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Mailman School of Public Health researchers have found that thimerosal - the mercury preservative in vaccines - can cause autism-like symptoms in mice, but only when the mice have a gene that makes them susceptible to autoimmune disease after exposure to mercury.

The results, published June 8 on the Molecular Psychiatry website, came nearly a month after the Institute of Medicine released a report concluding no connection exists between thimerosal-containing vaccines and autism and recommended researchers pursue other hypotheses to explain why the rate of autistic disorders has increased 10-fold since 1985.

"We're not implying that mercury and susceptibility to autoimmune disease are linked to human autism based on this study, but we feel it's deserving of more research," says Dr. Mady Hornig, associate professor of epidemiology and director of translational research in the Jerome L. and Dawn Greene Infectious Disease Laboratory in the Mailman School.

Drs. David Chian, staff associate in the Greene laboratory and W. Ian Lipkin, director of the Greene laboratory, also participated in the research.

Dr. Hornig and her colleagues tested thimerosal's effect on autoimmune-susceptible mice because some studies show families with autistic children have high rates of autoimmune diseases.

They administered a series of thimerosal injections, based on the timing and dosage of the U.S. immunization schedule for children, to 7-day-old mice from the susceptible strain - SJL/J - and two other strains.

After 24 weeks of observation, the researchers found that only the SJL/J mice developed features resembling autism after the thimerosal injections. Compared with the two other strains that received thimerosal, the SJL/J mice had larger brains, structural abnormalities in brain regions that control emotion and cognition, smaller body size, abnormal response to novel environments, and decreased exploration of the environment.

The researchers are now looking for a human counterpart to the susceptibility gene in SJL/J mice. If they find one, Dr. Hornig says epidemiological studies can seek a relationship between autism and thimerosal in people with the gene. The large epidemiological studies that so far have shown no connection between autism and thimerosal have not considered the involvement of susceptibility genes, she says.

In July 1999 the U.S. Public Health Service agencies, the American Academy of Pediatrics, and vaccine manufacturers agreed that thimerosal levels in vaccines should be reduced or eliminated as a precautionary measure. Only influenza vaccines - which are not given to children under 6 months - currently contain thimerosal.

The study was supported by the M.I.N.D. Institute of the University of California/Davis, Coalition for Safe Minds, the Ellison Medical Foundation, and the NICHD.

—Susan Conova

The International AIDS Society-USA (IAS-USA) published recommendations for the treatment of adult HIV infection in the July 14 issue of the Journal of the American Medical Association, incorporating scientific knowledge about the virus that researchers have gained since the last publication of HIV recommendations in 2002 and helping refine choices for initial treatment of HIV infection. Dr. Scott Hammer, Harold C. Neu Professor of Infectious Diseases and chief of the division of infectious diseases at P&S, co-chaired the panel.

The recommendations include new drugs to fight the disease and knowledge regarding different drug combination regimens. The recommendations also address progress in identifying drug toxicities - particularly lipid problems that can lead to higher risk of cardiovascular disease - permitting patients and clinicians to make more informed treatment choices.

"The evolution of antiretroviral therapy over the course of the HIV pandemic has been remarkable but many challenges still lie before us," says Dr. Hammer. "Guidelines for therapy, whether for the developed or the developing world, are an iterative process and will require future updating to keep in step with the scientific advances in the field and to assist clinicians and patients in the management of antiretroviral therapy."

Contrary to widely held beliefs that men are the sole perpetrators in seriously abusive relationships, new research shows that women bear the brunt of the abuse, but both partners in those relationships are abusive toward their partners, according to a study by psychologists at Columbia University Medical Center, King's College and the University of Wisconsin.

The researchers also found, unexpectedly, that less serious abuse (abuse that did not result in bruises, broken bones, calls to the police, or agency involvement) was usually directed from the woman to the man. Prior research had suggested that less serious abuse was perpetrated by both men and women.

The results have implications for domestic violence prevention and treatment programs which exclusively target the male partner, says lead author Dr. Miriam Ehrensaft, professor of psychiatry at P&S and the New York State Psychiatric Institute. Treatment, she says, should address the aggression of both partners.

