Body

BOSTON - In individuals with functional neurological disorder (FND), the brain generally appears structurally normal on clinical MRI scans but functions incorrectly (akin to a computer software crashing), resulting in patients experiencing symptoms including limb weakness, tremor, gait abnormalities and non-epileptic seizures. In some cases, childhood maltreatment may have been a contributing factor, yet links between risk factors such as childhood abuse and brain mechanisms for the development of FND remain poorly understood. In a new study published in Molecular Psychiatry, researchers led by investigators at Massachusetts General Hospital (MGH) examined the brains of individuals who experienced early-life trauma, some with FND and others without the condition. The findings may provide a better understanding of what happens in the brains of some patients with FND, as well as those with various other trauma-related brain disorders.

In the study of 30 adults with FND and 21 individuals whose clinical depression diagnoses served as controls, some of the participants in both groups had experienced early-life maltreatment, as determined through questionnaires. In FND patients only, differences in the severity of childhood physical abuse correlated with differences in connections between certain regions of the brain--for example, between the limbic regions which control emotions, arousal and survival instincts among other functions, and the primary motor cortex which is involved in voluntary movements.

"Motor and limbic circuits were more strongly interconnected in individuals with FND reporting a greater severity of childhood physical abuse," explained lead author Ibai Diez, PhD, a senior research fellow in Neurology and Radiology at MGH. This finding may lead to potentially important insights on the plastic brain mechanisms involved in promoting increased cross-talk between motor control circuits and emotion processing circuits.

In additional assessments, investigators examined how the expression of genes in a publicly available data set from the Allen Institute related to brain areas showing prominent plastic effects correlated to the degree of early-life physical abuse in patients with FND. As background, some genes in the literature have been shown to increase risk for developing brain disorders after experiencing early-life maltreatment. The researchers found that brain areas showing prominent functional re-organization in patients with FND were the same brain areas highly expressing genes involved in neuroplasticity and nervous system development.

"Our study has potential implications regarding our understanding of brain-trauma relationships not only in patients with FND but also across the greater spectrum of trauma-related brain disorders," said senior author David Perez, MD, MMSc, director of the MGH FND Clinical and Research Programs.

Perez stressed that although childhood maltreatment may be a risk factor for the development of FND in some individuals, there are many social, environmental, and biological factors that likely influence the development of FND later in life.

"More work is needed to understand how the brain mechanisms underlying FND in those without prominent childhood maltreatment may be the same or different as those individuals with FND with a high burden of childhood adversity," he said.

BOSTON - In a new discovery, researchers at Massachusetts General Hospital (MGH) have detected widespread inflammation in the brains of veterans diagnosed with Gulf War Illness (GWI). These findings, published online in the journal Brain, Behavior, and Immunity on February 3, could serve as a guidepost for identifying and developing new therapies for people with GWI, as well as many other chronic conditions that have recently been linked to inflamed brain tissue, or neuroinflammation.

About 30 percent of soldiers who fought in the 1991 Gulf War suffer from GWI. Veterans with GWI display a range of symptoms, including fatigue, chronic pain and cognitive problems such as memory loss. The cause of GWI is unknown, but several potential culprits are suspected. They include exposure to nerve gas, as well as medicine given to protect against this neurotoxin; exposure to pesticides; and the stress of extreme temperature changes, sleep deprivation and physical exertion during deployment

Many of the symptoms of GWI overlap with those of another condition, fibromyalgia, notes the senior author of the study, Marco Loggia, PhD, whose laboratory at MGH's Athinoula A. Martinos Center for Biomedical Imaging focuses on understanding the brain mechanisms of pain and neuroinflammation in humans. Last year, Loggia and his colleagues showed in another study that fibromyalgia patients have extensive neuroinflammation. "So, we asked, Do veterans who have Gulf War Illness demonstrate evidence of neuroinflammation, too?"

To find out, Loggia and his team collaborated with the Gulf War Illness Consortium at Boston University, which helped them to recruit Gulf War veterans. The study included 23 veterans, of whom 15 had GWI, as well as 25 healthy civilian subjects. All study participants' brains were scanned using positron-emission tomography (PET) imaging, which measured levels of a molecule called translocator protein that rises in the presence of neuroinflammation. The scans detected little evidence of neuroinflammation in the healthy controls and veterans who were free of GWI. By contrast, the study found extensive inflammation in the brains of veterans with GWI, "particularly in the cortical regions, which are involved in 'higher-order' functions, such as memory, concentration and reasoning," says Zeynab Alshelh, PhD, one of two research fellows in Loggia's lab who co-led the study. "The neuroinflammation looked very similar to the widespread cortical inflammation we detected in fibromyalgia patients," says Alshelh.

