a period of 3 to 4 hours. The recommended dose is two inhalations 4 times a day. Patients may take additional inhalations if required; however, total number of inhalations should not exceed 12 in 24 hours (Medical Economics, 2005).

Tiotropium inhalation powder (Spiriva Handihaler) is an anticholinergic bronchodilator used once daily for maintenance treatment of COPD. Once daily usage of this long-acting bronchodilator reaches peak effect in 3 hours and exerts therapeutic effects for 24 hours. Maximum improvement in FEVl and FVC occurs after the drug reaches a pharmacodynamic steady state at approximately 1 week. This medication is not to be used for acute episodes of bronchospasm. The handihaler is a DPI device which requires insertion of a Spiriva capsule (18 meg of tiotropium blended with lactose) (Boehringer Ingelheim Pharmaceuticals, 2004; Medical Economics, 2005).

Maintenance Inhalers: Corticosteroids

Flucatisone (Flovent Inhalation Aerosol), available as an HFA or CFC-propelled device, is a long-acting inhaled corticosteroid available in several dose strengths (44 meg, 110 meg, and 220 meg). After inhalation, flucatisone exerts initial effects within 24 hours; maximum benefit occurs after 1 to 2 weeks of treatment. Corticosteroids offer a cumulative therapeutic effect over several weeks in asthma and for some patients with COPD. For patients who do not experience adequate effects within 2 weeks of starting treatment, dosage increases may provide additional improvement. As with all corticosteroids, it is desirable to use the lowest effective dosage to reduce possibility of side effects. Flucatisone pMDIs are not recommended for children under 12 years of age (Medical Economics, 2005). Flucatisone was available as a DPI device (Flovent Rotadisk) manufactured by Glaxo SmithKline. Due to low product utilization, this product was discontinued (Lippincott, Williams, & Wilkins, 2004).

Budesonide (Pulmicort Turbuhaler) is a corticosteroid supplied for DPI. This DPI provides approximately 200 meg of budesonide per inhalation. The Pulmicort Turbuhaler contains 200 inhalation doses with an indicator which appears when 20 doses remain. The patient should discard the turbuhaler when empty because these devices are not reusable (Astra Zeneca, 2002).

Flunisolide (Aerobid Inhaler System) is a corticosteroid supplied as a CFC-propelled pMDI. Each activation of the inhaler delivers 250 meg of flunisolide, and each canister contains 100 inhalations. A mentholated form of the inhaled corticosteroid is available as the Aerobid-M Inhaler. The recommended dose is two inhalations twice daily (morning and evening) as maintenance treatment in asthma (Medical Economics, 2005).

Beclamethasone (Qvar Inhalation Aerosol) is a corticosteroid available in doses of 40 meg and 80 meg and supplied as an HFA propellant inhaler device. The recommended dose is one to two inhalations as directed by the physician for persistent asthma in patients over 5 years of age. Maximum therapeutic benefit of this corticosteroid requires 3 to 4 weeks of use. The dose of this medication should be titrated to the lowest effective dosage which provides adequate control of asthma. Patients are often started on this inhaler as they are being weaned from oral corticosteroids (Medical Economics, 2005).

Triamcinolone (Azmacort Inhalation Aerosol) is a corticosteroid available in dosages of 200 meg and 400 meg, and supplied as a CFC propellant pMDI. The recommended adult dosage is two inhalations of 200 meg 3 to 4 times a day or four inhalations of 400 meg twice a day. Maximum daily intake should not exceed 1,600 meg ( Medical Economics, 2005).

Mometasone is a corticosteroid undergoing clinical trials as a DPI which can be administered once daily. Each inhalation delivers 400 meg of mometasone. A recent study found comparable efficacy of flucatisone 125 meg administered via pMDI twice a day and mometasone 400 meg DPI once daily in patients with persistent asthma (Wardlaw et al., 2004).

Combination Inhalers: Corticosteroid with LongActing Beta-2 Adrenergic Agonist

The Advair Diskus contains a combination of flucatisone and salmeterol, which are two distinct classes of medications. Flucatisone is a corticosteroid and salmeterol is a selective long- acting beta-2 adrenergic receptor agonist. This DPI is available as Advair Diskus 100/50, Advair 250/50, and Advair 500/50, which represent the flucatisone dose (100 meg, 250 meg, or 500 mcg)/ salmeterol dose (50 meg) per inhalation. The recommen\ded starting dose is Advair 100/50 twice daily (morning and evening) approximately 12 hours apart. Following administration of Advair Diskus, peak plasma concentrations of flucatisone were achieved in 1 to 2 hours and those of salmeterol were achieved in 5 minutes (Medical Economics, 2005). Advair Diskus is indicated for longterm, twice daily, maintenance treatment of airway obstruction in asthma and COPD. This inhaler is not indicated for relief of acute bronchospasm. An inhaled shortacting beta-2 adrenergic agonist (for example, albuterol) should be used to relieve acute shortness of breath due to bronchospasm. Use of Advair more than twice daily is not recommended because excessive beta adrenergic stimulation can occur with high doses of salmeterol. Improvement in bronchospasm and inflammation following inhaled administration can occur within 30 minutes of treatment, although maximum benefit may not be achieved for 1 week or longer. Patients who do not respond adequately to the starting dosage after 2 weeks of therapy may require a higher strength of Advair (Medical Economics, 2005).

A recent study compared the combination of flucatisone 100 mcg/ salmeterol 50 meg delivered via diskus with flucatisone 100 meg and salmeterol 50 meg alone in patients with persistent asthma. The combination flucatisone/salmeterol diskus was more effective in improving morning and evening PEFR than the individual agents used alone. Additionally, patients who used the combination diskus required less rescue albuterol (Murray et al., 2004).

Combination Maintenance Inhaler: Anticholinergics with Short- Acting Beta-2 Adrenergic Agonists

Combiuent Inhalation Aerosol is a combination of ipratropium (a long-acting, anticholinergic, bronchoconstrictor antagonist) and albuterol (a beta-2 adrenergic bronchodilator). This is available as a CFC propellant pMDI containing 200 inhalations of 21 meg of ipratropium and 120 mg of albuterol. Primarily indicated for COPD, the aerosol causes peak improvement in FEV1 occurring within 1 hour; therapeutic effects endure for 4 to 5 hours. Studies show that this combination therapy is more effective than either ipratropium or albuterol administered alone (Chrischilles, Gilden, Kubisiak, Rubenstein, & Shah, 2002; Rodrigo & Rodrigo, 2000). The recommended dose for adults is two inhalations 4 times daily, not to exceed 12 inhalations in 24 hours (Medical Economics, 2005).

Cromolyn inhaler. The Intal Inhaler contains cromolyn, a unique anti-inflammatory agent, in a CFC propellant pMDI. Cromolyn inhibits antigen-stimulated mast cell release of inflammatory mediators. Cromolyn is used most often to prevent exercise-induced bronchospasm and should be used on a daily, long-term basis. Peak therapeutic effects are seen after several weeks of daily scheduled use. Intal should be used shortly before exposure to the precipitating antigen or factor, as well as on a daily basis. The Intal inhaler provides 112 inhalations from the 8.1 g canister and 200 inhalations from the 14.2 g canister. Each inhalation dispenses 800 meg of cromolyn, with recommended dosage schedule of two inhalations 4 times a day for adults and children at least 5 years of age. Within 10 to 15 minutes before anticipated exposure to bronchospasm-inducing factors, the patient should take two inhalations of cromolyn (Medical Economics, 2005; Randolph, 2000).

Nursing Implications of Pulmonary Inhaler Treatment

Precautions with use of CFC propellant inhalers. CFC propellants are being phased out in all aerosol devices to protect the environment. However, some inhaler medications are still supplied using these substances. These pressurized canisters should never be punctured, used, or stored near open flames, or in heat greater than 120 F (Medical Economics, 2005).

Precautions with use of (HFA) propellant inhalers. HFA (hydrofluoroalkane) propellants, safe for the environment, do not have any pharmacologie activity except at extremely high dosages. At doses of 300 to 1,300 times the maximum human exposure, tremor, dyspnea, salivation, and ataxia were the adverse effects observed in laboratory animals. HFAs do not accumulate in the bloodstream and are eliminated rapidly (Medical Economics, 2005). These are similar findings with CFC propellants. These pressurized canisters should never be punctured, or used or stored near open flames, or in heat greater than 120 F. Prior to initial use, four priming actuations are necessary; if the canister is not activated for 2 weeks or more, priming is necessary before use. Cleaning of the device once a week is recommended. These canisters should never be immersed in water; hence, the “float test” to check for canister emptiness, as with CFC devices, is contraindicated in HFA devices (Medical Economics, 2005).

Precautions with use of dry powder inhalers. Some dry powder inhalers use lactose as an ingredient in the medication mixture. Patients allergic to lactose or milk products should not use this type of inhaler due to the potential for hypersensitivity reactions. Specific powder formulations and capsules should only be used with their corresponding specific inhaler devices. Inhaler devices are not interchangeable (Medical Economics, 2005).

Adverse Effects of Beta-2 Adrenergic Agonist Inhalers

Paradoxical bronchospasm. All beta-2 adrenergic agonist inhalers can stimulate immediate airway hyperactivity which leads to acute bronchospasm. This side effect requires discontinuation of inhaler therapy immediately (Medical Economics, 2005).

Possible cardiovascular side effects. Whether they are short- acting or long-acting, beta-2 adrenergic agonists can have cardiovascular side effects. Histologically, beta-2 adrenergic receptors are located primarily within bronchiole smooth muscle; beta-1 adrenergic receptors are located within the cardiovascular system. Stimulation of beta-2 adrenergic receptors in the bronchioles leads to relaxation of the bronchiole smooth muscle, initiating therapeutic bronchodilation in asthma and COPD. However, a population of beta-2 adrenergic receptors in the heart also can be stimulated by these medications. Studies have shown that beta-2 adrenergic agonists can increase systolic blood pressure, heart rate, and cardiac contractility, thus increasing oxygen consumption by the myocardium (Guhan et al., 2000; Rossinen, Partanen, Stenius- Aarniala, & Nieminen, 1998). The patient can experience tachycardia, palpitations, and elevated blood pressure. Additionally, ECG changes such as flattening of the T wave, prolongation of the QT interval, and ST segment depression have been reported (Medical Economics, 2005). Health care providers therefore must be cautious with use of beta-2 adrenergics in patients with coronary insufficiency, dysrhythmias, heart failure, and hypertension.

Patients often suffer COPD, asthma, and cardiovascular conditions concurrently, and require treatment with both bronchodilator and cardiovascular medications. Limited research compares long-acting beta-2 adrenergic inhalers and their cardiovascular side effects. In a comparison study of formoterol and salmeterol (Guhan et al, 2000), investigators found that both medications caused an early dose- dependent increase in heart rate and glucose concentrations, and a fall in diastolic blood pressure and plasma potassium concentration. Formoterol caused an early increase in systolic blood pressure and a more rapid onset than salmeterol, whereas salmeterol had more prolonged activity.

In hypertensive patients with asthma or susceptibility to bronchospasm, beta-adrenergic blockers may be contraindicated. To reduce blood pressure, beta blocker antihypertensive drugs are intended to inhibit specific, cardioselective, beta-1 adrenergic receptors in the heart and vascular walls. However, some concomitant blockade of beta-2 adrenergic receptors can occur, resulting in bronchospasm in susceptible individuals (Medical Economics, 2005).

Metabolic side effects. Beta-2 adrenergic receptors are located in the smooth muscle of the bronchioles, blood vessels, genitourinary tract, uterus, gastrointestinal tract, liver, skeletal muscle, and pancreas. Consequently, beta-2 adrenergic stimulants can cause side effects involving these organs. In the liver, beta-2 adrenergic agonists stimulate glycogenolysis and gluconeogenesis (McPhee et al., 2000). The hepatic effect can cause hyperglycemia, which is significant in diabetic patients. Also, beta-2 adrenergic stimulation of skeletal muscle can cause tremors in some patients. Beta 2-adrenergic drugs should be used with caution in patients with coronary insufficiency, dysrhythmias, hypertension, hyperthyroidism, seizure disorders, diabetes, or susceptibility to hypokalemia (Medical Economics, 2005).

Drug-drug interactions and other effects. Patients should not take other sympathomimetic drugs, monoamine oxidase (MAO) inhibitors, or tricyclic antidepressants while taking beta-2 adrenergic agonists. Digitalis levels need careful monitoring because adrenergic agonists can cause elevation of digitalis blood levels. Beta-2 adrenergic agonists should be used cautiously in pregnant and nursing women. No adequate, well-controlled studies assure safety in these populations. These medications are safe for children 4 years of age and older. Patients should not use more inhalations than as directed by their physician. Some persons experience oropharyngeal irritation from the inhaled aerosol. Patients can rinse their mouths out with water after completion of inhalations to prevent oropharyngeal irritation (Medical Economics, 2005).

Adverse Effects of Anticholinergic Inhalers

Although inhaler medications are absorbed minimally into the bloodstream, some potential exists for systemic effects. Anticholinergic drugs can cause parasympathetic blockade of the heart, ocular ciliary muscle, gastrointestinal wall muscles, and bladder muscle (McPhee et al., 2000). Caution should be used wi\th administration of these inhaled drugs in patients with narrow angle glaucoma, prostate enlargement, or bladder neck obstruction. Patients should be warned not to spray these medications into the eyes because precipitation of glaucoma can occur. Mydriasis, eye pain, blurred vision, tachycardia, palpitations, nervousness, urinary retention, and constipation are reported side effects. No studies document use of these drugs in pregnant or nursing women. Safety of these drugs in children under age 12 has not been established. These drugs are safe when used in conjunction with beta- 2 adrenergic agonists and corticosteroid inhalers (Medical Economics, 2005).

Adverse Effects of Corticosteroid Inhalers

Inhaled corticosteroids may be used in patients with asthma and COPD being weaned off oral corticosteroids. After withdrawal of oral corticosteroids, a number of months is required for full recovery of hypothalalmic-pituitary-adrenal axis function. Patients being weaned from oral corticosteroids should be assessed for signs of adrenal insufficiency, or hypotension, fatigue, depression, lassitude, weakness, joint pain, myalgias, nausea, and vomiting, particularly during times of stress or postoperatively. Persons who have been on long-term oral corticosteroids may be immunosuppressed and susceptible to infections such as chicken pox and measles. Because corticosteroids can cause immunosuppression, inhaled corticosteroids should be used with caution in patients with tuberculosis, systemic fungal infections, bacterial, viral, or parasitic infections, or ocular herpes simplex. Inhaled corticosteroids also increase risk of osteoporosis, cataracts, and adrenal suppression in adults (Clark & Lipworth, 1997; Patel, 2004; Wilson, Clark, Devlin, McFarlane, & Lipworth, 1998). Due to the wide number of possible adverse effects, the lowest dosage of inhaled corticosteroids which provide control for asthma or COPD is recommended (Medical Economics, 2005).

A reduction in growth velocity has been observed in those taking long-term oral corticosteroids, and has been under investigation in children and adolescents who use inhaled steroids. Some studies have found suppression of adrenal function and inhibited growth and bone development in children who use high doses of inhaled corticosteroids. Suppression of growth in children on high doses of inhaled corticosteroids has been detected but appears temporary and not associated with reduced adult height (Alien, 2004; Clark, Clark, & Lipworth, 1996; Goldberg et al., 2002). A recent 3-year study of inhaled budesonide use in children revealed no effect on adrenal function (Bacharier et al., 2004). Although there are disparities in research findings, most investigators agree that the benefits of inhaled corticosteroids in children outweigh the risks of poorly controlled asthma. No adequate studies in pregnant or nursing women are available.

Candida albicans infection of the oropharynx (“thrush”) has been experienced by some long-term users of inhaled corticosteroids. Rinsing out the mouth after inhaler use may prevent these infections. Inhaled corticosteroid therapy should be interrupted temporarily to administer antifungal medications to eliminate Candida infection (Medical Economics, 2005).

Drug-drug interactions. Flucatisone is metabolized in the liver by the cytochrome p 450 enzyme system. Ritonavir, a protease inhibitor used in treatment of HIV infection, is a potent inhibitor of this hepatic cytochrome system. The concomitant use of ritonavir and flucatisone resulted in elevated blood levels of flucatisone. This also occurred with another hepatic cytochrome inhibitor, ketoconazole. Therefore, ritonavir and ketoconazole should not be used in conjunction with flucatisone (Medical Economics, 2005).

Adverse effects ofcromofyn. Few adverse effects have been reported with cromolyn inhalers. Throat irritation, bad taste, bronchospasm, cough, wheeze, and nausea are rare adverse effects. Cromolyn has not been evaluated adequately in pregnant or nursing women, or children younger than age 5 (Medical Economics, 2005; Randolph, 2000).

The Challenge of Patient Education in Inhaler Treatment

For some patients, the coordinated technique needed to obtain the full dose of medication from a squeeze-and-breathe pMDI is challenging. Studies show that many patients do not use proper technique, resulting in inadequate delivery of medication (Crompton, 2004; Girard & Roche, 2002; Molimard et al., 2003; Richter, 2004; Rubin & Durotoye, 2004). Poor technique often results in oropharyngeal deposition of medication which can lead to laryngeal irritation, hoarseness, and Candida infection of the throat (Mirza, Kasper Schwartz, & Antin-Ozerkis, 2004). Medication inhalation may be facilitated with the use of a spacer, which is a short tube attached to the inhaler. Spacers can only be used with some pMDIs, not all devices. The spacer acts as a holding chamber that keeps the medication from escaping into the air. Releasing the medication into the spacer chamber allows the patient extra time to inhale more slowly and increases the amount of mist reaching the lungs (Dempsey, Wilson, Coutie, & Lipworth, 1999; Melani et al., 2004). The Aerochamber P/us is a spacer device which can be used with a pMDI. A built-in whistle alerts the patient if inhalation flow is too fast. An optional mask and detailed patient instructions accompany this product (Forest Pharmaceuticals, 2004; Medical Economics, 2005).

Molimard and colleagues (2003) studied 3,811 patients who used different inhaler devices for 1 month. These investigators found that 76% of patients made at least one error with use of pMDIs compared to 49% to 55% with breath-actuated inhalers. Treatment- compromising errors were made by 11% to 12% of patients who used the Aerolizer, Autohaler, or Diskus, compared to 28% and 32% of patients respectively treated with pMDI and Turbuhaler. Another group of researchers evaluated patient use of the Turbuhaler and found that fewer than 50% of patients demonstrated correct technique when using the device (Epstein, Maidenberg, Hallet, Khan, & Chapman, 2001). However, according to Welch and colleagues (2004), the Turbuhaler was easier to use and preferred by patients compared to pMDIs. Investigators found that asthma patients learned proper use of the Pulmicort Turbuhaler more easily than the Flovent, Vanceril, and Aerobid pMDI devices.

In summary, high numbers of patients with asthma and/or COPD do not use inhaler devices correctly resulting in suboptimal therapeutic results.

Also, studies show that many patients fail to hold inhaled medication in their lungs for the full 10 seconds (Epstein et al., 2001; Girard & Roche, 2002; Newman, 2004). This final step in the inhaler technique is required for optimal pulmonary absorption of medication, regardless of type of device used.

DPIs have some advantages over pMDIs. DPIs are environmentally friendly and breath-activated, requiring no coordinated activation by the patient. However, the delivery of medication depends on the strength of patient inspiration. Patients with asthma and COPD, particularly those experiencing bronchospasm, have weak inspiratory strength which limits effectiveness of breath-actuated MDIs or DPIs (van der Palen, 2003).

Table 2.

Patient Education Materials

Lastly, patients may have difficulty keeping track of medication doses remaining in their inhaler. A recent study revealed that a large percentage of patients did not keep track of canister doses and unknowingly continued to use empty pMDIs for up to twice the intended duration (Rubin & Durotoye, 2004). Manufacturers recommend that patients write the date of initial use on the canister and calculate the doses used. To track dose utilization, the patient needs to note the first day of use on the canister and count the number of days of use. The canister’s inhalation capacity should be divided by how many inhalations are used per day. For example, an average pMDI holds 200 inhalations. If the current month has 30 days and a patient began using the inhaler on the first day of the month, taking two puffs twice a day, the following calculation method is used:

* 30 days x 2 puffs x 2 times per day =120 inhalations used

* 200 inhalations in canister 120 inhalations used = 80 inhalations remaining

The problem arises when a patient does not keep a record of the days of inhaler use or uses the inhaler various numbers of times per day. This is a common problem for patients using inhaler devices without built-in dose counters. Alternatively, an attachment called The Doser (MEDITRACK Products, 1999), ordered by a pharmacist, can be placed on top of a pMDI which can track doses used.

Research shows there is no one ideal inhaler device currently available. All inhaler devices require detailed patient instruction. Health care providers should provide stepby-step verbal instruction and written patient education materials. A patient demonstration is necessary with professional feedback about technique. With the varied devices available, many nurses and physicians may lack the expertise to teach proper use of specific inhalers. Each device is accompanied by patient instructions. In addition, some pharmaceutical Web sites provide instructional videos or downloadable materials (see Table 2).

Both persistent asthma and COPD are chronic inflammatory conditions with potential for acute bronchospastic episodes.

Patients should be warned not to spray these medications into the eyes because precipitation of glaucoma can occur.

References

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Forest Pharmaceuticals, Inc. (2004). The Aerochamber-plus valved holding chamber. Retrieved February 16, 2004, from http:// www.aerochambervhc.com

Girard, V., & Roche, N. ( 2002). Misuse of corticosteroid metered- dose inhaler is associated with decreased asthma stability. European Respiratory Journal, 19(2), 246-251.

GlaxoSmithKline. (2004a). How to use Serevent Diskus (salmeterol xinofoate inhalation powder). Retrieved January 1, 2005, from at http://serevent.com/usage_ instructions.html

GlaxoSmithKline. (2004b). Advair Diskus instructions (flucatisone propionate 100 meg and salmeterol 50 meg inhalation powder). Retrieved January 1, 2005, from http://advair.com//printables/ asthma_inhaler

Goldberg, S., Einot, T., Algur, N., Schwartz, S., Greenberg, A.C., Picard, E., et al. (2002). Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: Comparison between dry powder inhaler and pressurized metered-dose inhaler attached to spacer. Annals of Allergy, Asthma, & Immunology, 89(6), 566-571.

Guhan, A.R., Cooper, S., Oborne, J., Lewis, S., Bennett, J., STattersfield, A.E. (2000). Systemic effects of formoterol and salmeterol: A dose-response comparison in healthy subjects. Thorax, 55(8), 650-656.

Highland, K.B., Strange, C., & Heffner, J.E. (2003). Long term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Annals of Internal Medicine, 138, 969- 973.

Lippincott, Williams, & Wilkins. (2004). News capsules: Flovent Rotadisk discontinued. Retrieved January 1, 2005, from http:// www.edruginfo.com/nc_ floventrotadiskdiscontinued

McPhee, S.J., Lingappa, VR., Ganong, W.F, & Lange, J.D. (2000). Pathophysiology of disease: An introduction to clinical medicine (3rd ed.). New York: Lange Medical Books/McGraw Hill.

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MEDITRACK Products. (1999). The doser. Retrieved on February 16, 2004, from http://www.doser.com

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Mirza, N., Kasper Schwartz, S., & Antin-Ozerkis, D. (2004). Laryngeal findings in users of combination corticosteroid and bronchodilator therapy. Laryngoscope, 114(9), 1566-1569.

Molimard, M., Raherison, C., Lignot, S., Depont, R, Abouelfath, A., & Moore, N. (2003). Assessment of handling of inhaler devices in real life: An observational study in 3811 patients in primary care. Journal of Aerosol Medicine, 16(3), 249-254.

Murray, J., Rosenthal, R., Somerville, L., Blake, K., House, K., Baitinger, L., et al. (2004). Flucatisone propionate and salmeterol administered via Diskus compared with salmeterol or flucatisone propionate alone in patients suboptimally controlled with short- acting beta2-agonists. Annals of Allergy, Asthma, & Immunology, 93(4), 351-359.

National Asthma Education and Prevention Program (NAEPP). (2003). Expert panel report: Guidelines for the diagnosis and management of asthma update on selected topics-2002. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health/ National Heart, Lung, & Blood Institute (NIH/NHBLI). Bethesda, MD: National Institutes of Health.

National Asthma Education and Prevention Program (NAEPP). (1997). Guidelines for the diagnosis and management of asthma: Expert panel report 2. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health/ National Heart, Lung, & Blood Institute (NIH/NHBLI). Bethesda, MD: NIH.

National Institutes of Health /National Heart, Lung, & Blood Institute (NIH/NHBLI)/ World Health Organization (WHO) Workshop Report. (2003). Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Retrieved January 1, 2005, from http://www.goldcopd.com

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Ten Capriotti, DO, MSN, CRNP, RN, is a Clinical Associate Professor, Villanova University, College of Nursing, Villanova, PA.

Copyright Anthony J. Jannetti, Inc. Jun 2005

ABSTRACT

During World War II, 36 conscientious objectors participated in a study of human starvation conducted by Ancel Keys and his colleagues at the University of Minnesota. The Minnesota Starvation Experiment, as it was later known, was a grueling study meant to gain insight into the physical and psychologic effects of semistarvation and the problem of refeeding civilians who had been starved during the war. During the experiment, the participants were subjected to semistarvation in which most lost >25% of their weight, and many experienced anemia, fatigue, apathy, extreme weakness, irritability, neurological deficits, and lower extremity edema. In 2003-2004, 18 of the original 36 participants were still alive and were interviewed. Many came from the Historic Peace Churches (Mennonite, Brethren, and Quaker), and all expressed strong convictions about nonviolence and wanting to make a meaningful contribution during the war. Despite ethical issues about subjecting healthy humans to starvation, the men interviewed were unanimous in saying that they would do it all over again, even after knowing the suffering that they had experienced. After the experiment ended, many of the participants went on to rebuilding war-torn Europe, working in the ministries, diplomatic careers, and other activities related to nonviolence. J. Nutr. 135: 1347-1352, 2005.

KEY WORDS: * experiment * history * starvation * Keys

On November 19, 1944, 36 healthy young men entered the brick confines of the Laboratory of Physiological Hygiene at the University of Minnesota, where they were to embark on a grueling medical experiment. The men had responded to a brochure that asked: “Will You Starve That They Be Better Fed?” (1) (Fig. 1). World War II was coming to a close, and Allied forces, entering cities in German-occupied Europe, encountered starved, emaciated civilians, many of whom had survived by subsisting on bread, potatoes, and little else. Relatively little was known scientifically about human starvation or how to deal with refeeding people who had undergone this extreme degree of deprivation. In 1944 Ancel Keys, then a young professor of physiology at the University of Minnesota and a consultant to the War Department, asked how civilians would be affected physiologically and psychologically by such a limited diet and what would be the most effective way to provide postwar rehabilitation (2). To answer these questions, Keys proposed a bold human experiment: to subject volunteers to semistarvation and then refeed them.

The results of the research, later known as the Minnesota Starvation Experiment, were published by Keys and his colleagues in the classic 2-volume monograph, The Biology of Human Starvation, in 1950 (3), providing a unique addition to the nutrition literature. The 1385-page text presented the first comprehensive record of the physiological and psychological effects of starvation and refeeding, included detailed test results for each of the participants, and provided an extensive bibliographic literature review. Beyond the sheer depth of technical information the experiment made publicly available, members of Keys’ research team prepared a relief worker’s manual that focused on the psychological effect of starvation, with an eye toward practical field application related to the attitude and behavior patterns of those who have experienced starvation (4). The understanding that starvation dramatically alters personality and that nutrition directly and predictably affects mind as well as body is one of the legacies of the experiment. The results of the experiment also affected general scientific attitudes about the mutability of the human body, suggesting that diet alone could have a large effect on basic body functions, e.g., blood pressure, cholesterol level, resting heart rate, areas previously considered relatively fixed. The experiment continues to be cited by researchers exploring the effects of food deprivation on the cognitive and social functioning of those with anorexia nervosa and bulimia nervosa (5,6). In some cases, sharing the details of the experiment with patients has also proved therapeutically beneficial in explaining the effect of starvation on their own bodies (7). In addition, the data have been useful in exploring metabolic adaptation (8,9), as researchers look to find insights into the clinical management of cachexia and obesity and the prediction and treatment of weight changes related to illness and injuries (10- 12).

In 1944, the prospect of finding healthy young men who would volunteer for such an ordeal presented a challenge because many were overseas serving in the military. However, stateside, there were conscientious objectors who had refused to serve in the war and received 4E classification from their draft boards. Conscientious objectors were assigned to the Civilian Public Service (CPS), where they participated in activities such as soil conservation, forest maintenance, and firefighting in work camps operated by the Historic Peace Churches (Mennonites, Quakers, and Brethren) (13). As the war progressed, conscientious objectors were also given the opportunity to volunteer for alternative service projects, including various medical experiments in which they served as human “guinea pigs.” Keys obtained approval from the War Department to find suitable healthy men among the 12,000 conscientious objectors across the country. Brochures asking for volunteers were printed and disseminated among the work camps and sites of the CPS, and within a few months, Keys received >400 positive responses. Of these, 100 were interviewed and examined before 36 subjects were finally selected. The experiment was funded by the Office of the Surgeon General, organizations related to the Mennonites, Brethren, Quakers, and Unitarians, and some private industry groups.

FIGURE 1 Recruitment brochure cover for the Minnesota Experiment. May 27, 1944.

The main objective of the Minnesota Experiment was to characterize the physical and mental effects of starvation on healthy men by observing them under normal (baseline) conditions, subjecting them to semistarvation, and then following them under conditions of rehabilitation. The study commenced in November 1944 with a standardization period of 3 mo in which the men received ~3200 kcal (13,389 kJ) of food/d. This was followed by a 6-mo semistarvation period, beginning on February 12, 1945, in which they received ~1800 kcal (7531 kJ) of food/d, with the starvation diet reflecting that experienced in the war-torn areas of Europe, i.e., potatoes, turnips, rutabagas, dark bread, and macaroni. The final 3 mo were a nutritional rehabilitation period, in which the men were randomly assigned to 1 of 4 energy intake groups; each energy level was subdivided into 2 protein levels, and each protein level into 2 vitamin levels.

During the study, participants were assigned to various housekeeping and administrative duties within the laboratory and were allowed to participate in university classes and activities. The participants were expected to walk 22 mi (35.4 km)/wk and expend 3009 kcal (12552 kJ)/d. The Laboratory of Physiological Hygiene, located in the South Tower of the football stadium at the University of Minnesota, also served as their dormitory. Keys referred to these windowless rooms as “our cage” (1). Extensive tests were given to the participants throughout the experiment. Body weight, size, and strength were recorded, and basic functions were tracked using X- rays, electrocardiograms, blood samples, and metabolic studies. Psychomotor and endurance tests were given as the men walked or ran on the laboratory treadmills, and participants received intelligence and personality tests from psychologists. Each man was required to keep a personal journal during the experiment.

Almost 60 years after the Minnesota Experiment, 19 of the 36 original participants were still alive and 18 were interviewed in an oral history project conducted from July 2003 through February 2004. The purpose of the project was to document how World War II conscientious objectors remember their participation in the Minnesota Experiment. The names of the participants have been published (3). A letter was sent to each participant, inviting him to take part in a tape-recorded, structured interview. After oral consent was obtained, 14 participants were interviewed in their homes or offices, and 4 were interviewed by telephone. The protocol was approved by the Institutional Review Board of the Johns Hopkins School of Medicine.

Each man was in his 80s when interviewed and each spoke passionately when discussing why he chose to be a conscientious objector. The men universally stated a simple, solid conviction not to kill another human being. For some, the conviction was borne of an upbringing in one of the Historic Peace Churches. Others were influenced by pacifist writers such as Wilfred Grenfell (1865- 1940), leaders of peace fellowships, or the teachings of the Oxford Movement. Still others saw the life and work of Mahatma Gandhi (1869- 1948) as a testament to the potential effectiveness of nonviolence. William Anderson put it most succinctly: “No one could make me kill anyone else.” Carlyle Fr\ederick stressed that conscientious objection was not unpatriotic: “[Some] thought conscientious objection would be almost like being a traitor. But I was not objecting to my country as much as what my country was doing. In other words, my definition of patriotism included my refusal to kill.”

Despite their sincere belief that taking up arms was not the answer, many struggled with the desire to do something of real meaning for their country. Marshall Sutton remembered, “Our friends and colleagues in other places were putting their lives on the line, and you know, we wanted to do the same.” Samuel Legg spoke in similar terms: “So we in the CPS camps had been griping about not having what we called significant work, which very often it wasn’t. A lot of it was boondoggling . . . We were full of idealism . . . Everyone else around us is pulling down the world; we want[ed] to build it up.”

Those selected to participate in the Minnesota Experiment were a well-educated group of conscientious objectors; all had completed some college coursework, 18 had graduated, and a few had already begun graduate-level coursework. Many took advantage of the opportunity to take coursework at the University of Minnesota during the experiment, a few completing enough to obtain additional degrees. Initially, the blue pants, white shirts, and sturdy walking shoes they were issued upon arrival were all that distinguished them from other members of the community. During the standardization period, the men felt well-fed and full of energy. Many initially volunteered in local settlement houses, participated in music and drama productions in Minneapolis, and took advantage of the various cultural activities available throughout the city. Robert Villwock played the accordion and called square dances for local groups, and Wesley Miller ushered for the Minneapolis Symphony Orchestra in exchange for attending the concerts for free.

On d 1 of semistarvation, February 12, 1945, the men sat down to a meal that included a small bowl of farina, two slices of toast, a dish of fried potatoes, a dish of jello, a small portion of jam, and a small glass of milk. Although the precise nutrition content of meals and the individual results from various tests and measurements are presented in scientific detail in The Biology of Human Starvation, the participants painted a more vivid picture of their daily lives during the experiment. The men ate their meals together in Shevlin Hall on the campus. Two meals were served Monday through Saturday, at 0800 and 1800 h, and on Sunday there was one slightly larger meal served at 1245 h. Originally, the football team also received meals at about the same time, but the campus authorities later announced a change in the schedule so that the players would not be fraternizing with conscientious objectors. Participants were supposed to lose ~2.5 lb (1.1 kg)/wk to reach the desired 25% weight reduction by the end of the semistarvation period. The amount of food each man received at mealtimes depended on how well he was progressing toward his weekly goal. Usually reductions and additions were made in the form of slices of bread. Daniel Peacock remembered that emotions could run quite high in the cafeteria when one man received even just a little bit more food: “We were given our food along a cafeteria line and if the guy ahead of you is given five slices of bread, that’s pretty hard to conceal. And if you’re only getting three, that’s pretty touchy.” He also spoke of the anxiety that accompanied the Friday night posting of the upcoming week’s rations: “. . . every Friday late in the day . . . they would post a list of all our names and what our rations would be for the following week . . . [the] calories . . . either minus or plus . . . Some of us . . . we’d go off to a movie. In other words, we delayed seeing that list; we dreaded seeing that list for fear that it was certainly going to reduce our rations . . . It’s pretty darn certain that it’s going to be bad news because we’re supposed to be descending.”

The men slept in a large dormitory-style room with 2 rows of cots positioned with an aisle down the middle. Daniel Peacock described the lack of privacy and explained how it was in keeping with the spirit of the experiment:

The showers were all one huge line of showers. No partitions or anything. And even the commodes were all open. There was no privacy anywhere . . . And in a way it’s just as well because part of being a guinea pig is that they’re going to look at everything that they can look at, touch and feel every part of your body in one way or another, at one time or another, for one reason or another.

After one participant broke diet and was excused from the experiment, a buddy system was implemented that required the men to travel in twos when outside of the Laboratory. Jasper Garner was thankful for the buddy system for reasons of physical practicality, as they were growing weaker by the day: “. . . before the buddy system, I was in Dayton’s department store downtown going to go in. It’s got a rotating door. I couldn’t push it. I got stuck. Had to wait until somebody came along. And then the other one was, you know, the library doors. Oh you know, they’re big, and I couldn’t pull them. I had to wait until somebody . . . let me scoot in after.”

Nearly all the men remembered the walks they took with their buddies to fulfill their weekly 22-mi (35.4-km) walking requirement. Although some of the requirement could be met indoors on the treadmill, many preferred to use the paths along the banks of the Mississippi River. Jasper Garner recalled one particular strategy for meeting the requirement: “Roscoe Hinkle and I figured out we’d take the eleven mile walk every Sunday night, and then we had half of our walking done, and the rest of the week was no problem at all. In contrast to some, who suddenly on Saturday night are walking on the treadmill for hours to get in the time.”

