The largest study of its kind to date shows that women may not be able to learn as well shortly before menopause compared to other stages in life [Neurology, 72(21): 1850-1857].

For a four-year period, researchers studied 2,362 women between the ages of 42 and 52 had at least one menstrual period in the three months before the study started.

The women were given three tests: verbal memory, working memory and a test that measured the speed at which they processed information.

Scientists tested the women throughout four stages of the menopause transition: premenopausal (no change in menstrual periods), early perimenopausal (menstrual irregularity but no "gaps" of 3 months), late perimenopausal (having no period for three to 11 months) and postmenopausal (no period for 12 months).

The study found that processing speed improved with repeated testing during premenopause, early perimenopause and postmenopause, but that scores during late perimenopause did not show the same degree of improvement. Improvements in processing speed during late perimenopause were only 28 percent as large as improvements observed in premenopause.

For verbal memory performance, compared to premenopause, improvement was not as strong during early and late perimenopause. Improvements in verbal memory during early perimenopause were 29 percent as large as improvements observed in premenopause. During late perimenopause, verbal memory improvement was seven percent as large as in premenopause.

Combined, these findings suggest that during the early and late perimenopause women do not learn as well as they do during other menopause transition stages.

"These perimenopausal test results concur with prior self-reported memory difficulties - 60 percent of women state that they have memory problems during the menopause transition," said Gail Greendale, MD, with the David Geffen School of Medicine at the University of California, Los Angeles. "The good news is that the effect of perimenopause on learning seems to be temporary. Our study found that the amount of learning improved back to premenopausal levels during the postmenopausal stage."

The study also found that taking estrogen or progesterone hormones before menopause helped verbal memory and processing speed. In contrast, taking these hormones after the final menstrual period had a negative effect: postmenopausal women using hormones showed no improvement in either processing speed scores or verbal memory scores, unlike postmenopausal women not taking hormones. "Our results suggest that the 'critical period' for estrogen or progesterone's benefits on the brain may be prior to menopause, but the findings should be interpreted with caution," said Dr. Greendale.

The National Institutes of Health (NIH), the National Institute on Aging, the National Institute of Nursing Research and the NIH Office of Research on Women's Health supported the study.

Canadian researchers have identified tissue afflicted with a condition known as Barrett's Esophagus from chemical fingerprints associated with the disease, which can lead to esophageal cancer [The Analyst, 134(6): 1240 - 1246] .

"The advantage to using microscopes with synchrotron light is that it allows us to identify chemical biomarkers inside specific cells," said Luca Quaroni, a scientist at the Canadian Light Source, Canada's national centre for synchrotron research, who conducted the synchrotron analysis. "Often the differences between healthy and malignant tissue can be quite small, but the differences seen here were quite striking. This is a good proof of concept for developing a traceable technique that matches what can be seen at the macroscopic scale using microscopic samples."

The team analyzed preserved samples of healthy and diseased tissue that Alan Casson, head of the Department of Surgery at the University of Saskatchewan, collected during esophageal biopsies.

Using a technique known as Fourier Transform Infrared Microscopy, the researchers identified specific chemicals- known as biomarkers - within the individual cells that make up the tissue. It was found that increased concentrations of particular biomarkers such as glycoproteins were associated with the Barrett's tissue.

Barrett's Esophagus (BE) occurs when the cells that normally line the esophagus - the tube that connects our throat to our stomach - are replaced by cells that resemble those that line the intestine. While BE only affects approximately one percent of Americans, the number of people diagnosed with the condition is on the rise, with the increasing incidence of chronic heartburn (gastro-esophageal reflux disease or GERD) considered a risk factor for developing BE. The disease in turn can lead to an aggressive form of cancer known as esophageal adenocarcinoma.

Currently, diagnosing BE depends on the skill and experience of individual pathologists examining biopsy samples from patients, often relying on subjective criteria. Identifying biomarkers that can be associated with a particular condition provides an additional tool for diagnosis.

The traditional stroke symptoms are well known and include a sudden onset of numbness or weakness on one side of the body, trouble talking, loss of vision, or coordination problems.  But in women, doctors and bystanders should be paying attention to something else, according to Lynda Lisabeth, PhD, MPH, researcher in the department of neurology at the University of Michigan Health System (U-M).

"What we're finding is that women experience what is considered non-traditional symptoms," said Dr. Lisabeth, who presented research findings on acute stroke symptoms at the 2009 International Stroke Conference in February. "The non-traditional symptom that stood out was altered mental status, meaning confusion, disorientation or a loss of consciousness."

Symptoms such as sudden numbness of the face, arm or leg are a warning sign of what's happening in the body during a stroke which is a loss of blood supply to the brain because of a blocked or ruptured artery.

While larger scale studies focusing on stroke in women are warranted, the gender differences U-M researchers identified may contribute to delay in treatment for women and could signal a need to change public health campaigns, Dr. Lisabeth said.

The study examined ischemic strokes, the kind experienced by 80 percent of stroke victims, and transient ischemic attack, called mini-strokes because symptoms go away quickly. Researchers examined the cases of 461 men and women and classified their symptoms as either traditional or non-traditional.

Altered mental status was the most common non-traditional symptom and it was more likely to be reported in women, the study showed. Researchers do not know why women's symptoms were different.

But the differences in symptoms may have consequences if slow recognition of stroke signs cause a delay in treatment, the researcher says.

"The only treatment that is currently FDA approved in the United States for stroke is tPA (tissue plasminogen activator), or what we call a clot-busting drug," Dr. Lisabeth explained. "To administer tPA, people with stroke have to get to the hospital within three hours of symptom onset. So any delay on the part of actually getting to the hospital or delays once at the hospital could literally mean the difference between getting the therapy, or not getting the therapy."

Each year 800,000 Americans experience a stroke. Hispanic Americans and African Americans have a greater risk having a stroke, and to die from it. Intensive rehabilitation can help some overcome loss of function, but stroke remains a leading cause of disability. It is the third leading cause of death.

Men have an increased risk of stroke across most age groups. But in the oldest age groups, women's risk is higher, and since women live longer than men, women actually have an increased lifetime risk for stroke.

Several studies have suggested that women experience greater in-hospital delays such as longer triage times, longer time to see a physician and longer times to head imaging, which is critical for the diagnosis of stroke, compared with men, and have 30 percent lower odds of receiving tPA. Causes of these disparities are unclear, but could result from the different symptom presentation in women.

"We're hoping to understand those clinical implications and that information may lend itself to targeting stroke public health messages to women so that they can understand what it means to have one of these non-traditional stroke symptoms, and again emphasizing the urgency to seek care," said Dr. Lisabeth, who is also an assistant professor in the department of epidemiology in the U-M School of Public Health.

A new Web site intended to be a clearinghouse for questions about raising and educating a deaf child has been launched by the Center for Education Research Partnerships at the National Technical Institute for the Deaf, a college of Rochester Institute of Technology.

The Web site, www.educatingdeafchildren.org, is intended to answer questions from parents, teachers and other professionals who work with deaf children.

Approximately 90 percent of deaf children have hearing parents, so many times those parents feel overwhelmed and at a loss to find resources to answer questions they may have.

The information on the site is intended to provide full and objective information. A number of resources are listed, and visitors to the site are able to post questions to be answered by experts in that field.

A sampling of questions already addressed include:

• How will parents communicate with their deaf child?
• Will hearing aids help?
• Is my child a candidate for a cochlear implant?
• How will my child interact with peers?

The Web site also has a calendar to list upcoming events of related interest. Submissions from the community are encouraged.

Project partners include the American Society for Deaf Children, Hands & Voices, the National Deaf Children's Society and the Alexander Graham Bell Association for the Deaf and Hard of Hearing.

The Web site is sponsored in part by the Daisy Marquis Jones Foundation in Rochester, N.Y. and receives additional funding from Oxford University Press.

UCLA scientists have discovered a variant of a gene called CACNA1G that may increase a child's risk of developing autism, particularly in boys (Molecular Psychiatry Online, May 19, 2009).

Classic autism strikes boys four times more often than girls. When including the entire spectrum of autism disorders, such as the milder Asperger syndrome, boys are diagnosed 10 times more often than girls.

"This is a strong finding," said Stanley Nelson, MD, professor of human genetics at the David Geffen School of Medicine at UCLA. "No one has scrutinized the role that CACNA1G plays in autism.

