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Researchers from Boston University School of Medicine (BUSM) report variants in a new gene, PLXNA4, which may increase the risk of developing Alzheimer’s disease (AD). The discovery of this novel genetic association may lead to new drug treatment options that target PLXNA4 specifically. These findings appear in the Annals of Neurology.
AD is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older, and more than 40 percent of people age 85 and older. Genetic factors account for much of the risk for developing AD with heritability estimates between 60 percent and 80 percent. However much of the genetic basis for the disease is unexplained. Less than 50 percent of the genetic contribution to AD is supported by known common genetic variations.
Using data from the Framingham Heart Study, the researchers obtained strong evidence of an association with several single nucleotide polymorphism in PLXNA4, a gene which had not been previously linked to AD. They then confirmed this finding in a larger dataset from the Alzheimer’s Disease Genetics Consortium and other datasets. Next, they performed a series of experiments in models that pinpointed the mechanism by which this gene affects AD risk. “Importantly, this is one of few single studies which go from gene finding to mechanism,” explained corresponding author Lindsay Farrer, PhD, Chief of Biomedical Genetics and professor of medicine, neurology, ophthalmology, epidemiology and biostatistics at BUSM.
According to the researchers a form of the protein encoded by this gene promotes formation of neurofibrillary tangles consisting of decomposed tau protein, one of the two pathological hallmarks of the disease. “We showed that PLXNA4 affects the processing of tau as it relates to neurofibrillary tangles, the primary marker of AD. Most drugs that have been developed or that are in development for treating AD are intended to reduce the toxic form of beta-amyloid, a sticky substance that accumulates in the brain of persons with AD, and none have been very effective. Only a few drugs have targeted the tau pathway,” added Farrer.
This study was supported by grants from the National Institute on Aging (R01-AG025259, P30-AG13846, R01-AG0001, U24-AG021886, U24-AG26395, R01-AG041797 and P50-AG005138), the Alzheimer Association, the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (#A110742), and the Evans Center for Interdisciplinary Biomedical Research (ECIBR) ARC on “Protein Trafficking and Neurodegenerative Disease” at Boston University.
To view the complete findings of the study, PLXNA4 is Associated with Alzheimer Disease and Modulates Tau Phosphorylation.
How can engaged patients improve health care?
BUSM’s Suzanne Mitchell, MD, and other expert panelists tackled the question during a recent TEDMED#GreatChallenges discussion, “Examining the Case for Patient Activation Measures.”
Research indicates clinical sites using the Patient Activation Measure (PAM) — a tool developed by researchers at the University of Oregon to measure patients’ knowledge, skills and confidence for managing their health — save between $260 and $3,700 per patient annually. The benefits of patient engagement extend far beyond the scope of revenue reports by promoting better communication between patients and providers.
“We’re trying to figure out how to personalize people’s care, because one size doesn’t fit all,” said Dr. Mitchell, bringing valuable insight from the clinical perspective to the discussion. “I think we can see the PAM used as a way of personalizing care, as a way of informing patients where they’re at and what they need. It could also be used as an assessment of whether a particular intervention has worked successfully to increase a person’s level of or their ability to engage in managing their own health care.”
Sustainable patient engagement is increasingly important to health care providers and administrators. To read more about the current discussion, visit George Washington University’s School of Public Health blog.
A new study shows that stress may play a role in the development of obesity.
Using experimental models, researchers at Boston University School of Medicine (BUSM) showed that adenosine, a metabolite released when the body is under stress or during an inflammatory response, stops the process of adipogenesis, when adipose (fat) stem cells differentiate into adult fat cells.
Previous studies have indicated adipogenesis plays a central role in maintaining healthy fat homeostasis by properly storing fat within cells so that it does not accumulate at high levels in the bloodstream. The current findings indicate that the body’s response to stress, potentially stopping the production of fat cell development, might be doing more harm than good under conditions of obesity and/or high levels of circulating blood fat.
The process is halted due to a newly identified signaling from an adenosine receptor, the A2b adenosine receptor (A2bAR) to a stem cell factor, known as KLF4, which regulates stem cell maintenance. When A2bAR is expressed, KLF4 level is augmented, leading to inhibition of differentiation of fat stem cells. The correlation between these two factors leads to an interruption of fat cell development, which could result in issues with fat storage within the cells and it getting into the bloodstream.
While the majority of the study was carried out in experimental models, the group also showed that A2bAR activation inhibits adipogenesis in a human primary preadipocyte culture system. Finally, analysis of adipose tissue of obese subjects showed a strong association between A2bAR and KLF4 expression in both subcutaneous (under the skin) and visceral (internal organ) human fat.
