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Tuesday, September 2, 2008

Value of Direct-to-consumer Drug Advertising Oversold

Newswise — Direct-to-consumer advertising may not be giving big pharma such a big bang for their buck after all. Despite the billions spent on bringing drug marketing campaigns straight into patients’ living rooms, such strategies have a modest effect at best—and in some cases, no effect at all.



“People tend to think that if direct-to-consumer advertising wasn’t effective, pharma wouldn’t be doing it,” says Harvard Medical School professor Stephen Soumerai, principal investigator on the study. “But as it turns out, decisions to market directly to consumers is based on scant data.”

This study was based at the Department of Ambulatory Care and Prevention of Harvard Medical School and Harvard Pilgrim Health Care and appears September 2 online in the British Medical Journal. It is the first-ever controlled study of direct-to-consumer advertising (DTCA) of pharmaceuticals.

Currently, the United States and New Zealand are the only countries that allow drug companies to advertise directly to patients. When the U.S. Food and Drug Administration eased advertising restrictions on the pharmaceutical industry in 1997, consumer advertising jumped 330 percent over the next 10 years. As of 2005, pharma was spending about $5 billion annually on such campaigns. Some data implied that such ads increased prescriptions, but these studies simply correlated ads with sales, begging the question, are drugs that sell more simply advertised more?

But examining the effects of advertising on sales via a controlled study is problematic. Given the overwhelming amount of advertising in the U.S., how do you find two groups that are very similar, yet one is exposed to pharmaceutical advertising and the other isn’t?

The answer: Canada.

DTCA is illegal in Canada. Not surprisingly, however, national borders are leaky and American media—television and magazines and radio, replete with pharma ads—regularly crosses into Canada. As a result, Canadians, like Americans, are swamped with these ads, with one key exception.

All American advertisements are in English. Yet Canada has a significant French-speaking population. In the Canadian province of Quebec, approximately 80 percent of its 7.5 million population speak French as their first language, and tend to get most of their news from French-language media. As a result, residents of Quebec, on the whole, are far less exposed to DTCA than other Canadians.

Quebec, then, functioned as a control group for the study. The researchers compared prescription rates for advertised drugs in English-speaking Canadian provinces with rates in Quebec, where residents were purportedly less exposed to those same ads.

“It’s not an absolutely perfect control group,” says Michael Law, first author on the paper. “There’s obviously a small percentage of Quebec residents who are exposed to English language media. But as control groups go for this sort of observational study, it’s about as good as you get.”

Law and Soumerai chose to look at three specific drugs: Enbrel (rheumatoid arthritis), Nasonex (nasal allergies), and Zelnorm (irritable bowel sydrome). All three drugs were on the market for at least one year before the DTCA campaign began, and none were advertised in Canada through “softer” consumer ads, that is, ads that may mention the drug by name without identifying the relevant conditions.

The basic question was simple: did use of these drugs increase faster in English-speaking regions after American DTCA campaigns began?

Using information from IMS Health Canada, a health information company that receives data from a panel of about 2,700 Canadian pharmacies, the researchers analyzed prescription statistics for each of these three drugs for a five-year period.

They found that for two of the drugs, Enbrel and Nasonex, DTCA had no effect whatsoever. Prescription patterns in English-speaking Canada and in Quebec remained identical both before and after DTCA campaigns began.

Sales for Zelnorm, however, did spike noticeably in English-speaking Canada as soon as the ad campaign began. While prescriptions for this drug increased by over 40 percent, this jump was relatively short-lived, and after a few years, prescription rates in both groups resumed identical patterns. A similar analysis of U.S. Medicaid prescriptions found a slightly higher, but similarly brief, jump in sales.

The researchers hypothesize that DTCA may not be as effective as other types of consumer advertising due to the unique complexity of the marketing/sales trajectory.

With a typical consumer product, an individual sees an ad and then can choose to simply go out and buy the item. “But pharmaceuticals aren’t typical consumer products,” says Soumerai. “A person needs to see an ad, get motivated by that ad, contact their doctor for an appointment, show up at the appointment, communicate both the condition and the drug to the doctor, convince the doctor that this drug is preferable to other alternatives, then actually go out and fill the prescription. This is a chain of events that can break at any point.”