As semistarvation progressed, the enthusiasm of the participants waned; the men became increasingly irritable and inpatient with one another and began to suffer the powerful physical effect of limited food. Carlyle Frederick remembered “. . . noticing what’s wrong with everybody else, even your best friend. Their idiosyncrasies became great big deals . . . little things that wouldn’t bother me before or after would really make me upset.” Marshall Sutton noted, “. . . we were impatient waiting in line if we had to . . . and we’d get disturbed with each other’s eating habits at times . . . I remember going to a friend at night and apologizing and saying, ‘Oh, I was terrible today, and you know, let’s go to sleep with other thoughts in our minds.’ We became, in a sense, more introverted, and we had less energy. I knew where all the elevators were in the buildings.” The men reported decreased tolerance for cold temperatures, and requested additional blankets even in the middle of summer. They experienced dizziness, extreme tiredness, muscle soreness, hair loss, reduced coordination, and ringing in their ears. Several were forced to withdraw from their university classes because they simply didn’t have the energy or motivation to attend and concentrate (3).

Food became an obsession for the participants. Robert Willoughby remembered the often complex processes the men developed for eating the little food that was provided: “. . . eating became a ritual . . . Some people diluted their food with water to make it seem like more. Others would put each little bite and hold it in their mouth a long time to savor it. So eating took a long time.” Carlyle Frederick was one of several men who collected cookbooks and recipes; he reported owning nearly 100 by the time the experiment was over. Harold Blickenstaff recalled the frustration of constantly thinking about food:

I don’t know many other things in my life that I looked forward to being over with any more than this experiment. And it wasn’t so much . . . because of the physical discomfort, but because it made food the most important thing in one’s life-. . . food became the one central and only thing really in one’s life. And life is pretty dull if that’s the only thing. I mean, if you went to a movie, you weren’t particularly interested in the love scenes, but you noticed every time they ate and what they ate.

Several of the men, like Max Kampelman, agreed that nearly immediately after semistarvation began, all interest in women and dating was lost: “I can tell you, the sex drive disappeared. There was none.” Samuel Legg recalled that the most poignant moment in the experiment for him was related to an emotional reaction caused by his increasing physical weakness and exhaustion:

I was walking along . . . [with my] buddy . . . it was deep into the semistarvation, and we were tired . . . we would look for driveways when we got to a cross street . . . so we wouldn’t have to walk up one step to get from the road to the sidewalk . . . And so we would walk in the gutter for awhile, looking for a driveway. We were tired and weak. And so we were standing at a corner waiting for a light or something, and a kid came along on a bicycle, and he was really moving, pumping away . . . And I looked at him and said, “Wow, look at that boy. He’s really whizzing.” And then I said to myself, “I know where he’s going. He’s going home for supper. And I’m not.” And then for a very brief, I hope it was brief, moment . . . I suddenly hated the boy . . . I hate at this point to tell you this, because it doesn’t speak very well for me. But I remember . . . with . . . horror that I could feel such a thing. So utterly irrational, but there it was. And you ask an experience that I remember; I sure remember that. That was rough.

FIGURE 2 Life magazine photograph of conscientious objectors during starvation experiment. July 30, 1945. Volume 19, Number 5, p. 43. Credit: Wallace Kirkland/Time Life Pic\tures/Getty Images.

The men became more noticeable around campus as they began to manifest visible signs of starvation, sunken faces and bellies, protruding ribs, and edema-swollen legs, ankles, and faces. Other problems such as anemia, neurological deficits, and skin changes became apparent. Suddenly, the story reached millions of Americans. Robert McCullagh remembered: “Well, there was a long period when nobody gave any attention to it because they didn’t even know the experiment was going on. But somewhere it broke . . . we were then besieged by the Minneapolis and St. Paul press. They wanted to know all about the experiment. And then out of that I think grew the contact with Life magazine.” The July 30, 1945 edition of Life magazine carried an article entitled “Men Starve in Minnesota,” with several striking photographs of the volunteers (14) (Figs. 2, 3). Local papers began tracing the progress of the human “guinea pigs” and detailing their bodily decline. Even with the increased media attention, the design and execution of the experiment remained constant. The St. Paul Dispatch reported: “. . . the . . . men on the starvation diet have lost so much physically and mentally that their ambition is gone, their will to go forward is gone, and they cannot do heavy work such as farming, mining, forestry, lifting and many other types of work necessary to rebuild war-torn Europe” (15). The Minneapolis Star-Journal described: “. . . one of the men was walking past a bakery and was so tempted by the rich odors wafting from the place that he rushed in and bought a dozen doughnuts. He gave them to children in the street and watched with relish as they ate them” (16). An article in The Christian Advocate provided details of some of the various tests administered:

A smaller treadmill can be speeded up for exhaustion tests. It is also used for psycho-motor checking while the men walk. For instance, the men try to guide a stylus through a maze without touching the sides and another device records their reaction time to signal lights. They take tapping tests to determine muscular coordination. The ataxiameter measures body sway or sense of balance. Another gadget-and incidentally, many of them have been invented by experimenters here in the laboratory-will determine the angle of vision (17).

Despite the challenges of starvation, there was a determination among the men that somehow kept them committed. When each was asked if he had ever considered withdrawing, the reply was repeatedly firm and succinct: “No.” Harold Blickenstaff recalled:

I had just decided that this was what I was going to do and so I was going to do it . . . and so I would say walking by a bakery was like walking by a bank. It might be nice to have what’s in there, but it’s out of the question. I never debated whether or not I should break diet or do anything else.

Daniel Peacock suggested that there was a religious element in their dedication: “. . . the experiment kind of became our religion in a way. And we were keeping the faith with that. And that was a pretty big job. So I think it would be fair to say that during that year that experiment was almost our religion. That’s what we were dedicated to.” Marshall Sutton found a certain kind of discipline in the stress that helped him to get through the experiment: “I worked on keeping a discipline every day of some reading, and just sitting in silence, and it fitted in my state of being.” Both Max Kampleman and Roscoe Hinkle suggested that the relatively extensive coursework they took at the university provided them with a distraction that facilitated their commitment. Dan Miller was more succinct: “Damn it, it was will power! Don’t try to fuzz it up with something else.”

FIGURE 3 Life magazine photograph of conscientious objector being examined on a tilting table during starvation experiment. July 30, 1945. Volume 19, Number 5, p. 45. Credit: Wallace Kirkland/Time

The 3-mo rehabilitation period began at the end of July 1945 and continued until October 20, 1945. With VE Day in Europe on May 8, 1945, and the Japanese surrender on August 14, 1945, the results of the experiment were becoming increasingly relevant. Several of the men, like Earl Heckman, expressed disappointment that the results were not available in a more timely manner: “We had hoped to have an effect on the world hunger situation following the war . . . [but] the experiment was a little late.” Although the complete monograph was not published until 1950, Keys released early results related to the most effective of the various rehabilitation diets before the experiment even ended (18,19). At a conference in Chicago in 1945, Keys noted:

Enough food must be supplied to allow tissues destroyed during starvation to be rebuilt. . . our experiments have shown that in an adult man no appreciable rehabilitation can take place on a diet of 2000 calories [actually 2000 kcal (8368 kJ)] a day. The proper level is more like 4000 [4000 kcal (16,736 kJ)] daily for some months. The character of the rehabilitation diet is important also, but unless calories are abundant, then extra proteins, vitamins and minerals are of little value (20).

Keys also stressed the dramatic effect that starvation had on mental attitude and personality, and argued that democracy and nation building would not be possible in a population that did not have access to sufficient food. Information from the experiment was shared with various national and international organizations and the military as they worked to develop a postwar relief plan.

For some, the rehabilitation period proved the most difficult part of the experiment. Many were surprised when they initially lost additional weight after being provided a bit more food, a result of losing the excess edema fluid in their bodies. Charles Smith remembered dropping to 99 lb (45 kg), a difference of >50 lb (22.7 kg) from his weight at the beginning of the semistarvation period. Although Harold Blicken-staff remained slightly above the 100-lb (45.3 kg) mark, he referred to himself as a “ninety pound weakling.” William Anderson reported that in many ways rehabilitation was “no better” than the semistarvation period, partially because there was not a noticeable relief from feelings of hunger. Roscoe Hinkle noted that the rehabilitation period “. . . turned out to be worse for me than anything else . . . I had troubles because I didn’t really feel that I was coming back at all.” Initially the lowest energy group received 2200 kcal (9205 kJ), only about 400 kcal (1674 kJ) more than in semistarvation, but Keys eventually increased this number when the men were not showing marked signs of improvement. The men reported that reduced dizziness, apathy, and lethargy were the first signs of recovery, but that feelings of tiredness, loss of sex drive, and weakness were slow to improve (3). Robert McCullagh noted that he could tell he was beginning to recover when his sense of humor finally returned.

None of the men remembered being provided with detailed instructions for recommended diet or activities after they left, and all agreed that they were not “back to normal” after the 3-mo rehabilitation period. Although they were warned to be careful not to overeat on d 1, they were free to eat as they wished. Henry Scholberg remembered being taken to the hospital to have his stomach pumped because he “just simply overdid.” Harold Blickenstaff was sick on the bus on the way back from one of the several meals he had d 1; he found that he simply “. . . couldn’t satisfy [his] craving for food by filling up [his] stomach.” Many also reported eating excessively after they left Minnesota; Jasper Garner described it as a “year-long cavity” that needed to be filled. Many, like Roscoe Hinkle, put on substantial weight: “Boy did I add weight. Well, that was flab. You don’t have muscle yet. And getting] the muscle back again, boy that’s no fun.” Estimates for how long it took to fully recover ranged from 2 mo to 2 y, but none of the men believed there were any negative long-term health effects from participation. There were some suggestions that Lester Glick had expressed resentment about having developed tuberculosis at the end of the rehabilitation period, but his obituary in 2003 noted: “During WWII he was in the alternative service for conscientious objectors . . . serving as a subject for a groundbreaking University of Minnesota starvation experiment” (21).

Ultimately, data from 32 of the 36 participants were included in the final monograph and tables. Two volunteers broke diet and were excused from the experiment; one stopped at various shops for sundaes and malted milks and later stole and ate several raw rutabagas and the other consumed huge amounts of gum and admitted to eating scraps of food from garbage cans. Both also suffered severe psychological distress during the semistarvation period, resulting in brief stays in the psychiatric ward of the university hospital. Another participant broke diet and later suffered some urological complications that prevented his data from being included, but he was asked to stay on and help in the kitchen. Initially the participants were allowed to chew gum, but some of the men began chewing up to 40 packages/d. One of the participants was later excluded because his pattern of weight loss was not consistent with the amount of food intake and energy expenditure, and there was concern raised about excessive gum chewing.

When specifically asked to reflect on how the experiment was explained to them and how they were treated throughout, several pointed out that recruitment information for the experiment and the descriptions provided by the scientists during the selection interviews stressed the difficulty of the proposed endeavor. Max Kampelman noted:

They explained what was going to happen. There was nothing held back. They explained that they could not assure me that there wo\uld be no permanent damage . . . They did not know what would happen. This is what they were trying to find out . . . really they emphasized the discomfort . . . this was not going to be an easy task down the road.

Most also spoke of a feeling of medical safety throughout the experiment. Robert McCullagh noted, “I knew that they were keeping track of me and that nothing was going to happen to me physically.” Charles Smith felt secure due to the: “. . . very high levels of professional responsibility . . . there was no physical threat to one’s long-term survival because you were surrounded by experts who were watching you very closely.” At times, the men seemed almost apologeric about the relative medical safety, wanting to make clear that they distinguished their hunger from that of those starving in unmonitored environments. Samuel Legg’s concluding comment related to this issue: “The difference between us and the people we were trying to serve: they probably had less food than we did. We were starving under the best possible medical conditions. And most of all, we knew the exact day on which our torture was going to end. None of that was true of people in Belgium, the Netherlands, or whatever.”

Participants remembered Keys for his professionalism, always in his white coat with notebook in hand and sparing with conversation. The men were both reassured by his presence and expressed that they felt safe in his hands. Marshall Sutton commented that the university accepted the conscientious objectors and the project “because Ancel Keys accepted [them].” Richard Mundy suggested that perhaps Keys and the staff, upon seeing the dramatic physical effect of starvation, had more ethical concerns about the experiment than the participants themselves: “Mrs. Keys said that Dr. Keys went through terrible times during the experiment as we lost weight and became gaunt and so on. And he would come home and say, ‘What am I doing to these young men? I had no idea it was going to be this hard.'” Perhaps the strongest testament to Keys’ leadership is the fact that the participants agreed that if the clocks were turned back, they would again make the same decision to participate, even after having experienced the physical sacrifice required. Although, like Daniel Peacock, most of them added: “Now remember, I’d do it again if I were 24 again!”

After the Minnesota Experiment, many of the participants continued to follow their convictions about peace. Seven of the 18 interviewed participated in Heifers for Relief, a program that delivered livestock shipments to postwar Europe; the men were responsible for cleaning and caring for the animals on boat trips across the Atlantic. From 1948 to 1950, Harold Blickenstaff worked on a transport team in Poland to bring building materials to people whose homes had been destroyed during the war, and participated in international voluntary work camps in Europe. Samuel Legg worked with the American Friends Service Committee to raise money for food to be sent to Germany, and later spent time in France and Switzerland working on various Quaker projects. Marshall Sutton went with the American Friends Service Committee to feed refugees in Gaza in the Middle East, and spent most of his career working on and leading Quaker projects in the United States. Robert McCullagh went to Yale Divinity School and then to campus ministries in California, South Dakota, and Hawaii. Robert Villcock attended the University of Chicago Divinity School and worked in university and parish ministries in the Midwest. William Anderson was ordained a Methodist minister in Mozambique, and spent nearly 30 years working in South Africa, Mozambique, and Kenya. Max Kampelman went on to a career in politics, law, and diplomacy. He headed the U.S. delegations to the Geneva negotiations on nuclear and space arms reductions in 1974 and the Madrid East-West Conference on Human Rights in the early 1980s, and was later appointed vice-chairman for the United States Institute of Peace. Many of the other participants served as distinguished professors and educators. Despite these various accomplishments, the men continued to look back on participation in the Minnesota Experiment as one of the most important and memorable activities in their lives. Wesley Miller reported, “It’s colored my whole life experience . . . [and was] one of the most important things I ever did . . . I’m proud of the work the Civilian Public Service did during the war.” Samuel Legg seemed to speak for all of the men when he commented, “I think probably most of us are feeling we did something good and are glad we did it, and that helps us live a better life.”

ACKNOWLEDGMENTS

We thank Carolyn Williams for her assistance in locating the contact information for the interviewees, Henry Blackburn for his advice early in the research process, and Kathy Ramel for her help in accessing various articles from the time of the experiment.

0022-3166/05 $8.00 2005 American Society for Nutritional Sciences.

Manuscript received 30 December 2004. Initial review completed 3 February 2005. Revision accepted 3 March 2005.

LITERATURE CITED

1. Keys, A. (1944) Will You Starve That They Be Better Fed? Brochure dated May 27, 1944.

2. Keys, A. (1990) Recollections of pioneers in nutrition: from starvation to cholesterol. J. Am. Coll. Nutr. 9: 288-291.

3. Keys, A., Brozek, J., Henschel, A., Mickelsen, O. & Taylor, H. L. (1950) The Biology of Human Starvation, Vols. I-II. University of Minnesota Press, Minneapolis, MN.

4. Guetzkow, H. G. & Bowman, P. H. (1946) Men and Hunger: A Psychological Manual for Relief Workers. Brethren Publishing House, Elgin, IL.

5. Tyrka, A. R., Waldron, I., Graber, J. A. & Brooks-Gunn, J. (2002) Prospective predictors of the onset of anorexic and bulimic syndromes. Int. J. Eating Disord. 32: 282-90.

6. Williamson, D. A., White, M. A., York-Crowe, E. & Stewart, T. M. (2004) Cognitive-behavioral theories of eating disorders. Behav. Modif. 28: 711-738.

7. Garner, D. M. (1997) Psychoeducational principles in the treatment of eating disorders. In: Handbook for Treatment of Eating Disorders (Garner, D. M. & Garfinkel, P. E., eds.), pp. 145-177. Guilford Press, New York, NY.

8. Doucet, E., St-Pierre, S., Aimeras, N., Despres, J. P., Bouchard, C. & Tremblay, A. (2001) Evidence for the existence of adaptive thermogenesis during weight loss. Br. J. Nutr. 85: 715- 723.

9. Dulloo, A. G., Jacquet, J. & Montani, J. P. (2002) Pathways from weight fluctuations to metabolic diseases: focus on maladaptive thermogenesis during catch-up fat. Int. J. Obes. Relat. Metab. Disord. 26 (suppl. 2): S46-S57.

10. Hoffer, L. J. (2003) Protein and energy provision in critical illness. Am. J. Clin. Nutr. 78: 906-911.

11. Kaysen, G. A. (2000) Malnutrition and the acute-phase reaction in dialysis patients-how to measure and how to distinguish. Nephrol. Dial. Transplant. 15: 1521-1524.

12. Chang, H. R., Dulloo, A. G. & Bistrian, B. R. (1998) Role of cytokines in AIDS wasting. Nutrition 14: 853-863.

13. Frazer, H. T. & O’Sullivan, J. (1996) We Have Just Begun to Not Fight: An Oral History of Conscientious Objectors in Civilian Public Service During World War II. Twayne, New York, NY.

14. (1945) Men Starve in Minnesota: Conscientious Objectors Volunteer for Strict Hunger Tests to Study Europe’s Food Problem. Life 19: 43-46.

15. Quigley, W. (1945) Conchies’ Tests at U Disclose-Many In Europe Must Starve. St. Paul Dispatch, July 26, 1945.

16. (1945) Food Dreams Come True: ‘U’ Conchies to Become ‘Regulated Gourmets’. Minneapolis Star-Journal. July 26, 1945.

17. (1945) They Starve That Others May Be Fed. The Christian Advocate 1945: 788-790.

18. Keys, A., Brozek, J., Henschel, A., Mickelsen, O. & Taylor, H. L. (1945) Experimental Starvation in Man. A Report from the Laboratory of Physiological Hygiene, University of Minnesota. University of Minnesota, Minneapolis, MN.

19. Keys, A., Brozek, J., Henschel, A., Mickelsen, O. & Taylor, H. L. (1946) Rehabilitation Following Experimental Starvation in Man. A Report from the Laboratory of Physiological Hygiene, University of Minnesota. University of Minnesota, Minneapolis, MN.

20. (1945) ‘U’ Experiment Proves Starved People Can’t Be Taught Democracy. Minneapolis Star-Journal. September 26, 1945: 18.

21. (2003) Obituary of Lester J. Click [Online], The Clarion Ledger, March 2, 2003. http://www.clarionledger.com/news/miss/ deaths/2003030207.html [accessed July 3, 2003].

Leah M. Kalm and Richard D. Semba1

The Johns Hopkins School of Medicine, Baltimore, MD

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

Copyright American Institute of Nutrition Jun 2005

Compulsive or obligatory exercising, also known as anorexia athletica, is a disorder in which a person is compelled to exercise beyond what is considered normal and healthy. The individual with anorexia athletica typically suffers with serious underlying issues of anxiety, stress, depression and/or anger stemming from poor self- image. The extra exercise is a misguided attempt to gain a temporary sense of power and self-control.

Although anorexia athletica is not recognized in the same way that anorexia nervosa and other eating disorders are, the disorders often go hand in hand. It is not unusual for those with this disorder to be preoccupied with food and body weight.

For the compulsive exerciser, self-esteem is tied to their workouts or athletic performance. He or she continually thinks or talks about exercise, weight gain or loss and what to eat or not to eat.

People with anorexia athletica are driven to exercise, rather than getting enjoyment from the workout. They will turn down invitations to social events or avoid spending time with friends and family in order to exercise, and often hide the truth about how much time is spent working out.

Symptoms of anorexia athletica include:

– Finding ways to exercise despite injury or sickness.

– Dissatisfaction with performance or athletic achievements, mind- set of pushing harder or doing better.

– Lying about or justifying excessive amounts of time spent exercising. She may define herself as an athlete or insist excessive workouts are healthy.

– Mood swings. Changes in mood, including irritability, anger or anxiety can be brought about if the person is not able to exercise, or can be caused by continually overtraining.

– Workouts regularly exceed the intensity, frequency or duration required for good health.

– Preoccupation with working out, body fat/weight and diet.

– Avoiding or taking time from relationships, work, school and other obligations to exercise.

– Feeling driven to exercise, forgetting that physical activity can be enjoyable.

– Self-esteem rests on workout performance.

The health consequences, mental and physical, are numerous for those with compulsive exercise disorder. The cumulative effect of regular excessive exercise weakens the body, rather than strengthens it.

Health concerns include:

– Dry hair and skin; hair loss.

– Damage to bone, loss of bone density, leading to osteoporosis; stress fractures.

– Digestive difficulties.

– Slowed heart rate and low blood pressure.

– Dehydration and possible kidney problems.

– Depression, chronic tiredness, fatigue.

– Difficulty sleeping, insomnia.

– Muscle and joint weakness and damage, suppressed immune function. This is caused by repeated bouts of exercise without proper rest and recovery time.

– Vitamin/mineral deficiencies, muscle loss because of rigid eating behaviors.

– Women who exercise too much may develop amenorrhea (loss of menstrual cycle).

– Heart problems. Too much exercise is bad for the heart, especially if combined with an eating disorder.

– Too much exercise can lead to the release of excessive free radicals, which have been linked to cellular mutations and cancer.

For those suffering with body-image disorders, treatment can help to re-establish a healthy relationship with food and exercise. An estimated 80 percent of those who seek professional help make significant progress or recover completely.

Marjie Gilliam is an International Sports Sciences Association master certified personal trainer and fitness consultant. She owns Custom Fitness Personal Training Services. Write to her in care of the Dayton Daily News or contact her at 878-9018 or by e-mail at [email protected]. Her Web site is marjie.hypermart.net.

(c) 2005 Marjie Gilliam

PARENTS CAN HELP

More and more, compulsive exercise and eating disorders affect youngsters. A child’s self esteem is easily influenced by remarks made by parents and peers and by the media. Tips for parents:

– Do not focus on a child’s weight. Instead, set a good example by encouraging healthy foods and fun activities.

– If your child is overweight, don’t continually dwell on foods he cannot have.

Emphasize healthy choices. For example, let your child choose which favorite fruits, vegetables and healthy snacks she would like you to buy when grocery shopping. Allow the child to help you fix healthy meals.

– Participate in physical activities with your child when possible and make exercise fun. Encourage activities with family and friends, such as bike riding or a day at the pool, or head to the park for a walk or friendly game of baseball or volleyball.

Children take their cues from you and will often emulate what they see and hear. Avoid making negative comments or dwelling on your or someone else’s weight issues or appearance in front of your child. Focus on your child’s positive attributes.

– Avoid putting pressure on your child to perform. Instead, give support. Emphasize your child’s strengths and guide him patiently through difficulties. Children are eager to please, and even a little praise will go a long way toward building self-confidence.

PALMDALE – Antelope Valley residents can exercise, cool off or just play this summer in six public swimming pools.

Palmdale’s pools at Courson Park and McAdam Park open today. Los Angeles County Department of Parks and Recreation pools at George Lane Park in Quartz Hill and Everett Martin Park in Littlerock will open Saturday.

Webber Pool at Jane Reynolds Park in Lancaster will open July 4. Lancaster’s indoor Eastside Pool is open year-round.

The pool schedules in Palmdale are:

–McAdam Pool, 38115 30th St. E., (661) 267-5653: Recreational swim, 2:30-4:15 p.m weekdays and 1-3 p.m. and 3:30-5:15 p.m. weekends. Family swim, 7:30-9 p.m. Mondays and Thursdays. Swim team, 6:30-7:30 p.m. weekdays. Swim lessons, 9-11:20 a.m. and 4:45-6:10 p.m. weekdays. Adult lap swimming 12-12:50 p.m. weekdays.

–Courson Park Pool, 38226 10th St. E., (661) 267-5611: Recreational swim, 2:30-4:30 p.m. weekdays and 1-3 p.m. and 3:30- 5:15 p.m. Saturdays and Sundays. Adult lap swimming, 12-12:50 p.m. weekdays. Senior citizen swim, 1-1:55 p.m. weekdays. Swim lessons, 9- 11:20 a.m. and 4:45-6 p.m. weekdays.

Palmdale’s pools have no admission charge for recreational swim times or senior citizen swimming.

Palmdale’s adult lap swimming costs $38 for each four-week session.

The pool schedules in Lancaster are:

–Eastside Pool, 45045 5th St. E., (661) 723-6255: Recreational swimming, 1:30-3 p.m. weekdays and 1:30-3:30 p.m. Saturdays and Sundays. Early bird lap, 5:45-7 a.m. weekdays. Noon lap, 11:45 a.m.- 1 p.m. daily. Senior and therapy, 10:30-11:30 a.m. weekdays. Evening laps, 8:30-9:30 p.m. Mondays, Wednesdays and Fridays. Swim lessons, 8:10-10 a.m. Mondays through Thursdays and 4:20-7:50 p.m. Tuesdays and Thursdays. Swim team, 4- 5:30 p.m. Monday, Wednesday and Friday.

–Webber Pool, 716 W. Oldfield St., (661) 723-6288: Pool will open July 4 and will close Sept. 5. Recreational swimming, 1-3 p.m. weekdays and 1-4 p.m. Saturday and Sunday. Swim lessons, 9-10:50 a.m. Monday through Thursday and 9-11:30 a.m. Saturdays.

Admission fees at Eastside Pool are $1 for ages 4-12 years and seniors 55 and up, $1.25 for ages 13-16, and $1.75 for 17 years and older. Children age 3 and under are free. Lap swim is $1.75 for ages 16 and up; and $1 for seniors age 55 and older. Webber Pool admission is 75 cents for ages 4 years and up. Lap swim is $1.75 for ages 16 years and up and $1 for seniors 55 and up.

Pool schedules for Los Angeles County-operated parks are:

–George Lane Park pool, 5520 W. Ave. L-8, Quartz Hill, (661) 943- 2000: Swimming lessons, 10 a.m.-noon weekdays. Recreational swim, 12:30-5 p.m. daily. Swim team, 5-6 p.m. weekdays. Lap swimming, 6-8 p.m. weekdays.

–Everett Martin Park pool, 35548 92nd St. E., Littlerock, (661) 944-1449: Swimming lessons, 10 a.m.-noon weekdays. Recreational swim, 12:30-5 p.m. daily. Swim team, 5-6 p.m. weekdays. Lap swimming, 6-8 p.m. weekdays.

The Los Angeles County pools will close at 5 p.m. Sept. 5. There are no fees for swim lessons or recreation swimming. Swim lessons are 55- minute sessions for a two-week period. Lap swimming is $7 a week.

When Dad decided it was time for his boys to learn how to swim, he took us down to the Green River near Woodbury, Ky., and pretty much threw us in. Unlike the old Red Skelton story, we didn’t have to fight our way out of a grass sack to find the surface.

With a little encouragement, some downright fear and a genetic sense of survival, we learned how to swim in those muddy waters.

There were no Red Cross lessons and certainly no municipal swimming pool around to safely learn how to swim. There was nothing but a sand bar and a need to survive.

Which brings me to yet another poor decision I made recently, in an effort to bring the joy of swimming to my grandkids who live out in the country — hundreds of miles from the Green River at Woodbury.

At one of those giant discount stores, I spotted a massive 18- foot vinyl swimming pool suspended from the ceiling. In the middle was a poster depicting a half-dozen kids frolicking in the crystal clear waters of an “Easy-Set” backyard pool.

“Perfect,” I thought. “This will keep the kids out of the cattle ponds with the dogs and within sight of their mom.”

Then came the fun part. “Make sure the `Easy-Set’ pool is on level ground,” the instructions read.

“Hmmm, looks level to me. Start blowin’ her up,” I ordered. Within seconds, the pool was aired up and ready to be filled.

After the first hour of running the garden hose into the pool, I realized this could take a while. Then, it dawned on me they aren’t on a municipal water system, and all the water would have to be pumped out of the ground.

“She ain’t never run dry in 50-odd years,” I was assured.

That’s when the garden hose started sputtering, and belched out about 50 gallons of mud into the center of the pool.

“Shut her down,” I shouted. “I think we need to let it settle out a bit.”

By now, I could see that the south end of the pool was about two feet lower than the north end. That’s fine, I thought, thinking it would simply be easier for the kids to climb in on the lower end.

Studying the situation a little further, I was reminded that one of our local fire departments offered a pool filling service for a small fee. This, I thought, would clear up the muddy pool situation created by the well that ran dry in the middle of the filling process.

One tanker load later, the only thing that was clear was the realization that I had created an “Easy-Set” farm pond, complete with a layer of mud on the bottom.

Then came the joy of adding chemicals. “You need some flocculent,” one salesman told me. “Lots of chlorine and a load of clarifier,” another said.

Another salesman said to throw the kids in the pool, turn on the filter and let them stir everything around until it clears up.

None of that worked. Now all I have are several mud-filled filters and a bunch of kids who don’t care what color the water is, so long as they can jump in and play.

Reminds me of the Green River at Woodbury, Ky.

* Readers can contact Len Wells at (618) 842-2159 or [email protected]

Abstract: Obstructive sleep apnea (OSA) is a serious condition that is common among neurological patients. If undiagnosed and untreated, it may lead to hypertension, coronary heart disease, pulmonary hypertension, myocardial infarction, stroke, psychiatric disorders, cognitive impairment, and, ultimately, death. One of the first steps in identifying OSA is to recognize its signs and symptoms. Nursing knowledge of OSA facilitates referral, diagnosis, and treatment of this potentially life-threatening condition.

Obstructive sleep apnea (OSA) is a common, potentially life- threatening condition. An estimated 80%-90% of Americans with OSA have not been diagnosed (Kapur, Strohl, & Redline, 2002). If untreated, OSA may lead to hypertension, coronary heart disease, pulmonary hypertension, myocardial infarction, stroke, psychiatric disorders, cognitive impairment, and, ultimately, death. OSA may present at any time across the lifespan, from early childhood to older age. The incidence of OSA in patients with certain neurological conditions such as Parkinsonism, myotonic dystrophy, and myasthenia gravis is higher than in the general population, primarily due to impairment of the nerves controlling the muscles of the upper airway. Neurological disorders and OSA can coexist and, potentially, exacerbate each other (Vaughn & D’Cruz, 2003).

One of the first steps in identifying individuals with OSA is educating nurses about the symptoms of and risk factors for this disorder so they can identify and refer appropriate patients for evaluation. Nurses working with patients who have neurological disorders must receive OSA-related education. Certain clinical features of OSA and neurological disorders are the same, making it more challenging to identify sleep problems. This article presents an overview of OSA and related health conditions, with an emphasis on neurological conditions, risk factors and symptoms, and assessment to guide nurses in identifying patients whose sleep patterns require further evaluation.

Overview

OSA is characterized by repeated episodes of apnea (the cessation of breathing for at least 10 seconds) and/or hypopnea (an airflow reduction of at least 30%), accompanied by a 4% drop in blood oxygen saturation level during sleep due to obstruction of the pharyngeal airway despite persistent respiratory efforts (Kryger, Roth, & Dement, 2000). To describe the severity of this disorder, sleep literature uses the terms apnea index (AI), which is the number of apneas per hour, and hypopnea index (HI), which is the number of hypopnea episodes per hour. In addition, the terms apnea-hypopnea index (AHI) and respiratory disturbance index (RDI) are used interchangeably to reflect the sum of apneas and hypopneas per hour.

Pathology and Implications

The primary pathophysiologic event that occurs in instances of OSA is occlusion or near occlusion of the pharynx during sleep. When patients are awake, pharyngeal muscles are sufficiently activated to maintain patency of the upper airway. While they are asleep, however, there is decreased activation of this musculature. In OSA patients, the normal narrowing of the upper airway progresses to complete collapse during inspiration, or possibly at end- expiration. When patients exert increased effort to inspire against the occluded airway, it makes the situation worse by creating more negative airway pressure. Occlusion continues until arousal occurs and the resulting increased tone of the pharyngeal muscles reopens the airway. These “micro-arousals” may occur at rates of more than 90 per hour-whenever an apneic or hypopnic event disrupts sleep- with patients usually unaware they have occurred. When these apneic events are lengthy (some last for 2 minutes or longer), they can result in significant oxygen desaturation and decrease sleep levels necessary for physical and psychological restoration. Current criteria identify mild OSA as an AHI of 5-15, moderate OSA as an AHI of 15-30, and severe OSA as an AHI higher than 30 events per hour (American Academy of Sleep Medicine Task Force, 1999).

Incidence in Neurological Conditions

Any neurological condition that results in impaired tone of the upper airway muscles can add to airway obstruction and result in OSA, especially when the individual has additional risk factors, such as obesity or hypothyroidism. Obstruction can occur at the pharyngeal level because of primary bulbar weakness or the inability of the diaphragm and intercostal muscles to overcome changes in airway resistance. This problem is magnified during rapid eye movement (REM) sleep due to the natural loss of intercostal muscle tone during that period.

Common neurological and neuromuscular disorders associated with a higher incidence of OSA in adults include congenital myopathies, neuropathies, myotonic dystrophy, Duchenne’s dystrophy, mitochondrial encephalomyopathy, myasthenia gravis, stroke, epilepsy, Parkinsonism, and Alzheimer’s disease (Kryger et al., 2000). Neuromuscular disorders that may be associated with OSA in children include, but are not limited to Duchenne’s dystrophy, myotonic dystrophy, nemaline myopathy congenital muscular dystrophy, cerebral palsy, spinal muscular atrophy, transverse myelitis, and poliomyelitis (Seddon & Khan, 2003).

Sleep disturbance in patients with epilepsy frequently is overlooked, but may contribute to decreased daytime functioning and increased seizure activity (Bazil, 2000). Malow et al. (2003) studied adults and children with epilepsy, and found that 50% of those with both epilepsy and some risk factors for OSA who had a polysomnogram (sleep study) did have OSA. In addition, when treated with continuous positive airway pressure (CPAP) therapy, their seizure frequency was reduced by 45%. It is especially important to identify OSA in patients with epilepsy because most antiepileptic drugs’ sedating effects can worsen OSA. (Manni & Tartara, 2000). Manni et al. (2003) found the coexistence of OSA with epilepsy to be 10.2% among the epilepsy patients they studied (15.4% of the men and 5.4% of the women). They reported that older age at onset of seizures was related significantly to comorbidity with OSA. Malow, Levy, Maturen, and Bowes (2000) found that one-third of the studied epilepsy surgery candidates with histories of medically refractory epilepsy had OSA diagnosed following polysomnography. Previously undiagnosed OSA was common in these patients, especially among the men, older subjects, and those with seizures during sleep.

OSA, which frequently is identified in stroke patients, may be a factor in stroke development secondary to hypertension that results from nightly episodes of hypoxia and chronically elevated sympathetic tone, or a stroke that occurs due to impaired upper airway musculature control (Lattimore, Celermajer, & Wilcox, 2003; Yaggi & Mohsenin, 2004). Bassetti and Aldrich (1999) found that 62% of the stroke and transient ischemic attack patients they studied had an AHI index higher than 10. Wessendorf, Teschler, Wang, and Schreiber (2000) reported the prevalence of sleep-disordered breathing (primarily OSA) was 61% in first-time stroke patients. Good, Henkle, Gelber, Welsh, and Verhulst (1996) studied sleep- disordered breathing and functional outcomes following stroke. They found that 68% of studied stroke patients had an AHI higher than 20, and 53% had an AHI higher than 30, with desaturation events primarily due to obstructive apneas. They also found that sleep- disordered breathing, especially OSA, was an independent predictor of worse functional outcome during the rehabilitation period, and was associated with a higher mortality rate at 1 year.

Up to 60% of adult patients with myasthenia gravis have an above- average number of apneas and hypopnea periods during sleep. Duration of illness has been correlated with the severity of apneas in these patients (Amino et al., 1998).

Maria et al. (2003) found that 60% of patients with idiopathic Parkinson’s disease (PD) who participated in their study met the criteria for OSA. In addition, they found that study participants with more severe PD had more severe OSA.

Risk Factors

Most patients diagnosed with OSA are obese, with more than 60% weighing at least 20% above the recommended body weight for their height. This relationship may be caused by decreased airway size resulting from fat deposits in the neck area.

Gender also appears to influence the incidence of OSA. The incidence in men is higher than in women in all age groups; after menopause, however, the incidence in women approaches that of men. It is thought that estrogen exerts a respiratory stimulant effect that may provide some protection to premenopausal women (Keef, Watson, & Naftolin, 1999). Men also tend to have shorter, thicker necks, which may result in decreased upper airway size.

