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News Article | May 8, 2017
Site: www.eurekalert.org

New research from Boston Children's Hospital and Beth Israel Deaconess Medical Center (BIDMC) shows that chronic sleep loss increases pain sensitivity. It suggests that chronic pain sufferers can get relief by getting more sleep, or, short of that, taking medications to promote wakefulness such as caffeine. Both approaches performed better than standard analgesics in a rigorous study in mice, described in the May 8, 2017 issue of Nature Medicine. Pain physiologist Alban Latremoliere, PhD, of Boston Children's and sleep physiologist Chloe Alexandre, PhD, of BIDMC precisely measured the effects of acute or chronic sleep loss on sleepiness and sensitivity to both painful and non-painful stimuli. They then tested standard pain medications, like ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil. Their findings reveal an unexpected role for alertness in setting pain sensitivity. The team started by measuring normal sleep cycles, using tiny headsets that took electroencephalography (EEG) and electromyography (EMG) readings. "For each mouse, we have exact baseline data on how much they sleep and what their sensory sensitivity is," says Latremoliere, who works in the lab of Clifford Woolf, PhD, in the F.M. Kirby Neurobiology Center at Boston Children's. Next, unlike other sleep studies that force mice to stay awake walking treadmills or falling from platforms, Alexandre, Latremoliere and colleagues deprived mice of sleep in a way that mimics what happens with people: They entertained them. "We developed a protocol to chronically sleep-deprive mice in a non-stressful manner, by providing them with toys and activities at the time they were supposed to go to sleep, thereby extending the wake period," says Alexandre, who works in the lab of Thomas Scammell, MD, at BIDMC. "This is similar to what most of us do when we stay awake a little bit too much watching late-night TV each weekday." To keep the mice awake, researchers kept vigil, providing the mice with custom-made toys as interest flagged while being careful not to overstimulate them. "Mice love nesting, so when they started to get sleepy (as seen by their EEG/EMG pattern) we would give them nesting materials like a wipe or cotton ball," says Latremoliere. "Rodents also like chewing, so we introduced a lot of activities based around chewing, for example, having to chew through something to get to a cotton ball." In this way, they kept groups of six to 12 mice awake for as long as 12 hours in one session, or six hours for five consecutive days, monitoring sleepiness and stress hormones (to make sure they weren't stressed) and testing for pain along the way. Pain sensitivity was measured in a blinded fashion by exposing mice to controlled amounts of heat, cold, pressure or capsaicin (the agent in hot chili peppers) and then measuring how long it took the animal to move away (or lick away the discomfort caused by capsaicin). The researchers also tested responses to non-painful stimuli, such as jumping when startled by a sudden loud sound. "We found that five consecutive days of moderate sleep deprivation can significantly exacerbate pain sensitivity over time in otherwise healthy mice," says Alexandre. "The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli." Surprisingly, common analgesics like ibuprofen did not block sleep-loss-induced pain hypersensitivity. Even morphine lost most of its efficacy in sleep-deprived mice. These observations suggest that patients using these drugs for pain relief might have to increase their dose to compensate for lost efficacy due to sleep loss, thereby increasing their risk for side effects. In contrast, both caffeine and modafinil, drugs used to promote wakefulness, successfully blocked the pain hypersensitivity caused by both acute and chronic sleep loss. Interestingly, in non-sleep-deprived mice, these compounds had no analgesic properties. "This represents a new kind of analgesic that hadn't been considered before, one that depends on the biological state of the animal," says Woolf, director of the Kirby Center at Boston Children's. "Such drugs could help disrupt the chronic pain cycle, in which pain disrupts sleep, which then promotes pain, which further disrupts sleep." The researchers conclude that rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits or sleep-promoting medications at night, coupled with daytime alertness-promoting agents to try to break the pain cycle. Some painkillers already include caffeine as an ingredient, although its mechanism of action isn't yet known. Both caffeine and modafinil boost dopamine circuits in the brain, so that may provide a clue. "This work was supported by a novel NIH program that required a pain scientist to join a non-pain scientist to tackle a completely new area of research," notes Scammel, professor of neurology at BIDMC. "This cross-disciplinary collaboration enabled our labs to discover unsuspected links between sleep and pain with actionable clinical implications for improving pain management." "Many patients with chronic pain suffer from poor sleep and daytime fatigue, and some pain medications themselves can contribute to these co-morbidities," notes Kiran Maski, MD, a specialist in sleep disorders at Boston Children's. "This study suggests a novel approach to pain management that would be relatively easy to implement in clinical care. Clinical research is needed to understand what sleep duration is required and to test the efficacy of wake-promoting medications in chronic pain patients." Alexandre (BIDMC) and Latremoliere (Boston Children's) were co-first authors on the paper. Woolf (Boston Children's) and Scammell (BIDMC) were co-senior authors. Ashley Ferreira and Giulia Miracca of Boston Children's and Mihoko Yamamoto of BIDMC were coauthors. This work was supported by grants from the NIH (R01DE022912, R01NS038253). The Neurodevelopmental Behavior and Pharmacokinetics Cores at Boston Children's Hospital, the metabolic Physiology Core at BIDMC (P30DK057521) and P01HL09491 also supported this study. Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 404-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the primary pediatric teaching affiliate of Harvard Medical School. For more, visit our Vector and Thriving blogs and follow us on our social media channels @BostonChildrens, @BCH_Innovation, Facebook and YouTube. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | February 21, 2017