"We found that a common form of the gene occurs more frequently in the DNA of families that have two or more sons affected by autism, but no affected daughters," he explained. "Our study may explain why boys are more susceptible to the disorder than girls."

Dr. Nelson and his colleagues zeroed in on a region of Chromosome 17 that previous studies have tied to autism. The research team scoured the DNA of 1,046 members of families with at least two sons affected by autism for common gene variants.

A variant is a gene that has undergone subtle changes from the normal DNA yet is shared by a significant portion of the population.

The researchers used tools of the Human Genome Project to scan thousands of variants across all genes in the suspicious region of the chromosome and to pluck out the most common forms.

"We wanted to identify what was happening in this region of Chromosome 17 that boosts autism risk," said Dr. Nelson. "When the same genetic markers kept cropping up in a single region of the DNA, we knew we had uncovered a big clue."

The researchers traced the genetic markers to CACNA1G, which helps move calcium between the cells. They discovered that the gene has a common variant that appears in the DNA of nearly 40 percent of the population.

"This alternate form of CACNA1G consistently increased the correlation to autism spectrum disorder, suggesting that inheriting the gene may heighten a child's risk of developing autism," observed Dr. Nelson.

How the gene contributes to higher autism risk remains unclear, but he emphasized that it cannot be considered a risk factor on its own.

"This variant is a single piece of the puzzle," Dr. Nelson said. "We need a larger sample size to identify all of the genes involved in autism and to solve the whole puzzle of this disease."

Next, the researchers plan to sequence the gene in people who possess the altered variant in order to identify the exact change that increases autism risk. These subtle variations offer potential markers for the real mutation causing greater susceptibility to the disease.

Dr. Nelson's coauthors included Samuel Strom, Jennifer Stone, John ten Bosch, Barry Merriman, Rita Cantor and Daniel Geschwind, all of UCLA. The study was funded by the National Institute of Mental Health and Cure Autism Now, which has since merged with Autism Speaks.

The DNA samples and clinical data were provided by families who donated blood to the Los Angeles-based Autism Genetic Resource Exchange (AGRE), a program created and funded by Cure Autism Now.

A clinical trial led by a University of North Carolina at Chapel Hill researcher concludes that radiofrequency ablation is an effective treatment for dysplasia in people with Barrett's esophagus, a condition that can lead to deadly gastrointestinal cancer [New England Journal of Medicine, 360 (22) 2277-2288].

"These results show there is a substantial difference between treatment with radiofrequency ablation and a placebo or 'sham' treatment," said Nicholas Shaheen, MD, principal investigator of the study, associate professor in the UNC School of Medicine and the UNC Gillings School of Public Health and director of the UNC Center for Esophageal Diseases and Swallowing. "It's a strongly positive finding."

Barrett's esophagus is a condition in which repeated acid reflux causes the cells that normally line the esophagus to be replaced by a different type of cell, similar to those normally found in the intestines. This process is called intestinal metaplasia. By itself Barrett's is not a life-threatening problem, but a small percentage of people with Barrett's will develop esophageal adenocarcinoma, an especially deadly form of cancer.

Radiofrequency ablation (RFA), a non-invasive technique that uses thermal energy, or heat, to destroy cells, is very effective at destroying abnormal cells in the esophagus. The new UNC-led study is the first randomized trial to evaluate radiofrequency ablation for treating dysplasia, a more advanced stage of Barrett's esophagus in which the abnormal cells acquire precancerous traits.

The RFA system used in the study uses thermal energy provided by a set of electromagnetic coils on the surface of a balloon, Dr. Shaheen said. "The balloon is placed in the area of the esophagus where the offending cells are and the balloon is inflated. Energy is then passed through the electromagnetic coils and, because we know how far apart the coils are spaced and how much energy is being put through them, we get a very reliable depth of burn, such that you can kill the abnormal cells on the inner surface without damaging the whole organ."

In the study, 127 people were randomized to receive either radiofrequency ablation or a simulated, "sham" version of the procedure at one of 19 participating medical centers. Among those with low grade dysplasia who received radiofrequency ablation, 90.5 percent were free of dysplasia 12 months after treatment, compared to 22.7 percent in those who received the sham procedure. Among those with high grade dysplasia, 81 percent who received radiofrequency ablation had complete eradication of intestinal metaplasia, compared to 19 percent in the sham group.

Overall, 77.4 percent of study participants treated with RFA had complete eradication of intestinal metaplasia, compared to 2.3 percent in the sham group. There was also less progression towards disease in the RFA group, 3.6 percent vs. 16.3 percent, and significantly more sham subjects developed esophageal adenocarcinoma, 9.3 percent vs. 1.2 percent.

The study concluded that RFA demonstrated a high rate of eradication of dysplasia and intestinal metaplasia and that these changes reduced the risk of progression towards dysplasia and the risk of developing cancer.

Funding for the study was provided by BARRX Medical Inc., which manufactures the HALO360 radiofrequency ablation system used in the study, the Investigator-Sponsored Study Program of AstraZeneca and a grant from the National Institutes of Health.

California senate President pro Tem Darrell Steinberg (D-Sacramento) announced the establishment of the Senate Select Committee on Autism (ASD) & Related Disorders which will build on the trailblazing work and important contributions of the three-year California Legislative Blue Ribbon Commission on Autism, which ended in November 2008.

"This Select Committee signals California's ongoing bipartisan commitment to individuals with autism and their families," Sen. Steinberg said. "It will provide a legislative forum for research, analysis, deliberations, and outreach on the most pressing issues and concerns facing families who are dealing with ASD."

The committee's upcoming activities will focus on issues related to establishing appropriate health insurance coverage; early identification and treatment; and promoting appropriate employment and housing for individuals with ASD.

The select committee soon will establish a series of task forces and working groups that will work with consumers, advocates and leaders throughout the state to deal with the autism epidemic. The committee will be working with some of the state's most distinguished leaders who are committed to advancing strong and effective autism public policy.

For More Information

• The Help Group, online: www.thehelpgroup.org

Molecules that selectively interfere with protein production can stop human cells from making the abnormal molecules that cause Huntington's disease, researchers at UT Southwestern Medical Center have found [Nature Biotechnology, 27 (5): 478-484].

These man-made molecules also were effective against the abnormal protein that causes Machado-Joseph disease, a neurological condition similar to Huntington's. The work has been done only in cultured cells, and it will take years before the effectiveness of this process can be tested in patients, the researchers cautioned.

"I wouldn't want to give Huntington's patients or gene carriers any false hope, but I am excited about where this work might go in the future," said David Corey, PhD, professor of pharmacology and biochemistry at UT Southwestern and senior author of the study.

The researchers' approach relies on interfering with the steps by which genetic information in cells is "translated" from DNA to make proteins, which carry out vital biological functions.

Huntington's and Machado-Joseph are fatal inherited diseases caused by abnormal repeats of a small segment in a person's DNA, or genetic code, represented by the letters CAG. These mutations result in the body producing malfunctioning proteins that cause the diseases. The more repeats, the worse the disease, and the earlier in life it appears. A person with the disease carries one normal copy of the gene and one mutated copy in his or her cells.

In Huntington's, this CAG repeat occurs in a gene called huntingtin, and in Machado-Joseph, it occurs in a gene called ataxin-3. A person with Huntington's can have up to 100 CAG repeats. CAG repeats are involved in several other neurodegenerative diseases, including Fragile X syndrome, the most common form of mental retardation, and myotonic dystrophy.

While these genes are best known for the devastating effects of their mutated forms, their normal forms are essential for embryonic development, nerve function and other bodily processes. Any treatment that interferes with the mutant forms must leave the normal forms as unaffected as possible, Dr. Corey said. "Attempting to intervene is very risky, but because the problem is important, it's worth doing," he said.

In the current study, the researchers created short lengths of molecules that resemble ribonucleic acid (RNA), the chemical cousin of DNA. These mimics, called PNAs and LNAs, were specifically designed to bind to CAG repeats, preventing cells from creating the abnormal proteins. The researchers also designed short lengths of RNA called small interfering RNA, or siRNA, to interfere with CAG repeats.

In cells from Huntington's patients, the PNAs, LNAs and siRNAs decreased the amount of mutant protein produced, in some cases up to 100 percent. The effect was greatest when the compounds interfered with long lengths of CAG repeats; the effectiveness varied, however, among cells taken from different patients.