What might cause neuroinflammation? The central nervous system has legions of immune cells that protect the brain by detecting bacteria, viruses, and other potentially harmful agents, then producing inflammatory molecules to destroy the invaders, explains Loggia. However, while this response can be beneficial in the short term, it may become exaggerated, says Loggia, "and when that happens, inflammation becomes pathological--it becomes the problem."

Research by Loggia's lab and other investigators has also implicated neuroinflammation in a number of additional conditions, including chronic pain, depression, anxiety, autism, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease and migraine. The findings of the GWI study, says Loggia, "could help motivate a more aggressive evaluation of neuroinflammation as a potential therapeutic target."

CLEVELAND, Ohio (February 12, 2020)--Lumbar disc degeneration and resulting lower back pain become greater concerns with age and disproportionately affect women more than men, likely as a result of decreasing estrogen levels during menopause. A new study demonstrates that vitamin D deficiency, smoking, high body mass index (BMI), and osteoporosis are risk factors for greater back pain. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Lumbar disc degeneration is a common musculoskeletal disease that often causes lower back pain. Previous studies have shown the effect of estrogen on disc degeneration, which partially explains why degeneration is more severe in postmenopausal women than in men of the same age. In addition to lower estrogen concentrations, vitamin D deficiency is common during the postmenopause period.

Vitamin D is critical in maintaining levels of calcium and phosphorus, helping to prevent bone diseases such as rickets and osteoporosis. Recent studies have shown that vitamin D deficiency is associated with lower back pain and that supplementation can relieve this pain and improve musculoskeletal strength. But few studies have been conducted regarding the role of vitamin D in spinal degeneration, especially in postmenopausal women.

This new study evaluated vitamin D status in postmenopausal women and its relationship with disc degeneration and lower back pain. It concluded that vitamin D deficiency is highly prevalent in postmenopausal women and that a serum concentration of vitamin D less than 10 ng/mL, indicating severe deficiency, should be considered an indicator of severe disc degeneration and lower back pain. It further identified additional risk factors such as smoking, high BMI, and osteoporosis for lower back pain beyond vitamin D deficiency.

Study results appear in the article "Does vitamin D status influence lumbar disc degeneration and low back pain in postmenopausal women? A retrospective, single-center study."

"This study shows that very low vitamin D levels were linked to a greater likelihood of moderate to severe lower back pain and more severe lumbar disc degeneration, possibly because of the beneficial effects vitamin D has on nerve and muscle pain sensitivity, muscle strength and mass, and inflammation. Although not all women need vitamin D supplementation, this speaks to the importance of avoiding severe vitamin D deficiency states," says Dr. Stephanie Faubion, NAMS medical director.

A decade-spanning trial found that for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, two common methods of treatment actually do not have an impact on their long-term survival. The study, called PEXIVAS, was co-led by Peter A. Merkel, MD, MPH, chief of Rheumatology in the Perelman School of Medicine at the University of Pennsylvania, and was the largest ever conducted in vasculitis. It demonstrated that survival and progression to kidney failure (with the need for dialysis) for patients with ANCA-associated vasculitis remained virtually unchanged whether or not they underwent plasma exchange or if they took approximately half the typically prescribed dosage of oral glucocorticoids - which are commonly referred to as "steroids." The study was published today in the New England Journal of Medicine.

"This work should be the basis for a significant change in the standard of care for this type of vasculitis," said Merkel, a professor of Medicine at Penn and the principal investigator of the NIH-sponsored Vasculitis Clinical Research Consortium. "Adopting the changes in treatment we studied will greatly reduce our patients' discomfort and their risk of developing several serious side effects from the current therapies."

In ANCA-associated vasculitis, a person's immune system attacks their small- and medium-sized blood vessels, resulting in inflammation and destruction. It is an organ- and life-threatening condition. The kidney is especially vulnerable, and the majority of patients with ANCA-associated vasculitis are at major risk of developing kidney failure.

