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Fisetin, a naturally occurring compound found in strawberries and other fruits and vegetables, slows the onset of motor problems and delays death in three models of Huntington's disease, according to researchers at the Salk Institute for Biological Studies. The study, published in the online edition of Human Molecular Genetics, sets the stage for further investigations into fisetin's neuroprotective properties in Huntington's and other neurodegenerative conditions.

Huntington's disease (HD) is an inherited disorder that destroys neurons in certain parts of the brain and slowly erodes victims' ability to walk, talk and reason. It is caused by a kind of genetic stutter, which leads to the expansion of a trinucleotide repeat in the huntingtin protein. When the length of the repeated section reaches a certain threshold, the bearer will develop Huntington's disease. In fact, the longer the repeat, the earlier symptoms develop and the greater their severity.

One of the intracellular signaling cascades affected by mutant huntingtin is the so-called Ras/ERK pathway. It is activated by growth factors and is particularly important in brain development, learning, memory and cognition.

In earlier studies, Pamela Maher, Ph.D., a senior staff scientist in the Salk Cellular Neurobiology Laboratory, had found that fisetin exerted its neuroprotective and memory-enhancing effects through the activation of the Ras/ERK signaling pathway. "Because Ras/ERK is known to be less active in HD, we thought fisetin might prove useful in the condition," Maher says.

Maher and her team began their study by looking at a nerve cell line that could be made to express a mutant form of the huntingtin protein. Without treatment, about 50 percent of these cells will die within a few days. Adding fisetin, however, prevented cell death and appeared to achieve it by activating the Ras-ERK cascade.

The researchers then turned their attention to Drosophila. In collaboration with J. Lawrence Marsh, Ph.D., a professor of developmental and cell biology at the University of California, Irvine, Maher tested fisetin in fruit flies overexpressing mutant huntingtin in neurons in the brain. The affected flies don't live as long as normal flies and also have defective eye development. When they were fed fisetin, however, the HD flies maintained their life span and had fewer eye defects.

Finally, Maher and her team tested fisetin's effects in a mouse model of HD. HD mice develop motor defects early on and have much shorter life spans than normal control animals. When Maher and her team fed them fisetin, the onset of the motor defects was delayed, and their life span was extended by about 30 percent.

"Fisetin was not able to reverse or stop the progress of the disease," Maher notes, "but the treated mice retained better motor function for longer, and they lived longer."

Fisetin, which also has anti-inflammatory properties and maintains levels of glutathione, a major cellular antioxidant that plays a key role in protecting against different types of stress in cells, has not yet been tested in humans. But Maher's findings suggest that the compound may be able to slow down the progression of Huntington's disease in humans and improve the quality of life for those who have it. While she cautions that it won't necessarily be effective for people already in the advanced stages of the disease, for those in the early stages or who are presymptomatic, fisetin might help.

Furthermore, once their safety and efficacy are proved in humans, the advent of substances like fisetin might prompt more people to be tested for the mutation. "Cells are damaged and dying before there are overt symptoms," Maher says. "If patients know they have the mutation, then they could potentially start treatment before they start showing symptoms, which might be more effective than waiting for the symptoms to appear, as many do now."

Maher's lab has developed a variety of fisetin derivatives that are more potent in cell-based assays than the fisetin used in the study, and she plans further tests to see which combination is most effective in HD and other neurodegenerative disorders.

In the meantime, does she recommend eating a lot of strawberries to gain fisetin's benefits?

"It probably couldn't hurt," she says.

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Energy drink consumption is strongly linked with risks of heavy drinking and alcohol dependence

Energy drinks are commonly consumed by teens and college students
A new study shows that energy drink consumption is strongly associated with increased risks for heavy drinking and alcohol dependence
These results call for more scrutiny regarding the possible negative health effects of energy drinks and public education about the risks of consuming energy drinks with alcohol
A hallmark of college life is staying up late to study for an exam the following morning, and many students stay awake by consuming an energy drink. Also increasing in popularity is the practice of mixing alcohol with energy drinks. But these drinks are highly caffeinated and can lead to other problems, in addition to losing sleep. Unfortunately, the contents of energy drinks are not regulated.

