New Breast Pap Smear Detects Early Cellular Changes; May Prevent Onset of Breast Cancer

DURHAM, N.C. — Long before a woman feels an ominous lump in her breast, Victoria Seewaldt, M.D., can test her for subtle signs that breast cancer may be brewing in a few errant cells amidst thousands of healthy ones. Never before has such a possibility existed, and Seewaldt is brimming with excitement.

“This is potentially the ‘breast pap smear’ that we never had before,” said Seewaldt, a scientist and breast oncologist at the Duke Comprehensive Cancer Center. “Just as we do with a cervical pap smear, we can now survey cells from the whole breast, examine them under the microscope and test for early changes that often precede breast cancer. Then we can give women a preventive agent to see if we can eradicate her abnormal cells and thus prevent cancer from developing.”

The new test, developed at University of Kansas Medical Center and refined at the Duke Comprehensive Cancer Center, will be undergoing clinical trials at three centers nationwide. It is far more sensitive than a mammogram because a pathologist analyzes each cell for specific molecular changes that are common to many breast cancers, said Seewaldt, director of Duke’s new Breast Health Clinic. It is especially useful for detecting changes in dense breasts, which are typically quite difficult to image using mammography.

In the test, physicians use a slender needle to extract cells from segments of the entire breast. Doctors then test each breast cell for specific genetic changes, as well as for abnormally shaped cells that are deemed “atypical.”

Carol Fabian, M.D., at the University of Kansas Medical Center, has shown that even a smattering of atypical cells confers a four-fold increase in a woman’s risk of breast cancer. And many scientists have linked specific gene alterations with the development of breast cancer. But further than that, scientists are unclear as to how breast cancers arise.

The new “breast pap smear” will help characterize a cell as it transforms from normal to abnormal, and then eventually into a malignant cell, said Seewaldt. Understanding how cells behave very early in the process of becoming cancerous can help doctors assess a woman’s potential cancer risk — and hopefully even prevent cancer — long before cellular changes have become irreversible, she said.

“Ninety percent of breast cancers occur randomly, without a family history of the disease or a known genetic mutation in the woman, said Seewaldt. “Clearly, we don’t understand how most breast cancers arise, and we don’t know how the various agents we give to patients actually repair what is malfunctioning.

“The new test will define what early changes in the breast looks like, and furthermore, it will tell a woman early on if a preventive treatment is really working in her own body.”

In particular, the test will detect the presence or absence of a specific gene called RAR beta. This gene regulates how breast cells use vitamin A in order to maintain their proper health. Studies have shown that RAR beta loses its ability to function in many women with breast cancer.

If RAR beta is present inside cells, vitamin A can do its job: regulating how breast epithelial cells grow, divide and eventually die at the appropriate time. Without RAR beta, vitamin A doesn’t work and breast epithelial cells embark on the road toward cancer. Hence, RAR beta is a good molecular “marker” by which to assess the potential risk of developing breast cancer.

Even a few breast epithelial cells that show loss of RAR beta function could signal an increased risk for breast cancer, said Seewaldt. A few abnormal cells likely reside in a field of many abnormal cells. Thus, a woman who shows even a sprinkling of cells without RAR beta will be given a preventive agent such as beta-carotene, flax seed oil, tamoxifen or a COX 2 inhibitor to determine if one of these agents can eradicate the abnormal cells.

“RAR beta gives us a potential marker to monitor if the preventive agents we’re giving have an impact on preventing breast cancer,” said Seewaldt. “We’ll test the women before, during and after treatment to see if any of the various agents are able to reduce the number of abnormal cells.”

Women aged 35 to 55 who are at high risk for breast cancer are eligible to join the clinical trial. High risk is defined as having two first degree relatives who had breast cancer; an abnormal breast biopsy or mammogram or a carrier of BRCA 1 or 2 — genes that confer a 90 percent lifetime risk of breast cancer.

Despite these criteria, Seewaldt cautions that there is no definitive way to measure risk without a test because the majority of breast cancers develop at random.

“As women in America, we are all at risk for breast cancer,” said Seewaldt. “Mammograms and self breast exams are good tests for looking at cancer, but they don’t always do a good job of finding early changes in the breast.”

While the test is only available at three clinical sites (Duke, Kansas and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University) as part of a clinical trial, Seewaldt hopes it will ultimately be available at numerous sites around the country. The test is cheap and so simple to administer and analyze that even a basic clinical laboratory could carry it out, she added. It requires only a syringe and pap smear fluid — no refrigeration or special preservation — and a simple “PCR” test to amplify genes that even a high school student could perform in the laboratory.

The test works as follows: the breast is first numbed with a local anesthetic, a slender needle is inserted into the inner quadrant of the breast, then it is slightly withdrawn and reinserted eight to 10 times in precisely defined segments of the breast. The process, called random fine needle aspiration, is repeated on the breast’s outer quadrant to ensure that cells are extracted from the entire breast.

