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The incidence of heart disease is on the rise, and new therapeutic strategies are needed. Approaches based on stem cells, which can potentially preserve or even regenerate heart muscle cells damaged by ischemia – a hallmark of heart disease – are especially promising. Now, thanks to an $11.6-Million Program Project Grant (PPG) from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) under award number P01HL134608, scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) are poised to explore new possibilities in stem cell-based treatments for heart repair and regeneration. The project is aimed specifically at better understanding the regenerative capabilities of stem cell-derived microvesicles known as exosomes. The Principal Investigator on the new award is Raj Kishore, PhD, Professor of Pharmacology and Medicine and Director of the Stem Cell Therapy Program in the Center for Translational Medicine at LKSOM. According to Dr. Kishore, exosomes offer an exciting opportunity to develop a cell-free approach to stem cell-based therapy for heart disease.  “Previous attempts at stem cell therapy for heart disease did not work as hoped,” Dr. Kishore said. “In many cases, the stem cells themselves were injured by inflammation in the heart following injection or were not functioning optimally, having been weakened from disease, such as diabetes, or age.” Exosomes differ from stem cells in that they are not actually cells. Rather, they are tiny packages, roughly 50-150 nanometers in diameter, which are secreted by stem cells and taken up by neighboring tissue cells. They carry stem cell-specific small RNAs, proteins, and other cargo that mimic stem cell functions once released inside cells, giving them beneficial properties. “In heart cells, the cargo inside exosomes can carry out stem cell activities necessary for cardiac repair,” Dr. Kishore explained. Many questions remain, however, about the function of stem cell-derived exosomes in the heart. It is unknown, for example, whether factors such as a patient's age or disease characteristics modify the ability of exosomes to repair or regenerate heart tissue. To answer those questions, Dr. Kishore and colleagues Walter Koch, PhD, the William Wikoff Smith Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, and Director of the Center for Translational Medicine at LKSOM, and Steven R. Houser, PhD, Senior Associate Dean for Research, Vera Goodfriend Professor of Cardiovascular Medicine, Chair of the Department of Physiology, and Director of the Cardiovascular Research Center at LKSOM, devised three collaborative projects. Each of the researchers leads a specific project as part of the new grant. In Dr. Kishore's laboratory, work is focused on understanding the function and content of exosomes from bone marrow stem cells in healthy versus diabetic animals and animals with severe inflammation. “We want to know whether diabetes, which is common in heart disease patients, and inflammation from heart damage change exosome function or affect their cargo, and if so, what changes occur,” he said. “Identifying specific disease-related alterations in exosome molecules will allow us to target and modify the molecules in ways that are beneficial therapeutically for the heart.” Dr. Koch's team is examining signaling pathways in cardiac stem cells involving G-coupled receptor kinase-2 (GRK2). GRK2 inhibition potentially facilitates heart repair through mechanisms that involve alterations to the cargo of secreted exosomes. The third project explores exosomes from cortical bone stem cells, originally discovered in Dr. Houser's laboratory, and their role in heart repair. “This research gives us the opportunity to explore the idea that cell-based exosomes can be used to enhance repair of the heart after a heart attack,” Dr. Houser explained. “Exosomes from cortical bone stem cells may contain factors that could reduce cardiac injury and enhance regeneration.” The new award also funds two scientific cores supporting all 3 projects – an exosome isolation and characterization core directed by Dr. Kishore, and an animal surgery and physiology core led by John Elrod, PhD, Assistant Professor of Pharmacology at the Center for Translational Medicine at LKSOM. “This NIH Award is a testament to what we have built here at Temple,” Dr. Koch said. “Dr. Kishore has shown great leadership in organizing this multi-component grant.” The outcomes of the various projects are expected to have important impacts on the basic scientific understanding of exosomes in the heart and on clinical aspects of heart disease. “The goal will be to translate our findings into novel therapies for patients with heart disease,” Dr. Houser added. Editor’s Note: The content above is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