Race also may be an OSA risk factor. In African Americans and Asians, the syndrome occurs twice as often as in Caucasians, and tends to be more severe in the former groups (Ong & Clerk, 1998). This may be explained by differences in skull and upper airway shapes in certain ethnic populations.

Increasing age also is a risk factor for OSA (Shochat & Pillar, 2003). Most patients with OSA are 40 years of age or older, with the incidence increasing slightly with age. The weight gain that frequently occurs with aging may have a bearing on this finding. The increase\d incidence of OSA also may be due to an age-related decrease in muscle tone in the upper airways, allowing tissue in the pharyngeal area to collapse more readily.

OSA also is associated with acromegaly and hypothyroidism (Kryger et al., 2000). Narrowing of the upper airway due to abnormalities of ventilatory effort or mucoprotein deposition on the tongue and in the nasopharynx are two possible mechanisms for OSA in these patients.

In children, enlarged tonsils and adenoids are a significant OSA risk factor, primarily during early childhood (Nieminen, Tolonen, & Lopponen, 2000). Adenoid enlargement (hyperplasia) is normal in childhood, and it is not clear why some children develop hyperplasia severe enough to cause obstruction, while others do not. Neither adenoid thickness nor airway size, as determined by X ray, is a strong predictor of obstruction. Hyperplasia most commonly occurs at about the age of age 5, but symptoms have been reported in infants as young as 2 months.

Any myopathy, neuropathy, or neurological condition that causes weakness of the upper airway musculature predisposes an individual to OSA development. Neurological impairment, primarily impairment of the genioglossus muscle, is considered the main factor that causes this predisposition.

Other medical conditions, such as nasal obstruction secondary to rhinitis, sinusitis, allergies, tumors, or cysts, place individuals at higher risk of obstruction. Rheumatoid arthritis that involves the temporomandibular joint also may predispose individuals to develop OSA.

Tobacco use is also known to have a determintal effect on sleep. Smokers have a fourfold to fivefold greater risk than those who never smoked of having at least moderate sleep-disordered breathing (Wetter, Young, Bidwell, Badr, & Palta, 1994). It is thought that cigarette smoking elicits mucosal edema, thereby contributing to a narrowed airway.

Symptoms

Individuals with OSA may present with a variety of symptoms with which nurses should be familiar (Fig 1); some of these symptoms appear during both waking hours and the usual sleep period. Excessive daytime sleepiness is one of the most frequently reported OSA symptoms. Naps taken during the day are not refreshing, and the person awakens feeling even more groggy. Those with OSA frequently are involved in motor vehicle collisions, as it is often difficult for them to stay awake while driving. Individuals with OSA often fall asleep while watching television, reading, or participating in other sedentary activities. Daytime sleepiness can have life- threatening consequences for teens and adults who drive during the day.

Children past the age of 8 or 9 years typically present with many symptoms similar to those of adults. It is important to note that younger children may present with hyperactivity and/or aggressive behavior rather than excessive sleepiness, because younger children often fight sleepiness with agitation. These symptoms may result in an incorrect diagnosis of attention deficit hyperactivity disorder (ADHD), when, in fact, the correct diagnosis is OSA, most often caused by hypertrophy of the adenoids and/or tonsils.

Characteristic loud pharyngeal snoring is reported in the majority of patients diagnosed with OSA. Typical loud snoring occurs first, followed by periods of decreased sound and apnea. These periods of apnea often last from 20 seconds to 2 or more minutes, usually ending with a loud snort. This cycle typically repeats itself many times throughout the night, on an intermittent basis, with patients usually unaware of their abnormal respiratory patterns and snoring. Consequently, a spouse or other family member often first identifies the problem by observing these abnormal breathing patterns. It is not unusual for patients who are evaluated at sleep disorder centers to experience 200-600 apnea events throughout the night.

Periodic leg jerks, other abnormal sleep movements, and general restlessness often are observed as individuals reposition themselves to facilitate respiratory efforts. The exact mechanism by which these leg jerks develop and are related to OSA is not clearly understood.

Cognitive changes, such as periods of confusion, the inability to concentrate, or short-term memory impairment, also occur frequently with OSA. Morning headaches in the frontal area that resolve about 2 hours after awakening also may occur. These symptoms are thought to occur as the result of high levels of carbon dioxide retention after apneas and/or hypopnea episodes that result in cerebral vasodilation. It is not uncommon for oxygen saturation levels to drop 15% or more immediately following apneic events, and these desaturations may contribute to decreased mental alertness and shortened attention span throughout the waking hours.

Fig 1. List of common awake and sleeping symptoms

Personality changes, including anxiety, depression, irritability, and decreased sexual drive or impotence, also may occur as a result of severely disrupted sleep patterns. Work and school performance, as well as personal relationships often suffer because of the personality changes induced by sleep fragmentation and lack of REM sleep.

OSA causes cardiac stress, which increases the secretion of atrial natriuretic peptide, which in turn stimulates the kidneys, and increases urine production and abdominal pressure. These actions form the basis for nocturia in adult OSA patients and nocturnal enuresis in children with OSA. It is not unusual for adults with OSA to awaken and urinate several times during the night (Umlauf et al., 2004)

Gastroesophageal reflux is another frequently observed symptom among OSA patients. Reflux occurs secondary to decreased airway pressures during periods of upper airway obstruction and a subsequent increase in breathing effort and abdominal pressure.

Continual sympathetic stimulation during the night often leads to cardiovascular symptoms that persist during waking hours. These symptoms include elevations of blood pressure, sinus arrhythmias, and nocturnal angina (Foresman, Gwirtz, & McMahon, 2000). It is believed that these symptoms, which occur in response to decreased oxygen saturation levels, result in cardiac hypoxia. On average, systolic and diastolic blood pressure increase approximately 25% with apnea events, with the greatest elevations occurring during REM sleep when desaturation is most severe. The exact mechanism by which these increased values persist into the waking hours is not understood. Marcus, Greene, and Carroll (1998) found that children with OSA had a significantly higher diastolic, but not systolic, pressure during both sleeping and waking hours, with pressure slightly lower during sleep. Adults with OSA often have elevated systolic and diastolic measurements.

Nursing Interventions

Nurses can help OSA patients prevent life-threatening physiologic changes and improve the quality of their lives and the lives of those around them. Nursing intervention begins with assessment, and continues with referral and educational and psychological support.

Assess symptoms and risk factors. The first important nursing intervention occurs during the nurse’s initial contact with the patient, when the nurse identifies risk factors and assesses for symptoms. The patient should be asked about excessive daytime sleepiness, headaches, and difficulty with work, school, or social relationships. A history of alcohol intake, smoking, and nighttime symptoms, such as urinary frequency, should be obtained. Also ask family members or caregivers if they have witnessed the patient exhibiting apneas during sleep, snoring, or changes in mood or personality. A list of appropriate questions to elicit this information is presented in Fig 2. Also ask the patient to maintain a sleep diary for about a week in which he or she documents total hours of sleep, exact bedtime, bedtime rituals, frequency of awakenings, number of naps, and feelings of overall sleepiness during the day. A physical exam may reveal additional information suggestive of OSA, and should include measurements of body weight, height, pulse, and blood pressure. Inspect the oral cavity, looking for enlarged tonsils, adenoids, or tongue, and for the presence of a large, droopy, soft palate. Look at the nasal passages carefully for patency. Careful cardiac auscultation should be performed with attention to the presence of arrhythmias or signs of pulmonary hypertension, such as an increased pulmonic component to the second heart sound. To get a better idea of the patient’s breathing behavior, it is helpful to ask a family member or caregiver to mimic the way the patient breathes.

Refer for medical evaluation. Prompt referral to a physician certified in sleep medicine is important. The definitive test for OSA is an overnight polysomnogram performed in a certified sleep laboratory. Following the study, results are interpreted, a diagnosis is made, and treatment prescribed, depending upon the findings. Weight loss is encouraged for obese or overweight patients. In children, removing tonsils and adenoids often results in obstruction relief. In adults, treatment most often includes a prescription for CPAP. In mild cases or for patients who are not able to tolerate CPAP, an oral mandibular advancement device might be prescribed (Yantis, 2003). This device, usually fitted by a dentist or oral surgeon, advances the mandible slightly, bringing the tongue forward and slightly increasing the diameter of the airway space. The long-term effects of the various upper airway tissue reduction procedures such as somnoplasty and laser-assisted uvulopalatopharyngeoplasty have yet to be proven beneficial.

Fig 2. Sleep apnea assessment questions

Following diagnosis, it is important to provide psychological support, because OSA can be a frightening diagnosis. Patients may have difficulty adjusting to treatments, such as CPAP devices. Promote airway patency by advising patien\ts to avoid the ingestion of alcohol (especially before bedtime) and sedating medications. Weight loss is an important factor in reducing the amount of excess tissue around the upper airway. Encourage patients to avoid using nasal sprays, which may cause rebound nasal congestion. Also advise patients to wear a medic-alert bracelet or necklace that can alert medical personnel to their OSA.

Application to Neuroscience Nursing Practice

It is incumbent upon neuroscience nurses to assess for OSA and refer when appropriate (Bader & Littlejohns, 2004). Patients with untreated OSA have decreased oxygen saturation levels, which may worsen neurological or neuromuscular symptoms. In turn, these symptoms can exacerbate OSA because of decreases in muscle strength, respiratory effort, or cognitive function. Neuroscience patients may develop a circular pattern of disease/disorder and OSA advancement if their disorder goes undiagnosed and untreated.

Assessing neuroscience patients for OSA may be problematic because of their neuroscience disorder (s). Nevertheless, assessment is necessary if symptoms are noted. Stroke patients or patients with neuromuscular disorders that affect speech may not be able to articulate the answers to questions clearly or appropriately. In these instances, ask family members to describe behaviors such as snoring, any worsening of the underlying condition, or increases in seizure activity. In some patients, swallowing difficulties may be more pronounced; assess for choking potential. Also assess for decreases in neurological status after rest or sleep periods accompanied by snoring. For patients in rehabilitation programs, watch for sleep occurrences that may indicate OSA during therapies or while they are eating. Again, assess patients for abnormal movements during sleep. It is easiest for neuroscience nurses to monitor inpatients while they are sleeping. If the patient is at home, instruct family members to report OSA signs or symptoms to the healthcare provider for evaluation. Finally, if the patient takes blood pressure medications and the dosages or types of medications change, evaluate sleeping patterns for possible OSA.

Summary

Most of us equate sleep with rest, but sleep is a potential menace for millions of people. In patients with neurological disorders, the incidence of OSA is increased, making careful nursing assessment imperative. By identifying and promptly referring these patients for evaluation, nurses become an important part of their improved health and quality of life.

Continuing Education Credit

The Journal of Neuroscience Nursing is pleased to offer the opportunity to earn neuroscience nursing contact hours for this article online. Go to www.aann.org, and select “Continuing Education.” There you can read the article again or go directly to the posttest assessment. The cost is $15 for each article. You will be asked for a credit card or online payment service number.

The posttest consists of 10 questions based on the article, plus several assessment questions (e.g., How long did it take you to read the article and complete the posttest?). A passing score of 80% (8 of 10 questions correct) on the posttest and completion of the assessment questions yields 1 nursing contact hour for each article.

Sources for Information About Sleep Apnea

National Sleep Foundation

729 15th Street NW, 4th floor

Washington, DC 20005

www.sleepfoundation.org

National Heart, Lung, and Blood Institute

P.O. Box 30105

Bethesda, MD 20824-0105

http://www.nhlbi.nih.gov/health/public/sleep/index.htm

American Sleep Apnea Association

www.sleepapnea.org/geninfo.html

The American Sleep Disorders Association

Web address: http://www.asda.org

Stanford University-Sleep Apnea Information and Resources

www.Stanford.edu/~dement/apnea.html

The Yale Center for Sleep Disorders

www.info.med.yale.edu/intmed/sleep

Any myopathy, neuropathy, or neurological condition that causes weakness of the upper airway musculature predisposes an individual to OSA development.

References

American Academy of Sleep Medicine Task Force. (1999). Sleep- related breathing disorders in adults: Recommendations for syndrome definition and measurement techniques in clinical research. Sleep, 22, 667-689.

Amino.A., Shiozawa, Z., Nagasaka.T, Shindo, K., Ohnshi, K.,Tsunoda, S., et al. (1998). Sleep apnoea in well-controlled myasthenia gravis and the effect of thymectomy.Journal of Neurology, 22(2), 77-80.

Bader, M. K., & Littlejohns, L. R. (Eds.). (2004). AANN core curriculum for neuroscience nursing (4th ed.). St. Louis: Saunders.

Bassetti, C., & Aldrich, M. (1999). Sleep apnea in acute cerebrovascular diseases: Final report on 128 patients. Sleep, 22,217-223.

Bazil, C. W. (2000). Sleep and epilepsy. Current Opinion in Neurology, /3(2), 171-175.

Foresman, B., Gwirtz, P., & McMahon, J. (2000). Cardiovascular disease and obstructive sleep apnea: Implications for physicians. Journal of the American Osteopathic Association, 700,360-369.

Good, D., Henkle, J., Gelber, D.,Welsh, J., & Verhulst, S. (1996). Sleep-disordered breathing and poor functional outcome after stroke. Stroke, 27, 252-259.

Kapur, V, Strohl, K., & Redline, S. (2002). Underdiagnosis of sleep apnea syndrome in U.S. communities. Sleep Breath, 6, 49-54.

Keef, D. L.,Watson, R., & Naftolin, F. (1999). Hormone replacement therapy may alleviate sleep apnea:A pilot study. Menopause, 6,186-187.

Kryger, M., Roth, T., & Dement, W. (2000). Principles and practice of sleep medicine (3rd ed.). Philadelphia: Saunders.

LattimoreJ., Celermajer, D., &Wilcox, I. (2003). Obstructive sleep apnea and cardiovascular disease. Journal of the American College of Cardiology, 41,1429-1437.

Malow, B.A., Levy, K., Maturen, K., & Bowes, R. (2000). Obstructive sleep apnea is common in medically refractory epilepsy patients. Neurology, 55,1002-1007.

Malow, B.A.,Weatherwax, K., Chervin, R., Hovan,T., Marzec, M., Martin, C., et al. (2003). Identification and treatment of obstructive sleep apnea in adults and children with epilepsy: A prospective pilot study. Sleep Medicine, 4,509-515.

Manni, R., &Tartara, A. (2000). Evaluation of sleepiness in epilepsy. Clinical Neurophysiology, 111 (Suppl. 2), 111-114.

Manni, R., Terzaghi, M., Arbasino, C, Sartori, L, Galimberti, C., & Tartara, A. (2003). Obstructive sleep apnea in a clinical series of adult epilepsy patients: Frequency and features of the comorbidity. Epilepsia, 44, 836-840.

Marcus, C. L., Greene, M., X Carroll, J. (1998). Blood pressure in children with obstructive sleep apnea. American Journal of Respiratory Cellular Molecular Biology, 157, 1098-1103.

Maria, B., Sophia, S., Michalis, M., Charalampos, L., Andreas, P., John, M., et al. (2003). Sleep breathing disorders in patients with idiopathic Parkinson’s disease. Respiratory Medicine, 97, 1151- 1157.

Nieminen, P.Tolonen, U., & Lopponen, H. (2000). Snoring and obstructive sleep apnea in children. Archives of Otolaryngeologic Head and Neck Surgery, /26(4), 481-486.

Ong, K., & Clerk, A. (1998). Comparison of the severity of sleep- disordered breathing in Asian and Caucasian patients seen at a sleep disorders center. Respiratory Medicine, 92,843-848.

Seddon, P. C., & Khan,Y. (2003). Respiratory problems in children with neurological impairment. Archives of Disease in Childhood, 88(1), 75-78.

Shochat.T., & Pillar, G. (2003). Sleep apnea in the older adult: Pathophysiology, epidemiology, consequences and management. Drugs and Aging, 20,551-560.

Umlauf, M., Chasens, E., Greevy, R., Arnold, J., Burgio, K., & Pillion, D (2004). Obstructive sleep apnea, nocturia and polyiiria in older adults. Sleep, 27,139-144.

Vaughn, B.V, & D’Cruz, O. F. (2003). Obstructive sleep apnea in epilepsy. Clinics in Chest Medicine, 24, 239-248.

Wessendorf,T.,Wang,Y., Schreiber,A., &Teschler, H. (2000). Fibrinogen levels and obstructive sleep apnea in ischemic stroke. American Journal of Respiratory and Critical Care Medicine, 162, 2039-2042.

Wetter, D., Young,T., Bidwell.T., Badr, M.S., & Palta. M. (1994). Smoking as a risk factor for sleep-disordered breathing. Archives of Internal Medicine, 154, 2219-2224.

Yaggi, H., & Mohsenin,V . (2003). Obstructive sleep apnoea and stroke. lancet Neurology, 3(6), 223-237.

Yantis, M. A. (2003). Assisting patients using positive airway pressure therapy. Home Healthcare Nurse, 27(3), 160-167.

Questions or comments about this article may be directed to Mary Ann Yantis, PhD RN, Baylor University, Louise Herrington School of Nursing, 3700 Worth St., Dallas, TX 75246, or by e-mail to [email protected]. She is an assistant professor, Baylor University, Louise Herrington School of Nursing, Dallas, TX.

Jacquelin Neatherlin, PhD RN CNRN, is an associate professor, Baylor University, Louise Herrington School of Nursing, Dallas, TX.

Copyright 2005 American Association of Neuroscience Nurses 0047- 2606/05/3703/0000150$5.00

Copyright American Association of Neurosurgical Nurses Jun 2005

Abstract: Neuroleptic malignant syndrome (NMS) is a potentially lethal condition that has been described in patients with idiopathic Parkinson’s disease (PD) after long-term dopaminergic medications are suddenly stopped or moderately decreased. If patients with PD develop severe rigidity, stupor, and hyperthermia, L-Dopa withdrawal should be suspected and the dopaminergic drug restarted as soon as possible to prevent rhabdomyolysis and renal failure. Nurses who are knowledgeable about NMS can provide prompt identification of the PD patient’s condition and prevent a potentially lethal cascade of symptoms.

A 72-year-old white male diagnosed with Parkinson’s disease (PD) 14 years ago, presented to our clinic with a temperature of 102.5F, decreased mental status, rigidity, and stiffness. The patient’s wife reported that her husband’s freezing episodes had intensified over the past week and that his mental status had declined. His weakness and confusion caused him to spend the previous night on the bathroom floor. The fire department was called the next day to assist her in rifting him so she could transport him to the hospital. One month before this incident, the patient had a bilateral deep brain stimulator (DBS) placed into his basal ganglia to treat tremors and dyskinesias related to PD. The surgical hospital course had been unremarkable.

Physical Examination

The patient presented with altered mental status, inability to follow commands, hallucinations, confusion, and inability to ambulate or perform activities of daily living. His temperature was 102.5F, and his neck and extremities were rigid. There were resting pronation and supination tremors of both hands, with marked pill- rolling actions of the fingers. Mild to moderate dysarthria, hypophonia with a monotone voice, and hypomimia were observed. Surgical sites were healed without signs of infection. Blood pressure was normal to hypotensive, and the patient was tachycardie. The findings of the rest of the examination were unremarkable.

A neurologist reviewed preoperative and postoperative medications and discovered that the carbidopa/ levodopa 25 mg/100 mg dose had been reduced by tab every 3 hours after the DBS implant had been turned on and programmed according to presenting PD symptoms. Pramipexole was continued at 0.5 mg tid, and selegiline 5 mg qd had been discontinued.

Abnormal Diagnostic Tests/Results

The abnormal laboratory test results found at the time of admission gave an indication that immediate intervention was required (Table 1). A chest X ray revealed a few interstitial lung markings consistent with shallow inspiration, but were otherwise normal. A lumbar puncture was negative for infection, and an electrocardiogram revealed tachycardia. A magnetic resonance imaging (MRI) brain scan demonstrated normal brain parenchyma, evidence of metallic electrodes in the basal ganglia, and no evidence of acute abnormality. Cultures and sensitivities of blood, cerebrospinal fluid, sputum, and urine were obtained. The sputum culture revealed moderate Pseudomonas aeruginosa; the rest of the cultures remained negative for 72 hours. A large amount of blood and protein, without bacteria, was noted in the urine specimen. Because of the uncertainty of the diagnosis, tests also were obtained for fecal leukocytes, St. Louis encephalitis IgM, and West Nile virus IgM; all these tests were negative. The admitting diagnosis was possible pneumonia, rhabdomyolysis, and urinary tract infection. By the second day of his hospitalization, the patient’s condition met the diagnostic criteria for neuroleptic malignant syndrome (NMS) secondary to dopamine withdrawal.

A definite diagnosis of NMS requires both essential features and associated symptoms, which are listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, American Psychiatric Association, 2000). The essential symptoms exhibited by the patient that allowed for this diagnosis were hyperthermia and severe muscle rigidity. His associated symptoms included changes in level of consciousness, leukocytosis, tachycardia, diaphoresis, incontinence, and laboratory evidence of muscle injury in the form of extreme elevations of creatine kinase (CK) levels (12,542 U/L) (Nicholson & Chiu, 2004).

Major Nursing Issues

This patient’s major nursing issues were hyperthermia, possible dehydration, stiffness and rigidity, and altered mental status. All of these conditions rendered him unable to perform his activities of daily living. Nurses played a major role in providing supportive care, including adequate hydration, proper nutrition, and fever reduction.

Table 1. Laboratory Tests on Admission

Table 2. Laboratory Tests on Hospital Day 7

The patient’s presenting symptoms and abnormal laboratory values provided nurses with clinical information that required them to take action before a diagnosis was made by the neurologist. The 102.5F fever was critical and predisposed this patient to seizures and further dehydration. The nurse administered antipyretics for hyperthermia and intravenous (IV) fluids. Dantrolene sodium (Dantrium) was ordered as a direct-action muscle relaxant. This drug acts directly on skeletal muscle to interfere with intracellular calcium movement. By blocking the calcium release from the muscle, the activation of acute catabolism associated with neuroleptic malignant syndrome is halted, thus reducing the risk of rhabdomyolysis (Maloni & Ross, 2004). Anticoagulant therapy, such as heparin, may be ordered to prevent disseminated intravascular coagulation (DIC).

Comfort measures for the patient included tepid sponge baths and placement on a temperature-regulating blanket to decrease temperature elevations. Due to abnormalities in his chest X ray and arterial blood gas (ABG) analysis, this patient needed to cough and deep-breathe several times every hour to clear secretions that cause pneumonia. He also needed oxygen by nasal cannula at 2-3 liters to increase his blood oxygen level and promote bronchodilation; this oxygenation also improved his mental status. Antibiotics were administered as ordered.

The elevated blood urea nitrogen (BUN) indicated that he probably was dehydrated. Although the BUN is directly related to the metabolic function of the liver, it also represents the excretory function of the kidney. The nurse placed a urinary catheter to monitor his urine output, expecting at least 30 cc/hour to ensure adequate kidney function. The nurse began IV fluids of 0.9% normal saline at 90 cc/hour because his sodium level was slightly abnormal (131 mmol/L), and monitored oral and IV fluid intake. His urine specific gravity of 1.026 was another indication of dehydration. Although creatinine clearance was normal, protein in his urine indicated kidney function was abnormal.

The presence of large amounts of blood in the urine may have indicated ensuing rhabdomyolysis, a condition with extreme enzyme elevations caused by skeletal muscle destruction. These high enzymes could mean many things, but primarily indicates muscle catabolism and injury possibly caused by hyperthermia and muscle rigidity. The patient’s troponins were normal, which ruled out cardiac muscle involvement. Empiric antibiotic therapy was started to cover the elevated white blood cell (WBC) count and sputum pseudomonas. Dopaminergic medications were administered at the preoperative level to restore dopamine levels.

Discussion

NMS is an uncommon, life-threatening, idiosyncratic reaction to the acute withdrawal of anti-Parkinsonian agents (Sanga & Nomura, 2003). The observed clinical signs demonstrating autonomie dysfunction are hyperthermia, tachycardia, tachypnea, diaphoresis, altered consciousness, and hyper- or hypotension. Other signs of NMS include rigidity, leukocytosis, tremors, and marked elevation of serum CK. A serious complication of NMS is rhabdomyolysis, which is an acute, fulminating, and potentially fatal disease of the skeletal muscles that destroys muscle tissue. It is evidenced by extreme CK levels (12,542 U/L in this patient) , hyperkalemia, myoglobinuria, and acute renal insufficiency. The patient maintained normal serum potassium levels and urinary output and did not develop rhabdomyolysis. With conditions that may involve damage to skeletal muscle, hydration should be adequate to dilute the urine and flush the myoglobin out of the kidney to prevent rhabdomyolysis from occurring (Craig, 2004). Other complications of NMS include respiratory failure, myocardial infarction, hepatic failure, and DIC. The mortality rate is 15%-20% (Davis, Caroff, & Mann, 2000). There have been more than 200 cases of NMS in older adults reported in the medical literature (Nicholson & Chiu, 2004). It appears that even a moderate withdrawal of dopaminergic agents in the older Parkinson’s patient may trigger NMS. Older patients may be more susceptible to NMS because dopamine activity decreases with age (Nicholson & Chiu).

Outcomes

Data indicate the average duration of NMS is approximately 7-10 days (Davis et al., 2000). By the 4th hospital day, his mentation cleared and the elevated enzymes were decreasing. The WBC was normal and hemaruria and proteinuria were absent. Serum sodium level had normalized as well as the BUN. Table 2 demonstrates that the patient’s laboratory results returned to normal on day 7 of his hospital admission and resolution of \NMS, and coincides with this patient’s recovery time. The DBS was turned off on day 7 to prepare for a brain MRI with contrast and because the neurologist wanted to monitor the patient off stimulation for 5 days before it was restarted on day 13 at its preadmission settings. Tremor was visible off stimulation during those 5 days.

This patient survived NMS through the prompt treatment and supportive care given to him upon his hospital admission. However, he required intensive inpatient physical and occupational therapy because of his prolonged bedrest. The length of stay for this hospital admission was 23 days.

Summary

To prevent NMS in Parkinson’s patients, nurses must be cognizant of the narrow safety margin for withdrawing dopaminergic agents. The presence of NMS poses a significant mortality risk for the fragile geriatric population. Nurses who understand this critical condition and who are knowledgeable about the risks, warning signs, and treatment for NMS are able to explain to worried family members the course of treatment and offer realistic hope for a complete recovery.

Acknowledgment

Special thanks to Naomi Nelson, PhD RN, for editing expertise.

References

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR (pp. 795-798). Washington, DC: Author.

Craig, S. (2004, December 29). Rhabdomyolysis. Retrieved February 8, 2005, from http://www.emedicine.com/emerg/topic508.htm

Davis, J. M., Caroff, S. N., & Mann, S. C. (2000).Treatment of neuroleptic malignant syndrome. Psychiatric Annals, 30,325-334.

Maloni, H., & Ross, A. R (2004). Degenerative disorders. In M.K. Bader & L.R. Littlejohns, (Eds.), AANN core curriculum for neuroscience nursing, (4th ed.), St. Louis, MO: Saunders.

Nicholson, D., & Chiu.W (2004). Neuroleptic malignant syndrome. Geriatrics Advisor, 59(8), 36-40.

Sanga, M., & Nomura, S. (2003).A case of malignant syndrome associated with a Parkinsonism patient. Japanese Journal of Psychopharmacology, 23,91-95.

Questions or comments about this article may be directed to Constance Ward, MSN RN BC, Neurology Care Line-127PD 2002 Holcombe Blvd., Houston, TX 77030, or by e-mail to constance. [email protected]. She is a clinical coordinator, Parkinson’s Research, Education & Clinical Center, Michael E. DeBakey VA Medical Center, Houston, TX.

Copyright 2005 American Association of Neuroscience Nurses 0047- 2606/05/3703/0000160$5.00

Copyright American Association of Neurosurgical Nurses Jun 2005

New Haven, Conn. – A new Yale University research survey of 1,000 adults nationwide reveals that while Americans are deeply divided on many issues, they overwhelmingly believe that the United States is too dependent on imported oil.

The survey shows a vast majority of the public also wants to see government action to develop new “clean” energy sources, including solar and wind power as well as hydrogen cars.

92% of Americans say that they are worried about dependence on foreign oil

93% of Americans want government to develop new energy technologies and require auto industry to make cars and trucks that get better gas mileage

The results underscore Americans’ deep concerns about the country’s current energy policies, particularly the nation’s dependence on imported oil. Fully 92 percent say this dependence is a serious problem, while 68 percent say it is a “very serious” problem.

Across all regions of the country and every demographic group, there is broad support for a new emphasis on finding alternative energy sources. Building more solar power facilities is considered a “good idea” by 90 percent of the public; 87 percent support expanded wind farms; and 86 percent want increased funding for renewable energy research.

According to Gus Speth, dean of the Yale School of Forestry & Environmental Studies, “This poll underscores the fact that Americans want not only energy independence but also to find ways to break the linkage between energy use and environmental harm, from local air pollution to global warming.”

Results of the poll indicate that 93 percent of Americans say requiring the auto industry to make cars that get better gas mileage is a good idea. Just 6 percent say it is a bad idea. This sentiment varies little by political leaning, with 96 percent of Democrats and Independents and 86 percent of Republicans supporting the call for more fuel-efficient vehicles.

These findings come on the heels of Congress’ rejection of a proposal to require sport utility vehicles and minivans to become more fuel-efficient and achieve the same gasoline mileage as passenger cars.

“This poll suggests that Washington is out of touch with the American people – Republicans, Democrats and Independents, young and old, men and women-even S.U.V. drivers-embrace investments in new energy technologies, including better gas mileage in vehicles,” said Dan Esty, director of the Yale Center for Environmental Law and Policy, which commissioned the survey.

The survey also revealed broad support for action to improve air and water quality but growing discomfort with “environmentalists.” Likewise, the public’s confidence in TV news as a source of environmental information has fallen sharply.

This survey is one element of a broader research project at the Yale School of Forestry & Environmental Studies focused on environmental attitudes and behavior. Funding for this project, directed by Associate Dean Dan Abbasi, is being provided by the Betsy and Jesse Fink Foundation and Hartford-based United Technologies Corp., which has been ranked as Fortune Magazine’s “Most Admired” aerospace company based on criteria including social responsibility.

The survey was conducted on behalf of the Yale School of Forestry & Environmental Studies by Global Strategy Group from May 15 to 22, 2005. The survey was conducted using professional phone interviewers. The nationwide sample was drawn from a random digit dial (RDD) process. Respondents were screened on the basis of age, i.e., to be over the age of 18. The survey has an overall margin of error of ±3.1% at the 95% confidence level. The survey questions and full results can be found at the website http://www.yale.edu/envirocenter for the Yale Center for Environmental Law and Policy.

On the Web:

Yale University

INDIANAPOLIS ““ Our brains hold many of the mysteries of who we are and why we do what we do. Unlocking the mystery of how exposure to violent media affects our brains is the focus of Indiana University School of Medicine research published in the May/June issue of the Journal of Computer Assisted Tomography.

Investigators, led by Vincent P. Mathews, M.D., professor of radiology, concluded that media violence exposure may be associated with alterations in brain function whether or not prior aggressive behavior is involved.

This study builds on earlier research that showed exposure to violent media affects the brains of youths with aggressive tendencies differently than the brains of non-aggressive youths. The preliminary results, released in December 2002, showed less brain activity in the frontal lobe of youths with an aggression disorder as they watched violent video games.

In the current study, functional magnetic resonance imaging (fMRI) was used to show activity in the brain when study participants performed a concentration test called a counting Stroop task.

Participants were shown a number that is repeated and they are to respond to the number of times they saw the number. For example, if participants are shown “222” the correct answer would be “three” because the number “2” is shown three times. Previous research has shown that Stroop tasks require participants to concentrate by using the part of the brain responsible for decision-making and self-control.

Two groups each of 14 boys and five girls were involved in the study. All the members of one group had a chronic pattern of violent behavior and had been diagnosed with disruptive behavior disorder (DBD). The second or control group had no history of behavior problems.

Members of both groups had been exposed to different amounts of violent media in their everyday lives over the past year. Fifty-eight percent of the DBD group was determined to have high exposure compared to 42 percent of the control group. Media violence exposure was defined as the average amount of time per week that the adolescents watched television or played video games depicting human injury.

The fMRI brain images revealed that members of the control group with high prior exposure showed less activity in the frontal cortex of the brain, an area linked to attention and self-control. All of the DBD group, even those without high violent media exposure, showed a similar pattern of frontal cortex activity. Less activity in the frontal cortex has been linked to poorer self control and attention problems.

In contrast to the DBD group and the control group with high media violence exposure, the members of the control group without high violent media exposure showed more frontal cortex activity.

“This observation is the first demonstration of differences in brain function being associated with media violence exposure,” said Dr. Mathews. “We found that individuals in the control group with high media violence exposure showed a brain activation pattern similar to the pattern of the aggressive group.”

William Kronenberger, Ph.D., associate professor in the Department of Psychiatry, who has collaborated with Dr. Mathews on these ongoing studies, cautioned that more research is needed before conclusions can be drawn that media violence exposure causes the brain activation differences.

He warned that any association between media violence exposure and brain functioning should be taken seriously while this additional research is conducted.

“We found high rates of exposure to violent television and video games in teens, but we are just beginning to explore the possible implications of this exposure for brain and behavioral development,” said Dr. Kronenberger.

“There are myriad articles showing that exposure to violent TV especially causes individuals to be more aggressive. We are studying the neurological and self-control processes that underlie the aggressive behavior.”

On the Web:

Indiana University

Retroperitoneal bleeding is one of the most serious, potentially lethal complications of anticoagulation therapy. Although well documented in fully heparinized and coumadinized patients, there are only few reports of life-threatening hemorrhages in low-molecular- weight heparin (LMWH)-treated patients. We present a case of almost fatal spontaneous retroperitoneal bleeding in a 71-year-old woman with pneumonia and acute coronary syndrome. After receiving combination therapy with Lovenox (enoxaparin), aspirin, and Plavix for 5 days, she developed acute hemorrhagic shock and possible intra- abdominal compartment syndrome. Urgent computed tomography scan of the abdomen and pelvis was performed and showed a left retroperitoneal hematoma. The patient’s condition continued to deteriorate, which prompted emergent exploration. After evacuating 3 L of free blood from the peritoneal cavity, we managed to stabilize the patient. Our case of spontaneous retroperitoneal bleeding adds to the growing number of cases in which enoxaparin has been associated with severe bleeding. A high index of suspicion is necessary if the patient displays any of the signs and symptoms that suggest major hemorrhage. It appears that those at highest risk receive doses approaching 1 mg/kg subcutaneously every 12 hours, have renal impairment, are of advanced age, and receive concomitant medications that can affect hemostasis. On average, a retroperitoneal hematoma occurs within 5 days of therapy with enoxaparin. In high-risk patients, enoxaparin activity (anti-factor Xa) should be carefully monitored.

LOW-MOLECULAR-WEIGHT HEPARINS (LMWHS) have proven to be as safe and effective as unfractionated heparin for the prophylaxis and treatment of acute coronary syndrome (ACS), non-Q-wave myocardial infarction (NQWMI), venous thrombosis, and pulmonary thromboembolism. As a result of their safety and efficacy, along with the advantages of decreased laboratory monitoring and outpatient administration, the prescription of LMWH has altered clinical practice in the United States.1 However, a high incidence of local bleeding complications has been reported with enoxaparin (Lovenox), mostly at the injection or instrumentation sites. There have also been reports of more severe bleeding complications, such as abdominal wall hematomas, including rectus muscle sheath hetnatomas, and only a few reports of retroperitoneal hematomas, with a high morbidity and mortality.2 We would like to add another case of an enoxaparinassociated, almost fatal, retroperitoneal hematoma, which led to an abdominal compartment syndrome.