The samples of breast tissue are analyzed for signs of atypia, including a critical alteration to RAR beta in which the gene is silenced by methylation. Methylation is thought to be triggered by environmental factors such as diet, nutrition, smoking and chemical exposures. These environmental triggers prompt a group of molecules to attach to a gene and convey a message to silence or reduce its expression. The gene itself remains unchanged, which is why scientists can’t search for a mutation in the gene.

Seewaldt describes methylation as like putting gum on a light switch. The light isn’t broken, but it can’t be switched on.

When RAR beta isn’t turned on, it can’t signal two other important tumor suppressor genes — CBP and p300 — which are also critical in regulating how a cell grows.

One key to reversing the methylation of RAR beta could lie in vitamin A and substances similar to vitamin A, said Seewaldt. Her recent studies have shown that vitamin A can actually demethylate RAR beta. In doing so, vitamin A initiates an important feedback loop that suppresses tumor growth in this way:

• Vitamin A turns on the RAR beta gene

• The RAR beta gene expresses a protein called a receptor

• The receptor acts like a dock that receives messages from hormones, vitamins, and the environment and conveys them inside the cell

• the messages are transmitted to CBP and p300

• CBP and p300 express their own proteins that enable the cell to better utilize vitamin A for its tumor-suppressing activities.

Seewaldt likens the process to a relay race. If one first runner doesn’t connect with the next runner, the entire loop is broken.

“We’ve always known that vitamins are important in the prevention of cancer, but here is a clear-cut example at the cellular level demonstrating that normal amounts of fresh vegetables — leafy greens, carrots, sweet potatoes — may be very important in preventing breast cancer.”

Seewaldt said the ultimate goal of the clinical trial and its associated research is to identify which cellular changes progress to become cancer, and which cellular changes are benign.

“What cellular changes promote the growth of breast cancer, and which agents can halt that progression? These are the questions we hope to answer.”

Thermal Scanning Offers Promise of Early Arthritis Detection

DURHAM, N.C. – A device developed to scan computer circuit boards for defects can detect the earliest signs of hand osteoarthritis, researchers at Duke University Medical Center have found.

The thermal scanner, sensitive enough to detect differences of a tenth of a degree Fahrenheit revealed that the temperature of finger joints is proportional to the severity of osteoarthritis. The study showed that finger joints are warmer than average – a sign of inflammation — in the first stage of osteoarthritis. In contrast, X-rays of fingers at this early stage of the disease produce inconclusive findings, said Virginia Kraus, M.D., a rheumatologist and associate professor of medicine at Duke University Medical Center.

The researchers’ temperature scans also showed that as osteoarthritis symptoms increased in severity, the joints tended to cool. The researchers’ analysis showed that the progressively cooler joint temperatures correlate with increasing disease severity revealed in X-rays of the same joints, Kraus said.

X-rays remains the standard clinical technique for diagnosing osteoarthritis, Kraus said. But thermal scanning holds promise for detecting osteoarthritis in the first stage of the disease, before joint changes become apparent on X-rays and before symptoms such as pain and joint enlargement appear, she said. “As we learn more about early stages of the disease, I think we’ll be able to intervene earlier, when there will be more chance of making a difference,” Kraus said.

The study was published in the July, 2004 issue of Rheumatology. Funding was provided by the National Institutes of Health.

Osteoarthritis results from the complex interaction among genetics, inflammation, mechanical forces and cellular and biochemical processes, Kraus said. The disease progresses through distinct stages visible with X-rays, including formation of bony spurs called osteophytes, progressive loss of joint space and joint erosion and remodeling. However, these X-ray changes occur relatively late in the process of osteoarthritis, which is one reason why joint symptoms of arthritis and X-rays often don’t coincide, Kraus said

The Duke study examined 91 people with clinical hand osteoarthritis in both hands and a minimum of three joints with bony enlargements. The majority were women (80.2 percent) and most were right-handed (86 out of 91).

The researchers analyzed three joints on each finger, excluding thumbs, with the thermal scanner, resulting in 2,184 joint measurements. The conditions ranged from joints with no apparent arthritis to joints with the highest score on a radiographic scale for arthritis. About half of the study subjects took anti-inflammatory drugs called NSAIDS, but there was no apparent effect of NSAID use on joint surface temperature, found the researchers. NSAIDS, or non-steroidal anti-inflammatory drugs, include aspirin, ibuprofen and naproxen.

The researchers observed significant temperature differences between non-osteoarthritis and osteoarthritis-affected joints. The researchers relied on the Kellgren Lawrence grading system to categorize the joints by X-rays: grade KL0 is a normal joint, grade KL1 is a joint with a small bony growth, or osteophyte, of doubtful significance. The scale stops at KL4, which marks severe joint space narrowing and large osteophytes.

The study showed joints meeting the KL1 criteria were significantly warmer than KL0 joints, while KL2 through KL4 joints were colder than KL0 joints. These results support the idea that the earliest phase of hand osteoarthritis represents an inflammatory phase of the disease, Kraus said. However, the drop in temperature as the disease worsens is an enigma. “It’s unclear if it’s from disuse or lack of blood supply, but temperature somehow diminishes as bony enlargements grow,” Kraus said.

