News Article | May 11, 2017
BOSTON - Brucellosis is an infectious disease of livestock that may be transmitted to farm workers or consumers of unpasteurized dairy products. Easy to spread and hard to detect, the bacteria that cause the illness, Brucella species, are considered potential bioterror weapons. Yet, precisely because Brucella species are so dangerous to handle, research on this important disease-causing agent, or pathogen, has lagged behind that of other infectious diseases. Using an innovative method they developed to study the infectious process, investigators at Beth Israel Deaconess Medical Center (BIDMC) established a safer way to study Brucella. In an early test of the model, the research team observed a surprising and previously undocumented interaction during the infectious process. The presence of another pathogen appeared to improve the infectious potential of Brucella. The report was published in the journal Infection and Immunity. "Our toolkit is simple, versatile and applicable to any type of pathogen," said James Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC and Associate Professor of Pathology at Harvard Medical School. "This will be something that will help the scientific community study infectious disease more efficiently going forward because bacterial strains of interest can be constructed so easily, saving a lot of time and effort." Kirby and co-author Yoon-Suk Kang, PhD, a post-doctoral fellow in Kirby's lab used their technique to engineer a special strain of Brucella designed to emit colored light so they could more easily observe it infect host cells the lab. Common in goats, sheep, cattle, pigs and dogs, the four Brucella species capable of infecting humans are classified as potential biothreat organisms that must be studied in designated biosafety level 3 laboratories specially equipped to contain them. But Kirby and Kang, used another Brucella species, B. neotomae - known to infect only rodents - to see if it had enough in common with its more dangerous relatives to serve as a safer-to-handle investigational model for all Brucella species. While observing their custom strain, Kirby and Kang witnessed an unprecedented interaction between B. neotomae and Legionella pneumophila, the pathogen that causes Legionnaires' disease in humans. In addition to emitting light, the genetically-altered strain of B. neotomae was also designed to lack the physical structure it needs - a molecular syringe - to attack host cells. On their own, these engineered bacteria can't grow and multiply inside the host cell. However, when the host cells were co-infected with this strain of Brucella and L. pneumophila - also engineered to emit colored light - at the same time, the harmless B. neotomae thrived. In fact, Kirby notes this de-fanged version of B. neotomae grew better in the presence of L. pneumophila than virulent Brucella normally does without it. "Legionella provided all the factors Brucella needs for infection," said Kirby. "It was completely out of the blue. It highlights that pathogens can interact in unexpected ways. The whole is greater than the sum of its parts." The researchers' new technique creates the light-emitting bacteria by introducing genes for fluorescent proteins into their genomes. The concept itself is not new, but the genetic "tool kit" developed by Kirby and Kang greatly streamlines the process by using easy-to-manipulate genes called transposons - sometimes called jumping genes - to quickly and safely label the bacteria. Kirby and Kang's technique avoids one significant drawback to traditional means of labeling bacteria for study. Typically, scientists isolate bacteria for study by engineering drug-resistant strains and growing them in a petri dish infused with antibiotics, which will kill any bacteria not relevant to the experiment. "That's something we've been concerned about," said Kirby, whose lab also seeks to develop novel antimicrobials as drug-resistant bacteria become an increasing problem globally. "We don't want to make bacteria more resistant to antibiotics. Our toolkit won't confer resistance to anything that might be used in human therapy." This work was supported by grants to Kirby from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under award numbers R01AI099122, R21AI112694 and R21AI076691. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .
News Article | May 11, 2017
(BOSTON) - Leading hospital "superbugs," known as the enterococci, arose from an ancestor that dates back 450 million years -- about the time when animals were first crawling onto land (and well before the age of dinosaurs), according to a new study led by researchers from Massachusetts Eye and Ear, the Harvard-wide Program on Antibiotic Resistance and the Broad Institute of MIT and Harvard. Published online today in Cell, the study authors shed light on the evolutionary history of these pathogens, which evolved nearly indestructible properties and have become leading causes of modern antibiotic-resistant infections in hospitals. Antibiotic resistance is now a leading public health concern worldwide. Some microbes, often referred to as "superbugs," are resistant to virtually all antibiotics. This is of special concern in hospitals, where about 5 percent of hospitalized patients will fight infections that arise during their stay. As researchers around the world are urgently seeking solutions for this problem, insight into the origin and evolution of antibiotic resistance will help inform their search. "By analyzing the genomes and behaviors of today's enterococci, we were able to rewind the clock back to their earliest existence and piece together a picture of how these organisms were shaped into what they are today" said co-corresponding author Ashlee M. Earl, Ph.D., group leader for the Bacterial Genomics Group at the Broad Institute of MIT and Harvard. "Understanding how the environment in which microbes live leads to new properties could help us to predict how microbes will adapt to the use of antibiotics, antimicrobial hand soaps, disinfectants and other products intended to control their spread." The picture the researchers pieced together begins with the dawn of life. Bacteria arose nearly 4 billion years ago, and the planet has teemed with them ever since, including the sea. Animals first arose in the sea during the time known as the Cambrian Explosion, 542 million years ago. As animals emerged in a sea of bacteria, bacteria learned to live in and on them. Some bacteria protect and serve the animals, as the healthy microbes in our intestines do today; others live in the environment, and still others cause disease. As animals crawled onto land about 100 million years later, they took their microbes with them. The authors of the Cell study found that all species of enterococci, including those that have never been found in hospitals, were naturally resistant to dryness, starvation, disinfectants and many antibiotics. Because enterococci normally live in the intestines of most (if not all) land animals, it seemed likely that they were also in the intestines of land animals that are now extinct, including dinosaurs and the first millipede-like organisms to crawl onto land. Comparison of the genomes of these bacteria provided evidence that this was indeed the case. In fact, the research team found that new species of enterococci appeared whenever new types of animals appeared. This includes when new types of animals arose right after they first crawled onto land, and when new types of animals arose right after mass extinctions, especially the greatest mass extinction, the End Permian Extinction (251 million years ago). From sea animals, like fish, intestinal microbes are excreted into the ocean, which usually contains about 5,000 mostly harmless bacteria per drop of water. They sink to the seafloor into microbe-rich sediments, and are consumed by worms, shellfish and other sea scavengers. Those are then eaten by fish, and the microbes continue to circulate throughout the food chain. However, on land, intestinal microbes are excreted as feces, where they often dry out and most die over time. Not the enterococci, however. These microbes are unusually hardy and can withstand drying out and starvation, which serves them well on land and in hospitals where disinfectants make it difficult for a microbe. "We now know what genes were gained by enterococci hundreds of millions of years ago, when they became resistant to drying out, and to disinfectants and antibiotics that attack their cell walls," said study leader Michael S. Gilmore, Ph.D., senior scientist at Mass. Eye and Ear and Director of the Harvard Infectious Disease Institute. "These are now targets for our research to design new types of antibiotics and disinfectants that specifically eliminate enterococci, to remove them as threats to hospitalized patients," added Francois Lebreton, Ph.D., first author of the study and project leader for the Gilmore team. In addition to Drs. Earl, Gilmore and Lebreton, authors on the Cell paper include Abigail L. Manson, Ph.D., and Timothy J. Straub, of the Broad Institue of MIT and Harvard, and Jose T. Saavedra, of Massachusetts Institute of Technology. This research study was supported by Department of Health and Human Services/National Institutes of Health/National Institute of Allergy and Infectious Diseases grants AI072360, AI083214, HHSN272200900018C and U19AI110818. Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. Now united with Schepens Eye Research Institute, Mass. Eye and Ear is the world's largest vision and hearing research center, developing new treatments and cures through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. In the 2016-2017 "Best Hospitals Survey," U.S. News & World Report ranked Mass. Eye and Ear #1 in the nation for ear, nose and throat care and #1 in New England for eye care. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org. The Harvard Medical School (HMS) Department of Ophthalmology (eye.hms.harvard.edu) is one of the leading and largest academic departments of ophthalmology in the nation. More than 350 full-time faculty and trainees work at nine HMS affiliate institutions, including Massachusetts Eye and Ear, Massachusetts General Hospital, Brigham and Women's Hospital, Boston Children's Hospital, Beth Israel Deaconess Medical Center, Joslin Diabetes Center/Beetham Eye Institute, Veterans Affairs Boston Healthcare System, VA Maine Healthcare System, and Cambridge Health Alliance. Formally established in 1871, the department has been built upon a strong and rich foundation in medical education, research, and clinical care. Through the years, faculty and alumni have profoundly influenced ophthalmic science, medicine, and literature--helping to transform the field of ophthalmology from a branch of surgery into an independent medical specialty at the forefront of science. Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community. Founded by MIT, Harvard, Harvard-affiliated hospitals and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff, and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www. .