Some forms of these compounds left the normal forms of huntingtin and ataxin-3 proteins undisturbed, but other compounds partly or completely blocked their formation. In some cells, some of the RNA mimics drastically cut the production of both mutant and normal proteins - an undesirable effect, Dr. Corey said.

These findings indicate that further tweaking of the molecular structures of the RNA mimics will be needed to minimize the effects on normal proteins.

"It is encouraging that small chemical changes could substantially enhance selectivity," Dr. Corey said. "If we can test a handful of compounds and identify better ones, we have reason to believe that more testing will continue to produce significant improvement."

Because this study was done in cultured cells, and not in whole animals or humans, it does not indicate how much of the abnormal proteins must be blocked to treat the disease effectively, he said. "Fifty percent inhibition might be enough, but that remains to be determined," he stated.

In future studies, the researchers plan to try these RNA mimics in whole animals, using several different mutations of the genes.

Other UT Southwestern researchers from the Department of Pharmacology involved in the study were co-lead authors Dr. Jiaxin Hu, assistant instructor, and Dr. Masayuki Matsui, postdoctoral researcher; Dr. Keith Gagnon, postdoctoral researcher; and graduate student Jacob Schwartz; Dr. Jun Wu, assistant instructor in physiology; and Dr. Ilya Bezprozvanny, professor of physiology, also participated, as did researchers from Sigma-Aldrich Genopole Campus in France.

The study was funded by the High-Q Foundation, the National Institutes of Health, the Welch Foundation and the Ataxia MJD Research Project Inc.

Facial fractures from motor vehicle crashes appear to be decreasing, most likely due to design improvements in newer vehicles, according to a new report [Archives of Facial Plastic Surgery, 11(3):165-170].

Facial trauma is the most common injury among individuals involved in motor vehicle collisions, according to background information in the article. Fractures to the face often occur simultaneously with other injuries, including damage to the eyes and brain. In 2000, the National Highway Traffic Safety Administration estimated that facial injuries cost between $9,000 and $725,000 per injury in lost productivity, medical costs, emergency services and other expenses.

Brian T. McMullin, MD, plastic and reconstructive surgery resident at the Medical College of Wisconsin, Milwaukee, and colleagues analyzed records from a national database of individuals (drivers and front seat occupants) with facial fractures following motor vehicle crashes. Between 1993 and 2005, 167,391 individuals involved in collisions had one or more facial fractures, 55,150 had skull base fractures (breaks in the bones of the skull) and 196,855 had nasal fractures.

Each year during that time period, the incidence of facial fractures decreased. In addition, a decline in the probability of injury was associated with newer car models. "As older cars are scrapped and more vehicles with next-generation safety features enter the vehicle fleet, we would expect decreasing injury probabilities and ultimately overall decreased injury incidence for year-to-year trends," the authors wrote.

Individuals involved in side-impact collisions, in vehicles in which speed increased as a result of collision, who were taller or who collided with a stationary object, light truck, sports utility vehicle or van were significantly more likely to sustain facial fractures. "Occupants who were restrained with seat belts only, as well as those restrained with seat belts and air bags, were significantly less likely to have facial fractures," the authors write. "Air bags alone were not associated with a reduced probability of facial fractures, and there was no difference in injury probability between sexes or based on occupant weight."

"Restraint use continues to be the most significant element for facial and skull base injury prevention, and more research is necessary to elucidate the mechanisms for facial and skull base fractures in side impacts, as well as to determine the effectiveness of side impact supplemental restraint systems," they concluded.

The study was funded in part by a grant from the Medical College of Wisconsin Injury Research Center.

Coauthors of the study include John S. Rhee, MD, MPH, associate professor of otolaryngology; Frank A. Pintar, PhD, professor of neurosurgery; Aniko Szabo, PhD, associate professor of population health biostatistics; Narayan Yoganandan, PhD, professor of neurosurgery.

Researchers from the University of Vermont College of Medicine and Johns Hopkins School of Medicine sought to investigate the biological mechanisms of caffeine withdrawal in a recent study [Psychopharmacology, 204(4):573-585].

The researchers examined brain electrical activity and blood flow during caffeine withdrawal to examine what was taking place physiologically during acute caffeine abstinence, including the likely mechanism underlying the common "caffeine withdrawal headache."

The group examined caffeine's effects in a double-blind study, which involved the administration of caffeine and placebo capsules. Each participant's response to the caffeine or placebo was measured using three different measures - brain electrical activity via electroencephalogram (EEG); blood flow velocity in the brain via ultrasound; and participants' self-reports of subjective effects via questionnaires.

The team demonstrated that stopping daily caffeine consumption produces changes in cerebral blood flow velocity and quantitative EEG that are likely related to the classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness. More specifically, acute caffeine abstinence increased brain blood flow, an effect that may account for commonly reported withdrawal headaches.

Acute caffeine abstinence also produced changes in EEG (increased theta rhythm) that has previously been linked to the common withdrawal symptom of fatigue. Consistent with this, volunteers reported increases in measures of "tired," "fatigue," "sluggish" and "weary." Overall, these findings provide the most rigorous demonstration to date of physiological effects of caffeine withdrawal.

The researchers also discovered a provocative and somewhat unexpected finding - that there were no net benefits associated with chronic caffeine administration.

"In addition to looking at caffeine withdrawal, this rigorous design also permitted comparison of chronic caffeine maintenance with chronic placebo maintenance, which provides unique information about the extent to which there are net beneficial effects of daily caffeine administration," said Stacey Sigmon, PhD, research associate professor of psychiatry at the University of Vermont and first author on the study. "In contrast to what most of us coffee lovers would think, our study showed no difference between when the participant was maintained on chronic placebo and when the participant was stabilized on chronic caffeine administration. What this means is that consuming caffeine regularly does not appear to produce any net beneficial effects, based on the measures we examined."

Co-authors on the study, a collaboration between Dr. Sigmon and Roland Griffiths, PhD, at the Johns Hopkins University School of Medicine, include Ronald Herning, Warren Better and Jean Cadet of the National Institute on Drug Abuse Molecular Neuropsychiatry section.

A team of Utahns is collaborating on a stem cell therapy to fight amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

With $5 million dollars in funding from the National Institutes of Health (NIH), Linda Kelley, PhD, director of the University of Utah Cell Therapy Facility, James Campanelli, PhD, of University of Utah spin-out Q Therapeutics, Inc., and Utah native Nicholas Maragakis, MD, of The Johns Hopkins University School of Medicine in Baltimore, MD, have teamed up to bring the cell-based therapy to the point of human clinical trials to treat this deadly disease.

The four-year NIH grant will enable critical manufacturing and testing requirements necessary to gain U.S. Food and Drug Administration approval for human clinical trials.

Dr. Kelley, principal investigator on the grant and professor of internal medicine at the University of Utah School of Medicine, said the project is a collaboration in the truest sense. "While the University will be home to the grant, the stem-cell technology that Q Therapeutics brings to the table and the clinical expertise of Dr. Maragakis are essential to the project. We are pleased to help bring this groundbreaking therapy toward human use," Dr. Kelley said. "Our collaboration is a terrific example of how public-private partnerships can make innovative therapeutic products a reality."

According to Jack Brittain, University vice president for technology venture development, "The translational research that this funding supports-beyond basic research, but not yet in clinical trials-has been traditionally very difficult to fund. This award validates the approach being taken here at the University of Utah toward emerging technologies, such as regenerative medicine. This kind of collaboration between the University and its commercial spin-out companies is something we strive for and enthusiastically support."

ALS is a progressive neurodegenerative disease that kills certain nerve cells in the brain and spinal cord. As these cells degenerate, they lose the ability to send impulses that control muscle movement for speech, breathing, limb movement, and other functions, with death from respiratory failure typically occurring from two to five years after diagnosis. ALS affects roughly 30,000 people in this country.

The cell-based ALS therapeutic originates from research at the University of Utah by Mahendra Rao, MD, PhD, a co-founder of Salt Lake City-based Q Therapeutics, Inc.

In bringing together cell therapy and neurology, the collaboration focuses on two of seven life science industry sectors identified by the State of Utah for long-term development.

Dr. Maragakis, a Salt Lake City native and graduate of the University of Utah School of Medicine, added, "This is an important milestone in the development of therapeutics to treat those who suffer with ALS. Given the lack of good treatment alternatives for this fatal disease, this project could lead to a first-in-class therapy that significantly alters the course of disease for many ALS patients."

