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November 20, 2008


Ginkgo use fails to cut dementia risk

The medicinal herb ginkgo biloba does not reduce the risk of dementia or Alzheimer’s disease development in either the healthy elderly or those with mild cognitive impairment, according to a trial led by researchers at the School of Medicine. Ginkgo biloba didn’t affect the rate of coronary heart disease or stroke, either, the researchers found.

Findings from the Ginkgo Evaluation of Memory (GEM) Study were published Nov. 18 in the Journal of the American Medical Association.

Steven T. DeKosky, principal investigator of the multi-center trial, was director of Pitt’s Alzheimer’s Disease Research Center and chair of neurology at the time the study was conducted. He now is vice president and dean of the University of Virginia School of Medicine.

In the study, which was conducted at five medical centers between 2000 and 2008, 3,069 people age 75 or older who had no, or mild, cognitive impairment randomly were assigned to take twice-daily doses of either 120 milligrams of ginkgo biloba extract or a placebo. They were reassessed every six months for dementia using several well-established mental status tests. If changes were found that exceeded the expected “normal” changes in aging, a more extensive evaluation, including neuroimaging, was performed.

The researchers found no statistical difference in dementia or Alzheimer’s disease rates between the groups. Among those taking ginkgo biloba, 277 developed dementia. Among those in the placebo group, 246 developed dementia. Mortality rates also were similar.

A similarly sized trial is underway in Europe.

DeKosky noted that it’s possible that an effect would have been observed if the study had gone on longer, because it takes many years to progress from initial brain changes to clinical dementia. Therefore, the research team intends to conduct a follow-up analysis of brain function and structure in a subset of participants using magnetic resonance imaging.

Principal investigator of the Pitt site was Lewis H. Kuller of the Department of Epidemiology.

The trial was funded by the National Center for Complementary and Alternative Medicine, the National Institute on Aging and the National Heart, Lung and Blood Institute.


Arsenic may raise heart disease risk

When mice are exposed to arsenic at federally approved levels for drinking water, pores in liver blood vessels close, potentially leading to cardiovascular disease, said Pitt researchers in the Dec. 1 issue of the Journal of Clinical Investigation, available online now.

The study, while preliminary, also reveals how an enzyme linked to hypertension and atherosclerosis alters cells, and may call into question current Environmental Protection Agency (EPA) standards that are based solely on risks for cancer.

In the study, Aaron Barchowsky, professor of environmental and occupational health at the Graduate School of Public Health, and his research team looked at specialized cells in the liver called sinusoidal endothelial cells, which remove wastes from blood and enable nutrients to regulate metabolism.

After exposing mice to 10 -100 parts per billion (ppb) of arsenic over a two-week period, the cells were less able to remove damaged proteins from the blood and lost their characteristic pores or “windows,” severely compromising the cells’ ability to effectively exchange nutrients and waste. Barchowsky noted that despite their small size, mice usually are less sensitive to the effects of arsenic than people.

Arsenic is a naturally occurring mineral primarily found in groundwater. Drinking high levels of arsenic over many years has been linked to increased risks for lung, bladder and skin cancers, as well as heart disease, diabetes and neurological damage.

The current EPA standard for arsenic in public water systems is 10 ppb, reduced from 50 ppb in 2006. The standard applies only to drinking water sources that serve more than 20 people.

“These results are important since this type of cellular dysfunction, over time, can impair the body’s ability to clear fats and waste proteins that build up in blood vessels and can lead to cardiovascular diseases such as hypertension and atherosclerosis,” said Barchowsky.

Barchowsky said arsenic increased the activity of an enzyme called NADPH oxidase and the levels of oxidants it produces, compromising sinusoidal cell functions. Mice that lacked the enzyme did not have changes in liver blood vessels when exposed to arsenic and their cells were able to continue to function effectively.

“Our findings raise some concerns about whether current EPA-developed standards can effectively protect against cardiovascular risks posed by arsenic in drinking water,” said Barchowsky. “We are especially concerned about water from individual wells in small, rural and semi-rural communities that are exempt from the EPA requirement and often contain levels of arsenic that exceed the EPA limit.”

Co-authors included Adam Straub, Katherine Clark and Ashwin Chandra of the Department of Environmental and Occupational Health, Song Li and Xiang Gao of the Department of Pharmaceutical Sciences, Patrick Pagano of pharmacology and chemical biology and Mark Ross and Donna Stolz of the Center for Biologic Imaging.