The researchers examined ways to reduce both kidney failure and overall mortality by carefully studying two types of treatments. They looked into different dosages of glucocorticoids, a treatment known to be effective against ANCA-associated vasculitis but associated with substantial side-effects such as weight gain, infection, and the development of diabetes or osteoporosis. The team also studied plasma exchange (called plasmapheresis, a procedure that removes antibodies from the blood) because while it is used regularly to treat vasculitis, research has never proven it is effective.

Patient recruitment began in 2010 and led to the inclusion of 704 patients with ANCA-associated vasculitis spread across 95 medical centers internationally, making this the largest-ever trial of vasculitis. Patients were randomly assigned twice: once into a group for studying different glucocorticoid doses and another time to study plasma exchange.

To analyze glucocorticoid dosage, one group of patients took the regular dosage of steroids, while the other section was prescribed roughly half the dosage. To study the effectiveness of plasma exchange, half of the study population received plasma exchanges -- performed seven times over 14 days (the standard) after enrollment -- while the other half didn't receive any exchanges. Every patient was followed for up to seven years.

At the outset, the researchers believed that performing plasma exchanges would be beneficial for patients and that lowering the dose of glucocorticoids would not reduce the overall benefit for patients but would be safer, but data showed no significant difference in either comparison in terms of death or progression to kidney failure resulting in the need for hemodialysis. However, patients who received the lower doses of glucocorticoids had fewer serious infections compared to the patients receiving the higher-dose of glucocorticoids.

Researchers said these findings will likely lead to big changes in how this form of vasculitis is treated and set new standards of care for ANCA-associated vasculitis. That could benefit patients, particularly in reducing the cumbersome nature of their treatment.

"This means we may not have to do plasma exchanges, which involve a catheter, can be uncomfortable, and are expensive," Merkel said. "It's also a big story when it comes to the glucocorticoids because the ability to use less will reduce their toxicity and cut down on the chance for side effects. These are major results."

Columbia biomedical engineers have designed a novel probiotic strain that after a single dose can seek out solid tumors and safely deliver immune checkpoint inhibitors, resulting in tumor regression of treated and untreated cancer lesions.

New York, NY--February 12, 2020--Researchers at Columbia Engineering have engineered probiotics to safely deliver immunotherapies within tumors. These include nanobodies against two proven therapeutic targets--PD-L1 and CTLA-4. The drugs are continuously released by bacteria and continue to attack the tumor after just one dose, facilitating an immune response that ultimately results in tumor regression. The versatile probiotic platform can also be used to deliver multiple immunotherapies simultaneously, enabling the release of effective therapeutic combinations within the tumor for more difficult-to-treat cancers like colorectal cancer. The study is published today in Science Translational Medicine.

Antibodies that target immune checkpoints, PD-L1 and CTLA-4, have revolutionized cancer immunotherapy treatments, achieving success in a subset of cancers. However, systemic delivery of these antibodies can also cause substantial side effects with high percentages of patients reporting adverse reactions. Furthermore, although combinations of these therapies are more effective than single therapy regimens, they also produce severe toxicities, sometimes leading to drug discontinuation. The team, led by Tal Danino https://engineering.columbia.edu/faculty/tal-danino, assistant professor of biomedical engineering https://bme.columbia.edu/, aimed to address these challenges.

"We wanted to engineer a safe probiotic vehicle capable of delivering immune checkpoint therapies locally to minimize side effects," says Danino, who is also a member of the Herbert Irving Comprehensive Cancer Center https://cancer.columbia.edu/ and Data Science Institute. "We also wanted to broaden the versatility of the system by producing a range of immunotherapeutic combinations, including cytokines that could further elicit antitumor immunity, but are otherwise difficult to systemically deliver because of toxicity concerns."

Bacterial cancer therapy is not a new idea: in the 1890s, William Coley, a New York City surgeon, demonstrated that injection of live streptococcal organisms into cancer patients could shrink tumors. While his method was never widely adopted because radiotherapy was discovered around the same time and antibiotics were not widely available, physicians have been using a tuberculosis vaccine, BCG, as a therapy for bladder cancer for decades.

The Danino lab has pioneered engineered bacteria for cancer therapy, developing methods to characterize different strains of bacteria, therapeutics, and genetic control circuits to effectively release cancer drugs. In this most recent study, led by PhD student Candice Gurbatri, they sought to engineer a translational therapeutic platform that improved upon a previous lysis circuit.