News Article | May 17, 2017
Patients treated by older hospital-based internists known as hospitalists are somewhat more likely to die within a month of admission than those treated by younger physicians, according to the results of a study led by researchers at Harvard Medical School and Harvard T.H. Chan School of Public Health. The findings, published May 16 in BMJ, reveal the largest gap in patient mortality--1.3 percentage points--between hospitalists 40 and younger and those 60 and older. The researchers note that the absolute difference in death rates was modest yet clinically meaningful--10.8 percent among patients treated by physicians 40 and younger, compared with 12.1 percent among those treated by physicians 60 and older. That difference translates into one additional patient death for every 77patients treated by physicians 60 and older, compared with those treated by doctors 40 and younger. "This difference is not merely statistically significant, but clinically important--it is comparable to the difference in death rates observed between patients at high risk for heart disease who are treated with proper heart medications and those who receive none," said study senior investigator Anupam Jena, the Ruth L. Newhouse associate professor of Health Care Policy at Harvard Medical School and an internal medicine physician at Massachusetts General Hospital. Importantly, the researchers note, physician age made no difference in mortality outcomes for doctors who managed large numbers of patients. That finding, the research team said, suggests that treating more patients may have a protective effect on maintaining clinical skills. "Residency training sharpens the clinical skills of newly minted physicians because it exposes them to a great number of cases, but as physicians get farther away from residency their clinical skill may begin to decline somewhat," said study first author Yusuke Tsugawa, a researcher in the Department of Health Policy and Management at Harvard T.H. Chan School of Public Health. "Our observation that physicians' age is inconsequential so long as they treat a high volume of patients supports that notion." The differences in patient mortality rates between physicians in their 40s and 50s were far less pronounced--11.1 percent and 11.3 percent, respectively. However, patient death rates crept up at a regular pace as physicians got older. The difference in death risk persisted even when investigators accounted for patients' age and the severity of their conditions. Patient readmission rates were not affected by physician age, but cost of care was slightly higher among older physicians. The researchers caution that their study is strictly observational, showing only a link, rather than cause and effect, between physician age and patient outcomes. Additionally, the analysis focused on one subspecialty--hospitalists--and the findings may not apply to other specialists. However, the team added, the results warrant a more in-depth analysis to tease out precisely what factors may be contributing to the higher mortality seen among patients treated by older physicians. "Older physicians bring invaluable richness of knowledge and depth of experience, yet their clinical skills may begin to lag behind over time," Jena said. "The results of our study suggest the critical importance of continuing medical education throughout a doctor's entire career, regardless of age and experience." The link between clinical performance and physician age has long fascinated doctors, health care policy researchers and social scientists alike. Although older physicians' depth of experience can boost clinical performance, there has been a lingering concern that rapidly emerging scientific evidence, new technologies and changing clinical guidelines may prove challenging to keep up with and incorporate into practice. The study findings, the authors said, point to the importance of physicians participating in continuing medical education courses throughout the entire span of their professional lives. They also suggest that direct measurement of patient outcomes--rather than reliance on surrogate measures such as test scores--may be a more meaningful gauge of how physicians' skills evolve over time. To tease out the interplay between physician age and patient mortality risk, investigators analyzed more than 730,000 hospital admission records of Medicare patients, ages 65 and older, treated between 2011 and 2014 by more than 18,800 hospitalists. To further define physician characteristics and the hospital environment in which they practice, researchers linked patient admission records to data obtained from Doximity, an online professional network for practicing physicians, as well as to data from the American Hospital Association's annual survey, which collects and analyzes hospital infrastructure, staffing, demographics, organizational structure and service lines, among other factors. Co-authors included Joseph Newhouse and Alan Zaslavsky, of Harvard Medical School, and Daniel Blumenthal, of Massachusetts General Hospital. Yusuke Tsugawa was supported in part by the Abe Fellowship (Social Science Research Council and the Japan Foundation Center for Global Partnership). Anupam Jena was supported by the Office of the Director, National Institutes of Health (NIH Early Independence Award, under grant 1DP5OD017897-01). Harvard Medical School has more than 11,000 faculty working in 10 academic departments located at the School's Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children's Hospital, Brigham and Women's Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.
