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Newswise — PHILADELPHIA, PA — An online training program called HeadCoach increases managers' confidence in their ability to prevent and manage mental health issues among their staff, reports a trial in the July Journal of Occupational and Environmental Medicine. HeadCoach offers "a suite of both responsive and preventive strategies to help managers better understand and support the mental health needs of their staff," according to the report by Aimée Gayed, MCrim, of University of New South Wales, Sydney, and colleagues. In the study, 87 managers at Australian companies were assigned to the online training program; another 123 managers were assigned to a waiting list control group. About 37 percent of managers assigned to HeadCoach completed all modules of the program. This group had increased confidence in their ability to create a workplace that supported the mental health needs of their direct-report employees. The improvement remained significant at four months after training. Managers who completed training also used more responsive and preventive behaviors to create a mentally healthy working environment. The study wasn't able to show a significant impact on employees' psychological symptoms, based on follow-up questionnaires in 173 employees. Mental health problems such as anxiety, depression, and stress-related disorders are a major contributor to work absences and disability. Factors in the workplace may precipitate mental health conditions. Managers can play a key role in reducing the impact of work-related mental health risk factors, but they are uncertain of how to do so. "HeadCoach online mental health training is an effective and scalable way to improve managers' confidence and workplace practices around mental health," Ms. Gayed and coauthors conclude. They acknowledge the need for more research to show an impact on employees' mental health symptoms, including studies comparing online and face-to-face training programs.
Newswise — PHILADELPHIA -- Nearly a million Americans live with thyroid cancer and doctors will diagnose more than 50,000 new cases this year. Fortunately, the survival rate for this kind of cancer is one of the best. Five years after diagnosis, more than 98 percent of patients are survivors. Now a team of researchers led by Alliric Willis, MD, a thyroid surgeon in the Department of Surgery in the Sidney Kimmel Medical College at Thomas Jefferson University and researcher with the Sidney Kimmel Cancer Center – Jefferson Health, finds nearly a quarter of low-risk thyroid cancer patients receive more treatment than necessary. The practice carries potential long-term risk to the patient and added financial costs. The discovery could help to shift how doctors treat thyroid cancer patients. “Just as a patient can be at risk of under treatment, a patient can be at risk of over treatment,” says Dr. Willis, who published the work in the journal Surgical Oncology. “Our research really shines light on the fact that we are not treating all patients the same.” The thyroid is a butterfly-shaped gland that sits over the airway in the neck. The gland makes hormones that help to control heart rate, blood pressure, body temperature and how the body uses energy. When cells grow out of control in the thyroid, cancer develops. Typical treatment for thyroid cancers that have not spread to other parts of the body begins with surgical removal of the gland. After completing surgery, patients can then go on to receive a second therapy known as radioactive iodine ablation. Radioactive iodine ablation is therapy taken as a pill. Because iodine is preferentially taken up by the thyroid gland, which relies on iodine to produce hormones, the radiation dose becomes concentrated there. The high amount of radioactivity in the iodine kills off any lingering cancer cells. Historically, patients have had fantastic results with radioactive iodine ablation treatment, Dr. Willis says. But the therapy does not come without costs. Experts estimate the financial cost of radioactive iodine ablation exceeds $9 million dollars  per year across the country. Additionally, for several days to weeks after surgery, patients who receive the radioactive iodine treatment must stay away from small children and pets. “They’re virtually in isolation because the radioactivity will be on their clothing and on their sheets,” Dr. Willis says. The dose of radioactivity in the treatment is so high that airport security has picked up radioactivity from patients as well as their spouses. The treatment also carries the risk of permanent long-term side effects such as altering patients’ perception of taste and the development of other cancers, particularly leukemia. Yet patients who have low-risk