Benjamin Wolozin, MD, PhD, associate professor of pharmacology and neurology at BUSM,
By Gina P Orlando
Researchers Find Insulin Status an Important Determinant of the Positive Effect of Weight Reduction on Vascular Function
Researchers from Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) have found that among obese people who had lost considerable weight, those with high insulin levels–a marker of insulin resistance in the body–were the most likely to experience better blood vessel function following the weight loss. These findings appear online in the Journal of the American College of Cardiology.
Obesity has emerged as one of the most critical health care problems in the U.S. and worldwide with nearly 70 percent of the U.S. population currently overweight or obese. Of major concern are the disproportionate cases of severe obesity (body mass index [BMI] ≥ 40 kg/m2), which tripled during the 1990s. Nearly a third of adults and 17 percent of children in the U.S. are now obese with 65 million additional cases estimated by 2030. While obesity confers serious health concerns and increased all-cause mortality, the vast majority of deaths are due to cardiovascular causes such as ischemic heart disease and stroke.
Researcher prospectively followed 208 overweight or obese patients (BMI ≥25 kg/m2) receiving medical/dietary (48 percent) or bariatric surgical (52 percent) weight loss treatment during a period of approximately one year. They measured plasma metabolic parameters and vascular endothelial function using ultrasound at baseline and following weight loss intervention, and stratified analyses by median plasma insulin levels.
They found that individuals with higher baseline plasma insulin levels (above median >12 uIU/ml), who had greater than 10 percent weight loss had significantly improved brachial artery macro-vascular flow-mediated vasodilation and micro-vascular reactive hyperemia. In contrast, vascular function did not change significantly in the lower insulin group (≤12 uIU/mL) despite similar degree of weight loss. In analyses using a five percent weight loss cut-point, only micro-vascular responses improved in the higher insulin group.
“Our study has shown that insulin status is an important determinant of the positive effect of weight reduction on vascular function with hyperinsulinemic patients deriving the greatest benefit,” explained corresponding author Noyan Gokce, MD, FACC, associate professor of medicine at BUSM and Director of Echocardiography at BMC. “Reversal of insulin resistance and endothelial dysfunction may represent key therapeutic targets for cardiovascular risk reduction in obesity,” he added. Their data also suggest that at least 10% weight loss is needed for comprehensive vascular benefit, which may in part explain the negative findings of the recently published Look Ahead study findings (NEJM 2013).
Funding for this study was provided by National Institutes of Health (NIH) grants HL081587,HL1145675; HL084213; HL109790; HL102299; HL081587; HL083801; HL083269; HL75795; K12 HL083781; HL081587; HL1145675; HL081587; HL1145675; HL084213 and P30DK046200.and an American Heart Association Postdoctoral Fellowship grant 12POST11780028.
With soaring obesity rates in the U.S., the American Medical Association has classified obesity as a disease. This major shift in healthcare policy brings much needed medical attention to obese patients. However, this definition of obesity focuses on a single criterion of Body Mass Index (BMI), which includes a large group of persons with high BMI who are metabolically healthy and not at high risk for type 2 diabetes, cardiovascular disease or obesity-associated cancers.
In a review article published online in Endocrinology, Gerald V. Denis, PhD, professor of pharmacology and medicine and James A. Hamilton, PhD, professor of physiology and biophysics at Boston University School of Medicine (BUSM), discusses the importance of eliminating healthy obese persons from unnecessary pharmaceutical treatments of the disease.
Previous studies have shown that the total volume of fat around the heart in obese persons is detrimental to some organ functions, but that total pericardial fat is not predicted by BMI. Thus, noninvasive imaging, such as magnetic resonance imaging (MRI), of pericardial fat could help to identify cardiovascular risks that are not clearly coupled with BMI. In addition, this could provide an opportunity to find blood biomarkers, which are the best indicators of relative metabolic status.
