Researchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilising a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 non-alcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
‘We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,’ said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
‘These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,’ said Mosher Ruiz. ‘We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.’ Boston University Medical Center

vA new study reveals a genetic link between chronic pancreatitis and alcohol consumption. Researchers from the University of Pittsburgh School of Medicine and more than 25 other health centres across the United States found a genetic variant on chromosome X near the claudin-2 gene (CLDN2) that predicts which men who are heavy drinkers are at high risk of developing chronic pancreatitis.

This finding enables doctors to identify people with early signs of pancreatitis or an attack of acute pancreatitis who are at very high risk for progressing to chronic pancreatitis, allowing them to take preventative action to slow the development of the disease, and give the pancreas a chance to heal. Once an individual develops pancreatitis it takes several years for the pancreas to deteriorate.

‘The discovery that chronic pancreatitis has a genetic basis solves a major mystery about why some people develop chronic pancreatitis and others do not,’ said David C. Whitcomb, M.D., professor of medicine, cell biology and physiology, and human genetics at the University of Pittsburgh School of Medicine and lead author of the report. ‘We also knew there was an unexpected higher risk of men developing pancreatitis with alcohol consumption, but until now we weren’t sure why. Our discovery of this new genetic variant on chromosome X helps explain this mystery as well.’

Over 100,000 Americans suffer from chronic pancreatitis, a progressive inflammatory disease characterised by abdominal pain and permanent damage to the pancreas. Most studies report excessive alcohol consumption as the major risk factor for adult-onset chronic pancreatitis. However, according to Dr. Whitcomb, who also is chief of the Division of Gastroenterology, Hepatology and Nutrition, only 3 percent of individuals who are alcoholics develop chronic pancreatitis, suggesting a pancreas-specific risk factor.

The study was conducted over 10 years and involved more than 2,000 patients, all of whom underwent DNA testing in a study funded by the National Institutes of Health. Researchers discovered that there was a common DNA variant on the X chromosome that is present in 26 percent of men without pancreatitis, but jumps to nearly 50 percent of men diagnosed with alcoholic pancreatitis. Women have two X chromosomes, so most women with the high-risk DNA variant on one X chromosome appear to be protected from alcoholic chronic pancreatitis by the other X chromosome, if it is normal. Men have one X chromosome and one Y chromosome, so if they inherit a high-risk X chromosome, there is no protection.

The factor on chromosome X does not appear to cause pancreatitis, but if pancreatic injury occurs for any reason such as gallstone pancreatitis or abdominal trauma, it is more likely that the person will develop chronic pancreatitis – especially if they also drink alcohol.

‘This information is important because the high-risk chromosome can be identified in patients who drink and have early signs of pancreatic injury,’ said Dhiraj Yadav, M.D., M.P.H., associate professor of medicine, Division of Gastroenterology, Hepatology and Nutrition at Pitt, and a co-investigator on the study. ‘If pancreatic injury and acute pancreatitis occur, patients must stop drinking immediately.’ University of Pittsburgh School of Medicine

New research, presented at the 54th Annual Meeting of the American Society of Hematology (ASH), has identified important associations between Plasmodium falciparum (Pf) malaria and endemic Burkitt Lymphoma (eBL) that may help researchers identify young children who are more susceptible to eBL.
Unlike previous studies in which malaria infection alone was considered the important factor, this study approached the evolving complexity and heterogeneity of the humoral immune response to Pf as a key component for risk of developing eBL in young children who reside in malaria endemic areas of Equatorial Africa. The circumstances potentially set the stage for the development of serological signatures as biomarkers to better indicate the risk of developing eBL during malaria infection.
The study, titled ‘Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium falciparum Malaria Stage-Specific Antigens,’ was authored by Jeffrey Bethony, Ph.D., associate professor in the department of microbiology, immunology, and tropical medicine (MITM) at the George Washington University (GW) School of Medicine and Health Sciences (SMHS), along with Amar Jariwala, M.D., assistant research professor in the department of MITM at GW SMHS, and Maria Candida Vila, graduate student at the GW SMHS Institute for Biomedical Sciences. This research was done in collaboration with Sam Mbulaiteye, M.D., infections and immunoepidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute, National Institutes of Health, who spent decades collecting the case and control sera in Ghana, as well as the study design and statistics.
The GW SMHS research team developed, optimised, and standardised an extensive panel of serological tests of recombinant Pf antigens representing several stages of the parasite life-cycle assayed in more than 700 cases and control samples from young children. These young children were either resident in Pf malaria endemic areas of Ghana, had eBL, or were the same age, sex, and of the same village to match a child who did not have eBL. Bethony and his colleagues used an immunomics approach to their antibody response to Pf malaria. This enabled different statistical and epidemiological associations to be made between a range of antibody response to Pf malaria antigens and eBL, establishing a pattern of immune responses rather than a single immune response, identifying the children who are at risk for developing eBL.
‘Plasmodium falciparum malaria has long been suspected as an important trigger to Epstein Barr Virus associated lymphoma of very young children living in Equatorial Africa,’ said Bethony. ‘Our study adds to this literature, explaining that it is not simply the presence or absence of Pf malaria infection, but the breath and complexity of the antibody response to malaria that may be the true indicating factor for who develops eBL and who does not.’
The study showed a significant increase in the risk of developing eBL in young children who had a distinct pattern of antibody responses to several different recombinant Pf malaria antigens, including some antigens which are vaccine candidates. Of special note, the study also found a significant decreased risk of eBL in children with antibodies to SE36, a vaccine candidate protein that has been associated with lower risk of malaria in epidemiological studies.
These results not only confirm a strong association between Pf malaria and eBL, but provide a new perspective on the long established relationship between Pf malaria and eBL. This could pave the way for future studies that use protein arrays, containing hundreds of recombinant proteins to develop an antibody signature for children most at risk of developing eBL during Pf malaria infection. George Washington University