Site: www.eurekalert.org

In less than one year, researchers have developed multiple vaccine platforms that provide robust protection against Zika virus challenge in animal models BOSTON - As public health officials warn that spring's warmer temperatures may herald another increase of Zika virus infections in the Caribbean and North and South America, researchers around the world are racing to develop safe and effective measures to prevent the disease. In a review paper published today in the journal Immunity, a group of leading vaccine scientists -- including Dan H. Barouch, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) -- outline advances in the hunt for a Zika vaccine and the challenges that still lie ahead. "The pace of preclinical and early clinical development for Zika vaccines is unprecedented," said Barouch, corresponding author and director of the Center for Virology and Vaccine Research at BIDMC. "In less than a year, our group and others have demonstrated that multiple vaccine platforms can provide robust protection against Zika virus challenge in animal models. However, unique challenges will need to be addressed in the clinical development of a Zika vaccine. " The recent outbreak of the Zika virus in the Americas began in Brazil nearly two years ago. By February 2016, the World Health Organization had declared the epidemic a global public health emergency, based largely on the virus' newly-established link to microcephaly and other major birth defects in babies born to infected mothers. The virus has also been associated with the neurologic disorder Guillain-Barré syndrome in adults. In a previously published paper, Barouch and colleagues, including Colonel Nelson L. Michael, MD, PhD, director of the Military HIV Research Program at the Walter Reed Army Institute of Research (WRAIR) and Stephen Thomas, MD, Upstate Medical University, State University of New York, demonstrated that three different vaccine candidates provided robust protection against Zika virus in both mice and rhesus monkeys. Several human clinical trials began last fall at test sites including BIDMC, WRAIR, and National Institute of Allergy and Infectious Diseases affiliated clinical trial sites. "The rapid advancement of Zika vaccine candidates into clinical trials reflects the uniquely focused and effective collaboration among scientists in the field to address this important global problem," said Barouch. Despite the accelerated pace of research, much remains unknown about the virus, raising unique challenges in developing a vaccine. Safety considerations are especially critical, given that the target population for a Zika vaccine would likely include men and women of childbearing age. Zika is a member of the flavivirus family of viruses, which includes West Nile virus, yellow fever virus, and dengue viruses, for which successful vaccines have been developed. Studies suggest that Zika-induced antibody responses may also cross-react with other flaviviruses, particularly dengue virus. Whether or not this antibody cross-reactivity may have clinical consequences is another consideration for Zika vaccines and requires further study. Co-authors include: Stephen J. Thomas, MD, Upstate Medical University, State University of New York, Syracuse; and Colonel Nelson L. Michael, MD, PhD, director, Military HIV Research Program, at Walter Reed Army Institute of Research (WRAIR). The review's authors acknowledge support from the U.S. Military Research and Material Command and the U.S. Military HIV Research Program; the National Institutes of Health (AI095985, AI096040, AI100663, AI124377); and the Ragon Institute of MGH, MIT, and Harvard. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | February 17, 2017
Site: www.eurekalert.org

BOSTON - A new study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) has found that lower levels of vitamin D in the blood increase the risk of clinical relapse in patients with Ulcerative Colitis (UC), an inflammatory bowel disease that causes long-lasting inflammation and ulcers in the colon. The study was published in the February issue of the journal Clinical Gastroenterology and Hepatology. Lower vitamin D levels have been associated with active disease in patients with UC, but it has been unknown whether they increase disease relapses. "Prior studies in patients with Crohn's disease and Ulcerative Colitis had linked low vitamin D levels to disease flare-ups," said senior author Alan Moss, MD, a gastroenterologist at the Digestive Disease Center at BIDMC and Associate Professor of Medicine at Harvard Medical School. "However, it has been unclear if the flare-up was lowering vitamin D levels, or if low vitamin D levels were causing the flare-up. We thought that if we looked at vitamin D levels when the disease was inactive and then followed patients moving forward, the impact of baseline vitamin D levels on future events may be clearer." Moss and colleagues collected vitamin D serum levels through a physician-blinded prospective study of 70 patients with UC in clinical remission who were followed up after a surveillance colonoscopy at BIDMC. The study measured vitamin D levels in blood samples and levels of inflammation through blood tests and biopsies. The researchers then followed the patients for 12 months and compared the data from participating patients who remained well and the others who experienced relapses. The investigators found the mean baseline vitamin D level to be lower in patients who later relapsed than those who did not. "Patients who had higher vitamin D levels when their disease was in remission were less likely to experience a relapse in the future," said John Gubatan, MD, a physician at BIDMC and first author of the study. "This suggests that higher vitamin D levels may play some role in preventing the UC relapse." The threshold level of blood vitamin D that was protective was greater than 35ng/ml, which is within the range recommended by the National Institutes of Health for a healthy individual. Ongoing work by Gubatan and Moss is now examining the link between vitamin D and a protein called cathelicidin in the cells lining the colon. The link may have beneficial effects on microbial composition, an important component of a healthy colon. Building on this research, investigators are trying to unravel how vitamin D may protect cells in the colon and the microbial composition of the bacteria, fungi, protozoa and viruses that live on and inside the human body, Moss noted. In addition to Moss and Gubatan, the study was performed at BIDMC by authors Shuji Mitsuhashi, Talia Zenlea, MD, Laura Rosenberg, MD, and Simon Robson, MB, ChB, FRCP, PhD. This work was supported by grants from the National Institutes of Health (K23DK084338) and a Rabb Research Award (ACM). Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | November 1, 2016
