'Rare' Brain Disorder May Be More Common Than Thought, Scientists Say ScienceDaily (Dec.

25, 2011) A global team of neuroscientists, led by researchers at Mayo Clinic in Florida, has found the gene responsible for a brain disorder that may be much more common than once believed. In the Dec. 25 online issue of Nature Genetics, the researchers say they identified 14 different mutations in the gene CSF1R that lead to development of hereditary diffuse leukoencephalopathy with spheroids (HDLS). This is a devastating disorder of the brain's white matter that leads to death between ages 40 and 60. People who inherit the abnormal gene always develop HDLS. Until now, a definite diagnosis of HDLS required examination of brain tissue at biopsy or autopsy. The finding is important because the researchers suspect that HDLS is more common than once thought and a genetic diagnosis will now be possible without need for a brain biopsy or autopsy. According to the study's senior investigator, neurologist Zbigniew K. Wszolek, M.D., a significant number of people who tested positive for the abnormal gene in this study had been diagnosed with a wide range of other conditions. These individuals were related to a patient known to have HDLS, and so their genes were also examined. "Because the symptoms of HDLS vary so widely -- everything from behavior and personality changes to seizures and movement problems -- these patients were misdiagnosed as having either schizophrenia, epilepsy, frontotemporal dementia, Parkinson's disease, multiple sclerosis, stroke, or other disorders," says Dr. Wszolek. "Many of these patients were therefore treated with drugs that offered only toxic side effects. "Given this finding, we may soon have a blood test that can help doctors diagnose HDLS, and I predict we will find it is much more common than anyone could have imagined," he says. Dr. Wszolek is internationally known for his long-term efforts to bring together researchers from around the world to help find cases of inherited brain disorders and discover their genetic roots. Dr. Wszolek's interest in HDLS began when a severely disabled young woman came to see him in 2003 and mentioned that other members of her family were affected. The

diagnosis of HDLS was made by his Mayo Clinic colleague, Dennis W. Dickson, M.D., who reviewed the autopsy findings of the patient's uncle, who had previously been misdiagnosed as multiple sclerosis, and subsequently, Dr. Wszolek's patient and her father. All members of the family had HDLS. Dr. Dickson had identified other cases of HDLS from Florida, New York, Oregon and Kansas in the Mayo Clinic Florida brain bank and knew of a large kindred in Virginia with similar pathology, based upon a presentation at the annual meeting of the American Association of Neuropathologists. With concerted efforts, Dr. Wszolek and collaborators at University of Virginia were able to obtain DNA samples from the Virginia kindred. Dr. Wszolek also sought other cases, particularly those that had been reported in the neuropathology literature, and he was able to obtain samples from Norway, the United Kingdom, Germany and Canada, and other sites in the U.S. He and his team of investigators and collaborators have since published studies describing the clinical, pathologic and imaging characteristics of the disorder, and they have held five international meetings on HDLS. In this study, which included 38 researchers from 12 institutions in five countries, the study's first author, Rosa Rademakers, Ph.D., led the effort to find the gene responsible for HDLS. Her laboratory studied DNA samples from 14 families in which at least one member was diagnosed with HDLS and compared these with samples from more than 2,000 disease-free participants. The gene was ultimately found using a combination of traditional genetic linkage studies and recently developed state-of-the art sequencing methods. Most family members studied -- who were found to have HDLS gene mutations -- were not diagnosed with the disease, but with something else, thus emphasizing the notion that HDLS is an underdiagnosed disorder. The CSF1R protein is an important receptor in the brain that is primarily present in microglia, the immune cells of the brain. "We identified a different CSF1R mutation in every HDLS family that we studied," says Dr. Rademakers. "All mutations are located in the kinase domain of CSF1R, which is critical for its activity, suggesting that these mutations may lead to deficient microglia activity. How this leads to white matter pathology in HDLS patients is not yet understood, but we now have an important lead to study."