New research indicates that individuals who have a high frequency of energy drink consumption (52 or more times within a year) were at a statistically significant higher risk for alcohol dependence and episodes of heavy drinking.

The results will be published in the February 2011 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

Amelia M. Arria, the lead author of the study, Director of the Center on Young Adult Health and Development at the University of Maryland School of Public Health, and a Senior Scientist at the Treatment Research Institute, said that prior research has highlighted the dangers of combining energy drinks with alcohol.

"We were able to examine if energy drink use was still associated with alcohol dependence, after controlling for risk-taking characteristics. The relationship persisted and the use of energy drinks was found to be associated with an increase in the risk of alcohol dependence."

The study utilized data from more than 1,000 students enrolled at a public university who were asked about their consumption of energy drinks and their alcohol drinking behaviors within the past 12 months. The researchers found that individuals who consumed energy drinks at a high frequency were more likely to get drunk at an earlier age, drink more per drinking session, and were more likely to develop alcohol dependence compared to both non-users of energy drinks and the low-frequency users.

The results of this study confirm and extend earlier research about the risks of energy drink consumption. A major concern is that mixing energy drinks with alcohol can lead to "wide-awake drunkenness," where caffeine masks the feeling of drunkenness but does not decrease actual alcohol-related impairment. As a result, the individual feels less drunk than they really are, which could lead them to consume even more alcohol or engage in risky activities like drunk driving.

"Caffeine does not antagonize or cancel out the impairment associated with drunkenness—it merely disguises the more obvious markers of that impairment," says Kathleen Miller, a research scientist from the Research Institute on Addictions at the University at Buffalo. According to her, the next steps in this research include identifying links between energy drinks and other forms of substance abuse, as well assessing the overall prevalence of energy drink use by adolescents and young adults.

"Also needed is research that directly assesses students' reported reasons for mixing alcohol and energy drinks. Anecdotal reports suggest that part of this phenomenon may be driven by the perpetuation of myths (e.g., mixing alcohol and caffeine reduces drunkenness, prevents hangovers, or fools a breathalyzer test) that could be debunked through further education."

Arria agrees, adding that further research and regulations are needed to curb this disturbing trend.

"The fact that there is no regulation on the amount of caffeine in energy drinks or no requirements related to the labeling of contents or possible health risks is concerning."

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Rolling back suggestions from previous studies, a Johns Hopkins study of 950 healthy men and women has shown that taking daily doses of a cholesterol-lowering statin medication to protect coronary arteries and ward off heart attack or stroke may not be needed for everyone.

In a study to be presented Nov. 16 at the American Heart Association's (AHA) annual Scientific Sessions in Chicago, the Johns Hopkins team found that nearly 95 percent of all heart attacks, strokes or heart-related deaths occurred in the half of study participants with some measureable buildup of artery-hardening calcium in the blood vessels; hence, only this subgroup might have benefited from preventive drug therapy. Seventy-five percent of all heart emergencies occurred in the quarter with the highest calcium scores.

The 47 percent of study participants with no detectable levels of calcium buildup in their blood vessels suffered about 5 percent of heart-disease related events during the six-year study, meaning that drug therapy may not have offered any coronary protection.

"Our results tell us that only those with calcium buildup in their arteries have a clear benefit from statin therapy, and those who are otherwise healthy and have no significant calcification should with their physician focus on aggressive lifestyle improvements instead of early initiation of statin medications," says study lead investigator Michael Blaha, M.D., M.P.H.

"While statin therapy can benefit healthy men and women with normal or even low cholesterol levels," adds Blaha, a cardiology fellow at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute, "it certainly is not the case that all adults should be taking it to prevent heart attack and stroke, because half are at negligible risk of a sudden coronary event in the next five to 10 years."

Results of the study underscore the importance of measuring coronary artery calcium deposits, Blaha says, in predicting who is really at risk of suffering a heart attack. High levels of C-reactive protein in the blood, a CRP score at or above 2 milligrams per liter, offered no predictive value after established risk factors are taken into account, including age, gender, ethnicity, hypertension, blood cholesterol levels, obesity, diabetes, smoking and a family history of heart disease. Study participants in the new analysis had varying blood levels of the inflammatory byproduct, believed by some to be a predictor of all kinds of coronary disease.