Site: www.eurekalert.org

(Boston)--Implanted medical devices such as left ventricular-assist devices for patients with heart failure or other support systems for patients with respiratory, liver or other end organ disease save lives every day. However, bacteria that form infectious biofilms on those devices, called device-associated infections, not only often sabotage their success but also contribute to the rampant increase in antibiotic resistance currently seen in hospitals. As reported in Biomaterials, a team led by Joanna Aizenberg, Ph.D., and Elliot Chaikof, M.D., Ph.D., at the Wyss Institute for Biologically Inspired Engineering and the Harvard John A. Paulson School of Engineering and Applied Sciences at Harvard University (SEAS), as well as the Beth Israel Deaconess Medical Center (BIDMC), has created self-healing slippery surface coatings with medical-grade teflon materials and liquids that prevent biofilm formation on medical implants while preserving normal innate immune responses against pathogenic bacteria. The technology is based on the concept of 'slippery liquid-infused porous surfaces' (SLIPS) developed by Aizenberg, who is a Wyss Institute Core Faculty member, Professor of Chemistry and Chemical Biology and the Amy Smith Berylson Professor of Materials Science at SEAS. Inspired by the carnivorous Nepenthes pitcher plant, which uses the porous surface of its leaves to immobilize a layer of liquid water, creating a slippery surface for capturing insects, Aizenberg previously engineered industrial and medical surface coatings that are able to repel unwanted substances as diverse as ice, crude oil and biological materials. "We are developing SLIPS recipes for a variety of medical applications by working with different medical-grade materials, tuning the chemical and physical features of these solids and the infused lubricants to ensure the stability of the coating, and carefully pairing the non-fouling properties of the integrated SLIPS materials to specific disturbing factors, contaminating environments and performance requirements," said Aizenberg. "Here we have extended our repertoire of materials classes and applied the SLIPS concept very convincingly to medical-grade teflon, demonstrating its enormous potential in implanted devices prone to bacterial fouling and infection." First, the team searched ex vivo for the teflon material that would work best with a selection of compatible lubricants to provide a long-lived repellent surface against a common device-associated bacterial strain. The most advantageous teflon-lubricant combinations had to preserve the anti-bacterial activity of innate immune cells that provide the natural first-line response against invading bacteria. The winning material was 'expanded polytetrafluoroethylene' (ePTFE). Used in prosthetic grafts for cardiovascular reconstruction, mesh for hernia repair, as well as implants in a wide variety of reconstructive surgery, ePTFE tested well with lubricants with proven acceptable safety profiles. Moving to a rodent model, the team compared bacterial and tissue responses to implanted hernia meshes with or without a SLIPS surface after infecting the animals with Staphylococcus aureus. "SLIPS coatings yielded extremely favorable responses in vivo: they resisted infection by bacteria and were associated with considerably less infiltrating immune cells and inflammatory abscesses than non-coated ePTFE," said Chaikof, who is a Wyss Institute Associate Faculty member, Chairman of the Roberta and Stephen R. Weiner Department of Surgery and Surgeon-in-Chief at BIDMC. "At present, patients who receive implants for the repair, reconstruction or replacement of diseased or damaged organs or tissues or otherwise depend upon temporary life sustaining support systems, often require antibiotics at the time of implantation to keep the risk of bacterial infection at bay. SLIPS coatings one day could obviate the widespread use of antibiotics, minimize the development of antibiotic resistant microorganisms, and enhance the capacity of temporary or permanent artificial devices to resist infection," said Chaikof. "This new study by Joanna and Elliot exemplifies the Wyss Institute model in which collaborations between basic scientists focused on industrial applications and clinicians working in the medical area are fostered in a way that can lead to unexpected developments -- in this case, one that has the potential to have a major positive impact in the clinical setting," said Don Ingber, M.D., Ph.D., Founding Director of the Wyss Institute, Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at SEAS. Previous medical SLIPS applications include coatings that can repel bacteria and blood from small medical implants, tools and surgical instruments that are made of steel or, more recently, coatings that help keep the glass surfaces of endoscopy and bronchoscopy lenses free from highly contaminating body fluids and thus transparent during procedures. The Wyss Institute for Biologically Inspired Engineering at Harvard University uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité - Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology. The Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and The Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. The Harvard John A. Paulson School of Engineering and Applied Sciences serves as the connector and integrator of Harvard's teaching and research efforts in engineering, applied sciences, and technology. Through collaboration with researchers from all parts of Harvard, other universities, and corporate and foundational partners, we bring discovery and innovation directly to bear on improving human life and society.


