Study outlines optimal therapy for breast cancer with BRCA mutation

Those are the findings of a 10-year study led by researchers at the University of Michigan Comprehensive Cancer Center. The study authors found that women with the genetic mutation who had their ovaries removed or took the anti-estrogen drug tamoxifen had lower rates of breast cancer recurrence or new breast cancers in the other breast.

Women who carry a mutation on the BRCA1 or BRCA2 gene are at an increased risk of breast cancer compared to women without the mutation. And once diagnosed with breast cancer, they face a higher rate of a second tumor occurring. Because of this, questions remain about whether these women should undergo breast-conserving surgery instead of mastectomy, which removes the entire breast.

In this study, published in the June 1 issue of the Journal of Clinical Oncology, researchers from 11 centers looked at 160 women with early breast cancer and the BRCA1 or BRCA2 gene mutations. The women were treated with lumpectomy, surgery to remove only the tumor, followed by radiation therapy. These women were compared to 445 similar women who were treated for breast cancer but did not carry the genetic mutations.

After 15 years, both groups of women had similar rates of the tumor reoccurring in the same breast. But among the women with the BRCA1 or BRCA2 mutations, those who were further treated by having their ovaries removed, a procedure called oophorectomy, were less likely to have a recurrence. Similarly, tamoxifen dropped the risk of same-breast recurrence for the mutation carriers by 58 percent.

Women with the genetic mutations had a significantly greater risk of developing breast cancer in the opposite breast than did the control group. After 15 years, 45 percent of the women with the mutation who had not undergone oopherectomy developed a second breast cancer in the other breast, compared to only 9 percent of those women without the genetic mutation.

Women with the mutation who took tamoxifen had a 69 percent reduction in breast cancer in the opposite breast. Among women who did not undergo oophorectomy, tamoxifen made a significant difference: 6 percent of those taking tamoxifen had a second cancer in the opposite breast after 15 years, compared to 54 percent of those who did not take tamoxifen.

�For women with early stage breast cancer who are BRCA1 or BRCA2 carriers, our 10-year data suggest that oophorectomy or tamoxifen in women treated with breast conservation and radiation therapy help to reduce the risk of recurrences and new primary cancers in the treated breast to levels comparable to those observed in women with early stage breast cancer who are not BRCA1 or BRCA2 carriers,� says lead study author Lori J. Pierce, M.D., professor of radiation oncology at the U-M Medical School.

Lifestyle, diet may stop or reverse prostate cancer progression

The research is the first randomized, controlled trial showing that lifestyle changes may affect the progression of any type of cancer. Study findings are published in the September issue of the Journal of Urology.

The study was directed by Dean Ornish, MD, clinical professor, and Peter Carroll, MD, chair of the Department of Urology, both of the University of California, San Francisco, and the late William Fair, MD, chief of urologic surgery and chair of urologic oncology, Memorial Sloan-Kettering Cancer Center.

The research team studied 93 men with biopsy-proven prostate cancer who had elected not to undergo conventional treatment for reasons unrelated to this study. The participants were randomly divided into either a group who were asked to make comprehensive changes in diet and lifestyle or a comparison group who were not asked to do so.

After one year, the researchers found that PSA levels (a protein marker for prostate cancer) decreased in men in the group who made comprehensive lifestyle changes but increased in the comparison group. There was a direct correlation between the degree of lifestyle change and the changes in PSA. Also, they found that serum from the participants inhibited prostate tumor growth in vitro by 70 percent in the lifestyle-change group but only 9 percent in the comparison group. Again, there was a direct correlation between the degree of lifestyle change and the inhibition of prostate tumor growth.

Bladder problems increase in men as they age, study reports

Their findings remind patients and their physicians that urination difficulties in men can be better cared for at early onset. Additionally, the study notes that as men age, the possibility increases that they will experience problems with urination.

"What we know is that many men ignore their symptoms and do not seek assistance with their physician until much later," said Andrew Rule, M.D., nephrologist and epidemiologist at Mayo Clinic and the lead author of the study. "What happens is men can end up with a bladder not working, perhaps needing a bladder catheter all the time. They also become at increased risk for bladder infections and even kidney failure problems."

The researchers looked at information in men from two tests: post-void residual and voided volume. The post-void residual test involved men urinating and then having an ultrasound scan to determine how much urine remained in the bladder. The voided volume test measured how much urine men could void with a full bladder.

Dr. Rule said that both tests are difficult to interpret in a patient because they can yield varying results with the same person each time. However, because the study relied on hundreds of men with multiple visits, those variations could be lessened. The study looked at a random sample of 529 men, ages 40 to 79, who were followed with the two tests every two years for up to 12 years.

Dr. Rule says the study presents some new data on the natural history of the post-void residual and void volume in men as they age.

Shock wave therapy for kidney stones linked to diabetes, hypertension

Risk for diabetes was related to the intensity of the treatment and quantity of the shock waves administered; hypertension was related to treatment of stones in both kidneys.