The study was funded by Pitt, the National Institute of Environmental Health Sciences, the National Heart, Lung and Blood Institute and the EPA.


More pesticides found to be deadly to frogs

Ten of the world’s most popular pesticides can decimate amphibian populations when mixed together even if the concentration of the individual chemicals are within limits considered safe, according to research by biological sciences professor Rick Relyea, published Nov. 11 in the online edition of Oecologia. Such “cocktails of contaminants” frequently are detected in nature, the paper noted, and the Pitt findings offer the first illustration of how a large mixture of pesticides can affect the environment adversely.

The results of this study build on a nine-year effort by Relyea to understand potential links between the global decline in amphibians, routine pesticide use and the possible threat to humans. Amphibians are considered an environmental indicator species because of their unique sensitivity to pollutants. Their demise from pesticide overexposure could foreshadow the fate of less sensitive animals, Relyea said.

In this study, Relyea exposed gray tree frog and leopard frog tadpoles to small amounts of 10 widely used pesticides: the insecticides carbaryl, chlorpyrifos, diazinon, endosulfan and malathion; and herbicides acetochlor, atrazine, glyphosate, metolachlor and 2,4-D.

He administered each of the pesticides alone, the insecticides combined, a mix of the five herbicides, or all 10 of the poisons.

Relyea found that a mixture of all 10 chemicals killed 99 percent of leopard frog tadpoles as did the insecticide-only mixture; the herbicide mixture had no effect on the tadpoles. While leopard frogs perished, gray tree frogs did not succumb to the poisons and instead flourished in the absence of leopard frog competitors.

Relyea also discovered that endosulfan — a neurotoxin banned in several nations but still used extensively in U.S. agriculture — is inordinately deadly to leopard frog tadpoles. By itself, the chemical caused 84 percent of the leopard frogs to die. “Endosulfan appears to be about one thousand times more lethal to amphibians than other pesticides that we have examined,” Relyea said. “Unfortunately, pesticide regulations do not require amphibian testing, so very little is known about endosulfan’s impact on amphibians, despite being sprayed in the environment for more than five decades.”

For most of the pesticides, the concentration Relyea administered (2-16 parts per billion) was far below the human-lifetime-exposure levels set by the EPA and also fell short of the maximum concentrations detected in natural bodies of water.

But the research suggests that these low concentrations, which can travel easily by water or wind, can combine into one toxic mixture. In the published paper, Relyea points out that declining amphibian populations have been recorded in pristine areas far downwind from areas of active pesticide use, and he suggests that the chemical cocktail he describes could be a culprit.

The paper is available at


Sickle cell cure found safe

A new study finds the form of bone marrow transplantation pioneered in part by Children’s Hospital pediatric hematologist/oncologist Lakshmanan Krishnamurti to be safe and effective in curing sickle cell disease.

The study appears in the November issue of the journal Biology of Blood and Marrow Transplantation.

The transplantation method, which relies on reduced-intensity conditioning (RIC), is less toxic to patients. It therefore can be offered to patients with severe sickle cell disease because it eliminates the life-threatening side effects generally associated with bone marrow transplantation.

Traditionally, bone marrow transplants require heavy doses of chemotherapy prior to transplant in order to destroy the recipient’s bone marrow so it will not reject the donated marrow. But with their bone marrow destroyed, transplant recipients become vulnerable to life-threatening complications.

In the study, Krishnamurti and colleagues report that six of seven sickle cell patients who received RIC bone marrow transplants in the last decade now have donor marrow and are free from symptoms of their sickle cell disease. Krishnamurti led five of the seven transplants in the study.

“Bone marrow transplant is the only known cure for sickle cell disease. But doctors have avoided performing them in these patients because complications from a traditional bone marrow transplant can be life-threatening,” said Krishnamurti, director of the Sickle Cell Program at Children’s Hospital.


PiB IDs plaques

In the largest study of its kind, Pittsburgh Compound B (PiB), an imaging agent that could facilitate the early diagnosis of Alzheimer’s disease, has been used to identify amyloid deposits in the brains of clinically older adults.

The findings, published in this month’s issue of the Archives of Neurology, could not only shed more light on how the illness progresses, but also open the door to the possibility of prevention strategies, said senior investigator William E. Klunk, professor of psychiatry and neurology in the School of Medicine.