The International Association of HealthCare Professionals is pleased to welcome James T. McGlowan Jr., MD, FAAOS, Orthopedic Surgeon, to their prestigious organization with his upcoming publication in The Leading Physicians of the World. Dr. James T. McGlowan Jr. is a highly trained and qualified orthopedic surgeon with an extensive expertise in all facets of his work, especially sports medicine. Dr. McGlowan Jr. has been in practice for more than 16 years and is currently serving patients within his own private practice, Arthroscopy Sports Medicine & Minimally Invasive Associates, with several locations in Massachusetts. He is also affiliated with Beth Israel Deaconess Hospital, Boston Out-Patient Surgical Suites, Steward Carney Hospital, and Steward Norwood Hospital. Dr. McGlowan, Jr. graduated with his Medical Degree in 1992 from the University of Tennessee School of Medicine. Following his graduation, he subsequently completed his General Surgery residency at New York University Medical Center, followed by his fellowship training at Kingsbrook Jewish Medical Center. Dr. McGlowan, Jr. then undertook his Orthopedic residency training and Research fellowship at SUNY at Buffalo School of Medicine and Biomedical Sciences, before completing his Orthopaedic Sports Medicine fellowship at the University of Massachusetts. Furthermore, he served a fellowship in Arthroscopy and Sport Medicine with the Boston Red Sox. Dr. McGlowan Jr. is certified by and Diplomat of the American Board of Orthopedic Surgery, and has earned the coveted title of Fellow of the American Academy of Orthopedic Surgeons, Fellow of the American Association of Orthopedic Surgeons. An inductee of Alpha Epsilon Delta, Beta Beta Beta, and Sigma Tau Delta, Dr. McGlowan Jr.  keeps up to date with the latest advances in his field by maintaining a professional membership with the Arthroscopic Association of North America and the American Orthopedic Society for Sports Medicine. For his wealth of experience and knowledge, Dr. McGlowan Jr. is the recipient of numerous awards and recognitions, and has participated in several presentations. In the past 16 years, he has performed over 6,000 successful arthroscopic joint procedures, 2000 reconstructive fracture procedures and 1,300 hip, knee and shoulder replacements. Dr. McGlowan performs minimally invasive hip, knee, and shoulder replacements. He also performs robotic patella femoral and partial knee replacements. Dr. McGlowan performs complex arthroscopic reconstruction surgery of the knee, shoulder, elbow and ankle. He has treated over 100 Division 1 athletes and athletes on scholarships post reconstructive surgery. He attributes his success to Jesus Christ, his parents, and his family. In his free time, Dr. McGlowan enjoys weight lifting, running, and volunteering in schools taking care of athletes. Learn more about Dr. McGlowan Jr. here: http://jamestmcglowanmd.com/ and be sure to read his upcoming publication in The Leading Physicians of the World. FindaTopDoc.com is a hub for all things medicine, featuring detailed descriptions of medical professionals across all areas of expertise, and information on thousands of healthcare topics. Each month, millions of patients use FindaTopDoc to find a doctor nearby and instantly book an appointment online or create a review.  FindaTopDoc.com features each doctor’s full professional biography highlighting their achievements, experience, patient reviews and areas of expertise.  A leading provider of valuable health information that helps empower patient and doctor alike, FindaTopDoc enables readers to live a happier and healthier life.  For more information about FindaTopDoc, visit http://www.findatopdoc.com


News Article | December 26, 2016
Site: www.eurekalert.org

BOSTON - Scientific research over the past decade has concentrated almost exclusively on the 2 percent of the genome's protein coding regions, virtually ignoring the other 98 percent, a vast universe of non-coding genetic material previously dismissed as nothing more than 'junk.' Now, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) reveals that one type -- called long non-coding RNA (lncRNA) -- may be critically important for controlling cellular components in a tissue-specific manner. Published online today in the journal Nature, the new research points to an lncRNA's key role in helping control processes related to muscle regeneration and cancer. Long non-coding RNAs appear to be transcribed from our DNA in a similar manner to coding messenger RNAs but are not translated into proteins. While lncRNA molecules do not produce correspondingly lengthy proteins, researchers have wondered whether some of these molecules may contain segments of sequences that can code for very short proteins, or polypeptides. "Whether such small, hidden polypeptides are actually functional, or represent 'translational noise' within the cell is still relatively unclear," said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. "Our team set about trying to understand to what extent lncRNA molecules might actually encode functional polypeptides, and how important such peptides might be." The investigators used computational analyses to predict potential polypeptides that could be encoded by known lncRNA molecules, and then they used mass spectrometry to determine if these putative polypeptides were actually expressed. "With this approach we actually identified many expressed hidden polypeptides and went on to characterize one in particular," Pandolfi explained. This specific lncRNA molecule is termed LINC00961 and encodes a 90 amino acid polypeptide. A variety of molecular and biochemical experiments revealed