“These insights strongly suggest that BMI alone is insufficient to classify patients as obese and unhealthy; metabolism, body composition, fat deposition and inflammatory status must be part of a comprehensive health evaluation,” said Denis.
Certain non-obese individuals may also benefit from a noninvasive imaging approach, as well. Although not apparent physically, many lean people experience significant risks for these same diseases because of chronic low-level inflammation and fat deposition in or around vital organs. Where BMI alone would exclude this group from screenings, weighing more factors that contribute to pericardial fat could save lives.
“By using a more individualized approach, some obese persons can be relieved of the additional stigma of classification in a major disease category. In addition, unnecessary medical interventions and costs can be reduced,” added Hamilton.
The work was supported in part by grants from the National Institutes of Health (NCI and NIDDK; R56 DK090455 –GVD) and a subcontract from the Boston Area Diabetes Endocrinology Research Center (BADERC; P30 DK057521). G.V.D. is Chair-Elect of the Obesity and Cancer Section of The Obesity Society.
A person’s skin pigment, which determines hair color and skin tone, is influenced by the melanocortin-1 (MC1R) gene receptor. For the population’s one to two percent of redheads, a mutation in MC1R accounts for their red hair color and typical light skin.
Now researchers from Beth Israel Deaconess Medical Center (BIDMC) and Boston University School of Medicine (BUSM) have discovered that the same MC1R mutation responsible for the red hair phenotype also promotes an important cancer-causing pathway. The new findings, reported on-line today in the journal Molecular Cell, help to explain the molecular mechanisms that underlie redheads’ well-known risk of developing melanoma, providing new insights for treating and preventing this dangerous type of skin cancer.
Melanoma is the least common but the most lethal of skin cancers. Accounting for 75 percent of all skin-cancer deaths, melanoma originates in pigment-producing skin cells called melanocytes. Melanoma is believed to be a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, cell differentiation and cell death and increase an individual’s susceptibility to ultraviolet (UV) radiation. Two types of UV radiation – UVA and UVB – can mutate DNA in skin cells and lead to melanoma.
“In this current study, we have demonstrated that the mutation MC1R-RHC promotes the PI3K/Akt signaling pathway when a red-haired individual is exposed to UV radiation,” explains co-senior author Wenyi Wei, PhD, an investigator in the Department of Pathology at BIDMC and Associate Professor of Pathology at Harvard Medical School. PI3K/Akt is a well-known cancer-causing pathway, implicated in breast cancer, ovarian cancer and lung cancer.
Previous work by the study’s co-senior author Rutao Cui, MD, PhD, a member of the BUSM Department of Dermatology, had demonstrated that MC1R plays a key role in protecting melanocytes from UV-induced DNA damage. In this current study, Wei and Cui wanted to find out how this was happening.
Led by co-first authors, Lixin Wan, PhD, a member of the Wei laboratory at BIDMC and Juxiang Cao, PhD, a member of the Cui lab at BUSM, the scientific team embarked on a series of experiments in both cell cultures and mouse models. Their experiments showed that in normal circumstances, MC1R was binding to PTEN, a well-known tumor suppressor gene. PTEN acts to safeguard against cancer; without PTEN, the end result is elevated signaling in the cancer-causing P13K/Akt pathway.
The team then went on to demonstrate that MC1R-RHC mutations found in red-haired individuals lacked this protective mechanism. “As a result, upon UVB exposure, we saw an increased destruction of PTEN in the mutated pigment cells,” says Wei. The team additionally found that in these same MC1R-RHC pigment cells, elevated PI3K/Akt activity was boosting cell proliferation and was synchronizing with another well-known cancer mutation in the BRAF gene (found in nearly 70 percent of human melanomas) to further accelerate cancer development. In support of these results, note Wei and Cui, another research group at Massachusetts General Hospital recently demonstrated that expression of the BRAF gene mutation in the melanocytes of mice carrying a mutated MC1R gene led to a high incidence of invasive melanomas.
