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By Gina P Orlando
BUSM Study Reveals B cells as Therapeutic Targets to Alter Obesity-Associated Inflammation and Type 2 Diabetes
New research from Boston University School of Medicine (BUSM) reveals that B cells regulate obesity-associated inflammation and type 2 diabetes through two specific mechanisms. The study, published in the Proceedings of the National Academies of Sciences, indicates the importance of continuing to explore B cells as a therapeutic target to treat these diseases. Barbara Nikolajczyk, PhD, associate professor of microbiology at BUSM, is the study’s senior author.
The incidence of diabetes continues to rise at alarming rates. According to the National Institute of Diabetes and Digestive and Kidney Diseases, the disease now affects approximately 25.8 million Americans. In 2007, the National Institutes of Health estimated that the direct and indirect costs of diabetes were a staggering $174 billion.
Type 2 diabetes, which is a common result of obesity, occurs when the body produces insulin but cannot use it properly (insulin resistance) or the body does not produce enough insulin. The body needs insulin to absorb glucose and generate energy. If the body does not produce and respond to insulin appropriately, it can, over time, lead to various complications such as cardiovascular disease, nerve damage, kidney disease and blindness.
Previous research has shown that B cells, which are white blood cells of the immune system, promote inflammation and can lead to the development of type 2 diabetes, but the mechanisms underlying B cell function were unclear.
The results of this study shed light on that question and indicate that B cells secrete a pro-inflammatory ratio of proteins called cytokines, which directly promote the insulin resistance that characterizes type 2 diabetes. The researchers also demonstrated that B cells directly regulate inflammatory T cells, an immune cell type known to cause insulin resistance in animal models of disease.
“Now that we have identified the specific mechanisms by which B cells promote inflammation, we can help develop novel, targeted approaches to treat type 2 diabetes,” said Nikolajczyk. “Our study supports the continued exploration of FDA-approved B cell depletion drugs, which are known to be generally safe and effective, as novel agents to prevent obesity-associated inflammation and type 2 diabetes.”
Research included in this study was supported in part by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grant award numbers R21DK089270 and R56DK096525 (PI: Nikolajczyk) and R56DK090455 (PI: Gerald Denis); the NIDDK’s Boston Area Diabetes Endocrinology Research Center Pilot Program and the Boston Nutrition Obesity Research Center under grant award number DK046200; the NIH’s National Institute of Dental and Craniofacial Research under grant award number 5R21DE021154 (PI: Nikolajczyk); the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Immunology Training Program under grant award number AI007309; the NIH’s National Heart, Lung, and Blood Institute’s Hematology Training Program under grant award number HL007501; and the Evans Center for Interdisciplinary Biomedical Research at BUSM (PI: Nikolajczyk and Denis).
Researchers at Boston University School of Medicine (BUSM) have, for the first time, identified a specific group of cells in the brainstem whose activation during rapid eye movement (REM) sleep is critical for the regulation of emotional memory processing. The findings, published in the Journal of Neuroscience, could help lead to the development of effective behavioral and pharmacological therapies to treat anxiety disorders, such as post-traumatic stress disorder, phobias and panic attacks.
There are two main stages of sleep – REM and non-REM – and both are necessary to maintain health and to regulate multiple memory systems, including emotional memory. During non-REM sleep, the body repairs tissue, regenerates cells and improves the function of the body’s immune system. During REM sleep, the brain becomes more active and the muscles of the body become paralyzed. Additionally, dreaming generally occurs during REM sleep, as well as physiological events including saccadic eye movements and rapid fluctuations of respiration, heart rate and body temperature. One particular physiological event, which is a hallmark sign of REM sleep, is the appearance of phasic pontine waves (P-waves). The P-wave is a unique brain wave generated by the activation of a group of glutamatergic cells in a specific region within the brainstem called the pons.