that the LINC00961 encoded polypeptide played an important role in modulating the activity of the mTORC1 protein complex, which is a critical sensor of nutrient availability within cells. The complex also regulates a variety of cellular processes including translation, metabolism, cell growth, and proliferation, and alterations in its function can lead to diseases such as cancer. Because the LINC00961 polypeptide appeared to specifically block mTORC1's ability to sense stimulation with amino acids, the investigators named the peptide encoded by the lncRNA SPAR (Small regulatory Polypeptide of Amino acid Response). Pandolfi and his team found that the SPAR encoding lncRNA is highly expressed in a number of tissue types, including muscle. Experiments conducted in mice demonstrated that through its effects on mTORC1, the SPAR polypeptide helps regulate the muscle's ability to regenerate and repair after injury. Specifically, expression of LINC00961 is blocked following muscle injury in mice, leading to reduced levels of SPAR and maximal mTORC1 activity to promote tissue regeneration. "The experimental approach we used allowed us to eliminate expression of the SPAR polypeptide, while maintaining expression of the host lncRNA," said lead author Akinobu Matsumoto, PhD, research fellow at the Cancer Center at BIDMC and lead author of the study. "We are able to ascribe this function to the coding function of the lncRNA rather than any non-coding function it may also have." The findings suggest that therapeutic strategies that restrict expression of SPAR in injured muscle may promote a more rapid regeneration of tissue. The results suggest that lncRNAs may have diverse roles and functions. Although they may not code for large proteins, lncRNAs may produce small polypeptides that can fine tune the activity of critical cellular components. The findings also expand the repertoire of peptide-coding genes in the human genome that should be studied and annotated. The study also provides insights on how mTORC1 activity may be attuned to meet the distinct needs of a specific tissue. "An ability to target such modulators could be of great advantage from a therapeutic perspective, allowing for control of mTORC1 activity in cells or tissues that express such modulators while not affecting its activity and function in other tissue and cell types," explained co-author John Clohessy, PhD, Instructor in Medicine at BIDMC and a senior member of Pandolfi's research team. Indeed, a key feature of many lncRNAs is that their expression is often highly tissue-specific. Thus, targeting small polypeptides encoded by lncRNA molecules may provide the key to regulating common cellular components in a tissue-specific manner. Because the mTORC1 complex is frequently deregulated in conditions such as cancer, the research team is now seeking to determine if SPAR can influence additional cellular functions of mTORC1 that might be involved in different diseases. "We are very excited about this discovery," said Pandolfi. "It represents a new and startling mechanism by which important sensory pathways can be regulated within cells, and we believe it will have important implications for how we approach the design of therapies and treatments in the future." Study coauthors include BIDMC investigators Akinobu Matsumoto, Alessandra Pasut, Jacqueline Fung, Emanuele Monteleone, and John G. Clohessy. Other co-investigators include Masaki Matsumoto and Keiichi I. Nakayama of Kyushu University, Riu Yamashita of Tohoku University, and Alan Saghatelian of the Salk Institute for Biological Studies. This work was supported in part by the National Institutes of Health grants R01 CA082328 and R35 CA197529. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | December 19, 2016
Site: www.eurekalert.org

BOSTON - Neuroscientists at Beth Israel Deaconess Medical Center (BIDMC) have mapped the brain injuries - or lesions - that result in delusional misidentification syndromes (DMS), a group of rare disorders that leaves patients convinced people and places aren't really as they seem. In a study published in the journal Brain, Michael D. Fox, MD, PhD, Director of the Laboratory for Brain Network Imaging and Modulation and the Associate Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC and colleagues reveal the neuro-anatomy underlying these syndromes for the first time. "How the brain generates complex symptoms like this has long been a mystery," said Fox. "We showed how complex symptoms can emerge based on brain connectivity. With a lesion in exactly the right place, you can disrupt the brain's familiarity detector and reality monitor simultaneously, resulting in bizarre delusions. Understanding where these symptoms come from is an important step toward treating them." Delusional misidentification syndromes are among the most striking and least understood disorders encountered in neurology and psychiatry. First documented nearly a century ago, Capgras syndrome is a rare disorder in which patients recognize a family member while simultaneously experiencing that person as unfamiliar, leading to the conclusion that an imposter is impersonating their loved one. Conversely, the Fregoli delusion is the belief that strangers are actually loved ones in disguise. Misidentification delusions can also apply to pets and places. Fox and colleagues, including lead author R. Ryan Darby, MD, the Sidney R. Baer, Jr. Foundational Fellow in the Clinical Neurosciences at the Berenson-Allen Center at BIDMC, identified 17 patients with delusional misidentification syndromes and mapped them onto a standardized brain atlas. Then, using the lesion network mapping technique they