By Jenny C Leary
Utilizing MRI to Measure Blood Flow Over Atherosclerotic Plaques May Aid in Detection of Dangerous Plaques
(Boston) – Researchers from Boston University School of Medicine (BUSM) have shown that using magnetic resonance imaging (MRI) to measure blood flow over atherosclerotic plaques could help identify plaques at risk for thrombosis. The findings, which appear in the March issue of Circulation Cardiovascular Imaging, offer a non-invasive application in the diagnosis and treatment of patients with atherosclerosis.
Atherosclerosis is a chronic disease of the human vascular system associated with lipid (cholesterol) accumulation and inflammation. It can remain silent and undetected for many years, but can cause acute cardiovascular events such as stroke or heart attack. This often occurs when a high-risk, dangerous atherosclerotic plaque disrupts at the vessel surface facing the blood, followed by partial or complete blockage of blood flow through the lumen by a thrombus. An unmet challenge of diagnostic medicine is to find such plaques before disruption occurs in order to prevent these occurrences.
While most studies have focused on the plaque within the vessel wall, the flow of blood in the vessel (hemodynamics) also is known to be important in the progression and disruption of plaques.
In this study the researchers, led by James A. Hamilton, PhD, professor of biophysics and physiology at BUSM, found that the measurement of endothelial sheer stress (ESS), which is the indirect stress from the friction of blood flow over the vascular endothelium surface, can identify plaques in the highest risk category. After performing a non-invasive MRI examination of the aorta in a preclinical model with both stable and unstable plaques, a pharmacological “trigger” was used to induce plaque disruption. Low ESS was associated with plaques that disrupted and had other “high-risk” features, such as positive remodeling, which is an outward expansion of the vessel wall that “hides” the plaque from detection by many conventional methods.
These results are consistent with previous studies that examined coronary arteries of other experimental models using invasive intravascular ultrasound method to measure features of vulnerability but without an endpoint of plaque disruption, which is the outcome of the highest risk plaques.
“Our results indicate that using non-invasive MRI assessments of ESS together with the structural characteristics of the plaque offers a comprehensive way to identify the location of “high-risk” plaque, monitor its progression and assess the effect of interventions,” said Hamilton. “Early identification of “high-risk” plaques prior to acute cardiovascular events will provide enhanced decision making and might improve patient management by allowing prompt aggressive interventions that aim to stabilize plaques.”
This research was supported by grant funding from the National Institutes of Health’s National Heart, Lung and Blood Institute (NHLBI) under grant award number 5P50HL083801.The study’s co-authors are Ning Hua, PhD, Tuan Pham, BSc, and Alkystis Phinikaridou, PhD (currently at King’s College London).
Could lead to the development of broad spectrum antivirals for deadly viruses
Researchers at Boston University School of Medicine (BUSM) have identified a new chemical class of compounds that have the potential to block genetically diverse viruses from replicating. The findings, published in Chemistry & Biology, could allow for the development of broad-spectrum antiviral medications to treat a number of viruses, including the highly pathogenic Ebola and Marburg viruses.
Claire Marie Filone, PhD, postdoctoral researcher at BUSM and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), is the paper’s first author and led this study under the leadership of John Connor, PhD, associate professor of microbiology at BUSM and the study’s corresponding author. John Snyder, PhD, professor of chemistry at Boston University (BU) and researchers from the Center for Chemical Methodology and Library Development at BU (CMLD-BU) were collaborators on this study.
Viruses are small disease-causing agents (pathogens) that replicate inside the cells of living organisms. A group of viruses known as nonsegmented, negative sense (NNS) ribonucleic acid (RNA) viruses cause common illnesses such as rabies, mumps and measles. These pathogens also cause more serious deadly diseases, including Ebola, Hendra and Nipah. Currently, there are no approved and effective treatments against these viruses, which, according to data from the Centers for Disease Control and Prevention, are associated with mortality rates up to 90 percent following infection.
“Identifying broad-spectrum antivirals is an important step in developing successful therapies against these and other viruses,” said Filone. The basic idea of a broad spectrum antiviral is similar to that of broad spectrum antibacterials in that they would allow one drug to serve as a common treatment for many different viral illnesses.
In this study, researchers identified a new chemical class of compounds that effectively blocked genetically diverse viruses from replicating by limiting RNA production by the virus in cell culture. These indoline alkaloid-type compounds inhibited a number of viruses from replicating, including Ebola.