Shock wave lithotripsy uses shock waves to break up an impassable kidney stone into smaller, sandlike pieces which can be passed spontaneously, usually within a month. The patient and the lithotriptor that emits the shock waves are placed in a water bath. Water allows easier conduction of the shock waves through the patient's tissue and precise focus on the kidney stone.

"This is a completely new finding," says Amy Krambeck, M.D., Mayo Clinic urology resident and lead study investigator. "This opens the eyes of the world of urology to the fact that hypertension and diabetes are potential side effects. We can't say with 100 percent certainty that the shock wave treatment for the kidney stones caused diabetes and hypertension, but the association was very strong. The risk of developing diabetes after shock wave lithotripsy is almost four times the risk of people with kidney stones treated with medicine, and the risk of developing hypertension is one and one-half times, which is a significant risk increase."

The study, which is the first examination of the effects of shock wave lithotripsy over the long term, involved reviewing charts of 630 patients treated with shock wave lithotripsy in 1985 at Mayo Clinic. The researchers sent those still alive a questionnaire; almost 60 percent responded. The researchers matched the patients treated with lithotripsy to patients similar in age, gender and initial time of seeing a urologist for kidney stones who received a different treatment, medicine. Nineteen years post-treatment, those treated with lithotripsy had 3.75 times the risk of having diabetes as those given the other kidney stone treatment. The degree of increased risk rose with greater number and intensity of shocks administered. Those treated with lithotripsy also had 1.47 times the risk of having hypertension -- high blood pressure -- than those who received the other kidney stone treatment; risk was highest for those who had both kidneys treated.

Scalpel-free surgery could reduce risk of HIV and hepatitis

"While these rates are alarming, they are not entirely unexpected. General precautions have been in effect for some time to prevent the spread of disease to health care workers in the operating room," said Martin A. Makary, M.D., assistant professor of surgery and public health at Johns Hopkins and lead author of a report in the May 2005 issue of the Annals of Surgery.

"Given the high incidence of these infections, however, we have developed new strategies such as 'sharpless' surgery-a surgical technique which uses high-technology alternatives to needles and knives. We advocate using these techniques whenever possible in high-risk settings to further protect health care workers from accidental transmission," added Makary.

Sharpless surgical techniques include laparoscopy, electrocautery to replace scalpel incisions, and skin clips or glue instead of sewing to close or repair wounds.

Previous studies have shown that health care workers are injured in about 7 percent of operations. As many as 87 percent of surgeons will receive an injury that breaks the skin -- thus allowing for possible disease transmission - at some point in their career. There are an estimated 40,000 new cases of HIV each year, and hepatitis C is increasing at an even faster rate, according to the report. The study concludes that by studying the rates of HIV and hepatitis B and C among patients presenting for surgery, a more accurate incidence of disease is measured within a community, bypassing the selection bias of traditional statistics of known infected patients presenting to primary care clinics. Furthermore, the authors report that blood-borne pathogens are associated with certain types of operations.

The researchers also found that the operations associated with the greatest risk of infection - lymph-node biopsy, soft-tissue-mass excision and abscess-drainage cases - were often assigned to the most inexperienced surgeons-in-training, placing them at greatest risk.

"Sharpless surgical techniques combined with traditional precautions and early education for surgery trainees are the most practical ways to reduce the risk of infection to health care workers," said Makary.

The researchers studied 709 consecutive adult general surgery operations performed between July 2003 and June 2004 in the community surgical service at The Johns Hopkins Hospital including inpatient, emergency department and outpatient surgical procedures. Data were collected on HIV, hepatitis B and hepatitis C test results, type of operation, age, sex and history of intravenous drug use.

The researchers found that 38 percent of all operations involved a bloodborne pathogen, and almost half (47 percent) of all men tested positive for at least one infection. HIV accounted for 26 percent of infections, hepatitis B for 4 percent, hepatitis C for 35 percent, and co-infection with HIV and hepatitis C accounted for 17 percent of infections. In addition, bloodborne pathogen infection was found in up to 65 percent of patients with a history of intravenous drug use and in as many as 71 percent of patients undergoing a soft-tissue abscess procedure or lymph-node biopsy.

While the patients in this study tend toward low socioeconomic status and increased substance use, most university hospitals in the United States are located in urban areas and serve a similar patient population, added Makary.

Other authors on the report are Eric S. Weiss, Theresa Wang, Dora Syin, Peter Pronovost, David Chang and Edward Cornwell III.

Surgery found to be best remedy for hammer hand

"In the past, treatment of hypothenar hammer syndrome has been controversial, and physicians have been searching for some way to treat it," says Craig Johnson, M.D., chair of Mayo Clinic's Division of Plastic Surgery and lead study investigator. "From our study, it's clear that people with this syndrome shouldn't be treated with medication or other treatments, but with surgery."

Dr. Johnson explains that symptoms improved in 78 percent of the patients in his study who underwent a bypass grafting operation and that he witnesses an almost immediate relief in his patients with this surgery.