thyroid cancer—cancers that are small and have not spread to other parts of the body—do not benefit from the additional treatment. “Low-risk thyroid cancer patients have a five-year survival rate that is greater than 97 percent, whether they receive radioactive iodine ablation after appropriate surgery or not,” Dr. Willis says. In 2015, the American Thyroid Association released guidelines for thyroid cancer treatment that indicated radioactive iodine ablation is not always necessary for patients with low-risk thyroid cancer. Based on the guidelines, Dr. Willis and team sought to identify groups of patients that are most at risk of being overly treated for thyroid cancer. “This is really important when we're talking population health and managing the  increasing cost of health care by more effectively and efficiently using our resources,”  says Dr. Willis. The researchers analyzed more than 32,000 thyroid cancer cases identified through the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) database. They found more than half of patients were low-risk. About 25 percent of the low-risk patients received radioactive iodine ablation treatment, the researchers report. Patients younger than 65 years old were most at risk of overtreatment, according to the study. Men were also more at risk of over treatment as were Hispanic and Asian patients. “Young healthy patients are certainly going to be willing to receive whatever treatment may benefit them, but again we're talking about something that's been demonstrated to be over treatment,” Dr. Willis says. Some low-risk patients had their lymph nodes removed in addition to the thyroid gland, even when the cancer had not spread to the lymph nodes. These patients were more likely to go on and have radioactive iodine ablation treatment. “That's particularly interesting because that tells you they may be in a setting where people are more aggressive in their approach to surgery and subsequent treatments,”  Dr. Willis says. “This is where guidelines such as those outlined by the American Thyroid Association, can really help. The guidelines can say this more extensive treatment is unnecessary. You will not have better outcomes because of it.” Dr. Willis hopes that his team’s research will make people more aware of the fact that some patients are at risk of over treatment. “I think it will make people more mindful of following recommended guidelines with all patients so that we can give each patient the most effective treatment and get the best outcomes possible,” he says.   Article reference: Ambria S. Moten, Huaqing Zhao, Alliric I. Willis, “The overuse of radioactive iodine in low-risk papillary thyroid cancer patients,” Surgical Oncology, https://doi.org/10.1016/j.suronc.2019.05.011, 2019.
Newswise — WASHINGTON—Women exposed to triclosan are more likely to develop osteoporosis, according to a study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.Triclosan is an endocrine-disrupting chemical being widely used as an antibacterial in consumer goods and personal care products, including soaps, hand sanitizers, toothpaste, and mouthwash. A person can be exposed to triclosan via consumer products and contaminated water. The FDA also banned triclosan from over-the-counter hand sanitizer in recent years.“Laboratory studies have demonstrated that triclosan may have potential to adversely affect the bone mineral density in cell lines or in animals. However, little is known about the relationship between triclosan and human bone health,” said the study’s corresponding author, Yingjun Li, Ph.D., of Hangzhou Medical College School of Public Health in Hangzhou, China. “As far as we know, this is the first epidemiological study to investigate the association between triclosan exposure with bone mineral density and osteoporosis in a nationally representative sample from U.S. adult women.”In this study, researchers analyzed data from 1,848 women in the National Health and Nutrition Examination Survey to determine the link between triclosan and bone health. They found women with higher levels of triclosan in their urine were more likely to have bone issues.Other authors of the study include: Shaofang Cai of The Second Affiliated Hospital of Xiamen Medical College in Xiamen, China; Jiahao Zhu, Chunhong Fan, Yaohong Zhong, and Qing Shen of Hangzhou Medical College; and Lingling Sun of The Second Affiliated Hospital of Zhejiang University School of Medicine in Hangzhou, China.The study received funding support from the National Natural Science Foundation of China and the Medical Science and Technology Project of Zhejiang Province.The study, “Association Between Urinary Triclosan with Bone Mass Density and Osteoporosis in the US Adult Women, 2005-2010,” will be published online, ahead of print.