“It may seem counterintuitive, but our body needs fat tissue in order to function properly, and certain biochemical cellular processes are necessary for this to happen,” said Katya Ravid, DSc/PhD, professor of medicine and biochemistry at BUSM and director of the Evans Center for Interdisciplinary Biomedical Research who led the study. “Our study indicates that a dysfunction resulting from stress or inflammation can disrupt the process of fat tissue development, which could have a negative impact on processes dependent on proper fat cell homeostasis.”
This study is part of ongoing research interest and investigations by researchers in Ravid’s lab examining the differentiation of bone marrow and tissue stem cells and the role of adenosine receptors in this process.
Published in the Journal of Biological Chemistry, this study was done in collaboration with Noyan Gokce, MD, associate professor of medicine at BUSM and physician at Boston Medical Center; and Anna Eisenstein, graduate student of Ravid. This research was funded in part by grants awarded to Ravid by the National Heart, Lung and Blood Institute under grant award number HL93149 and the Boston Nutrition Obesity Research Center under grant award number DK046200. Gocke’s research is supported by the NIH under grant award number R01HL114675-02. Ravid also is an established Investigator with the American Heart Association.
BUSM researchers have released a guide to help primary care doctors navigate the new May 2014 American Heart Association/American Stroke Association guidelines on transient ischemic attacks (TIA).
TIA’s, commonly known as “mini-strokes” can be the first and only warning sign of a larger, debilitating stroke to come. The most common symptoms are temporary weakness on one side or speech disturbance. These ostensibly minor symptoms often prompt patients to see their primary care doctor instead of presenting to an emergency room or neurology clinic. This expert commentary, authored by Shuhan Zhu, MD, fourth year neurology resident, and Michael Perloff, MD, PhD, assistant professor of neurology at BUSM, offers insight into how primary care doctors can properly and expeditiously manage this complex and serious medical condition. The summary and recommendations appear in the American Journal of Medicine
This article includes evidence-based, up-to-date information about the shift away from a time-based definition to an ischemic tissue-based approach (reversible tissue damage) in diagnosing TIA, underscoring the increasing importance of brain imaging modalities with CT or MRI in the evaluation of TIA-like symptoms. Primary care doctors are also encouraged to use validated risk calculators like the ABCD2 score to estimate the risk of stroke following a TIA.
The best management, the authors advise, is prevention. They advocate compliance with anti-platelet or anti-coagulation therapy, rigorous management of cardiac risk factors like hypertension and diabetes, as well as lifestyle modification like smoking and alcohol cessation.
Emergency Medical Service (EMS) responders felt better prepared to respond to an active shooter incident after receiving focused tactical training according to a new study in the journal Prehospital and Disaster Medicine. This is the first study to specifically examine the EMS provider comfort level with respect to entering a scene where a shooter has not yet been neutralized or working with law enforcement personnel during that response.
Incidents such as the Columbine High School shooting, the Virginia Tech campus shooting, the 2009 Fort Hood shooting, the movie theater shooting in Aurora, Colorado, and more recently, the Sandy Hook elementary school shooting remind us of the relative frequency of these events compared to most other mass casualty incidents for which EMS trains and prepares.
For this study, EMS providers responded to an anonymous survey both before and after a four-hour training session on joint EMS/police active shooter rescue team response. Survey questions focused on individual provider comfort level when responding to active shooter incidents compared to conventional HAZMAT incidents; comfort with providing medical care in an active shooter environment; perception of EMS provider role in an active shooter incident; and the appropriate timing of EMS response at the scene.
The survey results showed that more participants felt adequately trained to respond to an active shooter incident after focused training (87 percent) compared to before the training (36 percent) regardless of a providers prior tactical experience. Additionally, more EMS providers felt more comfortable working jointly on rescue operations with law enforcement personnel in response to an active shooter incident after training participation (93 percent) compared to before the training (61 percent).
According to the researchers, despite rapid deployment of law enforcement to neutralize an active shooter, it is not uncommon for a significant amount of time to pass before law enforcement has rendered the scene “safe.” “Unfortunately this unintentionally prolongs the time before victims can receive life-saving care on the scene, as well as at a definitive care facility,” explained lead author Jerrilyn Jones, MD, a clinical instructor of emergency medicine at Boston University School of Medicine and EMS Fellow at Boston EMS. “Our study showed that after receiving appropriate training, EMS providers felt better equipped to work on joint rescue operations even if an active shooter was still present,” added Jones, who also is an emergency room physician at Boston Medical Center.
The researchers recommend further studies be undertaken to determine the significance of such training as well as the mortality impact on patient outcomes.