The study used data from nearly 1,000 New Zealanders who have been followed by mental health researchers since age 3. The researchers assessed the level and consequences of violence in the subjects' romantic relationships around age 26 and related that to previous mental health assessments. Overall, 9 percent of the group (37 men and 38 women) were, or had been, in a seriously abusive relationship within the past three years.

In seriously abusive relationships, the researchers found that both partners used abusive acts toward their partner. Women and men who became involved in those relationships had a history of aggression since adolescence, but the men also had longstanding behavior problems since childhood and abnormal personalities since adolescence.

"The findings prompt the novel hypothesis that woman-to-man abuse is the common pattern, but escalation to serious abuse requires a male partner with a history of psychopathology," Dr. Ehrensaft says.

The research is published in the May issue of the Journal of Abnormal Psychology.

—Susan Conova

A drug normally used to treat hemophilia is one of the first effective treatments for intracerebral hemorrhage (ICH), the most damaging and fatal type of stroke, according to an international, multicenter study led by CUMC researchers.

The Phase II trial tested NovoSeven, the medication from Novo Nordisk of Copenhagen, Denmark, in a randomized, double-blind, placebo-controlled study of 400 patients in 20 countries. The drug, given within three hours of the hemorrhage's onset, cut progressive bleeding by about 50 percent as measured by CT scans and reduced mortality by 35 percent. On average, for every six patients who received the treatment, one case of death or severe disability was prevented, says Dr. Stephan Mayer, associate professor of clinical neurology and neurosurgery and principal investigator of the study.

The study also showed a small increase in thromboembolic side effects, specifically stroke and heart attack. "But the benefits of limiting the bleeding in the brain vastly outweigh these minimal side effects," Dr. Mayer says.

"There is no question that these results are a major advance in the field of ICH research," Dr. Mayer says. "The trial data, suggesting the wait for an effective treatment for ICH may soon be at an end, will be welcomed by stroke specialists worldwide. This development could benefit many thousands of lives a year."

Currently, the only treatment for intracerebral hemorrhage is to put someone on life support. Surgery is also an option but it has not been proved to help, Dr. Mayer says.

Intracerebral hemorrhages account for about 15 percent of all strokes. Most strokes, 80 percent, are due to blood vessel blockages in the brain and the remaining 5 percent are caused by brain aneurysms. Strokes, which occur in about 700,000 Americans a year, are a leading cause of disability and the third leading cause of death in the United States.

The study was funded by Novo Nordisk.

—Matthew Dougherty

A new study by researchers at CUMC and colleagues in Iceland indicates that epilepsy and attention deficit hyperactivity disorder (ADHD) may share a common pathway - a finding that may lead to better treatment plans for these children.

This is the first population-based study to show that in children with both disorders, ADHD appears before the first seizure. "Learning problems noted in children with epilepsy may be due to one type of ADHD, specifically ADHD Predominantly Inattentive (ADHD-I) type, rather than to epilepsy or anticonvulsant medications," says Dr. W. Allen Hauser, professor of neurology at P&S and epidemiology at the Mailman School and senior author of the paper.

The investigators found that children with newly diagnosed epilepsy are 2.5 times more likely to have had ADHD-I. "The link between ADHD-I and epilepsy suggests there is something about these children's brains that gives rise to both conditions," says Dr. Dale Hesdorffer, assistant professor of epidemiology at Mailman and first author of the paper. The study, which appears in the July issue of the Archives of General Psychiatry, involved 327 Icelandic children between 3 and 16 years of age. Drs. Hauser and Hesdorffer are both members of the CUMC Gertrude H. Sergievsky Center, which integrates epidemiology with genetic analysis and clinical investigation to explore all phases of diseases of the nervous system.

The study was funded by the National Institute of Neurological Disorders and Stroke.

—Matthew Dougherty

In two new studies, chemotherapy has been shown for the first time to extend the life of men with advanced prostate cancer. The chemotherapy drug, doce taxel, was shown to increase the overall survival of men with androgen- independent prostate cancer by 20-24 percent. These studies usher in a new era of treatment in prostate cancer and change previous beliefs that advanced prostate cancer was untreatable.

"Docetaxel is definitely a new standard of care," says Dr. Daniel Petrylak, associate professor of medicine in P&S and one of the study's lead investigators. "Future studies will show if doce taxel can be combined with different agents to further improve survival and if docetaxel is effective in earlier stage prostate cancers."