News Article | May 25, 2017
New England College of Business (NECB) announced today that it is hosting a webinar entitled, “Living WELL, Working WISE Webinar – Mindfulness, What is it and What Can it Bring to the Workplace?” The webinar is free of cost and will feature Jody Daniels, Workplace Mindfulness Project Manager at the Center for Mindfulness and Compassion. With more than two decades of experience in human resources and six years of experience as a mindfulness practitioner, Daniels regularly provides top-notch mindfulness training programs and workshops for businesses and community organizations. Daniels will begin by introducing participants to the concept of mindfulness and walking them through the foundations of the practice. She will then delve into the specifics of mindfulness in the workplace, and detail the different ways in which organizations can incorporate mindfulness training into their culture. Daniels will also discuss the positive effects mindfulness can have on employees, and, as a result, their employers. There are several common myths about mindfulness, which, one by one, she will debunk. Finally, participants will be led through the process of getting started practicing mindfulness. The webinar will take place on Wednesday, June 28 at 11 a.m. EST. The Webinar ID is 507-566-227. RSVP for this online event here. About New England College of Business Founded in 1909, New England College of Business (NECB) is a leading higher education institution offering quality education and online degrees at the undergraduate and graduate levels. Serving students across the United States, NECB is an online college accredited by the New England Association of Schools and Colleges (NEASC) and is licensed by the Massachusetts Department of Higher Education. For information on NECB, visit https://www.necb.edu/, follow NECB on Twitter or connect with the school on Facebook. About the Center for Mindfulness and Compassion (CMC) Founded in 2014, CMC is a vibrant center integrating evidence-based mindfulness and compassion practice to foster an inclusive, caring and multi-cultural community that allows individuals to thrive. CMC is located within Cambridge Health Alliance and is affiliated with the Department of Psychiatry at Harvard Medical School. CMC’s mission is to integrate evidence-based mindfulness and compassion through five main channels: scientific research, patient care, workplace well-being, programming for the local community, and professional training and education. Jody is the Workplace Mindfulness Project Manager and an instructor in Mindfulness-Based Stress Reduction (MBSR) at the Center for Mindfulness and Compassion at Cambridge Health Alliance. She is also an adjunct professor in the graduate healthcare management program at the University of Massachusetts, Lowell. Formerly a senior V.P. with over 20 years’ experience in human resources with a mid-size healthcare organization, Jody also has over eight years’ clinical experience as a psychiatric social worker at various academic medical centers. She has trained at the Center for Mindfulness in Medicine, Health Care and Society at UMass Medical School in Worcester, MA and has been a mindfulness practitioner for the past six years.