The fertile soil of California's Central Valley has long made it famous as one of the nation's prime crop-growing regions. But it's not just the soil that allows for such productivity. Crops like potatoes, dry beans and tomatoes have long been protected from bugs and weeds by the fungicide maneb and the herbicide paraquat. Scientists know that in animal models and cell cultures, such pesticides trigger a neurodegenerative process that leads to Parkinson's disease. Now, researchers at UCLA provide the first evidence for a similar process in humans [American Journal of Epidemiology, 169(8): 919-926].

In a new epidemiological study of Central Valley residents who have been diagnosed with Parkinson's disease, researchers found that years of exposure to the combination of these two pesticides increased the risk of Parkinson's by 75 percent. Further, for people 60 years old or younger diagnosed with Parkinson's, earlier exposure had increased their risk for the disease by as much as four- to six-fold.

Beate Ritz, MD, PhD, professor of epidemiology at the UCLA School of Public Health, and Sadie Costello, PhD, a former doctoral student at UCLA who is now at the University of California, Berkeley, found that Central Valley residents who lived within 500 meters of fields sprayed between 1974 and 1999 had a 75-percent increased risk for Parkinson's.

In addition, people who were diagnosed with Parkinson's at age 60 or younger were found to have been at much higher risk because they had been exposed to maneb, paraquat or both in combination between 1974 and 1989, years when they would have been children, teens or young adults.

The researchers enrolled 368 longtime residents diagnosed with Parkinson's and 341 others as a control group.

Parkinson's disease is a degenerative disorder of the central nervous system that often impairs motor skills, speech and other functions. It has been reported to occur at high rates among farmers and in rural populations, contributing to the hypothesis that agricultural pesticides may be partially responsible.

Until now, however, data on human exposure has been unavailable, largely because it has been too hard to measure an individual's environmental exposure to any specific pesticide.

"Because pesticides applied from the air or ground may drift from their intended treatment sites - with measurable concentrations subsequently detected in the air, in plants and in animals up to several hundred meters from application sites - accurate methods of estimating environmental exposures in rural communities have long been sorely needed," said Dr. Ritz, the senior study author and vice chair of the School of Public Health's epidemiology department.

Drs. Ritz, Costello and colleague Myles Cockburn, PhD, from the University of Southern California, developed a geographic information system-based tool that estimated human exposure to pesticides applied to agricultural crops. This GIS tool combined land-use maps and pesticide-use reporting data from the state of California. Each pesticide-use record includes the name of the pesticide's active ingredient, the amount applied, the crop, the acreage of the field, the application method and the date of application.

Research subjects were recruited between 1998 to 2007; telephone interviews were conducted to obtain their demographic and exposure information. Detailed residential history forms were mailed to subjects in advance of their interviews and were reviewed in person or over the phone. The researchers recorded and added lifetime residential histories and estimated ambient exposures into the system for all historical addresses at which participants had resided between 1974 and 1999, the period covered by the pesticide-use data.

"The results confirmed two previous observations from animal studies," Dr. Ritz said. "One, that exposure to multiple chemicals may increase the effect of each chemical. That's important, since humans are often exposed to more than one pesticide in the environment. And second, that the timing of exposure is also important."

She noted that this is the first epidemiological study to provide strong evidence that maneb and paraquat act synergistically to become neurotoxic and strongly increase the risk of Parkinson's disease in humans.

Of particular concern, Dr. Ritz said, and consistent with other theories regarding the progression of Parkinson's pathology, is that the data "suggests that the critical window of exposure to toxicants may have occurred years before the onset of motor symptoms when a diagnosis of Parkinson's is made."

In addition to Drs. Ritz and Costello, study authors included Jeff Bronstein, UCLA professor of neurology, and Xinbo Zhang of USC. The authors declare no conflicts of interest.

The research was supported by the National Institute of Environmental Health Science, the National Institute of Neurological Disorders and Stroke, and the Department of Defense Prostate Cancer Research Program. In addition, initial pilot funding was provided by the American Parkinson Disease Association.

Eating a Mediterranean diet appears to be associated with less risk of mild cognitive impairment-a stage between normal aging and dementia-or of transitioning from mild cognitive impairment into Alzheimer's disease, according to a recent report [Archives of Neurology, 66(2):216-225].

"Among behavioral traits, diet may play an important role in the cause and prevention of Alzheimer's disease," the authors write as background information in the article.

Previous studies have shown a lower risk for Alzheimer's disease among those who eat a Mediterranean diet, characterized by high intakes of fish, vegetables, legumes, fruits, cereals and unsaturated fatty acids, low intakes of dairy products, meat and saturated fats and moderate alcohol consumption.

Nikolaos Scarmeas, MD, and colleagues at Columbia University Medical Center, New York, calculated a score for adherence to the Mediterranean diet among 1,393 individuals with no cognitive problems and 482 patients with mild cognitive impairment. Participants were originally examined, interviewed, screened for cognitive impairments and asked to complete a food frequency questionnaire between 1992 and 1999.

Over an average of 4.5 years of follow-up, 275 of the 1,393 who did not have mild cognitive impairment developed the condition. Compared with the one-third who had the lowest scores for Mediterranean diet adherence, the one-third with the highest scores for Mediterranean diet adherence had a 28 percent lower risk of developing mild cognitive impairment and the one-third in the middle group for Mediterranean diet adherence had a 17 percent lower risk.

Among the 482 with mild cognitive impairment at the beginning of the study, 106 developed Alzheimer's disease over an average 4.3 years of follow-up. Adhering to the Mediterranean diet also was associated with a lower risk for this transition. The one-third of participants with the highest scores for Mediterranean diet adherence had 48 percent less risk and those in the middle one-third of Mediterranean diet adherence had 45 percent less risk than the one-third with the lowest scores.

The Mediterranean diet may improve cholesterol levels, blood sugar levels and blood vessel health overall, or reduce inflammation, all of which have been associated with mild cognitive impairment. Individual food components of the diet also may have an influence on cognitive risk. "For example, potentially beneficial effects for mild cognitive impairment or mild cognitive impairment conversion to Alzheimer's disease have been reported for alcohol, fish, polyunsaturated fatty acids (also for age-related cognitive decline) and lower levels of saturated fatty acids," they write.

Additional studies are needed to confirm the role of this or other dietary factors in the development of cognitive impairment and Alzheimer's disease, the researchers concluded.

The study was supported by grants from the National Institute on Aging.

Social isolation may increase a person's chance of dying after a stroke, according to the results from an animal study (PNAS, March 23, 2009).

Courtney DeVries, PhD, of the Departments of Psychology and Neuroscience at the Institute of Behavioral Medicine Research at Ohio State University in Columbus, and colleagues report that individually housed male mice had lower survival rates and experienced more brain damage from the stroke than those housed with female mice.

The researchers show that only 40 percent of socially isolated mice survived seven days past a surgically-induced stroke, whereas all of the cohabiting mice survived such a stroke. The authors found that the socially isolated male mice had higher levels of several pro-inflammatory compounds in the areas of their brain surrounding the stroke site, which could help explain the higher death rates and brain damage.

Treatment of the socially isolated mice with an antibody to block the effects of one of these pro-inflammatory compounds eliminated the differences in stroke severity. These results indicate that social isolation can alter the outcome of a stroke by increasing the inflammatory response to the damaged brain tissue, the authors concluded.

Researchers suggest that physical frailty, which is common in older persons, may be related to Alzheimer's disease pathology [Neurology, 71 (4): 499-504].

For the study, researchers from Rush University Medical Center in Chicago examined the brains of 165 people who had been participants in a larger community study of chronic diseases of aging. While participants were alive, physical frailty measurements were taken yearly including grip strength, time to walk eight feet, body composition and tiredness. After death, the brains of these participants were checked for the plaques and tangles that are signs of Alzheimer's disease pathology.

Of the participants in the study, 36 percent of the group had dementia, or showed signs of memory loss. "Interestingly, Alzheimer's disease pathology was associated with physical frailty in older persons both with and without dementia," said study author Aron S. Buchman, MD.

"The level of frailty was approximately two times higher in a person with a high level of [Alzheimer's disease] pathology compared with a person with a low level of [Alzheimer's disease] pathology," said Dr. Buchman. The results remained the same regardless of whether a person had a history of other diseases and regardless of their level of physical activity.

A previous study of the same group of participants while they were alive suggested that older people who are physically frail with no cognitive impairment appear to be at higher risk of developing Alzheimer's disease as compared to those who were less frail. "Together both of these studies suggest that frailty can be an early indicator of Alzheimer's disease pathology and may appear before memory loss," Dr. Buchman said.

