BreakThrough Digest Medical News |
- Exercise is key in the fight against Alzheimer’s disease
- ‘Broken heart syndrome’ protects the heart from adrenaline overload
- Finding brings scientists 1 step closer to Parkinson’s drug
- Clinical trial first to test heart drug regimen for Duchenne muscular dystrophy
| Exercise is key in the fight against Alzheimer’s disease Posted: 26 Jun 2012 09:00 PM PDT In a recent Journal of Biological Chemistry “Paper of the Week,” research led by Ayae Kinoshita at the Kyoto University Graduate School of Medicine in Japan reveals the benefits of exercise in combating Alzheimer’s disease.
The most common cause of dementia, Alzheimer’s disease results in the loss of cognitive faculty. In the majority of cases, Alzheimer’s disease occurs after age 65, and factors such as diet and exercise appear to play a role in its development, with high-fat diets as a risk factor. Kinoshita’s research compared the effects of 1) diet control, 2) voluntary exercise and 3) diet control plus exercise in an Alzheimer’s disease mouse model. The results showed that exercise was more beneficial than diet control in reducing ?-amyloid formation (a defining characteristic of Alzheimer’s disease) and restoring memory loss induced by a high-fat diet in these mice. Moreover, Kinoshita’s team found that the effect of diet control plus exercise was not significantly different than exercise alone. They attribute the positive effects of exercise to increased degradation of ?-amyloid deposits in the brain. “Based on the results in this research,” Kinoshita suggests, “exercise should be given priority to prevent Alzheimer’s disease.” From the article: “Exercise is more effective than diet control in preventing high fat diet-induced ?-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice” by Masato Maesako, Kengo Uemura, Masakazu Kubota, Akira Kuzuya, Kazuki Sasaki, Naoko Hayashida, Megumi Asada-Utsugi, Kiwamu Watanabe, Maiko Uemura, Takeshi Kihara, Ryosuke Takahashi, Shun Shimohama and Ayae Kinoshita Read the Paper in Press version here: http://www.jbc.org/content/early/2012/05/14/jbc.M111.315358.abstract. Corresponding author: Ayae Kinoshita, School of Human Health Sciences, Kyoto University Graduate School of Medicine in Kyoto, Japan; email: akinoshita@hs.med.kyoto-u.ac.jp ### About the American Society for Biochemistry and Molecular Biology The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society’s student members attend undergraduate or graduate institutions. For more information about ASBMB, visit www.asbmb.org. Written by Danielle Gutierrez Contact: Angela Hopp |
| ‘Broken heart syndrome’ protects the heart from adrenaline overload Posted: 26 Jun 2012 09:00 PM PDT
A condition that temporarily causes heart failure in people who experience severe stress might actually protect the heart from very high levels of adrenaline, according to a new study published in the journal Circulation. The research provides the first physiological explanation for Takotsubo cardiomyopathy, also called “broken heart syndrome” because it affects people who suffer severe emotional stress after bereavement, and suggests guidance for treatment.
Around 1-2% of people who are initially suspected of having a heart attack are finally discovered to have this increasingly recognised syndrome. The Imperial College London study, which simulated the condition in an animal model, suggests that the body changes its response to adrenaline by switching from its usual role in stimulating the heart to reducing its pumping power. Although this results in acute heart failure, most patients make a full recovery within days or weeks. The researchers propose that the switch in the heart’s response to adrenaline might have evolved to protect the heart from being overstimulated by the particularly high doses of adrenaline that the body releases during stress. Patients with Takotsubo cardiomyopathy, most often older women, experience symptoms that resemble a heart attack, but heart tests reveal no blockage in the coronary arteries; instead the heart has a balloon-like appearance caused by the bottom of the heart not contracting properly. The same condition is sometimes seen in people who are injected with adrenaline to treat severe allergic reactions. In this new research, the authors simulated the condition by injecting high doses of adrenaline in anaesthetised rats. In these rats, as in Takotsubo patients, heart muscle contraction was suppressed towards the bottom of the heart. The researchers found that these rats were protected from an otherwise fatal overstimulation of the heart, indicating that adrenaline acts through a different pathway from usual, and that this switch protects the heart from toxic levels of adrenaline. The study also examined drugs that might be useful for treating Takotsubo cardiomyopathy. Some beta blockers, used to treat high blood pressure, angina and heart failure, reproduced or enhanced the features of Takotsubo, giving new insights into the protective effects of these