"Post-surgery, patients feel their hands are warmer right away, though ulcers take a little longer to heal," he says. "Most people do quite well and get back to work quickly."

Patients with this condition have a damaged ulnar artery, a key means of blood flow to the hand. In addition to the sensory damage, they also can develop small ulcers in their fingertips resulting in blackened fingers or even gangrene, due to lack of oxygenation.

"Many times they can't do their jobs due to pain," says Dr. Johnson. "They have cold intolerance, so often they can't go outside when it's cold or handle anything chilled, like cold meat. They also can't hold heavy objects."

The treatment found to improve these symptoms, bypass grafting surgery, involves removing the damaged portion of the artery, which Dr. Johnson describes as clotted much like a clogged lead pipe. The artery's blood flow is then restored by replacing the section of blocked artery with a vein graft.

In this study, Dr. Johnson studied 115 hands in 101 patients evaluated at Mayo Clinic. Medical and surgical treatment options pursued were evaluated by chart review and postoperative phone calls for all patients, and by duplex scan, an ultrasound of the arteries that measures blood flow, for those who underwent bypass surgery. The patients studied included 98 males and three females; most were laborers.

An average of 3.5 years post-treatment, 29 of the 41 patients treated with medication or sympathectomy -- surgery to interrupt the nerve pathway -- showed no change in symptoms, seven were worse and five showed symptom improvement.

Two types of excision operations were used for the remaining 60 patients studied. Four received excision of the damaged portion of the ulnar artery or surrounding vessels followed by ligation, or binding; symptoms in three out of four of these patients were unchanged post-surgery. The other 56 patients were treated with surgical excision of the damaged ulnar artery or surrounding vessels followed by bypass grafting; 78 percent of these patients improved, losing their pain and cold intolerance and returning to work. Of the 22 percent who showed no change or worsening of symptoms following bypass grafting surgery, 86 percent of the patients had continued smoking.

Dr. Johnson explains that quitting smoking is key to a lasting effect of the bypass grafting surgery, thus he tries not to operate on patients who continue to smoke. "Smokers do well for awhile, but over time their bypass graft gets clotted," he explains.

The cause of hypothenar hammer syndrome is unknown. Previously the condition has been thought to be task or work related due to use of the palm as a hammer, but this is yet unsettled, says Dr. Johnson. "It's not entirely certain whether you have to be running a jackhammer for 20 years or laying concrete to develop this syndrome." There could also be a genetic predisposition to the syndrome, he indicates. Dr. Johnson points to a need for further research into the origins of this syndrome.

Obesity surgery translates to cardiac benefit

In a study presented at the American College of Cardiology's 55th Annual Scientific Session, a team of researchers from the Mayo Clinic in Minnesota evaluated the effect of bariatric surgery on longterm cardiovascular risk and estimated prevented outcomes. ACC.06 is the premier cardiovascular medical meeting, bringing together over 30,000 cardiologists to further breakthroughs in cardiovascular medicine.

The team completed a historical study between 1990 and 2003 of 197 patients with class II-III obesity who undertook Roux-en-Y gastric bypass surgery (sometimes referred to as "stomach stapling"), compared to 163 control patients enrolled in a weight reduction program. With an average follow-up time of 3.3 years, the team recorded changes in cardiovascular risk factors such as cholesterol levels, body mass index (BMI) and diabetes criteria.

Though the team originally estimated a higher 10-year risk for cardiac events in the surgical group at the start of the study due to their associated conditions, researchers found at follow-up that the patients had a much lower risk than the control group for having a heart complication (18.3 vs. 30 percent). Using the study parameters and risk models based on previously published data, the team estimated that for every 100 patients, the surgery would prevent 16.2 cardiovascular events and 4.1 overall deaths, as compared to the control group. However, should the number of deaths during surgery approach 4 percent, the protective effect is limited, as may be in the case in centers with very low volumes of weight loss surgeries.

Experimental shingles vaccine proves effective in nationwide study

In one of the largest adult vaccine clinical trials ever, researchers have found that an experimental vaccine against shingles (zoster vaccine) prevented about half of cases of shingles--a painful nerve and skin infection--and dramatically reduced its severity and complications in vaccinated persons who got the disease. The findings appear in the June 2 issue of The New England Journal of Medicine.

The Shingles Prevention Study, conducted over 5 �-years, was led by the Department of Veterans Affairs (VA) and carried out in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and Merck & Co., Inc. (Whitehouse Station, NJ).

"This is very promising news for older persons," says Stephen E. Straus, M.D., an infectious diseases specialist at NIAID and Director of the NIH National Center for Complementary and Alternative Medicine, who participated in the design, oversight and conduct of the trial. "These striking results indicate for the first time that we can use a vaccine to prevent shingles, one of the most common and debilitating illnesses of aging. And among vaccine recipients who did get shingles, the episodes generally were far milder than they otherwise would have been."

"For some people, shingles can result in months or even years of misery," comments study leader Michael N. Oxman, M.D., an infectious disease specialist at the San Diego VA Healthcare System and the University of California, San Diego.