Penn Medicine pilot finds increased job fulfillment, decreased burnout for critical care physicians working seven- versus 14-day rotations Newswise — PHILADELPHIA – Shortening the length of rotations in a medical intensive care unit (MICU) from the traditional 14-consecutive day schedule to only seven days helps mitigate burnout among critical care physicians, according to a new Penn Medicine pilot study. The study, published today in the American Journal of Respiratory and Critical Care Medicine, is the first to validate the efficacy of a truncated rotation in reducing the rate of burnout among critical care physicians. The team found the shorter rotations not only led to lower burnout rates – by as much as 41 percent – but the change also resulted in increased job fulfillment. “In critical care medicine, periods of extreme stress can contribute to high burnout. Our study shows that organizations can implement new strategies, such as shorter staffing rotations, that have a real impact on burnout rates and job fulfillment,” said the study’s lead author, Mark E. Mikkelsen, MD, MSCE, chief of Medical Critical Care and an associate professor of Medicine. “Based on our findings, we changed our scheduling approach to limit the number of consecutive days per rotation, and ensure adequate non-clinical time between rotations.” Work-related burnout, characterized by emotional or physical exhaustion as well as feeling cynical or detached, is common among physicians – particularly, intensivists, or critical care physicians, who care for critically ill patients. Recent research shows nearly half of the 10,000 critical care physicians practicing in the United States reported symptoms of severe burnout, which can lead to compassion fatigue, decreased quality of care and job turnover. In May 2018, Penn Medicine launched a pilot initiative across four critical care rotations, spanning the Hospital of the University of Pennsylvania (HUP) and Penn Presbyterian Medical Center, to identify effective strategies to mitigate burnout and maximize fulfillment. The team, who had found high rates of burnout among intensivists at the end of 14-day rotations, tested a strategy proposed by the Critical Care Societies Collaborative that called for limiting the maximum number of days worked consecutively. As a part of the pilot, intensivists in one unit, the Founders 9 MICU at HUP, had the option to attend for the traditional 14-day rotation or change their schedule to a seven-day rotation. Rotations in two other units were capped at seven consecutive days, while intensivists in the fourth unit worked a two-week rotation, with one weekend off. From May 2018 to February 2019, the team administered more than 180 surveys to 29 physicians at different points throughout the rotations, including on day seven of a 14-day rotation and between clinical rotations. They found burnout and fulfillment varied by the clinical rotation and length of rotation. For example, intensivists in in the Founders 9 MICU, a 24-bed unit staffed by two critical care physicians, fellows and internal medicine residents, responded with 61 percent burnout and 47 percent fulfillment rates. Meanwhile, the intensivists working a seven-day rotation in the Donner 3 MICU at HUP – an 8-bed unit, staffed by one critical care physician and two advanced practice providers – responded with a 24 percent burnout and 76 percent fulfillment rates. “While our main focus was measuring burnout and fulfillment rates, we also wanted to ensure the shorter rotations did not negatively impact our ability to educate the next wave of physicians whom are training here,” said author Meeta Prasad Kerlin, MD, MSCE, an assistant professor of Medicine and associate fellowship program director in the division of Pulmonary, Allergy and Critical Care. “Based on feedback from our critical care physicians, fellows, and residents, we found the shorter rotations may have, in fact, led to better education, as faculty felt they could be more engaged and energetic.” Additional Penn authors on the study include Brian J. Anderson, Lisa Bellini, William D. Schweickert and Barry D. Fuchs.
Newswise — Charlottesville, Va. (June 24, 2019)—Metabolomics, the study of small molecules the body produces during metabolism (metabolites) may be a future key to identifying diabetes-related kidney disease. The finding will be presented today at the American Physiological Society (APS)/American Society of Nephrology (ASN) conference, Control of Renal Function in Health and Disease, in Charlottesville, Va. Diabetes-related kidney disease is a common complication associated with type 2 diabetes. Diagnosis typically requires surgical biopsy of the kidney, “therefore, seeking noninvasive biomarkers to aid diagnosis and management is urgently needed,” wrote researchers from Nanfang Hospital of Southern Medical University in China and University of Pittsburgh School of Medicine. The research team studied metabolites in the blood of three groups of adults with diabetes. One group had type 2 diabetes without kidney disease. One group had early-stage diabetes-related kidney disease. One group had advanced diabetes-related kidney disease. The three groups were compared with healthy adults without diabetes. Using a current database containing numerous known metabolites, the researchers identified only seven metabolites shared among all the groups. Although all the volunteers had the same differentially expressed metabolites, the metabolites varied according to whether or not they had diabetes or early- and late-stage kidney disease. “Surprising differences in small-molecule metabolites may reflect underlying [diabetes-related kidney disease] and serve as biomarkers for [its] occurrence and development,” the researchers wrote. These results may help “establish an early warning system for [type 2 diabetes] patients to monitor the onset of [diabetes-related kidney disease] in the clinic setting,” said Dong Zhou, MD, PhD, of the University of Pittsburgh School of Medicine and co-author of the study. Haiyan Fu, MD, PhD, of Nanfang Hospital of Southern Medical University in China, and Dong Zhou, MD, PhD, of the University of Pittsburgh School of Medicine, will present “Metabolomics reveals signature of diabetic kidney disease” in the session “Renal Consequences of Obesity, Metabolic Syndrome and Diabetes” on Monday, June 24, at the Boar’s Head Resort.  