News Article | May 24, 2017
Cancer -- the second leading cause of death in the United States -- claims more than 600,000 lives each year. Beyond the devastating human toll on individuals and families, the disease can drain a person's financial resources and strain the healthcare system as a whole. Since its passing in 2010, the Affordable Care Act -- commonly known as Obamacare -- has helped assuage some of the most devastating medical and financial burdens associated with cancer by improving insurance coverage and access to critical services. These are some of the findings in a series of newly published studies in a special May-June edition of The Cancer Journal documenting the effects of the law on cancer care in America. As the White House moves forward with its efforts to repeal Obamacare, it should strive to preserve -- and further boost -- these important advances, according to an introduction penned by Harvard Medical School professor health care policy expert Nancy Keating, who served as guest editor for the issue. "The ACA has improved access to and affordability of cancer-related care for millions of Americans," Keating said. "But some critical gaps remain and more needs to be done to ensure that all Americans with cancer have access to affordable cancer care of high quality. Efforts to repeal and replace the ACA must not lose sight of that goal." Each year more than 1.6 million Americans are diagnosed with cancer, a number projected to increase to 2.6 million by 2050. The ACA has provided access to health insurance for more than 20 million previously uninsured Americans. The act made it illegal for insurers to deny coverage based on current or previous cancer diagnosis and removed the limits on lifetime insurance coverage that a person can receive. The evidence so far suggests that key provisions of the ACA have improved access to screening and led to earlier diagnoses, particularly among people with lower education and income. By expanding eligibility for coverage under Medicaid -- the joint federal-state health insurance program for low-income people, women, children and those with disabilities -- the ACA has also ensured access to cancer treatments for more people and broadened access to clinical trials, Keating added. The Obamacare provision that made it possible for young adults to remain on their parents' insurance until age 26 has also led to higher rates of HPV vaccination--a critical preventive measure for cervical cancer--and greater use of effective treatments for women diagnosed with the disease, the research shows. In 2010, total spending on oncology care was $124 billion, and that number continues to rise. As more and more Americans live into older age, the number of cancer diagnoses will rise in coming years, Keating said. Coupled with ballooning spending on cancer care fueled by newer, more expensive treatments, this is bound to create financial turmoil for both individuals and the health care system as a whole. Out-of-pocket costs for individuals with cancer can lead to "financial toxicity," which experts now recognize as a side effect of cancer. The consequences of this financial burden, which are well-documented, include high rates of bankruptcy and delays in receiving cancer care and treatment. Higher costs bring devastating financial consequences. Cancer patients are more than twice as likely to experience bankruptcy than people without cancer, which can in turn lead to higher mortality rates. In light of this troubling trend, Keating said, it is ever more critical to preserve and enhance ACA provisions that can help curb the spending growth and reduce out-of-pocket expenses for cancer patients. Harvard Medical School has more than 11,000 faculty working in 10 academic departments located at the School's Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children's Hospital, Brigham and Women's Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.
News Article | May 4, 2017
Already extolled for their health benefits as a food compound, omega-3 fatty acids now appear to also play a critical role in preserving the integrity of the blood-brain barrier, which protects the central nervous system from blood-borne bacteria, toxins and other pathogens, according to new research from Harvard Medical School. Reporting in the May 3 issue of Neuron, a team led by Chenghua Gu, associate professor of neurobiology at Harvard Medical School, describes the first molecular explanation for how the barrier remains closed by suppressing transcytosis--a process for transporting molecules across cells in vesicles, or small bubbles. They found that the formation of these vesicles is inhibited by the lipid composition of blood vessel cells in the central nervous system, which involves a balance between omega-3 fatty acids and other lipids maintained by the lipid transport protein Mfsd2a. While the blood-brain barrier is a critical evolutionary mechanism that protects the central nervous system from harm, it also represents a major hurdle for delivering therapeutic compounds into the brain. Blocking the activity of Mfsd2a may be a strategy for getting drugs across the barrier and into the brain to treat a range of disorders such as brain cancer, stroke and Alzheimer's. "This study presents the first clear molecular mechanism for how low rates of transcytosis