"With no other disease have we found so many affected families so quickly," says Dr. Wszolek. "That tells me this disease is not rare, but quite common." He adds, "It is fantastic that you can start an investigation with a single case and end up, with the help of many hands, in what we believe to be a world-class gene discovery." The study was funded by a Mayo benefactor and the Mayo Foundation. Additionally, Mayo Clinic in Florida is a Morris K. Udall Parkinson's Disease Research Center of Excellence supported by the National Institute of Neurological Disorders and Stroke. http://www.sciencedaily.com/releases/2011/12/111225144314.htm

Can Nerve Growth Factor Gene Therapy Prevent Diabetic Heart Disease? ScienceDaily (Dec. 20, 2011) Diabetes is a major risk factor for cardiovascular disease and can reduce blood supply to the heart tissue and damage cardiac cells, resulting in heart failure.

New research has investigated if nerve growth factor (NGF) gene therapy can prevent diabetic heart failure and small vascular disease in mice. The study by Professor Costanza Emanueli, British Heart Foundation Senior Research Fellow and colleagues of the Bristol Heart Institute in the Regenerative Medicine Section of the School of Clinical Sciences at the University of Bristol is published online inDiabetes, which is the journal of theAmerican Diabetes Association. Scientists believe that NGF has a protective effect on the cardiovascular system but the possibility that cardiac NGF gene therapy could prevent diabetes-induced heart failure has not been previously studied. The team investigated whether increasing the myocardial level of NGF by using adenoassociated viral (AAV) vectors could prevent the diabetic heart from failure. AAVs are small non-enveloped, single-stranded DNA viruses that can potentially infect all cell types. They exist in different forms, allowing to better target different cells for gene therapy, including after AAV injection in a vein. Importantly, at variance from more popular viral vectors, AAVs allow for virtually permanent increased level of a therapeutic protein. Professor Emanueli said: "Our study represents a major advance in tackling heart disease in diabetics, a leading cause of death in the western world. It also represents one important step forward in our goal for translating NGF-based therapies in cardiovascular patients. "The critical scientific finding from our research is that diabetes reduces cardiac level of NGF. Most importantly, engineering the diabetic heart with AAVs to make it produce NGF can prevent heart failure." Professor Jeremy Pearson, Associate Medical Director at the BHF, added: "Targeted gene therapy is now becoming a realistic prospect for several human diseases. This

study suggests that there is real promise for NGF gene therapy in future to alleviate heart failure in diabetic patients -- a major and often fatal complication of their disease." Type 1 diabetes mellitus was induced in mice by damaging their insulin producing pancreatic cells with streptozotocin. Non-diabetic age-matched control mice were studied for reference. Murine NGF mRNA expression in the heart was measured by real-time RT-PCR in mice at 12 weeks of diabetes or controls. In separate experiments, at two weeks of diabetes, cardiac expression of human NGF or the AAV control -Gal genes was induced by either intra-myocardial injection of adeno-associated virus vectors serotype 2 (AAV2) or systemic injection of AAV9, which is especially able to target cardiac cells. Non-diabetic mice received AAV2- -Gal or AAV9- -Gal. The researchers found diabetes lowered the cardiac expression of endogenous NGF mRNA. A progressive deterioration of cardiac function and left ventricular chamber dilatation appeared in -Gal-treated diabetic mice. At 12 weeks of diabetes, -Galtreated mice showed myocardial microvascular rarefaction, hypoperfusion, more interstitial fibrosis and increased apoptosis of endothelial cells and cardiomyocytes. NGF gene therapy using either AAV2 or AAV9 prevented diabetes-induced cardiac dysfunction, reduced cardiac apoptosis and preserved cardiac microvasculature and blood flow. The research results suggest that NGF gene therapy might have a tremendous therapeutic potential for the treatment of diabetic cardiomyopathy and encourage further translational efforts for the final benefit of diabetic patients. However, before this gene therapy approach can be trialled in patients, additional preclinical studies need to be performed in order to verify not only the efficiency and the safety of AAVs-mediated NGF in type 1 diabetes, but also to find the most efficient AAV serotype, as well as the optimal dose and delivery route to be used.