“Because the production of viral RNA is the first step in successful replication, it appears that we have uncovered an Achilles heel to halt virus replication,” said Filone. “These compounds represent probes of a central virus function and a potential drug target for the development of effective broad-spectrum antivirals for a range of human pathogens.”
Research highlighted in this press release was funded in part by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) under grant award numbers RO1 AI1096159-01 and K22AI-064606 (PI: Connor).
Barbara Gilchrest, MD, professor and Chair Emeritus of the department of dermatology at Boston University School of Medicine (BUSM) and dermatologist at Boston Medical Center (BMC), has been named a 2012 Charter Fellow of the National Academy of Inventors (NAI). Gilchrest is among four faculty members at Boston University nominated to the NAI in 2012.
This year’s charter fellows, who are elected by their peers, represent 98 innovators from 54 universities and non-profit research institutes. This professional distinction is accorded to academic inventors who have demonstrated a highly prolific spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society.
Board certified in internal medicine and dermatology, Gilchrest received her medical degree from Harvard Medical School and completed residencies in internal medicine and dermatology at Harvard-affiliated hospitals. Prior to her appointment as Chair, Gilchrest held academic appointments at Harvard Medical School and Tufts University School of Medicine. She has clinical and laboratory-based research interests in skin aging and pigmentation and has published extensively based on her pioneering work in these fields. Gilchrest is a member of the Institute of Medicine of the National Academy of Sciences and was cited in the book, 100 Best Doctors in America.
NAI Charter Fellows will be inducted by the U.S. Commissioner for Patents, Margaret A. Focarino, from the United States Patent and Trademark Office, during the 2nd Annual Conference of the NAI on Feb. 22, 2013, in Tampa, Fla. Fellows will be presented with a special trophy and a rosette pin.
In the November 14 issue of the Journal of the American Medical Association (JAMA), medical clinicians and researchers advocate for new techniques to fight drug overdoses. Alexander Walley, MD, MSc, assistant professor at Boston University School of Medicine, co-authored the article with Leo Beletsky, JD, MPH, assistant professor at Northeastern University School of Law and Bouvé College of Health Sciences, who served as the paper’s lead author, and Josiah Rich, MD, MPH, professor at Brown Medical School.
The article specifically focuses on the national problem of fatal overdoses from opioid drugs, which include the street drug heroin and prescription drugs such as oxycodone. According to the article, opioid overdose kills 16,000 Americans annually and affects all sectors of society. The article calls for federal, state and local authorities to act in concordance to improve awareness about drug overdose and increase availability of the life saving drug, naloxone.
Naloxone is a critical medication that acts to quickly to reverse the effects opioid overdose. However, the authors describe several barriers impeding more effective use of naloxone. For example, although naloxone is generic, there is a critical supply shortage, making the drug expensive. Furthermore, many doctors are fearful of increased liability if they prescribe naloxone and worry about facilitating risky behavior.
In order to increase supply, the authors call for the federal government to streamline naloxone importation. They ask for the U.S. Food and Drug Administration to facilitate the clearance of easier to administer forms of the drug, such as a nasal spray or an “epi-pen” like auto injector instead of the current method, which utilizes unwieldy needles. They also call for clinicians to be educated about the benefits of naloxone for their patients. Additionally, the authors call on state and local authorities to increase awareness and offer patient education about drug overdose and naloxone therapy.
“Community-based overdose prevention programs that include overdose education and naloxone access could help avert unnecessary, preventable death,” said Walley, who also is a physician at Boston Medical Center.
-Written by David Mosbach, MD
The Boston University School of Medicine (BUSM) Division of Graduate Medical Sciences Office of Postdoctoral Affairs is celebrating National Postdoc Appreciation Week (NPAW) Sept. 17-21. This is the second year that events will be held on the medical campus. The activities held during Appreciation Week will help increase awareness of postdocs and recognize the contributions they make to research at BUMC.
Three special events are being held celebrating the contributions and achievements of BUMC postdocs:
Careers in Communicating Science: Journals, Blogs, Netcasts and Tweets
- Monday, Sept. 17
- 3- 4:30 p.m.
- Room L-201/203
- 72 East Concord St.
Ice Cream Social
- Tuesday, Sept. 18
- 1-3:20 p.m.
- Talbot Green
- (Rain location: Hiebert Lounge 14th Floor, 72 East Concord St.)
Film Screening: Losing Control
- Thursday, Sept. 20
- 5:30-7:50 p.m.