Dr. Petrylak presented his findings in June at the American Society of Clinical Oncology's annual meeting, along with Dr. Mario Eisenberger of Johns Hopkins, who presented results from a separate Phase III trial of docetaxel.

In the United States, about 220,000 men are diagnosed with prostate cancer every year. In most men the disease progresses slowly, however, more than 29,000 men are expected to die from hormone refractory prostate cancer in the United States in 2004. This makes prostate cancer the second leading cause of cancer death in men in the United States.

Hormone therapy, which reduces the amount of testosterone available to promote tumor growth, can stop or shrink the metastases for several years, but invariably the cancer becomes resistant to hormone therapy.

Until now, no treatment has been shown to extend the lives of men with advanced, hormone-insensitive cancer. These men are usually treated with a combination of two chemotherapy agents - prednisone and mitoxantrone - that reduced pain but was unable to prolong life.

In Dr. Petrylak's multi-center trial, 334 patients were treated with an experimental combination of docetaxel and another anticancer drug called estramustine, while 332 patients were treated with the standard treatment, prednisone and mitoxantrone.

The docetaxel group lived a median of 18 months, compared with 16 months for men who received the standard treatment. Overall, the reduction in the risk of death was 20 percent.

Dr. Petrylak combined the doce taxel with estramustine because his previous Phase I and II studies had shown a synergistic effect between the two agents. The combination of doce taxel and estramustine was piloted by Dr. Petrylak's research group in the Irving Center for Clinical Research; the first trial was opened in 1996. In that initial study, the median survival of patients treated with docetaxel and estramustine was 23 months.

The other recent trial of docetaxel, led by Dr. Eisenberger, found similar results, although they combined doce taxel with a different drug, prednisone.

The FDA has approved the combination of docetaxel and prednisone for men with androgen-independent prostate cancer in June of this year.

The research was supported by the National Cancer Institute, Aventis Pharmaceuticals, and Pharmacia Upjohn.

—Susan Conova

Clinical trials of the first vaccine aimed at Parkinson's disease are being planned at CUMC following a successful test in mice, in which the vaccine prevented the death of neurons in the brain.

"The beauty of the approach we used here is that the vaccination produces the beneficial effects akin of a gene therapy, but without having to inject any gene or viral vector," says one of the study's authors, Dr. Serge Przedborski, professor of pathology and neurology in the Center for Neurobiology and Behavior. The research was a collaborative effort between the lab oratory of Dr. Serge Przedborski and of Dr. Howard Gendelman, director of the Center for Neurovirology and Neurodegenerative Disorders at the University of Nebraska Medical Center.

The vaccine, called copolymer-1 (Cop-1), does not prevent Parkinson's disease from occurring, but slows the disease's progression once it starts. Over time, the disease causes tremors, rigidity, and slowness of movement as it kills dopamine-producing neurons that help control movement.

Cop-1 works by reducing the inflammation in the brain that is responsible for much of the cell death. When injected, the immune system generates T cells that travel to the brain, turn down the inflammation, and increase the production of protective factors.

In the mice, the T cells prevented the death of about half the neurons that died in mice that did not receive the vaccine. Full results were published in the June 22 Proceedings of the National Academy of Sciences, USA.

Human trials of Cop-1 are planned next year for patients with Parkinson's disease and are currently under way for patients with ALS, which involves the same inflammatory processes as Parkinson's. The drug is already approved to prevent relapses in multiple sclerosis, a neuroinflammatory disease.

The research is supported in part by the NIH.

—Susan Conova

Researchers at CUMC have found a way to predict who is most likely to respond to treatment for lung cancer by monitoring the activity of 42 genes from small biopsies taken from the tumors.

The findings represent a step toward personalized treatment for lung cancer, in which patients will receive the most effective treatment for their particular type of cancer.

"The gene signatures of the tumors should help us improve lung cancer survival by identifying the patients most likely to benefit from current treatments and giving us ideas for alternative therapies for the other patients," says the study's senior author, Dr. Charles Powell, assistant professor of medicine at P&S. The research was published in the July 15 issue of American Journal of Respiratory and Critical Care Medicine.

Dr. Powell and his colleagues are now conducting trials to test the utility of the genetic testing in the clinic.

—Susan Conova


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