This hypothesis may in fact explain the disparate effects of DTCA on these three drugs. For Enbrel and Nasonex, there are a number of over-the-counter and prescription alternatives that doctors would likely recommend as first-line treatments.

Zelnorm, however, was the only drug on the market in both the United States and Canada for constipation-predominant irritable bowel syndrome. The researchers suggest that Zelnorm would have sold very well without the consumer advertising.

In March of 2007, Zelnorm was pulled from the market due to FDA concerns that it may increase risk for heart attack and stroke.

One hundred years of marketing experience and recent studies indicate that face-to-face promotion of drugs to doctors by pharmaceutical representatives is far more effective than DTCA.

This research was supported by Harvard Medical School and Harvard Pilgrim Health Care, The Social Sciences and Humanities Research Council of Canada, The Alberta Heritage Foundation for Medical Research, and the Agency for Healthcare Research and Quality.

The funding and data sources for this study had no role in study design; in the collection, analysis, and interpretation of data; or in the writing of the report.

Full citation:

British Medical Journal, early online publication September 2, 2008

“Effect of illicit direct-to-consumer advertising on use of etanercept, mometasone, and tegaserod in Canada: controlled longitudinal study”

Michael R Law(1), Sumit R Majumdar(2), and Stephen B Soumerai(1)

1-Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 2-Division of General Internal Medicine, Department of Medicine, 2E3.07 Walter Mackenzie Health Sciences Centre, University of Alberta Hospital, Edmonton, Alberta, Canada

Harvard Medical School http://hms.harvard.edu/hms/home.asp has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.

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Most Vaccine-Allergic Children Can Still be Safely Vaccinated, Experts Say

Newswise — With close monitoring and a few standard precautions, nearly all children with known or suspected vaccine allergies can be safely immunized, according to a team of vaccine safety experts led by the Johns Hopkins Children’s Center. Writing in the September issue of Pediatrics, the multicenter research team offers pediatricians a step-by-step tool for quickly identifying children with allergic reactions to vaccines, and a much-needed guide, they say, to safely immunize those who are allergic.

Serious allergic reactions to vaccines are extremely rare — one or two per million vaccinations, according to some estimates — but when they happen, such episodes can be serious, even life-threatening, making it critical for pediatricians to instantly spot true allergic reactions and differentiate them from more benign nonallergic responses, investigators say. It is also crucial that pediatricians design a safe immunization plan for children with confirmed vaccine allergies. Children who have had one allergic reaction are believed to be at a higher risk for future reactions, typically more serious than the first.

“We cannot reiterate enough that the vaccines used today are extremely safe, but in a handful of children certain vaccine ingredients can trigger serious allergic reactions,” says Robert Wood, M.D., lead author on the paper and chief of pediatric Allergy and Immunology at Hopkins Children’s. “For the most part, even children with known allergies can be safely vaccinated.”

Given recent outbreaks of vaccine-preventable infections like measles, mumps and whooping cough in the United States, and measles and polio overseas, it is essential to safely vaccinate as many children as possible, investigators say.

Combing through available evidence on vaccine safety and allergies, the Hopkins-led team developed a sequence of instructions – an algorithm – that prompts physicians one step at a time on how to evaluate and immunize children with known or suspected vaccine allergies.

The guidelines are intended for doctors and parents who are uncertain about vaccine safety in children who have already had or are at high risk for having allergic reactions to vaccines.

In such cases, the Hopkins-led group advises a workup by an allergist, including skin prick testing—a prick on the skin or an injection under the skin with a small dose of vaccine or the suspected allergen from the vaccine—or blood tests that would detect the presence of characteristic antibodies that patients develop to allergens, such as antibodies to gelatin or egg proteins used in several common vaccines.

In many cases, allergic children can be vaccinated using alternative forms of a vaccine that are free of the allergen. Even if allergen-free formulations are unavailable, many children can still be vaccinated and remain under physician supervision for several hours after vaccination. Another option is testing the child to check for immunity. If blood tests show the child has already developed protective antibodies, it may be OK, at least temporarily, to withhold further doses of the vaccine, researchers write.

“Vaccines save lives, and parents should know that children who have had allergic reactions after a vaccine are likely to have developed protection against infection as a result of the vaccination,” says investigator Neal Halsey, M.D., an infectious disease specialist at Hopkins Children’s, and professor of International Health at the Johns Hopkins University Bloomberg School of Public Health.