- Keefer Auditorium
- 72 East Concord St.
The Appreciation Week evolved out of National Postdoc Appreciation Day and has become the nation’s largest celebration of postdoctoral scholars. In 2010, NPAW culminated with the passage of H.RES. 1545 by the U.S. House of Representatives on Sept. 24, 2010, which nationally recognizes NPAW.
Since 2009 participation for the event has grown: in 2011, 171 events were hosted at 89 institutions in 30 states and Canada. Past events have included wine and cheese receptions, postdoc picnics, professional development workshops, and networking events.
BUMC NPAW is coordinated by Yolanta Kovalko, Administrative Manager, Office of Postdoctoral Affairs (OPA). Contact Yolanta at Yolanta@bu.edu
For more information about BUMC OPA and to RSVP for the Careers in Communicating Science: Journals, Blogs, Netcasts and Tweets Talk, email: Yolanta@bu.edu
To RSVP for the Ice Cream Social, visit http://www.bumc.bu.edu/gms/gateway/post-doc/professional-development/upcoming-events/rsvp-ice-cream-social/
To RSVP for the Movie, Losing Control and Panel Discussion, visit http://www.bumc.bu.edu/gms/gateway/post-doc/professional-development/upcoming-events/movie-losing-control/
Accountable care organizations, supported by federal health care reform, are enough of an improvement over the failed capitation arrangements of the 1990s to make them a “worthy experiment,” but they are not a cure-all for controlling health care costs, according to an analysis co-authored by a researcher from the BU Schools of Medicine and Public Health.
In the September issue of Health Affairs, Austin Frakt, a health economist who is an assistant professor of health policy and management at BUSPH and assistant professor of psychiatry at BUSM, and co-author Rick Mayes, an associate professor of political science at the University of Richmond, examine the lessons learned during the failed cost-capitation effort of the 1990s. The rise and fall of capitation payments — a fixed lump-sum per patient paid to health care providers to cover all care — offers a stark example of how difficult it is for providers to assume “meaningful financial responsibility” for patient care, Frakt and Mayes argue.
They say that while capitation offered some advantages for payers and providers, such as more control over the provision of the care, it also had limitations, such as a greater financial risk for providers who could not offer medical care for less than the lump sum, as well as incentives to “stint” on care. After an increase in popularity, the lump-sum payment system was largely abandoned, with most providers returning to the traditional fee-for-service model, meaning they are paid for whatever services they render.
Frakt and Mayes note that policy makers “have again turned their attention toward new methods to control volume, including exhibiting renewed interest in shifting cost risk to providers, as capitation did in the 1990s.” Yet, they write, “the capitated arrangements of that era proved unsustainable. Is history doomed to repeat itself?”
Not necessarily, the duo says. They see some promise in the newest attempts to shift financial risk onto providers by creating accountable care organizations (ACOs) — networks of providers responsible for the care of a defined group of patients and, in part, for the cost and quality of that care. ACOs have the goal of providing financial incentives for coordinated and judicious provision of appropriate, high-quality health care. The organizations can secure bonuses if their spending on patients falls below a designated benchmark and they meet quality targets.
Frakt and Mayes say some of the lessons of capitation appear to have informed the new ACO models, which don’t put providers at the same high degree of risk for health care costs that capitation did. If ACOs fail to meet benchmarks, the financial penalties — if any– are relatively modest. And because most ACOs have relatively large patient bases, they may be better able to spread risk.
“Accountable care organizations offer an opportunity to increase quality and reduce spending, while potentially avoiding some of the larger dangers that doomed capitation,” the analysis says. “Nevertheless, they are not without their own limitations and challenges.”
Frakt and Mayes note that some experts are skeptical that the newer models can save significant amounts of money, arguing that only full capitation or similar models will work. Yet, Frakt and Mayes say, policy makers and stakeholders “are justifiably wary of repeating the failed capitation experiment. It is not yet evident how to resolve this Catch-22. Full capitation did not succeed, but models that fall short of it might not, either.
“The United States remains in the same situation it has been in for decades: unsure of how to bend the cost curve while maintaining or improving the quality of care,” they conclude. “With accountable care organizations, the search for the’ sweet spot’ between provider and payer risk continues.”
The full article is available here: http://content.healthaffairs.org/content/31/9/1951.full
-By Lisa Chedekel
Two Boston University School of Medicine (BUSM) faculty members have been named to a consortium that will investigate better ways to treat and diagnose post-traumatic stress disorder (PTSD).