The American Society for Bone and Mineral Research awarded Michael F. Holick, PhD, MD, of Boston University School of Medicine (BUSM), with the 2014 Louis V. Avioli Award. Holick, a professor of medicine, physiology and biophysics at BUSM, is internationally known for revolutionizing the understanding of vitamin D and its role in disease prevention.
The award honors a member of the American Society for Bone and Mineral Research (ASBMR) for fundamental contributions to bone and mineral basic research. It is named for ASBMR’s first president and founding member, Louis Avioli, MD, who was one of the world’s leading medical authorities on osteoporosis and calcium metabolism. Holick will be recognized at the ASBMR Annual Meeting in September by the society’s president, Roberto Civitelli, MD.
“I am honored to receive this award named for my very close friend and trusted colleague,” said Holick. “I collaborated with Louis on multiple occasions, and he provided samples of blood from his patients that I used to identify, for the first time, 25-hydroxyvitamin D3 in human blood. This discovery led me to receiving a masters’ degree in biochemistry.”
Holick has revolutionized the field of vitamin D research with the identification of 1,25-dihydroxyvitamin D3, for which he received his PhD degree, which led to therapies for metabolic bone diseases, hypocalcemic disorders and psoriasis. His work raised awareness of the vitamin D deficiency epidemic and its role in causing metabolic bone disease and osteoporosis and increasing the risk of autoimmune diseases, type 2 diabetes, infectious diseases, heart disease and common deadly cancers. He has helped develop guidelines for the prevention and treatment of vitamin D deficiency with vitamin D supplementation and sensible sun exposure.
The author of more than 500 publications, Holick received his doctorate in biochemistry and attended medical school at the University of Wisconsin before completing a residency in medicine at Massachusetts General Hospital.
Sachs, who is board certified by the American Board of Surgery, was named assistant professor of surgery at BUSM and an attending surgeon in the section of surgical oncology at BMC.
After receiving his medical degree from New York Medical College, Sachs completed a residency in general surgery at Beth Israel Deaconess Medical Center and a fellowship in surgical oncology at Johns Hopkins Hospital in Baltimore, MD. His clinical interests include alimentary tract surgery with a special focus in hepatic and pancreatobiliary disease. He attained a Masters of Public Health in clinical effectiveness and his research pertains to surgical outcomes and education.
Siracuse, board certified by the American Board of Surgery, is also taking on the role of assistant professor of surgery and assistant professor of radiology at BUSM and an attending surgeon in the division of vascular and endovascular surgery at BMC.
He received his medical degree from New York Medical College and completed his residency in general surgery at Beth Israel Deaconess Medical Center. Siracuse completed a research fellowship in the Harvard-Longwood Vascular Research Training Program and a clinical fellowship in vascular and endovascular surgery at New York-Presbyterian Hospital/Columbia University College of Physicians and Surgeons and Weill Cornell Medical College. His research and clinical interests include minimally invasive and open treatment of aortic aneurysms, critical limb ischemia, cerebrovascular disease, dialysis access, thoracic outlet syndrome and venous disease.
At a ceremony to honor John Noble, MD, BUSM professor of general internal medicine and Ewa Kuligowska-Noble, MD, BUSM professor of radiology, they stand in front of the bookcase that houses the collection of rare books assembled by Noble and donated by the couple to the BUSM Alumni Library.
“We are here today to celebrate two leadership careers at Boston University in radiology and medicine,” said Dean Karen Antman, MD. “We thank them for making this collection of rare and important titles available to our medical and graduate students to read from the original texts, realizing their historical context.”
The gift is a collection of unique and historical medical books from the Noble’s personal medical library. John Noble carefully selected these books during 35 years of service at BUSM. The collection includes rare Vesalius volumes, many works by and about William Osler, books on infectious diseases such as smallpox from the 1700s, books published as early as the 1500s, and textbooks edited by John Noble himself.
“The smartest thing we ever did was to come to Boston University, working with such a variety of people and caring for some of the most difficult patients,” said John Noble. “It has been a wonderful place to spend our lives. We are pleased to have this collection here in the Alumni Medical Library to give present and future generations the opportunity to see things from perspectives that are no longer easy to attain.”
It is important to John Noble that the books be placed in a highly visible location in the library, rather than stored in a locked archives room where they would not be seen and enjoyed. Both he and his wife have expressed hope that their donation might inspire other physicians or faculty to donate additional materials, thus potentially helping to build an even more robust collection of historical medical texts.
“Building such an inspiring collection requires knowledge, passion and commitment,” said Mary Blanchard, director of the Alumni Medical Library. “This valuable collection sets a foundation and brings perspective to the entire BU medical campus community. We are deeply grateful to Dr. Noble and Dr. Kuligowska-Noble.”