Shingles, also known as herpes zoster, is caused by reactivation of the virus that causes chickenpox. Once chickenpox infection has run its course, the virus is not eliminated; rather, it retreats to clusters of sensory nerve cells usually located near the spinal cord, where the virus persists in a dormant state. As immunity weakens with advancing age, the virus can reactivate, multiply in and damage sensory nerve cells to cause pain. It then migrates to the skin, causing the blistering rash of shingles.

Generally, shingles first manifests as pain, itching or tingling in an area of skin on one side of the body or face. Then a painful blistering rash develops in that same area of skin; the rash can take two to four weeks to heal.

Hair-generating multipotent stem cells found in hair follicles

Using an animal model, a research team led by Yann Barrandon at the EPFL (Ecole Polytechnique Federale de Lausanne) and the CHUV (Lausanne University Hospital) has discovered that certain cells inside the hair follicle are true multipotent stem cells, capable of developing into the many different cell types needed for hair growth and follicle replacement.

In an article appearing in the Oct 3 advance online edition of the Proceedings of the National Academy of Sciences, they demonstrate that these holoclones can be used for long-term follicle renewal.

In 2001, Barrandon was part of a French research team who reported in the scientific journal Cell that stem cells could be used to generate skin containing hair and sebaceous glands in mice. But at that time it was unclear whether the stem cells in hair follicles were true stem cells, capable of long-term renewal, or multipotent progenitor cells that would not permanently engraft in the follicle.

In the current PNAS study, the Swiss researchers have answered that question, using rat whisker hair follicles to demonstrate that the clonogenic keratinocytes in hair follicles are true stem cells.

Barrandon's group isolated stem cells from rat whisker follicles, labelled them, and grew them in culture for 140 generations. They then implanted progeny cells into the skin of newborn mice whose hair follicles were just being formed. This skin was then grafted onto athymic (nude) mice. Some cells were incorporated into developing follicles, but other follicles were completely made up of labelled cells. Each progeny cell contributed to the formation of eight different types of cell in the follicle, including those of the outer root sheath, inner root sheath, the hair shaft, the sebaceous gland and the epidermis.

After 125 days, a biopsy was taken from the graft, and labelled stem cells were isolated, subcloned, cultivated and then once again transplanted. The rat whisker stem cells participated again in forming all the cell types needed to form the hair follicle and sebaceous glands, resulting in hair bulbs that underwent repeated normal phases of growth, rest and regeneration. The fact that the transplanted cells participate in the hair cycle over long periods of time shows that they are true multipotent stem cells and not progeniture cells.

Study finds new drug is potent treatment for CML

BOSTON--A laboratory study led by researchers at Dana-Farber Cancer Institute has shown that a potent and highly selective therapy for chronic myelogenous leukemia (CML) may ultimately be more effective than Gleevec�, the current standard of care. The researchers report in the February issue of Cancer Cell that the new compound, AMN107, is about 20 times more potent than Gleevec and is effective in treating Gleevec-resistant disease in model systems. Discovered by and in development with Novartis Pharma AG, AMN107 is a small molecule tyrosine kinase inhibitor.

"While Gleevec represents a major treatment advance for CML � approximately 95 percent of patients treated with Gleevec achieve remission � there clearly is a need for therapies that produce longer remissions, are active against advanced disease, and can be used when Gleevec loses effectiveness," says Dana-Farber's James Griffin, MD, senior author of the study.

Gleevec shuts down CML by blocking the function of Bcr-Abl, the abnormal tyrosine kinase protein in the leukemic cells that causes them to grow too quickly. However, it does not bind very tightly to this protein, and patients can develop a resistant type of Bcr-Abl that no longer binds to Gleevec at all.

Using rational drug design to circumvent these shortcomings, researchers at Novartis determined the crystal structure of Bcr-Abl, and then constructed compounds that would lock into the receptor more securely than Gleevec. Investigators at Dana-Farber tested the new compounds to measure their effectiveness against CML in laboratory cell cultures and mice with the disease.

Data from the study published in Cancer Cell showed that in experiments with laboratory samples of CML cells, AMN107 killed the cells more effectively than Gleevec. In follow-up studies with mice with a human form of CML, AMN107 produced lengthier remissions than Gleevec and triggered remissions in animals in which the disease had become resistant to Gleevec. Side effects in the animals were minimal.

Synthesized in August 2002, AMN107 entered early Phase I clinical studies in May 2004 � 21 months later. Data presented last December at the American Society of Hematology showed that AMN107 had demonstrated significant clinical activity in the most challenging setting: Gleevec resistant accelerated and blast crisis CML patients.

"We're very encouraged by the results so far," remarks Griffin, who is also a professor of medicine at Harvard Medical School. "This is an elegant example of how rational drug design �� developing drugs based on a molecular understanding of cell structures and processes �� can be used to attack human diseases."