The latest findings from the Johns Hopkins-led Multi-Ethnic Study on Atherosclerosis, or MESA, are believed to be the first to pinpoint precisely who among the more than 6 million healthy American adults with normal blood-cholesterol levels and, thus, potential candidates for preventive statin therapy, would benefit from a statin's cardio-protective effects. Rosuvastatin, marketed as Crestor, is one particular statin drug effective in preventing heart attack and stroke in some individuals, according to results of the landmark JUPITER trial published in 2008.

In the JUPITER trial, short for the Justification for the Use of Statins in Primary Prevention: An Interventional Tool Evaluating Rosuvastin, daily doses of 20 milligrams per liter of blood per day halved the number of potentially fatal coronary blockages in some 18,000 adults, all with high CRP levels.

To check these findings, the Johns Hopkins team selected MESA study participants who met the same criteria set for the JUPITER study. The MESA subgroup came from a pool of 7,000 ethnically diverse adults, including African Americans, Chinese Americans, Caucasians and Hispanics – all monitored at Johns Hopkins and five other medical centers in North America.

A statistical comparison of results showed that few if any heart attacks or strokes would have been prevented within five years had anyone taken the medication, unless there was already some calcium buildup in their blood vessels. In people with moderate calcium buildup, one heart attack would have been averted in every 94 people treated, and one stroke in every 54.

For people with higher coronary calcium scores, the numbers of patients one needed to treat to prevent a heart attack or stroke were 24 and 19, respectively, which Blaha says were superior numbers to those in the JUPITER study or any prior statin trial.

According to study co-investigator and cardiologist Roger Blumenthal, M.D., a professor and director of the Ciccarone Preventive Cardiology Center at Johns Hopkins, "statin therapy should not be approached like diet and exercise as a broadly based solution for preventing coronary heart disease.

These are lifelong medications with potential, although rare side effects, and physicians should only consider their use for those patients at greatest risk, especially those with high coronary calcium scores."

Blumenthal points out that as many as 5 percent of people on statins develop serious side effects, such as muscle pain. One in 255 will develop diabetes.

Blumenthal recommends that all people monitor their risk factors for heart disease, according to their age and gender, diabetes, blood-cholesterol levels, hypertension and smoking, and if recommended by their physician, get a coronary calcium CT scan to gauge their actual risk.

Coronary heart disease remains the nation's leading cause of death, responsible for one in five deaths in adults in the United States.

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Widely prescribed for their cholesterol-lowering properties, recent clinical research indicates that statins can produce a second, significant health benefit: lowering the risk of severe bacterial infections such as pneumonia and sepsis. A new explanation for these findings has been discovered by researchers at the University of California, San Diego School of Medicine and Skaggs School of Pharmacy & Pharmaceutical Sciences, who describe for the first time how statins activate the bacterial killing properties of white blood cells.

The research is published in the November 18, 2010 issue of Cell Host & Microbe.

Led by Victor Nizet, MD, professor of pediatrics and pharmacy, and Christopher Glass, MD, PhD, professor of medicine and cellular & molecular medicine, the UC San Diego team found that phagocytes (white blood cells that kill and ingest harmful bacteria, foreign particles and dead or dying cells) became more effective after being exposed to statins.

Surprisingly, the statin-induced improvement in bacterial killing did not correspond to increased uptake of bacteria by these specialized white blood cells. Rather, the researchers found that statins stimulated the phagocytes to release "extracellular traps" – specialized webs of DNA-based filaments embedded with anti-microbial peptides and enzymes capable of ensnaring and killing bacteria before they spread in the body.

The findings have broad ramifications, said Glass, given the popularity of statins for controlling high cholesterol levels. Statins are the world's most-prescribed class of medication. An estimated 30 million Americans alone take the drug under commercial names like Lipitor, Zocor and Crestor. "Clinical research indicates that perhaps 100 million Americans have elevated cholesterol levels that could benefit from statin therapy," said Glass. "Thus any statin-associated changes to immune system function are certain to impact millions of people."