FINDINGS In a two-year UCLA-led study, nearly two-thirds of people with advanced melanoma responded positively to a treatment that combines the immunotherapy drug pembrolizumab with a herpes virus called talimogene laherpareovec, or T-VEC. Researchers led by Dr. Antoni Ribas found that the treatment's side effects were manageable, and comparable to side effects for people who took either pembrolizumab or T-VEC as a standalone treatment.   BACKGROUND    UCLA scientists are testing the combination of pembrolizumab (marketed as Keytruda) and T-VEC (marketed as Imlygic) as a treatment option for people with advanced melanoma that doesn't fully respond to either treatment separately.   T-VEC is a genetically modified version of the herpes simplex virus that causes cold sores, but is safe to use. T-VEC has already been approved for the treatment of melanoma and it works both by directly killing cancer cells and using a protein that attracts immune cells into the cancers. Pembrolizumab has become a standard-of-care treatment for advanced melanoma, and it is also being used to treat non-small-cell-lung cancer, cancers of the head, neck, kidney and bladder, and Hodgkin's disease. It works by taking the "brakes" off of the body's immune system, enabling it to attack cancer.   According to Ribas, people whose melanoma does not respond to pembrolizumab often lack a type of T cell called CD8+ in their tumors; the lack of CD8+ cells seems to prevent immunotherapy drugs from working. But the researchers believe those people might benefit from a combination therapy, because T-VEC attracts CD8+ immune cells to the tumors and pembrolizumab allows them to attack the cancer cells. METHOD The phase 1 clinical trial evaluated 21 people with advanced melanoma. Researchers injected patients' melanoma tumors with T-VEC for six weeks and then gave them infusions of pembrolizumab. Sixty-two percent of the patients had a partial or complete response, meaning that their tumors either shrank or were no longer detectable. IMPACT The combination therapy could provide an alternative treatment for people with melanoma whose tumors don't respond to other therapies. It also being tested in  people with head, neck and colon cancers.   AUTHORS Ribas, the study's lead author, is director of the immunology program at UCLA's Jonsson Comprehensive Cancer Center, professor of hematology and oncology at the David Geffen School of Medicine at UCLA, and a member of the Parker Institute for Cancer Immunotherapy.    JOURNAL The study is published online in the Cell. It is the first full report clinical trial to be published in the journal.   FUNDING Funding was provided by Amgen and Merck.   DISCLOSURES Ribas has received consulting fees from Amgen and Merck.   VIDEO ABSTRACT A video abstract of the study is available for media use. YouTube link: https://youtu.be/pm46mQ7SeXU. For a broadcast-quality version, please contact Peter Bracke at PBracke@mednet.ucla.edu.  

The most complete assessment yet of chronic disease in adult survivors of childhood cancer found they have a nearly two-fold greater cumulative burden of chronic health problems than the general public. The St. Jude Children’s Research Hospital study appears today in The Lancet and offers insights for improving health care delivery. Researchers used a statistical method called cumulative burden to track the lifelong impact of 168 chronic health conditions on 5,522 St. Jude adult survivors of childhood cancer, most enrolled in the St. Jude Lifetime Cohort study (St. Jude LIFE), and 272 community volunteers with no history of pediatric cancer. By age 50, the average pediatric cancer survivor had 17.1 chronic health conditions, including 4.7 that were severe/disabling, life-threatening or fatal. In contrast, the community volunteers averaged 9.2 chronic health conditions, of which 2.3 fell into those same categories. “The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions, some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said first and corresponding author Nickhill Bhakta, M.D., an assistant member of the St. Jude Department of Global Pediatric Medicine. “The results suggest that childhood cancer survivors may benefit from the integrated, specialized health care delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems,” he said. The models include patient-centered medical homes, which aim to provide patients with comprehensive, coordinated services to address their medical and psychosocial needs. Currently, most adult survivors rely on primary care providers, in consultation with medical specialists, to coordinate care and ensure survivors receive recommended health screenings and follow-up care. The U.S. is home to more than 420,000 childhood cancer survivors, a number that is expected to grow as cure rates improve and survivors live longer. St. Jude LIFE is a unique resource to identify, understand and begin to address the challenges survivors face. In this ongoing study, long-term childhood cancer survivors treated at St. Jude periodically return to campus for comprehensive clinical and functional tests and screenings. “This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by health care providers to disentangle and manage—time that community providers are unlikely to have,” Bhakta said. Previous studies from researchers at St. Jude and other centers have reported that survivors often have unrecognized and unmet health care needs. Historically, survivors have also struggled to maintain health insurance and access needed care. The study is the first to quantify and compare the cumulative burden of chronic disease in a clinically assessed group of childhood cancer survivors and community volunteers matched for age and sex. Cumulative burden was calculated using data from the comprehensive clinical assessments