Memories of fearful experiences can lead to enduring alterations in emotion and behavior and sleep plays a natural emotional regulatory role after stressful and traumatic events. Persistence of sleep disturbances, particularly of REM sleep, is predictive of developing symptoms of anxiety disorders. A core symptom of these disorders frequently reported by patients is the persistence of fear-provoking memories that they are unable to extinguish. Presently, exposure therapy, which involves controlled re-exposure to the original fearful experience, is considered one of the most effective evidence-based treatments for anxiety disorders. Exposure therapy produces a new memory, called an extinction memory, to coexist and compete with the fearful memory when the fearful cue/context is re-encountered.
The strength of the extinction memory determines the efficacy of exposure therapy. A demonstrated prerequisite for the successful development of an extinction memory is adequate sleep, particularly REM sleep, after exposure therapy. However, adequate or increased sleep alone does not universally guarantee its therapeutic efficacy.
“Given the inconsistency and unpredictability of exposure therapy, we are working to identify which process(es) during REM sleep dictate the success or failure of exposure therapy,” said Subimal Datta, PhD, director and principle investigator at the Laboratory of Sleep and Cognitive Neuroscience at BUSM who served as the study’s lead author.
The researchers used contextual fear extinction training, which works to turn off the conditioned fear, to study which brain mechanisms play a role in the success of exposure therapy. The study results showed that fear extinction training increased REM sleep. Surprisingly, however, only 57 percent of subjects retained fear extinction memory, meaning that they did not experience the fear, after 24 hours. There was a tremendous increase of phasic P-wave activity among those subjects. In 43 percent of subjects, however, the wave activity was absent and they failed to retain fear extinction memory, meaning that they re-experienced fear.
“The study results provide direct evidence that the activation of phasic P-wave activity within the brainstem, in conjunction with exposure therapy, is critical for the development of long-term retention of fear extinction memory,” said Datta, who also is a professor of psychiatry and neurology at BUSM. In addition, the study indicates the important role that the brainstem plays in regulating emotional memory.
Future research will explore how to activate this mechanism in order to help facilitate the development of new potential pharmacological treatments that will complement exposure therapy to better treat anxiety and other psychological disorders.
According to the National Institute of Mental Health, anxiety disorders affect approximately 40 million American adults each year. While anxiety can sometimes be a normal and beneficial reaction to stress, some people experience excessive anxiety that they are unable to control, which can negatively impact their day to day life.
Research included in this study was supported in part by the National Institutes of Health’s National Institute of Mental Health under grant award number MH 59839 (PI: Datta) and the National Institute of Neurological Disorders and Stroke under grant award number NS 34004 (PI: Datta).
Researchers at Boston University School of Medicine (BUSM) and VA Boston Healthcare System (VA BHS) have found that cognitive behavioral therapy (CBT) can help relieve pain for people with painful diabetic neuropathies. The study, which is the first of its kind to examine this treatment for people with type II diabetes mellitus, is published in the March issue of the Journal of Pain.
Type II diabetes mellitus is the most common form of the disease and affects more than 20 million Americans. The onset of type II diabetes mellitus is often gradual, occurring when a person is unable to make or use insulin efficiently. As a result, abnormally high levels of sugar accumulate in the blood, resulting in a condition called hyperglycemia.
Untreated hyperglycemia can develop into diabetic neuropathies, or nerve damage, which causes painful burning and stinging sensations in the hands and feet and permanent nerve damage. Although pain medications for this condition exist, they often have negative side effects such as headaches, dizziness and nausea.
Researchers led by John D. Otis, PhD, an associate professor of psychiatry at BUSM and clinical psychologist at the VA BHS, assessed whether CBT, a psychological, goal-oriented treatment approach aimed at changing maladaptive thoughts and illness supporting behaviors, could be of benefit to veterans with painful diabetic neuropathies.
The study, which was conducted at the VA BHS, compared participants receiving CBT to those receiving treatment as usual. The participants were U.S. veterans age 18 and older who had been diagnosed with type II diabetes and experienced neuropathic pain for more than three months.