recently developed, Darby and colleagues determined that all 17 lesions were functionally connected to an area of the brain called the retrosplenial cortex - thought to be involved in perceiving familiarity. Sixteen of the 17 lesions were also connected to a region in the right ventral frontal cortex, associated with belief evaluation. The scientists compared the data to 15 control brain injuries that led to delusions other than misidentification delusions. "Lesions causing all types of delusions were connected to belief violation regions, suggesting that these regions are involved in monitoring for delusional beliefs in general," Darby said. "However, only lesions causing delusional misidentifications were connected to familiarity regions, explaining the specific bizarre content - abnormal feelings of familiarity - in these delusions. In other words, lesions had to be connected to both regions to develop delusions like Capgras." The scientists note that their network mapping technique does not involve obtaining functional neuroimaging (fMRI) from the patients studied. Rather, data from normal patients determines which regions of the brain are normally connected to the mapped lesion locations. While this methodology carries several advantages, it does not prove these two regions are dysfunctional in delusional patients following the lesion. Doing so would require recruiting a large number of patients with the rare disorder to a follow up study, noted Darby. However, the new information gleaned from their study may help patients' families cope with a loved one's misidentification delusions -- which sometimes disappear as mysteriously as they come on. "The impact on the patient's family can be heart-breaking," said Darby. "I've seen patients who, thinking their homes were replicas, would pack their bags every night, hoping to return to their 'real' home. Patients who believe a spouse is an imposter often lose intimacy. In these cases, even just knowing that the delusion has a name and is part of a neurological disorder can be helpful for family members." Study coauthors include Simon Laganiere, MD, and Alvaro Pascual-Leone, MD, PhD, of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC; and Sashank Prasad, MD, of the Department of Neurology at Brigham and Women's Hospital. This work was supported by funding from the Sidney R. Baer, Jr. Foundation; grants from the National Institutes of Health (R01HD069776, R01NS073601, R21 NS082870, R21 MH099196, R21 NS085491, R21 HD07616, R25NS065743, K23NS083741); the Football Players Health Study at Harvard University; Harvard Catalyst | The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH, UL1 RR025758), and the American Brain Foundation. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | November 14, 2016
Site: www.eurekalert.org

BOSTON - A new study led by clinician-researchers at Beth Israel Deaconess Medical Center (BIDMC) testing the safety and effectiveness of anticoagulant strategies for patients with atrial fibrillation who undergo stenting procedures has shown that therapies combining the anticoagulant drug rivaroxaban with either single or dual anti-platelet therapy (DAPT) were more effective in preventing bleeding complications than the current standard of care. Principal Investigator C. Michael Gibson, MD, Chief of Clinical Research in the Division of Cardiovascular Medicine at BIDMC, reported the new research findings today online in The New England Journal of Medicine and simultaneously presented the findings at the American Heart Association's Scientific Sessions 2016 in New Orleans. The PIONEER AF-PCI randomized clinical trial involved more than 2,100 patients at 430 sites in 26 countries. Each year, nearly 1 million patients in the United States undergo percutaneous coronary intervention (PCI) and are implanted with stents positioned to treat narrowed coronary arteries. Following PCI, patients receive dual anti-platelet therapy - a combination of aspirin and a second blood-thinning medication - to prevent the formation of blood clots in the stent. Approximately 5 to 8 percent of patients undergoing PCI have atrial fibrillation, the most common type of cardiac arrhythmia and an important risk factor for stroke. These patients typically take a blood thinner, such as warfarin (Coumadin), to prevent stroke. "In managing the stented patient with atrial fibrillation, a pharmacologic strategy must carefully balance the risk of stent thrombosis, or blood clot, with the risk of bleeding complications," said Gibson, who is also Professor of Medicine at Harvard Medical School and chairman of the PERFUSE (Percutaneous/Pharmacologic Endoluminal Revascularization for Unstable Syndromes Evaluation) Study Group. "This trial, which tested two entirely new strategies, now provides us with randomized clinical trial data demonstrating that a combination of rivaroxaban with anti-platelet therapy is successful in minimizing bleeding while preventing clotting." Current guidelines call for combining three drugs - DAPT plus a vitamin K antagonist (VKA) anticoagulant - in a strategy known as "triple therapy." But as the authors note, this approach may result in excess major bleeding rates of 4 to 12 percent within the first year of treatment. The PIONEER AF-PCI trial studied men and women over age 18 with atrial fibrillation who had undergone a PCI procedure with stent placement. The study subjects were randomly assigned to one of three groups: Group 1 received reduced dose rivaroxaban plus a P2Y-12 inhibitor monotherapy; Group 2 received very low dose rivaroxaban plus DAPT; and Group 3 received VKA plus DAPT. The findings showed that among patients with atrial