Prior research had described various anti-inflammatory properties of statins, suggesting that these effects could contribute to a reduction in disease severity during severe infections. Nizet and Glass explored a different hypothesis: That statins might actually aid the body in clearing itself of infectious microbes. The researchers focused on Staphyloccocus aureus, more commonly called "staph," a frequently antibiotic-resistant human pathogen responsible for everything from minor skin infections to life-threatening meningitis and sepsis. Mice treated with statins were more resistant to staph infections, and phagocytes isolated from these mice were more effective at killing staph bacteria. Simple exposure of freshly isolated human white blood cells to statins in a test tube markedly increased their ability to kill staph and other important disease causing bacteria. In each case, the increased killing correlated with greater release of the DNA-based extracellular traps by the phagocytes.

The UCSD findings demonstrate that statins have important pharmacological effects beyond inhibiting cholesterol production. "We found these drugs fundamentally alter how white blood cells behave upon encountering bacteria," Nizet said. "In our studies with staph bacteria, the net effect of statin treatment was to improve bacterial killing and extracellular trap formation. These same changes might not be so consequential for defense against less virulent bacteria that are easily susceptible to uptake and killing within phagocytes."

The research also sheds important new light on the clinical phenomenon of reduced infection severity in patients receiving statins, the scientists said. It indicates that levels of cholesterol or related lipid molecules can be sensed by white blood cells and used as signals to control their inflammatory and antibacterial activities. Nizet and Glass recommend that future research explore whether the potential of cholesterol-lowering agents combined with antibiotics can be harnessed to optimize the treatment of certain difficult infectious disease conditions.

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Scientists discover how estrogen works and flip its switch to reap benefits without risks

Estrogen is an elixir for the brain, sharpening mental performance in humans and animals and showing promise as a treatment for disorders of the brain such as Alzheimer's disease and schizophrenia. But long-term estrogen therapy, once prescribed routinely for menopausal women, now is quite controversial because of research showing it increases the risk of cancer, heart disease and stroke.

Northwestern Medicine researchers have discovered how to reap the benefits of estrogen without the risk. Using a special compound, they flipped a switch that mimics the effect of estrogen on cortical brain cells. The scientists also found how estrogen physically works in brain cells to boost mental performance, which had not been known.

When scientists flipped the switch, technically known as activating an estrogen receptor, they witnessed a dramatic increase in the number of connections between brains cells, or neurons. Those connections, called dendritic spines, are tiny bridges that enable the brain cells to talk to each other.

"We created more sites that could allow for more communication between the cells," said lead investigator Deepak Srivastava, research assistant professor in neuroscience at Northwestern University Feinberg School of Medicine. "We are building more bridges so more information can go from one cell to another."

The findings will be presented Nov. 17 at Neuroscience 2010 in San Diego. Peter Penzes, associate professor of physiology and of psychiatry and behavioral sciences at the Feinberg School, is the senior investigator.

Previous research has shown an increase in dendritic spines improves mental performance in animals. In humans, people who have Alzheimer's disease or schizophrenia often have a decrease in these spines.

"We think there is a strong link between the number of dendritic spines and your mental performance," Srivastava said. "A major theory is if you increase the number of spines, it could be a way to treat these significant mental illnesses. "

Northwestern scientists also found strong clues that estrogen can be produced in cortical brain cells. They identified aromatase, a critical protein needed to produce estrogen, to be in precisely the right spot in the brain cell to make more dendritic spines.

"We've found that the machinery needed to make estrogen in these brain cells is near the dendritic spines," Srivastava said. "It's exactly where it's needed. There's a lot of it in the right place at the right time. "

Next, Srivastava said, he wants to further identify the key molecules involved in the dendritic spine production and target them in the same way as the estrogen receptor in order to ultimately be able to treat schizophrenia and other mental disorders.