Practices used in policing injection drug users in Russia might contribute to HIV transmission and overdose mortality.
A study, conducted by researchers from Boston University Schools of Medicine and Public Health, in collaboration with St. Petersburg Pavlov State University, sought to discover the effect police arrests had on the health outcomes of a cohort of HIV-positive people with lifetime of injection drug use.
Those who were arrested by police were more likely to share needles—increasing HIV transmission—and to overdose, according to the study published in the Journal of the International AIDS Society. Their research also found no indication that police arrests reduce drug use.
“We already know that addressing individual risk behaviors is important in reducing HIV transmission among people who use drugs, who are most at risk for HIV infection,” said lead author Karsten Lunze, MD, MPH, DrPH, a BUSM assistant professor of medicine. “Our study adds that drug laws and policies, and the way they are enforced, are also important to prevent the spread of HIV.”
By linking the impact of police tactics with health outcomes of injection drug users, the researchers identified the need to create prevention programs for modifying individual behaviors and to address policing practices as part of the HIV risk environment.
“Instead of arresting people who use drugs, there should be more of a focus on facilitating access to treatment,” said Jeffrey Samet, MD, MA, MPH, a professor of medicine and community health sciences at BUSM and BUSPH who also led the study. “Public health and public safety working together can help address the increasing problem of HIV among people who use drugs.”
Further research needs to relate these findings to the operational environment of law enforcement and to understand how police interventions among injection drug users can improve, rather than worsen, the HIV risk environment, the researchers said.
The full text of the study: Punitive policing and associated substance use risks among HIV-positive people in Russia who inject drugs.
Boston University School of Medicine (BUSM) received major funding from the National Institute on Aging (NIA) as part of a national effort to identify rare genetic variants that may protect against and contribute to Alzheimer’s disease risk.
The four-year, $3 million grant, “Identifying Risk and Protective Variants for AD Exploring their Significance and Biology” is led by Sudha Seshadri, MD, professor of neurology at BUSM and a Senior Investigator at the Framingham Heart Study and for the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. This project is linked to CHARGE projects at two other universities which all together received grants totaling more than $10 million. Other BU investigators who are part of the CHARGE project are Anita DeStefano, PhD, Adrienne Cupples, PhD, and Josee Dupuis, PhD, who are professors of biostatistics, and Honghuang Lin, PhD, assistant professor of medicine.
“As a neurologist treating patients with Alzheimer’s disease, it is very exciting to see the increased recognition, at a national level, of the need to find more effective preventive and therapeutic measures,” said Seshadri.
Alzheimer’s disease, a progressive neurodegenerative disorder, has become an epidemic that currently affects 5.2 million people in the United States with economic costs that are higher than those of heart disease or cancer. Available drugs only marginally affect disease severity and progression. While there is no way to prevent this devastating disease, the discovery of genetic risk factors for Alzheimer’s is bringing researchers closer to learning how the genes work together and to identifying the most effective intervention for the disease.
Genetics is a cornerstone of identifying targets for Alzheimer’s disease therapies. This movement began in 2011, when President Barack Obama signed into law the National Alzheimer’s Project Act (NAPA), mandating support for Alzheimer’s research and health and long-term care services for affected individuals across all federal agencies. One of the first projects mandated by NAPA was the Alzheimer’s Disease Sequencing Project (ADSP). With this funding, CHARGE becomes a member of the National Institute of Aging-mandated Sequence Analysis Consortium, which also includes three National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Centers.
CHARGE investigators will analyze whole exome and whole genome sequence data generated from 6,000 subjects with Alzheimer’s disease and 5,000 elderly individuals who do not have Alzheimer’s disease. They also will study data from approximately 100 large families, mostly of Caribbean and Hispanic descent, that include multiple individuals with Alzheimer’s disease to identify rare genetic variants that either protect against or cause Alzheimer’s disease. They will also be contributing additional CHARGE data from over 11,000 subjects with information on genetic sequence and AD-related traits.
“AD currently has no effective treatment thus prevention is the primary strategy to combat this disease,” said Boston University School of Medicine Dean Karen Antman, MD. “This is an exciting opportunity for our faculty to develop novel approaches that might ultimately delay or prevent AD.”
CHARGE is a collaboration of an international group of investigators. Eric Boerwinkle, PhD at the University of Texas, Houston and Baylor College of Medicine and Ellen Wijsman, PhD at the University of Washington will lead other funded CHARGE projects. Cornelia van Duijn, PhD who is a consultant on behalf of Erasmus University in the Netherlands.
This research at Boston University is supported by the National Institute on Aging grants U01-AG049505.