of 3,010 survivors enrolled in St. Jude LIFE and the 272 community volunteers. Rather than counting a health problem once at diagnosis, cumulative burden tracks health conditions as they occur, capturing subsequent heart attacks, cancer diagnoses or other recurring conditions that are missed by other statistical approaches. The analysis also included 21 variables related to survivors’ cancer treatment, including cumulative doses of radiation and chemotherapy agents. Statistical methods were used to calculate the cumulative burden of an additional 2,512 long-term St. Jude cancer survivors. The survivors’ cumulative burden varied substantially, based in part on survivors’ age at diagnosis, cancer treatment and treatment era. Second cancers, cardiovascular disease and endocrine disorders were significant contributors to survivors’ cumulative burden. A Web-based tool for calculating the cumulative burden of individual patients is in development to help patients and health care providers better understand and manage health care for individuals. Cumulative burden should also help researchers designing clinical trials understand the risks and benefits of different treatment strategies. The senior authors are Leslie Robison, Ph.D., chair of the St. Jude Department of Epidemiology and Cancer Control, and Yutaka Yasui, Ph.D., a member of the St. Jude Department of Epidemiology and Cancer Control. The other authors are Kirsten Ness, Malek Baassiri, Hesham Eissa, Frederick Yeo, Wassim Chemaitilly, Matthew Ehrhardt, Johnnie Bass, Michael Bishop, Kyla Shelton, Lu Lu, Sujuan Huang, Zhenghong Li, Eric Caron, Jennifer Lanctot, Carrie Howell, Timothy Folse, Daniel Green, Daniel Mulrooney, Gregory Armstrong, Kevin Krull, Tara Brinkman, Raja Khan, Deo Srivastava and Melissa Hudson, all of St. Jude; Qi Liu of the University of Alberta, Canada; and Vijaya Joshi, of the University of Tennessee Health Science Center, Memphis. The study was supported in part by grants (CA195547, CA21765) from the National Cancer Institute, the St. Baldrick’s Foundation and ALSAC, the fundraising and awareness organization of St. Jude.  

People with severe emphysema may breathe better after a minimally invasive procedure that places valves in the airways leading to diseased portions of their lungs, according to a randomized, controlled trial published online in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine. In “A Multicenter RCT of Zephyr® Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM),” European researchers report results from the first multicenter randomized, controlled trial comparing the therapeutic approach developed by Pulmonx Corp. to standard of care. The one-way Zephyr® valve keeps air from entering diseased regions of the lung, allowing healthier regions to expand and function better. The authors note that previous studies of the valves, which are placed using a bronchoscope, found that for patients with severe emphysema, this minimally invasive therapy represents an alternative to lung volume reduction surgery. Patients undergoing endobronchial valve (EBV) therapy appear to experience similar improvements in lung function, shortness of breath, exercise intolerance and quality of life--without the morbidity and mortality previously associated with surgery. “EBVs have been shown to work in single center trials, but these studies tend to be performed at centers, and by physicians, with considerable experience, so the results may not be generalizable to other centers,” said lead study author Samuel V. Kemp, MD,  a respiratory physician and an expert in Interventional bronchoscopy at Royal Brompton Hospital, in the U.K. “What is interesting about this multicenter trial is that the results are at least as good as the single center studies, even though some of the investigators were new to the technique.” Zephyr® valves have been certified for human use in Europe, but are not widely available to patients in all health care systems. The valves have not been approved in the U.S., though a clinical trial of the technology is underway to support an application to the Food and Drug Administration for approval. The European study enrolled 97 patients from 17 medical centers. The patients were all ex-smokers over the age of 40 who had severe heterogeneous emphysema (emphysema isolated to certain parts of the lung).  Sixty-five were randomly assigned to the EBV arm. On average, they received four valves to cut off diseased portions of their lungs that did not receive collateral ventilation (ventilation of the alveoli through passages that bypass the normal airways). The other patients received standard of care based on each medical center’s protocols for caring for patients following bronchoscopy. The researchers found: After three months, 55.4 percent of the EBV group had a ≥ 12 percent improvement (the minimum improvement the authors decided in advance would be clinically significant) in FEV1, the amount of air that can be forcefully exhaled in one second, compared to 6.5 percent of controls. After six months, the percentage of those in the EBV group meeting the minimum FEV1 improvement were 56.3 percent, compared to 3.2 percent of controls. The average increase in FEV1 in the EBV group was nearly 30 percent. After six months, secondary endpoints among those in the EBV group were