drugs. Levosimendan, a different type of drug given in heart failure to stimulate the heart without going through the adrenaline receptor pathways, had a beneficial effect. “Adrenaline’s stimulatory effect on the heart is important for helping us get more oxygen around the body in stressful situations, but it can be damaging if it goes on for too long,” said Professor Sian Harding, from the National Heart and Lung Institute (NHLI) at Imperial College London, who led the study. “In patients with Takotsubo cardiomyopathy, adrenaline works in a different way and shuts down the heart instead. This seems to protect the heart from being overstimulated.” Study co-author Dr Alexander Lyon, also from the NHLI at Imperial, and consultant cardiologist at Royal Brompton Hospital, set up one of the first specialist services in the UK to look after people who have experienced Takotsubo cardiomyopathy. “Currently it is not fully known how to treat these patients,” he said. “Insights from this work show that the illness may be protecting them from more serious harm. We’ve identified a drug treatment that might be helpful, but the most important thing is to recognise the condition, and not to make it worse by giving patients with Takotsubo cardiomyopathy more adrenaline or adrenaline-like medications.” “At the Royal Brompton Hospital and Imperial College London we are leading a European initiative to bring together experts to understand this recently recognised cardiac syndrome, and we hope the findings from this work will lead to new treatment strategies for these patients during the acute phase of their illness, and to prevent recurrence”. The study was funded by the British Heart Foundation (BHF), the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Academy of Medical Sciences. Dr Shannon Amoils, Research Advisor at the BHF, said: “This is a fascinating study which presents a possible explanation for the signs of Takotsubo cardiomyopathy, a rare condition that’s usually preceded by intense emotional or physical stress. Patients usually have symptoms that resemble those of a heart attack but nearly all fully recover after a short time. “The study also provides new insights into how the heart may protect itself from stress, which opens up exciting avenues of exploration for research. We must remember though that this is a study in rats, and the findings need to be confirmed in people before we can be sure of their relevance to patients.” ### For further information please contact: Sam Wong Notes to editors
1. Reference: H Paur et al. ‘High levels of circulating epinephrine trigger apical cardiodepression in a ?2-1 adrenoceptor/Gi-dependent manner: a new model of Takotsubo Cardiomyopathy’ Circulation, published online 25 June 2012. 2. About Imperial College London Consistently rated amongst the world’s best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment – underpinned by a dynamic enterprise culture. Since its foundation in 1907, Imperial’s contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges. In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK’s first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible. Website: www.imperial.ac.uk 3. About the British Heart Foundation 4. About the Wellcome Trust 5. Royal Brompton & Harefield NHS Foundation Trust is a national and international specialist heart and lung centre based in Chelsea, London and Harefield, Middlesex. The Trust helps patients from all age groups who have heart and lung problems and is the country’s largest centre for the treatment of adult congenital heart disease. www.rbht.nhs.uk 6. The independent Academy of Medical Sciences promotes medical science and its translation into benefits for society. The Academy’s elected Fellows are the United Kingdom’s leading medical scientists and scholars from hospitals, academia, industry and the public service. www.acmedsci.ac.uk The Academy’s ‘Starter Grants’ scheme provides modest funds to enable research active Clinical Lecturers to pursue research work, gather preliminary data and so further strengthen applications for longer-term fellowships and funding. 7. About BBSRC BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond. Funded by Government, and with an annual budget of around £445M (2011-2012), we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals. For more information about BBSRC, our science and our impact see: http://www.bbsrc.ac.uk Contact: Sam Wong |
| Finding brings scientists 1 step closer to Parkinson’s drug Posted: 26 Jun 2012 09:00 PM PDT
Van Andel Institute announces that researchers at Lund University in Sweden have published a study detailing how Parkinson’s disease spreads through the brain. Experiments in rat models uncover a process previously used to explain mad cow disease, in which misfolded proteins travel from sick to healthy cells. This model has never before been identified so clearly in a living organism, and the breakthrough brings researchers one step closer to a disease-modifying drug for Parkinson’s.