“Most children who have had an allergic reaction after a vaccine can still be vaccinated against other diseases safely and some can receive additional doses of vaccines they might have reacted to,” Halsey adds.

Many children with known vaccine allergies who have low levels of protective antibodies and require more doses can be vaccinated safely under the guidelines. In some cases, children with known allergies can be given antiallergy medications, such as antihistamines and corticosteroids, before vaccination to help ward off or lessen the allergic reaction. For a step-by-step guide to vaccine administration in children with known or suspected vaccine allergy, see the full text of the article at http://pediatrics.aappublications.org/future/122.3.shtml.

Immunizations of children with known vaccine allergies should always be administered under medical supervision in a clinic equipped to treat life-threatening allergic reactions or in a hospital intensive-care unit. Patients can usually go home after an hour or two if they have no adverse reactions.

True allergies typically cause immediate reactions, involving the immune system as a whole that occur within a few minutes to a few hours of vaccination. By contrast, delayed reactions, which occur within days, even weeks after vaccination, are generally benign and are rarely, if ever, dangerous.

Symptoms of immediate allergic reactions include hives, swelling, wheezing, coughing, low blood pressure, vomiting, diarrhea, and can lead to full-blown anaphylaxis, a life-threatening allergic reaction.

The research was funded by the Centers for Disease Control and Prevention.

Co-investigators on the research: Melvin Berger, M.D. Ph.D., University Hospitals of Cleveland; Stephen Dreskin, M.D. Ph.D., University of Colorado; Rosanna Setse, M.D. M.P.H., Johns Hopkins University Bloomberg School of Public Health; Renata Engler, M.D., Walter Reed Army Medical Institute; Cornelia Dekker, M.D., Stanford University School of Medicine. The Clinical Immunization Safety Assessment Network, consisting of six medical research centers with expertise in immunization safety, was part of the study.

Conflict of interest disclosure for Hopkins investigators: Halsey has received research support from vaccine manufacturer Wyeth and is a consultant for vaccine manufacturers GlaxoSmithKline and Merck.

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Playing, and Even Watching, Sports Improves Brain Function

Newswise — Being an athlete or merely a fan improves language skills when it comes to discussing their sport because parts of the brain usually involved in playing sports are instead used to understand sport language, new research at the University of Chicago shows.

The research was conducted on hockey players, fans, and people who’d never seen or played the game. It shows, for the first time, that a region of the brain usually associated with planning and controlling actions is activated when players and fans listen to conversations about their sport. The brain boost helps athletes and fans understanding of information about their sport, even though at the time when people are listening to this sport language they have no intention to act.

The study shows that the brain may be more flexible in adulthood than previously thought. “We show that non-language related activities, such as playing or watching a sport, enhance one’s ability to understand language about their sport precisely because brain areas normally used to act become highly involved in language understanding,” said Sian Beilock, Associate Professor in Psychology at the University of Chicago. “Personality of older fathers has been suggested to explain the association between mental disorders and advancing paternal age,” the authors write. “However, the mental disorders associated with increasing paternal age are under considerable genetic influence.” Therefore, there may be a genetic link between advancing age of the father and bipolar and other disorders in offspring.

“As men age, successive germ cell replications occur, and de novo [new, not passed from parent to offspring] mutations accumulate monotonously as a result of DNA copy errors,” the authors continue. “Women are born with their full supply of eggs that have gone through only 23 replications, a number that does not change as they age. Therefore, DNA copy errors should not increase in number with maternal age. Consistent with this notion, we found smaller effects of increased maternal age on the risk of bipolar disorder in the offspring.”

(Arch Gen Psychiatry. 2008;65[9]:1034-1040. Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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Children of Older Fathers More Likely to Have Bipolar Disorder

Newswise — Older age among fathers may be associated with an increased risk for bipolar disorder in their offspring, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Bipolar disorder is a common, severe mood disorder involving episodes of mania and depression, according to background information in the article. Other than a family history of psychotic disorders, few risk factors for the condition have been identified. Older paternal age has previously been associated with a higher risk of complex neurodevelopmental disorders, including schizophrenia and autism.