also clinically and statistically significant, including being able to walk nearly 80 meters longer in six minutes, retaining 750 fewer milliliters of air (residual volume) upon maximum expiratory effort, exhibiting less shortness of breath on the modified Medical Research Council Dyspnea Scale and reporting higher quality of life on the St. George’s Respiratory Questionnaire. The most common adverse event in the EBV group was a collapsed lung, which occurred in 29.2 percent of the patients. After six months, 30 of the 32 participants in the control arm left the study and received EBV therapy. The authors will continue to follow those who received EBVs for up to two years. “There has been a lot of skepticism about valves, largely owing to poorly designed early trials,” Dr. Kemp said. “TRANSFORM proves that EBVs are a safe and effective treatment for appropriately selected patients with severe emphysema.  “For these patients, the benefits of EBVs are far greater than standard medical therapy, so it is important that patients be assessed by a multidisciplinary team to determine if this treatment will help them breathe better.” Dr. Kemp added that for those patients with collateral ventilation, valves are not suitable and patients should be considered for lung volume reduction surgery.   The study was sponsored and funded by Pulmonx Corporation, Redwood City, California, U.S.A. Contact for Article Samuel V. Kemp, MD S.Kemp@rbht.nhs.uk +44 207 351 8021  

Researchers at UC Davis and other institutions have shown that mothers who take recommended amounts of folic acid around conception might reduce their children’s pesticide-related autism risk. In the study, children whose mothers took 800 or more micrograms of folic acid (the amount in most prenatal vitamins) had a significantly lower risk of developing autism spectrum disorder (ASD) – even when their mothers were exposed to household or agricultural pesticides associated with increased risk. The study appears today in the journal Environmental Health Perspectives.  “We found that if the mom was taking folic acid during the window around conception, the risk associated with pesticides seemed to be attenuated,” said Rebecca J. Schmidt, assistant professor in the Department of Public Health Sciences and first author on the paper. “Mothers should try to avoid pesticides. But if they live near agriculture, where pesticides can blow in, this might be a way to counter those effects.”  In the paper, which used data from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, researchers looked at 296 children between 2 and 5 who had been diagnosed with ASD and 220 who had developed typically. Mothers were interviewed about their household pesticide exposure during pregnancy, as well as their folic acid and B vitamin intake. The team also linked data from California Pesticide Use reports, which provide important details about agricultural spraying, with the mothers’ addresses.  Mothers who took less than 800 micrograms and encountered household pesticides had a much higher estimated risk of having a child who developed an ASD than moms who took 800 micrograms of folic acid or more and were not exposed to pesticides. The associated risk increased for women exposed repeatedly. Women with low folic acid intake who were exposed to agricultural pesticides during a window from three months before conception to three months afterward also were at higher estimated risk.  “Folic acid intake below the median and exposure to pesticides was associated with higher risk of autism than either low intake or exposure alone,” said Schmidt, a UC Davis MIND Institute faculty member. “The mothers who had the highest risk were the ones who were exposed to pesticides regularly.”  While folic acid did reduce the associated risk of a child developing autism, it did not entirely eliminate it.  “It would be better for women to avoid chronic pesticide exposure if they can while pregnant,” Schmidt said.  The authors caution that this is a case-control study that relied heavily on the participants’ memories. In addition, they have yet to establish a causal link. However, these results certainly warrant larger studies to validate them. The team is also eager to investigate the mechanisms that contribute to folic acid’s possible protective effects.  “Folate plays a critical role in DNA methylation (a process by which genes are turned off or on), as well as in DNA repair and synthesis,” said Schmidt. “These are all really important during periods of rapid growth when there are lots of cells dividing, as in a developing fetus. Adding folic acid might be helping out in a number of these genomic functions.”  Other researchers included Janie F. Shelton, Lora Delwiche, Robin L. Hansen, Sally Ozonoff, Deborah H. Bennett, Irva Hertz-Picciotto and Daniel Tancredi at UC Davis; Vladimir Kogan and Heather E. Volk at UCLA; and Claudia C. Ma Erin and C. McCanlies at the National Institute for Occupational Safety and Health.  This study was funded by the National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, part of the National Institutes of Health (R21-ES021330, R01-ES015359, P01-ES11269, 2K12HD051958, R21-ES19002, P30-ES023513 and U54-HD079125); The Environmental Protection Agency STAR program (R-42 829388 & R833292) and the UC Davis MIND Institute.  