“Parkinson’s is the second most common neurodegenerative disorder after Alzheimer’s disease,” said Patrik Brundin M.D., Ph.D., Jay Van Andel Endowed Chair in Parkinson’s Research at Van Andel Research Institute (VARI), Head of the Neuronal Survival Unit at Lund University and senior author of the study. “A major unmet medical need is a therapy that slows disease progression. We aim to better understand how Parkinson’s pathology progresses and thereby uncover novel molecular targets for disease-modifying treatments.” Previous research demonstrates that a misfolded protein known as alpha-synuclein protein gradually appears in healthy young neurons transplanted to the brains of Parkinson’s patients. This discovery gave rise to the group’s hypothesis of cell-to-cell protein transfer, which has since been demonstrated in laboratory experiments. In the current study, published this week in the PLoS ONE, researchers for the first time were able to follow events in the recipient cell as it accepts the diseased protein by allowing it to pass its outer cell membrane. The experiments also show how the transferred proteins attract proteins in the host cell leading to abnormal folding or “clumping” inside the cells. “This is a cellular process likely to lead to the disease process as Parkinson’s progresses, and it spreads to an increasing number of brain regions as the patient gets sicker,” said Elodie Angot, Ph.D., of Lund University’s Neuronal Survival Unit, and lead co-author of the study. “In our experiments, we show a core of unhealthy human alpha-synuclein protein surrounded by alpha-synuclein produced by the rat itself. This indicates that this misfolded protein not only moves between cells but also acts as a “seed” attracting proteins produced by the rat’s brain cells,” said Jennifer Steiner, Ph.D., of Lund University and Van Andel Institute’s Center for Neurodegenerative Science, the study’s other lead author. These findings are consistent with results from previous laboratory cell models and for the first time extend this observation into a living organism. However, it remains unclear exactly how alpha-synuclein gains access from the extracellular space to the cytoplasm of cells to act as a template for naturally occurring alpha-synuclein, causing the naturally-occurring protein to, in turn, misfold. Further studies are needed to clarify this important step in the process. The discovery does not reveal the root of Parkinson’s disease, but in conjunction with disease models developed by Lund University researchers and others, could enable scientists to develop new drug targets aimed at mitigating or slowing the effects of the disease, which currently strikes more than 1% of people over the age of 65. ### Link to the study here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039465 About the Neuronal Survival Unit, Faculty of Medicine, Lund University:
The research at Neuronal Survival Unit, Lund University, Sweden is focused on pathogenetic mechanisms and pharmacological treatment in cell and animal models of Parkinson’s and Alzheimer’s diseases. We also study cell replacement therapy with stem cells in attempts to repair brains in animal models of Parkinson’s diseases. The group’s mission is to understand neurodegenerative diseases and develop new therapies that are of benefit to patients and their caregivers. http://www.med.lu.se/expmed/neuronal_survival_unit About Van Andel Research Institute:
Established by Jay and Betty Van Andel in 1996, Van Andel Institute is an independent research organization dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process. This is accomplished through the work of over 200 researchers in more than 20 on-site laboratories and in collaborative partnerships that span the globe. www.vai.org Contact: Tim Hawkins |
| Clinical trial first to test heart drug regimen for Duchenne muscular dystrophy Posted: 25 Jun 2012 09:00 PM PDT The first landmark randomized clinical trial for a cardiac drug regimen in Duchenne muscular dystrophy (DMD) is testing whether earlier treatment can stop or slow down heart damage that usually kills people with the disease.
The study is a collaboration of Cincinnati Children’s Hospital Medical Center, Ohio State University (OSU) and The Christ Hospital in Cincinnati. Extensive research ? including studies in mouse models of DMD ? suggests an anti-fibrosis drug long used to treat heart attack victims, eplerenone, could help people with the disease, said Kan Hor, MD, a principal investigator and a physician/researcher at Cincinnati Children’s. Disease-associated heart damage is the leading cause of death in patients between ages 20 and 30 ? the maximum life span for people with DMD. A key element of the new treatment approach is using enhanced cardiac magnetic resonance imaging, Hor said. The technique ? more sensitive than standard echocardiogram tests now used in DMD ? is designed to catch minute declines in heart function much earlier in a child’s life. “Standard diagnostic techniques rarely catch significant heart damage in DMD in the first decade, although research shows scar tissue is already developing in many patients before it’s clinically detectable through current methods,” said Hor, who works in the Cincinnati Children’s Heart Institute. “We want to determine the optimal time point to detect these early changes in heart function and start cardiac therapy with anti-fibrotic medication.” A genetic disease that affects mostly boys, DMD is the most common form of muscular dystrophy. Most children begin losing the ability to walk between the ages of 7 and 13. With decades of research, testing and increased emphasis on multidisciplinary care, physicians have been able to use steroids and other drugs to preserve some ambulation, pulmonary function and push survival ages well into the 20s. Still, there remains no consensus on how to best manage DMD-associated heart fibrosis and disease, Hor said. Often, between the ages of 7 and 10, echocardiogram results show the heart is functioning normally by conventional measures ? delaying needed heart treatment in an intensely time-sensitive disease. Evidence-driven approach