Case Presentation

A 71-year-old female was initially hospitalized for community acquired pneumonia. She had a past medical history of hypertension, chronic obstructive pulmonary disease from heavy smoking, and steroiddependent arthritis. The patient did not have a history of any bleeding disorders or coagulopathies. She was not taking antiplatelet or anticoagulant agents. Admission laboratory values included a creatinine of 1.1 mg/ dL, hemoglobin of 11.9 g/dL, and hematocrit of 35 per cent. The patient was started on levofloxacin and bronchodilators. Enoxaparin, 40 mg daily administered subcutaneously, was added for venous thrombosis prophylaxis. Her shortness of breath gradually improved; however, on the fifth hospital day, she experienced acute discomfort in the chest. Her workup revealed abnormal cardiac enzymes and electrocardiogram, which led to a diagnosis of acute coronary syndrome (ACS). The patient was transferred to the CCU and was started on a Tridil drip, aspirin 325 mg per day, Plavix 75 mg per day, and the enoxaparin was increased to 1 mg per kilogram subcutaneously every 12 hours. Laboratory values at this time were a creatinine of 1.3 mg/dL, hemoglobin of 12.0 g/dL, platelets of 346,000 per mm, activated partial thromboplastin time (aPTT) of 24 seconds, prothrombin time (PT) of 14.2, international normalized ratio (INR) of 1.25, troponin I was normal, and a moderately elevated lactate dehydrogenase (LDH). The patient was scheduled for cardiac catheterization, but the symptoms started to subside and she was reluctant to undergo the procedure. Seventy-two hours later, the patient developed acute, tearing pain in the left flank and back that was increasing in severity, a rapid increase in heart rate, and, shortly thereafter, a drop in her blood pressure. The CCU team worked to rule out a new cardiac event. A dopamine drip was started because of hemodynamic instability and fluid challenges were given.

Surgery was then consulted. Our team evaluated the patient and found a pulsatile tender mass in the left hypogastrium. The patient appeared somnolent but arousable, and she was in significant abdominal distress. Dark blue ecchymoses were found in the left side of the abdominal wall. The foley catheter stopped draining urine. Systolic blood pressure barely measured 65-75 mm/Hg and the heart rate was 130/min. Parallel to the aggressive fluid management, a stat CAT scan of the abdomen and pelvis with intravenous contrast was ordered (Fig. 1 A-IC). Findings showed a huge left-sided retroperitoneal hematoma, measuring 15 18 cm, compressing the bladder and displacing the bowels to the cephalad direction. No evidence of a ruptured aortic aneurysm was found. The patient was intubated and mechanically ventilated. Despite all attempts to stabilize the patient, including transfusing 5 units of packed red blood cells, 2 units of fresh frozen plasma, and 4 units of platelets, her blood pressure remained at 70/30 mm Hg, she was anuric, and the hemoglobin and hematocrit declined from 11.9 g/dL to 7.0 g/dL and 34 per cent to 19.4 per cent, respectively. Her abdomen was extremely distended, firm to the touch, and had absent bowel sounds. Both lower extremities were cool to the touch, with significantly diminished femoral pulses. Ventilatory management was complicated by increasing peak inspiratory pressures, an elevated WBC of 38,000/mm with a left shift, and worsening lactic acidosis. An intraabdominal compartment pressure could not be measured because of a totally compressed and displaced bladder by the hematoma. With the fear of bowel ischemia and abdominal compartment syndrome, urgent operation became mandatory. An exploratory laparotomy was performed, which revealed an extensive retroperitoneal hematoma with rupture into the free peritoneum with more than 2500 cc of free blood. There was no evidence of ongoing bleeding or gangrenous bowel. We evacuated a significant amount of blood and retroperitoneal clot. The abdomen was closed primarily after a pelvic drain was placed. Shortly after laparotomy, the patient’s hemodynamics began to stabilize. The need for vasopressors was limited. The patient was transferred back to the ICU, and she started to make minimal urine.

FIG. 1. Arrows indicate relroperitoneal hematoma. A, Retroperitoneal hematoma extending into the pelvis. B, Some compression of the bladder due to retroperitoneal hematoma. C, Extension of the hematoma deep into the pelvis lateral to the bladder.

In the postoperative period the patient needed prolonged ventilatory support and developed a mild nonoliguric renal failure that did not require hemodialysis. Twenty-eight days later, the creatinine was 1.4 and the patient was tolerating a regular diet. There were no neurological deficits present, and her cardiac function was stable. The patient was discharged to a rehabilitation facility in good condition.

Discussion

Enoxaparin (Lovenox) is a commonly used, injectable, low- molecular-weight heparin that was first approved by the Food and Drug Administration in 1993 for prevention and treatment of thromboembolic diseases. The bioavailability and anticoagulant predictability of enoxaparin is clearly better than unfractionated heparins. In all but high-risk patients, the need for anticoagulation monitoring is unnecessary due to its dose- independent clearing mechanism and longer halflife.3

Retroperitoneal hematoma most commonly occurs as a result of trauma. However, anticoagulation therapy, vascular lesions, tumors, or surgical complications have also been seen as causes. Severe retroperitoneal hemorrhage is an infrequent complication of enoxaparin use. There are only a few reported cases in the world literature of a patient with enoxaparininduced spontaneous retroperitoneal bleeding.4 The ESSENCE study3 showed that enoxaparin was more effective than intravenous unfractionated heparin in reducing the incidence of death, myocardial infarction, or recurrent angina in patients with ACS. However, enoxaparin therapy is not without risks. Among 1528 patients receiving enoxaparin and aspirin for ACS, 17 cases (1%) of major bleeding episodes were reported that included intraocular, intracranial, major abdominal wall, injection- site and retroperitoneal hematomas. In these cases, hemoglobin declined by at least 3 g/dL or a transfusion requirement of 2 or more units of blood products was needed.

The clinical presentation of retroperitoneal hematoma in anticoagulated patients may be varied, and the incidence may be on the rise due to the increasing number of patients prescribed enoxaparin. The clinical manifestations range from leg-hip pain or paresis to abdominal/flank/back pa\in with or without bruises or a catastrophic shock. An early CT scan of the abdomen, preferably with intravenous contrast, is of great value in order to rule out other life-threatening conditions, such as ruptured or leaking abdominal aortic aneurysms, tumors, etc.3

With patients receiving anticoagulation, we should be very vigilant for suspicious signs and symptoms that suggest major bleeding (i.e., hemodynamic instability; back, flank, hip pain; bruising, nausea, vomiting, neurological deficiencies, hematuria, etc.) in order to reverse anticoagulation rapidly and initiate other therapeutic measures.

Knowing that enoxaparin clearance is affected by renal insufficiency as noted in the elderly, extra precaution should be taken in the treatment of these patients, especially if the creatinine clearance is

Use of other medications, in particular antiplatelet agents, which are especially common and recommended in ACS, NQWMI, and postcoronary angioplasties and stents, certainly increases the possible risk of bleeding complications.6

Because enoxaparin is mostly active against factor Xa, anti- factor Xa values should be monitored in the high-risk population. Anti-factor Xa values that are elevated above the determined therapeutic range should raise the suspicion for potential for complications.

In this case, the anti-factor Xa was not measured. Concomitant use of enoxaparin and antiplatelet drugs certainly put the patient at an increased risk for complications. Despite the proven benefits of enoxaparin in the management of ACS, its use has significant risks. Aggressive surgical intervention provided a successful outcome in our case.

Conclusion

Treatment of enoxaparin-induced hemorrhagic complications is multifactorial and should be carried out in a well monitored ICU setting. This includes:

1. Discontinuation of the anticoagulant.

2. Protamine sulfate, as an intravenous bolus of 0.5 to 1.0 mg per 1 mg of enoxaparin administered, given in order to try to reverse the effects of enoxaparin, provided the last dose was given no more than 8 hours ago.

3. Blood products given judiciously and aggressively.

4. Close hemodynamic monitoring and frequent serial hemoglobin and coagulation monitoring.

5. Avoiding instrumentation if possible.

6. The consideration of surgical intervention if all other measures fail to stabilize the patient.

Morbidity and mortality are very high in retroperitoneal bleeds, with significant perioperative and postoperative complications.

Our case of spontaneous retroperitoneal bleeding adds to the growing number of cases in which enoxaparin has been associated with severe bleeding. A high index of suspicion is necessary if the patient displays any of the signs and symptoms that suggest major hemorrhage. It appears that those at highest risk receive doses approaching 1 mg/kg subcutaneously every 12 hours, have renal impairment, are of advanced age, and receive concomitant medications that can affect hemostasis. On average, a retroperitoneal hematoma occurs within 5 days of therapy with enoxaparin. In high-risk patients, enoxaparin activity (anti-factor Xa) should be carefully monitored.

REFERENCES

1. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low molecular-weight heparin with unfractionated heparin for unstable coronary artery disease: Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337;447-52.

2. Montoya JP, Pokala N, Melde SL. Retroperitoneal hematoma and Enoxaparin. Ann Intern Med 1999;131;796-7.

3. Lovenox (package insert) Bridgewater, NJ: Aventis Pharmaceuticals, Inc., 2003.

4. Chan-Tack KM. Fatal spontaneous retroperitoneal hematoma secondary to Enoxaparin. South Med J 2003;96;58-60.

5. Dabney A, Bastani B. Enoxaparin-associated severe retroperitoneal bleeding and abdominal compartment syndrome: a report of two cases. Intensive Care Med 2001;27:1954-7.

6. Gonzalez C, Penado S. The clinical spectrum of retroperitoneal hematoma in anticoagulated patients. Medicine 2003;82: 257-62.

MARTIN ERNITS, M.D., PRADEEP S. MOHAN, M.D., LOUIS G. FARES, II, M.D., F.A.C.S., HOWARD HARDY, III, M.D., F.A.C.S.

From the Department of Surgery, Seton Hall University Surgical Residency Program at St. Francis Medical Center, Trenton, NJ

Address correspondence and reprint requests to Pradeep S. Mohan, M.D., 125 Glenwood Ave., Burlington, NJ 08016.

Copyright The Southeastern Surgical Congress May 2005

ABSTRACT

Objective To devise a validated measure of vaginal rugae and assess the relationships between vaginal rugae and important clinical parameters.

Methods Two techniques of assessing vaginal rugae were developed and their inter-/ intra-observer variability assessed. Examination variability was assessed using intraclass correlation and by way of an analysis of the absolute difference between the two rugal quantitations. After validating the assessment technique, the rugal quantitations of 88 women were compared to clinical parameters such as age, estrogen status, stage of prolapse, parity, history of anterior vaginal wall surgery, and body mass index. Linear regression analysis was used to assess the relationships between vaginal rugae score and these clinical parameters.

Results The mean age and body mass index of the subjects were 56 years (standard deviation (SD) 13.8 years) and 30.4 kg/m^sup 2^ (SD 7.5 kg/m^sup 2^), respectively. The median parity was 2 (range 0- 1.1). A history of anterior vaginal wall surgery was present in 29% of subjects and 46% were estrogen-deficient. Scores for the two techniques to quantitate vaginal rugae were normally distributed. Both techniques demonstrated satisfactory interexaminer reliability. Increasing age and deficient estrogen status were found to be independent predictors of less vaginal rugae.

Conclusions Vaginal rugae can be reliably quantitated. Loss of vaginal rugae is associated with estrogen deficiency and advancing age.

Key words: VAGINA, RUGAE, ESTROGEN, PELVIC ORGAN PROLAPSE

INTRODUCTION

Vaginal rugae are transverse epithelial ridges most commonly seen on the outer third of the female vagina. Reportedly, the infant vagina at birth closely resembles the mature state, with deep cryptic rugae presumably secondary to maternal estrogen exposure; yet, as estrogen concentrations subside, the vagina becomes thin, dry, non-elastic and non-rugated1. A similar mechanism apparently accounts for the non-rugated appearance of the vagina in postmenopausal women. Rugae are also thought to flatten or stretch with some forms of anterior vaginal wall support defects2. Thus, vaginal rugae are believed to render insight into the hormonal and structural integrity of the vagina and may be useful in caring for women with symptomatic vaginal atrophy and/or prolapse.

Despite the potential utility of evaluating rugae, we cannot identify any reported standardized scale to quantify vaginal rugae. Furthermore, these presumed associations between vaginal rugal appearance and hormonal status or pelvic organ prolapse have never been objectively confirmed. We set out to establish a reproducible and accurate descriptive scale of vaginal rugae and to correlate it with important clinical parameters such as hormone status and stage and location of pelvic organ prolapse.

METHODS

The Institutional Review Board at the Cleveland Clinic approved this research and all subjects were provided written informed consent before participation. Two examinations utilizing a standardized technique were prospectively performed by five possible health-care providers on 88 women presenting to the gynecology clinic at the Cleveland Clinic Foundation. The examiners included three faculty members (M.D.B., M.D.W. and M.F.P.), one urogynecology fellow (J.L.W.), and one nurse with extensive experience examining women. All examinations were done with the patient in the supine lithotomy position using a standard gynecological examination table. The first 53 women were used to determine the interexaminer and intraexaminer reliabilities of two devised techniques to quantitate vaginal rugae. To assess interobserver reliability, a duplicate examination was performed by a second examiner blinded to the initial examiner’s results. The intraexaminer reliability portion of the study was derived from those women whose routine medical care required a second visit to the Cleveland Clinic Foundation gynecology clinic. Intraexaminer reliability was assessed by a repeat examination done at a minimum of 3 weeks after the initial examination by one of the original two examiners.

Assessment of anterior vaginal wall rugae was performed along with the standard pelvic examination using two different techniques. The first technique involved examination of a point 3 cm distal from the urethra along the anterior vaginal wall. With a ring forceps placed at this point, the number of transverse ridges contained within the ring opening (1.5 cm in vertical length) at rest and with straining was determined (Figure 1). In the second technique, overall visual impression (qualitative measure) of anterior vaginal wall rugae at rest and straining was assessed on a 10 cm visual analog scale (VAS) with endpoints, ‘no rugae’ and ‘maximum rugae’ (Figures 2 and 3).

Historical and clinical parameters were collected on 88 subjects including age, body mass index, estrogen status, history of anterior vaginal wall surgery, International Continence Society pelvic organ prolapse quantification (POPQ) stage and parity. While serum estrogen was not measured, estrogen exposure was considered present if the patient was premenopausal or currently using oral or vaginal estrogen preparations.

Figure 1 Drawing of rugae assessment technique utilizing a ring clamp placed 3 cm from the urethral meatus along the anterior vaginal wall. The number of transverse ridges is recorded within the border of the ring

Figure 2 Visual analog scale for the global assessment of vaginal rugae

Interexaminer and intraexaminer examination reliabilities were evaluated utilizing intraclass correlation. Intraclass correlation coefficients (ICC) between 0.81 and 1.00 were considered near perfect agreement between the two examinations. ICC values between 0.61 and 0.80 were considered satisfactory agreement, and values between 0.41 and 0.60 are regarded as poor agreement. Additionally, the absolute difference between the two examinations, both intra- and interexaminer, of rugal quantitations were determined for the transverse ridge number and VAS techniques. Standard least squares linear regression analysis was used to determine independent predictors for vaginal rugae quantity. Because the VAS technique demonstrated better inter- and intraexaminer reliabilities, the rest results from both examiners were used in the regression analysis. Visual analog score was used as the dependent variable, and age, body mass index, history of vaginal surgery, estrogen status, and POPQ stage of prolapse were considered independent variables. Both higher-order terms and interaction terms were explored. All statistical tests were evaluated at the 0.05 level of significance. Statistical analysis was performed using SPSS 11.5 (Chicago, IL, USA).

Figure 3 Drawing of vaginal rugae demonstrating the range of visually assessed vaginal rugae from none to maximum

RESULTS

The mean age of subjects was 56 (SD 13.8) years, the mean body mass index was 30.4 kg/m^sup 2^ (SD 7.5 kg/m^sup 2^) and the median parity was 2 (range 0-11). Twenty-nine percent of subjects had a history of anterior vaginal wall surgery and 46% were estrogen- deficient. Thirty-five percent of subjects had Stage III or IV pelvic organ prolapse by the POPQ system. Another 34% of subjects had Stage II pelvic organ prolapse, with 18 and 13% of subjects having Stage O or I pelvic organ prolapse, respectively. Both the rugae ridge quantity and visual analog score data were normally distributed. Scores for both the transverse ridge number and VAS were not significantly different between rest and straining; subsequently, only rest values are reported. Fifty-three women were used to determine the interexaminer reliability of the two rugal quantification methods. Seventeen women returned for repeat examination to determine the intraexaminer reliability. The interobserver correlation for the transverse ridge quantitation was 0.61 (p

With reference to the interobserver reliability, the mean absolute difference in the two transverse ridge quantitation results was 1.3 (95% confidence interval (CI) 0.93-1.67). The mean absolute difference between the two examinations results using the visual analog scale was 1.8 cm (95% CI 1.42-2.18). Likewise with reference to the intraobserver reliability of the examination, the mean absolute difference between the repeat transverse ridge quantitations was 2.3 (95% CI 1.83-2.77), while the repeat VAS score absolute difference was 2.7 cm (95% CI 2.22-3.18).

Linear regression of the historical and clinical parameters (age, body mass index, parity, history of vaginal surgery, estrogen status, and POPQ stage) to predict the results of the VAS technique to measure anterior vaginal rugae found age and deficient estrogen status as independent predictors of lower vaginal rugae score (age, examiners 1 and 2,p = 0.006; estrogen status, examiner 1, p = 0.03; examiner 2, p = 0.04). Stage of prolapse, body mass index, parity and history of anterior vaginal wall surgery demonstrated no relation to rugae score.

DISCUSSION

Vaginal rugae are believed to yield important clues as to the str\uctural integrity and hormonal status of the lower genital tract. We have demonstrated that use of a 10 cm visual analog scale renders reliable intra- and interexaminer results. The numbering of transverse ridges 3 cm from the urethra along the anterior vaginal wall, while demonstrating satisfactory interexaminer reliability, is limited by poor intraexaminer reliability. This deficiency is likely due to the small numbers of women who were re-examined. The technique, however, is further limited by assessing vaginal rugae only at the distal anterior vagina. Alternatively, the visual analog scale technique renders a more global assessment of anterior vaginal wall rugae. Despite the reported value of assessing vaginal rugae, we have not identified any reported technique on how to quantify vaginal rugae.

Reliable assessment of vaginal rugae is the first step in determining the validity of the claimed associations between rugae appearance and those clinical parameters ascribed to it. Based on our observations, a global impression via a VAS is best suited to objectify assessment of vaginal rugae.

While it has been apparently assumed that estrogen affects vaginal rugae, we have documented a quantifiable association. Our study did not measure serum estrogen concentrations nor made a distinction between oral or topical estrogen, and this limitation is acknowledged. Postmenopausal vaginal atrophy is common and the diagnosis ordinarily made with visual inspection of the epithelium3. Visual inspection of the vaginal epithelium includes a subconscious assessment of the quality and quantity of the vaginal rugae. Nilsson and colleagues’ showed that administration of oral estrogen resulted in a shift in the vaginal maturation index and pH. A high vaginal pH (>6) was found to be a good, accessible marker for vaginal atrophy. Vaginal pH was not obtained as part of this study but it would be notable if vaginal pH were correlated with a quantified assessment of vaginal rugae, since both seem to be associated with estrogen exposure. Yet, other studies have failed to find an association between estrogen levels and the vaginal maturation index4. Furthermore, the same and other studies fail to document an association between postmenopausal symptomatology and estrogen levels4 or vaginal atrophy5. Use of a VAS to quantify the visual inspection of the vaginal epithelium may be a useful tool to further explore some of these issues regarding vaginal atrophy and postmenopausal symptomatology.

Anterior vaginal prolapse, or cystocele, is thought to result from site-specific support defects within and around the trapezoidal pubocervical connective tissue suspending the anterior vaginal wall and bladder6. Some have suggested that anterior vaginal wall support defects can be predicted by the appearance of the anterior vaginal wall rugae. For example, loss of mid-line vaginal rugae would be associated with a defect in the mid-line connective tissue supports. Creation of a scaled assessment of vaginal rugae alone is of little practical value, yet the long-held belief among seasoned vaginal surgeons that vaginal rugae could be used to identify vaginal wall defects (lateral, central or apical) had not been examined in a quantified manner. There appears to be no association between vaginal support and vaginal rugae. We have already documented poor inter- and intraexamiiier reliabilities with the clinical evaluation of anterior vaginal wall support defects7. Taken together, we are dubious of the value that assessing vaginal rugae has in determining the presence and location of anterior vaginal support defects.

The effect of age, independent of hormone status, is interesting. Conceptually, given the association between age and surface skin wrinkles, one might expect more rugae with advancing age, but this is an oversimplification. Indeed, age effects on the skin include epidermal flattening, loss of normal rete ridge pattern, papillary dermal elastin, increased disorganized reticular dermal elastic fibers, lessened dermal collagen, altered dermal collagen fiber morphology, and decreased dermal microvasculature8. Perhaps, the known thinning of skin that occurs with aging8 also occurs in the vagina and, in effect, leads to less visible rugae. Better understanding of the mechanism behind formation of vaginal rugae would shed light on the identified age effect on rugae appearance.

In conclusion, we have devised a technique to objectify the clinical evaluation of vaginal rugae. Using the VAS technique, more vaginal rugae have been shown to be a marker of estrogen exposure, yet age alone appears to cause a diminution of vaginal rugae independent of estrogen loss. The utility of vaginal rugae in assessing patients with pelvic organ prolapse is unclear but appears limited.

Conflict of interest Nil.

Source of funding Nil.

References

1. DeCherney AH, Pernoll ML, eds. Current Obstetric and Gynecologic Diagnosis and Treatment, 8th edn. New York: McGraw- Hill, 1996

2. Shull BL. Clinical evaluation of women with pelvic support defects. Clin Obstet Gynecol 1993;36:939-51

3. Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the postmenopause: cytology, histology and pH as methods of assessment. Maturitas 1995;21:51-6

4. Stone SC, Mickal A, Rye PH. Postmenopausal symptomatology, maturation index, and plasma estrogen levels. Obstet Gynecol 1975;45:625-7

5. Davila GW, Singh A, Karapanagiotou I, et al. Are women with urogenital atrophy symptomatic? Am J Obstet Gynecol 2003;188:382-8

6. Richardson AC, Lyon JB, Williams NL. A new look at pelvic relaxation. Am J Obstet Gynecol 1976;126:68-73

7. Whiteside JL, Barber MD, Paraiso MF, Hugney CN, Walters MD. Clinical evaluation of anterior vaginal wall support defects: interexaminer and intraexaminer reliability. Am J Obstet Gynecol 2004;191:100-4

8. Cook JL, Dzubow LM. Aging of the skin: implications for cutaneous surgery. Arch Dermatol 1997;133:1273-7

J. L. Whiteside, M. D. Barber, M. F. Paraiso and M. D. Walters

The Cleveland Clinic Foundation, Department of Gynecology and Obstetrics, Cleveland, Ohio, USA

Correspondence: Dr J. L. Whiteside, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon NH 03756, USA

ORIGINAL ARTICLE

2005 International Menopause Society

DOI: 10.1080/13697130500042490

Received I 1-06-04

Revised 17-07-04

Accepted 17-07-04

Copyright CRC Press Mar 2005

ANN ARBOR, Mich. — While breast cancer is a significant health threat ““ striking 211,000 American women each year ““ a new study finds most women have a distorted view of their risk.

When asked to estimate the lifetime risk of breast cancer, 89 percent of women overestimated their risk, with an average estimate of 46 percent ““ more than three times the actual risk of 13 percent, according to a study by University of Michigan Health System researchers.

“Breast cancer is so commonly in the news, and most of us can think of friends or relatives who have been diagnosed with it. That leads us to overestimate how common it really is. We forget that we know a lot of people with breast cancer because we know a lot of people,” says senior study author Peter Ubel, M.D., professor of internal medicine at the U-M Medical School and director of the Center for Behavioral and Decision Sciences in Medicine.

Results of the study appear in the June issue of the journal Patient Education and Counseling.

In the study, researchers surveyed 356 women. Half the women were asked to estimate the average woman’s lifetime risk of developing breast cancer, and half were not asked for an estimate. Both groups then received information on breast cancer risk.

The group that did not estimate risk beforehand was asked whether the 13 percent risk was higher or lower than they had expected. Only 37 percent said the actual risk was lower than they had expected ““ compared to 89 percent of women in the other group who initially thought the risk was much higher.

The researchers then asked women from both groups how anxious or relieved the information made them and whether they thought a 13 percent risk was high or low.

The women who did not give an estimate first were more likely to feel anxious about the breast cancer risk information, 25 percent vs. 12 percent of women who gave an estimate first. At the same time, twice as many women who gave an estimate beforehand said they were relieved by the actual risk, 40 percent vs. 19 percent.

“After estimating that 46 percent of women will be diagnosed with breast cancer, when they find out it’s actually 13 percent, that seems relatively low and women feel a sense of relief,” says lead study author Angela Fagerlin, Ph.D., research investigator in internal medicine at the U-M Medical School and with the VA Ann Arbor Healthcare System.

The researchers suggest doctors can use these findings to help patients who seem particularly concerned about their risk of breast cancer.

“Doctors need to be in touch with their patients’ needs. If a woman is unduly anxious about her risk of breast cancer, and that anxiety is ruining her life, it might help to ask her what she thinks her chance of breast cancer really is. She is likely to overestimate that risk, and now the doctor will have a chance to tell her the true risk and, potentially, put her mind at ease,” says Ubel, a staff physician at the VA Ann Arbor Healthcare System.

At the same time, the researchers stress, overestimating the risk does not diminish the importance of prevention strategies, such as yearly mammograms and monthly breast self exams.

On the Web:

University of Michigan

TOILET WORRY

I have read that loose, pale-coloured stools are a sign of fat malabsorption. I have had consistently yellow, foul-smelling stools (with undigested bits in them) for as long as I can remember. Also, after going to the toilet I often feel nauseous. What could be the cause? Does it mean that my body is deficient in ‘good fats’ and vitamins?

When the intestine is unable to properly digest and absorb fats, the stools become pale, bulky and smelly. They usually float in the lavatory pan, and are difficult to flush away. Sometimes it is even possible to see floating oil droplets in the toilet water. Fat malabsorption can be caused by many different problems. If the pancreas or liver are not working properly, in conditions such as cystic fibrosis and liver disease, the intestine is unable to break down and absorb food. In conditions such as coeliac disease, which is caused by an abnormal reaction to wheat and other foods that contain gluten, the intestine loses its ability to absorb nutrients. If people with coeliac disease avoid all foods containing gluten, the intestine recovers and regains its ability to absorb food normally. Some vitamins, especially A, D and K, are fat-soluble vitamins: if you are not absorbing fat properly, you can become deficient in these vitamins. You need to have tests to see if you are suffering from malabsorption. If you are, then the cause needs to be identified and treated. Your first stop should be your GP. The next stop should be a gastroenterologist.

TUNNEL PAIN

I have been bothered for several years by carpal tunnel syndrome. It gives me severe ‘pins and needles’ in one or both hands, but only during the night after about four hours of sleep. I either massage the hands or hang them out of the bed, but the condition keeps returning. Sleep disturbance is a problem. My GP offers no solution. My daughter had the same problem, and it was dealt with by surgery of the wrist. Is this the only option? What causes this, and why do I get it at night?

Carpal tunnel syndrome is caused by physical pressure on a nerve that runs just below the inner surface of the wrist. The nerve, which is called the median nerve, passes through a narrow stretch of tissue called the carpal tunnel, and this is where the condition gets its name. Your symptoms are absolutely typical. The pain and numbness is always worse at night, and it affects the thumb, index and middle fingers, and half of the ring finger. If it continues for a long period, it can cause permanent weakness in the hand. Surgery to relieve pressure is usually a last resort, and the condition sometimes resolves without it. It would be sensible for your GP to check that your thyroid gland is not underactive and that you do not have diabetes, as these can both cause the syndrome. If you are OK, I strongly suggest that you get a special wrist splint to wear at night. This often cures the problem without surgery.

Key words: Drug safety * Europe * Pharmacovigilance * Post- marketing studies * UK

ABSTRACT

The granting of regulatory approval allows medical practitioners to prescribe a drug in a controlled way to a group of patients defined within the licence. Prior to this, the new product may have been evaluated often in less than 5000 patients and usually in a selected environment in which many patients have been excluded, including for example, women of childbearing potential, the elderly and children. Co-existent disease and the concomitant use of a number of common drug treatments also frequently exclude patients from pre-licensing trials. It is hardly surprising, therefore, that many adverse drug reactions are only detected once the product has been prescribed to the general population. National and international regulatory bodies, therefore, provide systems for post- marketing pharmacosurveillance, although participation in these by clinicians is generally voluntary and under-reporting is widespread. Post-marketing surveillance (PMS) studies are not generally an integral component to launching a new drug and many clinicians are sceptical over data generated in trials which do not conform to the ‘gold standard’ randomised control trial (RCT) design. However, in dismissing such studies, a great opportunity to obtain information, often from many thousands of subjects, is being missed. This article discusses post-marketing pharmacovigilance and the role of PMS studies in the context of current UK and European legislation.

Introduction

Estimates suggest that bringing a new drug to market is an expensive exercise costing somewhere in the region of 500 million ($800 million) and taking on average 10 years-12 years for the successful completion of clinical trials, specifically designed to gain approval by the regulatory bodies’2. Very few therapeutic molecules complete the successful journey from, laboratory discovery to the pharmacist1 and only three out of ten products launched ever recoup their development costs. A 20-year patent usually protects all new drugs, although most of this time is taken up during the development phase, such that the ‘in-use’ factual patent term can be less than 8 years. This places enormous pressures on pharmaceutical companies to achieve a substantial market share as soon as possible.

In 2004 two high profile pharmaceutical companies arguably marketing two well-known drugs experienced significant financial embarrassment and media attention. Following consultation with the European regulatory authorities, AstraZeneca issued a ‘Dear Doctor’ letter, in June 2004, in which attention was drawn to the risk of rhabdomyolysis with rosuvastatin (Crestor) and in the UK, the Medicines and Healthcare Products Regulatory Agency (MHRA) recommended a starting dose of 1Og in all patients3. A few months later a press release from Merck announced the withdrawal of rofecoxib (Vioxx) because of an increased cardiovascular risk in patients taking the drug for more than 18 months4. These are, however, only the latest in a series of actions needed to be taken by a number of companies marketing a whole range of pharmaceutical products. While some companies have been criticised for aggressive marketing of new drugs, the most important question which now needs asking is how do we bring new therapies into clinical practice quickly enough to benefit patients while at the same time provide maximum protection.

Acquiring regulatory approval

The process involved in obtaining regulatory approval, which allows new therapeutic products into the market place, is complex, although detailed guidance and advice can be found on the website of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH] (www.ich.org) and the European Medicines Agency EMEA (www.emea.eu.int).

Most health-care professionals are familiar, however, with some of the regulatory requirements, including Phase I, II and III clinical trials. Phase I trials, usually addressing pharmacokinetic and pharmacodynamic properties of the drug, define pharmacological safety in a relatively small number of healthy volunteers. Phase II, exploratory therapeutic trials, are the first attempts to show proof of concept in a relatively small number of patients with disease, usually a few hundred, in very controlled circumstances, typically over periods of around 3 months. Finally, Phase III trials are therapeutic confirmatory studies, performed on much larger groups of subjects, often in excess of 1500 subjects. The inclusion and exclusion criteria while strict, more closely match the general ‘target’ disease population; the studies may be conducted over 6- and 12-month periods and are usually of the random control trial (RCT) ‘gold standard’ design.

On average, approximately 4500 individuals will be exposed to a new drug during the development programme. This is clearly insufficient to reliably detect an adverse drug reaction (ADR) with, for example, an incidence of 1 in 10000, which for a commonly prescribed drug may be considered to be an unacceptably high safety/ efficacy ratio.

While contributing to the acquisition of regulatory approval and a product licence, these early studies, therefore, rarely provide answers to many questions posed by health-care professionals. They are usually performed on highly selected groups of patients often with an under-representation of large groups including women of childbearing age, the elderly and also children5-7. Co-existent disease and concomitant use of a number of common drug treatments often leads to study exclusion. While demonstrating therapeutic benefits, comparative data with existing therapies are usually not available nor are long term end-points and safety profiles. For these reasons regulatory agencies such as the Committee on Safety of Medicines (CSM) and the MHRA, the EMEA and the Food and Drug Administration (FDA) all have Systems in place for monitoring drug therapies and in particular close surveillance of new drugs.

Monitoring new drugs after general release

In 1964 following the well-known problems with thalidomide, the Yellow Card Scheme was introduced in the UK8. This provided a mechanism of postmarketing pharmacosurveillance of suspected ADRs. In 2002 an electronic card system was introduced but as with the original yellow card, its success is dependent upon the reporting of ADRs to the CSM by doctors on a voluntary basis.

The CSM also encourages the reporting of all suspected ADRs to new drugs and vaccines marked with an ‘inverted black triangle’ in the British National Formulary (BNF), Nurse Preservers’ Formulary (NPF), MIMS, the ABPI Compendium of Datasheets and Summaries of Product Characteristics, and advertising material9.

A black triangle will be assigned to a product if the drug is a new active substance. However, a product containing previously licensed active substances may also be monitored if it is a new combination of active substances. Black triangles can also be added if administration of a product is via a novel route or drug delivery system, or if there is a significant new indication which could alter the established risk/benefit profile of that drug. As with the yellow card scheme, the reporting of ADRs for black triangle drugs is voluntary.

Information received by the CSM and MHRA is evaluated and where appropriate feedback is provided. Product information is updated ‘routinely’ as necessary when there are safety concerns. Three to four times each year serious drug safety issues are communicated via the Current Problems in Pharmacovigilance bulletin mailed to all doctors, dentists, pharmacists and coroners in the UK. Not infrequently urgent safety issues including a newly identified ADR or drug withdrawal are communicated via letter, fax or via the Chief Medical Officer’s EPINET. Along with other governmental pharmacovigilance centres around the world reports are also submitted to the ICH, the EMEA and also the WHO programme for International Drug Monitoring.

Despite these procedures, concerns remain over drug safety, particularly when new products are released into general use following the limited information gained from trials designed for regulatory purposes. Systems dependent upon voluntary monitoring of ADRs lead to an under-reporting, which is common and widespread10- 14. Although serious ADRs are more likely to be reported10, overall rates of spontaneous reporting are often well below 10% of all ADRs11-13.

There are, however, other methods by which ADRs can be identified, evaluated and monitored. These include observational safety studies, usually sponsored by the market authorisation holder, prescription event monitoring (PEM) as undertaken by the Drug Safety Research Unit at the University of Southampton and follow-up via large computerised databases such as the General Practice Research Database (GPRD).

Post-marketing surveillance (PMS) studies

Company sponsored PMS studies are regarded by many as studies generating poor quality data that do not match that from clinical RCTs and which cannot stand up to the rigors of high quality external peer-review. Much of the criticism arises from the traditional view that such studies are really ‘seeding’/marketing trials designed by a company aimed at promoting sales of new drugs. However, to dismiss such studies as having no \role deprives us of a potentially valuable source of information obtained from real-life patients that have not been subject to, nor excluded by, standardised clinical trial circumstances.

In an attempt to provide studies of greater scientific credibility that could withstand peer-review scrutiny, the Safety Assessment Marketed Medicines (SAMM) guidelines were developed in the UK in 1994 by a working group that comprised the Medicines Control Agency (now MHRA), CSM, the Association of the British Pharmaceutical Industry (ABPI), the British Medical Association (BMA) and the Royal College of General Practitioners (RCGP)15. Guidelines are also available in other European countries including the Netherlands and Germany and in the UK there are also clear guidelines for Phase IV clinical trials, where medication is provided by the sponsoring pharmaceutical company. Multinational studies including pan-European multicentre studies have the great advantage of allowing many thousands of patients to be recruited. In this respect pan-European guidance is provided by the PostAuthorisation Safety Study (PASS) guidelines16 which are very similar to the SAMM guidelines.

In the UK, a SAMM study has been defined as ‘a formal investigation conducted for the purpose of assessing clinical safety of marketed medicines in clinical practice’ and the guidelines are intended to cover all company-sponsored studies carried out to evaluate the safety of marketed medicines. Such studies may be hypothesis-generating, to identify previously unrecognised safety issues or hypothesis testing, to investigate possible hazards. The design of the study will depend upon the objectives but may include observational cohort studies, case-control studies, case surveillance and clinical trials.

Company sponsored observational PMS studies are those subject to the greatest scepticism but are also those capable of producing some of the most useful data to health-care professionals. Guidance here is very clear and includes:

(i) Patients included in the study should be representative of the general population of users.

(ii) Comparator groups should normally be included (i.e. identical patients on an alternative therapy).

(iii) Only once a drug has been prescribed as a result of normal clinical practice can the patient be entered into the study. Recruitment into the study must then be in accordance with study protocol.

For all studies the general advice is also clear:

(i) Companies are advised to discuss the draft study plan with the MCA (now MHRA) and then submit a finalised plan to the MHRA before starting the study. Standard regulatory requirements for reporting ADRs must be fulfilled and both interim and final reports should be submitted to the MHRA.

(ii) Appropriate ethics committee approval is required.

(iii) The companies’ medical department is responsibility for the conduct and quality of the study under the supervision of a named UK registered medical practitioner.

(iv) Where an agent for the company performs the study, the agent should identify a UK registered medical practitioner to supervise the study and liaise with the company.

(v) An independent advisory board should be appointed to oversee the study.

(vi) Studies should not be conducted for the purposes of promotion and company representatives should not be involved in such a way that it could be seen as a promotional exercise.

(vii) Study payment to doctors to recompense for time and expenses should be in accordance with BMA guidelines.

Pharmaceutical studies that adhere to these guidelines should, therefore, be scientifically credible and contribute in a meaningful way to our understanding of the drug being evaluated. Probably the most important feature of a PMS study, which is often overlooked, is that the decision is made to prescribe the drug as part of routine clinical practice before the patient is entered into the study. This lack of randomisation is a critical feature of a PMS study as it leads to the monitoring of real-life clinical use of the new drug. The decision by the clinician to ‘prescribe before entering’ based on clinical circumstances should also reduce pharmaceutical company intervention and bias.

Combined with other post-marketing schemes and Phase IV clinical trials, PMS studies registered with the MHRA, that have appropriate Multicentre/Local Research Ethics Committee MREC/LREC approval, an independent steering committee for data monitoring and that adhere to all other PASS or SAMM regulatory guidelines, will increase our confidence in the validity and importance of the data generated.

Most recently in November 2004, the ICH issued a new tripartite guideline on pharmacovigilance planning (designated E2E) for recommendation to the regulatory bodies of the European Union, Japan and USA17. The guideline is intended to assist with the planning of pharmacovigilance, especially in the post-marketing period. It will make it mandatory that the applicant pharmaceutical company of a new drug, or of an existing product undergoing significant change in its usage or where new safety concerns have arisen, formulate a Pharmacovigilance Plan with advice from the regulator, which will be based upon a safety specification detailing the important identified risks of a drug, important potential risks and important missing information. The ICE E2E document, also endorsed by the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) and which will be implemented during 2005 in the European legislation for pharmacovigilance (volume 9) by the EMEA, will lead to the involvement in the design, and the monitoring of follow-up and the completion of pharmacoepidemiological studies by the EMEA. A further contribution to the development of a European Risk Management Strategy will be the inclusion of detailed regulation for the implementation of PMS studies as a follow-up measure that may be a condition for approval of a drug.

What are the benefits of PMS studies?

Searches of electronic databases reveal an increasing number of PMS studies, often on many thousands of patients. In some instances data confirm that of the original early phase clinical trials, although in many others, novel hypothesis-generating data provide invaluable ADR information. In a recent study which looked at the differences between the characteristics of treated populations and treatment patterns in clinical trials and post-marketing settings for tacrine, simvastatin and celecoxib, the authors concluded that ‘their results plead for systematic ad hoc observational post- marketing studies for any novel and/or expensive medicine…’5. This view has recently been endorsed by clinicians in the USA with a request for a more integrated and comprehensive approach to post- market approval surveillance, following recent concerns over restenosis rates with the novel Cypher stent in patients with coronary artery disease18.

The potential benefits of a PMS study are that reallife patients are being evaluated in real-life situations and because of a lack of tight inclusion and exclusion criteria, large numbers may be recruited. The consequences, therefore, are that infrequent (1 in 1000) yet important adverse reactions can be documented in studies enrolling 10000-20000 patients. In Germany, PMS studies are already considered to be an integral component to the launching of a new drug, with some studies exceeding 50 000 patients.

Although such studies in the UK are not commonplace, we are now starting to see high quality PMS studies with the potential to play an increasing role in patient safety and our understanding of how new drugs behave in the general population. Following the recent launch of a new basal insulin analogue, insulin detemir, Novo Nordisk and Kendle International (Novo Nordisk’s partner contract research organisation) initiated a large international observational PMS study, PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation). The primary endpoint is to evaluate the incidence of serious ADRs, including major hypoglycaemic events, during treatment with insulin detemir. The secondary endpoints include weight change, fasting blood glucose variability and HbA1 . The study will involve 25000 patients and 5000 clinicians world-wide. Importantly, prior to starting the study, advice was sought from the appropriate regulatory body (MHRA), ethics committee approval was granted, an independent steering Committee was established to monitor the data and remuneration to clinicians is in line with the BMA fee schedule for PMS studies19.

While there are obvious safety benefits for the patient there are advantages too for clinicians and pharmaceutical companies. Following the launch and almost immediate withdrawal of the thiazolidinedione, troglitazone in the UK, the subsequent release of rosiglitazone and pioglitazone has been accompanied by guidelines from the National Institute of Clinical Excellence (NICE), recommending 2-monthly liver function tests for the first 12 months for all patients prescribed either of these agents20. These drugs have now been prescribed to many thousands of patients, and unlike troglitazone, hepatic toxicity does not appear to be a side effect. A properly conducted PMS study could by now have produced evidence for consideration by NICE to reduce what many diabetologists believe to be a waste of valuable time and expense in performing unnecessary tests. The respective pharmaceutical companies would also benefit, not only by having additional safety data on their products but probably by increased sales which have almost certainly been held back by the burdens associated with prescribing these drugs.

The way forward

High quality, scientifically credible, efficacy and safety data are needed for all drugs so that we can prescribe to our patients with confidence. The Department \of Health, on behalf of the UK Clinical Research Collaboration, is leading the work to establish a new UK clinical research network to facilitate the conduct of randomised prospective trials of interventions and other well designed studies in the broad area of clinical research21. This should include good PMS studies. As clinicians we need to appreciate the benefits of well-conducted and properly regulated PMS studies so that we can encourage pharmaceutical companies to invest in them and develop mutually beneficial collaborations between clinicians, regulatory bodies and pharmaceutical companies. This appreciation could begin with the incorporation and teaching of all types of clinical studies into our undergraduate curriculum training programmes at university. These activities could be extended to post- graduate education and even continuing medical education. Ultimately, data obtained from well-conducted PMS studies, analysed by independent advisory groups, should be written up for peer- review publication and should be viewed positively by editors of good quality journals.

When a licence for a new product is submitted a pharmaceutical company must provide all ‘positive’ and ‘negative’ data and a summary of this is available to the public through European Public Assessment Reports (EPARs), produced by the EMEA on the granting of a licence. In addition the ABPI actively encourages the publication of all clinical trial data including those that show both ‘positive’ and ‘negative’ results to minimise publication bias. Although the ABPI have produced a website for companies to publish information from clinical trials (www.cminteract.com/clintrial/), this remains voluntary. As clinicians we should encourage companies to commit to this or other independent and transparent electronic databases.

Finally, the European Risk Management Strategy, conducted by the EMEA, including the E2E ICH guideline, due to be implemented this year22, should have a significant impact on pharmaceutical companies seeking regulatory approval for new products including the need for more widespread implementation of post-marketing pharmacoepidemiological safety studies.

Conclusions

The safety of medicines we give to our patients is of paramount importance.

The costs and time involved in the development of new products are great and place enormous pressure on companies to recoup some of the costs as quickly as possible. Acquiring regulatory approval for a new drug allows us to begin to understand how it might behave in an unselected, real-life, population. Post-marketing pharmacovigilance employing a variety of complementary approaches supported by new European legislation provides us with the opportunity of providing early access to the latest forms of treatment combined with the highest standards of medical care and safety.

Acknowledgements and declaration of interests

Novo Nordisk Ltd have provided support for the publication of this manuscript, but I have received no financial support or sponsorship from Novo Nordisk Ltd or Kendle International as reimbursement for writing this article, which expresses my own views without influence from outside sources.

I am grateful to Alan Davies (Kendle International) and Chris Martin (Novo Nordisk) for information and helpful comments on the manuscript, including the provision of clinical data searches.

References

1. The Association of the British Pharmaceutical Industry. http// www. abpi.org.uk/statistics/intro.asp [last accessed 4 March 2005]

2. DiMassi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ2003;22:151- 85

3. New prescribing advice for the 40 mg dose of Crestor (rosuvastatin) http://medicines.mhra.gov.uk/ [last accessed 4 March 2005]

4. Merck. Merckannounces voluntary worldwide withdrawal of VIOXX”. http://www.vioxx.com/vioxx/documents/english/ vioxx_press_release.pdf [last accessed 4 March 2005]

5. Martin K, Bgaud B, Latry P, Miremont-Salam G, Fourier A, Moore N. Differences between clinical trials and post-marketing use. Br J Clin Pharmacol 2003;57:86-92

6. Schmucker DL, Vesell ES. Underrepresentation of women in clinical drug trials. Clin Pharmacol Ther 1993;42(Suppl):l 1-5

7. Bugeja G, Kumar A, Banerjee AK. Exclusion of elderly people from clinical research: a descriptive study of published reports. Br Med J 1997;315:1059

8. The yellow card scheme: how the yellow card scheme protects patients. https://www.mhra.gov.uk/medicines/safety/ yellowcard/ howprotects.htm [last accessed 4 March 2005]

9. Monitoring the safety and quality of medicines; new drugs under intense surveillance, http://medicines.mhra.gov.uk/ourwork/ monitorsafequalmed/newdrugs/newdrugs.htm [last accessed 4 March 2005]

10. Heeley E, Riley J, Layton D, Wilton LV, Shakir SAW. Prescription-event monitoring and reporting of adverse drug reactions. Lancet 2001;358:1872-73

11. Smith CC, Bennett PM, Pearce HM, et al. Adverse reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines. Br J Pharmacol 1996;42:423-9.

12. Mittmann N, Knowles SR, Gomez M, Fish JS, Cartotto R, Shear NH. Evaluation of the extent of under-reporting of serious adverse drug reactions: the case of toxic epidermal necrolysis. 18. Drug Safety 2004;27:477-87

13. Begaud B, Martin K, Haramburu F, Moore N. Rates of reporting of adverse drug reactions in France. J Am Med Assoc 2002;288:1588

14. Backstrom M, Mjorndal T, Dahlqvist R. Under-reporting of serious adverse drug reactions in Sweden. Pharmacoepidemiol Drug Saf 2004; 13:483-7

15. Guidelines for company-sponsored Safety Assessment of

Marketed Medicines (SAMM) guidelines. Medicines Control Agency, Committee on Safety of Medicines, Royal College of General Practitioners, British Medical Association and association of British Pharmaceutical Industry (November 1993). Br J Pharmacol 1994;2:95-7 22.

16. Pharmacovigilance medicinal products for human and veterinary use, vol. 9: section 1.5. Company-sponsored post-authorisation studies. http://www.eudravigilance.org/human/docs/Vol9en.pdf [last accessed 4 March 2005]

ICH harmonised tripartite guideline. Pharmacovigilance planning E2E. http//www.fda.gov/cder/guidance/6002dft.pdf [last accessed 4 March 2005]

Mehran R, Leon MB, Feigal DA, et al. Post-market approval surveillance: a call for a more integrated and comprehensive approach. Circulation 2004; 109:3073-7

BMA fees guidance schedule, section 6, April 2003 http://www/ bma.org.uk [last accessed 4 March 2005]

Guidance on the use of glitazones for the treatment of type 2 diabetes. http://www.nice.org.uk/pdf/TA63_Glitazones_ Review_Guidance.pdf [last accessed 4 March 2005]

Department of Health. Research for Patient Benefit Working Party. Final report 2004. http://www.dh.gov.uk/ assetRoot/04/08/26/75/ 04082675.pdf [last accessed 4 March 2005]

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2937_2, Accepted for publication: 09 March 2005

Published Online: 18 March 2005

doi:10.1185/030079905X41426

Stephen Gough

Division of Medical Sciences, University of Birmingham, Birmingham, UK

Address for correspondence: Professor Stephen C. L. Gough, Division of Medical Sciences, Institute of Biomedical Research (2nd floor), The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. email: [email protected]

Copyright Librapharm Apr 2005

A phenomenon known as ischemic preconditioning (IP), in which blood flow to muscle is reduced and then restored, has previously been shown to increase muscle function, especially in the heart. A new study published online June 6, 2005 in Muscle & Nerve explores the link between the protective effect of IP in skeletal muscles and the substance that triggers hibernation. The journal is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/mus.

During certain types of vascular or reconstructive surgery, it is sometimes necessary to block blood flow, which may cause tissue damage. This problem might potentially be alleviated if a pharmacological substance was able to achieve IP. Hibernation in mammals is thought to confer cardiac benefits similar to IP. Researchers led by Jinback Hong, Ph.D. of the department of biomedical engineering at the University of Minnesota in Minneapolis, MN, set out to explore whether pretreatment with the chemical that induces hibernation (hibernation induction trigger or HIT) would have the same protective effect as IP in skeletal muscles and the mechanism by which this effect might occur. The study involved removing muscle tissue from 77 pigs, and subjecting it to hypoxia (a reduction of oxygen supply) for 90 minutes, followed by 120 minutes of reoxygenation. The muscles were then divided into several groups that were treated with plasma from hibernating woodchucks (HWP), plasma from woodchucks active in the summer (SAWP), HWP plus naloxone (an opiate receptor antagonist), HWP plus potassium channel blocker, and various control groups. After 30 minutes and 120 minutes of reoxygenation, the HWP group showed significantly more muscle activity, as measured by twitch force, than the other groups. The HWP group was also not significantly different than a control group that was not subjected to hypoxia.

In discussing the effect of serum taken from a hibernator on the skeletal muscles of a nonhibernator, the authors state: “Such an acute response may also suggest that preconditioning with HIT or a similar agonist could be employed for humans in certain clinical situations, such as during vascular and musculoskeletal reconstructive surgery (e.g., a total knee replacement).” They note that since the HWP group recovered to the same level of force as the group that was not exposed to hypoxia, the protective factors in the plasma of the hibernating woodchucks safeguarded the muscle quite optimally.

One of the pathways that has been identified in IP and the subsequent protection of muscle is the opening of potassium channels, which in heart muscle is associated with the accumulation of opioids. The researchers attempted to determine if this same mechanism was involved in HIT’s protective effects. They administered a potassium channel blocker with the HWP, using dimethylsulfoxide (DMSO) as a solvent. However, since DMSO is itself associated with a decreased twitch force, the results were inconclusive. When the opiate receptor antagonist naloxone was used, the results showed that it weakened the effects of HWP, suggesting that HWP works in part through some type of action on opioid receptors.

The researchers conclude that “pharmacological preconditioning of skeletal muscle to reduce necrosis [tissue death] associated with hypoxia/reperfusion could provide clinical benefits such as improved recovery time and fewer postsurgical complications for patients who have endured prolonged regional skeletal muscle ischemia.”

On the Web:

John Wiley & Sons, Inc.

MAYWOOD, Ill.  – A simple blood test can quickly identify what type of congestive heart failure (CHF) a patient has, improving diagnostic accuracy; eliminating the need for extensive diagnostic tests, such as heart muscle biopsy or exploratory surgery; and enabling the patient to be treated sooner, according to a study published in the June 7 Journal of the American College of Cardiology. After blood is drawn, the test results are ready in 15 minutes.

In the study, researchers at Loyola University Health System found significantly higher levels of the cardiac hormone, brain natriuretic peptide (BNP), in the blood of patients with one type of CHF, restrictive cardiomyopathy (RCMP), versus another type of CHF, constrictive pericarditis (CP).

“This is an important discovery because, while the symptoms are similar for both types of heart failure, the diagnosis, treatment and prognosis are very different,” said lead author Dr. Fred Leya, professor of medicine/cardiology, Loyola University Chicago Stritch School of Medicine; and director, interventional cardiology and director, cardiac catheterization lab, Loyola University Health System, Maywood, Ill. “By examining the BNP level in congestive heart failure patients, we can quickly determine whether they have RCMP or CP. As a result, we can provide the appropriate treatment much sooner.”

Five million people in the U.S. have CHF, where the heart weakens and becomes unable to pump adequate amounts of blood. When blood returning from the body to the heart is not pumped fast enough, it starts to back up into the lungs. CHF symptoms include shortness of breath, swollen legs, swollen liver and fatigue, which could also be signs of other conditions. Some CHF may go undetected for months, even years.

All people have some level of BNP, but the heart muscle releases excessive amounts of the hormone in response to heart failure. Therefore, as expected, CP and RCMP patients had higher levels of BNP than patients with a normal heart. Yet, RCMP patients had significantly elevated BNP levels compared to CP patients.

“The reason for this is because CP patients have a rigid or scarred pericardium ““ the sac-like membrane covering the heart,” said Leya. “As a result, the chambers of the heart are “restrained,” and cannot expand and fill with blood to function normally. When this happens, the heart muscle wall cannot stretch as much and release BNP.” Left untreated, CP can be life-threatening, and a surgical procedure to remove part of the pericardium may be necessary.

With RCMP, the heart muscle stiffens so that not enough blood can enter the ventricles, the lower chambers of the heart. However, unlike with CP patients, the pericardium is not rigid or scarred. Therefore, higher levels of BNP can be more easily released. In some cases, early diagnosis and treatment can prevent further damage. In other cases, treatment is aimed at decreasing the workload of the heart. Eventually, a heart transplant may be necessary.

For the study, Leya and colleagues measured BNP levels in 11 patients suspected of having CP or RCMP. Five patients had RCMP and six had CP, as confirmed by hemodynamic assessment. “The mean plasma BNP levels of the RCMP group were four times that of the CP group,” said Leya, who is developing a registry of patients to further expand the study.

Co-authors of the study with Leya are Dr. Dinesh Arab, Dr. Dominique Joyal, Krystyna M. Shioura, Dr. Bruce E. Lewis, Dr. Lowell H. Steen and Dr. Leslie Cho.

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Loyola University Health Systems

In an unusual but fruitful collaboration between Tibetan Buddhist monks and neuroscientists, researchers have uncovered clues to how mental states–and their underlying neural mechanisms–can impact conscious visual experience. In their study, reported in the June 7 issue of Current Biology, the researchers found evidence that the skills developed by Tibetan Buddhist monks in their practice of a certain type of meditation can strongly influence their experience of a phenomenon, termed “perceptual rivalry,” that deals with attention and consciousness.

The work is reported by Olivia Carter and Jack Pettigrew of the University of Queensland, Australia, and colleagues at the University of Queensland and the University of California, Berkeley.

Perceptual rivalry arises normally when two different images are presented to each eye, and it is manifested as a fluctuation–typically, over the course of seconds–in the “dominant” image that is consciously perceived. The neural events underlying perceptual rivalry are not well understood but are thought to involve brain mechanisms that regulate attention and conscious awareness.

Some previous work had suggested that skilled meditation can alter certain aspects of the brain’s neural activity, though the significance of such changes in terms of actually understanding brain function remains unclear.

To gain insight into how visual perception is regulated within the brain, researchers in the new study chose to investigate the extent to which certain types of trained meditative practice can influence the conscious experience of visual perceptual rivalry.

With the support of His Holiness the Dalai Lama, 76 Tibetan Buddhist monks participated in the study, which was carried out at or near their mountain retreats in the Himalaya, Zanskar, and Ladakhi Ranges of India. The monks possessed meditative training ranging from 5 to 54 years; among the group were three “retreatist” meditators, each with at least 20 years of experience in isolated retreats.

The researchers tested the experience of visual rivalry by monks during the practice of two types of meditation: a “compassion”-oriented meditation, described as a contemplation of suffering within the world combined with an emanation of loving kindness, and “one-point” meditation, described as the maintained focus of attention on a single object or thought, a focus that leads to a stability and clarity of mind.

Whereas no observable change in the rate of “visual switching” during rivalry was seen in monks practicing compassion meditation, major increases in the durations of perceptual dominance were experienced by monks practicing one-point meditation. Within this group, three monks, including two of the retreatists, reported complete visual stability during the entire five-minute meditation period. Increases in duration of perceptual dominance were also seen in monks after a period of one-point meditation.

In a different test of perceptual rivalry, in this case prior to any meditation, the duration of stable perception experienced by monks averaged 4.1 seconds, compared to 2.6 seconds for meditation-naïve control subjects. Remarkably, when instructed to actively maintain the duration, one of the retreatist monks could maintain a constant visual perception during this test for 723 seconds.

The findings suggest that processes particularly associated with one-point meditation–perhaps involving intense attentional focus and the ability to stabilize the mind–contribute to the prolonged rivalry dominance experienced by the monks. The researchers conclude from their study that individuals trained in meditation can considerably alter the normal fluctuations in conscious state that are induced by perceptual rivalry and suggest that, in combination with previous work, the new findings support the idea that perceptual rivalry can be modulated by high-level, top-down neural influences.

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Cell Press

First in a two-part series

The patient was partially sedated as she headed for a dental appointment that December morning in 2003. Groggy and horizontal in the back seat of her sister’s car, she was just blocks from the dentist’s office when her cell phone rang.

“Your procedure’s been canceled,” her husband told her. “Your doctor had an accident.”

Meanwhile, a few blocks farther south, a little drama was unfolding. Earlier that morning, according to a police report, Murray police had received a call from a worried employee: Her boss’s car was in the parking lot, but nobody answered when the employee banged on the office door.

When police pried the door open they found the dentist, Kathleen McCombs, sitting on the floor, an oxygen mask over her face. McCombs, who had come highly recommended and was on an insurance list of preferred providers, had been up all night inhaling nitrous oxide, according to police.

It would take another day, and some luck, for the patient to find out the barest of details. It would take several months, and filing a government records request, to get the police report. And only later did she learn, from public records purchased from the Utah Division of Occupational and Professional Licensing, that the dentist’s nitrous abuse dated back to 1999, when she entered the state’s confidential drug “diversion” program, which she’d successfully completed just seven months before.

Why, the patient wondered, was she only finding this out now?

Meanwhile, two days after the dentist’s “accident,” the patient got a phone call. “Hi,” said a cheerful staffer. “I’m calling to see if we can reschedule your surgery.” By then, the patient, Deseret Morning News reporter Lois Collins, had found another dentist to do the work. But she wondered about the dentist’s other patients who weren’t privy to the information she now had.

That question spawned others. How much do any of us know about the doctors who diagnose us, put us under, cut us open, care for us? How much can we find out? Are we, as patients, protected from doctors who could harm us?

Most Utah doctors do not do drugs or sexually molest their patients. Most are not incompetent. Many, in fact, are exceptional.

But to wade through even a few of the reams of disciplinary reports on file at the state’s Division of Occupational and Professional Licensing (DOPL) is to be reminded that doctors can be disappointingly human; that they are tempted by the painkillers they prescribe and sometimes sloppy about the care they provide.

One clue to a doctor’s history can be found at www.dopl.utah.gov. The Web site will tell you if your doctor has licenses to practice medicine and dispense controlled substances; whether those licenses are active, revoked, suspended, surrendered or on probation; and the years when past disciplinary actions occurred. If you pay DOPL $12, you can get some details.

But even if you’re savvy enough to investigate your doctor, there are important facts you won’t find out.

— You can’t find out whether DOPL is currently investigating or negotiating a disciplinary action against your doctor, a process that can take months or even years. While investigation and negotiation continue, a doctor is usually allowed to keep working.

— You can’t find out if your doctor was ever in a confidential treatment program for drug or alcohol abuse, or is in treatment now while he continues to practice. Even if DOPL once issued an emergency suspension of your doctor’s license, if he then went into the confidential drug program the disciplinary action will not be listed on the Web site.

— You can’t find out whether a hospital has ever disciplined your doctor. You cannot find out whether a hospital wanted to discipline your doctor but backed down because it feared your doctor would sue. Hospital information is not available to the public, although it occasionally surfaces in a lawsuit if the doctor does sue the hospital.

— You can’t find out whether your doctor did poorly during his training, perhaps being shuttled from one residency to another. Medical school and residency programs operate on confidentiality — even DOPL isn’t privy to this. A doctor interviewed for this story tells this joke: “What do you call the person who graduated last in his class in medical school? Doctor.”

— You can’t find out how many malpractice lawsuits your doctor has settled. Like hospital disciplinary actions, malpractice settlements must be reported to the National Practitioners Data Bank — but the version available to the public does not include names.

— You can’t assume doctors on your health insurance provider list have never been disciplined. When the Deseret Morning News cross-checked the names of doctors who have been put on probation by DOPL in the past three years against the “preferred provider” lists of several of Utah’s largest health insurance companies, nearly all the disciplined doctors had made at least one of the go-to lists.

— You can’t pick every doctor who will care for you. Patients don’t select an anesthesiologist, an emergency room doctor, the after-hours-clinic crew. There’s no way to look them up in advance.

— You can’t always tell if the doctor doing a procedure was adequately trained to do it. For instance, a doctor may learn to do cosmetic laser treatments at a weekend retreat.

— And you can’t find out about doctors who have not been investigated or have been investigated but never disciplined. Malpractice attorney Eric Nielson complains about a doctor he calls “one of the most incompetent doctors I’ve ever run into” but has no black marks against him from DOPL.

The many things you can’t find out make it difficult to assess how well you’re protected by the regulatory bodies and the health- care system that you probably assume keeps you safe. The things you can’t find out make it difficult to know if that doctor whose name you see in the Yellow Pages is the doctor you want to trust your skin or feet or life to.

At the same time, the things you can find out about your doctor – – the fact that he has been put on probation, for example — may not mean he’s a doctor you should avoid. There are degrees of culpability and potential harm to patients (a doctor might be in trouble because his secretary forged a prescription, or he might be injecting the drugs himself; he might have kept sloppy records or negligently killed a patient), and a doctor with a history of misconduct may have been rehabilitated.

The circumstances that led to discipline in the first place may even have been stacked against him. There is a Utah doctor, for example, who had sleep apnea but was misdiagnosed, prescribed Ritalin and became addicted. Now his medical license is restricted, and he’s trying to get his life back together.

In researching this story, reporters attended licensing board meetings and consulted patients, doctors, malpractice attorneys and five years’ worth of the quarterly online newsletters that DOPL publishes about disciplined health practitioners. This story includes names of some who illustrate gaps in what patients can know about their doctors, but readers should not assume those named here are “bad” doctors or that the doctors not named here are “good.”

Doctors named in this story have been given a chance to tell their story. Many accepted. Periodontist McCombs was among those who chose not to respond on the record.

The government checks up on restaurants, dropping in to see if the cooks are washing their hands, and it periodically keeps tabs on meat-packing plants and grocery deli departments. But the state doesn’t do random checks on doctors’ offices. DOPL doesn’t have enough staff or funding to do that, and it’s doubtful such monitoring would help — DOPL would have to be lucky enough, to use one real example, to show up just when a doctor was stealing Lortab from a co-worker’s purse.

The system for ferreting out questionable doctors seems more hit and miss than you might suppose. DOPL scans the Utah Controlled Substance Database, which primarily identifies people who are doctor shopping for drugs, where it might discover a doctor writing too many prescriptions. Regulators also use it to look into cases where the police, FBI or state fraud units are involved.

That’s how Dr. Alexander Theodore came to DOPL’s attention earlier this

year. The state Insurance Department is investigating the doctor for allegedly operating an OxyContin drug ring in Salt Lake County.

But DOPL relies chiefly on complaints, mostly from patients or their families, occasionally from hospitals, colleagues and insurance companies. If there are no complaints filed, DOPL may not have that doctor on its radar.

Doctors who don’t practice at hospitals are among the hardest to keep tabs on because there’s no one responsible for monitoring or reporting them, says Dr. Marc Babitz, a member of the state Physician’s Licensing Board, which acts as an advisory body to DOPL on discipline matters regarding physicians. And most “doctoring” isn’t done in hospitals but in doctors’ offices. The American Society of Anesthesiologists estimates that 10 million surgeries nationwide now take place in doctors’ offices and free-standing clinics.

Hospitals must tell DOPL and the federal practitioners database when they take away or restrict a doctor’s privileges for more than 30 days. But sometimes a hospital will place restrictions on a doctor for 29 days to avoid reporting, according to several sources.

“It is rare, almost nonexistent, that action taken by a hospital short of revoking his privileges or suspending his staff membership is brought to the attention of the division,” says former DOPL director David Robinson. “You may have a physician who is displaying practice patterns that don’t meet professional standards, and patients have no way of knowing about it.”

“When hospitals try to discipline a doctor, there is a 95 percent chance they will be sued” by the doctor, says a midlevel health- care administrator, voicing a sentiment the Deseret Morning News heard repeatedly. So hospitals sometimes shy away from taking away a doctor’s privileges to practice there On the other hand, says Salt Lake attorney James McConkie, “a good doctor can get crosswise with a hospital and get drummed out.”

If a doctor does lose his privileges to practice at a hospital, patients won’t be able to find out why — unless he sues the hospital. That’s how details about Utah County doctor James A. Brinton surfaced in the early 1990s.

Brinton made headlines after he sued Intermountain Health Care for canceling his hospital privileges at Utah Valley Regional Medical Center and Orem Community Hospital. According to court documents, the hospitals charged that some of the doctor’s hysterectomy patients suffered complications, that a misdiagnosis may have contributed to a baby’s death, and that he delivered more babies than was safe. The case eventually went to the Utah Supreme Court, where Brinton lost.

The Supreme Court never looked at the merit of the allegations the hospitals made, Brinton says. It focused simply on whether a hospital had a right to deny privileges as long as it had an established process and followed it. Because he lost privileges at IHC hospitals, his application at Mountain View in Payson was originally denied. When he appealed the decision to the hospital, he won. He has never been disciplined by DOPL.

Loss of hospital privileges doesn’t automatically trigger DOPL disciplinary action. Between 1991 and 2003, the federal data bank shows that Utah hospitals reported 17 physicians had lost hospital privileges — but only eight of these doctors have ever been disciplined by DOPL, according to the data bank.

DOPL doesn’t know how many of the 7,500 physicians licensed in Utah actually practice here, in part because doctors often have licenses in more than one state. When a doctor gets in trouble in one place, it may take a while for another state to find out, so scrutiny is delayed.

In the spring of 1994, six weeks after he surrendered his license in Idaho in the midst of disciplinary proceedings, Dr. Bradley Spaulding got a job in Utah, where he also had a license, as Milford’s only surgeon. The Idaho investigation accused him of providing care in an emergency room “while under the influence of drugs.”

Although he was not yet on DOPL’s radar, Spaulding soon got in trouble in Utah. Spaulding had told officials at Milford Valley Memorial Hospital about his drug problems and his treatment, but the hospital assumed it was past history. When Spaulding relapsed, the hospital took drastic steps to restrict his access to drugs and the hospital pharmacy. Six months after his move to Utah, DOPL ordered a “quality review process” of his clinical skills and required him to write his prescriptions in serially numbered triplicate.

DOPL revoked Spaulding’s Utah medical license in 1997. According to DOPL files, for several months he had been writing patients prescriptions for painkillers that he then used himself.

In a lawsuit against Spaulding and the hospital, one patient alleges that his drug use contributed to a botched delivery. Some patients loved him, says former Milford hospital administrator John Gledhill. “He was a great doc.” Doctors in places like Milford — not just rural but “frontier,” says Gledhill — are overworked and always tired, “on call pretty much 24 hours a day.”

After losing his license in Utah, Spaulding moved to New York for a residency program. A check with New York’s licensing agency reveals that this month his license was suspended. Spaulding told the Deseret Morning News that he is retiring from medicine for health reasons.

“I think (DOPL) really did treat me fairly. . . . I think they’re making a valiant effort to salvage physicians that have difficulty and still protect the public. It’s a tough, tough job,” he says.

“Drugs and sex.” That’s how Diana Baker sums up the cases her division is working on most of the time. Baker is chief of the DOPL bureau that oversees physician discipline.

DOPL doesn’t keep statistics on such things, but according to the past five years of DOPL’s online newsletters, incompetence or negligence accounted for roughly eight of the 100 physicians whose licenses were either revoked, suspended, voluntarily surrendered or were put on probation

That doesn’t mean that sloppy doctoring doesn’t happen. In fact, most of the complaints made about doctors to DOPL are categorized as incompetence and negligence. But drugs and sex allegations are easier to prove.

Incompetence and negligence are “a very subjective thing,” says DOPL director Craig Jackson. Medicine isn’t like car repair, where the car runs or it doesn’t. Even with very good care, complications occur, people die, and a bad result may have been influenced by extenuating circumstances — as well as by many different people, since medicine is not always practiced one-on-one. It is for those very reasons that malpractice lawsuits aren’t necessarily a good measure of whether a doctor’s “good” or “bad.”

Incompetence may be a matter of chronic ineptness, or of advancing age. “Aging, which eventually affects every physician,” writes Dr. Gregory Skipper, medical director of the Alabama Physician Health Program, “causes decreased memory and motor function, sometimes to a dangerous degree, and some physicians are unwilling to appropriately decrease their practice commensurate with their decreasing ability. How is the public to be protected?” DOPL may not know about such a doctor if a complaint isn’t filed. It only found out one Utah doctor was suffering from dementia when he didn’t properly keep track of the drugs in his office.

Competency cases “are a judgment call,” says licensing board member Babitz, and “that means that a colleague of the physician in question has to be willing to criticize their performance.” There are social and legal constraints to that kind of finger-pointing, such as fear of lawsuits, says Babitz, who adds that “fortunately, I don’t think that there are many incompetent doctors who are practicing.”

The state requires 40 hours of continuing medical education every two years, and many specialty boards are tightening their rules, increasingly requiring members to recertify periodically. But most board-certified doctors in practice before 1996 are “grandfathered in.” The federal database doesn’t list a single case of specialty board discipline in Utah in the past 12 years. There are also fly- by-night “boards” that don’t test competency, Utah Medical Association spokesman Mark Fotheringham warns. They sell “certification” and they’re “not worth the paper they’re printed on,” he says.

DOPL’s 16 investigators — who handle all licensing, from hair dressers to brain surgeons — take an average of 150 days to complete an investigation, but some may drag on for a year or two. Too many cases for too few staffers, and reluctance of physician colleagues to say bad things about each other, are among factors that slow investigations. History shows it could take another year or more, once the doctor hires a lawyer, for discipline to be meted out. Meanwhile, the doctor, innocent until proven guilty, continues to practice.

Some observers say that DOPL is thorough and tough. “What happened to me was so traumatic and damaging — and not just to me but to the people around me,” says one practitioner who ran afoul of DOPL in the 1990s. He said today’s DOPL is more compassionate.

Others see DOPL as too narrow in its focus. “It’s nearly useless to check with DOPL to find out if a doctor is good or bad,” argues malpractice attorney Frank Carney, because DOPL “only covers egregious deviations from proper care.” DOPL’s mission, set forth in state statute, requires that doctors provide only a minimum standard of care. A doctor doesn’t have to be a good doctor. He just can’t be a really, really bad doctor. To discipline, DOPL must show that the doctor exhibited “gross” negligence or unprofessional conduct, or a pattern of such behavior — allegations that must be verified by another physician.

Efforts to make it easier to discipline have been strongly opposed by the state’s strong doctor lobby, says a DOPL insider. Insiders also admit they don’t prosecute a case they’re not sure they’ll win, since proving a case requires money, effort and time.

And, too, DOPL is sometimes hampered when a doctor is arrested for a crime but his sentence is plea-bargained by a county attorney. “That hurts us when we try to discipline them,” says Dan T. Jones, DOPL bureau manager over dentists, chiropractors and a handful of other professions.

“In Utah, if I saw (a disciplinary action) so much as filed (by DOPL), I’d run the other way, because it’s so hard to go through the hoops to get it filed,” says a former DOPL insider, who adds that “it’s easier to go after nurses and social workers than doctors. A physician can put a hundred thousand (dollars) into his defense, or whatever it takes.”

Dr. Richard Sperry, chairman of the PLB, acknowledges DOPL’s limitations. “I think we agree to license some people, as a licensing board, that most of us around the table would never choose to have work on us or a family member. It’s tough as a board to put that aside. We have to be reminded the standard isn’t ‘Would you choose this person?’ “

In some ways, DOPL is like a mother whose three children are all clamoring for her attention. One child is the aching, diseased public. Another is the doctor whose livelihood is at stake. The third is a health-care system that needs doctors to keep it running. The good mother wants to keep everybody happy.

“It’s such a delicate balance,” says Dr. George Van Komen, a past chairman of Utah’s Physician Licensing Board and former president of the national Federation of State Medical Boards. “These are physicians — colleagues — who have the same training you have. You know how hard they worked to get where they’re at. You would like to see them succeed in medical practice. But we do not want to run the risk of harming the public.”

Some doctors would like to be tougher on colleagues whose actions or lifestyles could harm patients. But they say they often are constrained by agreements worked out when the lawyers for both sides weigh in. The result is, essentially, a plea bargain.

Consider the case of Dr. Layfe Anthony. In February 2002, Anthony pleaded “no contest” to a charge of negligent homicide in the death of a Bunkerville, Nev., woman who came to him for outpatient liposuction in late 1999. That night, the DOPL file states, Anthony allowed her husband to pick up a syringe filled with medication for her uncontrolled pain, and take it back to Nevada to inject her. She died the next day. DOPL says Anthony did not have a nurse anesthetist present and did not monitor her vital signs during the procedure. A second liposuction patient died in 2000.

DOPL took action against his license eight months after the second death, issuing an emergency order barring him from doing surgery or prescribing controlled substances. DOPL later handed down a five-year probation.

Anthony “should have had his license revoked,” argues licensing board member Dr. David McCann. Under probation, he is still allowed to practice but only under the supervision of another physician. Anthony declined to be interviewed for this story. His attorney, Peter Stirba, however, says that Anthony is a model probationer.

Still, the frustration of McCann and several other PLB members is apparent at meetings in which Anthony has appeared before the board, which must monitor his probation but had no say in designing its terms. His probation requires that Anthony improve his medical skills, but at the February PLB meeting, McCann blasted his efforts.

“You’ve found people to go to bat for you, but you’ve not done one thing yourself,” McCann told him. “It’s not like we’re against you. But you’re not taking any initiative.”

This is the frank discussion you won’t find in the sanitized, pared-down newsletter that DOPL publishes quarterly on its Web site. And you won’t see those details in DOPL reports.

Even when you pay the $12 for the full DOPL file, mysteries remain. A file may say “voyeuristic conduct” or “delivered infants contrary to established protocols.” You may discover a record has been expunged: a limited record of the facts remains, but the stipulation and other documents are gone, no reason given.

In one case, DOPL investigated a physician and filed a petition alleging sexual misconduct, which the doctor denied. Four years later, DOPL dismissed its petition “with prejudice” — it can’t be resurrected later — and no disciplinary action was taken. But the documents that provided these details are still available from DOPL, a fact that stuns the physician, who thought they’d disappeared along with the charges.

A patient who stumbles onto the document, as the Deseret Morning News did, has no way of assessing its merit. Should the doctor have been disciplined? Should the file have been destroyed? And why did it take four years, from the time DOPL first filed the petition against the doctor, until it was dismissed?

DOPL declined to talk about the case.

As Dr. Charles Walton, head of the DOPL drug diversion program says, “It’s hard to know, literally, what goes on behind closed doors.”

He’s talking about doctors who do drugs when nobody is looking, who write prescriptions and then steal some of the pills back, who try to keep their addictions a secret from patients and colleagues. But there are other doors, too: behind them sit investigators and lawyers, hospital administrators and insurance company executives — all trying to balance the needs of patients with the needs of the health-care system and the livelihoods of all concerned.

On the other side of those doors sit the patients, both trustful and litigious, grateful and a little wary.

“I’m not sure patients shop that well,” says PLB president Sperry. “I’m not sure they’re great judges of quality, so unless there’s a disaster, I think they pick somebody and ride out the storm.”

Dr. Michael Crookston, psychiatrist and medical director of LDS Hospital’s Dayspring program, emphasizes the point with a tale of two doctors. One, a gifted doctor technically, puts off patients with a lousy bedside manner. Another, “one of the worst doctors I’ve seen,” is well-loved by patients because he prays with them.

There are many things about their doctors that patients do not and cannot know. But patients aren’t entirely powerless. They can ask their doctors questions: Do you have current board certification? How many surgeries like mine did you do last year? What’s your success rate? Have you been in treatment for drug or alcohol abuse? Attorney Carney says, on that last one, not to be surprised if an outraged doctor kicks you out of his office.

Patients can ask if a doctor is properly trained to do the procedure. Where did the doctor learn to do varicose vein surgery? Will there be a nurse anesthetist present? If the dentist does orthodontics, where was he trained? Does he have board certification or did he just take a weekend course?

Toupta Boguena didn’t think to ask whether the person who did her laser surgery in the summer of 2001 was qualified. The native of Chad, then a BYU student, wanted to look good for a wedding, so she called the number on an advertising coupon. It turned out that although a doctor ran the stand-alone laser clinic, he delegated operation of the laser to one of his staff who was not formally trained, and the laser itself wasn’t recommended on people with dark skin. Boguena ended up with second-degree burns that disfigured her for months. She sued and won. Checking with DOPL would have made no difference. The physician has never been disciplined.

Patients can ask friends to recommend doctors they trust. And they can complain to the state if they believe a doctor poses a danger. When Janet Brown felt like her father’s surgeon seriously botched what should have been a routine hernia surgery, the family talked seriously about suing. They complained to the hospital through an attorney, and they collected horror stories from the nursing staff about the doctor. It never occurred to any of them, she said, to call DOPL. According to DOPL’s Web site, the doctor has never been disciplined.

“When all is said and done,” says Carney, “the only real way to learn about who the bad and good doctors are is to be a doctor — or a trial lawyer. They, and no one else, know which closets have the skeletons. But the average patient is wandering in the dark without a lamp when it comes to choosing a physician.”

Thankfully, he says, most of the time it doesn’t matter. “The great majority of our doctors are well-trained and good, caring people doing their best, day in and day out. There are obviously those few who are not; a patient must just hope that she doesn’t meet one.”

Monday: Second chances for doctors in trouble

E-mail: [email protected]; [email protected]

The only thing I knew about Poison Ivy, other than her rivalry with Batman, was that old rule of thumb: “Leaves of three, let it be.”

But in the brush-filled back lot we wanted to clear for a new swing set, it seemed everything came in threes – maples, oaks, gum trees, clover.

Then again, haven’t a lot of those rhyming rules been debunked? For instance, “Red wine in the morning, sailors take warning” and “Whiskey at night, sailor’s delight.” I’ve tested them out, and they’re just old wive’s tales.

So even though a neighbor cautioned us about the triple threat of poison ivy, oak and sumac, my husband and I put on some garden gloves and plunged in.

And other than squabbling over the proper assembly of the swing set by Flexible Flyer, which prints instructions exclusively in Aramaic, everything went fine. That is, until 48 hours later, when my husband’s forearms broke out in an itchy rash that quickly spread and began to ooze.

Now, I wouldn’t be the first neutral observer to wonder aloud whether men possess any threshold whatsoever for enduring discomfort. Or if, in fact, they experience the common sore throat, back ache or allergic rash the way others experience childbirth.

But that’s a story for another day. A day my husband is out of town. Suffice it to say, he was in enough distress from the poison ivy that friends, customers and even strangers who passed him in the street started offering him home remedies they swore would cure the rash, as if by magic.

My favorites, I think, were horse urine, supposedly a natural solvent to wash away the poison “urushoil,” and white shoe polish, which he was told contains a caking pipe clay similar to the drying agent in calamine. Because, as we know, calamine lotion is so expensive and hard to find.

But the sheer breadth of these folk cures – and the bizarre variety – has led me to two possible theories about the origins of home remedies.

The first, I call the “Drunken Hunting Trip Theory.” When a calamity occurs under fully anesthetized, but otherwise less than ideal circumstances, people improvise primitive first aid with the materials at hand.

Thus, the fellow who advised my husband to cauterize the rash by pouring gasoline on it and then lighting it on fire with a “poof,” being careful not to let the flame burn out of control. (As an analgesic, the same man recommended Texas Pete, which is also good in Bloody Marys.)

On the other hand, the “Drunken Hunting Trip” scenario might not explain the horse urine folk remedy, or another favorite of mine, treating poison ivy with meat tenderizer.

This leads to my second and more likely theory, the “Big Fat Greek Wedding Theory,” in honor of Michael Constantine’s Gus Portoka los, who sprayed Windex to cure everything from warts to rheumatism.

Here’s how this theory works:

1) Patient tests out home remedy because he happens to have it handy (e.g., baking soda, witch hazel, etc.) and it’s “just common sense” that it must work for something;

2) Home remedy neither kills patient nor lands him in the ER;

3) Ailment eventually goes away;

4) Patient concludes that home remedy did the trick and begins recommending this free miracle cure to others, who repeat the process.

There, in a nutshell, is the definition of “homeopathic” medicine – homeopathic being the fear, prevalent in men, that to seek a pharmacist’s advice in general, and to apply that pink calamine lotion in particular, is a humiliating and unmanly admission of defeat.

And rather than wear that badge of cowardice – or use Benadryl, Tecnu or the other shelf full of proven remedies – my husband has prolonged his agony with everything in the pantry.

Foaming peroxide made him grimace, the way Patrick Swayze did when stitching up his own knife wound in “Roadhouse.” More soothing was an oatmeal bath, but he slipped in the tub. Somebody suggested egg whites left to dry and form a crust, but the neighborhood cats followed him around. He’s now tried salt, lemon juice, even tequila.

Isn’t there a rhyme about that? Tequila at dawn, sailors be warned…

Contact Lorraine Ahearn at 373-7334 or [email protected] {SEND} YES

Binding gold nanoparticles to a specific antibody for cancer cells could make cancer detection much easier, say medical researchers from the University of California, San Francisco and Georgia Institute of Technology.

The researchers are a father and son, working together on opposite coasts. Their study findings are reported in a recent edition (May 11) of the journal Nano Letters, published by the American Chemical Society.

Principal author is Ivan El-Sayed, MD, assistant professor of otolaryngology at UCSF Medical Center, who conducted the study with his father, Mostafa El-Sayed, PhD, director of the Laser Dynamics Laboratory and chemistry professor at Georgia Tech.

“Gold nanoparticles are very good at scattering and absorbing light,” said Mostafa. “We wanted to see if we could harness that scattering property in a living cell to make cancer detection easier. So far, the results are extremely promising.”

Many cancer cells have a protein, known as epidermal growth factor receptor (EFGR), all over their surface, while healthy cells typically do not express the protein as strongly. By conjugating, or binding, the gold nanoparticles to an antibody for EFGR, suitably named anti-EFGR, the researchers were able to get the nanoparticles to attach themselves to the cancer cells.

“After we added the nanoparticle-bound antibody to cells, using a simple technique known as darkfield microscopy, we saw the cancer cells light up under the microscope,” said Ivan. “The healthy cells don’t bind the particles well and are dark compared to the cancer. Since the particles have color, we can test multiple antibodies at the same time with a white light. Using simple optics, we can develop low cost techniques for rapid automated detection of cancer in biopsies. Further, we hope to use the scattering and absorption properties to develop techniques to detect cancer in humans without a biopsy.”

In the study, the research team found that the gold nanoparticles have 600 percent greater affinity for cancer cells than for noncancerous cells. The researchers tested their technique using cell cultures of two different types of oral cancer and one nonmalignant cell line. They found two features of the particles to be useful for cancer detection. First, with a microscope, they could see the cells shining. Second, they could measure changes in the amount of light absorbed by the particle as the antibody bound to its target.

According to Ivan, the changes in absorption may be particularly useful in cancer and cell research to measure molecules interacting inside living cells. The change in the absorption spectrum of the gold nanoparticles is also found to distinguish between cancer cells and noncancerous cells. Since nanoparticles of different shapes and sizes absorb and scatter light differently, multiple color probes can be made which may detect many molecules at the same time.

What makes this technique so promising, the researchers explained, is that it doesn’t require expensive high-powered microscopes or lasers to view the results, as other techniques require. All it takes is a relatively simple, inexpensive microscope and white light.

Another benefit is that the results are instantaneous. “If you take cells from a cancer stricken tissue and spray them with these gold nanoparticles that have this antibody, you can see the results immediately. The scattering is so strong that you can detect a single particle,” said Mostafa.

Finally, the technique isn’t toxic to human cells. A similar technique using artificial atoms known as quantum dots uses semiconductor crystals to mark cancer cells, but the semiconductor material is potentially toxic to the cells and humans.

“The wonderful thing about colloidal gold is that it has been used in humans for 50 years,” Ivan said. “For example, a radioactive form of it has been used to search for cancer and we know how it is handled by the body.”

“This technique is very simple and inexpensive to use,” said Ivan. “We think it holds great promise in making cancer detection in humans and under the microscope easier, faster and less expensive.”

While the technique is not ready to be used in patients, Ivan said it holds much promise for oral cancer patients he treats in his practice at UCSF Medical Center. “Oral cancer is deadly and tends to recur. Our best chance to save lives is to catch it early, and this method might allow that.” He added that this technique could be used to detect a number of cancers, including stomach, colon and skin cancers.

“Our findings also have strong implications for this technique’s value to cancer research,” Ivan added. “By watching the particle change colors in living cells we can identify molecular interactions within the cells. This may help us unravel the inner workings of a cancer cell and produce better treatments. The fact that we can see one particle is exciting.”

On the Net:

University of California – San Francisco

WHEN it comes to growing old gracefully, few could argue that French women do it with a certain je ne sais quoi. So the latest anti-ageing beauty supplement from France has caused something of a stir. Inversion Femme is a supplement which claims to improve skin, hair, nails and figure. But does it work? We asked five writers to try a six-week course and report back.

. .

CLAUDIA CONNELL, 38, is single and lives in Balham, South-West London.

EVERY morning for the past six weeks I have been starting the day in much the same way: a gentle stretch, a bowl of cereal – oh, and 100mcg of something that includes shark cartilage. Cartilage de raquin (to give it the correct label) is one of the baffling list of ingredients contained in the Inversion Femme capsules which claims to improve your skin, hair and nails and, over time, lead to weight loss.

The inclusion of a bit of shark gristle didn’t put me off – like most women I’d eat barbed wire if I thought it would knock a few years and pounds off me. When it comes to handing over my hard- earned cash for ‘miracle’ products I am the biggest mug going. I once spent a small fortune on a mail order cellulite cream that claimed to contain a ‘patented, fat-eating enzyme’. It stuck to my thighs and buttocks like chewing gum and I spent two days trying to scrape it off with a spatula.

So, every day I washed down my two red and silver Inversion Femme capsules with a large glass of water and a healthy dose of cynicism.

As a committed sceptic I was almost disappointed when, after just two weeks, I had to admit that something was happening.

I’ve always had a clear complexion but it seemed to take on a youthful glow that has been missing for most of my 30s.

Several people told me I looked well and a couple asked if I had been away. One friend even accused me of having Botox.

By coincidence, I had my highlights redone the day I started to take the capsules. As I am naturally fair and my hair grows slowly I usually leave it about ten weeks before having my roots retouched.

But after six weeks of taking the pills I had an inch and a half of regrowth and had to book another appointment. My hair, which I usually cut only twice a year, has been growing like a weed.

However, the most noticeable change has been in my new ‘Footballers’ Wives’ nails, which appear to have become diamond hard and unbreakable.

When I am not typing on my laptop I am usually scrubbing and cleaning and, consequently, my nails usually reach optimum length and break every two weeks. But for the first time in living memory I am having to cut them because they are getting too long.

The makers claim that after two months on the pills many women start to notice they have a slimmer silhouette.

Well, so far my weight and shape remain unchanged but should the pounds start dropping off then I really will be writing to the Vatican and insisting they officially declare Inversion Femme a modern-day miracle.

ANNA PASTERNAK, 37, lives in Oxfordshire with her fiance, Martin, a chartered surveyor, and their 18-month-old daughter, Daisy.

FOR me, the Holy Grail of beauty is flawless skin. My complexion quest has seen me boiling Chinese bark and drinking the foul residue or washing my face in May dew.

There is no fad, no miracle cure I don’t buy into. So when I was offered a course of Inversion Femme, I was as elated as if I had been given a phial of the elixir of life.

Pills that would put a spring in my step, inject some natural vitality into my skin, strengthen my nails and hair, while smoothing my wrinkles and my waistline, sounded – almost – too good to be true. Call me gullible, but I couldn’t wait to fling these best- selling Gallic capsules down my throat.

For the first few days, I took the morning queasiness, the low- lying headache and the never-ending need to go to the loo, as a welcome price to pay for youthful zest.

When I had a terrible outbreak of spots, I put it down to the detoxing effects and looked on the bright side hey, at least I had the skin of a teenager, even if I didn’t feel like one yet.

Two spotty weeks and an overdose of Evian later, the joke was over. I had envisaged a dewy glow, not an adolescent spot-fest. I wish I could tell you that at least my sausage roll of postbaby tummy flab was shrinking or that I couldn’t believe my soaring energy levels, but I can’t.

By week four, my hair, nails and figure looked exactly the same and in spite of immune-boosting borage oil and cholesterol-lowering chromium in my daily doses of goodness, I felt and looked the same; washed-out as ever.

Usually a blind believer who could take a placebo and convince myself of the benefits, I became suspicious. So I did a controlled experiment and stopped taking the pills for a few days. I swear I felt better. My spots subsided and I felt more my old, if tired, self.

Back on the pills, my skin rebelled again. Disappointed, I ditched Inversion Femme and shirked the last two weeks of my journalistic responsibilities. At least I have woken up to one fact: beauty really does come from within; not from a packet of supplements which, as far as I’m concerned, were a con and which, finally, turned me into a cynic.

LOWRI TURNER, 40, is single and lives in North London with her two sons, Griffin, four, and Merlin, two.

WE’RE used to being sold the notion of youth in a jar, but youth in a pill? Just like those incredibly expensive lotions and potions that promise to take ten years off you – just so long as you massage them in on the hour, every hour, in small circular motions standing on your head with the wind in an easterly direction.

So the claims made by Inversion Femme were ones I took with a handful of salt. Isn’t this just another way to get silly women to part with hard-earned cash, I thought.

However, I decided to put my cynicism aside and give them a try. I could certainly do with some help. I suffer from dry skin and occasional eczema, conditions that have become more marked since I had children.

I know I should be dabbing myself with organic tea tree oil and putting muslin bags (home-made, of course) full of oats under a running tap in the bath. I am well aware that I should be munching on sprouted seeds and sipping aloe vera juice, but who has the time? Only Bridget Jones types can manage things such as daily body brushing. The only brushing I do is with a dustpan, trying to scrape up corn flakes off the carpet.

So, a pill seemed ideal. Quick and easy. I will admit I didn’t always remember to take it, or rather them.

You are supposed to swallow three a day, two red ones in the morning and a silver one at night.

Plus, they are rather large, not quite horse pill-sized, but slightly daunting to swallow. On the occasions I did forget, I would have to shovel a handful down in one go to try to catch up, which I know isn’t quite the recommended method.

But, hey, a girl’s gotta do what a girl’s gotta do.

After six weeks on the pills, the results were cautiously positive. I won’t say that I have developed the body of a sylph, but I do think my complexion has improved. It seems smoother and more even-toned.

As for my hair, I don’t see any change. It has yet to turn into the sort of lustrous mane you see on shampoo ads, but then maybe that’s asking a bit much.

My coiffure is so bleached, without half a ton of conditioner Ainsley Harriott could scour pans with it.

We’re talking a handful of pills here, girls, not a magic lamp and genie.

DIANA APPLEYARD, 43, is married to television journalist Ross, 43, and the couple have two children, Beth, 17, and Charlotte, 11.

The family live in Oxfordshire.

AGE has crept up on me in my 40s in all kinds of sneaky, underhand ways.

No longer can I starve myself for a week and drop half a stone. The fat that used to fall away when I stopped eating biscuits and chocolate is somehow a lot less moveable – it is determined to cling on.

Those lines around my eyes which seemed barely noticeable in my 30s have suddenly become far more pronounced. My skin is dry and flaky in patches. My nails have started to develop calcium spots, and are far more brittle than they were.

In short, I appear to have begun the long, slow process of drying up and crumbling away. At this rate, I may soon resemble a walnut.

When I started taking the pills my two lovely daughters said: ‘Please, not more useless pills that will make no difference whatsoever.’ I have a shelf full of things such as red clover pills, which I take with great enthusiasm for a week and then get bored and stop. If I’m not Claudia Schiffer by week two, then they’re useless. But I was determined to stick with Inversion Femme.

The first thing I noticed was that within two weeks my nails were noticeably stronger. The white patches had disappeared, and they were less inclined to break. My hair, always rather straw-like, appeared to be more glossy and thick. My skin seemed less dry, and the lines under my eyes definitely less pronounced.

Eye bags, which are the bane of my life, seemed less puffy. I decided to combine taking the pills with a radical improvement in my diet – ie, less chocolate, white bread and ice cream, fewer biscuits – and I stepped up my exercise programme.

I have lost about half a stone in weight, but I don’t know if that is the pills or the fact that I am not pigging out on organic shortbread with every coffee break. I have noticed that I have more energy – the pills contain Vitamin B which is supposed to be good for energy release.

I feel generally more ‘zingy’ and like any normal woman I have celebrated this new ‘feelgood’ factor by rushing out and buying new clothes.

It may be spring, it may be lack of sugar, it may be red and grey pills which look more like suppositories but I definitely feel younger. As long as I don’t stand too close to my 17-year-old daughter, of course.

BEL MOONEY, 58, is the author of more than 25 books and the mother of two grownup children.

She lives in Bath.

IT FEELS rather unfair that I have reached the point of reviewing the Inversion Femme supplement when I am recovering from a rotten cold and feel significantly under par.

But then, the manufacturers don’t promise health, just a ‘beauty insurance’ for skin, hair, nails and waistline.

The idea of beauty in a tablet is less appealing to me than in a pot, simply because I always forget to take supplements, although this time my record was better than usual. And I detest swallowing fat pills, whereas stroking an unguent on your face is a pleasure.

I can’t honestly say I’ve noticed a huge difference in my appearance, though I’m aware that exercise would help. The trouble is that my idea of exertion is to take a dog around the block. Not good.

But, to take each of the claims in turn, I take very good care of my skin each day, and so wouldn’t expect to notice much difference.

Like most women I resist the encroachments of age, but am too sensible to think wrinkles can be got rid of by swallowing a pile of trace elements.

Coming to the claims for hair and nails I think there is a slight difference.

Like many women my age who once rejoiced in ‘big hair’, I’m plagued by its gradual loss, and just lately it has been looking a lot thicker. But that could be because I was put on to the latest cutting-edge products by a nice lady in Space NK.

In fairness, it will probably be a combination of the two. Similarly my horrible, stubby, flaking nails seem somewhat stronger so that they even merit a coat of colourless varnish.

But my waistline is the same.

I will say this – off and on for years now I have tried to make myself take a pile of supplements, and always end up with a basket of bottles rapidly approaching their sell-by dates, simply because I get bored.

So to pop three pills a day, though a hard habit for me to get into, isn’t that bad, and I’m willing to believe it does good. After all, what harm can it do?

Although apparently uncommon, fungal contamination of saline-filled breast implants is readily preventable, according to a study in the July 1 issue of The Journal of Infectious Diseases, now available online. The key steps are to use closed systems for filling the devices and to adhere to the strict moisture control and operating room ventilation standards in force at major hospitals. The potential benefits of these precautions could be considerable, since 265,832 women in the United States underwent cosmetic or reconstructive breast surgery in 2000 alone, and most received saline-filled implants. Moreover, increasing numbers of non-surgeons are performing cosmetic breast surgery in outpatient clinics, ambulatory surgery centers, or physician offices, where the risk of complications is especially likely without precautions. This study is a case in point.

The investigators, Marion A. Kainer, MBBS, MPH, and coworkers at the Centers for Disease Control and Prevention studied an outbreak in 2000-2001 that involved five women whose implants were found to contain black sediment during revision surgery for cosmetic breast augmentation; the sediment was subsequently identified as Curvularia, a fungus commonly found in soil. All women had been treated in 2000 at an ambulatory surgical facility, where an initial in-house investigation failed to find a source of contamination.

Dr. Kainer and colleagues conducted an extensive investigation to identify factors contributing to the outbreak. They found that sterile saline used to fill the implants was stored directly under a portion of ceiling sheetrock that had been water-damaged a few years before and was still moist. The investigators isolated Curvularia from an air sample taken from the supply room. They also discovered that air was flowing into the operating room associated with the contamination, rather than out of it as infection control guidelines stipulate. Furthermore, sterile saline was poured into a bowl in the operating room before the patient arrived and left exposed to the air until it was drawn into a syringe and injected into the implants.

The investigators concluded that “ambulatory or outpatient surgical centers need to: (1) follow hospital recommendations for regular maintenance of HVAC systems and balancing of airflow in operating rooms; (2) follow infection control guidelines; and (3) include infection control staff in all stages of planning, construction, or renovation of healthcare facilities and HVAC systems.” They recommended as well that operating rooms be maintained at positive airflow pressure and that surgeons should always use closed systems to fill breast implants.

On the Net:

Infectious Diseases Society of America

PULLMAN, Wash. – A disease you are suffering today could be a result of your great-grandmother being exposed to an environmental toxin during pregnancy.

Researchers at Washington State University reached that remarkable conclusion after finding that environmental toxins can alter the activity of an animal’s genes in a way that is transmitted through at least four generations after the exposure. Their discovery suggests that toxins may play a role in heritable diseases that were previously thought to be caused solely by genetic mutations. It also hints at a role for environmental impacts during evolution.

“It’s a new way to think about disease,” said Michael K. Skinner, director of the Center for Reproductive Biology. “We believe this phenomenon will be widespread and be a major factor in understanding how disease develops.”

The work is reported in the June 3 issue of Science Magazine.

Skinner and a team of WSU researchers exposed pregnant rats to environmental toxins during the period that the sex of their offspring was being determined. The compounds ““ vinclozolin, a fungicide commonly used in vineyards, and methoxychlor, a pesticide that replaced DDT ““ are known as endocrine disruptors, synthetic chemicals that interfere with the normal functioning of reproductive hormones.

Skinner’s group used higher levels of the toxins than are normally present in the environment, but their study raises concerns about the long-term impacts of such toxins on human and animal health. Further work will be needed to determine whether lower levels have similar effects.

Pregnant rats that were exposed to the endocrine disruptors produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however, and when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems. The effect persisted through all generations tested, with more than 90 percent of the male offspring in each generation affected. While the impact on the first generation was not a surprise, the transgenerational impact was unexpected.

Scientists have long understood that genetic changes persist through generations, usually declining in frequency as the mutated form of a gene gets passed to some but not all of an animal’s offspring. The current study shows the potential impact of so-called epigenetic changes.

Epigenetic inheritance refers to the transmission from parent to offspring of biological information that is not encoded in the DNA sequence. Instead, the information stems from small chemicals, such as methyl groups, that become attached to the DNA. In epigenetic transmission, the DNA sequences ““ the genes ““ remain the same, but the chemical modifications change the way the genes work. Epigenetic changes have been observed before, but they have not been seen to pass to later generations.

While this research focused on the impact of these changes on male reproduction, the results suggested that environmental influences could have multigenerational impacts on heritable diseases. According to Skinner, epigenetic changes might play a role in diseases such as breast cancer and prostate disease, whose frequency is increasing faster than would be expected if they were the result of genetic mutations alone.

The finding that an environmental toxin can permanently reprogram a heritable trait also may alter our concept of evolutionary biology. Traditional evolutionary theory maintains that the environment is primarily a backdrop on which selection takes place, and that differences between individuals arise from random mutations in the DNA. The work by Skinner and his group raises the possibility that environmental factors may play a much larger role in evolution than has been realized before. This research was supported in part by a grant to Skinner from the U.S. Environmental Protection Agency’s STAR Program.

On the Net:

Washington State University

Children living close to high voltage overhead power lines at birth may be at an increased risk of leukaemia, finds a large study in this week’s BMJ.

But the authors emphasise that these results may be due to chance and further research is needed to find out whether there really is a link.

The authors will present their full findings at an embargoed press briefing on Thursday 2 June 2005 at 11.00am, BMA House, London, UK.

About one child in 2000 develops leukaemia before the age of 15 years.

Although we don’t yet understand its causes, researchers have studied a variety of possible explanations including genetic susceptibility, ionising radiation, unusual patterns of exposure to infection, and electromagnetic fields.

The electric power system produces extremely low frequency electric and magnetic fields, and since 1979 there has been concern that these fields may be associated with cancer. In 2001, the International Agency for Research on Cancer classified extremely low frequency magnetic fields as “possibly carcinogenic” while others, such as the UK Childhood Cancer Study, dispute the risk.

Over 29,000 children with cancer, including 9,700 with leukaemia, were included in the study, the largest of its kind to date. The children were aged 0-14 years and were born in England and Wales between 1962 and 1995. They were compared with a group of control children individually matched for sex, approximate date of birth, and birth registration district. The distance of each child’s home address at birth from the nearest high voltage power line was calculated.

Children who lived within 200m of high voltage power lines at birth appeared to have a 70% raised risk of leukaemia compared with those who lived beyond 600m. There was also a slightly increased risk for those living 200-600m from the lines at birth.

To put these risks into perspective, about five of the 400-420 cases of childhood leukaemia that occur annually in England and Wales may be associated with power lines.

No excess risk was found for other childhood cancers.

The finding that the increased leukaemia risk extends so far from the line is surprising in view of the low average level of exposure to magnetic fields at these distances, say the authors. There is no accepted biological mechanism to explain these results; indeed, the relation may be due to chance or some other factor associated with living near power lines.

In an accompanying editorial, Heather Dickinson from the University of Newcastle upon Tyne agrees that, even if the effect is causal, it could account for only a tiny proportion of cases.

She says, “Magnetic fields from power lines are very weak ““ only about 1% of the earth’s magnetic field which affects all of us all the time ““ so it would be surprising if they caused leukaemia. The increased risk closer to power lines may reflect some other factor that varies geographically.” The study didn’t measure the magnetic field from either the power lines or other sources.

“We don’t yet fully understand the aetiology of childhood leukaemia,” she says. “Nevertheless, we are now reasonably sure that it often involves damage to DNA before birth, and an unusual pattern of exposure to infections after birth.

Further insights into the causes of childhood leukaemia will almost certainly come through advancing technology helping us understand the molecular events which drive leukaemic changes,” she concludes.

British Medical Journal

D. Douglas Thomas had a problem trying to schedule a pingpong tournament a few years ago.

There was no place to have it in Naperville.

So his group, which was part of the park district’s New Horizons seniors program, went to Wheaton instead.

“I was upset,” Thomas says. “We had to go out of town because we didn’t have the facilities.”

As Naperville’s population continues to grow, so does the need for indoor recreation space, park leaders say.

They expect a recreation master plan the district is compiling – which should be done by the end of the year – to confirm a belief that Naperville is land-rich but facilities-poor when it comes to recreation.

The plan, park leaders say, will tell them what most residents want and provide a road map for future programs and facilities.

They haven’t talked specifics, but park users already have thrown out ideas, including building a central sports facility with amenities such as an indoor swimming pool, fitness center and basketball and volleyball courts.

“We’re a very large suburb, a very wealthy suburb, and we have nothing,” resident Jerry Stoeckigt said at a recent park forum. “Naperville is really behind the ball when it comes to a central sports core facility.”

Land-rich

Naperville Park District’s focus in past decades has been on acquiring – instead of developing – land, officials say.

The district maintains more than 155 parks and facilities, including Centennial Beach and two golf courses, totaling more than 2,500 acres.

Its priority on acquiring space while it was still available, even during periods of tremendous growth, made it one of the best communities in the state when it came to planning for the future, said Ted Flickinger, president of the Illinois Association of Park Districts.

Now it needs to catch up on developing that land, he said.

In a town known for setting trends, a perceived shortage of indoor space for park activities baffles many, especially as state- of-the-art recreation centers have popped up in Aurora, Elgin, Glenview and elsewhere.

Dawn Summers, who lives on the city’s southwest side, said her old hometown of Palatine, with about 67,000 residents, has more indoor amenities than Naperville – a town of 138,000.

“Other municipalities with less median income have more indoor facilities,” Thomas said. “I say, ‘Why?'”

Facilities-poor

Naperville Park District has no indoor swimming pool. It has no indoor track, no indoor basketball or volleyball or tennis or racquetball courts. It has no fitness center or theater or dance studio.

It doesn’t even have its own community center. The district leases the downtown Alfred Rubin Riverwalk Community Center – home to senior, early childhood and dance activities – from the city.

The largest recreation center it does own is The Barn, an 11,000- square-foot facility whose main room is 2,700 square feet – smaller than many Naperville homes.

The facility, in Knoch Park on Martin Avenue at West Street, contains three classrooms and the main room and obviously is limited in what it can provide, Recreation Superintendent Brad Wilson said.

As a result, the district relies heavily on school partnerships, using their gyms and facilities for rapidly growing dance, art and swimming programs.

“Naperville has done a wonderful job of cooperating with the schools,” Flickinger said. “But the schools are even running out of space.”

Southern growth

A need for more indoor space is nothing new. But until now, residents haven’t been willing to pay for it.

In 1999, voters overwhelmingly rejected a proposed $48 million park district tax increase that would have funded, among other things, an indoor recreation center with a 50-meter pool.

The need only has grown since then, supporters say, particularly on the city’s burgeoning southwest side.

In this year alone, the park district will build a maintenance garage and two park support buildings in the area – none of which will provide any recreational opportunities.

“We’d love to establish more of a presence in south Naperville,” Wilson said.

That’s no secret. For years, city and park leaders have envisioned a central location near Route 59 and 95th Street that combines the Frontier Sports Complex, 95th Street Library, Neuqua Valley High School and, someday, a community center.

“Both the city and the park district have very much wanted to see a campus concept take place,” park board President Pam Swafford said. “That’s why it’s natural for us to look toward that location.”

And one facility might not be enough.

“My guess is that (the master plan is) going to indicate we’ll need more indoor space than what one building can provide,” Swafford said.

At this point, any facilities would be welcome by many southwest- side residents, Summers said.

Summers, who lives in the Tall Grass subdivision, said she’d love to sign up for preschool classes.

“But it’s hard to justify driving 40 minutes round trip (to downtown) for a 25-minute class,” she said.

Although the Heritage YMCA Group’s 95th Street Family Center is nearby, it’s often crowded and many residents don’t want to buy full one-year memberships, she said.

Possibilities

Suggestions vary on what amenities the district could and should provide. Some residents are pushing for gyms, meeting spaces, a banquet facility or a fitness center.

Former park Commissioner Mary Lou Wehrli tosses some other suggestions into the mix: kitchen facilities, a production studio, a sports and performance auditorium, a parking deck, an art gallery and areas for gymnastics, day care, teens and seniors.

Others say the city’s most pressing need is for an indoor aquatic center.

Most city subdivisions built in the past 20 years offer an outdoor pool, which has cultivated a passion for swimming in many children, says Nina Menis, Naperville Unit District 203’s director of community relations.

But in winter, the number of swimmers drops sharply, says Gerry Cassioppi, a longtime indoor swimming facility advocate.

“It’s clear to me from just doing preliminary research that this is not something you’re going to build and just hope people buy into it,” said Cassioppi, a District 203 school board member. “The demand is there.”

Naperville Central High School’s pool is open only to swimming clubs and Naperville North’s pool doesn’t meet guidelines to host competitions.

Central aquatics director Bill Salentine said he often receives calls from residents interested in open swim times. He said the city also could use an indoor competitive pool, as well as a zero- depth pool, or one that gradually deepens as you wade into it.

“And it would be booked for as much time as they allowed it to be,” he said.

Still, the park district’s last tax-increase request to build a pool failed. Community leaders say that doesn’t mean there wasn’t a need; it means the request wasn’t communicated well, the facility wasn’t centrally located and it was packaged as an all-or-nothing deal with other facilities and trails.

Models

Park leaders are studying recreation centers – both nearby and across the nation – that could serve as models for a possible project here.

While they have no specific ideas in mind, they say they want to be ready for the next step if the recreation master plan identifies a need for more space.

“We’re not trying to jump to any conclusions regarding any type of facility,” Wilson said.

There are several communities with top-notch recreation centers Naperville could look to.

Glenview Park District’s 165,000-square-foot Park Center boasts an indoor aquatic complex, fitness center, cultural arts wing, three- lane track, senior center, banquet room and cafe.

Schaumburg Park District’s one and only tax increase request in 1978 was to build its Community Recreation Center.

That 119,000-square-foot facility, which has been renovated twice, features a senior center, dance rooms, aerobics studio, fitness center, piano lab, gym and three indoor pools and water slides.

That’s just one of several recreation centers in the district, which has been honored for its facilities. But Director Jean Schlinkmann said the town of 75,000 still could use more recreation space.

Fox Valley Park District residents approved a referendum proposal – that didn’t increase taxes – to build Aurora’s Eola Community Center, which opened in 1993, said Tom Rowe, the facility manager at the time.

The 130,000-square-foot center, which contains a fitness club, track, dance studio, gym and a branch of the Aurora Public Library, attracts some Naperville residents who are unable to get into their own programs because of waits, Rowe said.

The district’s Vaughan Athletic Center, set to open in September on Aurora’s west side, will be even bigger – more than 220,000 square feet – and more expensive – $25 million.

That facility boasts a fitness center, aerobic and spinning rooms, three indoor pools, nine tennis courts, indoor track and multi-court field house.

The Centre of Elgin – a 185,000-square-foot recreation center owned by the city – features a field house, indoor courts, aquatics facility with two pools, a climbing tower and a banquet facility, among other things.

The $40 million center, built in 2002 and partly funded by casino taxes, was part of a downtown development project, Centre Manager Teena Mackey said.

Arlington Heights Park District features a satellite concept with five community centers.

It may be more costly than having one central building, but it’s what residents wanted, said Brian Huckstadt, parks and planning director.

“They wanted that small-town feel,” he said.

Uncertainties

Not everyone is convinced Naperville needs more recreation space.

Cassioppi said he’d hesitate to support anything more than an indoor aquatics facility.

“That’s where the demand in this community is,” he said. “To stretch it beyond that, you start running into additional costs and additional issues.”

An indoor facility with a fitness center, for example, could compete with the private sector, he said. That’s likely what soured support for the last proposal, he said.

Nicki Anderson, president of Reality Fitness and a former board member of the Naperville Area Chamber of Commerce, says an indoor recreation center is unnecessary.

“I don’t believe there’s a need,” she said. “Bike paths, nature walks, those are things I find of value. We have plenty of health clubs in the area.”

An even grayer area than who-supports-what is how one or any new facilities would be funded.

Options include partnering with private groups, courting corporate sponsorships, borrowing money and asking voters to increase property taxes.

It’s too early to talk specifics, park leaders say. The recreation master plan – partly based on resident input – will determine their next steps.

But however they proceed, leaders say any plans will reflect residents’ desires.

“We want to provide what the community is asking for,” Swafford said.

IT WAS three days before my sister’s wedding. She was getting married in Ireland and I was to be a bridesmaid. I was really excited as I prepared for it and made an appointment to have my bikini line waxed in my lunch break.

It was no big deal as I’d been having it done four times a year for several years at the same salon. I’d never had any reactions or problems.

Waxing always hurts a bit but this time it really hurt. The wax felt hotter than normal and the beauty therapist seemed to be having trouble removing it with the fabric strips. She kept going over and over the same area.

When she’d finished, I walked back to work. But the stinging was getting worse. By the time I reached the office, 10 minutes later, I was in agony. It felt like severe sunburn.

When I went to the loo to have a look there were two bright red strips of raw flesh on my bikini line. I was so shocked that I got one of my colleagues to take a look. She said I should go straight back to the salon to complain.

When I got there the manager didn’t take me very seriously, even after I showed her the evidence. She just offered me a refund and a bottle of body oil!

The pain was getting worse all the time. When I got back to work I asked our company lawyer for advice. He said I might actually be owed some damages for the pain and trauma. He helped me write a letter and told me to take photos and go to my doctor.

By the time I saw the GP the next morning, I couldn’t walk properly – I was bow-legged. I couldn’t bear to wear trousers or even knickers.

The GP examined me and said I had a serious burn. It wasn’t a heat burn but a chemical burn. He told me he couldn’t treat it because putting anything on a chemical burn can cause a reaction and make it worse. I was told to leave the area alone and let it heal. I wasn’t even able to wash myself.

The next day my boyfriend and I had to travel from our home in London to Ireland for the wedding by car. It was the longest and most painful journey of my life. I couldn’t bear the pain of sitting down. Nor could I sleep at night. I had to lie on my back with my legs apart.

I took strong painkillers to help me cope. Instead of being happy and excited about my sister’s wedding, all I could think about was how much pain I was in.

On the day itself, I put on my bridesmaid’s dress and, bow- legged and knickerless, walked down the aisle in agony.

The day after the wedding the burn began blistering. Then pus came out and it scabbed over. Within a week the pain eased, but now it was incredibly itchy. But, of course, I couldn’t scratch.

I was on a family holiday but I couldn’t even wear a bikin – sex was completely out of the question. It was two weeks before I could shower – until then I had to have sponge baths, like a hospital patient.

I felt so unattractive and my boyfriend said my bikini line looked really gross. He wasn’t mean about it, but he couldn’t pretend not to notice. The area was raw, then it cracked and I had dry, flaky skin for a couple of months. It wasn’t exactly a turn- on.

Once the scabs had gone I was left with a horrible, dark brown scar on each side. I went back to the GP and he couldn’t tell whether it would fade or be permanent. I worried that I would be disfigured for life.

I spoke to my lawyer again. The salon had sent an apology letter, but nothing else. He told me to write again, stressing the embarrassment and trauma of my experience. He said I should ask for pounds 1,500 compensation.

After a year of legal wrangling, the salon finally agreed to pay me pounds 1,000 in compensation. I was pleased to get the money but it didn’t make up for ruining my sister’s wedding for me.

Nobody ever found out what was wrong with the wax as it had been thrown away. But I do know that the therapist should not have kept going back over the same area of skin.

After a year my scar began to fade. Today, it’s no longer noticeable but the experience put me off having any type of hair removal for a long time.

Now I use cold wax strips at home and I would never have another hot wax treatment. It wasn’t worth all that pain and upset for vanity’s sake. Thank God I didn’t have a brazilian!

HOW TO HAVE A SAFE WAX

Follow these tip to ensure your next waxing session is as pain- free as possible.

Check out the salon. “Make sure the reception area looks clean and the staff are well-informed,” advises Kirsty Jobson, from Saks Beauty Salons. “If you’re worried about anything, don’t be embarrassed to just pick up a price guide and leave.”

Don’t have a sauna, hot bath or shower 24 hours before or after the treatment, as too much heat on sensitive areas can lead to soreness.

Make sure the hair to be waxed is at least a quarter of an inch long so the wax can grip it. But make sure it’s not too long – waxing long hair is more uncomfortable and can lead to tearing the skin.

Once in the treatment room, make sure the therapist gives you a full consultation. If you’ve never been there before it’s a good idea to have a patch test on a small area of skin, to see how it reacts.

Your therapist should explain the procedure so you know what clothes to take off, what to leave on, and feel comfortable.

She should test the wax for temperature on her wrist.

The therapist should always wash her hands before beginning and wear disposable gloves when waxing the bikini area, as blood spotting is common.

The therapist should use a new spatula, clean bed roll and new towel.

Your skin should be held taut. If it’s not, it can lead to bruising or even tearing of the skin.

Relax during the waxing procedure. When you’re tense, the follicle closes and the wax won’t reach the root of the hair.

Don’t wax when you’ve got your period as your skin is extra sensitive around this time.

DON’T SUFFER IN SILENCE

NOT all salon treatments are about pampering, but while “no pain, no gain” may be true when it comes to waxing, plucking or having your spots squeezed, there’s only so much you can put up with in the name of beauty.

“Therapists aren’t mind-readers, so it’s important to speak up if you feel uncomfortable at any point during a treatment,” says Janet Ginnings, facialist and body therapist to stars including Elle “The Body” Macpherson.

“A good therapist will ask you if everything’s okay and make you feel confident enough to speak out if something doesn’t feel right,” she adds.

So speak up if… Your eyes are stinging Wax feels too hot Massage strokes are so hard they make you flinch Blasts from your stylist’s hairdryer burn your scalp Spot extractions are too painful

York County swimmers may have to drive a little longer and dive a little deeper into their pockets to find refreshing cool water this summer. Several local public pools are no longer accepting members, and many of those that are have increased their fees.

The Lake Club in Spring Grove disbanded; the York Township Community Center pool was sold; and The Four Points by Sheraton in Manchester Township no longer accepts members due to liability concerns.

Spring Valley Pool of Red Lion general manager Gary Alcorn said operational costs like a possible chlorine surcharge, liability insurance increases and salary jumps are behind the $5 to $10 increase the pool has on its membership costs.

Another big culprit, he says, is the high gas price. The increase at the pump has trickled down to increasing the cost of chlorine, food and other supplies. But it does also have its benefits.

“If anything, the gas prices will cause people to think about staying close to home more, and it may make membership more appealing,” he said.

After two years of poor swimming weather, Alcorn said he hopes things will change. Last year, he said there were only two 90- degree days. The days also tended to start out cloudy and not clear until after noon, when many families already made plans.

“You do have much of that mentality of farmers maybe this will be a nice year,” Alcorn said. “We’re getting tired of rain and mold and algae growth.”

But after 35 years of riding the tide as the general manager of the pool, Alcorn said we’re due a sunny and hot summer.

“Get the sunblock out,” he said.

HANOVER Codorus State Park Pool

Open: 11 a.m. to 7 p.m. daily. Open May 28 to May 30; closed May 31 to June 3; open June 4-5; closed June 6-10; open June 11 to Aug. 21; closed Aug. 22-26; open Aug. 27-28; closed Aug. 29-Sept. 2; open Sept. 3-5; closed for season Sept. 6.

Membership fees: For Pennsylvania residents: $50 for individuals; $125 for a family of four, $25 for each additional child taller than 38 inches. For nonresidents: $75 for individuals; $180 for a family of four, $35 for each additional child taller than 38 inches. Daily rates for Pennsylvania residents: $4; after 4:30 p.m., $2; camper with a permit, $3; camper after 4:30 p.m., $1. Daily rates for nonresidents: $7; after 4:30 p.m., $2; camper with a permit, $3; camper with a permit after 4:30 p.m., $1. Children shorter than 38 inches are free.

Pool features: Holds 680,000 gallons of water and is about a quarter acre in size. Clover-leaf shaped with an island in the middle. Deepest part is 5 feet. Outside. Not heated. The park also has boat rentals, fishing on Lake Marburg, camping, picnic facilities, disc-golf course, hiking trails, bridle trails and an area for riding mountain bikes.

For details: Call 637-2816.

RED LION Copper Beech Golf and Swim

Open: 11 a.m. to 7 p.m. May 28.

Membership fees: $183.75 for a single, $341.25 for a couple, $446 for three and $577.50 for unlimited immediate family. Guest rate is $6.

Pool features: Sand beach area and a baby pool. Tiki Bar with alcoholic and nonalcoholic drinks. Can be reserved for private parties. Also a driving range.

For details: Call 244-8609.

Spring Valley Pool

Open: 11 a.m. to 8 p.m. Memorial Day weekend through Labor Day. The pool is open until 11 p.m. for occasional Friday night moonlight swims.

Membership fees: $210 for a single, $325 for a couple, $441 for a family. Guest rate is $7.

Pool features: Outside pool. Not heated. Fifty-by-100 feet with a 40-by-40 foot diving well. Baby pool with expanded kiddie play area. Lap lane. Diving tank with diving board. Snack bar. Playground. Volleyball, tennis and basketball courts and baseball field. Picnic pavilion with grill. Certified lifeguards. Swimming lessons available.

For details: Call 244-7912.

SPRINGETTSBURY TOWNSHIP Penn Oaks Swim Club : AWAITING DETAILS

Open:

Membership fees:

Pool features:

For details: Call 600-1682.

Pine Ridge Swim & Tennis Club

Open: 11 a.m. to 8 p.m. daily through Labor Day. Open until 10 p.m. on Fridays.

Membership fees: $175 for an individual, $270 for a family of two, $310 for three, $340 for four, $50 for each additional. $60 for 10 visits, $7 for the day. Seniors get a special half-price discount.

Pool features: Snack bar. Tennis and volleyball courts. Half- basketball court. Two water slides. High and low diving boards. Game room. Three covered pavilions. Grills with $5 charge for propane. Certified lifeguards.

For details: Call 755-9577.

WEST MANCHESTER TOWNSHIP Green Valley Swimming Pool and Batting Cages

Open: 11 a.m. to 8 p.m. daily, starting May 28. Moonlight swims until 10 p.m. Tuesday and Friday; DJ starts at 7 p.m.

Membership fees: $170 for an individual, $260 for two people, $315 for three, and $35 for each additional person; $90 for the first grandparents, $35 each additional grandparent. Kids under 2 are free. Guest rate is $7 or 10 passes for $60 in advance.

Pool features: Outdoor. Not heated. Eighty-by-150 feet, ranging in depth from 2 feet to 12 feet. Lap-shallow water pool with three lap lanes, 60-by-100 and 2.5 to 4 feet. There are three diving boards, two sliding boards, a baby pool and certified lifeguards. Green Valley also offers a snack bar, game room, tennis, volleyball and basketball courts, softball and soccer fields, and batting cages. Horseshoe pit. There is also a picnic area with 11 gas grills, 130 picnic tables and playground.

For details: Call 764-2037.

Lincolnway Pool Inc.

Open: Saturday before Memorial Day, noon to 8 p.m. daily. When school closes, 11 a.m. to 8 p.m. Moonlight swims every Wednesday from 7 to 10 p.m. for members and guests.

Membership fees: $150 for one person, $250 for two people, $300 for three people, $35 for each additional person in the family. First grandparent is $90 and $35 for each additional grandparent. Guest rate is $7 per person.

Pool features: Outdoor. Not heated. One-hundred-by-150 feet with a 140-foot water slide. Baby pool. Tennis, basketball and volleyball courts. Game room. Snack bar. Two picnic pavilions with several grills. Three diving boards. Certified lifeguards.

For details: Call 792-9639.

WINDSOR TOWNSHIP Wisehaven Swim & Tennis Club

Open: 10 a.m. to 8 p.m. daily, starting May 28.

Membership fees: $240 for husband and wife; first child 3 years and older, $80; second child 3 years and older, $75; each additional child 3 years and older, $55. Senior citizen rate for an individual is $155, and for a couple it is $195. Individual rate is $200. There is an initiation fee for new memberships, $100 for a couple, $65 for individuals. The guest rate is $7 per person for any one 3 years and older.

Pool features: Outside pool. Not heated. Holds 360,000 gallons of water. Open-air decks. Large pavilion. Picnic area with grills. Lap pool is 145,000 gallons of water. High and low diving boards. Water slide. Baby pool (16 to 18 inches in depth) that is separate with its own slide and kids’ playground. Tennis, basketball, sand and concrete volleyball courts. Playground. Snack bar. Video game room. Certified lifeguards.

For details: Call 755-4327 or visit http:// www.wisehavenpool.com.

YORK Farquhar Park Pool

Open: 11 a.m. to 7 p.m. Saturdays and Sundays, starting June 4. Open 4 to 7 p.m. weekdays through June 12. After June 12, the hours are 11 a.m. to 7 p.m. daily, weather permitting.

Membership fees: $65 for city residents ages 18 and older and/or YMCA members, $90 for nonresidents; $50 for city residents ages 5- 17 and/or YMCA members, $75 for nonresidents; free for city residents ages 4 and younger, $40 for nonresidents. Daily admission is $6 for all others.

Pool features: Outside. Not heated. Mushroom fountain. Interactive play structure. Pool has 1 million gallons of water and a 156-foot water slide. Picnic tables. Police security. Snack bar. Certified lifeguards. Swim lessons from the YMCA will be available.

For details: Call 843-7884, ext. 260.

Schelling: Ueber das Wesen der Menschlichen Freiheit (1809)

“Dies ist die allem endlichen Leben anklebende Traurigkeit, die aber nie zur Wirklichkeit kommt, sondern nur zur ewigen Freude der Ueberwindung dient. Daher der Schleier der Schwermut, der ber die ganze Natur ausgebreitet ist, die tiefe unzerstrliche Melancholic alles Lebens.”

“Nur in derPersnlichkeit ist Leben; und allePersnlichkeit ruht auf einem dunkeln Grunde, der allerdings auch Grund der Erkenntnis Sein mu.”

(“This is the sadness which adheres to all mortal life, a sadness, however, which never attains reality, but only serves the everlasting joy of overcoming. Whence the veil of depression, of heavy-heartedness which is spread out across the whole of nature, hence the profound, indestructible melancholy of all life.”

“Only in personality is there life; and all personality rests on a dark ground, which, however, must also be the ground of cognition.”)

Schelling, among others, attaches to human existence a fundamental, inescapable sadness. More particularly, this sadness provides the sombre ground on which consciousness and cognition are founded. This sombre ground must, indeed, be the basis of all perception, of every mental process. Thought is strictly inseparable from a “profound, indestructible melancholy.” Current cosmology provides an analogy to Schelling’s belief. It is that of “background noise,” of the elusive but inescapable cosmic wave-lengths which are the vestiges of the “Big Bang,” of the coming of being into being. In all thought, according to Schelling, this primal radiation and “dark matter” entail a sadness, a heaviness of heart (Schwermut) which is also creative. Human existence, the life of the intellect, signifies an experience of this melancholy and the vital capacity to overcome it. We are, as it were, created “saddened.” In this notion there is, almost undoubtedly, the “background noise” of the Biblical, of the causal relations between the illicit acquisition of knowledge, of analytic discrimination and the banishment of the human species from innocent felicity. A veil of sadness (tristitia) is cast over the passage, however positive, from homo to homo sapiens. Thought carries within itself a legacy of guilt.

The notes which follow are an attempt, wholly provisional, to understand these propositions, to grasp, tentatively, some of their implications. They are necessarily inadequate because of the spiral whereby any attempt to think about thinking is itself enmeshed in the process of thought, in its self-reference. The celebrated “I think, therefore I am” is finally an open-ended tautology. No one can stand outside it.

We do not really know (in Wirklichkeif) what “thought” is, what “thinking” consists of. When we try to think about thinking, the object of our inquiry is internalized and disseminated in the process. It is always both immediate and out of reach. Not even in the logic or delirium of dreams can we reach a vantage point outside thought, an Archimedean pivot from which to circumscribe or weigh its substance. Nothing, not the deepest probes of epistemology or neurophysiology, has taken us beyond Parmenides’ identification of thought with being. This axiom remains at once the wellspring and boundary of western philosophy.

We have evidence that processes of thought, of conceptual imaging, persist even during sleep. Some modes of thinking are totally resistant to any interruption whatever, as is breathing. We can, for short spells, hold our breath. It is by no means clear that we can be thoughtless. There are those who have labored to achieve this condition. Certain mystics, certain adepts of meditation have aimed at vacancy, at an entirely receptive because void state of awareness. They have aspired to inhabit nothingness. But such nothingness is itself a concept, charged with philosophical paradox and, where it is achieved by directed meditation and spiritual exercises, as in Loyola, emotionally replete. St. John of the Cross characterizes the suspension of mundane thought as brimful of the presence of God. A true cessation of the pulse-beat of thought, exactly like the cessation of our physiological pulse-beat, is death. For a time, a dead person’s hair and nails continue to grow. To the best of our understanding, there is no prolongation of thought however brief. Hence the suggestion, in part gnostic, that only God can detach Himself from His own thinking in a hiatus essential to the act of creation.

To revert to Schelling and the assertion that a necessary sadness, a veil of melancholy attaches to the very process of thought, to cognitive perception. Can we try and clarify some of the reasons? Are we entitled to ask why human thought should not be joy?

1.

So far as we are aware, so far as we can “think thinking”-I will come back to that awkward phrase-thought is limitless. We can think of and about anything. What lies outside or beyond thought is strictly unthinkable. This possibility, itself a mental demarcation, lies outside human existence. We have no evidence for it either way. It persists as a hidden category of religious and mystical conjecture. But it can also figure in scientific, cosmological speculations, in the concession that a “theory of everything” lies outside and beyond human understanding. Thus we can think/say: “this problem, this topic surpasses our cerebral potentialities either at present or for ever.” But within these ill-defined, always fluid and perhaps contingent confines, thought is without end, without any organic or formally prescriptive stopping point. It can suppose, i magine, assemble, play with (there is nothing more serious and, in certain regards enigmatic, than play) anything without knowing whether there is, whether there could be anything else. Thought can construe a multiplicity of universes with scientific laws and parameters wholly different from our own. Science-fiction generates such “alternatives.” A well-known logical conundrum postulates that our own universe is only a nanosecond old and that the sum of our memories is incised in the cortex at the moment of birth. Thought can theorize that time has a beginning or none (there is a despotic sophism in the ruling that it makes no sense to ask about the moment before the Big Bang). It can produce models of space-time as bounded or infinite, as expanding or contracting. The class of counterfactuals-of which “if clauses, optatives and subjunctives are the grammatical encoding-is incommensurable. We can deny, transmute, “unsay” the most obvious, the most solidly established. The scholastic doctrine whereby the one and only limitation on divine omnipotence is God’s inability to change the past is unconvincing. We can readily both think and say such change. Human memory performs the trick daily. Thought-experiments, of which poetry and scientific hypotheses are eminently representative, know no boundaries. That humble monosyllable “let” which precedes conjectures and demonstrations in pure mathematics, in formal logic, stands for the arbitrary license and unboundedness of thought, of though manipulating symbols as language manipulates words and syntax.

Human thought reflects on our own existence. We suspect, though we do not know for certain, that animals cannot do this, even where primates share some ninety percent of our genome. We can model, we can devise mathematical expressions for, the “heat-death” of our universe by virtue of the thermodynamics of entropy. Or, on the contrary, we can advance arguments for eternal life, forresurrection- an appalling thought-or cyclical mechanisms of “eternal return” (as in Nietzsche). Not only innumerable ordinary men and women, but the begetters of religions, metaphysicians such as Plato, and certain psychologists, such as Jung, have rejected the axiom of finality, of psychic zero after corporeal demise. Thought can roam at liberty across the entire gamut of possibilities. It can, even prior to Pythagoras, wager on the transmigrations of the human soul. There is, there can be no verifiable evidence either way.

The infinity of thought is a crucial marker, perhaps the crucial marker of human eminence, of the dignitas of men and women as Pascal memorably declared (“thinking reeds”). It distinguishes what is signally human in the human animal. It enables the grammars of our speech to articulate remembrance and futurity, though we pause only rarely to take in the logical fragility of the future tense. Thought entails man’s mastery over nature and, within certain restrictions such as infirmity and mental affliction, over his own being. It underwrites the radical freedom of suicide, of bringing thought to a voluntary, freely-timed halt. So why the inescapable sadness?

The infinity of thought is also an “incomplete infinity.” It is subject to an internal contradiction for which there can be no resolution. We shall never know how far thought reaches in respect of the sum of reality. We do not know whether what seems open-ended is not, in fact, absurdly narrow and beside the point. Who can tell us whether much of our rationality, analysis and organized perception are not made up of puerile fictions? For how long, to how many millions, was the earth flat? We are indeed able to cogitate and phrase “ultimate questions”-“how did the cosmos come into being;is there any purpose to our Ii ves; does God exist?” This impulse to questioning engenders human civilization, its sciences, its arts, its religions. But nothing identifies Marx more closely with enlightenment innocence than his affirmation that mankind only poses those questions to itself for which there will be an answer. It is the opposite which comes closer to the truth. It is “jesting Pilate.” On absolutely decisive fronts we arrive at no satisfactory, let alone conclusive answers however inspired, however consequent the process of thought, either individual or collective, either philosophical or scientific. This internal contradiction (aporia), this destined ambiguity is inherent in all acts of thought, in all conceptualizations and intuitions. Listen closely to the rush of thought and you will hear, at its inviolate centre, doubt and frustration.

This is a first motive for Scliwennut, for heaviness of heart.

2.

Thought is uncontrolled. Also during sleep and, presumably, unconsciousness the current flows. Only very rarely are we in control. The pulse of thought looks to be manifold and many- layered. It can originate at somatic and psycho-somatic depths far beyond the reach of introspection (thoughts can rise out of deep- buried pain or pleasure). It is, very possibly, a prelinguistic phenomenon, a thrust of psychic energies prior to any executive articulation. But trapped in the great prison-house of language we arrive at no plausible, let alone “translatable” notion of what unspoken, unspeakable thinking could be like (does the deaf-mute come any closer?). It is just conceivable that the unspoken meaningfulness of music, so obviously somatic in some of its key components, provides some analogy. The levels which depth- psychology, such as psychoanalysis or hypnosis, identify as sub- conscious, let alone unconscious, are, so far as they surface in words, images, dreams or symbolic representations, superficial. They fall far short of the crust in the geophysics of the human psyche. And even at the surface, there is only intermittent control.

At each and every moment, acts of thought are subject to intrusion. A limitless congeries of external and internal elements will interrupt, deflect, alter, muddle any linear deployment of thought (Dante’s moto spirituelle). The stream is incessantly muddied, dammed and diverted. A sudden sight or sound, however marginal, any tactile experience, a wisp of tiredness or boredom, the wedge of sudden desire, will appropriate a thought-response. Sensory phenomenality (Sinnlichkeii) in its incommensurable aggregate and confusion, can master and re-direct thinking at virtually every moment in our lives (“it slipped my mind”). Day- dreaming, pathological misprisions-to be “out of one’s mind,” a precisely meaningless proposition-are merely accented, identifiable forms of perpetual discontinuities, of inherent drift. Soliloquies of concealed or unwanted thought go their anarchic ways underneath articulate, cognitively apprehended speech. Though it may be that the creative artist or visionary can sometimes dip into these deep and turbulent eddies. By far the greater volume of recall and forgetting lies at the blurred edges of willed thinking. The winds of thought-an ancient simile-their sources beyond recapture, blow through us as through innumerable cracks. Kafka heard “great winds from under the earth.”

Is it, in fact, possible to “think straight”? Can thought be made laser-like? Only at the price of trained, disciplined concentration and abstention from diversion. A number of activities depend on this narrowing and “monotone.” The mathematician at his analysis and proof seems able to shut off and out the world, sometimes for hours on end. As does the chess master at his board or the formal logician at his lemmas. At crucial stages at his work-table, the watch-maker behind his magnifying glass, the surgeon operating, suspend all inattention. We knit our brows, the virtuoso musician closes his eyes. Contemplatives, masters of meditation and their acolytes testify to spells, sometimes of astounding length, of absolute compaction, of an in-gathering of the psyche so exclusive of any dispersal that it allows a single, total intentionality. It may be that Bach’s solo partitas translate such “singularities”; but so does the suspension of breath of the marksman waiting to kill.

Such purities, such shafts of unwavering thought are accessible only to the relatively few, and their normal span is brief. They can occur at the summits of human excellence, as in what we know of Spinoza’s methods, or at trivial levels, as in the circus-arts of the memory acrobats capable of learning by heart and regurgitating extended series of random numbers or names. There is evidence, though fitful, that the implicit powers of ultimate concentration can burn out at a fairly young age. First order pure mathematics and theoretical physics are the prerogative of the young. Which does suggest that the generative means involved are in some vital regard neuro-physiological, indeed “muscular.” There is documentation, although too often anecdotal, to suggest that totalities of concentration comport not only temporary exhaustion but long-range mental collapse (notably in chess-masters and pure mathematicians or mathematical logicians). Prodigies in mnemonics rarely mature.

This allows the hypothesis whereby the involuntary, polymorphic wash of common thought is a safe-guard. It acts as a conservation of mental reserves in what may be virtually a neurological sphere. It enables us to respond more or less adequately to the spontaneous, often shapeless demands and stimuli of the everyday. The bursts of concentration in undeflected thinking, the coercion of absolute focus, may carry the risk of subsequent mental exhaustion or impairment. There is monomania in certain intensities of thought (lasers can burn). It is, none the less, a monomania without which many peaks of human understanding and accomplishment would not be feasible. Archimedes did not desist from his analysis of conic sections, though that focus meant death. Far, far more often than not, however, ordinary thinking is a messy, amateurish enterprise.

A second cause of “unzerstrliche Melancholie”(of “indestructible melancholy”).

3.

Thinking makes us present to ourselves. Physical sensations, notably pain, are instrumental. But to think of ourselves is the main constituent of personal identity. I cannot think that I am not except in a fantasized, merely verbal game. The cessation of thought, even where madness is active, is simultaneously, tautologically that of the ego.

No one, nothing can verifiably penetrate my thoughts. To have one’s thoughts “read” by another human being is nothing more than a figure of speech. I can altogether conceal my thoughts. I can mask and falsify their outward expression as I can that of my mien or body language. Hired mourners howl with grief over the remains of clients unknown to them. Even torture cannot elicit beyond doubt my inmost thoughts. No other human being can think my thoughts for me. This is the determinant reason, the ontological crux why no other man or woman can “die for me” in any literal sense. No one else can assume my death. I can die with, but never “for,” the other, however inalienable our bonds, our kinship. The blind, the deaf-mute, the immobilized victim of paralysis or motor-neuron disease can harbor, formalize and expound thoughts which reach to the edge of our universe. Thoughts are our sole assured possession. They make up our essence, our at-homeness or estrangement from the self. Their inwoven pressure is such that we may at times labor to hide them from our awareness, to silence them internally by means which psychology qualifies as amnesia or repression. It is doubtful that they remain irretrievable. I breathe therefore I think.

There follows a consequence whose enormity-in the proper sense of that word-is taken strangely for granted. No closeness, be it biological (identical or Siamese twins may represent a limit-case), emotional, sexual, ideological, be it that of a life-time of shared domestic or professional co-existence, will enable us to decipher beyond uncertainty the thoughts of another. The quest for telepathic communications and simultaneities is an attempt, almost certainly futile, to overcome this often maddening or tragic inhibition. As is the resort to truth-drugs in various obscenities of interrogation. The beloved lies in our arms, the treasured child in our embrace, the best friend clasps our hand. Yet we have no indubitable proof as to the thoughts being generated, registered inwardly at the relevant moment. So frequently in erotic union the current of thought, of the intensely imagined, pulses elsewhere. We make inner love to another. Under the adoring smile of the child, of the intimate friend, there can be the truth of boredom, indifference or even repulsion. The ability to lie, to conceive of and enact fictions is organic to our humanity. The arts, social conduct, language itself would be impossible without it. As Jonathan Swift so astutely allegorizes it, perfect truthfulness, perfect transparency of thought belongs to the animal kingdom. Men and women endure by virtue of recurrent disguise. But the mask is worn underneath the skin.

Yet observe the paradox. This inaccessible core of our singularity, this most inward, private, impenetrable of possessions is also a billionfold commonplace. Although expressed, voiced or unvoiced, in different lexical, grammatical and semantic forms, our thoughts are, to an overwhelming degree, a human universal, a common property. They have been thought, they are being thought, they will be thought millions and millions of times by others. They are endlessly banal and shop-worn. Used goods. The components of thinking in even the most private, personalized acts and moments in our existence-in sex, for examp\le-are clichs, interminably repeated. They enlist, most saliently in an age of mass-media or in one of restricted literacy, identical words and images. Our performative ecstasies, our taboo scenarios or approved rhetoric of sentimentality are shared, synchronically, with numberless other men and women. They are a mass-market merchandise labeled by the endlessly reiterative commonplaces of our language, our culture, our time and milieu. The phrase “sexual commerce” has a palpable connotation in our current structures of mass-consumption and public explicitness.

All this is an inescapable consequence of language. We are born into a linguistic matrix which is historically inherited and communally shared. The words, the sentences we use to convey our thinking, either internally or externally, belong to a common currency. They render intimacy democratic. In embryo, as it were, the dictionary inventories the near-totality of both actual and potential thought. Which, in turn, is made up of combinatorial assemblages of and selections from pre-fabricated counters. It may be that the grammatical rules and precedents on offer (the pieces in the Lego kit) pre-determine, place constraints on, the vast majority of our acts of thought and articulations of consciousness. The potentialities of construction are manifold, but also repetitive and bounded.

In consequence, true originality of thought, the thinking of a thought for the first time (and how would we know?) is exceedingly rare. As Alexander Pope famously observed, it is the verbal form not the content which gives an impression of novelty. Language and diverse symbolic codes may indeed articulate a thought, an idea, a conceptual image with unprecedented force, completeness or economy. The performative shock may be intense. But there is absolutely no way of knowing, let alone proving, that that very thought has never been emitted before, albeit in a less adequate, even defective or almost “mumbling” guise. It may have occurred to sub- or illiterate men and women, to the deaf-mute or the cerebrally impaired who very simply took no notice of it. It may be that in the pure and applied sciences, in technology, cumulative and collective development, the exchange of conjectures and refutations, generates a novum organum Yet even here much is re-discovered or arrived at simultaneously by different individuals and teams. The theory of natural selection, of calculus, of DNA provide well known instances. With his genius for awe, Einstein professed that he had had only two genuine ideas in his entire life.

In the “humanities,” taking that word in its widest circumference, in philosophy, the arts, literature, political and social theory, what we call “originality” is almost always a variant or innovation in form, in executive means, in the available media (bronze, oil paints, electric guitars). Such innovations and enabling discoveries are of immense significance and prodigality. They shape much of our civilization. But how many are “original” in any rigorous sense? How many are an authentic mutation? A new thought-act, an imagining without discernible precedent, is the ambition, acknowledged or not, of writers, painters, composers, thinkers. It can be realized outside dreams only where the relevant idiom is itself made new. Where there is some re-orientation of the available deluge of ordinary language and shared formal conventions. Poets have indeed striven to create new languages, as in Dada and certain experiments in futurism. The products have been more or less incomprehensible trivialities. Where verbal modes are new, who is to understand them? In what sense have metaphors been invented and by whom? The inventory of myths, of the “great stories” on which western literature feeds is that of a structure of themes and variations. Quantum leaps are (magnificently) rare. It may be that Sophocles “thought up” the Antigone-legend, though there were actual political-military precedents to suggest it. So far as we know, the Don Juan motif was a “find,” datable in time and place, with almost immediate and ubiquitous echo. But these inceptions are infrequent.

Such thinkers and begetters of argument as Plato, Aristotle, Paul of Tarsus, St. Augustine may have developed the linguistic and conceptual instruments with which to formulate and make widely accessible thoughts, images, metaphors of radical originality. This, however, is by no means certain. We may be stunned by the apposition in Sartre’s “le sale espoir” and find no previous public utterance of this irony. But it is exceedingly doubtful that his was the first intellect or sensibility to experience this notion and communicate it to himself. When Giordano Bruno characterizes as new the concept of an unbounded, multiple cosmos, when Saint-Just proclaims “happiness to be a new idea in Europe,” they are being eloquently rhetorical. Neither proposition was without precedent, some of it millennially ancient. Was romantic love truly invented in Provence during the twelfth century?

Thinking is supremely ours; buried in the uttermost privacy of our being. It is also the most common, shopworn, repetitive of acts. The contradiction cannot be resolved. A third reason for an anklebende Traurigkeit (for a “sorrow which adheres to us”).

4.

We have seen that there can be no final verification for the truth or error of subjective thought, for its sincerity or falsehood. What of public, systematic thinking, of that pursuit of objective truths which, since Parmenides, has been held to be the excellence of man in the west?

The values, logically formal or existential, diffuse or rigorous, which attach to the word “truth” are enmeshed in historical, ideological, psychological co-ordinates often arbitrary (“truth on one side of the Pyrenees” as Pascal put it). Even the experimentally demonstrable and empirically applicable truths of the sciences are underwritten by theoretical, philosophical pre-suppositions, by fluctuating “paradigms” always susceptible of revision or discard. Where it addresses, where it invokes “truth,” thought relativizes this criterion in the moment in which it adverts to it. There is no escape from this dialectical circularity. As a result, the history of truth, a concept which itself negates any absolute status-the absolute has no history-ranges from the most dogmatic, “revealed” fables to the most extreme skepticism and the modernist move, already implicit in classical skepticism, “anything goes.” However consequent, however scrupulous in its self-examination, a thought- act can postulate its attainment of truth solely where the process is tautological, where the result is a formal equivalence, as in mathematics or symbolic logic. All other statements of truths, doctrinal, philosophic, historical or scientific are subject to error, falsifiability, revision and erasure. Like those “superstrings” in today’s cosmology, “truths” vibrate in manifold dimensions inaccessible to any final proof (indeed, there is no clear view as to what such a “proof” could be). Existential thinking, the proceedings of thought in intellectual and daily life, cannot “break through” to any self-evident, incontrovertible, everlasting realm of truth. Yet it is just this realm which revealed creeds, which metaphysics as in Plato, Plotinus or Spinoza, promise and labor to attain. Thus there is in abstract thought, in epistemological methods a latent ground bass of nostalgia, an edenic myth of lost certitudes (we hear it, with poignant integrity, in a thinker such as Husserl). To think is to fall short, to arrive somewhere “beside the point.” At very best, thought breeds what Wallace Stevens called “supreme fictions.” Einstein would have it otherwise: “The creative principle resides in mathematics. In a certain sense, therefore, I hold it true that pure thought can grasp reality as the ancients dreamed” (where “dreamed” may be a more than Freudian lapse). To which one of the most authoritative of today’s cosmologists replies: “even within the basic domain of the basic equations of physics our knowledge will always be incomplete.”

The more fierce the pressure of thought, the more resistant the language in which it is encased. Language, as it were, is inimical to the monochrome ideal of truth. It is saturated with ambiguity, with polyphonic simultaneities. It delights in fantastication, in constructs of hope and futurity for which there is no proof. Perhaps this is why the great apes have hesitated to develop it. Human beings could not endure without what Ibsen called “life-lies.” Thought limited to logical propositions, best expressed non- verbally, or demonstrable factualities, would be madness. Human creativity, the life-giving capacity to negate the dictates of the organic, to say “No” even to death, depend integrally on thinking, on imagining counter-factually. We invent alternative modes of being, other worlds-Utopian or hellish. We re-invent the past and “dream forward.” But indispensable, magnificently dynamic as these thought-experiments are, they remain fictions. They nourish religions and ideologies, the libido is brimful of them (Shakespeare’s “lunatics, lovers and poets”). Language constantly seeks to enforce dominion over thought. In the stream of thought it generates whirlpools, which we call “mental disorders” and those log- jams known as obsessions. Yet the interference, the incessant “muddying of the waters” are also those of creativity. In this tidal surge, the act of pure concentration, the attempt to purge consciousness of its vital fictions, of the open-eyed hallucinations of desire, intent or fear, are, as we noted, exceedingly rare. They exact a discipline profoundly contrary to natural language, though available to mathematics and symbolic logic. When Einstein appeals to “pure thought,” it is precisely these he has in mind. Certain eminent philosophers have, in turn, attempted to make their linguist\ic articulations as “mathematical” as possible, as immune as possible from the mutinous joy of natural speech. But how many Spinozas, how many Freges or Wittgensteins are there, and to what degree have even these ascetics of truth prevailed? At twilight, Socrates sang.

This fundamental antinomy between the claims of language to be autonomous, to be liberated from the despotism of reference and reason-claims which are crucial to modernism and deconstruction-on the one hand, and the disinterested pursuit of truth on the other, is a fourth motive for sorrow (Unzerstrliche Melancholic).

5.

Thinking is almost incredibly wasteful. Conspicuous consumption at its worst. Neuro-physiological investigations have sought to localize and evaluate numerically “brain-waves” emitted by the cortex. They have tried to identify the quanta of energy, the rhythm of electromagnetic pulses associated with moments and clusters of concentrated thought. It does seem plausible that there are in what we call “thinking” components of neuro-chemical and electromagnetic energy, that the synapses in the human brain have their measurable output (the study of cerebral lesions provides evidence). But so far much remains conjectural and mappings are approximate. Intuitively, impressionistically, we do experience some analogy to muscular fatigue after sustained spells of sequential thought, of reflection under pressure. Problem-solvers in the exact and applied sciences, mathematicians, formal logicians, computer programmers, chess- players, simultaneous translators report phenomena of exhaustion, of “burn-out.” War-time cryptologists at their de-coding were among the first to register mental strain of extreme, “physical” intensity. Again, however, our understanding of such stress and of the mechanisms involved is rudimentary.

The point is this: thought processes, be they conscious or subconscious, the thought-stream within us articulate or unvoiced, during waking hours or sleep-those rapid eye movements much studied in recent decades-are, in overwhelming proportion, diffuse, aimless, dispersed, scattered and unaccounted for. They are, quite literally, “all over the place,” which makes the idiom “scatter-brained” entirely valid. The economics are those of an almost monstrous waste and deficit. There may be no other human activity more extravagant. We do not think about our thinking except in brief spells of epistemological or psychological focus. Very nearly the incessant aggregate and totality of thinking flits by unnoticed, formless and without use. It saturates consciousness and presumably the sub- conscious, but drains off like a thin sheet of water on baked earth. Even the notion of “forgetting” is too substantive. That of which we may have been thinking an hour ago may have left no trace whatever owing to contingent circumstances or the interference-effects of some task in hand. At best, it may have been arrested in writing or encoded in some other modes of semiotic markers. Japanese globe- trotters are said to employ specialists who identify for them the locale of their own photographs. But by far the iceberg mass of human thought vanishes unperceived, unrecorded in the trash-bin of oblivion. “Alms for oblivion.””What was I thinking when I said this or did that?” Or consider the banal disappointment when one awakes convinced of having dreamt a major insight, an elusive solution, of having composed significant poetry or music only to find recollection helpless and the bed-side pad covered with meaningless scribbling. Which frustration and embarrassment does not prove that the effaced, lost thought or imagining was not of signal merit and importance. It is simply out of reach, erased as are millions and millions of other thoughts tiding through us in unfathomable waste.

This suggests the science-fiction model of a society in which thinking is rationed. In which it is licensed only for certain hours or days and where such rations are distributed according to individual mental capacities and powers of concentration. A waste of thought would be regarded as vandalism or worse. Food, fuel can be rationed in war-time. The currency can be put under strict control. Why not regulate the infinitely valuable supply of thought, preserving it from waste and inflation? Science-fiction, to be sure. Yet are attempts in that direction not the core of totalitarian systems, of despotic ideologies be they religious or political? Efforts to ration thinking, to constrict it within permitted, circumscribed channels are at the very heart of tyranny. Anarchic, playful, wasteful thought is that which totalitarian regimes fear most. It is the Utopia of censorship to read not only the text, but the thoughts which underlie it or which it conceals. Hence the Orwellian trope of a “thought-police.”

Though they contain hyperboles of proud modesty, Einstein’s claim to have had only “two ideas” in his entire life, and Heidegger’s maxim that all major thinkers have only one thought which they expound and reiterate throughout their works, may point to a vital truth. The significant thinker in the humanities or the sciences would be one who perceives and exploits a decisive insight or concept, who fixes on one crucial discovery or connection. It is he or she who invests almost avariciously in a seminal thought-act or observation, exploiting its full potential. Darwin seems to represent an exemplary instance. Whereas the numberless plurality of human beings, even if brushed as it were in transit by first-class thoughts, by radical notice, pays no especial heed, does not “grab a hold” or press on to performative realization. How many recognitions go to waste in the indifferent deluge of unattended-to thinking, in the un- or overheard soliloquy of everyday and “everynight” cerebral emission? Why are we unable to encapsulate, put in ordered storage and potentiality-as does an electric battery-the possibly fruitful voltage generated by the sleepless arcs and synapses of our mental being? It is, precisely, this infinitely spendthrift, ruinous generation which we cannot, as yet, account for. But the deficit is beyond reckoning.

A fifth reason for frustration, for that “dark ground” (dunkler Grund).

6.

Thought is immediate only to itself. It makes nothing happen directly, outside itself. Fragile, disputed experiments in telekinesis have sought to show that thinking can produce minute material phenomena, effects of vibration or minimal displacement. Quantum physics, itself so enigmatic, has it that the act of observation alters the objective configuration of that which is being observed (Einstein found this supposition little short of monstrous). Here almost everything remains conjecture. Thinking has incommensurable consequences, but the inference of a direct continuum is, as Hume taught, inferential. It cannot be shown to be directly causal. The vast majority of habitual acts and gestures are “thoughtless.” They are performed instinctively or via acquired reflexes. Famously, the millipede would come to a suicidal halt if it thought about its next step. A chilling reflection if ever there was one. Automatism is decayed thought. But even where an action is most carefully and consciously “thought out,” where it follows on some internalized blueprint or an outward and articulate proposition, the sequence can only be inferred. Only God, so the theologians, experiences no hiatus between thought and consequence. That which He thinks is. That there is a connection between thought and existential, pragmatic consequence is a rational postulate without which we could not conduct our lives. So far, however, we possess no working model of the chain of generative phenomena, of the presumably immensely complex translation of the conceptual need or desideratum into neuro-physiological and muscular accomplishment. The neurochemistry which relates intention to effect can only be traced at rudimentary levels. In so many cases, it is as if cause comes after effect. Thought-acts seem to follow on unpremeditated, spontaneous enactments which thought then interprets and “figures” to itself in the past tense. (I wonder whether the spellbinding experience of dj-vu does not relate to this reversal.) Far more often, there is obliteration: “I have no idea of why I did so and so. My mind is a total blank.”

Interpositions between thought and act are as manifold, as diverse as is life itself. The shadows which fall between thinking and doing can never be exhaustively inventoried let alone classified. There are, in the most exacting of engineering or architectural constructs, minute deviations from design, from precise calibration. No painter, however skilled, can fully realize the transfer on to his canvas of his internal vision or of that which he believes he sees before him. Even in the strictest of forms, music embodies only partially the complex of feelings, ideas, abstract relations inward to its composer. The distance between felt pressures on sensibility, between the imagined and its linguistic utterance, is a mournful clich, a commonplace of never-ending defeat since the inception not only of literature but of the most urgent and intimate of human exchanges. “I cannot put it into words,” says the lover, say the griefstricken; but also the poet and the philosopher. The intimation of barriers, of interference effects or “white noise” is disturbingly physical. Sentiment, intuition, intellectual or psychological illumination, crowd at the inner edge of language but cannot “break through” to complete articulation (though the great writer somehow works closer to that edge and to the pulses of the pre-linguistic than do less privileged minds). Energies of recognition, metaphoric lightning flashes and momentary comprehension vibrate just out of reach. Eurydice recedes tantalizingly into darkness. Within the turbulent, polysemic magma of conscious and sub-conscious processes,incessant thought or its wholly mysterious antecedents, nocturnal as well as diurnal, are only fragmentarily recuperable. Coming to the lit surface via the simplifying constraints of language, of coercive logic, this generative force is always inhibited and deflected. Hence the doomed labors of the Surrealists in quest of “automatic” writing or virgin modes of speech. The aleatory is already conditioned by imperatives.

Thinking does not, cannot make it so. Even the most prudentially gauged and focused motion of thought is “bodied forth” (Shakespeare’s penetrating idiom) only imperfectly, only in part. The work of art, however sovereign, the political or military project, the material edification, the legal code or theological- metaphysical summa compromise with the ideal, with the necessary fiction of the absolute. A speck of chromatic impurity, all but imperceptible, remains in the black tulip, in the crystal symmetries of private or collective political, social design. The concept of perfection is an unfulfilled dream of thought, a conceptual abstraction, as is infinity. It is in the paradox of the existence within us of these two unattainable ideals that classical theology, in Anselm as in Descartes, locates its proof of the existence of God. Though in extremis, Wittgenstein spoke for every creative consciousness when he declared that the part of the Tractatus which mattered was that which remained unwritten.

Ineluctably, therefore, the totality of our futurities, of our projections, anticipations, plans-be they routine or utopian- carries within it a potential of disappointment, of prophylactic self-deception. A virus of unfulfilment inhabits hope. The grammars of optatives, of subjunctives, of every nuance of future tenses- these grammars being the irresponsible glory and morning light of the human mind-can never be guarantors. They do not entail and underwrite untainted fact. The odds may be overwhelmingly in our favor, induction may seem almost contractual and fool-proof, but to expect, to await, to hope for is a gamble. Whose only certainty is death. The consequences of our expectations, of that impatience which we call “hope,” fall short. Often they abort altogether (though there are dispensations in which they surpass our imaginings). Customarily, the anticipation, the projection, the fantasy and image exceed realization. If we hail experiences as “beyond our wildest dreams,” these dreams have been cautionary and threadbare. A revealing emptiness, a sadness of satiety follows on fulfilled desires (Goethe and Proust are the unsparing explorers of this accidia). The celebrated gloom post coitum, the longedfor cigarette after orgasm, are precisely those which measure the void between anticipation and substance, between the fabled image and the empirical happening. Human eros is close kin to a sadness unto death. If our thought-processes were less urgent, less graphic, less hypnotic (as in the gusts of masturbation and day-dreaming), our constant disappointments, the gray lump of nausea at the heart of being, would be less disabling. Mental break-downs, pathological evasions into unreality, the inertia of the brain-sick may, in essence, be tactics against disappointment, against the acid of frustrated hope. Such are the failed correlations between thought and realization, between the conceived and the actualities of experience, that we can neither live without hope-Coleridge’s “Work without hope draws nectar in a sieve, / And hope without an object cannot live”-nor overcome the bereavement, the mockery which failed hopes comport. “Hope against hope” is a powerful, but ultimately damning phrasing of the blight which thought casts on consequence.

A sixth Ursache or font for tristitia.

7.

There are, we saw, two processes which human beings cannot bring to a halt so long as they are alive: breathing and thinking. In fact, we are capable of holding our breath for longer periods than we are able to abstain from thought (if that is possible at all). On reflection, this incapacity to arrest thought, to take a break from thinking, is a terrifying constraint. It imposes a servitude of peculiar despotism and weight. At every single instant in our lives, waking or sleeping, we inhabit the world via thought. The philosophic-epistemological systems which seek to explain and analyze this habitation fall into two perennial categories. The first characterizes our consciousness and awareness of the world as being that of perception through a window. This model, founded somewhat naively on an analogy with ocular vision, underlies every paradigm of realism, of sensory empiricism. It authorizes a belief, however complex or attenuated, in an objective world, in an “out there” whose ideal and material elements are conveyed to us by conscious or sub-conscious input and the placement of this input by intuitive, intellectual and experimental means. The other epistemology is that of the mirror. It postulates a totality of experience whose only verifiable source is that of thinking itself. It is our minds, our neuro-physiology which project what we take to be the forms and substance of “reality.” Per se this is the irrefutable Kantian axiom: “reality,” whatever it may consist of, is inaccessible. It eludes any demonstrable, assured grasp. It may amount to a collective hallucination, a common dream. Extreme, playfully grave versions of this solipsism suggest that we are ourselves “such stuff as dreams are made on,” perhaps dreamt by a Demiurge or indeed, as Descartes speculates, by a demon. All thought about the world, all observation and understanding would be reflection, mappings in a mirror.

On one capital point these two opposed systems concur: the glass, be it window or mirror, is never immaculate. There are scratches on it, blind spots, curvatures. Neither vision through it nor reflection from it can ever be perfectly translucid. There are impurities and distortions. This is the crux: there is interposition between ourselves and the world we inhabit. Conceptualizations, observations (as in the “uncertainty principle”) are acts of thought. There are no innocent immediacies of reception, however spontaneous, however unthinking they seem. Theories of cognition, whether Descartes’s, Kant’s or Husserl’s struggle heroically to situate a point of unpremeditated immediacy, a point at which the self meets with the world without any presuppositions, without any interference by psychological, corporeal, cultural or dogmatic presumptions. Such “phenomenologists” strive to “see things as they are,” to make out the truth of the world’s presence and “thereness” either via the window or the mirror. But, as Gertrude Stein knew, there is no unwavering, re-insuring “there there.” No Archimedian point or tabula rasa has ever been con vincingly located. The identity of the “thinking reed,” the obscuring ubiquity of thought- processes acts as a screen. Experience, where it would be naked and Adamic, is filtered and essentially compromised. The expulsion from Eden is a “fall into thought.” Thus there is no element in existence which is not “sicklied o’er with the pale cast of thought.”

In consequence, even the most inventive, capacious, orderly of human intellects and imaginations operates within indirections and limitations which it cannot truly define, let alone measure. Everywhere the masterlight of the mind abuts on obscurity. Are there neuro-physiological, evolutionary limits to our conceptualizations and analyses of the world? Are there categorical bounds to human reason? Which are the inherent constraints-whether perceived or not- that pre-determine the reach and clarity of our boldest conjectures (conjectures which may, in fact, be entirely inadequate to or even out of touch with the actualities of the cosmos)? What proof have we, what proof could we have, that the progress of empirical investigation and theoretical construction is limitless, that the speculative intellect will continue on its seemingly open-ended journey through “seas of thought.” The most powerful of electron microscopes now appear to be nearing the limit of possible observation as, in haunting symmetry, are the most probing of radio telescopes. It is not that the light from remote galaxies does not reach us; it will never reach us in allegory of our solitude. How much of our proud science is also science-fiction, a model whose only demonstrable veritas is that of mathematics, of mathematics playing its own entranced games?

There has always been ground for suspicion in regard to the seemingly incontrovertible axioms of logic and the syntax in which they are so despotically incised. Do these axioms, do the sacrosanct rules which govern contradiction, do no more than externalize the local particularities of hominid cerebration, the architecture of our cortex? Just as vision may be held to enact the anatomy and physiology of the human eye. Each and every one of us has experienced frustrations of awareness, barriers to understanding. We “run up,” often viscerally, against impalpable but unyielding walls of language. The poet, the thinker, the masters of metaphor make scratches on that wall. Yet the world both inside and outside us murmurs words which we cannot make out. “Unheard tunes” are proclaimed to be the sweetest. Cezanne testifies in modest anger at the inability of his eye to penetrate in depth the landscape before him. Pure mathematics knows of the insoluble though there is no assured grasp of the source of such insolubility. The most inspired thinking is impotent in respect of death, an impotence which has generated our metaphysical and religious scenarios. (I will come back to this.) Thought veils as much as, probably far more, than it reveals.

A seventh reason for that Schleier der Schwermut (“veil of heaviness” of heart).

8.

This opacity makes it impossible to know beyond doubt what any other human being is thinking. As I note\d, we possess no indubitable insight into anyone else’s thoughts. Again, we pay too little attention to this enormity. It should strike terror. No familiarity, no analytic cunning can ensure or verify “mind- reading.” Neither hypnosis nor psychiatric techniques nor “truth- drugs” can extract in any verifiable way the thoughts of the other. His or her most vehement avowals, oral and written testimony under oath, naked confessions can deliver no fundamental, insured content. They may or may not express the most candid intent, the most purposed revelation. They may or may not disclose partial truths, fragments as it were of utmost sincerity and self-disclosure. They may or may not conceal felt meaning whether in toto or in part. Motions of disguise can range from the outright lie professed consciously to every shading of untruth and self-deception. The nuances of mendacity are inexhaustible. No laser of inquisitorial attention, no ear however acute, no cross-examination can elicit certitude. The mere question “what are you thinking, what have you in mind?” solicits answers which are themselves manylayered, which have, however unnoticed, passed through complex filters.

Hence the unsettled relations between thought and love. Hence the likelihood that love between thinking beings is a somewhat miraculous grace. Every man and every woman, every adult and every child uses what linguists call an “idiolect,” this is to say a personalized selection out of available language with private, singular, perhaps untranslatable counters, connotations and references which the recipient in dialogue cannot wholly or with certitude interpret. We try to translate to each other. We so frequently get it slightly or grossly wrong. But even this partial or flawed intelligibility of all communication lies only at the surface. The idiolects of thought, the privacies of the unspoken are of a much deeper and intractable order.

Even in moments and acts of extreme intimacy-perhaps most acutely at such moments-the lover cannot embrace the thoughts of the beloved. “What are you thinking, what am I thinking as we make love?” This exclusion makes the vaunted fusion of orgasm and its rhetoric of unison arguably trivial. As Goethe liked to point out, numberless men and women have clasped in the arms of thought lovers, remembered, wished-for, fantasized other than those they are making love to. This cognitive interposition, this mental reservation, involuntary or deliberate, blurred or graphic, can chime like a derisive echo beneath the cries and whispers of ecstasy. We shall never know what deep-lying inattention, absence, repulsion or alternative imagery deconstruct the manifest text of the erotic. The closest, most honest of human beings remain strangers, more or less partial, more or less undeclared to each other. The act of love is also that of an actor. Ambiguity is native to the word.

Thought is most legible, least covert during bursts of unchained, compacted energy. As in fear and in hatred. These dynamics, particularly on the instant, are difficult to fake, though virtuosos of duplicity and of self-control can attain greater or lesser concealment. The animals we deal with show us that our fears emit a distinctive scent. Perhaps there is a smell to hatred. Enlisting all levels of cerebral and instinctive thrust, hatred may be the most vivid, charged of mental gestures. It is stronger, more cohesive than love (as Blake intuited). It is so often nearer than is any other revelation of the self to truth. The other class of thought- experience in which the veil is torn apart is that of spontaneous laughter. At the instant in which we “get” the joke or chance on the comical sight, mentality is laid bare. Momentarily, there are no “second thoughts.” But this aperture to the world and to others lasts only very briefly and has the dynamics of the involuntary. In this regard, smiles are almost the antithesis to laughter. Shakespeare was much concerned with the smiling of villains.

Overall the scandal remains. No final light, no empathy in love, discloses the labyrinth of another human being’s inwardness. (Are identical twins, with their private language, truly an exception?) At the last, thinking can make us strangers to one another. The most intense love, perhaps weaker than hatred, is a negotiation, never conclusive, between solitudes.

An eighth reason for sorrow.

9.

Bodily functions and thinking are common to the species. Arrogantly, homo sapiens so defines himself. Strictly considered, each and every living man, woman and child is a thinker. This is as true of the cretin as it is of Newton, of the virtually speechless moron as it is of Plato. As I noted, seminal, inventive, life- enhancing thoughts may, at any time and in any place, have been thought by the sub-literate, the infirm, even the mentally handicapped. They have gone lost because they were not articulated or attended to even by the one who has done the thinking (“mute, inglorious Mutons” in a sense which extends far beyond literature). Like minute spores, thoughts are disseminated inward and outward a millionfold. Only a minute fraction survive and bear fruit. Hence the incommensurable waste which I have cited previously. But the confusion may reside elsewhere.

Our taxonomy, notably in the current political-social ambience, tends towards the egalitarian. Does this not disguise and falsify an obvious, but scarcely or uncomfortably noticed hierarchy? Vaguely, rhetorically we attach to certain acts of spirit and what we assume to be their consequences-the scientific insight, the work of art, the philosophic system, the historical deed-the label “great.” We refer to “great” thoughts or ideas, to products of intellectual, artistic or political genius. No less vaguely, we adduce “profound” as distinct from trivial or superficial thoughts. Spinoza descends into the mine-shaft; the man in the street customarily skates at the banal surface of himself or the world. Can these polarities, together with the innumerable gradations between them, be lumped together under one indistinct rubric? Can the mind’s flotsam and inchoate babble be covered by the same sloppy definition as the solution to Fermat’s last theorem or the Shakespearean begetting of enduring metaphor or mutations of sensibility? What factitiousness- picked up from the outset by caricaturists and vulgarians-inhabits Rodin’s “Thinker”?

All of us conduct our lives within an incessant tide and magma of thought acts, but only a very restricted portion of the species provides evidence of knowing how to think. Heidegger bleakly professed that mankind as a whole had not yet emerged from the pre- history of thought. The cerebrally literate-we lack an adequate term- are, in proportion to the mass of humanity, few. The capacity to harbor thoughts or their rudiments is universal and may well be attached to neuro-physiological and evolutionary constants. But the capacity to think thoughts worth thinking, let alone expressing and worth preserving is comparatively rare. Not very many of us know how to think to any demanding, let alone original purpose. Even fewer of us are able to marshall the full energies and potential of thought and of directing these energies towards what is called “concentration” or intentional insight. An identical label obscures the light-years of difference between the background noise and banalties of rumination common to all human existence (as it is perhaps also to that of primates) and the miraculous complexity and strengths of first-class thinking. Just beneath this eminent level there are the many modes of partial understanding, of approximation, of involuntary or acquired error (the physicist Wolfgang Pauli’s devastating phrase about false theorems: “they aren’t even wrong”).

A culture, a “common pursuit” of mental literacy, can be defined by the extent to which this secondary order of reception, of the subsequent incorporation of first-order thought into communal values and practices, is or is not widespread. Does seminal thought enter schooling and the general climate of recognition? Is it picked up by the inner ear, even if this process of audition is often stubbornly slow and fraught with vulgarization? Or are authentic thinking and its receptive valuation impeded, even destroyed (Socrates in the city of man, the theory of evolution among fundamentalists) by “unthinking” political, dogmatic and ideological denial? What murky but understandable mechanism of atavistic panic, of sub-conscious envy fuels the “revolt of the masses” and, today, the philistine brutality of the media which have made the very word “intellectual” derisive? Truth, taught the Baal Shem, is perpetually in exile. Perhaps it should be. Where it becomes too visible, where it cannot shelter behind specialization and hermetic encoding, intellectual passion and its manifestations provoke hatred and mockery (these impulses intertwine with the history of anti-semitism; Jews have often thought too loudly).

Can top-gear thinking be learned? Can it be taught? Drill and exercise can strengthen memory. Mental focus, spells of inwardness and concentration can be deepened by techniques of meditation. In certain Oriental and mystical traditions, in Buddhism for example, this discipline can attain almost unbelievable degrees of abstraction and intensity. Analytic methods, stringent formal consequentiality can be imparted and refined in the training of mathematicians, of logicians, of computer programmers and chess- masters. To prevent children from learning by heart is to lame, perhaps permanently, the muscles of the mind. Thus there is much in cerebral skills, in developed receptivity and interpretation which can be heightened and enriched by teaching and practice.

But so far as we know, there is no pedagogic key to the creative. Innovative, transformative thought, in the arts as in the sciences, in philosophy as in political t\heory, seems to originate in “collisions,” in quantum leaps at the interface between the subconscious and the conscious, between the formal and the organic in a play and “electric” art of psychosomatic agencies largely inaccessible both to our will and our comprehension. The empowering media can be taught-musical notation, syntax and metrics, mathematical symbolism and conventions, the mixing of pigments. But the metamorphic use of these means towards novel configurations of meaning and mappings of human possibility, towards a vita nuova of belief and feeling, can neither be predicted nor institutionalized. There is no democracy to genius, only a terrible injustice and lifethreatening burden. There are the few, as Hlderlin said, who are compelled to catch lightning in their bare hands.

This imbalance, along with its consequences, the maladjustment of great thought and creativity to ideals of social justice, is a ninth source of melancholy (Melancholie).

10.

French and German grammar help. They allow us to elide the preposition between the verb “to think” and its object. We are not constrained to think “about” this or that. We can “think it” immediately, without interposition. Das Leben denken (“to think life”); penser le destin (“to think destiny”). The force of this idiom is seductive. But it posits, inescapably, the epistemological uncertainty or duality which I referred to previously. Does the grammatical immediacy point to some mode of solipsism, to the supposition that the objects of thought are the dependent product of the act of thinking (as in Kant)? Or does the elision of any intermediate term authorize the belief that the object of thought has autonomy, that at certain levels of unimpeded focus human thought-acts do penetrate, do fully grasp that which they conceive or conceive of-the difference between these two marking precisely the alternative paths which philosophy has taken in the west? French and German grammatical fusions leave the issue of idealism as against realism open. Characteristically, English usage enforces a choice. It internalizes a fundamental, robust empiricism. The world is “thought about,” not “thought” in some mirroring motion of transcendental autism. Everyday French and German do communicate this common-sense option. Je pense , ich denke an. But philosophic and poetic discourse, notably from Master Eckhardt to Heidegger, enlists the possibility of symbiosis. This, perhaps, is the differentiation between philosophic-linguistic mentalities, between conventions of perception on either side of the Channel or between the European continent and North America (Emerson being an eminent exception). Here also is the locus of certain elemental untranslatabilities.

The “prime numbers” which thought addresses are constants, circumscribing our humanity. They are or ought to be supremely obvious. What is it “to be” and is it not, as Heidegger urges, the essential task of thought “to think (about) being”? To discriminate between multiple phenomenal existentiality and the facticity of things on the one hand and the concealed core of the essence of being (Seyn) itself. Why is there not nothing-Leibniz’s resounding challenge-should be the concern of thought-acts as primordial, as original, i.e. arising out of our origins, as is human life itself. Can we, contra Parmenides, think, conceptualize nothingness? It may be that every attempt to “think death”-a lamentably awkward phrasing in English-to think consequently about death, is a variant on this enigma of nullity. Innumerable creeds, mythologies, fantasies of transcendence are elaborations of thought-experiments which bear on death. Zero, our being made a vacuum, is to most of us “unthinkable” in both the emotional and logical sense of the word. From this stems the manifold architecture of myth and metaphor (many metaphors are concentrates of myth). Itself in perpetual motion and activity, human thought seems to abhor emptiness. It generates archetypally more or less consoling fictions of survival. Like a frightened child whistling, shouting in the dark we labor to avoid the black hole of nothingness. We do so even when the resulting scenarios are insultingly puerile and mere kitsch (those Elysian pastures and celestial choirs, those seventy-two virgins awaiting the martyrs for Islam).

Both spheres of thought, that of being and that of death, have been interpreted as sub-species of the never-ending efforts of the human intellect, of mortal consciousness, to think about, to “think” God. To attach to that monosyllable credible intelligibility. Plausibly, homo became sapiens, and cerebral processes evolved beyond reflex and bare instinct when the God-question arose. When linguistic means allowed the formulation of that question. It is conceivable that higher forms of animal life skirt the realization, the mystery of their own deaths. The matter of God looks to be specific and singular to the human species. We are the creature empowered to affirm or deny the existence of God. We had our spiritual beginnings “in the Word.” The fervent believer and the categorical atheist share an understanding of the issue. The hovering agnostic does not deny the question. The simple claim “I have never heard of God” would be felt to be absurd. Existence and death, as these pertain to “God”, are the perennial objects of human thought where that thought is not indifferent to the enigma of human identity, to our presence in some kind of world. We are-the famous ergo sum-in so far as we endeavor to “think being,””non-being” (death) and the relation of these polarities to the presence or absence, to the anthropomorphically phrased life or death of God. The partial recession of this concern from public and private affairs in the developed technocracies of the west, a recession antagonistic to the angry tides of fundamentalism, pervades our current political and ideological situation. A tolerant agnosticism demands ironic maturities, “negative capabilities” as Keats called them, difficult to muster. The savage simplifications

Whether to give birth in a clinical hospital setting or in a more natural home environment has been a topic of debate for years. Following is one woman’s story of natural childbirth.

* * *

Mindy Goorchenko knows in her bones that the time is near. Bring it on.

She’s still in pajamas: loose gray sweatpants and a light blue tunic that barely covers her massive belly, stretched 80 pounds larger than usual. It’s early. Her husband, Alex, and their 2-year- old, Wolfgang, are barely awake.

It is two days into her 40th week of pregnancy. Just after 7 a.m., labor begins.

They do not rush to the hospital.

Instead, Alex spreads a navy blue towel across the floor of the little bathroom in their modest Torrance condo — a welcome mat for their new arrivals.

The twins will be born at home.

He attaches a garden hose to the kitchen sink and brings it outside to fill what looks like a green plastic kiddie-pool (really a birthing tub) with warm water. He grabs the digital camcorder the couple got as a gift after Wolfgang was born.

“We’re about to do something that isn’t captured on film that frequently,” Mindy says. “Whatever the outcome, we want it captured.”

The couple doesn’t realize the video will also capture the attention of producers at The Discovery Channel, who will include it in their upcoming “Amazing Babies” program. It will find its way to birth educators around the world, become required viewing for midwifery programs and make Mindy a hero in the home birth movement.

For now, they are simply documenting the birth of their children.

Mindy, 26, turns off her brain and tunes into her instinct. The contractions are so intense, she surrenders, swaying with pain. With eyes closed, she leans over the bed and rests her weight on an exercise ball. Her giant belly grazes the beige-and-blue bedspread. A flicker of fear enters her mind: What if one of our babies dies? What if I do?

When Mindy found out she was pregnant, she planned for a home birth and began prenatal care with a certified nurse midwife. But 20 weeks in, she learned she was carrying twins and the midwife had to quit. Her license only covered traditional births — no twins, breeches or preemies.

The couple searched for other midwives and briefly considered going the traditional hospital route. But Mindy wasn’t comfortable with that. She feared surgery and intervention. Giving birth in a noisy room full of strangers would be too stressful a start for her children’s lives. The babies were conceived and gestated naturally, so they should be delivered that way, too.

In the hospital, she’d be like “a disaster waiting to happen.” She talked with Alex, she talked with doctors and she wrote in her journal. Deep in her soul she knew it would be safest at home.

She fills a sports bottle with water and sets it by the bathroom sink. Then it’s back to the exercise ball, swaying and moaning with her eyes at half-mast. The pain is a drug of its own, telling her how to move, inviting her to breathe deeply. She remembers working as a childbirth educator and labor supporter. Flashes of her past education pass through her mind, then fade. Birth is instinctive. Her body knows what to do.

An hour passes. Mindy takes off the tunic and sweatpants and staggers to the bathroom. She sits on the toilet. Her moans could be mistaken for sounds of pleasure, not pain. Wolfgang wants to nurse. He holds on to mommy’s huge belly and reaches up toward her breast.

“He’s my little helper, providing nipple stimulation,” Mindy laughs.

The couple wanted Wolfie to be born at home, too. But he came early, at 35 weeks, and his birth was complicated. Born with a rare bacterial infection, he spent his first 11 days of life in intensive care. He was whisked away from Alex and Mindy just seconds after he was born and carted off for examination. They felt powerless.

A home birth would provide autonomy and calm. But Alex, 27, wasn’t convinced it was a good idea until just a few weeks before Mindy went into labor. With no midwife present and no one to help in an emergency, the birth would be entirely their responsibility.

“There’s my bag,” Mindy says. She reaches beneath her and pulls out a bulging, white, mucousy sac that deflates as soon as she touches it.

“Close the sink,” she says, then drops the bag in.

She checks herself. “The baby’s still way up there.”

Mindy’s interest in birth began when she was 17. She found an old book called Spiritual Midwifery that told stories of birth as a natural, even spiritual experience. It was instantly clear that “part of our birthright as women is this amazing process of pregnancy, of life-bringing.” Yet it never seemed that way on TV or in movies.

Those women were always shown demanding drugs and screaming in demonic voices. It was doctors who knew what to do, not pregnant women.

‘Birth is naturally safe’

“We’ve put birth in the same category with illness and disease and it’s never belonged there,” said Carla Hartley of Redondo Beach, founder of Trust Birth and the Ancient Art Midwifery Institute. “Birth is naturally safe, but we’ve allowed it to be taken over by the medical community.

“Our bodies were designed to finish what we started.”

Mindy feels the baby’s head descend. She gets on her hands and knees and lets out a guttural moan.

She reaches beneath her to feel his head emerge, and she holds him as the rest of his tiny body glides out, covered in a sheer whitish slime.

The umbilical cord is a thick, wavy blue braid. It is 8:55 a.m., Jan. 25, 2004. Psalm Victor is born.

Mindy immediately brings her new son to her heart. She lays him on the towel that covers the floor and gently strokes his chest.

“Oh, big boy,” she says with relief, love and exhaustion.

One down, one to go.

In 2001, one in 33 births was a twin, according to Barbara Luke of WebMD.com. About half of all twins are born vaginally, she said. But when one is in a breech position or the second twin is larger than the first, the babies are usually delivered via cesarean section.

Taking a risk

“Twins are very complicated,” said Dr. Jeffrey Cowan, chief of obstetrics at Torrance Memorial Medical Center. Delivering twins safely at home, unattended, is “way out as far as an exception,” he said.

After 15 minutes of bonding with Psalm, contractions begin again. Mindy clamps his cord and uses a shoelace to tie off her end. It’s white but dotted with blood.

She sits on the toilet and holds onto the sink, swaying her upper body back and forth. Her thick brown curls fall against her face.

She stands, huge belly dangling, then sits again. She sips from the water bottle, tearing off the cap, and moans loudly.

“Want to get in the tub?” Alex asks.

“I’m going to stay right here,” she says, her voice heavy with breath. “I’ll get in the tub after they’re born. It’ll be nice to be relaxed.”

The contractions intensify, and she knows it’s time. She braces herself against the tub as she crawls onto her knees.

The water in the toilet is red with blood. The shoelace dangles from her body.

She reaches inside to check herself. What is that she feels? Is the baby’s hand near her face?

A foot comes out, along with a few drops of blood.

The foot emerges

“I see the foot. There’s the foot. What do you want me to do?” Alex asks.

“Nothing,” she says. “Just film.”

The baby is kicking her way out.

In her mind, Mindy knows that this type of breech birth is considered risky, especially in twins. If she was in the hospital, right now they’d be wheeling her into surgery.

My body knows what to do, she reminds herself.

She groans. The second foot slides out.

The body follows.

Mindy moans loudly as she pushes out the head. Her daughter is born with a splatter of blood. A train roars by outside.

“Oh, big girl, big girl,” Mindy says. “Oh my God. Hi baby. Hi precious girl.”

She caresses the nearly 9-pound newborn body and lovingly strokes her face.

“Look how big you are,” she says, turning to her husband. “Oh my God, they’re here.”

It is 9:22 a.m.

“You came out a funny way,” she tells Zoya Olga. “Mommy’s so proud of you. You did a great job.”Find out more

* Go to: www.earthbirthproductions.com; www.trustbirth.com.

Want to go?

* Mindy Goorchenko will lead a 10-week Birthworks childbirth education series beginning at 7:30 p.m. June 23 at The Path, 813 Torrance Blvd., Redondo Beach. Cost is $275 per couple. For information, call 310-809-2287.