The findings contribute to a larger Dana-Farber research effort, dubbed the "Kinase Project," which seeks to identify abnormal tyrosine kinases -- enzymes that spark or halt growth -- in cancer cells and test agents known to act against them.

The Cancer Cell study's lead author is Ellen Weisberg, PhD, of Dana-Farber. Co-authors include researchers at Dana-Farber, Novartis, Brigham and Women's Hospital, and Children's Hospital Boston.

Sources

Dana-Farber Cancer Institute.

Aspirin may not provide optimum anti-coagulation for all patients

Professor Andrew Szczeklik from Poland and Professor Graeme Hankey from Western Australia will present the latest findings on aspirin resistance at the XXth Congress of the International Society of Thrombosis and Haemostasis today.

"There are at least two possible explanations for the aspirin-resistance phenomenon," said Professor Szczeklik. "One is high levels of blood cholesterol, which can in itself promote coagulation events in the blood stream. In patients with highcholesterol levels, aspirin in in normal doses has hardly any anti-clotting effects, whereas treatment with a statin (inhibitor of cholesterol) significantly reduces blood clotting. In patients withcoronary heart disease, aspirin exerts it anti-coagulant effects only when blood cholesterol is in the 'normal' range."

Szczeklik went onto say, "A patients genetic make-up may alter their response to aspirin resistance.. For example, incoronary heart disease patients carrying one particular gene are resistant to the anti-coagulant action of aspirin and are at increased risk of an acute coronary event."

Anemia associated with higher risk of death in elderly

Increasing evidence indicates that anemia is common in the elderly population, but few studies have assessed the association of anemia with clinical outcomes, such as illness and death, according to background information in the article. Anemia is defined by the World Health Organization (WHO) as a hemoglobin concentration of less than 12 g/dL (grams per one tenth liter) for women and less than 13 g/dL for men.

Neil A. Zakai, M.D., of the University of Vermont College of Medicine, Burlington, compared the association of hemoglobin concentration and anemia status with subsequent death over the course of eleven years in elderly adults living in four U.S. communities. Hemoglobin concentrations were determined for participants recruited between 1989 and 1993. Participants were contacted biannually; telephone and clinic examinations were conducted alternately. Deaths were reviewed and classified as cardiovascular or noncardiovascular. Complete follow-up was available through June 2001 for this analysis.

Hemoglobin concentration was analyzed in two ways: by dividing the participants' baseline hemoglobin into five equal levels and by the WHO criteria for anemia. Based on the WHO criteria for anemia, 498 individuals were anemic on enrollment (8.5 percent of the 5,797 included in the analysis), the researchers report. The hemoglobin concentration for the 1,205 individuals in the lowest fifth was higher than the WHO criteria for anemia, and 41.3 percent of these 1,205 people did qualify as anemic by WHO standards.

First scientific data for Lybrel presented at ASRM meeting

Madison, N.J., Wyeth Pharmaceuticals, a division of Wyeth, announced that four scientific abstracts regarding Lybrel� (0.09 mg levonorgestrel/0.02 mg ethinyl estradiol tablets) were presented for the first time today at the 61st Annual Meeting of the American Society for Reproductive Medicine (ASRM) in Montr�al, Canada.

The studies investigated the effects of 0.09 mg levonorgestrel/0.02 mg ethinyl estradiol on ovarian activity, safety and efficacy, endometrial histology, and cycle-related symptoms. The New Drug Application (NDA) for the study drug, Lybrel, a combination low-dose oral contraceptive designed to be taken daily, 365 days a year, without a placebo phase or pill-free interval, was accepted for filing on July 27, 2005 and is currently under review by the U.S. Food and Drug Administration (FDA).

The research presented at the ASRM Annual Meeting includes investigational data on multiple effects of 0.09 mg levonorgestrel/0.02 mg ethinyl estradiol. The abstracts accepted for presentation are:

Investigation of Ovarian Activity

A six-month Phase 2 study entitled �Effect on Ovarian Activity of a Continuous-Use Regimen of Oral Levonorgestrel/Ethinyl Estradiol� reported that participants (n=37) taking 0.09 mg levonorgestrel/0.02 mg ethinyl estradiol experienced inhibition of ovulation. The study also reported that participants who stopped the study drug treatment demonstrated a return to ovulation. This was the first ever published investigational study of a combination oral contraceptive designed to be taken every day of the year without a placebo phase to specifically evaluate ovarian suppression and return to ovulation.

Investigation of Safety and Efficacy

An abstract entitled �Efficacy and Safety of a Continuous-Use Regimen of Levonorgestrel/Ethinyl Estradiol: North American Phase 3 Study Results� examined the contraceptive effects of 0.09 mg levonorgestrel/0.02 mg ethinyl estradiol and the adverse events experienced by the study participants (n=2,134) during the 12-month trial. Contraceptive efficacy was determined by the Pearl Index, a calculation of the pregnancy rate among study participants.

Women should be advised not to drink alcohol in pregnancy

Expectant mothers should be advised not to drink alcohol, as this may pose health risks to the foetus, argues an editorial in this week's BMJ.