Emma M. Frans, M.Med.Sc., of the Karolinska Institutet, Stockholm, Sweden, and colleagues identified 13,428 patients in Swedish registers with a diagnosis of bipolar disorder. For each one, they randomly selected from the registers five controls who were the same sex and born the same year but did not have bipolar disorder.

When comparing the two groups, the older an individual’s father, the more likely he or she was to have bipolar disorder. After adjusting for the age of the mother, participants with fathers older than 29 years had an increased risk. “After controlling for parity [number of children], maternal age, socioeconomic status and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 times more likely to be diagnosed as having bipolar disorder than the offspring of men aged 20 to 24 years,” the authors write.

The offspring of older mothers also had an increased risk, but it was less pronounced than the paternal effect, the authors note. For early-onset bipolar disorder (diagnosed before age 20), the effect of the father’s age was much stronger and there was no association with the mother’s age.

“Personality of older fathers has been suggested to explain the association between mental disorders and advancing paternal age,” the authors write. “However, the mental disorders associated with increasing paternal age are under considerable genetic influence.” Therefore, there may be a genetic link between advancing age of the father and bipolar and other disorders in offspring.

“As men age, successive germ cell replications occur, and de novo [new, not passed from parent to offspring] mutations accumulate monotonously as a result of DNA copy errors,” the authors continue. “Women are born with their full supply of eggs that have gone through only 23 replications, a number that does not change as they age. Therefore, DNA copy errors should not increase in number with maternal age. Consistent with this notion, we found smaller effects of increased maternal age on the risk of bipolar disorder in the offspring.”

(Arch Gen Psychiatry. 2008;65[9]:1034-1040. Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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PET Scans Help Identify Mechanism Underlying Seasonal Mood Changes

Newswise — Brain scans taken at different times of year suggest that the actions of the serotonin transporter—involved in regulating the mood-altering neurotransmitter serotonin—vary by season, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals. These fluctuations may potentially explain seasonal affective disorder and related mood changes.

“It is a common experience in temperate zones that individuals feel happier and more energetic on bright and sunny days and many experience a decline in mood and energy during the dark winter season,” the authors write as background information in the article. This is thought to be related to variations in brain levels of serotonin, which is involved in the regulation of functions such as mating, feeding, energy balance and sleep. The serotonin transporter, a protein that binds to serotonin and clears it from the spaces between brain cells, “is a key element in regulating intensity and spread of the serotonin signal.”


Nicole Praschak-Rieder, M.D., and Matthaeus Willeit, M.D., of the Centre for Addiction and Mental Health and the University of Toronto, Ontario, Canada, and colleagues studied 88 healthy individuals (average age 33) between 1999 and 2003. Participants underwent one positron emission tomography (PET) scan to assess serotonin transporter binding potential value, an index of serotonin transporter density. The higher the binding potential value, the less serotonin circulates in the brain. For the analysis, individual scans were grouped according to the season of the scan—fall and winter or spring and summer.

“Serotonin transporter binding potential values were significantly higher in all investigated brain regions in individuals investigated in the fall and winter compared with those investigated in the spring and summer,” the authors write. When they matched binding potential values to meteorological data, the researchers found that higher values occurred during times when there were fewer hours of sunlight per day.

“An implication of greater serotonin transporter binding in winter is that this may facilitate extracellular serotonin loss during winter, leading to lower mood,” the authors write. “Higher regional serotonin transporter binding potential values in fall and winter may explain hyposerotonergic [related to low serotonin levels] symptoms, such as lack of energy, fatigue, overeating and increased duration of sleep during the dark season.”

“These findings have important implications for understanding seasonal mood change in healthy individuals, vulnerability to seasonal affective disorder and the relationship of light exposure to mood,” they conclude. “This offers a possible explanation for the regular reoccurrence of depressive episodes in fall and winter in some vulnerable individuals.”

(Arch Gen Psychiatry. 2008;65[9]:1072-1078. Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: This study was supported by grants from the National Alliance for Research on Schizophrenia and Depression, the Austrian Science Foundation, the Canadian Institute for Health Research, the Ontario Mental Health Foundation, the Canada Foundation for Innovation and the Ontario Innovation Trust. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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Study Examines Relationship Between Low Birth Weight and Psychiatric Problems in Children

Newswise — Low-birth-weight children appear to be at higher risk for psychiatric disturbances from childhood through high school than normal-birth-weight children, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals. In addition, low-birth-weight children from urban communities may be more likely to have attention problems than suburban low-birth-weight children.