“Together, our findings provide a possible molecular mechanism as to why red-haired individuals harboring MC1R mutations are much more susceptible to UV-induced skin damage than individuals with darker skin, resulting in a 10-to100-fold higher frequency of melanoma,” says Wei.
The authors note that this newly established link between MC1R and PTEN will be a starting point for future studies, adding that it remains unclear why only MC1R genetic variants linked to the red hair phenotype – but not all MC1R variants – are unable to bind to PTEN following UV exposure.
“We think that MC1R variants, in combination with mutations in the BRAF gene, could be used as markers of an increased risk of developing melanoma,” explains Wei. The authors add that these new findings suggest that drug inhibitors that target the PI3K/Akt signaling pathway might be used in combination with Vemurafenib, a drug that targets the BRAF oncogenic protein, to treat melanoma patients who have both BRAF and MCIR variants.
The Boston Marathon bombing brought international attention back to the devastating effects of terrorism. There were numerous victims with severe injuries that needed immediate attention. A novel study in Arthritis Care & Research, a journal published by Wiley on behalf of the American College of Rheumatology (ACR), presents cases from Boston-area hospitals where victims were treated, examining the medical response and imagining technologies used to save lives and limbs.
On April 15, 2013, at approximately 2:49 p.m. two pressure-cooker bombs exploded one after the other at the Boston Marathon finish line. As a result of the bombings, there were three fatalities and 264 casualties, with the most severe injuries involving lower extremities of those located closest to the blasts. Shrapnel disbursed by the bombs included pieces of metal, nails and ball bearings. Injuries resulting from the Marathon bombing are relevant to the fields of rheumatology, rehabilitation, orthopedics and musculoskeletal imaging.
“In an era of terrorism, even clinicians serving non-military patients need to understand the spectrum of injuries caused by bomb explosions,” explains lead author Dr. Ali Guermazi, Professor of Radiology at Boston University School of Medicine and one of the many specialists treating bombing victims at Boston Medical Center. “Critically ill bomb-blast patients needed quick assessments of their injuries, which had the most devastating effects to the lower limbs.”
According to the Centers for Disease Control and Prevention (CDC), bombing survivors have the highest incidence of injury to soft tissue and musculoskeletal systems with the most extreme injury being traumatic amputation, which is reported in up to 3% of cases. The CDC defines primary blast injuries as those caused by the blast wave—extremely compressed air moving away from the explosion—that can damage the lungs, bowel and ears. As the wave moves from the site of the explosion it creates a vacuum, which pulls materials and debris back toward the source of the bomb blast—the refilling of this void is known as the blast wind.
Victims from the Boston Marathon bombing were subject to blast waves and blast wind resulting in soft tissue damage, limb fractures, and amputations. The study demonstrates the systematic need to exam each extremity for musculoskeletal, neurological and vascular damage. In accordance with previous evidence, radiography (X-ray) and computed tomography (CT-scan) should be used liberally to detect foreign objects, to define basic penetration patterns, and assess bony and soft tissue injuries.
Dr. Guermazi concludes, “While blast injuries within civilian populations are rare in the U.S., when they do occur it challenges the medical community to rapidly respond to concurrent evaluation and treatment of many victims. We suggest that in urgent situations, like the Boston Marathon bombing, radiology resources be used liberally to save the lives and limbs of patients.”
Lee Wetzler, MD, associate program director for research in the section of infectious diseases at Boston University School of Medicine (BUSM) and an attending physician in the section of infectious diseases in the department of medicine at Boston Medical Center, was awarded a four-year, $2.35 million grant from the National Institutes of Health (NIH) to study the development of a gonococcal vaccine. This goal of this work, which is being done in collaboration with Scott Gray-Owen, PhD, at the University of Toronto, is to develop a new model for gonococcal vaccine evaluation and prioritize the feasibility of vaccine candidates to guide future research.
Wetzler, who also is a professor of medicine and associate professor of microbiology at BUSM, has a three-phase plan for developing a gonococcal vaccine. First he will analyze the immune response to vaginal gonococcal infection in laboratory models. The second phase is to determine whether infection with live or killed organisms will provide any protection in this model. The final phase is the evaluation of several vaccine candidates consisting of several bacterial outer membrane antigens.
For the past 30 years, researchers have unsuccessfully been working on the development of a gonococcal vaccine. Increasing antibiotic resistance has made the development of a vaccine for this disease vital and now urgent. The Centers for Disease Control now recommends only one class of antibiotics to treat gonorrhea due to antibiotic resistance in the previous alternative treatment options. Cases of resistance in this remaining class of antibiotics also are a worsening problem with treatment failures seen abroad though not yet in the US.
Wetzler and his team investigate innate and adaptive immunity – primarily in regards to vaccine development. He has done extensive research and has more than 50 publications regarding mostly Neisseria gonorrhoeae and Neisseria meningitides, the pathogens responsible for gonorrhea and a common cause of meningitis respectively. The team analyzes specific bacterial surface molecules in order to determine which antigens will trigger the appropriate host immune response seen in vaccination.
According to Wetzler, gonorrhea has numerous medical and public health repercussions. “This disease has potentially devastating outcomes specifically in women, causing pelvic inflammatory disease, tubal fibrosis and ectopic pregnancies. Additionally, concurrent gonorrhea infection in HIV patients facilitates the transmission of HIV by increasing viral replication,” he said.
Worldwide 88 million new cases of gonorrhea develop each year. In the setting of limited treatment options, abatement of the disease via vaccine is crucial. Wetzler and his team are optimistic that over the next few years they will make significant headway in regards to prevent this widespread and morbid disease.
David Harris, MD, PhD, chair and professor of biochemistry and Benjamin Wolozin, MD, PhD, professor of pharmacology and experimental therapeutics and neurology at Boston University School of Medicine (BUSM), have received Massachusetts Neuroscience Consortium (MNC) Awards. Each will receive a $250,000 grant allowing their teams to explore new therapeutic targets for Alzheimer’s disease.
Harris is developing a novel approach to the therapy of Alzheimer’s disease based on targeting a newly recognized molecular pathway responsible for neurodegeneration. Based on this approach, drug compounds have the potential to overcome some of the limitations of existing medications. Current treatments are largely ineffective and do not halt the cognitive decline associated with the disease.
“This award will significantly enhance our ability to develop improved therapies for Alzheimer’s disease by allowing us to interact with industry partners, which is an important element of drug development,” said Harris.
Harris’ laboratory at BUSM investigates the molecular and cellular mechanisms underlying two classes of human neurodegenerative disorders: prion diseases and Alzheimer’s disease. Prion and Alzheimer’s diseases are part of a larger group of neurodegenerative disorders, including Parkinson’s, Huntington’s and several other diseases.
Wolozin is developing compounds that inhibit aggregation and toxicity caused by TDP-43, a protein that forms aggregates in Alzheimer’s disease as well as other diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. His research investigates the molecular and biochemical mechanisms that cause diseases of brain aging, such as Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis.
“This grant emphasizes the importance of collaboration between BUSM and development programs at major pharmaceutical companies in the Boston area,” said Wolozin.
Principal Investigator of the project, Wolozin is working with Marcie Glicksman, PhD, and Kevin Hodgetts, PhD, co-directors of the Laboratory for Drug Discovery in Neurodegeneration (LDDN) at Brigham and Women’s Hospital. The teams will divide the work between biology and chemistry.
MNC comprises six pharmaceutical companies that have joined together to identify new targets in neuroscience. Unique for its proposed short-term, results-oriented projects, the consortium funds research of an array of diseases in an attempt to bring patients and their families closer to a cure for certain neurodegenerative diseases.
Researchers from Boston University School of Medicine (BUSM) and George Washington University (GWU) have developed a method to rapidly identify pathogenic species and strains causing illnesses, such as pneumonia, that could help lead to earlier detection of disease outbreaks and pinpoint effective treatments more quickly. The findings are featured online in the journal Genome Research.
Emerging sequencing technologies have revolutionized the collection of genomic data for bioforensics, biosurveillance and for use in clinical settings. However, new approaches are being developed to analyze these large volumes of genetic data. Principal investigator Evan Johnson, PhD, assistant professor of medicine at BUSM, and Keith Crandall, PhD, director of the Computational Biology Institute at GWU, have created a statistical framework called Pathoscope to identify pathogenic genetic sequences from infected tissue samples.
This unique approach can accurately discriminate between closely related strains of the same species with little coverage of the pathogenic genome. The method also can determine the complete composition of known pathogenic and benign organisms in a biological sample. No other method can accurately identify multiple species or substrains in such a direct and automatic way. Current methods, such as the standard polymerase chain reaction detection or microscope observation, are often imperfect and time-consuming.
“Pathoscope is like completing a complex jigsaw puzzle. Instead of manually assembling the puzzle, which can take days or weeks of tedious effort, we use a statistical algorithm that can determine how the picture should look without actually putting it together,” said Johnson. “Our method can characterize a biological sample faster, more accurately and in a more automated fashion than any other approach out there.”
This work will be relevant in a broad range of scenarios. For example, in hospitals, this sequencing method will allow for rapid screening of thousands of infectious pathogens simultaneously, while being sensitive enough to monitor disease outbreaks caused by specific pathogenic strains. Veterinarians can even apply the method in their practices. This research is also applicable outside of clinical settings, allowing officials to quickly identify agents of bioterrorism (e.g. in a tainted letter) and harmful pathogens on hard surfaces, soil, water or in food products.
“This approach has the ability to drastically change the process for identifying and combating pathogens, whether they’re in a hospital, veterinarian’s office or salmon stream,” Crandall said. Researchers plan to conduct more studies to further verify the efficacy of their approach, and will soon begin to work with the aquaculture industry, helping fishermen with water-quality surveillance.
Funding for this research was provided in part by the National Institutes of Health’s (NIH) National Human Genome Research Institute under grant award number R01HG00569.
David J. Salant, MD, professor of medicine, pathology and laboratory medicine at Boston University School of Medicine (BUSM) and chief of the section of nephrology at Boston Medical Center (BMC) has been named the recipient of the 2013 Jean Hamburger Award from the International Society of Nephrology (ISN). The award was presented at the World Congress of Nephrology in Hong Kong on June 1.
The Jean Hamburger Award recognizes outstanding research in nephrology with a clinical emphasis. The award was established in memory of Jean Hamburger, the “Professeuer de Paris,” pioneer of clinical nephrology and founding president of the ISN.
The International Society of Nephrology is dedicated to advancing the diagnosis, treatment, and prevention of kidney diseases in the developing and developed world. The society aspires to eliminate kidney disease worldwide.
“Beginning with basic research in experimental models, we now made the recent discovery of a major target antigen in a common form of autoimmune glomerular disease,” said Salant. “This award really recognizes the contributions of a succession of outstanding colleagues and fellows at BUSM over the past three decades.”
Salant has written several key papers on immunological kidney diseases, as well as editorials, reviews and book chapters on glomerular diseases and vasculitis of the kidney. He has delivered keynote lectures at major scientific congresses and he served as chairman of the American Board of Internal Medicine Subspecialty Board of Examiners in Nephrology.
Salant earned his medical degree from the University of the Witwatersrand in Johannesburg, South Africa. He completed his residency at Johannesburg General Hospital, where he also gained extensive experience in renal transplantation, dialysis and other aspects of clinical nephrology before coming to BMC and BUSM. He also is director of the renal training program at BUSM.
A new Boston University School of Medicine (BUSM) study has found that low-income and minority parents may be more receptive to vaccinating their daughters against Human Papillomavirus (HPV), while white, middle-class parents are more likely to defer the vaccination. The findings appear online in the May issue of the Journal of Health Care for the Poor and Underserved.