He and study co-author Chester A. Mathis, professor of radiology and pharmaceutical sciences, invented the imaging compound, which binds to certain forms of amyloid protein plaques found in the brains of Alzheimer’s disease patients.

Results of the study, which was led by Howard J. Aizenstein, professor of psychiatry and bioengineering, Klunk said, “show that we can detect amyloid deposits before patients develop symptoms of Alzheimer’s disease. That means we might have a window of opportunity to slow or stop the process.”

One surprising finding was that detailed tests of brain functioning conducted by study co-authors Robert D. Nebes of psychiatry and Judith Saxton of neurology and psychiatry showed no decrease in functioning among participants whose scans revealed the presence of the Alzheimer-associated amyloid deposits.

In the study, 43 people age 65 to 88 who had no impairment on cognitive testing were scanned with PiB and positron emission tomography.

Nine of them (21 percent) showed early amyloid deposition in at least one area of the brain, which is similar to rates found in postmortem studies. That suggests there may be as many people in this age group with the early brain changes, but no visible symptoms, of Alzheimer’s disease as there are people with recognized Alzheimer’s disease.

“The good news is it appears the brain can tolerate these plaques for years before the effects are apparent,” Klunk noted. “The bad news is that by the time the symptoms emerge, the disease has had perhaps a 10-year head start.”

He cautioned, “We suspect that people with amyloid deposits and normal brain functioning have a high risk of developing Alzheimer’s disease in the future, but we do not yet have proof of this.” Therefore, study protocol prohibits telling the research participants the results of their PiB scans.

The researchers plan to follow these individuals for years in this and larger studies to understand fully how the presence of amyloid deposits translates into future risk for Alzheimer’s disease.

The research was supported by grants from the National Institute on Aging, the Alzheimer’s Association and the U.S. Department of Energy.


OFC size linked to alcoholism risk

A study suggests that genetic factors influence size variations in a certain region of the brain, which could in turn be partly responsible for increased susceptibility to alcohol dependence.

It appears that the size of the right orbitofrontal cortex (OFC), an area of the brain that is involved in regulating emotional processing and impulsive behavior, is smaller in teenagers and young adults who have several relatives who are alcohol dependent, according to psychiatry professor Shirley Hill.

In the research, which appears online in the journal Biological Psychiatry, Hill and her team imaged the brains of 107 teens and young adults using magnetic resonance imaging. They also examined variation in certain genes of the participants and administered a well-validated questionnaire to measure the youngsters’ tendency to be impulsive.

The participants included 63 individuals who were selected for the study because they had multiple alcohol-dependent family members, suggesting a genetic predisposition, and 44 who had no close relatives dependent on drugs or alcohol. Those with several alcohol-dependent relatives were more likely to have reduced volume of the OFC.

When the investigators looked at two genes, 5-HTT and BDNF, they found certain variants that led to a reduction in white matter volume in the OFC, which in turn was associated with greater impulsivity.

“We are beginning to understand how genetic factors can lead to structural brain changes that may make people more vulnerable to alcoholism,” Hill said. “These results also support our earlier findings of reduced volume of other brain regions in high-risk kids.”

These differences can be observed even before the high-risk offspring start drinking excessively, she added, “leading us to conclude that they are predisposing factors in the cause of this disease, rather than a consequence of it.”

The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism.


Lung research gets $3 million

Researchers at the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases in the Division of Pulmonary, Allergy and Critical Care Medicine have been awarded approximately $3 million from the National Institutes of Health to conduct the first study using novel biochip technology to compare gene activity in different smoking-related chronic lung diseases.

The studies, led by Naftali Kaminski, the Richard P. and Dorothy P. Simmons Endowed Chair in Interstitial Lung Disease and director of the Simmons Center; Steven Shapiro, Jack B. Myers Professor and chair of the Department of Medicine, and Frank Sciurba, associate professor of medicine and director of the Emphysema/COPD Research Center, will use DNA chips to examine the activity of all the genes in the human genome to design diagnostic tests that will allow physicians to guide therapy in the two most common cigarette-smoke-associated lung diseases: chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In the largest study of its kind in lung disease, the researchers plan to identify and validate gene signatures that characterize COPD and IPF and their underlying causes.

The work could lead to new personalized medicine approaches.

“This study will help us understand why one person responds to cigarette smoke by developing emphysema while another develops fibrosis, and then to rapidly translate this knowledge from bench to bedside,” Kaminski explained.


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