"These findings raise the possibility that Alzheimer's disease may contribute to frailty or that frailty and Alzheimer's disease share a common cause. We theorize that the accumulation of these plaques and tangles in the brain could affect the areas of the brain responsible for motor skills and simple movements years before the development of dementia," he added.

Studies show that about seven percent of people over age 65 are considered frail; that number jumps to 45 percent after age 85.

The study was supported by the National Institute on Aging, the Illinois Department of Public Health and the Robert C. Borwell Endowment Fund.

A type of white blood cell that is important to the immune system may provide hope for future new therapies for amyotrophic lateral sclerosis (ALS), as well as other neurodegenerative diseases, according to researchers at the Methodist Hospital in Houston [PNAS, 105 (40): 15558-15563] .

The researchers have shown that restoring functional T-cells, an immune system white blood cell, in a mouse model of ALS slows disease progression. T-cells play a critical role in protecting brain cells by enhancing the protective functions of supporting cells of the brain and spinal cord called glia.

Of the ALS cases caused by genetic factors, about 10 percent have a mutation in a gene called superoxide dismutase 1, or SOD1, which mops up the free radicals that damage cell function.

"In animal models of ALS, we and others have previously shown that reducing the levels of mutant SOD1 protein in glia slows the progression of the disease," said Dr. Stanley H. Appel, MD, last author and chairman of Neurology at Methodist. "However, in our current report, we demonstrate an alternative approach. In ALS mice with functional immune cells called CD4+ T-cells, the progression of the disease is again slowed and survival increased."

Co-lead authors David R. Beers, PhD, and Jenny S. Henkel, PhD, head the team of Methodist neurodegenerative disease scientists working with Dr. Appel, who also leads MDA/ALS Clinic and Research Center at the hospital. Their findings show the disease could be slowed in these mice if they received a bone marrow transplant and were able to produce T-cells again.

"It has been known for some time that T-cells are present at sites of injury in ALS patients as well as in mouse models of ALS, and until now, the role of these cells was unknown," said Dr. Beers. "This study demonstrates that T-cells, possibly CD4+ T-cells, through their interaction with microglia and astroglia, are protecting the cells in the spinal cord that cause muscle movement. It is now critically important to understand how T-cells provide this neuroprotection."

"We're currently looking at the sub-population of CD4+ T-cells that are providing this protection," said Dr. Henkel. "These cells may eventually provide a readily accessible target for therapeutic intervention not only for ALS but other neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases."

The study was supported by the National Institutes of Health and the Muscular Dystrophy Association.

A new study indicates that some aspects of peoples' cognitive skills - such as the ability to make rapid comparisons, remember unrelated information and detect relationships - peak at about the age of 22, and then begin a slow decline starting around age 27 [Neurobiology of Aging, 30(4):507-514].

"This research suggests that some aspects of age-related cognitive decline begin in healthy, educated adults when they are in their 20s and 30s," said Timothy Salthouse, PhD, a University of Virginia professor of psychology and the study's lead investigator.

He and his team conducted the study during a seven-year period, working with 2,000 healthy participants between the ages of 18 and 60.

Participants were asked to solve various puzzles, remember words and details from stories, and identify patterns in an assortment of letters and symbols.

Many of the participants in Dr. Salthouse's study were tested several times during the course of years, allowing researchers to detect subtle declines in cognitive ability.

Top performances in some of the tests were accomplished at the age of 22. A notable decline in certain measures of abstract reasoning, brain speed and in puzzle-solving became apparent at 27.

Dr. Salthouse found that average memory declines can be detected by about age 37. However, accumulated knowledge skills, such as improvement of vocabulary and general knowledge, actually increase at least until the age of 60.

"These patterns suggest that some types of mental flexibility decrease relatively early in adulthood, but that how much knowledge one has, and the effectiveness of integrating it with one's abilities, may increase throughout all of adulthood if there are no pathological diseases," he said.

However, he pointed out that there is a great deal of variance from person to person, and, he added, most people function at a highly effective level well into their final years, even when living a long life.

One of the unique features of this project in the University of Virginia Cognitive Aging Laboratory is that some of the participants return to the laboratory for repeated assessments after intervals of one to seven years.

"By following individuals over time, we gain insight to cognition changes, and may possibly discover ways to alleviate or slow the rate of decline," Dr. Salthouse said. "And by better understanding the processes of cognitive impairment, we may become better at predicting the onset of dementias such as Alzheimer's disease."

Dr. Salthouse's team also is surveying participants' health and lifestyles to see if certain characteristics, such as social relationships, serve to moderate age-related cognitive changes.

They hope to continue their studies over many more years, with many of the same participants, to gain a long-term understanding of how the brain changes over time.

A surgery at Loyola University Health System made it possible for a patient born without  a fully formed left ear to be fitted with a prosthetic that looks just like the real thing.

Ear-nose-throat surgeon Sam Marzo, MD, implanted three small metal screws in the side of patient Matthew Houdek's head. Each screw is fitted with a magnet, and magnetic attraction holds the prosthetic ear in place.

It takes only a few seconds for Houdek to put his prosthetic ear on in the morning and take it off when he showers or goes to bed. It doesn't fall off, and it's much more convenient than prosthetic ears that are attached with adhesive.

"I'm extremely happy with it," said Houdek, 25, who lives in Chicago. "It turned out better than I expected."

Houdek was born with a deformity called microtia (small ear). About 1 in 10,000 babies are born with this condition, in which one or both outer ears are under-developed or absent. On his left side, Houdek was born with just an ear lobe and a bump.

When Houdek was about 4 years old, a surgeon reconstructed a new ear from his rib cartilage. At first, the ear was the right size. But it did not grow as Houdek grew up. "As I got older, it became more of an issue," Houdek said.

The silicone prosthesis was made by Gregory Gion, a facial prosthetist based in Madison, Wis. The flesh-colored silicone prosthesis looks almost identical to Houdek's natural ear - right down to the small blood vessels. Houdek said everyone loves it. "And my mom almost cried when she saw it."

Like many people with microtia, Houdek also was born without an ear canal, a condition called congenital aural atresia. Dr. Marzo opened a new ear canal and lined it with a skin graft from Houdek's leg. Houdek now has partial hearing in his left ear.

"With a hearing aid, his hearing should be very good," said Dr. Marzo, an associate professor in the Department of Otolaryngology at Loyola University Chicago Stritch School of Medicine.

Scientists from the University of Rochester Medical Center have unraveled in unprecedented detail the cascade of events that go wrong in brain cells affected by HIV, a virus whose assault on the nervous system continues unabated despite antiviral medications that can keep the virus at bay for years in the rest of the body [PLoS One, 3(11): e3731].

The research reveals key steps taken in the brain by Tat, a protein that is central to HIV's attack on cells called neurons. Researchers discovered the receptor that Tat uses to attack neurons, and they were able to reverse the effects of Tat in the laboratory by blocking the receptor.

The discovery of a major molecular player in the process opens up a new avenue for researchers to explore in their efforts to prevent or treat HIV's neurological effects, for which there is no currently approved treatment. Researchers say that much of the molecular action that underlies HIV's attack on the brain also occurs in other diseases, such as Parkinson's and Alzheimer's diseases, and that the results spell progress for those conditions as well.

The powerful antiviral drugs that keep many HIV patients healthy for years don't completely eradicate the virus from the body, and in the brain, even the very low levels of that remain cause relentless damage. Scientists have observed that a large percentage of HIV patients - perhaps up to half - show evidence of neurologic disease from the virus,

"The current medications give many patients a new lease on life. But the virus is still taking a toll on the brain, even when the virus appears to be much less active elsewhere in the body," said the paper's corresponding author, neurologist Harris "Handy" Gelbard, M.D., Ph.D. of the University of Rochester Medical Center.

Dr. Gelbard was a newly minted pediatric neurologist embarking on his career when a good friend of his - a doctor with whom Dr. Gelbard had trained - became ill and died of AIDS in less than two years. His friend's struggle, and the severity of his neurological symptoms, touched Dr. Gelbard. Gradually, with the support of mentors, Dr. Gelbard came to focus on the neurological effects of HIV. He now leads a group of researchers funded by the National Institute of Mental Health that is trying to identify or create the first treatment for the neurological effects of HIV, known collectively as neuroAIDS or HIV dementia.