In normal human liver cells (left), Plasmodium parasites (red) develop into a circular, exoerythrocytic form that gives rise to malaria. But in cells lacking CXCR4 (right), the parasite remains trapped in its rod-shaped sporozoite form. Newswise — Researchers in Japan have discovered that the Plasmodium parasites responsible for malaria rely on a human liver cell protein for their development into a form capable of infecting red blood cells and causing disease. The study, which will be published June 12 in the Journal of Experimental Medicine, suggests that targeting this human protein, known as CXCR4, could be a way to block the parasite’s life cycle and prevent the development of malaria. According to the World Health Organization, there were an estimated 219 million cases of malaria in 2017, resulting in the deaths of approximately 435,000 people. Infected mosquitoes transmit Plasmodium parasites to humans in the form of rod-shaped sporozoites that travel to the liver and invade liver cells (hepatocytes). Once inside these cells, the Plasmodium sporozoites develop into spherical exoerythrocytic forms (EEFs) that eventually give rise to thousands of merozoites capable of spreading into red blood cells and causing malaria. “It seems likely that the transformation of Plasmodium sporozoites into EEFs is tightly controlled so that it only occurs in hepatocytes and not at earlier stages of the parasite’s life cycle,” says Masahiro Yamamoto, a professor at the Research Institute for Microbial Diseases of Osaka University. “However, we know very little about the host factors that regulate the differentiation of sporozoites in infected hepatocytes.” In the new study, Yamamoto and colleagues discovered that a hepatocyte protein called CXCR4 helps Plasmodium sporozoites transform into EEFs. Depleting this protein from human liver cells reduced the ability of sporozoites to develop into EEFs. Moreover, mice pretreated with a drug that inhibits CXCR4 were resistant to malaria, showing reduced levels of parasites in the blood and significantly higher survival rates following Plasmodium infection. Yamamoto and colleagues also identified a cell signaling pathway that causes hepatocytes to produce more CXCR4 in response to Plasmodium infection and determined that the protein aids the parasite’s development by raising the levels of calcium inside the cells. “Our study reveals that CXCR4 blockade inhibits Plasmodium sporozoite transformation in hepatocytes,” Yamamoto says. “Most anti-malaria drugs targeting Plasmodium-derived molecules eventually lead to drug resistance in these parasites. However, inhibitors targeting human proteins such as CXCR4 might avoid this problem and could be used prophylactically to prevent the development of malaria. Moreover, the CXCR4 inhibitor used in this study is already widely used in humans undergoing treatment for blood cancers, which could accelerate its repurposing as a new way of combating malaria.” Bando et al. 2019. J. Exp. Med. http://jem.rupress.org/cgi/doi/10.1084/jem.20182227?PR
Newswise — Researchers at the Fralin Biomedical Research Institute at Virginia Tech Carilion have revealed how a genetic message to produce healthy heart tissue is altered in the body during stress and aging to contribute to sudden cardiac death. The discovery published in today’s (Tuesday, May 28) Cell Reports centers on communication between heart cells and allows for the potential of developing targeted therapies to help people at risk of arrhythmias and heart attacks. Led by senior author James Smyth, an assistant professor with the Fralin Biomedical Research Institute’s Center for Heart and Reparative Medicine Research, scientists focused on how generally overlooked, untranslated regions of RNA that flank the genetic code become shorter during aging or while under stressful conditions. The slight change influences how the cell reads a genetic message to make proteins and build important cellular structures including channels that electrically couple the cells of the heart together to allow for coordinated contractions and the resultant efficient pumping of blood. “Typical understanding of the biology used to be as straightforward as ‘here’s the message, make a protein,’” said Smyth, who is also an assistant professor in the Department of Biological Sciences of the College of Science. “We know it is not that simple anymore.  