Participants attended 11, hour-long CBT sessions, which focused on teaching participants relaxation techniques and how to identify and challenge thoughts that contribute to pain. In addition, participants were taught how to keep active and plan enjoyable activities such as exercise, going for walks or having dinner with friends.
At a four-month follow-up, participants who received CBT reported feeling less pain and reported that pain was less interfering in their daily lives when compared to participants who received treatment as usual.
“This study demonstrates that the millions of people who are experiencing pain and discomfort from type II diabetes mellitus do not need to rely solely on medication for relief,” said Otis. “More broadly, the results of this study add to a growing body of literature demonstrating that cognitive behavioral therapy is an effective psychological treatment approach for chronic pain management,” he added.
This work was supported by a grant from the Veterans of Foreign Wars (VFW) to the diabetes research program at VA BHS.
Pedram Salimpour, MD, MPH, has been named a member of the Dean’s Advisory Board (DAB) at Boston University School of Medicine (BUSM). DAB members serve three-year-renewable terms actively participating in medical school strategic planning and external relations initiatives.
DAB members are leaders in medicine, technology, business and other sectors of society. They share a passion for basic science and clinical research, as well as their support for BUSM. Board members are uniquely positioned to help advance the school and its students, scientists and clinicians.
“Service as a Board Member is the culmination of personal and professional aspirations. It is my hope that together, with fellow Board Members and the leadership of Dean Karen Antman, we will leave a legacy of discovery and prosperity for BUSM,” said Salimpour.
Salimpour is CEO and co-founder of Champion Health Enterprises, a company focused on the creation of novel health ecosystems for Native American tribes and their business entities. He is president and co-founder of CareNex Health Services, a healthcare technology and client-services organization specializing in neonatal and perinatal disease management programs with presence in more than 40 percent of the neonatal intensive care units in the U.S. In 2006, CareNex was partially acquired by Wellpoint (NYSE: WLP). In 2007, Salimpour co-founded Plymouth Health and acquired a 306 bed hospital in San Diego, California from Tenet Healthcare Corporation (NYSE: TCH). From 2001 to 2005, he served as executive vice president and co-founder of NexCare Collaborative, a not-for-profit organization that assisted healthcare needs of more than 100,000 underserved children and families in Southern California.
President-elect of the Los Angeles County Medical Association, Salimpour is a member of the boards of directors of the University of California, Los Angeles (UCLA) School of Public Health and a founding board member of the School of Medicine at the University of California, Riverside. He is an adjunct professor of health and human services at the Center on Human Aging at San Diego State University and an associate professor of pediatrics at the University of California, Riverside School of Medicine.
In addition to his medical contributions, Salimpour received an Emmy Award for his news documentary, “The Face of America,” and received a commendation from the Governor of California for his record of service to the State.
Salimpour is a graduate of BUSM. An Alpha Omega Alpha National Research Scholar, he was the first two-time recipient of the American College of Physicians’ Research Award. He completed his residency at the University of Southern California Medical Center’s Keck School of Medicine and received his Masters of Public Health degree at the UCLA School of Public Health.
Edward Bernstein, MD, vice chair of academic affairs and professor of emergency medicine at Boston University School of Medicine (BUSM) and an emergency medicine physician at Boston Medical Center (BMC) has been named the recipient of the 2012 Jerome Klein Award for Physician Excellence. Selected by a senior committee of BUSM and BMC physicians, the award was presented at the Medical Executive Committee meeting on Dec. 14.
Established to honor Jerome Klein, MD, a pediatrician at BMC for his 50 years of service to the hospital, the award is given to a physician who mirrors Klein’s commitment and service as a mentor, leader, teacher, researcher and clinician.
“Ed is certainly a most worthy recipient and I am very appreciative for all that he has done for BMC and for our patients over his 25 years here,” said Ravin Davidoff, MD, chief medical officer at BMC, who presented the award.