Scientists have known that Tat, which helps HIV operate, replicate, and infect cells, is at the forefront of HIV's attack on the brain, bringing about severe inflammation. Immune cells within the brain go into overdrive, churning out substances that attract more immune cells, and white blood cells from the body flood in and join the fray, all clumping together to form destructive entities known as multinucleated giant cells.

"Suddenly the brain environment turns from nurturing to toxic, and the brain has to work much harder to send messages. Cells are on overdrive, spending a lot more energy to do the same things they used to do easily," said Dr. Gelbard, who is director of the Center for Neural Development and Disease at Rochester.

Other changes occur throughout the brain as well. Neurons that normally reach throughout the brain by forming networks of far-reaching, delicate extensions crucial for cell communication become damaged. Instead of sprouting healthy dendrites - projections that resemble tiny trees - neurons in the brain of an HIV patient have had parts of their dendrites abruptly torn off, in a process known as "synaptic pruning." The dendrites begin to look like a patch of severely damaged trees after a bad ice storm.

Such damage occurs in parts of the brain crucial for thinking, decision-making, and movement and memory. That accounts for symptoms like difficulties concentrating, forgetfulness, poor coordination, confusion, and gait disturbances. In later stages, neuroAIDS can cause outright dementia.

Dr. Gelbard's team discovered that Tat works through the ryanodine receptor to sicken neurons in two ways. Scientists have known that Tat makes vulnerable the mitochondria, organelles within neurons and other cells that are commonly considered the "power packs" or energy sources for cells. The team discovered that Tat destroys the ability of mitochondria to protect themselves from changes in levels of calcium.

The scientists discovered another effect of Tat as well. Tat has a dramatic effect on an organelle known as the endoplasmic reticulum, where proteins are actually assembled and folded. The researchers discovered that it's Tat's effects on the ryanodine receptor that cause an "unfolded protein response" seen in the brains of HIV patients. Shape is everything for proteins, and they're nearly always useless or harmful when they are unfolded or misfolded. The problem in HIV patients is exacerbated because protein folding requires a great deal of energy - energy that cells whose mitochondria are petering out aren't likely to have.

The team also showed, in mice, that a single exposure to Tat has long-lasting effects on the brain, causing problems with mitochondria and endoplasmic reticulum weeks later. Perhaps most striking, Dr. Gelbard says, is the observation that the exact same types of damage were seen in brain tissue of patients with HIV and neurologic disease but not in tissue from patients with HIV who did not have the neurologic disease.

The findings are in line with past findings from the team, which has shown that the central problem in HIV dementia is not that brain cells simply die. Rather, they become sick and lose their ability to communicate with each other. Because the cells are still alive, there is hope that the condition could be stopped or even reversed with proper treatment. Indeed, doctors commonly see patients who begin antiviral therapy and immediately are less confused and have improved brain functioning, but the effect generally fades as the disease progresses.

In their experiment, Dr. Gelbard's team was able to stop the harmful effects of Tat in neurons from mice by using the drug dantrolene, which blocks the ryanodine receptor. While the work offers a new target in the search for a drug that could be used in people to stop the effects of HIV dementia, he cautions that dantrolene has side effects and would not be appropriate.

"A lot of people are under the impression that HIV has been 'solved,' that somehow, it's no longer a problem. But the disease never went away, and it's a huge problem," said Dr. Gelbard, who is professor of Neurology, Pediatrics, and Microbiology and Immunology.

"There are a fair number of similarities between this brain disease and other diseases, such as Parkinson's or Alzheimer's," he added. "We hope that what we are learning can be applied to other diseases as well."

The first author of the paper is former graduate student John P. Norman, PhD, now with Exxon-Mobil. Other authors were Seth Perry, PhD, research assistant professor of neurology; graduate students Holly Reynolds and Michelle Kiebala; Sanjay Maggirwar, PhD, and Stephen Dewhurst, PhD, professors of microbiology and immunology; Karen De Mesy Bentley; David Volsky, PhD, of Columbia University Medical Center; and Margarita Trejo and Eliezer Masliah, MD, of the School of Medicine at the University of California at San Diego.

Scientists at Albert Einstein College of Medicine of Yeshiva University in New York, NY, have proposed a sweeping new theory of autism that suggests that the brains of people with autism are structurally normal but dysregulated, meaning symptoms of the disorder might be reversible [Brain Research Reviews, 59(2):388-392].

The central tenet of the theory is that autism is a developmental disorder caused by impaired regulation of the locus coeruleus, a bundle of neurons in the brain stem that processes sensory signals from all areas of the body.

The new theory stems from decades of anecdotal observations that some children with autism seem to improve when they have a fever, only to regress when the fever ebbs. A 2007 study in the journal Pediatrics took a more rigorous look at fever and autism, observing children with autism during and after fever episodes and comparing their behavior with autistic children who didn't have fevers. This study documented that children with autism experience behavior changes during fever.

"On a positive note, we are talking about a brain region that is not irrevocably altered. It gives us hope that, with novel therapies, we will eventually be able to help people with autism," said theory co-author Mark F. Mehler, MD, chairman of neurology and director of the Institute for Brain Disorders and Neural Regeneration at Einstein.

Autism is a complex developmental disability that affects a person's ability to communicate and interact with others. It usually appears during the first three years of life. Autism is called a "spectrum disorder" since it affects individuals differently and to varying degrees. It is estimated that one in every 150 American children has some degree of autism.

The researchers contend that scientific evidence directly points to the locus coeruleus-noradrenergic (LC-NA) system as being involved in autism. "The LC-NA system is the only brain system involved both in producing fever and controlling behavior," said study co-author Dominick P. Purpura, MD, dean emeritus and distinguished professor of neuroscience at Einstein.

The locus coeruleus has widespread connections to brain regions that process sensory information. It secretes most of the brain's noradrenaline, a neurotransmitter that plays a key role in arousal mechanisms, such as the "fight or flight" response. It is also involved in a variety of complex behaviors, such as attentional focusing (the ability to concentrate attention on environmental cues relevant to the task in hand, or to switch attention from one task to another). Poor attentional focusing is a defining characteristic of autism.

"What is unique about the locus coeruleus is that it activates almost all higher-order brain centers that are involved in complex cognitive tasks," said Dr. Mehler.

Drs. Purpura and Mehler hypothesize that in autism, the LC-NA system is dysregulated by the interplay of environment, genetic, and epigenetic factors (chemical substances both within as well as outside the genome that regulate the expression of genes). They believe that stress plays a central role in dysregulation of the LC-NA system, especially in the latter stages of prenatal development when the fetal brain is particularly vulnerable.

As evidence, the researchers point to a 2008 study, published in the Journal of Autism and Developmental Disorders, that found a higher incidence of autism among children whose mothers had been exposed to hurricanes and tropical storms during pregnancy. Maternal exposure to severe storms at mid-gestation resulted in the highest prevalence of autism.

Drs. Purpura and Mehler believe that, in children with autism, fever stimulates the LC-NA system, temporarily restoring its normal regulatory function. "This could not happen if autism was caused by a lesion or some structural abnormality of the brain," explained Dr. Purpura.]

"This gives us hope that we will eventually be able to do something for people with autism," he added.

The researchers do not advocate fever therapy (fever induced by artificial means), which would be an overly broad, and perhaps even dangerous, remedy. Instead, they say, the future of autism treatment probably lies in drugs that selectively target certain types of noradrenergic brain receptors or, more likely, in epigenetic therapies targeting genes of the LC-NA system.

"If the locus coeruleus is impaired in autism, it is probably because tens or hundreds, maybe even thousands, of genes are dysregulated in subtle and complex ways," said Dr. Mehler. "The only way you can reverse this process is with epigenetic therapies, which, we are beginning to learn, have the ability to coordinate very large integrated gene networks."

"The message here is one of hope but also one of caution," Dr. Mehler said. "You can't take a complex neuropsychiatric disease that has escaped our understanding for 50 years and in one fell swoop have a therapy that is going to reverse it - that's folly. On the other hand, we now have clues to the neurobiology, the genetics, and the epigenetics of autism. To move forward, we need to invest more money in basic science to look at the genome and the epigenome in a more focused way."

Eating tuna and other types of fish may help lower the risk of cognitive decline and stroke in healthy older adults, according to Finnish researchers [Neurology, 71(6): 439-446].