“Advances in neonatal medicine have raised the survivorship of low-birth-weight infants (2,500 grams [about 5.5 pounds] or less), especially very low-birth-weight infants (1,500 grams [about 3.3 pounds] or less) and extremely low-birth-weight infants (1,000 grams [2.2 pounds] or less),” according to background information in the article. Previous studies have reported that low-birth-weight children appear to have an increased risk of internalizing, externalizing and attention problems.

Kipling M. Bohnert, B.A., and Naomi Breslau, Ph.D., of Michigan State University, East Lansing, examined the long-term association between low-birth-weight and psychiatric problems among 413 children from a socially disadvantaged community in Detroit and 410 children from a middle-class Detroit suburb. Children’s psychiatric disturbances were rated by mothers and teachers at ages 6, 11 and 17. Psychiatric disturbances were separated into three categories: externalizing, including delinquent and aggressive behavior; internalizing, including withdrawn behavior and anxiety/depression; and attention, including characteristic symptoms of ADHD such as not being able to pay attention for long or difficulty following directions.

Low-birth-weight children were more likely to exhibit externalizing and internalizing problems than normal-birth-weight children in their community. “An increased risk of attention problems was associated with low birth weight only in the urban community and was greater among very low-birth-weight children (weighing 1,500 grams or less) than heavier low-birth-weight children (weighing 1,501 grams to 2,500 grams),” the authors write. “In the suburban community, there was no increased risk for attention problems associated with low birth weight. Psychiatric outcomes of low birth weight did not vary across ages of assessments.”

“Attention problems at the start of schooling predict lower academic achievement later, controlling for key factors that contribute to academic test scores, which in turn predicts termination of schooling and curtailed educational attainment,” the authors conclude. “Attention problems influence academic performance by reducing the time that students devote to class learning and homework assignments and hinder organization and work habits.

“Early interventions to improve attention skills in urban low-birth-weight children might yield better outcomes later.”

(Arch Gen Psychiatry. 2008;65[9]:1080-1086. Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: This work was supported by grants from the National Institute of Mental Health and from the National Institute on Drug Abuse. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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Family Therapy Helps Relieve Depression Symptoms in Bipolar Teens

Newswise — Family-focused therapy, when combined with medication, appears effective in stabilizing symptoms of depression among teens with bipolar disorder, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Between one-half and two-thirds of patients with bipolar disorder develop the condition before age 18, according to background information in the article. “Early onset of illness is associated with an unremitting course of illness, frequent switches of polarity, mixed episodes, psychosis, a high risk of suicide and poor functioning or quality of life,” the authors write. “The past decade has witnessed a remarkable increase in diagnoses of bipolar disorder in children and adolescents and, correspondingly, drug trials for patients with early-onset disorder. There has been comparatively little controlled examination of psychotherapy for pediatric patients.”

David J. Miklowitz, Ph.D., of the University of Colorado, Boulder, and colleagues conducted an outpatient randomized controlled trial among 58 adolescents (average age 14.5) with bipolar disorder who had experienced a mood episode in the prior three months. Between 2002 and 2005, 30 teens were randomly assigned to receive pharmacotherapy plus family-focused treatment for adolescents. Over nine months, they participated in 21 50-minute sessions. Therapy included the patient, parents and siblings and consisted of education about their disease, communication training and problem-solving skills training.

The other 28 teens were assigned to pharmacotherapy plus enhanced care, which involved three 50-minute family sessions that focused on preventing relapse. Independent evaluators, who did not know patient group assignments, assessed the teens every three to six months for two years.

A total of 60 percent of the family-focused therapy group and 64.3 percent of the enhanced care group completed the two-year follow-up; of those, 53 (91.4 percent) experienced a full recovery from their original mood episode. There were no differences between the two groups in rates of recovery or in the amount of time that elapsed before a subsequent mood episode. However, patients in the family-focused therapy group recovered from depressive symptoms more quickly, spent fewer weeks in depressive episodes over the two-year period and had an overall more favorable trajectory of depressive symptoms than those in the enhanced care group.