are achieved in central nervous system blood vessels to ensure the impermeable nature of the blood-brain barrier," Gu said. "There is still a lot we do not know about how the barrier is regulated. A better understanding of the mechanisms will allow us to begin to manipulate it, with the goal of getting therapeutics into the brain safely and effectively." The blood-brain barrier is composed of a network of endothelial cells that line blood vessels in the central nervous system. These cells are connected by tight junctions that prevent most molecules from passing between them, including many drugs that target brain diseases. In a 2014 study published in Nature, Gu and colleagues discovered that a gene and the protein it encodes, Mfsd2a, inhibits transcytosis and is critical for maintaining the blood-brain barrier. Mice that lacked Mfsd2a, which is found only in endothelial cells in the central nervous system, had higher rates of vesicle formation and leaky barriers, despite having normal tight junctions. In the current study, Gu, Benjamin Andreone, a neurology student at Harvard Medical School, and their colleagues examined how Mfsd2a maintains the blood-brain barrier. Mfsd2a is a transporter protein that moves lipids containing DHA, an omega-3 fatty acid found in fish oil and nuts, into the cell membrane. To test the importance of this function to the barrier, the team created mice with a mutated form of Mfsd2a, in which a single amino acid substitution shut down its ability to transport DHA. They injected these mice with a fluorescent dye and observed leaky blood-brain barriers and higher rates of vesicle formation and transcytosis--mirroring mice that completely lacked Mfsd2a. A comparison of the lipid composition of endothelial cells in brain capillaries against those in lung capillaries--which do not have barrier properties and do not express Mfsd2a--revealed that brain endothelial cells had around two- to five-fold higher levels of DHA-containing lipids. Additional experiments revealed that Mfsd2a suppresses transcytosis by inhibiting the formation of caveolae--a type of vesicle that forms when a small segment of the cell membrane pinches in on itself. As expected, mice with normal Cav-1, a protein required for caveolae formation, and that lacked Mfsd2a exhibited higher transcytosis and leaky barriers. Mice that lacked both Mfsd2a and Cav-1, however, had low transcytosis and impermeable blood-brain barriers. "We think that by incorporating DHA into the membrane, Mfsd2a is fundamentally changing the composition of the membrane and making it unfavorable for the formation of these specific type of caveolae," Andreone said. "Even though we observed low rates of vesicle formation and transcytosis in blood-brain barrier cells decades ago, this is the first time that a cellular mechanism can explain this phenomenon." By revealing the role of Mfsd2a and how it controls transcytosis in the central nervous system, Gu and her colleagues hope to shed light on new strategies to open the barrier and allow drugs to enter and remain in the brain. They are currently testing the efficacy of an antibody that potentially can temporarily block the function of Msfd2a, and whether caveolae-mediated transcytosis can be leveraged to shuttle therapeutics across the barrier. "Many of the drugs that could be effective against diseases of the brain have a hard time crossing the blood-brain barrier," Gu said. "Suppressing Mfsd2a may be an additional strategy that allows us to increase transcytosis, and deliver cargo such as antibodies against beta-amyloid or compounds that selectively attack tumor cells. If we can find a way across the barrier, the impact would be enormous." This work was supported by The National Institutes of Health (grants F31NS090669, NS092473), the Mahoney postdoctoral fellowship, the Howard Hughes Medical Institute, the Kaneb Fellowship, Fidelity Biosciences Research Initiative and the Harvard Blavatnik Biomedical Accelerator. Harvard Medical School has more than 11,000 faculty working in 10 academic departments located at the School's Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children's Hospital, Brigham and Women's Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.
News Article | May 8, 2017
New research from Boston Children's Hospital and Beth Israel Deaconess Medical Center (BIDMC) shows that chronic sleep loss increases pain sensitivity. It suggests that chronic pain sufferers can get relief by getting more sleep, or, short of that, taking medications to promote wakefulness such as caffeine. Both approaches performed better than standard analgesics in a rigorous study in mice, described in the May 8, 2017 issue of Nature Medicine. Pain physiologist Alban Latremoliere, PhD, of Boston Children's and sleep physiologist Chloe Alexandre, PhD, of BIDMC precisely measured the effects of acute or chronic sleep loss on sleepiness and sensitivity to both painful and non-painful stimuli. They then tested standard pain medications, like ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil. Their findings reveal an unexpected role for alertness in setting pain sensitivity. The team started by measuring normal sleep cycles, using tiny headsets that took electroencephalography (EEG) and electromyography (EMG) readings. "For each mouse, we have exact baseline