For the study, 3,660 people age 65 and older underwent brain scans to detect silent brain infarcts, or small lesions in the brain that can cause loss of thinking skills, stroke or dementia. Scans were performed again five years later on 2,313 of the participants. The people involved in the study were also given questionnaires about fish in their diets.

The study found that people who ate broiled or baked tuna and other fish high in omega-3 fatty acids (called DHA and EPA) three times or more per week had a nearly 26 percent lower risk of having the silent brain lesions that can cause dementia and stroke compared to people who did not eat fish regularly. Eating just one serving of this type of fish per week led to a 13 percent lower risk. The study also found people who regularly ate these types of fish had fewer changes in the white matter in their brains.

"While eating tuna and other types of fish seems to help protect against memory loss and stroke, these results were not found in people who regularly ate fried fish," said Jyrki Virtanen, PhD, RD, with the University of Kuopio in Finland. "More research is needed as to why these types of fish may have protective effects, but the omega-3 fatty acids EPA and DHA would seem to have a major role."

Types of fish that contain high levels of DHA and EPA nutrients include salmon, mackerel, herring, sardines, and anchovies.

"Previous findings have shown that fish and fish oil can help prevent stroke, but this is one of the only studies that looks at fish's effect on silent brain infarcts in healthy, older people," said Dr. Virtanen. Research shows that silent brain infarcts, which are only detected by brain scans, are found in about 20 percent of otherwise healthy elderly people.

The study was supported by the National Heart, Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, the Finnish Cultural Foundation, Helsingin Sanomat Centennial Foundation, the Finnish Foundation for Cardiovascular Research, the Yrjö Jahnsson Foundation and the University of Kuopio.

A glitch in the ability to move iron around in cells may underlie a disease known as Type IV mucolipidosis (ML4) and the suite of symptoms-mental retardation, poor vision and diminished motor abilities-that accompany it, research at the University of Michigan shows [Nature, 455: 992-996].

The same deficit also may be involved in aging and neurodegenerative diseases such as Alzheimer's and Parkinson's, says lead author Haoxing Xu, PhD, an assistant professor of molecular, cellular and developmental biology.

An interest in iron transport led Dr. Xu to investigate ML4, another symptom of which is iron-deficiency anemia. Perhaps, he and his collaborators reasoned, impaired iron transport could explain both the anemia and the other problems that go hand-in-hand with ML4, a genetic disorder that mainly affects Jews of Eastern European background. Children with ML4 begin showing signs of developmental delay and eye problems during the first year of life and typically fail to progress beyond the level of a 15-month-old. Although the disease is rare, recent discovery of some children with milder forms of the condition raises the possibility of additional mild, undiagnosed cases.

To explore the possible role of iron transport in the disease, Dr. Xu's group focused on a protein called TRPML1. A mutation in the gene that produces TRPML1 is known to cause ML4, so the protein seemed like a logical starting point for investigating mechanisms responsible for the disease, even though TRPML1 had never been shown to be involved in iron transport. The only protein with that distinction was DMT1, which facilitates iron uptake in the gut and in cells that will become red blood cells, but not in most other cell types.

"Essentially all cells, including nerve cells and muscle cells, need iron," Dr. Xu said. "We wondered what happens in those cells where DMT1 isn't found, and we thought there must be an unidentified iron transporter protein, possibly TRPML1."

TRPML1 has proved a difficult protein to study. Instead of residing in the cell's easily-accessed outer membrane, where many other proteins nestle, it hides in a tiny, interior pocket called lysosome. To probe the protein, the researchers had to modify a technique known as the patch clamp, in which a micropipette and electrodes are attached to a cell membrane to record the activity of individual or multiple proteins that serve as channels for charged particles (ions) moving in and out of cells. With their modification, which they call the lysosome patch clamp, Dr. Xu's group was able to record TRPML1 activity in the tiny lysosome.

They found that TRPML1 was indeed capable of ferrying iron out of the lysosome. But was there any evidence that interfering with that ability might result in ML4 symptoms? To address that question they studied defective TRPML1 proteins bearing the same mutations as those found in ML4 patients. Mutations associated with severe symptoms were the least adept at shuttling iron, while those associated with milder symptoms were more proficient, although still not fully functional.

Further experiments confirmed that when TRPML1 is defective, iron becomes trapped in the lysosome. One result of the buildup is formation of a brownish waste material, lipofuscin, known as the "aging pigment." In skin cells, lipofuscin is the culprit responsible for the dreaded liver spots that appear with increasing age, but in nerve, muscle and other cells, its accumulation has more serious consequences.

"How lipofuscin causes problems in neurons and muscles is not clear, but it's believed that this is garbage that, in time, compromises the normal function of the lysosome," Dr. Xu said. "And we know the lysosome is important for all kinds of cell biology, particularly the recycling of intracellular components, so if it's damaged, the cell is going to suffer."

Indeed, abnormal accumulation of lipofuscin is associated with a range of disorders including Alzheimer's disease, Parkinson's disease, and macular degeneration (a degenerative disease of the eye) and also contributes to the aging process.

"In a sense we can think of ML4 as really early onset of aging," Dr. Xu said.

Now that the connections among TRPML1, iron and lipofuscin are coming into focus, researchers have new avenues to explore for potential treatments, not only for ML4 but also for more common neurodegenerative conditions.

"If we can somehow manipulate the lysosome iron level, we probably can provide a treatment for the patient," Dr. Xu said. "We're not far enough along for those kinds of experiments yet, but now we know enough to work toward that goal."

Coauthors on the paper are postdoctoral fellows Xian-ping Dong and Xiping Cheng and undergraduate Eric Mills of U-M; Markus Delling of Children's Hospital Boston; Fudi Wang of the Chinese Academy of Sciences and Tino Kurz of the University of Linköping, Sweden.

The researchers received funding from the U-M Department of Molecular, Cellular and Developmental Biology and Biological Science Scholar Program.

While Maria Lyzen was being treated for breast cancer, she found she couldn't concentrate or decipher information, and just functioning day-to-day at home was difficult.

"I didn't know if it was a reaction to the trauma of being told that I had breast cancer. I was in my late 50's - was it the beginning of an aging symptom? Or was it the drugs that I was getting in terms of my chemotherapy? My doctor ordered a brain scan, and there was nothing unusual there, and I said, 'But there is something wrong with me,'" Lyzen said.

Researchers are only beginning to understand what Lyzen and others experience during cancer treatment. Patients often call this phenomenon - which includes loss of concentration, difficulty remembering and difficulty thinking clearly - "chemo brain." Now, researchers are beginning to study this phenomenon and all the possible factors that contribute to it.

"Women have complained for a long time now about cognitive changes that have occurred during the time that they've been treated for breast cancer. We now have some research that shows cognitive changes can and do occur during chemotherapy and also may persist for several years following the completion of chemotherapy," said Bernadine Cimprich, PhD, RN, associate professor of nursing at the University of Michigan (U-M) School of Nursing and a researcher at the U-M Comprehensive Cancer Center.

Dr. Cimprich has begun a study to look at problems of attention and working memory, including what causes these cognitive impairments, what effect chemotherapy has on these brain functions and how much other influences may play a role.

The researchers will use functional magnetic resonance imaging, or fMRI, which can test brain function while a person performs a mental task. Breast cancer patients receiving chemotherapy will be compared with patients not receiving chemotherapy and with healthy women who do not have breast cancer.

"The first step is to see whether there are changes in brain function related to adjuvant chemotherapy for breast cancer. Chemotherapy is one of the possible sources of these kinds of cognitive changes. But actually, there are other possible reasons that a woman might experience cognitive problems," Dr. Cimprich explained.

The traumatic impact of a cancer diagnosis and making important life-or-death decisions could affect cognitive function even before cancer treatment begins. The researchers also suspect that since not all women report experiencing chemo brain, some women may have a genetic susceptibility that makes them more sensitive to the effects of chemotherapy, including cognitive issues.

"Our ultimate goal and hope for this research is that it will give us information that will be a kind of basis or foundation for designing care or interventions so we can help women from the very beginning of their treatment to maintain their cognitive function and to conserve cognitive effort so that they can function at the highest possible level over the course of their breast cancer treatment and beyond," she said.

Lyzen says she regained much of her concentration since having completed breast cancer treatment two years ago. But, while concentration is much more difficult for her now, she's happy to know that researchers are taking the chemo brain phenomenon seriously.

"Whether people are having troubles because they're just having a traumatic response or whether it's chemo brain or whether it is because they are aging, it doesn't really matter. What matters is that they are getting the support and the acknowledgement that they are being heard. And that is very important not to be dismissed," she said.