Researchers have identified a way in which men can develop prostate cancer after contracting trichomoniasis, a curable but often overlooked sexually transmitted disease.
Previous studies have teased out a casual, epidemiological correlation between the two diseases, but this latest study suggests a more tangible biological mechanism.
John Alderete, a professor at Washington State University’s School of Molecular Biosciences, says the trichomoniasis parasite activates a suite of proteins, the last of which makes sure the proteins stay active.
‘It’s like switching a light switch on,’ he says. ‘Then, if you don’t control the brightness of that light, you can go blind. That’s the problem.’
Caused by a protozoan parasite, trichomoniasis is often referred to as the most common curable sexually transmitted infection. However, most infected people have no symptoms, so it often goes untreated.
‘Most women, it’s the Number One sexually transmitted infection,’ says Alderete. ‘We’re going to have at least 10 million women infected this year and an equal number of men because they all get infected if they come into contact with an infected partner.’
Infected women have a greater risk of pregnancy complications and HIV. Infected men have a 40 percent greater chance of developing prostate cancer, according to a 2006 study led by Siobhan Sutcliffe, a Washington University epidemiologist and co-author of the recent paper.
Sutcliffe cautions that the epidemiological link she found is not conclusive and compares the science to the early connections drawn between smoking and lung cancer.
‘It’s still in a really exploratory phase,’ she says.
A study after her 2006 research found no connection between trichomoniasis and prostate cancer, while a third out of Harvard found an even greater likelihood of cancer in infected men.
This latest study, she says, ‘is providing a molecular mechanism that might explain that association.’
Much of the study was done in a single building, WSU’s Biotechnology and Life Sciences Building, and involved two of the more accomplished researchers on the Pullman campus.
WSU cancer researcher Nancy Magnuson is an expert on the protein PIM1, a promoter of cancer cell growth, and identified the protein in the cascade of proteins leading from trichomoniasis to prostate cancer. WSU molecular biologist Ray Reeves brought to bear his expertise in HMGA1. The protein turns genes on and off and ended up being the actor making sure other proteins in the trichomoniasis-to-cancer sequence stay on.
Alderete hopes knowledge of the mechanism will lead to better diagnosis and treatment.
‘What this is also doing is telling the world, ‘People, this is a latent infection,” he says. ”You guys out there, if you’ve been exposed to it, you’ve got it in there, and we need now a diagnostic for you.” EurekAlert

New insights into certain muscle diseases, the filaminopathies, are reported by an international research team led by Dr. Rudolf Andre Kley of the RUB’s University Hospital Bergmannsheil in the journal Brain. The scientists from the Neuromuscular Centre Ruhrgebiet (headed by Prof. Matthias Vorgerd) at the Neurological University Clinic (Director: Prof. Martin Tegenthoff) cooperated with colleagues from eleven institutes in seven countries. Among other things they found that protection mechanisms to combat abnormal protein deposits do not work properly in filaminopathy patients. This opens up new starting points for therapies that the team aims to test on cell cultures.
Mutations in the filamin C gene (FLNC) cause filaminopathies, which are manifested through progressive muscle weakness to the point of loss of the ability to walk. Muscle fibres are composed of myofibrils, for the development and maintenance of which the protein filamin C is crucial. The mutations examined in the study bring about a so-called myofibrillar myopathy: the myofibrils disintegrate in certain places and mutant filamin C and other proteins aggregate massively in the muscle fibres.
The researchers showed that the diseased protein deposits interfere with the protein degradation usually occurring in cells. Normally, cells produce what are known as heat shock proteins, which promote the degradation of protein deposits and make sure that other proteins assume their correct three-dimensional structure. ‘However, these protection mechanisms only seem to be increasingly activated when the critical point is exceeded. It looks as if the ‘fire brigade’ was called too late’, says Dr. Kley. ‘We hope to positively influence the course of the disease by means of early treatment with substances that stimulate the production of heat shock proteins or affect the protein degradation in other ways. To study this, we have developed a cell culture model that allows us to carry out the first therapy studies in the laboratory.’
The study of filaminopathy patients also enables the researchers to describe the disease more accurately now. The heart is more affected by the disease than previously thought, which may cause sudden cardiac death. It was also confirmed that pathological remodelling processes in the leg muscles conform to a specific pattern, which is visible on magnetic resonance imaging pictures. ‘This enables us to distinguish filaminopathies from other muscle diseases within the group of myofibrillar myopathies’, explains Dr. Kley. Ruhr-University Bochum