- Ann Rasmusson, MD, associate professor of psychiatry at BUSM and psychiatrist and neuroendocrinologist at the Veterans Affairs (VA) Boston Healthcare System and National Center for PTSD
- Jennifer Vasterling, PhD, professor of psychiatry at BUSM, clinical investigator and chief of psychology at the VA Boston Healthcare System and National Center for PTSD
Draper Laboratory formed this consortium of nationally-recognized PTSD experts to improve diagnostic tools and treatment outcomes for the disorder. Bringing together experts from a variety of disciplines and institutions has several advantages, including the ability to look at the full spectrum of factors from neuroimaging to gene expression, and conduct human and animal studies in parallel, thus accelerating knowledge and development of solutions.
The consortium plans to develop solutions based on objective, clinical decision making by using sophisticated algorithms to integrate data from a spectrum of biomarkers including neuroimaging, psychophysiology, chemical assays and gene expression. The resulting diagnostic and treatment protocols will be more objective and personalized, complementing today’s primarily subjective means of evaluation and treatment selection.
Vasterling will lead the effort to integrate neurocognitive data, which includes measures such as memory, attention and other thinking skills that pertain to brain functioning. She will also help with the integration of psychometric measures (i.e., normed self-report measures and structured clinical interviews pertaining to psychosocial functioning and mental health diagnoses) with the biomarker information.
Rasmusson will lead the selection and development of methods for testing and measuring biomarkers from blood, cerebrospinal fluid, or other sources that characterize the function of an individual’s stress response system both at rest and when activated by general or trauma-related stressors. The aim is to identify stress system factors best addressed and treated on an individual basis—to prevent PTSD or aid recovery from extreme stress and prevent its long-term downstream medical and psychiatric consequences.
PTSD has been diagnosed in more than 200,000 troops returning from combat in Iraq and Afghanistan, but it is also commonly found in civilians who have been involved in an accident or assault, or have suffered the unexpected loss of a loved one. Approximately 8 percent of the U.S. population will suffer from PTSD at some point in their lives, which can lead to panic attacks, substance abuse, depression, suicide, and a host of serious medical complications, most notably, cardiovascular disorders.
The current state of the art in PTSD diagnosis is based on clinical interviews, so doctors have to rely on patients’ subjective reports. Although the clinical history is a good start, PTSD diagnosis and treatment selection would be better informed if reliable biomarkers of the condition were available, as is the case in many other areas of medicine.
Draper Laboratory is a not-for-profit, engineering research and development organization dedicated to solving critical national problems in national security, space systems, biomedical systems, and energy.
Researchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study, which is published online in Alcoholism: Clinical and Experimental Research, also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilizing a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 nonalcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
“We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,” said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
“These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,” said Mosher Ruiz. “We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.”
This research was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award numbers R01-AA07112 and K05-AA00219, the US Department of Veterans Affairs Medical Research Service and the Center for Functional Neuroimaging Technologies (award number P41RR14075).
Investigators at Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have identified a new gene linked to post-traumatic stress disorder (PTSD). The findings, published online in Molecular Psychiatry, indicate that a gene known to play a role in protecting brain cells from the damaging effects of stress may also be involved in the development of PTSD.
The article reports the first positive results of a genome-wide association study (GWAS) of PTSD and suggests that variations in the retinoid-related orphan receptor alpha (RORA) gene are linked to the development of PTSD.
Mark W. Miller, PhD, associate professor at BUSM and a clinical research psychologist in the National Center for PTSD at VA Boston Healthcare System was the study’s principal investigator. Mark Logue, PhD, research assistant professor at BUSM and Boston University School of Public Health and Clinton Baldwin, PhD, professor at BUSM, were co-first authors of the paper.
PTSD is a psychiatric disorder defined by serious changes in cognitive, emotional, behavioral and psychological functioning that can occur in response to a psychologically traumatic event. Previous studies have estimated that approximately eight percent of the U.S. population will develop PTSD in their lifetime. That number is significantly greater among combat veterans where as many as one out of five suffer symptoms of the disorder.
Previous GWAS studies have linked the RORA gene to other psychiatric conditions, including attention-deficit hyperactivity disorder, bipolar disorder, autism and depression.
“Like PTSD, all of these conditions have been linked to alterations in brain functioning, so it is particularly interesting that one of the primary functions of RORA is to protect brain cells from the damaging effects of oxidative stress, hypoxia and inflammation,” said Miller.