“To enhance full symptomatic and functional recovery among adolescents, family-focused treatment for adolescents may need to be supplemented with collaborative care interventions found effective in mania stabilization,” the authors conclude. The program’s emphasis on “reducing conflict in family relationships, enhancing social supports and teaching interpersonal skills may underlie its stronger effects on bipolar depression.”

(Arch Gen Psychiatry. 2008;65[9]:1053-1061.  Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: This study was supported by National Institute of Mental Health grants, a Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression and a Faculty Fellowship from the University of Colorado Council on Research and Creative Work (Dr. Miklowitz). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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Scientists Find Second Site for Prostate Cancer Gene

Newswise — Scientists at Wake Forest University School of Medicine and colleagues who are studying a prostate cancer gene called HNF1B have found a second independent site within the HNF1B gene on chromosome 17 (17q12) – increasing the number of genetic variants that may contribute to risk of developing the disease.

After comparing the newly-discovered site with a previously discovered site in the same gene among two large groups of patients in Sweden and at Johns Hopkins Hospital in Baltimore, “these data strongly suggest that the two sites are genetically independent,” said Jianfeng Xu, M.D., Dr. Ph.H., senior researcher on the study.

“We found another genetic variant associated with prostate cancer risk,” Xu said. “The more genetic variants we discover, the better off we are. As we find more of these, it improves our ability to predict prostate cancer risk.”

Xu, a professor of epidemiology and cancer biology and Director of the Center for Cancer Genomics, reported the results with 30 colleagues in the current on-line version of Nature Genetics.

The researchers conducted what they termed a “fine-mapping study” in the two groups, one called CAPS, from Sweden, that had 2,899 prostate cancer cases and 1,722 control participants, and the Johns Hopkins study that had 1,527 prostate cancer patients and 482 control participants.

They found two separate clusters of prostate-cancer-associated SNPs (single nucleotide polymorphisms), one in a region previously identified and one in a new region. The researchers then worked to see whether the genetic variants were associated with risk of developing the disease. They looked at the same locations in five other large studies of prostate cancer patients and found that prostate cancer risk was higher among men who had the genetic variants.

Earlier this year, the same research group reported in the New England Journal of Medicine that genetic variants have a strong cumulative effective. A man with four of the five previously discovered variants has a 400 percent increased risk of developing prostate cancer compared to men with none of the variants.

Xu said that as the number of genetic variants associated with prostate cancer risk continues to mount, it improves the precision of risk prediction. But he predicted that prostate cancer will be found to be polygenic, “not dependent on one gene, but a group of genes.”

Prostate cancer risk might be plotted on a bell-shaped curve, with men with a family history of the disease and multiple variants being at the upper end of the curve.

The researchers are exploring another finding, that the HNF1B gene is also associated with diabetes. But if a patient with the HNF1B gene has diabetes, the prostate cancer risk decreases, “We still don’t know how,” Xu said.

Collaborating with Xu were William B. Isaacs, Ph.D., from the Department of Urology at Johns Hopkins Medical Institutions in Baltimore, and Henrik Grönberg, M.D., Ph.Dl, from Karolinska Institute in Stockholm, Sweden.

Jielin Sun, Ph.D., and S. Lilly Zheng, M.D., of the Center for Cancer Genomics and the Center for Human Genomics at Wake Forest, are co-first authors of the paper. Additional co-authors from Wake Forest’s cancer genomics and human genomics centers are Lina D. Purcell, M.S., Zhengrong Gao, B.S., Seong-Tae Kim, Ph.D., Wennuan Liu, Ph.D., Yi Zhu, B.S., Latchezar Dimitrov, M.S., Jishan Sun, Ph.D., Tao Li, M.D., Ph.D., Aubrey R. Turner, M.S., Tamara S. Adams, M.S., and Bao-Li Chang, Ph.D. Fang-Chi Hsu is from the Department of Biostatistical Sciences at Wake Forest.

Wake Forest University Baptist Medical Center (www.wfubmc.edu) is an academic health system comprised of North Carolina Baptist Hospital, Brenner Children’s Hospital, Wake Forest University Physicians, and Wake Forest University Health Sciences, which operates the university’s School of Medicine and Piedmont Triad Research Park. The system comprises 1,154 acute care, rehabilitation and long-term care beds and has been ranked as one of “America’s Best Hospitals” by U.S. News & World Report since 1993. Wake Forest Baptist is ranked 32nd in the nation by America’s Top Doctors for the number of its doctors considered best by their peers. The institution ranks in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property.