Nick Brandon, head of psychiatry at Pfizer Inc., whose group collaborated with the Penzes lab for this work, added, "We are very excited by the emerging data in this area. There is a great deal of literature and precedent for a role of estrogen and estrogen signaling in major mental illnesses. This adds to our understanding of the specific neuronal functions. As we understand the effects of these specific estrogen receptor beta compounds in preclinical models, we are discovering effects on specific neuronal functions, which could be relevant for the treatment of cognitive disorders, depression and schizophrenia. "

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Scientists have identified a mysterious culprit that threatens headaches, stuffy noses, skin rash and other allergy symptoms when more than 500 million people worldwide drink wine. The discovery could help winemakers in developing the first low allergenic vintages — reds and whites with less potential to trigger allergy symptoms, they say. The new study appears in ACS' monthly Journal of Proteome Research.

Giuseppe Palmisano and colleagues note growing concern about the potential of certain ingredients in red and white to cause allergy-like symptoms that range from stuffed up noses to headaches to difficulty breathing. So-called wine allergies occur in an estimated 8 percent of people worldwide. Only 1 percent of those involve sulfites, sulfur-containing substances that winemakers add to wine to prevent spoilage and also occur naturally. But the wine components that trigger allergies in the remaining 7 percent are unclear. Studies suggest that glycoproteins — proteins coated with sugars produced naturally as grapes ferment — may be a culprit. However, scientists knew little about the structure and function of these substances in wine.

Their analysis of Italian Chardonnay uncovered 28 glycoproteins, some identified for the first time. The scientists found that many of the grape glycoproteins had structures similar to known allergens, including proteins that trigger allergic reactions to ragweed and latex. The discovery opens to door to development of wine-making processes that minimize formation of the culprit glycoproteins and offer consumers low-allergenic wines.

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ARTICLE FOR IMMEDIATE RELEASE "Glycoproteomic profile in wine: a 'sweet' molecular renaissance"

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Consumption of fructose-rich beverages, such as sugar-sweetened sodas and orange juice is associated with an increased risk of gout among women, although their contribution to the risk of gout in the population is likely modest because of the low incidence rate among women, according to a study that will appear in the November 24 print edition of JAMA. The study is being released early online to coincide with its presentation at the American College of Rheumatology annual scientific meeting.

Gout is a common and very painful inflammatory arthritis. "The increasing disease burden of gout in the United States over the last few decades (e.g., an annual incidence of 16/100,000 in 1977 vs. 42/100,000 in 1996) coincided with a substantial increase in soft drink and fructose consumption," the authors write. "Fructose-rich beverages such as sugar-sweetened soda and orange juice can increase serum uric acid levels and, thus, the risk of gout, but prospective data on the relationship are limited."

Hyon K. Choi, M.D., Dr.P.H., of the Boston University School of Medicine, and colleagues examined the relationship between intake of fructose-rich beverages and fructose and incidence of gout in a large group of women. The study consisted of data from the Nurses' Health Study, a U.S. prospective cohort study spanning 22 years (1984-2006). The researchers analyzed data from 78,906 women with no history of gout at the beginning of the study and who provided information on intake of beverages and fructose through validated food frequency questionnaires.

During 22 years of follow-up, the researchers documented 778 newly diagnosed cases meeting American College of Rheumatology survey criteria for gout. They found that increasing intake of sugar-sweetened soda was associated with increasing risk of gout. Compared with consumption of less than 1 serving per month, women who consumed one serving per day had a 74 percent increased risk of gout; and those with 2 or more servings per day had a 2.4 times higher risk. Diet soft drinks were not associated with the risk of gout.

Orange juice intake was also associated with risk of gout. Compared with women who consumed less than a glass (6 oz.) of orange juice per month, women who consumed 1 serving per day had a 41 percent higher risk of gout, and there was a 2.4 times higher risk with 2 or more servings per day. Also, compared with women in the lowest quintile (fifth) of free fructose intake, women in the highest quintile had a 62 percent higher risk of gout.

The authors note that although the relative risks of gout associated with fructose-rich beverages among women were substantial, the corresponding absolute risk differences were modest given the low incidence rate of gout among women.

The researchers add that their findings have practical implications for the prevention of gout in women, and that physicians should be aware of the potential effect of these beverages on the risk of gout. "Our data provide prospective evidence that fructose poses an increased risk of gout among women, thus supporting the importance of reducing fructose intake."