Using computational modeling, they first scanned multiple parameters to find the optimal circuit variants to maximize drug release within the tumor. This led to the integration of the circuit into the genome of a widely-used probiotic strain--E.coli Nissle 1917--resulting in a strain they call "SLIC," or the synchronized lysing integrated circuit. This SLIC probiotic strain is naturally capable of finding and growing within tumors in the body, but the genomic integration of this circuit ensures greater stability of the system and higher levels of therapeutic release.

"We have demonstrated that the engineered bacteria remain functional and localized within the tumor as the bacteria grow in mice for at least two weeks after treatment, preventing the microbes from affecting healthy tissue," says Gurbatri. Testing in mouse models further demonstrated that unlike previous iterations of the circuit, SLIC was able to clear tumors after a single dose, adding to its translational potential. Because the circuit is integrated into the genome, the stability of the platform greatly increases, thus negating the need for multiple injections of bacteria.

The research team used this probiotic delivery system to release nanobodies blocking PD-L1 and CTLA-4 within tumors in mouse models of lymphoma and colorectal cancer. It is already known that tumors express these checkpoints to stop the immune system, specifically T cells, from functioning properly. The goal of blocking PD-L1 and CTLA-4 is to remove the "brakes" and enable T cells to attack the cancer. A direct comparison to clinically relevant antibodies against the same target showed that their probiotic therapy was more effective, leading to complete tumor regression and prevention of metastatic formation in early and late-stage mouse models of lymphoma.

Leveraging the versatility of this system, the researchers sought to treat more difficult cancers, like colorectal, that have been less responsive to traditional immunotherapies. In this additional model, they paired the immune checkpoint nanobodies with a cytokine to further stimulate the immune system. A single dose of this probiotic cocktail resulted in tumor regression with no observed side-effects.

Says Gurbatri, "We showed that a triple combination of immunotherapies could effectively reduce tumor growth in a cancer that is generally less responsive to immunotherapy. We've demonstrated that one dose of our probiotic therapy results in continuous localized drug release and clearance of the bacteria population once tumors have cleared. These elements could be particularly beneficial in a clinical setting, where patients want and need minimally invasive and self-sustained therapies."

As the second-leading cause of death in the United States, cancer is a public health crisis that afflicts nearly one in two people during their lifetime. Cancer is also an oppressively complex disease. Hundreds of cancer types affecting more than 70 organs have been recorded in the nation's cancer registries--databases of information about individual cancer cases that provide vital statistics to doctors, researchers, and policymakers.

"Population-level cancer surveillance is critical for monitoring the effectiveness of public health initiatives aimed at preventing, detecting, and treating cancer," said Gina Tourassi, director of the Health Data Sciences Institute and the National Center for Computational Sciences at the Department of Energy's Oak Ridge National Laboratory. "Collaborating with the National Cancer Institute, my team is developing advanced artificial intelligence solutions to modernize the national cancer surveillance program by automating the time-consuming data capture effort and providing near real-time cancer reporting."

Through digital cancer registries, scientists can identify trends in cancer diagnoses and treatment responses, which in turn can help guide research dollars and public resources. However, like the disease they track, cancer pathology reports are complex. Variations in notation and language must be interpreted by human cancer registrars trained to analyze the reports.

To better leverage cancer data for research, scientists at ORNL are developing an artificial intelligence-based natural language processing tool to improve information extraction from textual pathology reports. The project is part of a DOE-National Cancer Institute collaboration known as the Joint Design of Advanced Computing Solutions for Cancer (JDACS4C) that is accelerating research by merging cancer data with advanced data analysis and high-performance computing.

As DOE's largest Office of Science laboratory, ORNL houses unique computing resources to tackle this challenge--including the world's most powerful supercomputer for AI and a secure data environment for processing protected information such as health data. Through its Surveillance, Epidemiology, and End Results (SEER) Program, NCI receives data from cancer registries, such as the Louisiana Tumor Registry, which includes diagnosis and pathology information for individual cases of cancerous tumors.

"Manually extracting information is costly, time consuming, and error prone, so we are developing an AI-based tool," said Mohammed Alawad, research scientist in the ORNL Computing and Computational Sciences Directorate and lead author of a paper published in the Journal of the American Medical Informatics Association on the results of the team's AI tool.

In a first for cancer pathology reports, the team developed a multitask convolutional neural network, or CNN--a deep learning model that learns to perform tasks, such as identifying key words in a body of text, by processing language as a two-dimensional numerical dataset.

"We use a common technique called word embedding, which represents each word as a sequence of numerical values," Alawad said.