If a stroke patient doesn't get treatment within approximately the first three hours of symptoms, there's not much doctors can do to limit damage to the brain.But now researchers report a technique that potentially could restore functions to patients weeks or even months after a stroke. The technique involves jumpstarting the growth of nerve fibers to compensate for brain cells destroyed by the stroke [Topics in Stroke Rehabilitation, 15(1):42-50].

"In the best-case scenario, this would open up the window of time that people could recover and go back to normal functional status," said Gwendolyn Kartje, MD, PhD, a professor in the department of cell biology, neurobiology and anatomy and department of neurology at Loyola University Chicago Stritch School of Medicine in Maywood, IL and chief of neuroscience research at Edward Hines Jr. VA Hospital in Hines, IL.

Dr. Kartje and colleagues described the experimental approach, called anti-nogo-A immunotherapy. Anti-nogo has dramatically improved functions in lab animals that have experienced strokes. And an ongoing clinical trial in Europe and Canada is testing anti-nogo in humans who have suffered spinal cord injuries.

Most strokes are caused by clots that block blood flow to one part of the brain, killing brain cells within hours. The drug TPA can minimize damage by dissolving the clot. But TPA is safe and effective only when given within about three hours of the onset of symptoms. Most patients don't receive treatment within that brief window. Patients typically arrive at the hospital too late, or hospitals do not begin administering TPA soon enough.

Anti-nogo is among several new approaches under study that potentially could reverse stroke damage, researchers wrote. Nogo-A is a protein that inhibits the growth of nerve fibers called axons. It serves as a check on runaway nerve growth that could cause a patient to be overly sensitive to pain, or experience involuntary movements. (The protein is called nogo because it in effect says to axons: "No go.") In anti nogo immunotherapy, an antibody disables the nogo protein.

The left side of the brain controls movements on the right side of the body, and vice versa. Thus, a stroke on the left side of the brain can cause paralysis on the right side of the body. In such a patient, anti-nogo would, it's hoped, spur the growth of axons from the healthy right side of the brain. These axons would then grow into the right side of the body and restore functions lost by the stroke.

Anti nogo has been tried on rats that have experienced strokes in old age. As in people, strokes in rats affect one side of the body. Following strokes, the rats were unable to pick up pellets of food with the front paw on the affected side. After anti-nogo, function in this paw was almost completely restored in some rats.

The Swiss pharmaceutical company Novartis is sponsoring a phase 1 clinical trial of anti-nogo for patients paralyzed by spinal cord injuries. Dr. Kartje believes anti-nogo also has great potential for stroke patients. A clinical trial for stroke patients could begin as early as 2012, she said. Loyola is among the potential sites for such a trial.

Anti nogo "offers the potential for stroke patients to recover, return to nearly normal functional status, and stay out of nursing homes," Dr. Kartje said. "Theoretically, there's no reason why this should not happen."

Dr. Kartje began studying the nogo protein in 1992, and has published numerous papers on the topic. Her lab at Hines is funded by the Veterans Administration, with additional funding from the National Institutes of Health, Neuroscience Institute at Loyola University Chicago Stritch School of Medicine, Falk Foundation and Illinois Regenerative Medicine Institute.

People whose parents or aunts and uncles have had a brain aneurysm are more likely to have one themselves, indicating that genetic risk factors passed down by generation are responsible. Prior studies had suggested that aneurysm ruptures affect the offspring or second generation as much as 20 years younger than older generations. This suggests that a genetic risk factor is accumulating with each generation and that aggressive screening should be performed. But a new study shows that may not be the case, and the aneurysms actually may happen at an older age (Neurology, Feb. 24, 2009).

The study involved 26 clinical centers in the United States, Canada, New Zealand, and Australia. Researchers identified 429 families with at least one case of a ruptured brain aneurysm. A brain aneurysm is a weak or thin spot in a blood vessel that can rupture, causing bleeding into the brain, or hemorrhage.

The researchers then evaluated all siblings in two generations of each family, for a total of 1,641 people. Of the 429 families, 54, or 12.5 percent, had cases of ruptured aneurysms in two generations of the family-either parent and child or aunt/uncle and niece/nephew.

Instead of occurring earlier, once the length of follow-up was accounted for, the study found that ruptured aneurysms tended to occur on average slightly later in life. Ruptured aneurysms were identified in the second generation 50 percent less often than the older generation of the family but the study suggests that the second generation will "catch up" in the number of aneurysm ruptures as that generation gets older.

"This finding is contrary to previous studies, which have suggested that 'genetic anticipation' occurs in brain aneurysms, meaning that subsequent generations are affected at an earlier age," said study author Daniel Woo, MD, with the University of Cincinnati in Ohio and member of the American Academy of Neurology. "Our study accounted for a similar length of follow-up in both generations, which may explain the differing result and that the risk in subsequent generations is increased over their entire life, not just at a younger age. The finding also suggests that we should be looking for all types of genetic risks, not just those that accumulate over generations, which are a very small group of risk factors."

The study was supported by grants from the National Institute of Neurological Disorders and Stroke.

Using injections of a small derivate of the protein insulin-like growth factor-1 (IGF-1), scientists at Whitehead Institute for Biomedical Research and MIT's Picower Institute for Learning and Memory in Cambridge, MA, have successfully treated a mouse model of the devastating neurological disorder Rett syndrome (PNAS Online, Feb. 9. 2009).

Rett syndrome is an inherited disease affecting one of 10,000 girls born. Infants with the disease appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. Loss of speech, reduced head size, breathing and heart rhythm irregularities, and autistic-like symptoms are common by age four. Some symptoms may be mediated with prescription drugs, but no cure or truly effective treatment for the disease exists.

Researchers showed that daily injections of an active fragment of IGF-1 in mice that expressed Rett-syndrome like symptoms could significantly reduce movement and respiratory irregularities. Although treated mice were not cured, the outcome is reason for optimism.

"This is the first realistic way for a drug-like molecule injected into the bloodstream to relieve Rett syndrome symptoms," said Whitehead Member Rudolf Jaenisch, MD, whose lab collaborated with the lab of MIT and Picower scientist Mriganka Sur, PhD, in the research.

In approximately 85 percent of girls with Rett syndrome, the disease is caused by loss of function of the MeCP2 gene, which is highly expressed during nerve cell maturation. Lack of MeCP2 expression impedes nerve cell growth, keeping the cells from forming projections, called spines, which are used for nerve-cell-to-nerve-cell communication. Recent genetic studies have shown that in mice with blocked MeCP2 expression, turning MeCP2 back "on" nudges the mice towards normal movement and lifespan-an indication that the disease could be reversible.

Although researchers have known which gene causes the vast majority of Rett syndrome cases, they have until now been unable to promote nerve cell maturation through administration of a drug, protein, or small molecule.

While researchers in Dr. Sur's lab had discovered that increased brain levels of IGF-1 promoted maturation of synapses, the connections between nerve cells that are the basis for brain functions, Emanuela Giacometti, a graduate student in Dr. Jaenisch's laboratory, was theorizing that IGF-1 might also increase the nerve cell spines in the lab's mouse model of Rett syndrome. Such mice lack the MeCP2 gene and at four to six weeks display symptoms quite similar to those in girls with Rett Syndrome, including difficulty walking, lethargy, and breathing and heart rhythm irregularities.

In a collaboration with the Sur lab to test how IGF-1 might affect these mice, Giacometti administered to two-week-old Rett mice daily injections of IGF-1 fragment. At six weeks, treated mice were significantly more active, had more regular breathing, and had more normal, regular heart rhythms than did untreated mice. In addition, the brains of treated mice were heavier and showed more nerve cell spines.

"Although the treated mice get better and their symptoms don't progress as fast as they normally would, the treated mice still get the symptoms. So it's definitely not a cure, but it could be a co-therapy," Giacometti says.

Dr. Sur is also excited by the prospect of finding a drug treatment for Rett syndrome and other forms of autism. IGF1 is approved by the US Food and Drug Administration (FDA) to treat severe IGF-1 deficiency. "This represents a way forward towards clinical trials and a mechanism-based treatment for Rett Syndrome. We very much hope our research can offer some help for the patients who have this terrible disorder."

The research is supported by the Rett Syndrome Research Foundation, the National Institutes of Health, the Simons Foundation, the Marcus Family Foundation and the Autism Consortium.