Bernstein has dedicated his career to incorporating public health into emergency medicine with a special focus on interventions to reduce substance abuse. This includes co-founding Project ASSERT (Alcohol and Substance Abuse Services, Education, and Referral to Treatment), which helps patients gain access to treatment for substance abuse and primary care services.
Bernstein expanded the project into the BNI-ART Institute, which provides training for health care providers to help patients overcome barriers to changing harmful behaviors, such as smoking or drug use. Bernstein serves as co-director of BNI-ART Institute/Project ASSERT at Boston University School of Public Health (BUSPH).
Prior to joining BMC and BUSM, Bernstein founded the emergency medicine residency program at the University of New Mexico. He has published dozens of articles in peer-reviewed journals and co-edited the textbook “Case Studies in Emergency Medicine and the Health of the Public.”
Bernstein received his medical degree from Stanford University School of Medicine and completed an internship in pediatrics at San Francisco General Hospital. He is board certified in both emergency medicine and family medicine.
Since the devastation of areas of New York and New Jersey caused by Hurricane Sandy, rescue teams from all over the country have been deployed to help. Ricky Kue, MD, associate professor of emergency medicine at Boston University School of Medicine (BUSM) and emergency medicine physician at Boston Medical Center (BMC) is one of those volunteers. As Medical Team Manager of Massachusetts Task Force 1 (MA-TF 1), a Federal Emergency Management Agency (FEMA) urban search and rescue team, Kue and 80 team members were mobilized for a week to assist with search and rescue operations in Queens and Staten Island.
Kue’s main responsibility was to tend to the healthcare needs of police, fire, Emergency Medical Services (EMS) and civilian volunteers. Kue and other medical personnel engaged in search operations, monitored team members for illness and injury and provided medical screening on a daily basis to help support the rescue missions.
“Our goal was for our team to be self-sufficient and not use local resources who were already dealing with disaster relief on a massive scale. Because of the risks associated with the rescues, we served as physicians and paramedics,” said Kue.
Upon arrival, the team searched collapsed buildings, trenches and aided people stranded in their homes due to the high water levels. Providing an extra hand, they ensured that residents who weren’t evacuated received the medical attention they needed.
In one particular situation Kue was stationed at his basecamp along the beach in Midland, an area in Staten Island that was hit the hardest. Medical assistance was needed for a woman with heart attack symptoms and EMS was not immediately available. Kue and another physician grabbed their medical equipment and ran to the woman’s home.
“I assessed her and fortunately she was not having a heart attack, but you could see that she was struggling. Despite the adversity this woman and the people of this community were faced with, the appreciation they showed was my most memorable experience during the mission,” said Kue.
Being deployed to this area hit home for Kue, who grew up in Queens, where his parents still live. Kue called his parents to see if they were okay as his convoy drove past their neighborhood. “I lived in NYC for 18 years and I’ve seen hurricanes growing up, but I never thought I’d see such devastation to my own borough. This was New York City’s Hurricane Katrina,” said Kue. Luckily, his family and childhood home were unharmed thanks to some emergency preparedness tips Kue has been offering his family for years.
Kue is also a Major in the U.S. Army Reserve and can be called for duty overseas at any time. “I couldn’t do this without support from my emergency medicine team at BMC and BUSM. They help cover my clinical duties so I can go out the door and deploy whenever necessary,” said Kue.
Massachusetts Task Force 1 (MA-TF 1) Urban Search and Rescue Team (US&R) is located in Beverly, Mass. Urban Search and Rescue teams are comprised of Police, Fire, EMS and Civilians and respond to major disasters under a contract with the Federal Emergency Management Agency (FEMA). Currently there are 150 people on the MA-TF 1 team.