Words that have a semantic relationship--or that together convey meaning--are close to each other in dimensional space as vectors (values that have magnitude and direction). This textual data is inputted into the neural network and filtered through network layers according to parameters that find connections within the data. These parameters are then increasingly honed as more and more data is processed.

Although some single-task CNN models are already being used to comb through pathology reports, each model can extract only one characteristic from the range of information in the reports. For example, a single-task CNN may be trained to extract just the primary cancer site, outputting the organ where the cancer was detected such as lungs, prostate, bladder, or others. But extracting information on the histological grade, or growth of cancer cells, would require training a separate deep learning model.

The research team scaled efficiency by developing a network that can complete multiple tasks in roughly the same amount of time as a single-task CNN. The team's neural network simultaneously extracts information for five characteristics: primary site (the body organ), laterality (right or left organ, if applicable), behavior, histological type (cell type), and histological grade (how quickly the cancer cells are growing or spreading).

The team's multitask CNN completed and outperformed a single-task CNN for all five tasks within the same amount of time--making it five times as fast. However, Alawad said, "It's not so much that it's five times as fast. It's that it's n-times as fast. If we had n different tasks, then it would take one-nth of the time per task."

The team's key to success was the development of a CNN architecture that enables layers to share information across tasks without draining efficiency or undercutting performance.

"It's efficiency in computing and efficiency in performance," Alawad said. "If we use single-task models, then we need to develop a separate model per task. However, with multitask learning, we only need to develop one model--but developing this one model, figuring out the architecture, was computationally time consuming. We needed a supercomputer for model development."

To build an efficient multitask CNN, they called on the world's most powerful and smartest supercomputer--the 200-petaflop Summit supercomputer at ORNL, which has over 27,600 deep learning-optimized GPUs.

The team started by developing two types of multitask CNN architectures--a common machine learning method known as hard parameter sharing and a method that has shown some success with image classification known as cross-stitch. Hard parameter sharing uses the same few parameters across all tasks, whereas cross-stitch uses more parameters fragmented between tasks, resulting in outputs that must be "stitched" together.

To train and test the multitask CNNs with real health data, the team used ORNL's secure data environment and over 95,000 pathology reports from the Louisiana Tumor Registry. They compared their CNNs to three other established AI models, including a single-task CNN.

"In addition to offering HPC and scientific computing resources, ORNL has a place to train and store secure data--all of these together are very important," Alawad said.

During testing they found that the hard parameter sharing multitask model outperformed the four other models (including the cross-stitch multitask model) and increased efficiency by reducing computing time and energy consumption. Compared with the single-task CNN and conventional AI models, the hard sharing parameter multitask CNN completed the challenge in a fraction of the time and most accurately classified each of the five cancer characteristics.

"The next step is to launch a large-scale user study where the technology will be deployed across cancer registries to identify the most effective ways of integration in the registries' workflows. The goal is not to replace the human but rather augment the human," Tourassi said.

LOS ANGELES (Feb. 12, 2020) -- Maternal factors, such as breast milk, have been shown to affect a baby's development, and previous animal studies have determined that a carbohydrate, the oligosaccharide 2'FL found in maternal milk, positively influences neurodevelopment. Now, in the first study done in humans, investigators at Children's Hospital Los Angeles in collaboration with the University of California, San Diego, have shown that 2'FL found in breast milk enhances cognitive development. Findings will be published in PLOS ONE on Feb 12.

In this cohort study of 50 mothers and their babies, investigators analyzed breast milk composition and frequency of feeding at 1 and 6 months of age. Cognitive development was measured at 24 months using the Bayley-III scale, a standardized test of infant and toddler development. The study showed that the amount of 2'FL in breast milk in the first month of feeding was related to significantly higher cognitive development scores in babies by 2 years of age. The amount of 2'FL in breast milk at 6 months of feeding was not related to cognitive outcomes, indicating that early exposure may be more beneficial.

Many studies have reported a positive effect of breastfeeding on cognitive development. "We wanted to specifically identify what was causing this effect," said Michael Goran, PhD, Director of the Diabetes and Obesity Program at The Saban Research Institute of Children's Hospital Los Angeles and senior author on the study.

"Through our high-throughput analytical platform we can quantify oligosaccharides like 2'FL and many others in hundreds of breast milk samples in a short period of time," says study collaborator and co-author Lars Bode, PhD, Professor of Pediatrics and Director of the Mother-Milk-Infant Center of Research Excellence at the University of California, San Diego. "This technology allows us to associate differences in milk composition with specific infant outcomes like cognitive development, validating existing data from preclinical models or generating entirely new hypotheses," Bode adds.