fibrillation who underwent intracoronary stent placement, the administration of rivaroxaban in one of two dose strategies reduced the risk of clinically significant bleeding in about one out of every 10 to 11 patients as compared with triple therapy including a vitamin K antagonist. The risks of rehospitalization and death from all causes were also reduced in about one out of every 10 to 15 cases. "This new treatment strategy benefits patient health as well as hospital finances," added Gibson. The PIONEER AF-PCI study is supported by Janssen Scientific Affairs LLC, and Bayer Health Care Pharmaceuticals. Study coauthors include BIDMC investigators Serge Korjian, MD and, Yazan Daaboul, MD,; Roxana Mehran, MD, and Jonathan Halperin, MD, of Mount Sinai Medical Center, New York; Christoph Bode, MD, of the University of Freiburg, Germany; Freek W.A. Verheugt, MD, of Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam; Peter Wildgoose, PhD, Mary Birmingham, PharmD, Juliana Ianus, PhD, and Paul Burton, MD, PhD, of Jansen Pharmaceuticals, Inc.; Martin van Eickels, MD, of Bayer Pharmaceuticals; Gregory Y.H. Lip, MD of The University of Birmingham Centre for Cardiovascular Services, Birmingham, UK; Marc Cohen, MD, of Newark Beth Israel Medical Center, Newark, NJ; Steen Husted, MD, of Aarhus University Hospital, Herning, Denmark; Eric D. Peterson, MD, MPH of Duke Clinical Research Institute, Durham, NC; and Keith AA Fox, MB, ChB, of the Royal Infirmary of Edinburgh, UK. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | February 22, 2017
Site: www.eurekalert.org

BOSTON - Sleep remains an enduring biological mystery with major clinical relevance, according to a review by clinician-researcher Thomas Scammell, MD, of Beth Israel Deaconess Medical Center (BIDMC) and colleagues. In recent decades, new technologies have allowed neuroscientists to identify multiple brain circuits that govern the sleep/wake cycle, as well as the factors that can influence it, such as caffeine and light. But the brain's complexity is still a stumbling block in understanding this ubiquitous and necessary animal behavior, the researchers wrote. Their review appeared today in the journal Neuron. "In the last ten years, neuroscientists have had access to new tools with which we can test the roles of very specific neurons in the brain," said lead author Scammell, a professor in the department of neurology at BIDMC. "When we know the specific relevant players in the brain, it allows us to develop therapies to help people get to sleep or help sleepy people be more alert during the day." Specifically, two technologies developed since 2000 allow neurologists to switch specific neurons on or off. In a process called chemogenetics, researchers use drugs that have an effect only in a genetically-defined group of cells to determine the neurons' role. Optogenetics uses laser light to turn on or turn off targeted brain cells. These techniques have revealed which neuronal circuits promote wakefulness and sleep throughout the brain, especially in the brain stem and the hypothalamus. "We can now interrogate neurons in a more precise way," said Scammell. "The techniques are very similar, but optogenetics works over a short time scale, on the order of seconds. With chemogenetics, we can watch over several hours what happens when we turn certain neurons on or off." Sleep researchers have also made important discoveries about the fundamental chemistry of sleepiness in recent years. In a major breakthrough in the late 1990s, scientists discovered a previously unknown chemical, a neurotransmitter called orexin, required for maintaining long periods of wakefulness. The loss of orexin production causes the common sleep disorder narcolepsy, which is characterized by chronic sleepiness and irregular REM sleep. Today, pharmaceutical companies make drugs that intentionally block the orexin system to treat insomnia. Researchers are also trying to develop drugs that mimic orexin to wake people up. "A drug that acts like orexin could be as great for patients with narcolepsy as insulin is for people with diabetes," said Scammell. Neuroscience research has also revealed the brain circuity governing circadian rhythms, the biological clock that synchronizes sleepiness and wakefulness with night and day. Located deep in the hypothalamus, the suprachiasmatic nucleus (SCN) regulates circadian rhythms and is capable of maintaining them for some time even in total darkness. However, the SCN is no match for the social norms surrounding people's sleep habits. "People increasingly use their electronic devices in bed, which tricks the brain into thinking it's being exposed to daylight," said Scammell. "The internal clock gets reset, making it much harder to wake up in the morning." Phones and tablets are just one of the reasons about a third of all American adults are sleep deprived, getting much less than the recommended seven to eight hours of sleep per night. That raises more questions about why some people need more or less than that, and why some people can tolerate a sleep deficit so much better than others. The links among lack of sleep or poor sleep and metabolic disease, cancer risk and mood disorders also require further study. With each of the brain's hundreds of thousands of neurons networked to each other, scientists will need a deeper knowledge of the brain's inner workings to understand how the circuits that regulate sleep interact. "There's tremendous dialog back and forth among these circuits," said Scammell, who notes today's technology allows scientists to monitor dozens of neurons at a time within one region of the brain. "Our ability to record activity in just a handful of neurons simultaneously is still not anything close to understanding the whole brain, but at least it's a step in the right direction." Study co-authors include: Elda Arrigoni, PhD, of BIDMC and Jonathan O. Lipton, MD, PhD, of Boston Children's Hospital. The work was supported by the National Institutes of Health (HL095491, DE022912, NS091126, and HD071026. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