http://www.sciencedaily.com/releases/2011/12/111220172626.htm

Female Shift Workers May Be at Higher Risk of Heart Disease ScienceDaily (Oct. 23, 2011) Women hospital staff working night shifts may be compromising their own health as they try to improve the health of patients, Dr. Joan Tranmer told the Canadian Cardiovascular Congress 2011, co-hosted by the Heart and Stroke Foundation and the Canadian Cardiovascular Society. See Also: Health & Medicine
y y y

Workplace Health Menopause Heart Disease

Science & Society

y y y

Industrial Relations Public Health Disaster Plan

Reference
y y y y

High density lipoprotein Hypercholesterolemia Ischaemic heart disease Health benefits of tea

Dr. Tranmer's study investigated the connection between shift work and risk factors for heart disease in female hospital employees who worked both shift and non-shift rotations. As a former nurse familiar with shift work and because of her concern about the health of the female hospital work force, Dr. Tranmer questioned whether late nights were taking their toll on the health of her fellow hospital employees. "As I walked through the hospital and talked with my colleagues, I was concerned about what I was seeing in a

lot of the workers," she said. "We did not know if this is related to shift work or other aspects of hospital work." Her study reinforced what she observed about the health of female hospital employees. Dr. Tranmer studied 227 women ranging in age between 22 and 66 (with a mean age of 46) from two hospitals in southeastern Ontario. The study included not only nurses but a variety of staff, including administrative employees as well as lab and equipment technicians, who worked a variety of rotations. She examined each of the women's possible risk factors associated with metabolic syndrome. The syndrome's five indicators are abdominal obesity (elevated waist circumference), high blood pressure, elevated blood glucose, elevated triglycerides, and low levels of high-density lipoprotein (HDL) cholesterol, also known as 'good cholesterol.' The women also completed a detailed survey about their work history and lifestyle. The findings of this study suggest that approximately one in five middle-aged women who do shift work have at least three risk indicators for heart disease. From the group, 17 per cent had metabolic syndrome, with at least three of the identified indicators. Thirty-eight per cent had high blood pressure. Of particular concern was the finding that 60 per cent of the participants had a waist circumference greater than 80 cm (31.5 inches). Abdominal obesity and elevated waist circumference are good predictors for risk of developing heart disease, stroke, high blood pressure, cholesterol and type 2 diabetes. The greater your waist circumference, the higher your risk of developing these conditions. The study found that age and current shift work status were significantly associated with increased risk. Women over 45 years, those who had reached menopause, had a shift work history of more than six years, and those currently working either 12 hour shifts or rotational shifts were more likely to have metabolic syndrome. Metabolic syndromewas present in eight per cent of those working shifts for less than six years, in 18 per cent in those working shifts for six to 15 years, and in 74 percent of those working shifts for more than 15 years. While the increase in prevalence of risk

factors is also associated with age, the influence of the combination of older age and shift work on risk raises concern. "Just how shift work contributes to the development of such risk factors isn't clear," says Dr. Tranmer. "It is possible that the disruption of biological rhythms, sleeping, eating, and exercise patterns may be factors." The research team is exploring these potential pathways in a current study. A Statistics Canada survey on the work-life balance of shift workers found that long work hours were associated with role overload. Shift workers were more likely to cut back on sleep, to spend less time with their spouse, and to worry about not spending enough time with family, compared with regular day workers. "All women should manage their weight and other risk factors, and this study shows women working shift work especially need to be aware," said Heart and Stroke Foundation spokesperson Dr. Beth Abramson. "We spend so many of our hours and days at work, it is important for employers and employees to create as healthy a work environment as possible -- especially for shift workers." She says that, given the prevalence of these cardiovascular risk factors, and in particular with abdominal obesity rates and the increasing age of the female hospital workforce, this study raises the need to examine workplace policy encouraging healthy behaviours for all employees. She recommends that women find out how they can protect their heart health through the Foundation's The Heart Truthcampaign (thehearttruth.ca), which educates women about identifying their risks and warning signs of heart disease and stroke, and shows them how to make lifestyle changes and take action to reduce their risk by as much as 80 per cent. "These women work so hard caring for others, but they need to take the time to properly care of their own health," says Dr. Tranmer. According to Statistics Canada,over 4 million workers aged 19 to 64 worked something other than a regular day shift in 2005. Of these shift workers, about 3.3 million worked full time (30 or more hours a week). Rotating shifts and irregular schedules were the most common types of shift work, accounting for 2.3 million full-time workers. Women