Boston University School of Medicine (BUSM) will present the 11th annual Sue Kim Hanson Lecture in Immunology at noon, Friday, Nov.16, in the School of Medicine’s Keefer Auditorium. The annual lecture honors Sue Kim Hanson, MA, and PhD ’02, a former researcher in BUSM’s Pulmonary Center. Hanson, her husband and their daughter were passengers on one of the airplanes that struck the World Trade Center on Sept. 11, 2001.
This year’s lecturer is Ruslan Medzhitov, MD, investigator at the Howard Hughes Medical Institute and David W. Wallace Professor of Immunobiology at Yale University School of Medicine.
The lecture, “Host Defense Strategies” will focus on Microbial infections, which pose a significant threat to our health and survival. Many encounters with pathogens go unnoticed because they are quickly eliminated by efficient immune defenses. But, some of these infections make us more vulnerable to unrelated secondary infections, such as the Influenza virus, which can lead to disease and even death. This presentation will detail lethal co-infections and the different ways the host organism protects itself from microbial challenges.
Medzhitov has dedicated his career to analyzing the innate immune system, inflammatory response, innate control of the adaptive immunity and host-pathogen interactions. He is nationally recognized for his work with Toll-like receptors, a component of the innate system that provide the adaptive system with the necessary information to create custom-made B and T cells that target specific bacterial or viral invaders. He was elected to the National Academy of Sciences in 2010 and was a co-recipient of the prestigious Shaw Prize in Life Science and Medicine in 2011.
Sue Kim Hanson moved to Boston and earned a master’s degree in medical sciences from BUSM in 1992. After graduation she joined the school’s Pulmonary Center and then entered BUSM’s doctoral program in the Immunology Training Program through the department of pathology and laboratory medicine.
Her dissertation project was an investigation of the role of interleukin-16 in immunity and targeted deletion of the interleukin-16 gene in mice. Her degree was awarded posthumously by unanimous vote by the dissertation committee.
“Sue was on her way to a promising career in molecular biology,” said David Center, MD, Gordon and Ruth Snider professor of pulmonary medicine and associate provost for translational research. “While her life was taken at an early age, her legacy lives on through this annual lecture. We are proud to remember and honor her and her family each year.”
Gregory Antoine, MD, chief of plastic and reconstructive surgery at Boston Medical Center (BMC) and associate professor of surgery and otolaryngology at Boston University School of Medicine (BUSM) was elected to the National Medical Association (NMA) Board of Trustees. Antoine will represent Region 1, which includes Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Puerto Rico, Rhode Island, Vermont and the U.S. Virgin Islands.
As a board member, Antoine is responsible for implementing policies and procedures voted on and approved by the NMA House of Delegates.
The mission of the NMA is to advance the art and science of medicine for people of African descent through education, advocacy and health policy to promote health and wellness, eliminate health disparities and sustain physician viability. The association represents the interests of more than 50,000 African American physicians and the patients they serve, with nearly 129 affiliated societies throughout the nation and U.S. territories.
“My goal is to maintain the viability and relevance of the largest historically black medical association and its peer reviewed Journal of the National Medical Association and expand our membership base,” said Antoine.
Antoine is the first African American plastic surgeon to head a division of Plastic and Reconstructive Surgery at a non-historically black medical school in the U.S. He is a veteran of both the U.S. Navy and Army, from which he retired as a Colonel with multiple awards and recognitions. His clinical interests include craniomaxillofacial, cosmetic, microvascular and pediatric plastic surgery. He specializes in head and neck reconstruction for congenital or post-traumatic defects.
After earning his medical degree from the State University of New York at Buffalo School of Medicine and Biomedical Sciences, Antoine completed his residency at Walter Reed Army Medical Center and Georgetown University Medical Center in Washington DC. He concluded his medical training with fellowships in craniomaxillofacial surgery at Eastern Virginia Graduate School of Medicine and hand and microvascular surgery at Minnesota Microsurgical Institute.