Frequent e-cigarette use does help smokers quit — a finding that Georgetown Lombardi Comprehensive Cancer Center researchers say supports the use of e-cigarettes as a cessation aid for those trying to quit cigarette smoking.  But, they note, an examination of a recent national survey uncovers important clues about who’s successful at quitting and why. The findings, published in Nicotine & Tobacco Research, examined a national survey of more than 24,500 current or recent former cigarette smokers, which is the largest sample of smokers studied to date. This study, along with a July study published in the BMJ, provide some of the strongest evidence so far on the link between use of e-cigarettes and cessation, says the study’s lead author David Levy, PhD, professor of oncology at Georgetown Lombardi. However, Levy notes, there are important nuances in the data that impact a person’s success in quitting cigarette smoking. “Both cigarette quit attempts and quit success were directly related to the number of days of e-cigarette use,” Levy explains. “The odds of quit success increased by 10 percent with each additional day of e-cigarette use.” The data also show that among those making at least one quit attempt, quit success was lower among individuals who had used e-cigarettes at some point in the past, but higher among those with at least 5 days of e-cigarettes use in the last month. The data is drawn from a special tobacco use survey that, since 1992-1993, has been taken every 3-4 years as part of a population survey conducted monthly by the U.S. Census Bureau. The latest tobacco use survey, taken from 2014-2015, was co-sponsored by the National Cancer Institute and the U.S. Food and Drug Administration.  This survey, the Tobacco Use Supplement to the Current Population Survey (TUS-CPS), is designed to track long-term trends in tobacco use, cessation attempts and tobacco-related policies. All states are represented, and participants are interviewed either by telephone or in person.  The latest TUS-CPS consisted of three samples collected in July 2014, and in January and May of 2015. These samples included more than 150,000 respondents. Levy and his Georgetown Lombardi colleagues examined the relationship between frequencies of e-cigarette use, cigarette quit attempts and cigarette abstinence. Because of the dates of the survey, it includes the more current types of e-cigarettes that are more effective at delivering nicotine. "Our findings are consistent with randomized trials and those observational studies that measure frequency of e-cigarette use. These results support the use of e-cigarettes — especially, consistent use — as an effective smoking cessation aid. Since e-cigarettes are generally estimated to have a small proportion of the mortality risks of cigarettes, this represents an important life-saving intervention that doctors can recommend when other forms of treatment fail,” says Levy. Study co-authors include Zhe Yuan, MS, Yuying Luo, MS, and David B. Abrams, PhD, all from Georgetown Lombardi Comprehensive Cancer Center. The authors report having no personal financial interests related to the study. The study was funded by grants from the National Institute of Drug Abuse (R01DA036497) and the National Cancer Institute (P01-CA200512). About Georgetown Lombardi Comprehensive Cancer Center Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute as a comprehensive cancer center — the only cancer center of its kind in the Washington, DC area. A part of Georgetown University Medical Center and MedStar Georgetown University Hospital, Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future.   About Georgetown University Medical Center Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.  

Sleep apnea, left untreated for even a few days, can increase blood sugar and fat levels, stress hormones and blood pressure, according to a new study of sleeping subjects. A report of the study’s findings, published in the August issue of The Journal of Clinical Endocrinology & Metabolism, adds further support for the consistent use of continuous positive airway pressure (CPAP), a machine that increases air pressure in the throat to keep the airway open during sleep.  “This is one of the first studies to show real-time effects of sleep apnea on metabolism during the night,” says Jonathan Jun, M.D., assistant professor of medicine at the Johns Hopkins University School of Medicine and the paper’s senior author. Obstructive sleep apnea (OSA) affects 20 – 30 percent of adults, according to studies published in the American Journal of Epidemiology and Lancet Respiratory Medicine. It occurs when the upper airway closes off during sleep, temporarily interrupting breathing. While it is known that OSA is associated with risks for diabetes and heart disease, there has been no consensus on whether OSA is a cause of these disorders or just a marker of obesity, which predisposes one to diabetes and heart disease.  