Hor and his colleagues theorize earlier diagnosis and treatment with anti-fibrotic medication could enhance quality of life and survival for people with DMD. They base this on a broad range of studies at Cincinnati Children’s and other institutions, including reviews of clinical data. One stark conclusion from those reviews is that, by the time current diagnostic methods catch DMD-associated heart disease after the age of 10, damage is often irreversible. By then, standard treatment with beta-blockers and angiotensin converting enzyme inhibitors provide little if any long-term benefit. One study co-authored by Hor reviewed the cases of 247 children with DMD. Thirteen percent of patients under the age of10 years already had significant evidence of cardiac scarring ? even though conventional tests indicated normal heart function. Standard echocardiograms now used in DMD look for declines in left ventricle ejection fraction (LVEF) ? a measure of heart muscle pumping ability. Although reliable for many heart conditions, functional assessments by echocardiograms are not sensitive enough to detect early DMD-associated heart disease, such as heart muscle fibrosis, scarring and important functional decline that precedes measurable LVEF reductions. To overcome this limitation, the clinical trial is using advanced cardiac magnetic resonance imaging (CMR) techniques. They include imaging with a contrast agent called gadolinium, which allows physicians to detect the early formation of heart muscle fibrosis while patients are still young and ejection fraction is normal. The image analysis includes an overlay tool that divides the heart into 24 equal sub-segments. As the heart beats, the segment grids move in line with the region of the heart they cover. The grids start out as perfectly square, but then contort in conjunction with a twisting motion the heart makes to force blood through the body. This allows physicians to measure heart function region by region to catch the smallest of declines. “On an individual basis, measuring each of the grids doesn’t tell you very much,” Hor explained. “But when you add up the grids, you can see cumulative changes and catch small but important declines in heart function. We believe this test will help us pick the best time to begin drug treatment.” Preclinical drug tests
The decision to test the drug eplerenone is based in part on extensive clinical studies of DMD patients at Cincinnati Children’s and in mouse models of DMD at OSU spear led by Dr. Hor’s collaborator Dr. Subha Raman. Another factor is its success in treating people with certain types of advanced heart disease. The drug is an aldosterone antagonist, a diuretic that helps the body get rid of excess fluid (tissue swelling) while retaining sufficient potassium levels. It blocks the buildup of fibrotic material and scarring that over time can turn heart muscle into non-functioning fatty tissue. The drug’s success in treating fibrosis in adult heart patients has led to it being sought for off-label treatment in patients with DMD, creating a sense of urgency behind the current clinical trial, Hor said. In the mouse studies, early treatment with eplerenone resulted in reduced heart fibrosis and improved cardiac function. Researchers treated two groups of mice, one at 8 weeks of age and a second at 4 weeks. As the mice aged, the researchers noted normal LVEF and functional improvement in both groups, although reported the benefit was more pronounced in mice treated earlier at 4 weeks. “The results of that research indicated that earlier treatment with this medication offers an excellent chance of preserving heart function, decreasing fibrosis and reducing cardiac death in DMD,” said Hor. The Phase 2/3 double-blind randomized clinical trial will treat 40 patients initially for one year, focusing on patients older than 7 years of age with evidence of heart muscle scarring but normal heart function as determined by LVEF. The study is supported in part by Ballou Skies, Parent Project Muscular Dystrophy (PPMD), and The Lindner Center for Research & Education at The Christ Hospital Foundation. Long time research collaborator, Dr. Wojciech Mazur from The Christ Hospital in Cincinnati, is also assisting with the trial. Hor said treatment with eplerenone will be compared to a placebo and current standard drug treatments. Depending on trial results, the research could move into a larger trial to include more patients at different stages of heart disease. Hor said he expects the current trial to take about 12-18 months to enroll patients and a little over two years to complete. ### For more information about the clinical trial, please call the study research coordinator at 513-803-0369 for Cincinnati Children’s and 614-688-8020 for Ohio State. Additional information is also available at: http://clinicaltrials.gov/ct2/show/NCT01521546?term=eplerenone&recr=Open&rank=15. For more information about the Cincinnati Children’s Heart Institute, please visit: http://www.cincinnatichildrens.org/service/h/heart-institute/default/. About Cincinnati Children’s
Cincinnati Children’s Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report’s 2012 Best Children’s Hospitals ranking. It is ranked #1 for neonatology and in the top 10 for all pediatric specialties. Cincinnati Children’s is one of the top two recipients of pediatric research grants from the National Institutes of Health. It is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at www.cincinnatichildrens.org. Contact: Nick Miller |
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