It's actually dynamically regulated. If the cell is stressed, that message will be read differently.” “Using traditional means of detecting levels of message or levels of RNA in cells during stress or aging, you wouldn't see the changes we saw,” Smyth said. “We focused on how this untranslated region could be changed during stress and how that could influence how the cell reads the message.” During stress, such as conditions of oxygen deprivation that occur during ischemic heart disease or stroke, the untranslated regions become shorter, which changes how the cell synthesizes the encoded protein products and limits intercellular communication in heart cells. Researchers focused on a gene called GJA1, which provides instructions to make Connexin 43, the gap junction protein. Gap junctions directly couple the contents of adjacent cells and are essential to normal heart function, where they enable the rapid and organized spread of electrical impulses between cells that cause contractions of the heart muscle. Malfunctions in this electrical communication can cause signals in the heart to become disorganized and lead to irregularities that can lead to sudden cardiac death. “The more we identify these molecular, very fundamental mechanisms, the sharper we're going to get in therapeutics,” Smyth said. “By manipulating this biology, we are figuring out the downstream factors acting on the DNA or RNA. Hopefully we have found a powerful angle to develop therapeutics, such as small molecules for precise, safer treatments.” Researchers studied cardiac cells, mouse cell lines, and aged mouse heart tissue where they found increases in the major GJA1-encoded protein — which should spell healthier conditions between heart cells — but they also observed increased, but truncated, untranslated regions of RNA that shut down synthesis of other GJA1-encoded proteins that modulate gap junction formation. Scientists also exposed cardiac cells derived from human-induced pluripotent stem cells to reduced oxygen, which also revealed an increase in truncated, untranslated regions, demonstrating that this is a common response of untranslated regions of RNA to physiological stress that is conserved across species. The response also takes place in a variety of cells. “This activity occurs in cancer, heart, and brain cells,” Smyth said. “When we saw that, we knew it was a powerful piece of biology, because it was happening everywhere.” The study is the latest resulting from more than four years of work by members of the Smyth lab and others at Fralin Biomedical, a university-level research institute of Virginia Tech. Michael Zeitz, a research scientist at Fralin Biomedical Research Institute, is the first author of the study, which also involved Stefanie Robel, an assistant professor at Fralin Biomedical Research Institute and the School of Neuroscience of the Virginia Tech College of Science; postdoctoral associate Thomas Taetzsch, and associate professor Gregorio Valdez of the Fralin Biomedical Research Institute and the Virginia Tech College of Science.  Fralin Biomedical Research Institute graduate students Patrick Calhoun of the Department of Biological Sciences; and Carissa James and Kijana George of the Translational Biology, Medicine and Health graduate program, were also members of the research team.  The work was supported by the National Institute of Health and the American Heart Association.
Newswise — People who drink alcohol while using medications that interact with it are higher risk of harm from overdose, falls, and traffic accidents. In recent years, there has been a documented increase in alcohol-related adverse drug reactions and acute emergency room admissions. One group of medicines, known as central nervous system (CNS) depressants, was implicated in over 40% of alcohol-related adverse drug reactions between 2005 and 2011. CNS depressants include the ‘sedative─hypnotic’  medications (anxiolytics and sleeping medications) as well as prescription opioids such as hydrocodone and oxycodone.  To further investigate the interplay of alcohol and prescription medications, researchers at Washington University have assessed the changing prevalence of CNS depressant use among regular drinkers. They analyzed data from over 37,000 adults who participated in the US National Health and Nutrition Examination survey (which is overseen by the Centers for Disease Control and Prevention) between 1999 and 2014. They found that among participants who reported drinking regularly (once a week or more), the proportion that used sedative─hypnotic medications doubled to 6% between 1999 and 2014 ─with the increase driven by a large rise in prescribed sleep medications. The prevalence of prescribed opioid use among regular drinkers remained relatively high at around 4%, despite the known risks. While regular drinkers were less likely than infrequent or non-drinkers to use anxiolytics or opioid medications, they were just as likely to use sleep medications. The research also showed that people aged 40 plus were up to five times as likely as those in their twenties to use sedative─hypnotic medications; rates of binge drinking are also known to have increased in the over 40 age group in recent years. The number of people at risk for adverse alcohol─drug reactions has therefore risen markedly. Exposure to sedative─hypnotic medications may still be increasing, whereas prescription opioid use is stable but alarmingly common among regular drinkers. The over forties in particular continue to face an unnecessarily high risk of alcohol-related adverse drug reactions and poor outcomes.