Previous metabolic studies in patients with OSA, the Johns Hopkins researchers say, usually collected data while participants were awake, thus obtaining only a snapshot of OSA’s aftermath, not the actual sleep period when OSA occurs. To better understand how OSA affects metabolism, researchers measured free fatty acids in the blood, glucose, insulin and cortisol (a stress hormone) while participants slept in a sleep laboratory at the Johns Hopkins Bayview Medical Center. Participants’ brain waves, blood oxygen levels, heart rates and breathing, along with eye and leg movements, were also recorded each night of the study. In total, Jun and colleagues drew blood samples from 31 patients with moderate to severe OSA and a history of regular CPAP use for two nights. The researchers drew samples every 20 minutes starting at 9 p.m. and until 6:40 a.m. Every participant spent one night at the lab with CPAP or after CPAP had been stopped for two nights, in random order, separated by one to four weeks. The average age of all participants was 50.8 years old and the average body mass index indicated obesity, a common characteristic of those with sleep apnea. Two-thirds of the study group was male and a quarter had a history of non-insulin dependent diabetes. Some 22.6 percent of participants were African American, 9.7 percent Asian, 64.5 percent Caucasian and 3.2 percent Hispanic. Jun and colleagues found that CPAP withdrawal caused recurrence of OSA associated with sleep disruption, elevated heart rate and reduced blood oxygen. CPAP withdrawal also increased levels of free fatty acids, glucose, cortisol and blood pressure during sleep. The more severe the OSA, the more these parameters increased. In addition, glucose increased the most in patients with diabetes. Increases in fatty acids, glucose and cortisol have all been linked to diabetes. The Johns Hopkins team also found that blood pressure increased and the arteries showed signs of stiffness in the morning without CPAP. Over time, increased blood pressure and vascular stiffness can contribute to cardiovascular disease. Jun emphasized that the study was limited by studying people with severe OSA and obesity, thus limiting the ability to apply the findings to all OSA patients. The researchers also did not compare CPAP use to a sham CPAP control group to exclude a potential placebo effect. But Jun says that the study provides further evidence that sleep apnea isn’t just a manifestation of obesity, diabetes and cardiovascular disease — it can directly aggravate these conditions. They are continuing to recruit patients in order to answer more questions about which patients are most vulnerable to the impacts of OSA.  This study emphasizes the importance of CPAP therapy for OSA to prevent its metabolic and cardiovascular consequences. Sometimes, patients with OSA have a hard time tolerating CPAP. It is important that these patients contact a sleep specialist who can assist them with CPAP use, or who can recommend alternative therapies. Other authors on this paper include Swati Chopra, Aman Rathore, Haris Younas, Luu V. Pham, Aleksandra Beselman, Il-Young Kim, Robert R. Wolfe and Vsevolod Y. Polotsky of The Johns Hopkins University; Chenjuan Gu of the Shanghai Jiao Tong University School of Medicine; and Jamie Perin of the University of Arkansas for Medical Sciences. Funding for the research was provided by the American Academy of Sleep Medicine Foundation Junior Faculty Award (106-JF-14), the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK072488), and the National Heart, Lung, and Blood Institute (1K08HL109475, R01HL133100, R01HL128970).  

UCLA RESEARCH ALERT   Brief primary care intervention cut risky drug use among Latinos by 40 percent   FINDINGS  New research finds that brief interventions in a primary care clinic can reduce patients’ risky substance use by 4.5 days per month — a 40 percent decline among the Latino patients surveyed — compared with people who did not receive the brief intervention. This corresponds to two fewer weekends of drug use per month, or one less day of use per weekend, or a shorter monthly binge period.   BACKGROUND The findings duplicate those of the Quit Using Drugs Intervention Trial, or Project QUIT — conducted by the same research team in 2011-2012 — which is aimed at reducing risky drug use. The risky use includes casual, frequent or binge use of illicit drugs, such as cocaine, heroin and methamphetamine, or the misuse of prescription medications, without showing physiological or psychological signs of severe substance use. The trial was conducted in a primary care clinic in East Los Angeles. Previous research demonstrated that a brief intervention by a primary care physician can significantly reduce risky drug use among patients. Subsequent research found that misuse of both prescription and illicit drugs is prevalent enough in Tijuana and East Los Angeles that community clinics in those areas should routinely, though discreetly, screen for it.   For this study the researchers took the same principles they used in Project QUIT and applied them in one of the community clinics where they had tested the intervention.   METHOD The trial was conducted from March through October 2013, with a follow-up after three months, and involved 65 people at a federally qualified health center in East Los Angeles. To reduce the stigma of bringing up a sensitive topic like substance use, several strategies were used. All individuals in the waiting room were approached by bicultural and bilingual research assistants, who introduced themselves as part of a UCLA research team. If they agreed to participate in the “living well” screening, they completed an anonymous, self-administered questionnaire on a “talking touch-screen” tablet computer. Of those people who screened positive for risky drug use, 32 received the intervention and 33 did not; 51 people completed the three-month follow-up.   