News Article | November 10, 2016
Site: www.eurekalert.org

BOSTON - A study led by researchers at Beth Israel Deaconess Medical Center (BIDMC), in collaboration with scientists at Walter Reed Army Institute of Research (WRAIR), Janssen Vaccines & Prevention B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson and Gilead Sciences, Inc., has demonstrated that combining an experimental vaccine with an innate immune stimulant may help lead to viral remission in people living with HIV. In animal trials, the combination decreased levels of viral DNA in peripheral blood and lymph nodes, and improved viral suppression and delayed viral rebound following discontinuation of anti-retroviral therapy (ART). The research team's findings appeared online today in the journal Nature. "The objective of our study was to identify a functional cure for HIV - not to eradicate the virus, but to control it without the need for ART," said lead author Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at BIDMC. "Current antiretroviral drugs, although they're lifesaving, do not cure HIV. They merely hold it in check. We are trying to develop strategies to achieve ART-free, long-term viral suppression." Typically, vaccines "teach" the body to rid itself of viral invaders by provoking an immune response. However, HIV attacks cells of the immune system. The virus kills the majority of infected immune cells but goes dormant in others. This reservoir of dormant, infected cells, where researchers believe HIV remains hidden during antiretroviral therapy, is the primary reason HIV cannot currently be cured. Barouch and colleagues are working on strategies to draw the virus out of hiding with the goal of eradicating it from the body. "We reasoned that if we can activate the immune cells that might harbor the virus, then the vaccine-induced immune responses might perform better seeking them out and destroying them," said Barouch, who is also a Professor of Medicine at Harvard Medical School. "Indeed, we saw the best results when we combined the vaccine together with the innate immune stimulant." In the two-year long study, researchers monitored the viral loads of 36 rhesus monkeys infected with simian immunodeficiency virus (SIV), a virus similar to HIV that infects non-human primates. After taking suppressive ART drugs for six months, the monkeys were given either the experimental vaccines - an adenovirus serotype 26 vector vaccine and an MVA vector vaccine (Ad26/MVA) - alone, the immune stimulant (an experimental drug that works on a protein of the immune system called TLR-7) alone, or the Ad26/MVA and stimulant combination. A control group received no active treatment. "We found the combination of Ad26/MVA vaccination and TLR7 stimulation proved more effective than either component alone," said Col. Nelson Michael, director of MHRP, who helped design the preclinical study. "This was especially striking in viral load set-point, which impacts the future course of the disease." The experimental vaccine induced a robust immune response, both in magnitude (the number of immune cells generated) and breadth (the number of places on the virus the vaccine can targets). To evaluate the efficacy of the vaccine and the immune stimulant, the researchers discontinued ART in all animals and continued to monitor their viral loads. Animals that received only the vaccine demonstrated some reduction of viral load, but the animals that were given the vaccine/immune stimulant combination showed a reduction in plasma viral RNA levels as well as a 2.5-fold delay of viral rebound compared to controls. All nine animals showed decreased viral loads, and the virus was undetectable in a third of the animals. "If all the animals' viral loads had been undetectable, that would have been a home run," said Barouch. "But the fact that all animals showed a reduction in viral load and three out of nine were undetectable, that's a solid base hit. It's definitely something that we can work from." Study coauthors include Erica Borducchi, Crystal Cabral, Kathryn E. Stephenson, Jinyan Liu, Peter Abbink, David Ng'ang'a, Joseph P. Nkolola, Amanda L. Brinkman, Lauren Peter, Benjamin C. Lee, Jessica Jimenez, David Jetton, Jade Modesir, Shanell Mojta, Abishek Chandrashekar and Katherine Molloy all of BIDMC; Galit Alter of the Ragon Institute of MGH, MIT, and Harvard; Jeff M. Gerold and Alison L. Hill of the Program for Evolutionary Dynamics at Harvard University; Mark G. Lewis, of Bioqual; Maria G. Pau, Hanneke Schuitemaker of Janssen Infectious Diseases and Vaccines; Joseph Hesselgesser and Romas Geleziunas of Gilead Sciences; Jerome H. Kim, Merlin L. Robb and Nelson L. Michael of the U.S. Military HIV Reseach Program, Walter Reed Army Institute of Research. This work was supported by the U.S. Army Medical Research and Material Command and the Military HIV Research Program, Walter Reed Army Institute of Research through its cooperative agreement with the Henry M. Jackson Foundation (W81XWH-11-2-0174). Funding was also provided by the National Institutes of Health (AI096040, AI124377, AI1266030) and the Ragon Institute of MGH, MIT, and Harvard. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .

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