UB-led research reveals how fluctuating air pollution at the Beijing Olympics affected local residents’ bodies at the level of metabolites Newswise — BUFFALO, N.Y. — A new University at Buffalo study based on levels before, during and after the Beijing Olympics reveals how air pollution affects the human body at the level of metabolites.  Researchers found that 69 metabolites changed significantly when air pollution changed. Their results were published today (May 29) in the journal Environmental Health Perspectives.  The study identified two major metabolic signatures, one consisting of lipids and a second that included dipeptides, polyunsaturated fatty acids, taurine, and xanthine. Many of those metabolites are involved in oxidative stress, inflammation, cardiovascular and nervous systems, researchers note.  The findings are based on the Beijing Olympics Air Pollution study, conducted during the 2008 Olympic Games in China, when temporary air pollution controls were implemented. The study was led by UB epidemiologist Lina Mu.  The study enrolled 201 adults prior to Beijing’s air quality improvement initiative, when air pollution was high. Researchers followed them during the Games, when air pollution was low, and afterward, when levels returned to their usual high in the city of 21 million people. A subset of 26 non-smokers aged 30 to 65 was selected for the metabolomics analysis.  Metabolites are small molecules that are the end products of environmental exposures, such as air pollution, and body metabolism. “Think of our body as a society. These metabolites fulfill different positions, such as teacher, farmer, worker, soldier. We need each one functioning properly in order to maintain a healthy system,” said Mu, PhD, associate professor of epidemiology and environmental health in UB’s School of Public Health and Health Professions.  “Our study found that the human body had systemic changes at the metabolite level before, during and after the 2008 Beijing Olympics, when ambient air pollution changed drastically,” said Zhongzheng Niu, a PhD candidate and a paper co-author.  The molecules mostly belonged to the lipid and dipeptide families.  The study provides researchers with a broader view of the molecular mechanism underlying the impact of air pollution on the human body. Most previous studies only looked at a small number of molecules. However, the human body is complex and molecules affect one another.  Mu and her colleagues used the “omics” method, a new platform that can measure a whole collection of all detectable metabolites — 886 in their study — simultaneously. Instead of examining these molecules one by one, Mu and her team used network analysis to analyze them all together.  “We found that these metabolites together depicted a relatively comprehensive picture of human body responses to air pollution,” said paper co-author Rachael Hageman Blair, associate professor of biostatistics at UB. She and her team developed the novel analysis method used in the study. The responses include cellular stability, oxidative stress, anti-oxidation and inflammation.  Researchers measured metabolomics repeatedly when air pollution was high, low and high. Such a design mimicked a “natural experiment” while controlling for variations unrelated to air pollution changes. This provided stronger evidence than previous studies.  Air pollution is an environmental exposure that can’t be avoided by people who live in places like Beijing. The World Health Organization reports that 91 percent of the world’s population lives in places where air quality exceeds WHO guidelines.  Once inhaled, air pollutants stimulate the body’s respiratory system, including the nose and lungs. Some cells in the body may be directly insulted by these air pollutants, their membrane may be broken, their secretion may be disordered, and they may send out signaling molecules to other organs for subsequent responses, Mu explains. Metabolites are all these broken membranes, secreted products and signals.  “Capturing these molecules tells us what is going on when people are exposed to air pollution,” Mu said.  Air pollution also induces cellular oxidative stress, which breaks cell membranes.  Researchers found that some molecules that serve as building blocks of cell membranes were elevated when air pollution levels rose. Broken cell membranes release different kinds of lipid molecules. Some of these lipid molecules, with the help of enzymes, turn to inflammatory molecules, which could be harmful to the body.  “The good thing is that we also found some protective molecules, namely antioxidants, also increased when air pollution is high, indicating our body has a defense system to reduce harm,” Mu said. Studies such as this one may help identify individuals most vulnerable to air pollution, as well as finding potential biological pathways to guide treatment that reduces harm to the body, Mu said.  Mu’s UB co-authors include Richard Browne, associate professor of biotechnical and clinical laboratory sciences, Jacobs School of Medicine and Biomedical Sciences; Matthew Bonner, associate professor of epidemiology and environmental health; and Mya Swanson, data manager/statistician, Department of Epidemiology and Environmental Health.  Furong Deng of Peking University is also a co-author.