People in the intervention group received advice from a clinician about how to quit or reduce their risky drug use; watched a video that reinforced the clinician’s advice; were given a health education booklet; and participated in up to two 20- to 30-minute follow-up telephone coaching sessions. The control patients received usual care and cancer screening information, consisting of both a “video doctor” presentation and an information booklet on cancer screening. The control group was given information about cancer screening, rather than about drugs, to provide them some level of attention in an area unlikely to affect their drug use. The primary outcome was self-reported reduction in the number of days of drug use over the past 30 days validated by urine drug testing.   IMPACT The findings, which showed greater success than the original study, support the idea that all patients should be discreetly screened for risky drug use during primary care visits to their doctors. Also, primary care doctors should be able to routinely provide their patients with advice on reducing risky drug use. If replicated in other clinics, this reduction in substance use could potentially affect an estimated 20 million risky drug users in the United States and prevent them from progressing to severe substance use requiring specialty treatment   AUTHORS The study’s authors are Dr. Lillian Gelberg, Ronald Andersen, Melvin Rico, Mani Vahidi, Steve Shoptaw, Barbara Leake and Kyle Singleton of UCLA; Guillermina Natera Rey of National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City; Martin Serota of AltaMed Health Services Corp., Los Angeles; and Sebastian Baumeister of Technical University of Munich in  Germany.   JOURNAL The study will be published in the peer-reviewed journal Drug and Alcohol Dependence.     FUNDING The research was funded by the National Institute on Drug Abuse of the National Institutes of Health, and by the U.S. State Department’s Bureau of International Narcotics and Law Enforcement.   Media Contact: Enrique Rivero 310-267-7120 erivero@mednet.ucla.edu  

An existing drug may one day protect premenopausal women from life-altering infertility that commonly follows cancer treatments, according to a new study. Women who are treated for cancer with radiation or certain chemotherapy drugs are commonly rendered sterile. According to a 2006 study from Weill Cornell Medicine, nearly 40 percent of all female breast cancer survivors experience premature ovarian failure, in which they lose normal function of their ovaries and often become infertile. Women are born with a lifetime reserve of oocytes, or immature eggs, but those oocytes are among the most sensitive cells in the body and may be wiped out by such cancer treatments. The current study, published in the journal Genetics, was led by John Schimenti, Cornell University professor in the Departments of Biomedical Sciences and Molecular Biology and Genetics. The study builds on his 2014 research that identified a so-called checkpoint protein (CHK2) that becomes activated when oocytes are damaged by radiation. CHK2 functions in a pathway that eliminates oocytes with DNA damage, a natural function to protect against giving birth to offspring bearing new mutations. When the researchers irradiated mice lacking the CHK2 gene, the oocytes survived, eventually repaired the DNA damage, and the mice gave birth to healthy pups. The new study explored whether the checkpoint 2 pathway could be chemically inhibited. “It turns out there were pre-existing CHK2 inhibitor drugs that were developed, ironically enough, for cancer treatment, but they turned out not to be very useful for treating cancer,” said Schimenti, the paper’s senior author. Vera Rinaldi, a graduate student in Schimenti’s lab, is the paper’s first author. “By giving mice the inhibitor drug, a small molecule, it essentially mimicked the knockout of the checkpoint gene,” Rinaldi said. By inhibiting the checkpoint pathway, the oocytes were not killed by radiation and remained fertile, enabling birth of normal pups. “The one major concern,” Schimenti said, “is that even though these irradiated oocytes led to the birth of healthy mouse pups, it’s conceivable that they harbor mutations that will become manifested in a generation or two, because we are circumventing an evolutionarily important mechanism of genetic quality control. This needs to be investigated by genome sequencing." When doctors recognize the need for oocyte-damaging cancer treatments, women may have their oocytes or even ovarian tissue removed and frozen, but this practice delays treatment. Also, when women run out of oocytes, women’s bodies naturally undergo menopause, as their hormonal systems shift. “That is a serious dilemma and emotional issue,” Schimenti said, “when you layer a cancer diagnosis on top of the prospect of having permanent life-altering effects as a result of chemotherapy, and must face the urgent decision of delaying treatment to freeze oocytes at the risk of one’s own life.” The study sets a precedent for co-administering this or related drugs and starting cancer therapy simultaneously, though such interventions would first require lengthy human trials. “While humans and mice have different physiologies, and there is much work to be done to determine safe and effective dosages for people, it is clear that we have the proof of principle for this approach,” Schimenti said. The study was funded by the National Institutes of Health.  