Cervical cancer incidence and mortality are markedly higher for low-income and minority women due to higher rates of HPV and limited access to screening and treatment. Vaccination for HPV has the potential to reduce health care disparities in cervical cancer rates if girls are vaccinated prior to sexual experimentation. Although providers felt that parents wanted to prevent cervical cancer in their daughters, some had concerns about safety of the vaccine and promoting early or unsafe sexual activity.
“Approximately 33,000 Americans will get an HPV-related cancer each year, many of which can be prevented by vaccination,” said the lead author Rebecca Perkins, MD, professor of obstetrics and gynecology at BUSM. “Solid communication between parents and providers is the key to improving HPV vaccination rates, which is what this study seeks to measure.”
Researchers interviewed 34 pediatric and family medicine physicians and nurse practitioners in four community health centers serving Boston’s low-income, minority populations. The providers answered open-ended interview questions about how they thought parents felt about vaccinating their daughters against HPV. They also were asked to role-play their HPV vaccination script using language they typically use to introduce the HPV vaccine to parents.
Immigrants, especially those from Latin America, viewed the vaccination more positively because they had experience with vaccine-preventable diseases and cervical cancer in their home countries. While providers did not note any difference in the sexual behaviors of adolescents from families of different ethnic backgrounds or incomes, they found that immigrant parents had more realistic impressions of their daughters’ sexual activity than White middle-class parents.
The findings of this study may be applicable to larger disparities seen nationwide in HPV vaccination rates. Funding for this study was provided by an American Cancer Society Mentored Research Scholar Grant MRSG- 09-151-01.
Domenic Ciraulo, MD, chief and chair of psychiatry at Boston Medical Center (BMC) and Boston University School of Medicine (BUSM) has been selected as one of the co-recipients of the inaugural Drew-Foley award by the Massachusetts Association of Mental Health (MAMH). The award was presented at the centennial anniversary of the MAMH Friend and Leader/Spirit of Compassion Reception on May 2.
This award is named after two former MAMH members, Paul Drew and Jim Foley, who were compassionate advocates for mental health care and advancement in the field of psychiatry. Drew served as the former executive vice president of BMC.
“I am honored to be a co-recipient of the first Drew-Foley Award. With their leadership and support our department was able to provide behavioral health programs to Boston’s neighborhoods,” said Ciraulo. “Whether responding to the drug problems with our city’s youth, or developing innovative programs for the mentally ill, we continue to support their work today,” he added.
With research support from the NIAAA, NIDA and the Department of Veterans Affairs, Ciraulo leads a research team that studies alcoholism and addiction with a focus on medication development, the interaction of psychosocial therapy and medication therapy, neuroimaging and clinical psychopharmacology. He has authored and co-authored more than 150 papers and has co-edited five books.
Ciraulo has served on national committees including FDA advisory panels, NIH scientific review groups and the American Psychiatry Association’s Council on Addiction Psychiatry. He is associate editor of the Journal of Clinical Psychopharmacology and a member of the editorial board of the American Journal of Drug and Alcohol Abuse.
A graduate of Georgetown University School of Medicine, Ciraulo completed his psychiatric residency at the Institute of Living at Hartford Hospital. Chief resident at the Somatic Therapies Unit of Massachusetts Mental Health Center, he also completed a Clinical Fellowship in Psychiatry at Harvard Medical School.
The Massachusetts Association of Mental Health is a private, not-for-profit tax-exempt corporation that is a leading voice for the creation of services for people with mental illnesses. The MAMH helps promote and advance community based housing, education, health care, employment and treatment for children, adolescents and adults with mental illnesses or emotional disorders. Its aim is to increase knowledge about mental illnesses and the effectiveness of treatment through educational outreach to the public at large or to specific segments, and to promote healthy life styles and behavior through preventative services and programs directed at children and adolescents. Since 1913, the MAMH has been recognized as an independent information resource within the mental health community.