made up 37 per cent of all full-time shift workers. The majority of women working shifts (69 per cent) worked part time. When asked if similar conclusions could be drawn for male shift workers, Dr. Tranmer said that much of our understanding about the associations between shift work and health come from studies that have predominantly included men so she wanted to focus on the link in women. The study was funded by the Canadian Institutes of Health Research.

http://www.sciencedaily.com/releases/2011/10/111023135642.htm

New Sensor to Detect Lung Cancer from Exhaled Breath ScienceDaily (Dec. 23, 2011) Tecnalia, through the Interreg project Medisen, is contributing to develop biosensors capable of detecting the presence of tumour markers of lung cancer in exhaled breath. This is possible because of the changes produced within the organism of an ill person, changes reflected in the exhaled breath of the patient and which enable determining the presence of this type of marker during the initial stages of the disease.

y y

Tecnalia, through the Interreg project Medisen, is contributing to develop biosensors capable of detecting the presence of tumour markers of lung cancer in exhaled breath. (Credit: Image courtesy of Elhuyar Fundazioa)

Some illnesses such as lung and stomach cancer or liver diseases which, due to the difficulty of diagnosis, have symptoms that are often confused with routine disorders. Therefore, in most cases, the disease is only detected at an advanced stage. New methods for early detection are being investigated as an urgent need. Tecnalia, through the Interreg project Medisen, is contributing to develop biosensors capable of detecting the presence of tumour markers of lung cancer in exhaled breath. This is possible because of the changes produced within the organism of an ill person, changes reflected in the exhaled breath of the patient and which enable determining the presence of this type of marker during the initial stages of the disease. Patients with lung cancer, treated in the Section of Medical Oncology of the Institute of Onco-Haemathology of the Donostia Hospital (IDOH) have collaborated in this phase of

the project. For that, the Ethic Committee of the Clinical Research of Euskadi (CEIC) gave the authorization to the Instituto Biodonostia for the clinical trials.

Human breath, whether from a healthy or ill person, is composed of a hundreds of organic compounds: acetone, methanol, butanol, hydrocarbons, amongst others. There is not a single specific component in the exhaled breath capable of acting as a marker for the diagnosis of lung cancer. A range of biomarkers and its combination should be selected. The compounds of interest are generally to be found at 1-20 parts per billion (ppb) in healthy human breath but can be increased 10-100-fold in the breath of sick patients. In order to be able to detect these changes the development of novel materials was required.

During the first phase of the project, breath samples were collected by the hospital staff by a breath collecting device. A detailed analysis of the most representative compounds present in the breath samples has been carried out and the family or families of compounds required to act as markers for the presence of lung cancer selected. Organic compounds have been analysed using gas chromatograph/mass spectrometry analysis (GC/MS). Then, the GC/MS results of breath tests have been analysed by statistical and structural algorithms to discriminate and identify "healthy and "cancerous" patterns that really provide information for the design of the sensor. In parallel, novel materials for the detection of the selected organic compounds have been developed by Tecnalia in order to increase the sensitivity of the devices. Participating together with Tecnalia in this project were the Instituto de Tecnologas Qumicas Emergentes de La Rioja (Inter-Qumica) designing the sensor device and the University of Perpignan (France) testing the novel materials. As a conclusion, the biosensors will facilitate the diagnosis of certain diseases; mainly those located in the lungs, at the initial stages of the illness, which could increase considerably the chances of survival. http://www.sciencedaily.com/releases/2011/12/111223091331.htm