Cory M. Edgar, MD, PhD has recently joined Boston Medical Center (BMC) as an orthopaedic surgeon and Boston University School of Medicine (BUSM) as an assistant professor of orthopaedic surgery. In addition he has been appointed as team physician for Boston University Athletics.
Edgar’s area of expertise is in using stem cells in the care of injured athletes to enhance soft tissue healing and grafts. His clinical interests include shoulder joint injuries, shoulder and knee joint instability and issues regarding treatment for patellar instability. His goal is to continue exploration through research and the development and application of biologics and regenerative medicine techniques in sports medicine procedures.
A graduate of BUSM, Edgar received his medical and doctoral degrees through the combined MD/PhD program. He continued his training at BMC through the orthopedic surgery residency program. Edgar completed a yearlong specialty training as a fellow in sports medicine at the University of Connecticut Health Center, where he served as a team physician.
Edgar sees patients at BMC’s Shapiro Ambulatory Care Center and at Boston University’s newly renovated Ryan Center for Sports Medicine and Rehabilitation.
Brian W. Jack, MD, has been appointed Chief of Family Medicine at Boston Medical Center (BMC) and Chair of the Department of Family Medicine at Boston University School of Medicine (BUSM). Jack was hired in 1997 as physician and Vice Chair in Family Medicine at BMC and associate professor at BUSM. In 2011, he was promoted to professor at BUSM.
Jack is the principal investigator of Project RED (Re-engineered discharge), which standardizes the hospital discharge process and improves the communication between provider and patient both during the hospital stay and post-discharge. Project RED is considered a blueprint for hospitals that are trying to reduce 30-day readmission rates and is currently being used at more than 300 hospitals nationally and internationally. Through his work, he and his team have been able to reduce hospital utilization—which includes both 30-day readmissions and emergency department visits—by about 30 percent.
Jack received his medical degree from the University of Massachusetts and completed his family medicine residency at Brown University, serving as chief resident, in 1984. He completed a fellowship in high risk obstetrics at Sacred Heart Medical Center, an affiliate of the University of Washington. In 1986, he joined the Family Medicine department at Brown, where he founded the maternal and child health fellowship program, the first academic fellowship program based in a community health center. In 1997, he joined the Department of Family Medicine at Boston University as the founding Vice Chair for Academic Affairs.
Jack has authored more than 100 peer-reviewed papers and book chapters; served on grant review panels for the National Institute of Child Health and Human Development, the Health Resources and Services Administration, Robert Wood Johnson Foundation and the Centers for Disease Control and Prevention; and reviewed papers for many leading medical journals. He has been Principal Investigator of grants from the Agency for Healthcare Research and Quality, the National Heart, Lung and Blood Institute, the Centers for Disease Control and Prevention, the Health Resources and Services Administration, and the Patient-Centered Outcomes Research Institute, among others.
Jack has received numerous awards and other recognition. For his work relating to improving patient safety at hospital discharge (Project RED), he received the Excellence in Patient Education Innovation award and was named Patient Safety Investigator of the Month by the Agency for Healthcare Research and Quality. He was also one of 20 nationally to be included on HealthLeaders magazine’s “People Who Make Healthcare Better” list. His article describing Project RED was the Society of Teachers of Family Medicine’s Paper of the Year and is included in the book, “50 Studies Every Doctor Should Know.” He received the Partner in Public Health Improvement award from the CDC.
Jack is clinical director of a Kellogg Foundation funded program in Lesotho focused on improving the quality of district health services, via a new family medicine training program he initiated. He has served as a consultant to USAID, the World Bank, the US Department of State, the China Medical Board and others on the development of primary care in Lesotho, Hungary, Albania, Jordan, Romania and Vietnam.
“Dr. Jack’s commitment to improving the health care experience will be of great benefit to our patients,” said BMC President & CEO Kate Walsh. “We look forward to the leadership he will provide to the department of Family Medicine and to the hospital.”