Newswise — Opioids often are the go-to pain killer for everything from back aches and injuries to post-surgical pain, as evidenced by the more than 300 million prescriptions written each year. While they can be effective for moderate to severe short-term pain, opioids are not without risk. Because they have significant side effects, including an increased risk of addiction and overdose, the American Society of Anesthesiologists suggests those who take opioids ask some tough questions – including if it is time to consider other options. Kathleen Callahan understands the dilemma. She suffers from a chronic condition that causes painful cysts that required multiple surgeries resulting in post-surgical and chronic pain for which she took opioids for years. Despite being on a high dose of opioids, Kathleen still had chronic pain. So she turned to Anita Gupta, D.O., Pharm.D., a physician anesthesiologist who specializes in pain medicine, to find an alternative.  “Opioids are a valuable tool for recovery and acute pain but when I was on them long-term, I couldn’t function and I wasn’t enjoying life. I couldn’t be involved in my children’s lives and my work was suffering,” said Kathleen, a mother of two who works in finance. “Dr. Gupta said she could help me manage my pain so my life was livable. With her help, I weaned off all the medication except for the occasional ibuprofen for bad days. Now I can exercise again. I can go to the gym. I can go out with my friends and enjoy myself. I go to my kids’ baseball games, school plays and other activities.”  “Kathleen and I had some difficult discussions. I didn’t think the medications were right for her anymore and I was truthful with her,” said Dr. Gupta. “She asked some hard questions and having these conversations really developed trust between us so I could help her move forward and cope with her pain. Since she’s been opioid-free she’s vibrant, energetic and successful in her career. She has her life back.” If you are taking opioids or your physician has prescribed them, the American Society of Anesthesiologists suggests asking yourself (and your physician) some tough questions: Why was I prescribed opioids? Some doctors assume patients will demand what many consider the strongest and most effective pain relief and therefore prescribe opioids automatically. But there are many medication and non-medication options, so ask your doctor if other pain relief methods might be effective. If you and your doctor decide opioids are the best option, ask how long you should take them. In most cases, opioids are most beneficial for short-term moderate to severe pain – such as a few days after surgery or an injury. If you continue to have pain, ask your physician about alternatives. Are opioids affecting my quality of life? Opioids have many side effects, ranging from severe constipation, mental fogginess and nausea to depression. Kathleen said she was “exhausted, cranky, depressed, constipated and gaining weight.” The opioids affected her relationship with her kids because she wasn’t involved in their lives. That’s when she realized opioids were worse than the pain itself, motivating her to seek other options. What are my concerns about taking opioids – or stopping them? With the media attention surrounding opioid risks, many people feel conflicted about taking them. They may: worry they are being judged by others; be concerned about becoming addicted and/or potentially overdosing; and fear they won’t be able to control their pain if they stop taking opioids. It’s important to talk to your physician if you have any of these concerns or others. For example, ask about obtaining naloxone, a drug that can reverse an overdose if injected quickly enough. If you take opioids when you don’t have pain or use more than directed, you may develop a dependence or addiction.     Is it time to consider other methods of pain management? Opioids are most effective in the short term. While some people with chronic pain find relief with opioids, they should be part of a “multimodal” plan, which features other methods of pain management. Discuss alternative therapies with your doctor, including: Injections or nerve blocks – Injection with local anesthetics can short circuit muscle and nerve pain. Electrical stimulation and spinal cord stimulation – Electrical impulses sent by devices that are implanted or worn on the body can block pain. Physical therapy – Strengthening muscles can improve function and decrease pain. Physical therapy may include other pain-easing methods such as whirlpools, ultrasound and massage. Acupuncture – Very thin needles placed in various parts of the body can interrupt pain signals. Biofeedback, meditation, deep breathing and relaxation – These methods can ease pain by controlling involuntary functions such as heart rate, as well as learning to ease muscle tension. Surgical procedures – In some cases, surgery can correct painful abnormalities or sever the nerves causing the pain.  What type of physician can best help manage my pain? If you have severe or ongoing pain, be sure to see a physician who specializes in pain management, such as a physician anesthesiologist. These specialists have received four years of medical school and additional training in a specialty, such as anesthesiology or physical medicine and rehabilitation, followed by an additional year of training to become an expert in treating pain. They have the expertise to best help you manage your pain. “These are the difficult questions that no one wants to discuss, but physicians and patients need to talk about them so the patient can get better,” said Dr. Gupta. “If they’re prescribed opioids, patients need  to ask how long they’re going to be on them as well as additional options for treating pain. With all the tools we have there is a lot more patients can do for their pain with their physicians’ help.” “My entire outlook on pain management has changed,” says Kathleen. “If I didn’t have a physician anesthesiologist on my medical team I believe right now I would be very overweight, inactive, not part of my children’s lives and clinically depressed. When you have a physician like Dr. Gupta who you trust and who shows you there’s another way, it’s just amazing. It’s night and day. I’m even starting to run in marathons.” For more information download ASA’s Asking the Hard Questions About Opioids. To learn more about the critical role physician anesthesiologists play before, during and after surgery, visit www.asahq.org/WhenSecondsCount. THE AMERICAN SOCIETY OF ANESTHESIOLOGISTSFounded in 1905, the American Society of Anesthesiologists (ASA) is an educational, research and scientific society with more than 52,000 members organized to raise and maintain the standards of the medical practice of anesthesiology. ASA is committed to ensuring physician anesthesiologists evaluate and supervise the medical care of patients before, during and after surgery to provide the highest quality and safest care every patient deserves. For more information on the field of anesthesiology, visit the American Society of Anesthesiologists online at asahq.org To learn more about the role physician anesthesiologists play in ensuring patient safety, visit asahq.org/WhenSecondsCount.  Like ASA on Facebook, follow @ASALifeline on Twitter.