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B-Vitamin Deficiency May Cause Vascular Cognitive Impairment

Newswise — A deficiency of B-vitamins may cause vascular cognitive impairment, according to a new study. Researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University used an experimental model to examine the metabolic, cognitive, and microvascular effects of dietary B-vitamin deficiency. Their findings appear in the August 26, 2008 issue of Proceedings of the National Academy of Sciences (PNAS).

“Metabolic impairments induced by a diet deficient in three B-vitamins -folate, B12 and B6- caused cognitive dysfunction and reductions in brain capillary length and density in our mouse model,” says Aron Troen, PhD, the study’s lead author. “The vascular changes occurred in the absence of neurotoxic or degenerative changes.”

Troen, who is an assistant professor at Tufts University’s Friedman School of Nutrition Science and Policy, explains, “Mice fed a diet deficient in folate and vitamins B12 and B6 demonstrated significant deficits in spatial learning and memory compared with normal mice.” Troen and colleagues observed similar but less pronounced differences between normal mice and a third group of mice that were fed a diet enriched with methionine.

“The B-vitamin-deficient mice also developed plasma homocysteine concentrations that were seven-fold higher than the concentrations observed in mice fed a normal diet,” adds Troen. Homocysteine is produced by the breakdown of a dietary protein called methionine. B-vitamins, including folate, vitamin B12, and vitamin B6, are required to convert homocysteine back to methionine, thereby reducing the blood concentration of homocysteine.

Studies have linked elevations in plasma homocysteine with an increased risk for cognitive impairment. “However,” Troen says, “it has not been determined that homocysteine is directly responsible. Based on the findings of our study, we theorize that a deficiency of B-vitamins induces a metabolic disorder that manifests with high homocysteine, as well as cerebral microvascular dysfunction.”

Troen and colleagues divided their study mice into three groups and fed each group a different diet for 10 weeks. While the control (comparison) group was fed a normal diet containing methionine and B-vitamins, the other two diets were designed to induce high homocysteine levels but through different metabolic mechanisms. One was methionine-enriched, and the other was deficient in B vitamins. Researchers measured blood concentrations of B-vitamins and homocysteine and assessed the brain anatomy and vasculature. They also evaluated psychomotor function by a battery of age-sensitive tests, such as holding on to a wire and walking a beam, and assessed spatial learning and memory with the Morris water maze, a well-validated and sensitive test of rodent cognitive function.

“It took longer, on average, for the B-vitamin-deficient mice to maneuver the water maze, compared with controls,” says Troen. “Longer latencies were associated with higher plasma homocysteine levels and shorter capillaries, particularly in the brain region called the hippocampus.” Troen adds, “Despite the vascular changes, the brain anatomy appeared normal, and there was no evidence of a cellular proliferation process called gliosis, which typically accompanies neurodegeneration.”

Irwin Rosenberg, MD, director of the Nutrition and Neurocognition Laboratory at the HNRCA, notes, “The elevated levels of homocysteine that were associated with vascular cognitive impairment in the mice in our study are comparable to the levels that are associated in older adults with an increased risk for Alzheimer’s disease and cerebrovascular disease, the latter of which manifests with conditions such as stroke and atherosclerosis. These findings may indicate that microvascular changes mediate the association between high homocysteine levels and human age-related cognitive decline.”

Troen and colleagues write that their study helps to “…define more precisely the mechanisms underlying cerebral microvascular disease, independent of or prior to the onset of irreversible neurodegeneration.” According to Troen, this work, which was funded by the U.S. Department of Agriculture, “may provide a model system in which to study the role of the brain's microvascular circulation in cognitive function.”

Troen AM, Shea-Budgell M, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH. Proceedings of the National Academy of Sciences. 2008 (Aug. 26); 105 (34): 12474-12479. “B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice.”

The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school’s eight centers, which focus on questions relating to famine, hunger, poverty, and communications, are renowned for the application of scientific research to national and international policy. For two decades, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University has studied the relationship between good nutrition and good health in aging populations. Tufts research scientists work with federal agencies to establish the USDA Dietary Guidelines, the Dietary Reference Intakes, and other significant public policies.

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