Participants in the study were approximately 500 male and female veterans and their intimate partners, all of whom had experienced trauma and approximately half of whom had PTSD. The majority of the veterans had been exposed to trauma related to their military experience whereas their intimate partners had experienced trauma related to other experiences, such as sexual or physical assault, serious accidents, or the sudden death of a loved one. Each participant was interviewed by a trained clinician, and DNA was extracted from samples of their blood.
The DNA analysis examined approximately 1.5 million genetic markers for signs of association with PTSD and revealed a highly significant association with a variant (rs8042149) in the RORA gene. The researchers then looked for evidence of replication using data from the Detroit Neighborhood Health Study where they also found a significant, though weaker, association between RORA and PTSD.
“These results suggest that individuals with the RORA risk variant are more likely to develop PTSD following trauma exposure and point to a new avenue for research on how the brain responds to trauma,” said Miller.
This study was supported by the National Institute on Mental Health of the National Institutes of Health under award number R01 MH079806 and a grant from the Department of Veterans Affairs.
BUSM Study Identifies Adenosine Receptor’s Role in Regulating High Fat Diet-Induced Obesity and Type 2 Diabetes
A recent study led by Boston University School of Medicine (BUSM) demonstrates that the A2b-type adenosine receptor, A2bAR, plays a significant role in the regulation of high fat, high cholesterol diet-induced symptoms of type 2 diabetes. The findings, which are published online in PLoS ONE, also identify A2bAR as a potential target for the treatment of type 2 diabetes.
Katya Ravid, DSc/PhD, professor of medicine and biochemistry and director of the Evans Center for Interdisciplinary Biomedical Research at BUSM, led this study. Colleagues from Ravid’s lab who collaborated on this research include Hillary Johnston-Cox, BSc (MD/PhD, 2014) and Milka Koupenova-Zamor, PhD. Noyan Gokce, MD, associate professor of medicine at BUSM, and Melissa Farb, PhD, a postdoctoral fellow at BUSM, also collaborated on the study.
Diets that are high in fat and cholesterol induce changes in how the body regulates blood glucose levels. Exercise induces an increased production adenosine, a metabolite produced naturally by cells. A2bAR, a naturally occurring protein receptor found in the cell membrane, is activated by adenosine. This receptor is known to play an important role in regulating inflammation, which is associated with type 2 diabetes and obesity.
To examine the association of A2bAR activation with a diet high in fat and cholesterol, the researchers used an experimental model that lacked A2bAR and compared the results with a control group. When the experimental model group was given a diet high in fat and cholesterol, there was an increase in the development of obesity and signs of type 2 diabetes. The signs demonstrated in the study included elevated blood glucose levels and increased in insulin levels. When the control group was given the same diet, however, the levels of A2bAR increased, resulting in decreased insulin and glucose levels and obesity.
A novel link also was identified between the expression of A2bAR, insulin receptor substrate 2 (IRS-2) and insulin signaling. The results showed that the level of IRS-2, a protein that has previously been shown to mediate the effect of insulin, was impaired in tissues of the experimental model lacking A2bAR, causing higher concentrations of blood glucose. When A2bAR was activated in the control group using a pharmacologic agent with a diet high in fat and cholesterol, the level of IRS-2 was upregulated, lowering blood glucose.
“The pharmacologic activation of A2bAR demonstrated its newly identified role in signaling down to regulate the levels of IRS-2, which then improved the signs of high fat diet-induced type 2 diabetes,” said Ravid.
The prevalence of type 2 diabetes and obesity continues to increase in developed countries and both factors are known to contribute to the development of cardiovascular disease. According to the World Health Organization, 346 million people worldwide have diabetes and 90 percent of those people have type 2 diabetes.
To correlate these results in humans, the researchers then examined fat tissue samples from obese individuals. The results showed that A2bAR expression is high in fat from obese individuals, marked by inflammation, compared to lean ones, and is strongly correlated with IRS-2 expression.
“Our study suggests the important role of A2bAR in maintaining the level of IRS-2, a regulator of glucose and insulin homeostasis,” added Ravid.
This study was funded in part by the National Heart, Lung and Blood Institute under award numbers HL93149 (Katya Ravid) and HL084213 (Noyan Gokce). Click on the following link to view the study online: http://dx.plos.org/10.1371/journal.pone.0040584