While the UK Department of Health advises that women can safely drink one or two units of alcohol per week, a team of psychiatrists in London highlight several studies which cast doubt on the guidance.

The authors looked at reports into foetal alcohol syndrome, a condition developed by some babies exposed to alcohol in the womb, resulting in stunted growth, facial abnormalities and neurocognitive deficits (brain disorders). An overarching foetal alcohol spectrum disorder - traceable to the pregnant mother's alcohol consumption say the authors - has also been identified.

Both the syndrome and disorder cause a wide range of behavioural disorders, they argue, including hyperactivity, problems with mental organisation, and difficulties in understanding the consequences of one's behaviour. Symptoms may also overlap with conditions such as autism and attention deficit hyperactivity disorder (ADHD).

Previously the syndrome was thought to be caused by mothers drinking heavily in pregnancy. But the authors argue that recent studies suggest that far less exposure to alcohol in the womb may put babies at risk � as little as one drink per week in one study. Individual differences in alcohol metabolism may protect most women when drinking small quantities, add the team, but it is currently impossible to predict who is at risk and who is not.

More research is needed to find out just how much alcohol may be damaging to a foetus, argue the authors. In the interim, the only safe message for expectant mothers is to abstain from alcohol, they conclude.

Birth control pill could cause long-term sexual problems

In the January issue of The Journal of Sexual Medicine, researchers have published a new investigation measuring sex hormone binding globulin (SHBG) before and after discontinuation of the oral contraceptive pill. The research concluded that women who used the oral contraceptive pill may be exposed to long-term problems from low values of "unbound" testosterone potentially leading to continuing sexual, metabolic, and mental health consequences.

Sex hormone binding globulin (SHBG) is the protein that binds testosterone, rendering it unavailable for a woman's physiologic needs. The study showed that in women with sexual dysfunction, elevated SHBG in "Oral Contraceptive Discontinued-Users" did not decrease to values consistent with those of "Never-Users of Oral Contraceptive". Thus, as a consequence of the chronic elevation in sex hormone binding globulin levels, pill users may be at risk for long-standing health problems, including sexual dysfunction.

Oral contraceptives have been the preferred method of birth control because of their ease of use and high rate of effectiveness. However, in some women oral contraceptives have ironically been associated with women's sexual health problems and testosterone hormonal problems. Now there are data that oral contraceptive pills may have lasting adverse effects on the hormone testosterone.

The research, in an article entitled: "Impact of Oral Contraceptives on Sex Hormone Binding Globulin and Androgen Levels: A Retrospective Study in Women with Sexual Dysfunction" published in The Journal of Sexual Medicine, involved 124 premenopausal women with sexual health complaints for more than 6 months. Three groups of women were defined: i) 62 "Oral Contraceptive Continued-Users" had been on oral contraceptives for more than 6 months and continued taking them, ii) 39 "Oral Contraceptive Discontinued-Users" had been on oral contraceptives for more than 6 months and discontinued them, and iii) 23 "Never-Users of Oral Contraceptives" had never taken oral contraceptives. SHBG values were compared at baseline (groups i, ii and iii), while on the oral contraceptive (groups i and ii), and well beyond the 7 day half-life of sex hormone binding globulin at 49-120 (mean 80) days and more than 120 (mean 196) days after discontinuation of oral contraceptives

Researchers identify genes associated with lung transplant rejection

Researchers at the San Francisco VA Medical Center (SFVAMC) and the University of California, San Francisco (UCSF) have identified six genes associated with lymphocytic bronchitis, which is thought to lead to obliterative bronchitis (OB), the most common cause of long-term failure of transplanted lungs.

The researchers hope their results will lead to an earlier, more sensitive, and more accurate standard test for chronic lung rejection, as well as greater understanding of the rejection process.

The study is being published in the September 2005 issue of the Journal of Heart and Lung Transplantation, currently available online.

In obliterative bronchitis, scar tissue forms in breathing passages of the transplanted lung, narrowing them and eventually making it impossible for the recipient to breathe. The exact cause is unknown, but it is believed to be related to rejection of the lung by the recipient's body.

"For lung transplant patients, the biggest barrier to long-term survival is control of rejection," says principal investigator George Caughey, MD, head of Pulmonary and Critical Care Medicine at SFVAMC. "If we know rejection is occurring, we can adjust the patient's medication to try and prevent it. But the problem with lung transplants is that it's hard to detect chronic rejection." Currently, he says, OB is best detected through a breathing test--but by the time the disease has a perceptible impact on the patient's ability to breathe, it's often too late to treat effectively.

Caughey and his fellow researchers studied lung biopsy samples from 22 lung transplant patients, with the goal of detecting genes and gene products associated with inflammation and formation of scar tissue in breathing passages. Using a customized version of a conventional laboratory technique, they found that they were able to look at hundreds of gene products simultaneously in lung tissue samples only a few millimeters across. "That was our first achievement: being able to accurately measure that many genes in small samples," notes Caughey, who is also a professor of medicine at UCSF. "We succeeded way beyond our expectations."

The researchers then correlated the genetic test results with results from microscopic pathology examinations, tissue cultures, X-rays, CT scans, and breathing tests in each patient. They identified six genes that correlate with lymphocytic bronchitis, potentially opening the way to a genetic test that would identify OB before it manifests. "The beauty of this approach is that it could be applied in a regular laboratory," Caughey says.

However, he cautions, "we need to validate this data in a larger, separate set of patients to prove that these biomarker genes actually work. And we're testing that now." Currently, Caughey's research team is studying biopsy samples from more than 100 UCSF lung transplant patients, who regularly undergo biopsies as part of standard follow-up care.

Another potential benefit of the research, predicts Caughey, will be a better understanding of lung rejection at the genetic level. In turn, he believes, this could lead to the development of medications that directly target genes responsible for the scarring process in the lung, instead of anti-rejection drugs that broadly compromise the immune system, which are the major tools currently available to fight lung rejection.

Co-authors of the study were Xiang Xu, MD, PhD, Jeffrey A. Golden, MD, Gregory Dolganov, PhD, Kirk D. Jones, MD, Samantha Donnelly, PhD, and Timothy Weaver, Bsc, all of UCSF.

###

The research is funded by a grant from the National Institutes of Health that is administered jointly by the Northern California Institute for Research and Education (NCIRE) and UCSF's Cardiovascular Research Institute, and is supported by the Diamond Family Foundation.

GERD likely to follow newly diagnosed asthma

In the first study to assess a connection between cases of gastroesophageal reflux disease (GERD) and asthma, in the same population, over the same time period, researchers found that patients who are diagnosed with asthma are at a significantly higher risk of a diagnosis of GERD.

Researchers from Spain, Sweden, and the United Kingdom examined data taken from the UK General Practice Research Database. Researchers followed a cohort of 5,653 patients recently diagnosed with GERD and 8,105 patients without GERD or asthma, for a mean time of 3 years and identified 103 cases of asthma in the GERD cohort and 99 cases of asthma in the control group.

During the same study period, researchers followed 9,712 patients with newly diagnosed asthma and 19,334 control subjects without asthma or GERD, for a mean of 2.8 years and found 219 patients with asthma developed GERD, compared to 241 control subjects who developed GERD during the study period.

Patients with asthma were most likely to receive a subsequent diagnosis of GERD within the first year of their diagnosis of asthma. Patients with a diagnosis of GERD were not found to be at significantly higher risk of developing asthma.

Source

The study appears in the July issue of CHEST, the peer-reviewed journal of the American College of Chest Physicians.

Pertussis vaccine proves effective in adults, adolescents

A vaccine to protect adults and adolescents against illness due to Bordetella pertussis infection--or whooping cough--has proved more than 90 percent effective in a national, large-scale clinical study, according to research results published in this week's issue of The New England Journal of Medicine.

The vaccine, researchers say, could be used to stem the increase in pertussis cases among adults and adolescents in the United States and thereby prevent the prolonged cough illness, which can result in hospitalization, pneumonia and cracked ribs in those populations. An important additional benefit of the vaccine may be to decrease transmission of the B. pertussis bacterium to infants, who are particularly vulnerable to severe illness, complications and death resulting from whooping cough. The illness annually affects 50 million people worldwide.

"During the 1990s, the number of reported pertussis cases among adolescents and adults more than doubled in the United States as the protective effects of earlier childhood immunizations have waned," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, which funded the study. "This new study shows that an effective adult acellular pertussis vaccine is feasible and if routinely used could provide the U.S. population greater protection against the disease."

Known as the Adult Pertussis Trial, the 2.5-year study involved 2,781 healthy individuals between 15 and 65 years of age. Volunteers were randomly assigned to one of two similarly sized groups that received either the acellular pertussis vaccine or the control hepatitis A vaccine (Havrix). For purposes of the trial, pertussis cases were defined as illnesses with a cough lasting at least five days that occurred more than 28 days after vaccination and were confirmed through blood and nasal mucus testing.

Elderly have higher risk for cardiovascular, respiratory disease

New data from a four-year study of 11.5 million Medicare enrollees show that short-term exposure to fine particle air pollution from such sources as motor vehicle exhaust and power plant emissions significantly increases the risk for cardiovascular and respiratory disease among people over 65 years of age. The study, funded by the National Institute of Environmental Health Sciences, a component of the National Institutes of Health, is the largest ever conducted on the link between fine particle air pollution and hospital admissions for heart- and lung-related illnesses.

The study results show that small increases in fine particle air pollution resulted in increased hospital admissions for heart and vascular disease, heart failure, chronic obstructive pulmonary disease, and respiratory infection. "The data show that study participants over 75 years of age experienced even greater increases in admissions for heart problems and chronic obstructive pulmonary disease than those between 65 and 74 years of age," said National Institutes of Health Director Elias A. Zerhouni, M.D.

The National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency provided funding to researchers at the Johns Hopkins Bloomberg School of Public Health for the study. The study results are published in the March 8, 2006 issue of the Journal of the American Medical Association.

According to the study, these findings document an ongoing threat from airborne particles to the health of the elderly, and provide a strong rationale for setting a national air quality standard that is as protective of their health as possible.

"These findings provide compelling evidence that fine particle concentrations well below the national standard are harmful to the cardiovascular and respiratory health of our elderly citizens," said NIEHS Director David A. Schwartz, M.D. "Now that the link between inhaled particles and adverse health effects has been established, we must focus our efforts on understanding why these particles are harmful, and how these effects can be prevented."

Fine particle air pollution consists of microscopic particles of dust and soot less than 2.5 microns in diameter � about thirty times smaller than the width of a human hair. These tiny particles primarily come from motor vehicle exhaust, power plant emissions, and other operations that involve the burning of fossil fuels. Fine particles can travel deep into the respiratory tract, reducing lung function and worsening conditions such as asthma and bronchitis.

The researchers based their fine particle analysis on 11.5 million Medicare enrollees who lived in 204 U.S. counties with populations larger than 200,000. Using billing records for 1999 to 2002, they tracked daily counts of hospital admissions for eight major outcomes � heart failure, heart rhythm disturbances, cerebrovascular events such as stroke or brain hemorrhage, coronary heart disease, peripheral vascular disease or narrowing of the blood vessels, chronic obstructive pulmonary disease, respiratory infection, and injury.

The investigators obtained daily measurements of fine particle concentrations from a network of air monitoring stations provided by the Environmental Protection Agency's Aerometric Information Retrieval Service. The average fine particle concentration for the 204 counties over the three-year period was 13.4 micrograms per cubic meter of air, slightly below the national air quality standard of 15 micrograms per cubic meter for an annual average.

"When we analyzed the data for heart failure, we observed a 1.28 percent increase in admissions for each 10 microgram per cubic meter increase in fine particle pollution," said Francesca Dominici, Ph.D., an associate professor of biostatistics with the Johns Hopkins Bloomberg School of Public Health and lead author on the study. "Most of these admissions increases occurred the same day as the rise in fine particle concentration, which suggests a short lag time between the change in pollution and the subjects' response."

The data also showed that the risk for air pollution-related cardiovascular disease was highest in counties located in the Eastern United States. "Identifying the various factors that might contribute to these differences between eastern and western regions is a very complex question that we must address," said Dominici.

According to Dominici, fine particles pose a significant health problem because they penetrate deep into the lungs, and some may even get into the bloodstream. "Now that we know that inhaled particles can affect cardiovascular and respiratory health, we must identify the specific characteristics of fine particles that produce these adverse health effects," she said. "In the meantime, these findings underscore the need for a national air quality standard that adequately protects the respiratory health of our citizens."

Sources

F. Dominici, D. Peng, M. Bell, L. Pham, A. McDermott, S.L. Zeger, J.M. Samet. Fine Particulate Air Pollution and Hospital Admissions for Cardiovascular and Respiratory Diseases. Journal of American Medical Association 295, March 2006.

Lack of sleep linked to increased risk of high blood pressure

f you're middle age and sleep five hours or less a night, you may be increasing your risk of developing high blood pressure, according to research reported in Hypertension: Journal of the American Heart Association.

"Sleep allows the heart to slow down and blood pressure to drop for a significant part of the day," said James E. Gangwisch, Ph.D., lead author of the study and post-doctoral fellow at Columbia University's Mailman School of Public Health.

"However, people who sleep for only short durations raise their average 24-hour blood pressure and heart rate. This may set up the cardiovascular system to operate at an elevated pressure."

Gangwisch said that 24 percent of people ages 32 to 59 who slept for five or fewer hours a night developed hypertension versus 12 percent of those who got seven or eight hours of sleep. Subjects who slept five or fewer hours per night continued to be significantly more likely to be diagnosed with hypertension after controlling for factors such as obesity, diabetes, physical activity, salt and alcohol consumption, smoking, depression, age, education, gender, and ethnicity.

The researchers conducted a longitudinal analysis of data from the Epidemiologic Follow-up Studies of the first National Health and Nutrition Examination Study (NHANES I). The analysis is based on NHANES I data from 4,810 people ages 32 to 86 who did not have high blood pressure at baseline. The 1982-84 follow-up survey asked participants how many hours they slept at night. During eight to 10 years of follow-up, 647 of the 4,810 participants were diagnosed with hypertension.

Compared to people who slept seven or eight hours a night, people who slept five or fewer hours a night also exercised less and were more likely to have a higher body mass index. (BMI is a measurement used to assess body fatness). They were also more likely to have diabetes and depression, and to report daytime sleepiness.

"We had hypothesized that both BMI and a history of diabetes would mediate the relationship between sleep and blood pressure, and the results were consistent with this," Gangwisch said.

Sleep deprivation has been shown previously to increase appetite and compromise insulin sensitivity.