data on how much they sleep and what their sensory sensitivity is," says Latremoliere, who works in the lab of Clifford Woolf, PhD, in the F.M. Kirby Neurobiology Center at Boston Children's. Next, unlike other sleep studies that force mice to stay awake walking treadmills or falling from platforms, Alexandre, Latremoliere and colleagues deprived mice of sleep in a way that mimics what happens with people: They entertained them. "We developed a protocol to chronically sleep-deprive mice in a non-stressful manner, by providing them with toys and activities at the time they were supposed to go to sleep, thereby extending the wake period," says Alexandre, who works in the lab of Thomas Scammell, MD, at BIDMC. "This is similar to what most of us do when we stay awake a little bit too much watching late-night TV each weekday." To keep the mice awake, researchers kept vigil, providing the mice with custom-made toys as interest flagged while being careful not to overstimulate them. "Mice love nesting, so when they started to get sleepy (as seen by their EEG/EMG pattern) we would give them nesting materials like a wipe or cotton ball," says Latremoliere. "Rodents also like chewing, so we introduced a lot of activities based around chewing, for example, having to chew through something to get to a cotton ball." In this way, they kept groups of six to 12 mice awake for as long as 12 hours in one session, or six hours for five consecutive days, monitoring sleepiness and stress hormones (to make sure they weren't stressed) and testing for pain along the way. Pain sensitivity was measured in a blinded fashion by exposing mice to controlled amounts of heat, cold, pressure or capsaicin (the agent in hot chili peppers) and then measuring how long it took the animal to move away (or lick away the discomfort caused by capsaicin). The researchers also tested responses to non-painful stimuli, such as jumping when startled by a sudden loud sound. "We found that five consecutive days of moderate sleep deprivation can significantly exacerbate pain sensitivity over time in otherwise healthy mice," says Alexandre. "The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli." Surprisingly, common analgesics like ibuprofen did not block sleep-loss-induced pain hypersensitivity. Even morphine lost most of its efficacy in sleep-deprived mice. These observations suggest that patients using these drugs for pain relief might have to increase their dose to compensate for lost efficacy due to sleep loss, thereby increasing their risk for side effects. In contrast, both caffeine and modafinil, drugs used to promote wakefulness, successfully blocked the pain hypersensitivity caused by both acute and chronic sleep loss. Interestingly, in non-sleep-deprived mice, these compounds had no analgesic properties. "This represents a new kind of analgesic that hadn't been considered before, one that depends on the biological state of the animal," says Woolf, director of the Kirby Center at Boston Children's. "Such drugs could help disrupt the chronic pain cycle, in which pain disrupts sleep, which then promotes pain, which further disrupts sleep." The researchers conclude that rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits or sleep-promoting medications at night, coupled with daytime alertness-promoting agents to try to break the pain cycle. Some painkillers already include caffeine as an ingredient, although its mechanism of action isn't yet known. Both caffeine and modafinil boost dopamine circuits in the brain, so that may provide a clue. "This work was supported by a novel NIH program that required a pain scientist to join a non-pain scientist to tackle a completely new area of research," notes Scammel, professor of neurology at BIDMC. "This cross-disciplinary collaboration enabled our labs to discover unsuspected links between sleep and pain with actionable clinical implications for improving pain management." "Many patients with chronic pain suffer from poor sleep and daytime fatigue, and some pain medications themselves can contribute to these co-morbidities," notes Kiran Maski, MD, a specialist in sleep disorders at Boston Children's. "This study suggests a novel approach to pain management that would be relatively easy to implement in clinical care. Clinical research is needed to understand what sleep duration is required and to test the efficacy of wake-promoting medications in chronic pain patients." Alexandre (BIDMC) and Latremoliere (Boston Children's) were co-first authors on the paper. Woolf (Boston Children's) and Scammell (BIDMC) were co-senior authors. Ashley Ferreira and Giulia Miracca of Boston Children's and Mihoko Yamamoto of BIDMC were coauthors. This work was supported by grants from the NIH (R01DE022912, R01NS038253). The Neurodevelopmental Behavior and Pharmacokinetics Cores at Boston Children's Hospital, the metabolic Physiology Core at BIDMC (P30DK057521) and P01HL09491 also supported this study. Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 404-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the primary pediatric teaching affiliate of Harvard Medical School. For more, visit our Vector and Thriving blogs and follow us on our social media channels @BostonChildrens, @BCH_Innovation, Facebook and YouTube. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .