Newswise — Researchers at UC Davis Health and UC San Francisco have found a way to teach a computer to precisely detect one of the hallmarks of Alzheimer’s disease in human brain tissue, delivering a proof of concept for a machine-learning approach to distinguishing critical markers of the disease. Amyloid plaques are clumps of protein fragments in the brains of people with Alzheimer's disease that destroy nerve cell connections. Much like the way Facebook recognizes faces based on captured images, the machine learning tool developed by a team of University of California scientists can “see” if a sample of brain tissue has one type of amyloid plaque or another, and do it very quickly. The findings, published May 15 in Nature Communications, suggest that machine learning can augment the expertise and analysis of an expert neuropathologist. The tool allows them to analyze thousands of times more data and ask new questions that would not be possible with the limited data processing capabilities of even the most highly trained human experts. “We still need the pathologist,” said Brittany N. Dugger, PhD, an assistant professor in the UC Davis Department of Pathology and Laboratory Medicine and lead author of the study. “This is a tool, like a keyboard is for writing. As keyboards have aided in writing workflows, digital pathology paired with machine learning can aid with neuropathology workflows.” In this study, she partnered with Michael J. Keiser, PhD, an assistant professor in UCSF’s Institute for Neurodegenerative Diseases and Department of Pharmaceutical Chemistry, to determine if they could teach a computer to automate the laborious process of identifying and analyzing tiny amyloid plaques of various types in large slices of autopsied human brain tissue. For this job, Keiser and his team designed a “convolutional neural network” (CNN), a computer program designed to recognize patterns based on thousands of human-labeled examples. To create enough training examples to teach the CNN algorithm how Dugger analyzes brain tissue, the UCSF team worked with her to devise a method that allowed her to rapidly annotate or label tens of thousands of images from a collection half a million close-up images of tissue from 43 healthy and diseased brain samples. Like a computer dating service that allows users to swipe left or right to label someone’s photo “hot” or “not,” they developed a web platform that allowed Dugger to look one-at-a-time at highly zoomed-in regions of potential plaques and quickly label what she saw there. This digital pathology tool — which researchers called “blob or not” — allowed Dugger to annotate more than 70,000 “blobs,” or plaque candidates, at a rate of about 2,000 images per hour. The UCSF team used this database of tens of thousands of labeled example images to train their CNN machine-learning algorithm to identify different types of brain changes seen in Alzheimer’s disease. That includes discriminating between so-called cored and diffuse plaques and identifying abnormalities in blood vessels.  The researchers showed that their algorithm could process an entire whole-brain slice slide with 98.7% accuracy, with speed only limited by the number of computer processors they used. (In the current study they used a single graphics card like those used by home gamers.) The team then performed rigorous tests of the computer’s identification skills to make sure its analysis was biologically valid. “It’s notoriously hard to know what a machine-learning algorithm is actually doing under the hood, but we can open the black box and ask it to show us why it made its predictions,” Keiser explained. Keiser emphasized that the machine learning tool is no better at identifying plaques than Dugger, the neuropathologist who trained the computer to find them in the first place. “But it’s tireless and scalable,” he said. “It’s a co-pilot, a force multiplier that extends the scope of what we can accomplish and lets us ask questions we never would have attempted manually. For example, we can look for rare plaques in unexpected places that could give us important clues about the course of the disease. To promote use of the tool, the researchers have made it and the study data publicly available online. This has already generated interactions with other researchers who have evaluated the data and the algorithms in their own labs. In the future, the researchers hope that such algorithms will become a standard part of neuropathology research, trained to help scientists analyze vast amounts of data, tirelessly seeking out patterns that could unlock new insights into causes and potential treatments for the disease.  “If we can better characterize what we are seeing, this could provide further insights into the diversity of dementia,” Dugger said. “It opens the door to precision medicine for dementias.” She added, “These projects are phenomenal examples of cross-disciplinary translational science; neuropathologists, a statistician, a clinician, and engineers coming together, forming a dialogue and working together to solve a problem.” Other study authors included: Charles DeCarli, Lee-Way Jin and Laurel Beckett from UC Davis; Ziqi Tang of UCSF and Tsinghua University in Beijing, China, and Kangway V. Chuang of UCSF. The study was funded by an NIH P30 AG010129, Paul G. Allen Family Foundation Distinguished Investigator Award and the China Scholarship Council. The authors declare no conflicting interests.
Newswise — In experiments with pregnant mice infected with the Zika virus, Johns Hopkins Medicine researchers report they have successfully used a long-standing immunosuppressive drug to diminish the rate of fetal deaths and birth defects in the mice’s offspring. The U.S. Food and Drug Administration-approved medicine, anakinra, once commonly used to treat rheumatoid arthritis and other autoimmune diseases in newborns and adults, has largely been replaced by more effective drugs. However, in the Zika-infected mouse experiments, the drug appears to interfere with inflammation in the pregnant animals’ placentas, the researchers say. There also is evidence the drug directly reduces inflammation in fetal brains. A report on the findings was published in the April issue of the Journal of Clinical Investigation Insights. “Until now, the focus of research has been on finding vaccines and antiviral drugs, but our study strongly suggests that the placental immune response should not be overlooked as a target for treatment,” says Irina Burd, M.D., Ph.D., associate professor of gynecology and obstetrics and director of the Integrated Research Center for Fetal Medicine at the Johns Hopkins University School of Medicine. “Using an FDA-approved drug already shown to be safe in infants shortens the time that we may be able to quickly start clinical trials and get a potentially effective preventative measure approved and available to help decrease the harmful effects of Zika.” According to the U.S. Centers for Disease Control and Prevention, 10% of babies born in the U.S. to women with a Zika infection during pregnancy develop fetal brain birth defects that range from slow head growth to microcephaly, a condition marked by a very small head due to brain abnormalities. Zika can be spread by infected mosquitos or unprotected sex from an infected person, and is passed from a pregnant woman to her unborn child. Pregnant women with Zika are also at increased risk for miscarriage. In Burd’s earlier work in 2014 in the American Journal of Reproductive Immunology with mouse models of newborn brain injury, she found that anakinra protected newborn mice from brain damage when the pregnant mothers were treated with inflammatory protein, notably interleukin-1beta. For this study, the researchers first wanted to see how Zika may affect the placenta in pregnant mice with the virus to try to figure out the cause behind the fetal deaths and birth defects. They compared pregnant mice infected with strains of Zika found in Nigeria, Puerto Rico and Brazil to pregnant mice not infected with the virus. They found that mice with Zika turned on the gene that makes the protein for interleukin-1beta at higher levels in the placenta compared to non-infected mice. They also found higher levels in the placenta of the interleukin-1beta protein. Because Zika causes early overproduction of interleukin-1beta, the researchers turned to the drug anakinra to test its potential for alleviating the damaging effects to fetal mice of mothers with Zika. The researchers injected mice placentas with either 10 milligrams per kilogram of anakinra or with fluid without the drug. After eight days of in utero exposure to the virus, 1.8% of the 322 mice infected with Zika but not given the drug had birth defects such as contracted limbs with tightened muscles, kinked tails, and fused fingers and toes. None of the mice given the drug showed signs of these birth defects. Comparable to the defects shown in the mice, human babies with microcephaly-caused defects may have limb contractures. The researchers say it is important to note that the defects noted in the mice may vary from humans because each species develops differently.  The researchers also say that more fetal mice treated in utero with anakinra survived to full-term birth compared to untreated mice. In the pregnant mice with Zika, 39.2% of the mothers had fetal deaths. In mice with Zika given the drug in utero, 20.8% of the mothers had fetal deaths. Next, the researchers wanted see if the drug protected the brains of the mice born to mothers with Zika from inflammation. The researchers took mice immune system cells from the brain, called microglia, and infected them with Zika. After a day, microglia with Zika had made more cells, showing that the Zika was causing inflammation. They treated microglia infected with Zika with anakinra, and after 24 hours there were fewer microglia, suggesting that the drug protected the brain cells from inflammation. Five days after birth, the mice born treated with anakinra completed neurological and physical assessments that tested balance, movement, vision, depth perception and coordination. For example, in the coordination test, the mice were put on their backs and researchers measured how long it would take them to flip over. Mice given the drug flipped over to become upright about one second faster on average than mice without treatment, which the researchers say was significant for this kind of test. The researchers believe the drug was responsible for reversing the neurodevelopmental abnormalities that caused longer performance times. “Currently, there is no cure for Zika, but our study suggests that there may be FDA-approved medications like anakinra that have the potential to combat some of the worst effects of the virus,” says Sabra Klein, Ph.D., associate professor of molecular microbiology and immunology at the Johns Hopkins University Bloomberg School of Public Health. “ “Future studies are urgently needed to determine the possible benefits of such a drug in people,” says Burd. “More and more countries are affected by Zika. And it would be great for us to continue doing this research with the same rigor and funding so we can continue to fight this not only in the United States but, globally.” Other researchers who participated in the study included Jun Lei, Meghan Vermillion, Bei Jia, Han Xie, Li Xie, Michael McLane, Jeanne Sheffield, Andrew Pekosz and Amanda Brown of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. This work was supported by funds from the Johns Hopkins Integrated Research Center for Fetal Medicine, Sheikh Abdullah Bugshan Fund, Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, ABOG/AAOGF Bridge Funding Award, the National Institutes of Health Office of the Director (T32 OD011089) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development grant for training veterinarians for careers in biomedical research (R01HD097608). The researchers report no conflicts of interest.
Results of a first-in-humans trial presented at AATS 99th Annual Meeting indicates the safety of a novel treatment for ischemia reperfusion injury where none has existed to-date. Newswise — TORONTO – May 5, 2019 – A new study, presented today at the American Association for Thoracic Surgery’s 99thAnnual Meeting, shows that a potential treatment for ischemia- reperfusion injury is safe for humans.  Building upon three decades of preclinical animal studies, this NIH-funded trial demonstrated, for the first time, the safety of Regadenoson (an adenosine 2A receptor agonist) in human lung transplant patients.  Ischemia-reperfusion injury is a major source of morbidity and mortality in lung transplant patients, and contributes to the less than optimal survival rates in lung transplant recipients.  Adenosine 2AR agonists like Regadenoson offer a potentially novel treatment for this common inflammatory complication where none exists today.  Researchers found no dose limiting toxicities in the non-randomized trial and no 30-day mortality.  The TCV lab at University of Virginia, under the direction of Dr. Irving Kron, has spent three decades studying the efficacy of A2AR agonists for lung transplant in rodents and large animals.  In humans, Regadenoson, (LexiscanTM), is clinically approved as a bolus for myocardial imaging, but its safety profile in the high risk lung transplant population as an infusion had not been established. This clinical trial was designed to assess the safety of regadenoson in human lung transplant recipients as a prequel to an efficacy trial. “It is gratifying to see this research move from bench to bedside, with decades of work culminating in a clinical trial,” said Senior Author, Dr. Christine Lau, Professor of Surgery in the Division of Thoracic & Cardiovascular Surgery at the University of Virginia. “As the field of lung transplants evolves rapidly, we continue to see ischemia-reperfusion injury, making the potential of a new treatment an exciting development.” With safety established, the next step for testing efficacy is a multi-institutional, randomized trial.  Additionally, because the treatment appears effective whether the drug is given to the donor lung or the recipient, future trials will use ex-vivolung profusion to administer the drug only to the donor lung, eliminating any risk to the patient. Presenting author Dr. Joshua A. Boys, MD explained, “This treatment has the potential to be the next big thing in the world of lung transplants. With further study, this can quickly move from a quality of life improvement therapy to one that greatly improves survival for the long term.”
Credit: Lesion photo courtesy of Kelly Nelson, National Cancer Institute, and photomicrograph courtesy of Markus Schrober and Elaine Fuchs, The Rockefeller University A macro and micro look at skin cancer: (left) A leg with a squamous cell carcinoma lesion and (right) a colorized photomicrograph of the cancer at the cellular level. Mohs micrographic surgery, the subject of a new paper from Johns Hopkins Medicine, is one of the most effective techniques for treating this type of malignancy.   Newswise — Sometimes a little gentle peer persuasion goes a long way toward correcting a large problem. That’s the message from researchers at Johns Hopkins Medicine and seven collaborating health care organizations which report that a “Dear Colleague” performance evaluation letter successively convinced physicians nationwide to reduce the amount of tissue they removed in a common surgical treatment for skin cancer to meet a professionally recognized benchmark of good practice. In a study published in the journal JAMA Dermatology, the researchers reported an immediate positive change in surgical behavior — an improvement that was sustained for one year — for 83 percent of the physicians notified that they were excising more-than-necessary amounts of tissue on a regular basis during Mohs micrographic surgery (MMS). The surgery is considered the most effective technique for treating many basal cell and squamous cell carcinomas, the two most common types of skin cancer. “This study demonstrates the tremendous power of physicians within a specialty to create peer-to-peer accountability and of using that accountability to reduce unnecessary treatment and lower health care costs,” says Martin A. Makary, M.D., Ph.D., senior author of the study, professor of surgery at the Johns Hopkins University School of Medicine and an authority on health care quality. He also serves as principal investigator of Improving Wisely, a national project to lower medical costs in the United States by implementing measures of appropriateness in health care. The new study, part of the Improving Wisely effort, was supported by a grant from the Robert Wood Johnson foundation. MMS, developed by Frederic Mohs at the University of Wisconsin in the 1930s, is a specialized technique for the treatment of skin cancer, the most common malignancy in the United States at greater than 5.4 million cases annually. Performed as an outpatient procedure, MMS is designed so that the surgeon can methodically remove cancerous tissue on the surface and all of its “roots” — extensions of the tumors that may exist under the skin or lie along blood vessels, nerves and cartilage. The surgery is conducted in stages, with stage 1 involving the removal of the visible cancer and a thin layer of surrounding tissue. The excised sample is then cut into sections, stained and examined microscopically while the patient waits. If residual cancer is found, the surgeon can elect right then to remove more tissue in successive stages. The process is repeated as many times as necessary. The American College of Mohs Surgery (ACMS) considers a surgeon’s annual mean stages per MMS case to be the measure of quality and appropriateness for the technique. Using that metric, the organization defines physicians whose practices are two standard deviations or more beyond the overall average as outliers who are performing excessive stages in MMS procedures. Because previous studies suggest that MMS practices vary widely among surgeons, the study by Makary, his team and the ACMS had two aims: evaluate outlier practice patterns using a big-data approach and then, test whether a peer-to-peer notification could change the behavior of surgeons not meeting the appropriateness standard. “This was an important goal because overuse of stages per case burdens patients with unnecessary and time-consuming surgical resections, and taxes the health care system with avoidable costs,” says Christine Fahim, Ph.D., M.Sc., one of the study authors, a postdoctoral fellow at the Johns Hopkins University School of Medicine and the Johns Hopkins Bloomberg School of Public Health, and implementation and intervention design lead for Improving Wisely. In their paper, the researchers describe how they used Medicare Part B claims to choose their study population of 2,329 U.S. surgeons who each performed more than 10 MMS procedures between Jan. 1 and Dec. 31, 2014. The claim forms included the number of stages done in each case, so individual and overall annual averages were easily calculated. Outliers and inliers (surgeons whose MMS performance was within the accepted range of appropriateness defined by the ACMS) were identified by their performances before they became part of the study population (as measured between Jan. 1, 2016, and Jan. 31, 2017). The study population was then divided into four groups: (1) 53 outliers, each of whom would receive an intervention letter indicating his or her performance, and urging an improvement in practice, (2) 87 outliers, each of whom would not receive an intervention, (3) 992 inliers who would receive a straightforward performance evaluation letter, and (4) 1,197 inliers who would not receive a letter. The intervention groups received their letters in February 2017. Each surgeon’s MMS performance, defined as annual mean stages per case, was measured pre-intervention (between Jan. 1, 2016, and Jan. 31, 2017) and post-intervention (between March 1, 2017, and March 31, 2018). The notified outlier group demonstrated a pre- to post-intervention decrease in mean stages per case from 2.55 to 2.31, with 44 of the 53 surgeons (83 percent) improving their MMS behavior. The non-notified outliers dropped from 2.56 to 2.46, with 69 percent making positive changes. The researchers attribute the drop by non-notified outliers to two factors: an awareness campaign by ACMS around the time the intervention letters went out and possible communications between surgeons who received the letters and their colleagues who did not. The performance of the inlier groups, as expected, remained statistically about the same. The researchers also estimated that the relatively inexpensive ($150,000 or about $144 per surgeon) peer-to-peer intervention saved $11 million in Medicare costs during the study period. “We observed an immediate and sustained improvement in quality with a simple intervention based on the spirit of physicians helping one another,” Makary says. “The low cost to implement the program relative to the significant savings achievable suggests that this model could be applied to other areas of medicine with broad financial implications. More importantly, we found that even small improvements in a physician’s performance can positively impact the many patients he or she treats.” The lead and corresponding author of the JAMA Dermatology paper is John Albertini of the Wake Forest University School of Medicine (Winston-Salem, North Carolina). Along with Makary and Fahim, the Johns Hopkins University School of Medicine (Baltimore, Maryland) co-authors are: Susan Hutfless, Peiqi Wang, Angela Park, Heidi Overton, William Bruhn, Tim Xu and Aravind Krishnan. Other co-authors are: Thomas Stasko, University of Oklahoma (Oklahoma City, Oklahoma); Allison Vidimos, Cleveland Clinic (Cleveland, Ohio); Barry Leshin, also at Wake Forest; Elizabeth Billingsley, Penn State Health (Hershey, Pennsylvania); Brett Coldiron, University Hospital (Cincinnati, Ohio); Richard Bennett, Bennett Surgery Center (Santa Monica, California); and Victor Marks, ACMS (Milwaukee, Wisconsin). The authors have declared no conflicts of interest.
Newswise — Among the most well-known disease carrying bugs in Texas are mosquitos, spiders, cockroaches and ticks. But the Kissing Bug is a serious, lesser known threat to Texans. While it has a cute name, many folks don’t know there’s a not-so-cute, deadly parasite the bug can transmit. Texas State Assistant Professor Dr. Paula Stigler Granados has spent several years researching Chagas disease, a “silent killer” carried through many Kissing Bugs. Dr. Stigler Granados recently shared what the disease means, especially for migrants, as well as those who may contract the disease locally without realizing it.  What is Chagas Disease? “The disease itself is interesting and complex,” explained Dr. Stigler Granados. Caused by a parasite called T. Cruzi, Chagas disease manifests itself in two stages: acute and chronic. During the acute phase of eight to 12 weeks, people may experience mild flu-like symptoms, itchiness at the site of the bite, or no symptoms at all. Once the acute phase is over, the person enters into the chronic stage, which can either be with or without symptoms. The beginning chronic stage of Chagas can last for years or even decades with no symptoms at all, hence the name “silent killer”. Many people will never know they have encountered a kissing bug or even know they have the disease. However, if the disease isn’t found and treated before the person develops symptoms, they may go on to develop symptoms and the disease will often be untreatable and fatal. Symptoms include irreversible cardiac complications (including heart failure) and sometimes intestinal issues such as megaesophagus and megacolon. Only 30-40% of infected individuals will go on to ever develop symptoms, while 60% can live out their lives with no complications.  Who is most at risk? The insects and the disease are more prevalent in Latin American countries partly due to climate and poorer living conditions. However, the insects are common in the southern U.S. and Chagas disease has been documented in the U.S. as early as the 1930’s.  Because Texas is an entry point for many migrants from areas where Chagas is more prevalent means consideration should be given on how to treat persons coming from higher risk areas. When people coming from Latin American countries are able to be seen by local physicians, the doctors aren’t often familiar with the disease and treatment options that are available. When time is of the essence, treatment cannot wait. Chagas disease is a relatively slow moving disease and is not contagious. It cannot be transmitted from animal to human or human to human, except it can be passed from mother to fetus. Pregnant women coming from endemic areas are encouraged to know their status to prevent passing on the disease to their children. Additionally, Texas residents are still at risk, regardless of where they come from. More than 60% of Kissing Bugs in the state have been found to carry the parasite. Although not commonly found in urban areas, they are attracted to any areas where they can easily access a blood meal. Rats nests, animal kennels, wooded areas and debris piles are all good living conditions for kissing bugs.  How is research changing the conversation? As Dr. Stigler Granados shared, “not everyone is talking about this disease- one of the biggest barriers is lack of awareness amongst the health communities in the United States.” Research, such as Dr. Stigler Granados’ recent study on healthcare gaps for patients, help connect the dots. Because Chagas is a zoonotic disease, animals can contract the disease as well. Veterinarians who are seeing the disease more often than physicians and are more familiar with the disease can actually help communities better understand their risks.  With such a huge lack of awareness in the U.S. about the disease, one of Dr. Stigler Granados’  biggest concerns is congenital transmission. If most pregnant women are seeking health care, it’s a great opportunity to implement a screening program to catch the disease early. Right now, she’s advocating for more physicians to  screen pregnant mothers in an effort to better understand prevalence. There are newly available effective and inexpensive treatment options for both the infants and the moms, making it a win-win situation when it is caught early.  “Once we start raising awareness with one audience of health professionals and mothers, we can work on providing greater education to others,” added Dr. Stigler Granados. She’s hoping to get approval on a grant to implement screening newborns, which would be a big milestone to help with understanding prevalence and leading to better diagnosis and treatment.
Newswise — The neuropeptide oxytocin blocks enhanced drinking in alcohol-dependent rats, according to a study published April 16 in the open-access journal PLOS Biology led by Drs. Tunstall, Koob and Vendruscolo of the National Institutes of Health, and Drs. Kirson and Roberto of The Scripps Research Institute. Targeting the oxytocin system, the authors note, may provide novel pharmaceutical interventions for the treatment of alcohol-use disorder. Administering oxytocin can decrease consumption, withdrawal symptoms, and drug-seeking behavior associated with several drugs of abuse, and shows promise as a pharmacological approach to treat drug addiction. But first, researchers need to understand how oxytocin mediates these effects in animal models. To address this question, Tunstall and colleagues tested the hypothesis that oxytocin administration could normalize the maladaptive brain changes that occur in alcohol dependence and thereby reduce alcohol drinking in an established rat model of alcohol dependence. The authors investigated oxytocin’s effects on dependence-induced alcohol consumption and altered signaling of the inhibitory neurotransmitter GABA in the central nucleus of the amygdala (CeA) -- a key brain region in the network affected by alcohol dependence. The experiments demonstrated that oxytocin administered systemically, intranasally or into the brain blocked excess drinking in alcohol-dependent but not in normal rats. Moreover, oxytocin blocked GABA signaling in the CeA. Taken together, these results provide evidence that oxytocin likely blocks enhanced drinking by altering CeA GABA transmission. These results provide evidence that aberrations in the oxytocin system may underlie alcohol use disorder and that targeting this system, possibly by intranasal administration, could prove a promising therapy in people who misuse alcohol.
Novel strategy could be useful component of comprehensive smoking cessation plan, study says WASHINGTON -- Smokers who are trying to quit may not always have to reach for a piece of nicotine gum to stave off a craving. Deliberately inhaling a pleasant aroma may be enough to reduce the urge to light up, at least temporarily, and could be used as part of an effective smoking cessation strategy, according to research published by the American Psychological Association. “Despite disappointing relapse rates, there have been few new approaches to smoking cessation in general and to craving relief in particular,” said lead author Michael Sayette, PhD, of the University of Pittsburgh. “Using pleasant odors to disrupt smoking routines would offer a distinct and novel method for reducing cravings, and our results to this end are promising.” The research was published in the. While smoking rates have fallen over the past 50 years, approximately 40 million Americans still smoke, according the U.S. Centers for Disease Control and Prevention. Most adult smokers want to quit and at least half report trying in the past year, yet half of those who try relapse within two weeks. “Even with nicotine replacement, relapse is common. New interventions are urgently needed to help the millions who wish to quit but are unable,” said Sayette. The researchers recruited 232 smokers, ages 18 to 55, who were not trying to quit at the time and were not using any other nicotine delivery system, such as gum or vaping. They were asked not to smoke for eight hours prior to the experiment and were required to bring a pack of their preferred cigarettes and a lighter with them. Upon arrival, the people first smelled and rated a number of different odors generally considered to be pleasant (e.g., chocolate, apple, peppermint, lemon or vanilla) as well as one unpleasant chemical odor, tobacco from the participant’s preferred brand of cigarettes and one blank (no odor). They were then asked to light a cigarette and hold it in their hands, but not smoke it. After 10 seconds, the participants verbally rated their urge to smoke on a scale of 1 to 100 before extinguishing the cigarette and putting it in an ashtray. The participants then opened a container that held either the scent they had rated most pleasurable, the scent of tobacco or no scent and sniffed it once before again rating their urge to smoke. They continued to sniff the container they were given for the next five minutes, rating their urge to smoke every 60 seconds. The average craving score just after lighting the cigarette was 82.13. Regardless of what odor they smelled, all participants experienced a decreased urge to smoke after sniffing the container, but the average craving scores for those who smelled pleasant odors dropped significantly more (19.3 points) than those who smelled tobacco (11.7 points) or received the blank (11.2 points). The researchers were not surprised by the findings, as they confirmed and extended results from a much smaller, exploratory study they had previously conducted, according to Sayette. “These days, replicating prior findings is not something I take for granted, and extending the research by showing that we can maintain the effect for as long as five minutes suggests it might offer enough time for a smoker to decide to avoid or leave their high-risk situation,” he said. Sayette believes that part of the reduction seen in all three conditions may be due to smokers extinguishing the cigarette and removing temptation. As for why pleasant aromas achieved a greater reduction in cravings, he thinks they may work by distracting smokers from thoughts of their craving to memories linked to these olfactory cues (e.g., peppermint reminded some of the smokers of childhood Christmas holidays spent at a grandparent’s home), but more research would need to be done to confirm his hypothesis.   “Our research suggests that the use of pleasant odors shows promise for controlling nicotine cravings in individuals who are trying to quit smoking,” said Sayette, who noted that additional research needs to be done to see if this strategy could prove useful alone or in combination with other approaches to smoking cessation. Article:  “Pleasant Olfactory Cues Can Reduce Cigarette Cravings,” by Michael Sayette, PhD, Mary Marchetti, BS, Lea Martin, PhD, and Molly Bowdring, MS, University of Pittsburgh, and Rachel Herz, PhD, Brown University. Journal of Abnormal Psychology. Published online April 15, 2019. Full text of the article is available from the APA Public Affairs Office and at Contact: Michael Sayette can be reached via email at or by phone at (412) 624-8799.
Newswise — ANN ARBOR, Michigan — A prototype wearable device, tested in animal models, can continuously collect live cancer cells directly from a patient’s blood. Developed by a team of engineers and doctors at the University of Michigan, it could help doctors diagnose and treat cancer more effectively. “Nobody wants to have a biopsy. If we could get enough cancer cells from the blood, we could use them to learn about the tumor biology and direct care for the patients. That’s the excitement of why we’re doing this,” says Daniel F. Hayes, M.D., the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center and senior author on the paper in Nature Communications. Tumors can release more than 1,000 cancer cells into the bloodstream in a single minute. Current methods of capturing cancer cells from blood rely on samples from the patient—usually no more than a tablespoon taken in a single draw. Some blood draws come back with no cancer cells, even in patients with advanced cancer, and a typical sample contains no more than 10 cancer cells. Over a couple of hours in the hospital, the new device could continuously capture cancer cells directly from the vein, screening much larger volumes of a patient’s blood. In animal tests, the cell-grabbing chip in the wearable device trapped 3.5 times as many cancer cells per milliliter of blood as it did running samples collected by blood draw. “It’s the difference between having a security camera that takes a snapshot of a door every five minutes or takes a video. If an intruder enters between the snapshots, you wouldn’t know about it,” says Sunitha Nagrath, Ph.D., associate professor of chemical engineering at U-M, who led the development of the device. Research shows that most cancer cells can’t survive in the bloodstream, but those that do are more likely to start a new tumor. Typically, it is these satellite tumors, called metastases, that are deadly, rather than the original tumor. This means, cancer cells captured from blood could provide better information for planning treatments than those from a conventional biopsy. The team tested the device in dogs at the Colorado State University’s Flint Animal Cancer Center in collaboration with Douglas Thamm, VMD, a professor of veterinary oncology and director of clinical research there. They injected healthy adult animals with human cancer cells, which are eliminated by the dogs’ immune systems over the course of a few hours with no lasting effects. For the first two hours post-injection, the dogs were given a mild sedative and connected to the device, which screened between 1-2 percent of their blood. At the same time, the dogs had blood drawn every 20 minutes, and the cancer cells in these samples were collected by a chip of the same design. The device shrinks a machine that is typically the size of an oven down to something that could be worn on the wrist and connected to a vein in the arm. For help with the design, the engineering team turned to Laura Cooling, M.D., a professor of clinical pathology at U-M and associate director of the blood bank, where she manages the full-size systems. “The most challenging parts were integrating all of the components into a single device and then ensuring that the blood would not clot, that the cells would not clog up the chip, and that the entire device is completely sterile,” says Tae Hyun Kim, Ph.D., who earned his doctorate in electrical engineering in the Nagrath Lab and is now a postdoctoral scholar at the California Institute of Technology. They developed protocols for mixing the blood with heparin, a drug that prevents clotting, and sterilization methods that killed bacteria without harming the cell-targeting immune markers, or antibodies, on the chip. Kim also packaged some of the smallest medical-grade pumps in a 3D-printed box with the electronics and the cancer-cell-capturing chip. The chip itself is a new twist on one of the highest-capture-rate devices from Nagrath’s lab. It uses the nanomaterial graphene oxide to create dense forests of antibody-tipped molecular chains, enabling it to trap more than 80 percent of the cancer cells in whole blood that flows across it. The chip can also be used to grow the captured cancer cells, producing larger samples for further analysis. In the next steps for the device, the team hopes to increase the blood processing rate. Then, led by Thamm, they will use the optimized system to capture cancer cells from pet dogs that come to the cancer center as patients. Chips targeting proteins on the surfaces of canine breast cancer cells are under development in the Nagrath lab now. Hayes estimates the device could begin human trials in three to five years. It would be used to help to optimize treatments for human cancers by enabling doctors to see if the cancer cells are making the molecules that serve as targets for many newer cancer drugs. “This is the epitome of precision medicine, which is so exciting in the field of oncology right now,” says Hayes. Note: Patients with questions about cancer treatment options can call the U-M Cancer AnswerLine at 800-865-1125. Funding: Susan G. Komen Foundation, the Fashion Footwear Charitable Foundation of New York/QVC Present Shoes on Sale, National Institutes of Health Citation: Nature Communications, “A temporary indwelling intravascular aphaeretic system for in vivo enrichment of circulating tumor cells,” doi: 10.1038/s41467-019-09439-9, published April 1, 2019
Newswise — ORLANDO, Fla., April 1, 2019 — Major depression, obesity and chronic pain are all linked to the effects of one protein, called “FK506-binding protein 51,” or FKBP51. Until now, efforts to inhibit this target have been hampered by the difficulty of finding something specific enough to do the job and not affect similar proteins. Now a research group has developed a highly selective compound that can effectively block FKBP51 in mice, relieving chronic pain and having positive effects on diet-induced obesity and mood. The new compound also could have applications in alcoholism and brain cancer. The researchers will present their results today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features nearly 13,000 presentations on a wide range of science topics. “The FKBP51 protein plays an important role in depression, obesity, diabetes and chronic pain states,” says Felix Hausch, Ph.D., the project’s principal investigator. “We developed the first highly potent, highly selective FKBP51 inhibitor, called SAFit2, which is now being tested in mice. Inhibition of FKBP51 could thus be a new therapeutic option to treat all of these conditions.” Hausch, who is at the Technical University of Darmstadt, started the project when studies were published linking the protein to depression. “I was intrigued by the peculiar regulatory role it seemed to play in cells,” he says. “And there was a known natural product that could serve as a starting point. Collectively, this looked like an interesting protein to work on.” FKBP51 is expressed in multiple places throughout the body, such as the brain, skeletal muscle tissue and fat. It also has multiple effects. For example, the protein can restrict the uptake of glucose and the browning of fat, so that the body stores fat instead of burning it. It also affects stress responses. So, Hausch and his colleagues figured that blocking this protein could be the key to developing drugs to treat a variety of conditions.   But FKBP51 looks a lot like its closest protein cousin, FKBP52. “These two proteins are very similar in structure, but they are doing opposing things in cells,” Hausch says. “We have this yin-yang situation. Selectivity between these two proteins is thought to be crucial, but this is hard to achieve since the two proteins are so similar. We discovered that FKBP51 can change its shape in a way that FKBP52 can’t, and this allowed the development of highly selective inhibitors.” The researchers have now used nuclear magnetic resonance techniques to detect a previously hidden binding site in FKBP51. The approach could help other researchers identify similar “cryptic” binding sites in challenging drug targets in the future, Hausch says. His team is now testing SAFit2, the lead FKBP51 inhibitor they developed from these studies, in animals. “It indeed helps mice cope better in stressful situations,” Hausch says. In mice, SAFit2 reduced stress hormone levels, promoted more active stress coping, was synergistic with antidepressants, protected against weight gain, helped normalize glucose levels and reduced pain in three animal models. According to Hausch, much more needs to be done to get FKBP1 inhibitors to the point where they could be used as a drug molecule in human testing. In the meantime, the team is also exploring FKBP51 inhibitors in other applications. So far, the group has conducted a number of mouse studies on the involvement of FKBP51 in alcoholism, but results are still preliminary. In addition, Hausch points out that certain types of glioblastoma tumors overexpress FKBP51. He hopes that this result indicates FKBP51 inhibitors could be used in cancer treatment, when patients’ tumors mutate beyond current drugs’ capacity to treat them. “We may be able to resensitize them to different types of chemotherapy using these specific inhibitors,” he says.   The researchers acknowledge support and funding from European Research Area Industrial Biotechnology, the Federal Ministry of Education and Research and the Pioneer Fund of the Technical University of Darmstadt.   The American Chemical Society, the world’s largest scientific society, is a not-for-profit organization chartered by the U.S. Congress. ACS is a global leader in providing access to chemistry-related information and research through its multiple databases, peer-reviewed journals and scientific conferences. ACS does not conduct research, but publishes and publicizes peer-reviewed scientific studies. Its main offices are in Washington, D.C., and Columbus, Ohio. This research will be presented at a meeting of the American Chemical Society.  
They are seizures, but they aren’t epilepsy. They’re called by many names: psychogenic non-epileptic seizures, non-epileptic attack disorder, dissociative seizures, stress-induced seizures, pseudoseizures. They’re not epilepsy, but they do cause upheaval in education, employment, relationships and independence. They’re ranked in the top three neuropsychiatric problems worldwide. Nina Pye was a college student in the United Kingdom when she began collapsing. After months of tests and frustration, she learned she had psychogenic non-epileptic seizures. That wasn't the end of the story; it was only the beginning. Here's Nina. Nina Pye: They started sometime in January 2015; I was at college doing performing arts. I can remember the first one. I was in a dance class and all of a sudden my heart started racing for no reason. You know how you get when you’re anticipating something and you’re kind of a bit nervous about it — you get a heart-racing feeling and it doesn’t feel good? I got that, and it was weird because there was nothing making me anxious; I love dance. There was no reason for me to feel like this. It felt like all the energy drained from my body. I felt like I was going to faint, but I didn’t feel faint, and I fell to the floor. I stayed there unable to move for a few seconds, and then I got back up again. It was so weird because I didn’t actually faint, and I’ve never fainted or had anything like that so I was like what happened? Did I lose my balance? It felt like I should have had control over it. I just got back up again, no big deal was made and I carried on. Something like a week or two later I fell down again, and this time I stayed down. I remember lying there unable to get up. I could hear everything going on around me but it felt very distant. I felt like I was slightly outside of my body — it was a really weird feeling. And I’m thinking “What’s going on?” I don’t feel like anything is seriously wrong with me, it’s just that my body wants to get on the floor for a while. It’s like spontaneous lying down, except I fall. This happened a few times and each time it got longer and longer and eventually it got long enough that my college called an ambulance. My dad had died in 2013 and it was all quite fresh and new for me. I was schooled at home until college, and I didn’t have a good relationship with my father. He was abusive. Despite that, I was close to my parents, so when he died it was surreal and I didn’t find a way of dealing with it. And my mum was ill as well, she had terminal cancer, so there was a lot of stress in my life at that point. When these attacks happened, I assumed they were some kind of stress reaction. I didn’t necessarily deal with things emotionally, so it would come out in a lot of physical issues, like stomach cramps, eating issues, anxiety, depression. So when this started happening I jumped to the conclusion that it was stress and probably nothing. When I went to the hospital, they started running tests. At first they thought it was my heart; they did the 24-hour monitor and all of that. They didn’t jump to seizures or epilepsy because it was just a faint, a collapse, there was no seizure-like activity. After the first couple of hospital visits, my experience with hospitals completely changed. The more often it happened, they just… paramedics assumed I was faking and was doing this as a cry for attention. I didn’t know what to feel. I wondered, “Is there something wrong? Am I putting this on and not knowing it?” They found nothing physically wrong. I was a bit malnourished but that was it. It went on for a couple of months before I told anyone else; I didn’t even tell my mum until they started getting more frequent and other people started seeing it happen. I was passed around from cardiologist to neurologist, went for all of these tests. It was a strange time because I’d never had anything like this. I’d had back surgery for scoliosis but this felt different and weird and concerning. They were talking about did I have a brain tumor, heart issues, all that. I started to shake when I went down and have spasms, and so they thought maybe I had epilepsy. This carried on for a few more months and I kept ending up in the emergency room, and some medical staff treated it seriously and others said oh she’s faking, it’s just an attention thing. I had paramedic after paramedic saying “This is what some people do — they find a thrill in having ambulances called for them.” I had paramedics ask me, “Don’t you realize we have actual lives to save?” Yeah, I do know that, I’ve lost a parent, I know what ambulances do. Do you think I want ambulances called for me? I know it’s not life threatening but I can’t help it. I can’t tell people that I don’t need an ambulance because I don’t know when these are going to happen. I went to stay with my family three or four months after these started. I had a seizure while I was there and ended up going to a hospital in London. Because my family saw it, they pushed to get a diagnosis and were doing research to try to figure out what it was. We discovered cataplexy and narcolepsy, and the symptoms fit. So I went to a private neurologist who referred me to a sleep center. Everything came back inconclusive; they said I had mild sleep apnea and that was it. But, I had a seizure there and they had a visiting neurologist and he saw it, and he said “Yeah, you have dissociative seizures. It happens to a lot of people who’ve had something psychologically traumatic in their life, or PTSD.” I suffer from PTSD. So when I found this out, I felt relieved but ashamed as well. I thought, “Oh, it really is all in my head then.” I judged myself. It didn’t help that they are called psychogenic seizures. I felt very misunderstood. I ended up homeless for a time, not because of the seizures but because of the breakdown in the relationship with my mum. I was kicked out of college because they couldn’t deal with the seizures, which I didn’t think was possible, that you could be kicked out for something you had no control over. It was a pretty dark time in my life. A few other things happened, and it was one thing after the other. Around mid-2015 it got so bad that I made attempts to end my life three times in one month. Then my family started to take me seriously and realized I was really unwell, both mentally and physically. They took me back to London to live with them. It was a relief because I didn’t have to live in a homeless unit, which was horrible. I had no money, couldn’t work, couldn’t go to college and I thought this was my life sentence, this strange condition that had just happened and had no cure. I couldn’t get on with any antidepressants, they caused me so many side effects that I couldn’t take them. There was no support, there was no counseling. Everything that I was referred to never happened. I got 6 weeks of cognitive behavioral therapy (CBT) and that was the only proactive treatment I had for my seizures. At my worst point I had 20 seizures a day. I was banging my head on doorframes or floors, I was collapsing in the middle of roads, grazing my legs and my elbows. How I escaped without broken bones I don’t know. Everywhere I went, there was such a lack of understanding. Later in 2015, the seizures began to ease up. I’d had my CBT by then and was beginning to deal with issues that had arisen from my father dying, and my PTSD was beginning to get a little better. I was able to have unbroken nights of sleep without awful dreams, and have a normal day, and go out and get some independence. It started to feel like “Okay, this is something I can work through and get over.” I qualified as a level 1 cricket coach; my uncle was involved in cricket coaching and I was looking for something to do, just anything, and I love sports and working with kids. That was amazing and because I was really into dance, I managed to teach the kids to dance. I had roomfuls of these 8, 9, 10-year-old boys who wanted to just play cricket and football — I had them dancing. I started making progress, and once I started it accelerated really fast. Looking back, now that the seizures have come and gone and come back again, I don’t think it was necessarily good that they went away so quickly, because I don’t think I found a way of dealing with them — I just found a way to suppress them. So while I made a huge amount of progress and I was able to dance again and have some independence, there was a lot I hadn’t dealt with. I joined a dance troupe that my cousin was running. It’s not really something that most people would consider doing for seizures but I did that for about four years. I just recently left. I think the dancing helped me deal with some of the stuff I’ve been through – it worked as therapy for me. And the traveling we got to do and all of it, it pushed me out of my comfort zone and gave me mental strength. I made close friendships with the other people in the band and became very close with my cousin, and things were going quite well. And then in May 2016 my mother passed away from her fight with cancer. 2017 I think was probably my best year, despite everything; I was moving house and traveling and dancing. There was a lot of stress as well, though, and I wasn’t really dealing with the fact that my mother had died. I was just engrossed in the practical matters and not dealing with the emotional side of things. So by the end of 2017, the seizures were creeping back into my life again. In 2018 there was a lot of stress, things going wrong, breakdowns in relationships. But it kind of prompted me to go okay, this time I really want to do it right – I want to find the root of what makes me have a seizure and deal with it so that they don’t come back at all. It didn’t really happen like that. Other things got in the way. In September 2018 I returned to education. As well as dance, my other passion is medicine; I’ve always been interested in medicine and wanted a career in it. I enrolled in an access to university course, which is quite intense – it fits two A-level years into one year. At the enrollment day I told the school that look, I have seizures and they’re reasonably under control, but they will happen from time to time. They said okay, that’s fine, and set up a treatment plan with me. It’s not just the seizures, it’s the anxiety and brain fog and the general feeling of exhaustion when you’re fighting against your own body. Unfortunately my grandfather passed away at the beginning of this year; he was like a second father to me, although recently we weren’t as close. I kind of pushed him away because I couldn’t deal with any more family issues. But it has still been a great loss for me, and the repeated pattern of not really dealing with it and pretending everything is fine has not really worked for me. Now, seizures happen about once a week. Sometimes I can go a few weeks without having one. I’m hoping to build up to the point where I can go many months without one, but I think that will take some time. I want to not repress anything and deal with everything properly. The past few months I’ve reached out to other people online who are going through similar things. I thought I was alone and this was such a rare condition and little understood, but I found groups of people going through the exact same thing. They had the same experiences with the medical profession and the lack of understanding. Some people who were trying to have jobs and support themselves, some trying to get through university and support themselves. They experienced the issues in relationships, and just how hard it is generally to cope with. However hard it is for anyone else to cope with, it’s harder for us; we can’t get away from it. I wish there was more knowledge and understanding about the difference between epileptic and non-epileptic seizures. I wish medical professionals especially knew the difference and the right ways to treat people. They kind of have two extremes: Treat it like epilepsy, which can be dangerous if you’re given medication for epileptic seizures, or the other extreme of there’s actually nothing wrong with you, which is unfair. It’s in interesting journey I’ve been on and the seizures are just a small part of it, but I feel very strongly about raising awareness about them and finding ways to get people to be more supportive and more help to be available and more understanding, more knowledge for people who suffer with these seizures and their families, friends and carers. Doctors and paramedics should know about this and should have training. I feel like it’s so inadequate, considering how many people suffer with these seizures and how many are initially diagnosed with epilepsy and then find out they’re non-epileptic seizures. In truth, it helps to have doctors who are “people people” – they like people, they get on with people. You have to face people all the time, and you have to face people on their worst day. They’re having the worst day of their live when you see them, especially in hospitals and emergency departments. It doesn’t take too much to just show a little bit of understanding. I know there are people who abuse the system. I know there are fakers, I know there are drug abusers, but at the end of the day, they’re ill too. It’s a different kind of ill. Everyone is ill, but if someone is going to all the trouble of faking something or going to all this trouble to get drugs, there’s something there that needs to be treated too.