The $16,000 scanner, loaned to Duke for the study, is used by computer manufacturers to detect defects in computer circuit boards, said Gabor Varju, M.D., lead author of the study and a pulmonary fellow at East Carolina University.

“Thermography was available in the 1970s and 1980s, but the technology was unreliable. The technology has improved to the point that we could do this study with reliable results,” Varju said.

In the future, thermography could be used help evaluate the effectiveness of osteoarthritis treatments by checking for changes in joint temperature, he said.

Other authors include Carl Pieper, assistant professor of radiology at Duke University Medical Center, and Jordan Renner, professor of radiology and allied health sciences at the University of North Carolina, Chapel Hill.

Thymus Transplant Might Save Babies Born Without Immune Systems

Durham, NC — Babies destined to die because they were born without a thymus — the organ that generates immune cells — can be given lifesaving tissue normally discarded during cardiac surgery on other infants, researchers have found.

Duke University Medical Center physicians have reported in the Aug. 1, 2003 issue of the journal Blood, successfully treating the immune disorder complete DiGeorge Syndrome in seven of 12 children who underwent an experimental thymus transplantation procedure. As many as one in 4,000 children in the United States are born each year with varying degrees of DiGeorge Syndrome, a condition in which the body does not produce adequate quantities of T cells, the cells that help the body fight infections. Between five and 10 children are born in the United States each year with complete DiGeorge Syndrome, a condition in which babies’ immune systems do not develop at all because they are born without a thymus.

All 12 patients in the Duke study were diagnosed with complete DiGeorge Syndrome. The 12 children were treated between 1993 and 2001 at Duke University Medical Center, the only center in the world currently offering the experimental thymus transplantation procedure.

The thymus rests on the heart and functions as a “schoolhouse” for immune cells. As cells pass through the thymus they are trained to become T cells, white blood cells that fight infection. A person without a thymus does not produce these T cells and, therefore, is at great risk for developing infections. By the time humans reach puberty, the thymus has completed most of its role in the body, shrinks in physical size and becomes dormant.

Without intervention, few children with complete DiGeorge Syndrome live to age 1, and none survive past 3 years of age. The seven surviving Duke patients are all well and living at home two to 10 years after receiving their transplants. Five patients in this study died, all from underlying congenital problems.

“Children born with complete DiGeorge Syndrome often face a host of medical challenges that can include heart problems, developmental disorders and deafness, but without treatment, infection resulting from immune deficiency is by far the factor that most often causes these children to die,” said Louise Markert, M.D., associate professor of pediatrics at Duke University Medical Center, and lead author of the study.

Markert and colleagues have pioneered the procedure to transplant thymus tissue into babies with DiGeorge Syndrome to enable their bodies to learn to fight infection. “Implanting thymus tissue early enough in life can provide these children with a chance to create a new immune system,” said Markert.

Transplantation is made possible because a small amount of thymus tissue is ordinarily discarded during neonatal heart surgeries. It must be excised in order for surgeons to expose the heart. Markert asks parents of babies undergoing heart surgery for permission to use any discarded thymus tissue to help a child with DiGeorge Syndrome.

The thymus tissue is then sliced thinly and cultured, and tested for any abnormalities or diseases. After preparing the tissue, surgeons implant the slices of thymus tissue into the quadriceps muscles of both legs of the complete DiGeorge Syndrome baby.

Without an immune system, the body cannot reject new organs. Therefore, matching the donor thymus tissue to the complete DiGeorge Syndrome baby is not necessary.

“We often find that parents, upon learning that they can help provide a second chance for another sick child, are delighted to donate tissue that otherwise would be discarded,” said Markert.

In treating babies with complete DiGeorge Syndrome, the Duke physicians aim to complete the thymus transplant as soon as possible after diagnosis. The children in the current study ranged in age from 33 days to 133 days at the time of transplantation. The babies are kept in isolation before and for several months after transplantation to prevent infection. Such isolation is necessary because the immune system will not develop until approximately five months after transplantation.

“We monitor the children quite intensively during the first year after transplantation,” said Markert. “We run several types of tests that can tell us whether the child’s body is forming immune cells and whether those cells are able to respond to potential infections in the body.”

One year after transplantation, the surviving seven patients had T cell counts ranging from 479 per cubic millimeter of blood to 1,580 per cubic millimeter. “A normal infant can expect to have a T cell count of over 1,500 per cubic millimeter,” said Markert. “We’re continuing to follow all of these patients to see how their T cell counts change as they grow and develop, but it is very encouraging to note that these children have suffered very few infections or other immune-related disorders since their immune systems began to take hold.”

According to the researchers, the survival rate and immunity levels in the children treated at Duke suggest that thymus transplantation should be considered as a standard treatment for immune deficiency in children with complete DiGeorge Syndrome. “There are other types of experimental treatments for complete DiGeorge Syndrome,” said Markert, “however, the results we’re reporting are better than with any other therapy and are the best one would expect given the heart and other congenital problems in these infants.”

The study was supported by grants from the National Institutes of Health and the American Association of Allergy, Asthma and Immunology Women Physicians in Allergy Award.

Joining Markert in the study were Duke colleagues Marcella Sarzotti, Ph.D.; Daniel Ozaki; Gregory Sempowski, Ph.D.; Maria Rhein; Laura Hale, M.D.; Marilyn Alexieff; Jie Li; Elizabeth Hauser, Ph.D.; Barton Haynes, M.D.; Henry Rice, M.D.; Michael Skinner, M.D.; Samuel Mahaffey, M.D., and James Jaggers, M.D., as well as Leonard Stein , M.D., and Michael Mill, M.D., of the University of North Carolina and Francoise Le Deist, M.D., of Laboratoire d’Immunologie Pédiatrique, Hôpital Necker–Enfants Malades, Paris, France.

Low-Carb Diet More Effective Than Low-Fat Diet

DURHAM, N.C. — People who followed a low-carbohydrate, high-protein diet lost more weight than people on a low-fat, low-cholesterol, low-calorie diet during a six-month comparison study at Duke University Medical Center. However, the researchers caution that people with medical conditions such as diabetes and high blood pressure should not start the diet without close medical supervision.

“This diet can be quite powerful,” said lead researcher Will Yancy, M.D., an assistant professor of medicine at Duke University Medical Center and a research associate at the Veterans Affairs Medical Center in Durham, N.C. “We found that the low-carb diet was more effective for weight loss,” Yancy added. “The weight loss surprised me, to be honest with you. We also found cholesterol levels seemed to improve more on a low-carb diet compared to a low-fat diet.”

The study is the first randomized, controlled trial of an Atkins-style diet approach, which includes vitamin and nutritional supplements. Along with losing an average of 26 pounds, dieters assigned to the low-carbohydrate plan lost more body fat, and lowered their triglyceride levels and raised their HDL, or good cholesterol, more than the low-fat dieters. The low-fat dieters lost an average of 14 pounds. Though the low-fat diet group lowered their total cholesterol more than the low-carb dieters, the latter group nearly halved their triglycerides and their HDL jumped five points. The low-carbohydrate group reported more adverse physical effects, such as constipation and headaches, but fewer people dropped out of the low-carbohydrate diet than the low-fat diet.

The results appear in the May 18, 2004, issue of the Annals of Internal Medicine. The research was funded by an unrestricted grant from the Robert C. Atkins Foundation. The study authors have no financial interest in Atkins Nutritionals, Inc.

The study builds on earlier results by the Duke University Medical Center researchers showing a low-carbohydrate diet can lead to weight loss — the first study of the low carbohydrate diet since 1980. Yancy and co-investigator Eric Westman, M.D., are currently testing whether a low-carbohydrate diet can help diabetics control their blood sugar levels.

Despite the considerable weight loss experienced by the low-carbohydrate dieters, Yancy does not recommend an Atkins-style plan for patients attempting to lose weight for the first time.

“Over six months the diet appears relatively safe, but we need to study the safety for longer durations,” Yancy said. He also cautioned that the diet could present certain health risks, such as elevations in LDL cholesterol levels, bone loss, or kidney stones. This and other recent studies of the low-carbohydrate diet have not demonstrated that these health risks occur over short durations, but they might occur in people on the diet for long-term. It is especially important that people on diuretic or diabetes medications be monitored by a doctor because the low-carbohydrate diet affects hydration and blood sugar levels, Yancy said.

The 120 study participants were randomly assigned to either the low-carbohydrate, high-protein diet or the low-fat, low-cholesterol, low-calorie diet. All were between 18 and 65 years old and in generally good health, with a body mass index (BMI) between 30 and 60, indicating obesity, and a total cholesterol level of more than 200 mg/dL. None had tried dieting or weight loss pills in the previous six months.

The low-carbohydrate group was permitted daily unlimited amounts of animal foods (meat, fowl, fish and shellfish); unlimited eggs; 4 oz. of hard cheese; two cups of salad vegetables such as lettuce, spinach or celery; and one cup of low-carbohydrate vegetables such as broccoli, cauliflower or squash. They also received daily nutritional supplements recommended by Atkins — a multivitamin, essential oils, a diet formulation and chromium picolinate. There were no restrictions on total calories, but carbohydrates were kept below 20 grams per day at the start of the diet.

The low-fat, low-cholesterol, low-calorie group followed a diet consisting of less than 30 percent of daily caloric intake from fat; less than 10 percent of calories from saturated fat; and less than 300 milligrams of cholesterol daily. They were also advised to cut back on calories. The recommended daily calorie level was 500 to 1,000 calories less than the participant’s maintenance diet — the calories needed to maintain current weight.

Study participants were encouraged to exercise 30 minutes at least three times per week, but no formal exercise program was provided. Both sets of dieters had group meetings at an outpatient research clinic regularly for six months.

Others members of the Duke research team were Maren Olsen, Ph.D.; John Guyton, M.D.; Ronna Bakst, R.D.; and Eric Westman, M.D., who was co-principal investigator for the study. The researchers maintained exclusive control of all data and analyses.

Nicotine Patch May Alleviate ‘Senior Moments’

DURHAM, N.C. – The nicotine patches that help smokers quit might also boost the recall of seniors with the mildest form of memory loss, according to results of a preliminary clinical trial on 11 people conducted at Duke University Medical Center. While nicotine itself has not been approved for long-term use, the research could point the way toward other nicotine-like drugs that might improve memory without the side effects of nicotine, according to the Duke researchers.

Previous research conducted by the Duke team and others has found evidence that nicotine might benefit people with a variety of disorders — including schizophrenia, attention deficit hyperactivity disorder and Alzheimer’s disease. However, the latest study is the first to examine the drug’s effects on people with age-associated memory impairment (AAMI), a common condition among older people characterized by so-called “senior moments.”

In a small sample of seniors, the researchers found that four weeks of nicotine treatment halved decision times on a standardized test of memory and increased participants’ ability to focus their attention – a skill critical for learning and memory. While receiving nicotine, seniors’ assessments of their own memories also showed small but significant improvement.

“In folks with relatively minor changes in their memory and thinking, there was some improvement with nicotine skin patches in the areas of attention and their general perception of their own memory,” said Duke geriatrician Heidi White, M.D. “We hope that will translate into treatments that allow people to actually function better in their daily lives.”

White and nicotine researcher Edward Levin, Ph.D., also at Duke, report their findings in a forthcoming issue of the journal Psychopharmacology (currently available online). Pharmacia, Inc. donated the nicotine and placebo patches.

The researchers emphasize that, despite the possible benefits of nicotine, the results should not encourage smoking. They also caution that nicotine patches have associated health risks – including nausea, dizziness, and increases in blood pressure and heart rate – and have not been approved for long-term use.

“While the results are encouraging, seniors should not try nicotine skin patches until larger studies testing the efficacy and safety of their use have been conducted,” Levin said.

Eleven participants over the age of 60 with AAMI completed the 10-week, double-blind clinical trial. Each senior wore a nicotine patch for four weeks and a placebo patch for an additional four weeks separated by a two-week resting period.

Clinicians monitored participants eight times over the course of the study to measure their medical condition and performance on three standard tests of memory

— the Clinical Global Impression (CGI) scale in which participants rated their own perception of improvement or decline in memory ability

— the Automated Neuropsychological Assessment Metrics battery including six tests measuring quickness of thinking, attention to a task, and memory and

–the Conners’ Continuous Performance Test, a longer computerized test of attentiveness.

The researchers reported that participants’ perceptions of their own memories were significantly improved after four weeks on the nicotine patch compared to the placebo patch, with more seniors receiving the drug reporting a small improvement in memory. While on the placebo patch, seniors on average reported no memory change.

The four-week nicotine patch treatment also cut seniors’ decision times from approximately 200 milliseconds to less than 100 milliseconds and significantly improved the consistency of participants’ performance on tests of reaction time, an indication that nicotine heightened attention in individuals with AAMI.

Participants reported only mild side effects of the patch treatments including skin irritation and nausea.

Nicotine’s activity in the brain stems from its ability to mimic the natural chemical acetylcholine, a nerve signal that plays a role in learning and memory among other functions, said Levin.

“Although nicotine isn’t naturally present in the body, the receptors that respond to it are,” he said. “The results of this study suggest that when used appropriately and under the right conditions, nicotine may alleviate the symptoms of mild forms of memory loss. In addition, such treatment may even attenuate the decline in memory function as people age.”

The Duke team and their colleagues at the University of Vermont and Georgetown University have received funding from the National Institute on Aging to pursue the benefits and safety of nicotine patches for the treatment of mild cognitive impairment (MCI), a slightly more severe form of memory loss than AAMI. Patients with MCI are at increased risk for developing the dementia characteristic of Alzheimer’s disease.

Behavioral Therapy Effective in Treatment of Insomnia

DURHAM, N.C. — New clinical data show that changing a person’s attitudes about sleep and teaching new habits is a promising treatment for insomnia and may be an alternative to medication for the treatment of persistent primary insomnia, a sleep disorder that affects up to 5 percent of Americans.

More than one-third of the adult population is bothered by insomnia at least some of the time and 10 percent to 15 percent have chronic, unrelenting insomnia, according to Jack D. Edinger, lead author of the study appearing in the April 11 issue of the Journal of the American Medical Association. Edinger is a medical psychologist with Duke University Medical Center and the Durham VA Medical Center.

“This study shows quite clearly that a cognitive behavioral insomnia therapy can be effective for people who have difficulty staying asleep at night,” Edinger said.

“Many patients were able to reach fairly normal levels of sleep with this treatment and without the use of sleeping pills, and the results lasted through six months of follow-up.”

In terms of this study, cognitive behavioral therapy (CBT) is a treatment that combines changing an individual’s beliefs and attitudes about sleep and then teaching that person how to implement new behavioral patterns or habits in order to improve sleep. For example, people are taught how to think about their sleep in a more constructive way (change of attitude) and also how to establish better sleep patterns by incorporating new habits such as getting out of bed at the same time each day (even if it means getting less sleep) and eliminating daytime napping.

The study also showed that the treatment leads to clinically significant sleep improvements within six weeks, Edinger noted.

CBT appears to be a promising, more universally effective treatment for insomnia, according to Edinger. Early results suggest CBT effectively addresses both sleep-onset and sleep-maintenance problems, and produces a better longterm outcome than do medication or placebo.

The study included 75 study participants with chronic primary sleep insomnia who were divided into three groups. Each group received either cognitive behavioral therapy, relaxation training or placebo therapy for six weeks. Those receiving cognitive therapy saw a 54 percent reduction in their wake time after sleep onset as compared to a 16 percent reduction for the group receiving relaxation therapy and 12 percent for the placebo group.

Currently, sedative hypnotics or antidepressants are often used for treating insomnia, but many experts feel that neither should be recommended for longterm treatment of chronic primary insomnia.

The study was funded by the National Institute of Mental Health and is one of the only studies done to date in the area of behavioral insomnia research that has used a double-blind, placebo control group design.

Thermal Scanning Offers Promise of Early Arthritis Detection

DURHAM, N.C. – A device developed to scan computer circuit boards for defects can detect the earliest signs of hand osteoarthritis, researchers at Duke University Medical Center have found.

The thermal scanner, sensitive enough to detect differences of a tenth of a degree Fahrenheit revealed that the temperature of finger joints is proportional to the severity of osteoarthritis. The study showed that finger joints are warmer than average – a sign of inflammation — in the first stage of osteoarthritis. In contrast, X-rays of fingers at this early stage of the disease produce inconclusive findings, said Virginia Kraus, M.D., a rheumatologist and associate professor of medicine at Duke University Medical Center.

The researchers’ temperature scans also showed that as osteoarthritis symptoms increased in severity, the joints tended to cool. The researchers’ analysis showed that the progressively cooler joint temperatures correlate with increasing disease severity revealed in X-rays of the same joints, Kraus said.

X-rays remains the standard clinical technique for diagnosing osteoarthritis, Kraus said. But thermal scanning holds promise for detecting osteoarthritis in the first stage of the disease, before joint changes become apparent on X-rays and before symptoms such as pain and joint enlargement appear, she said. “As we learn more about early stages of the disease, I think we’ll be able to intervene earlier, when there will be more chance of making a difference,” Kraus said.

The study was published in the July, 2004 issue of Rheumatology. Funding was provided by the National Institutes of Health.

Osteoarthritis results from the complex interaction among genetics, inflammation, mechanical forces and cellular and biochemical processes, Kraus said. The disease progresses through distinct stages visible with X-rays, including formation of bony spurs called osteophytes, progressive loss of joint space and joint erosion and remodeling. However, these X-ray changes occur relatively late in the process of osteoarthritis, which is one reason why joint symptoms of arthritis and X-rays often don’t coincide, Kraus said

The Duke study examined 91 people with clinical hand osteoarthritis in both hands and a minimum of three joints with bony enlargements. The majority were women (80.2 percent) and most were right-handed (86 out of 91).

The researchers analyzed three joints on each finger, excluding thumbs, with the thermal scanner, resulting in 2,184 joint measurements. The conditions ranged from joints with no apparent arthritis to joints with the highest score on a radiographic scale for arthritis. About half of the study subjects took anti-inflammatory drugs called NSAIDS, but there was no apparent effect of NSAID use on joint surface temperature, found the researchers. NSAIDS, or non-steroidal anti-inflammatory drugs, include aspirin, ibuprofen and naproxen.

The researchers observed significant temperature differences between non-osteoarthritis and osteoarthritis-affected joints. The researchers relied on the Kellgren Lawrence grading system to categorize the joints by X-rays: grade KL0 is a normal joint, grade KL1 is a joint with a small bony growth, or osteophyte, of doubtful significance. The scale stops at KL4, which marks severe joint space narrowing and large osteophytes.

The study showed joints meeting the KL1 criteria were significantly warmer than KL0 joints, while KL2 through KL4 joints were colder than KL0 joints. These results support the idea that the earliest phase of hand osteoarthritis represents an inflammatory phase of the disease, Kraus said. However, the drop in temperature as the disease worsens is an enigma. “It’s unclear if it’s from disuse or lack of blood supply, but temperature somehow diminishes as bony enlargements grow,” Kraus said.

The $16,000 scanner, loaned to Duke for the study, is used by computer manufacturers to detect defects in computer circuit boards, said Gabor Varju, M.D., lead author of the study and a pulmonary fellow at East Carolina University.

“Thermography was available in the 1970s and 1980s, but the technology was unreliable. The technology has improved to the point that we could do this study with reliable results,” Varju said.

In the future, thermography could be used help evaluate the effectiveness of osteoarthritis treatments by checking for changes in joint temperature, he said.

Other authors include Carl Pieper, assistant professor of radiology at Duke University Medical Center, and Jordan Renner, professor of radiology and allied health sciences at the University of North Carolina, Chapel Hill.

Low-Carb Diet More Effective Than Low-Fat Diet

DURHAM, N.C. — People who followed a low-carbohydrate, high-protein diet lost more weight than people on a low-fat, low-cholesterol, low-calorie diet during a six-month comparison study at Duke University Medical Center. However, the researchers caution that people with medical conditions such as diabetes and high blood pressure should not start the diet without close medical supervision.

“This diet can be quite powerful,” said lead researcher Will Yancy, M.D., an assistant professor of medicine at Duke University Medical Center and a research associate at the Veterans Affairs Medical Center in Durham, N.C. “We found that the low-carb diet was more effective for weight loss,” Yancy added. “The weight loss surprised me, to be honest with you. We also found cholesterol levels seemed to improve more on a low-carb diet compared to a low-fat diet.”

The study is the first randomized, controlled trial of an Atkins-style diet approach, which includes vitamin and nutritional supplements. Along with losing an average of 26 pounds, dieters assigned to the low-carbohydrate plan lost more body fat, and lowered their triglyceride levels and raised their HDL, or good cholesterol, more than the low-fat dieters. The low-fat dieters lost an average of 14 pounds. Though the low-fat diet group lowered their total cholesterol more than the low-carb dieters, the latter group nearly halved their triglycerides and their HDL jumped five points. The low-carbohydrate group reported more adverse physical effects, such as constipation and headaches, but fewer people dropped out of the low-carbohydrate diet than the low-fat diet.

The results appear in the May 18, 2004, issue of the Annals of Internal Medicine. The research was funded by an unrestricted grant from the Robert C. Atkins Foundation. The study authors have no financial interest in Atkins Nutritionals, Inc.

The study builds on earlier results by the Duke University Medical Center researchers showing a low-carbohydrate diet can lead to weight loss — the first study of the low carbohydrate diet since 1980. Yancy and co-investigator Eric Westman, M.D., are currently testing whether a low-carbohydrate diet can help diabetics control their blood sugar levels.

Despite the considerable weight loss experienced by the low-carbohydrate dieters, Yancy does not recommend an Atkins-style plan for patients attempting to lose weight for the first time.

“Over six months the diet appears relatively safe, but we need to study the safety for longer durations,” Yancy said. He also cautioned that the diet could present certain health risks, such as elevations in LDL cholesterol levels, bone loss, or kidney stones. This and other recent studies of the low-carbohydrate diet have not demonstrated that these health risks occur over short durations, but they might occur in people on the diet for long-term. It is especially important that people on diuretic or diabetes medications be monitored by a doctor because the low-carbohydrate diet affects hydration and blood sugar levels, Yancy said.

The 120 study participants were randomly assigned to either the low-carbohydrate, high-protein diet or the low-fat, low-cholesterol, low-calorie diet. All were between 18 and 65 years old and in generally good health, with a body mass index (BMI) between 30 and 60, indicating obesity, and a total cholesterol level of more than 200 mg/dL. None had tried dieting or weight loss pills in the previous six months.

The low-carbohydrate group was permitted daily unlimited amounts of animal foods (meat, fowl, fish and shellfish); unlimited eggs; 4 oz. of hard cheese; two cups of salad vegetables such as lettuce, spinach or celery; and one cup of low-carbohydrate vegetables such as broccoli, cauliflower or squash. They also received daily nutritional supplements recommended by Atkins — a multivitamin, essential oils, a diet formulation and chromium picolinate. There were no restrictions on total calories, but carbohydrates were kept below 20 grams per day at the start of the diet.

The low-fat, low-cholesterol, low-calorie group followed a diet consisting of less than 30 percent of daily caloric intake from fat; less than 10 percent of calories from saturated fat; and less than 300 milligrams of cholesterol daily. They were also advised to cut back on calories. The recommended daily calorie level was 500 to 1,000 calories less than the participant’s maintenance diet — the calories needed to maintain current weight.

Study participants were encouraged to exercise 30 minutes at least three times per week, but no formal exercise program was provided. Both sets of dieters had group meetings at an outpatient research clinic regularly for six months.

Others members of the Duke research team were Maren Olsen, Ph.D.; John Guyton, M.D.; Ronna Bakst, R.D.; and Eric Westman, M.D., who was co-principal investigator for the study. The researchers maintained exclusive control of all data and analyses.

Low-Carb Diet More Effective Than Low-Fat Diet

DURHAM, N.C. — People who followed a low-carbohydrate, high-protein diet lost more weight than people on a low-fat, low-cholesterol, low-calorie diet during a six-month comparison study at Duke University Medical Center. However, the researchers caution that people with medical conditions such as diabetes and high blood pressure should not start the diet without close medical supervision.

“This diet can be quite powerful,” said lead researcher Will Yancy, M.D., an assistant professor of medicine at Duke University Medical Center and a research associate at the Veterans Affairs Medical Center in Durham, N.C. “We found that the low-carb diet was more effective for weight loss,” Yancy added. “The weight loss surprised me, to be honest with you. We also found cholesterol levels seemed to improve more on a low-carb diet compared to a low-fat diet.”

The study is the first randomized, controlled trial of an Atkins-style diet approach, which includes vitamin and nutritional supplements. Along with losing an average of 26 pounds, dieters assigned to the low-carbohydrate plan lost more body fat, and lowered their triglyceride levels and raised their HDL, or good cholesterol, more than the low-fat dieters. The low-fat dieters lost an average of 14 pounds. Though the low-fat diet group lowered their total cholesterol more than the low-carb dieters, the latter group nearly halved their triglycerides and their HDL jumped five points. The low-carbohydrate group reported more adverse physical effects, such as constipation and headaches, but fewer people dropped out of the low-carbohydrate diet than the low-fat diet.

The results appear in the May 18, 2004, issue of the Annals of Internal Medicine. The research was funded by an unrestricted grant from the Robert C. Atkins Foundation. The study authors have no financial interest in Atkins Nutritionals, Inc.

The study builds on earlier results by the Duke University Medical Center researchers showing a low-carbohydrate diet can lead to weight loss — the first study of the low carbohydrate diet since 1980. Yancy and co-investigator Eric Westman, M.D., are currently testing whether a low-carbohydrate diet can help diabetics control their blood sugar levels.

Despite the considerable weight loss experienced by the low-carbohydrate dieters, Yancy does not recommend an Atkins-style plan for patients attempting to lose weight for the first time.

“Over six months the diet appears relatively safe, but we need to study the safety for longer durations,” Yancy said. He also cautioned that the diet could present certain health risks, such as elevations in LDL cholesterol levels, bone loss, or kidney stones. This and other recent studies of the low-carbohydrate diet have not demonstrated that these health risks occur over short durations, but they might occur in people on the diet for long-term. It is especially important that people on diuretic or diabetes medications be monitored by a doctor because the low-carbohydrate diet affects hydration and blood sugar levels, Yancy said.

The 120 study participants were randomly assigned to either the low-carbohydrate, high-protein diet or the low-fat, low-cholesterol, low-calorie diet. All were between 18 and 65 years old and in generally good health, with a body mass index (BMI) between 30 and 60, indicating obesity, and a total cholesterol level of more than 200 mg/dL. None had tried dieting or weight loss pills in the previous six months.

The low-carbohydrate group was permitted daily unlimited amounts of animal foods (meat, fowl, fish and shellfish); unlimited eggs; 4 oz. of hard cheese; two cups of salad vegetables such as lettuce, spinach or celery; and one cup of low-carbohydrate vegetables such as broccoli, cauliflower or squash. They also received daily nutritional supplements recommended by Atkins — a multivitamin, essential oils, a diet formulation and chromium picolinate. There were no restrictions on total calories, but carbohydrates were kept below 20 grams per day at the start of the diet.

The low-fat, low-cholesterol, low-calorie group followed a diet consisting of less than 30 percent of daily caloric intake from fat; less than 10 percent of calories from saturated fat; and less than 300 milligrams of cholesterol daily. They were also advised to cut back on calories. The recommended daily calorie level was 500 to 1,000 calories less than the participant’s maintenance diet — the calories needed to maintain current weight.

Study participants were encouraged to exercise 30 minutes at least three times per week, but no formal exercise program was provided. Both sets of dieters had group meetings at an outpatient research clinic regularly for six months.

Others members of the Duke research team were Maren Olsen, Ph.D.; John Guyton, M.D.; Ronna Bakst, R.D.; and Eric Westman, M.D., who was co-principal investigator for the study. The researchers maintained exclusive control of all data and analyses.

|| DukeMedNews || Low-dose HRT Could Cut Women’s Health Risk

This week on MedMinute … Hormone replacement therapy (HRT) can build bone strength in women. But HRT is linked to increased risk of heart disease and breast cancer. A small-scale study suggests that using a lower dose and different type of hormone may reduce those health risks.

Listen to MedMinute Audio

After much controversy, the confusion about hormone replacement therapy continues. Last year, a Women’s Health Initiative study found that HRT lowered the risk for osteoporosis but increased the risk for heart disease and breast cancer. Now a new study finds that a low-dose estrogen therapy might offer the benefits of HRT, without the risk.

Dr. Tracy Gaudet is director of the Center for Integrative Medicine at Duke University Medical Center.

“It looks very promising that a lower dose of estrogen and different type of estrogen can be very good for bone. They compared people not on the hormone to people on the hormone, and the people on the hormone clearly had better bone density.”

Gaudet says the size and duration of the study were limited, but the results show promise. Women taking estrogen had no more health problems than those not taking it, and bone density increased.

“We do know that estrogen is useful in that way. One of the important questions is: Could we use lower dose and/or a different type of estrogen and get the benefit without the risk? That’s a question we still don’t have the answer to.”

I’m Cabell Smith for MedMinute.