Newswise — Researchers have gained a greater understanding of the biology of staphylococcus skin infections in mice and how the mouse immune system mobilizes to fight them. A study appears this week in the Proceedings of the National Academy of Sciences of the United States of America. Community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) typically causes skin infections but can spread throughout the body to cause invasive infections such as sepsis, and possibly death. These CA-MRSA bacteria are becoming increasingly resistant to multiple antibiotics, making them especially difficult to treat. In healthy people, the body’s natural immune defenses typically keep CA-MRSA infections in the skin, and appropriate antibiotics can effectively treat them. However, patients who are immunocompromised have difficulty fighting the bacteria, which can become invasive and cause life-threating infections. “While the human immune responses that protect against S. aureus infections have remained elusive, we have as a start determined in mice that protective immunity against MRSA is orchestrated by specific immune cells called gamma/delta T cells, which upon infection travel from the lymph nodes to the infected skin to initiate the protective host response,” says Lloyd Miller, M.D., Ph.D., an associate professor of dermatology at the Johns Hopkins University School of Medicine. Miller notes that CA-MRSA and other multidrug resistant bacteria are becoming a bigger problem in health care, as most antibiotics no longer work against these infections and few new antibiotics are being developed in the pipeline. In the case of CA-MRSA, sometimes only two or three oral antibiotics remain that can treat these infections. Miller and his team are working to understand the specific details of the mouse immune system’s MRSA-fighting program to develop a way to probe the human immune system to develop alternative immune-based treatments that could work along with antibiotic regimens, or eliminate the need for antibiotics altogether. In their previous research, Miller and his team discovered that a cytokine protein called IL-17 is critical for turning on the host defense against staph infections. However, until know, they did not know which cell produced it, particularly which type of T cell. Also, there are two types of IL-17, one called IL-17A and the other IL-17F, but the researchers didn’t know if one or the other or both are required to mount the host response against CA-MRSA. So they teamed up with colleagues at the National Institutes of Health (NIH) who had engineered mice that would glow different colors depending on which form of IL-17 the mouse was making. The researchers then injected MRSA in the skin of these mice and found that the infected skin glowed green and red. They concluded this to mean that both types of IL-17 are involved in the immune response to the bacteria.  “We were fairly certain that IL-17 was being made by T cells but we didn’t know if it was the T cells that are normally in the skin or T cells that were migrating from the lymph nodes to the site of infection,” says Miller. Using the same glowing mice, the team asked what would happen if it blocked T cells from leaving the lymph nodes and treated the mice with FTY720 (fingolimod), a drug normally used to treat multiple sclerosis by keeping T cells from mobilizing from lymph nodes and minimizing inflammatory responses. After administering FTY720 to the mice that had an MRSA infection, the researchers saw no glowing, which informed them that the IL-17 seen at the site of the MRSA infection in the skin was made solely by T cells that had migrated from the lymph nodes. The researchers then extracted cells from the infection site as well as cells from the lymph nodes both before and after infecting the mice with MRSA. They labeled these cells with different colors depending on the types of proteins found on the surface of each cell. In mice without MRSA, a particular type of T cells called gamma/delta T cells expanded dramatically after infecting the mice with MRSA. The team then set out to determine which exact cells were expanding. Working with colleagues at the University of California, Davis, the team determined the genetic sequences of all of the T cell receptors in the mouse lymph nodes before and after infecting the mice with MRSA. They found that only one type of gamma/delta T cell clone expanded with a specific T cell receptor. What’s called the V gamma 6/Vdelta 4(+) expanded from 2% to over 20% to fight MRSA. “We think that this one single gamma/delta T cell clone is mediating the protective IL-17 response in mice,” says Miller. “What’s more is that these results really relied on having the latest technologies available to scientists today. We couldn’t have figured this out 10 years ago, for example. “While it is not known if there is an exact parallel cell type in humans, we’re encouraged that we can find something similar, which means we could be well on our way to developing new T cell-based therapies against MRSA.” Next steps for this team involve examining the T cell responses in humans to determine if a similar mechanism exists. Other authors on this paper include Mark Marchitto, Carly Dillen, Haiyun Liu, Robert Miller, Nathan Archer, Roger Ortines, Martin Alphonse, Alina Marusina, Advaitaa Ravipati, Yu Wang, Angel Byrd, Bret Pinsker, Isabelle Brown, Emily Zhang, Shuting Cai, Nathachit Limjunyawong and Xinzhong Dong of Johns Hopkins; Alexander Merleev, Scott Simon and Emanual Maverakis of the University of California, Davis; Michael Yeaman of the University of California, Los Angeles; Wei Shen and Scott Durum of the National Institutes of Health and Rebecca O’Brien of National Jewish Health. This work was supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (R01AR069502 and R01AR073665), the National Institute of Allergy and Infectious Diseases (R21AI126896 [L.S.M.], U01AI124319 [to MRY] and R01AI129302 [to SIS]), and federal funds from the National Cancer Institute under Contract Number HHSN261200800001E (MRA) (to S.D.) and the Office of the National Institutes of Health Director (1DP2OD008752 [to EM]).