Using a statistical technique called mediation analysis, the investigators were able to independently evaluate the effects of breastfeeding in general, and the effects of the oligosaccharide 2'FL.

"This enhanced cognitive development in the first 2 years of life raises the question of possible long term impact on a child¬-in school and beyond," said Paige Berger, PhD, RD, a postdoctoral research associate at CHLA and the first author of the study.

These observations allowed the team to conclude that the increased neurodevelopment provided by breastfeeding was due primarily to mothers who were producing more 2'FL for the baby to consume.

"We know that there are many different compounds in breast milk and the composition is dynamic - it changes over time and is highly variable between mothers," Dr. Goran said. "In addition to identifying the impact of oligosaccharide 2'FL, we also wanted to determine the timing of when it is most critical to a child's development."

While the investigators observed neuroenhancement explained by higher 2'FL during the first month of a baby's life, this effect was not observed when looking at 2'FL content of breast milk at the six-month time-point. Being able to identify factors critical to early neurodevelopment offers the possibility for supplementing women's breast milk in individuals who produce lower quantities of this important substance.

"For some women, breastfeeding is a challenge. For those that are not able to breastfeed or can only do so short-term, 2'FL could potentially be offered as an add-on to the nutrition their baby is receiving to better support cognitive development," said Dr. Berger.

Hamilton, ON (February 12, 2020) - A new group of antibiotics with a unique approach to attacking bacteria has been discovered, making it a promising clinical candidate in the fight against antimicrobial resistance.

The newly-found corbomycin and the lesser-known complestatin have a never-before-seen way to kill bacteria, which is achieved by blocking the function of the bacterial cell wall. The discovery comes from a family of antibiotics called glycopeptides that are produced by soil bacteria.

The researchers also demonstrated in mice that these new antibiotics can block infections caused by the drug resistant Staphylococcus aureus which is a group of bacteria that can cause many serious infections.

The findings were published in Nature today.

"Bacteria have a wall around the outside of their cells that gives them shape and is a source of strength," said study first author Beth Culp, a PhD candidate in biochemistry and biomedical sciences at McMaster.

"Antibiotics like penicillin kill bacteria by preventing building of the wall, but the antibiotics that we found actually work by doing the opposite - they prevent the wall from being broken down. This is critical for cell to divide.

"In order for a cell to grow, it has to divide and expand. If you completely block the breakdown of the wall, it is like it is trapped in a prison, and can't expand or grow."

Looking at the family tree of known members of the glycopeptides, researchers studied the genes of those lacking known resistance mechanisms, with the idea they might be an antibiotic demonstrating a different way to attack bacteria.

"We hypothesized that if the genes that made these antibiotics were different, maybe the way they killed the bacteria was also different," said Culp.

The group confirmed that the bacterial wall was the site of action of these new antibiotics using cell imaging techniques in collaboration with Yves Brun and his team from the Université de Montréal.

Culp said: "This approach can be applied to other antibiotics and help us discover new ones with different mechanisms of action. We found one completely new antibiotic in this study, but since then, we've found a few others in the same family that have this same new mechanism."

CLEVELAND, Ohio (February 12, 2020)--Skeletal muscle mass and strength are critical in helping prevent falls, fractures, and disability. Yet, they continue to decline during the menopause transition. A new study showed that the prolonged use (defined as ≥13 mo) of hormone therapy (HT) was associated with higher muscle mass and less chance of sarcopenia. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Sarcopenia is defined as a loss of skeletal muscle mass and strength that mostly affects older people. In addition to increasing the risk of falls and fractures, it can also increase the risk of diabetes and cardiovascular disease. Although sarcopenia is highly prevalent in postmenopausal women, there is no definitive evidence supporting its link with the decline in estrogen during the menopause transition. Multiple small-scale studies have been conducted to assess the association between HT use and muscle mass, but their results have been inconsistent.

This new study, which included more than 4,200 postmenopausal women, is one of the few large-scale studies known to assess the link between use of HT and muscle loss in postmenopausal women. More specifically, it focused on the duration of HT use and its effect on muscle mass and the prevalence of sarcopenia.

On the basis of study results, which appear in the article "The association between hormone therapy and sarcopenia in postmenopausal women: the Korea National Health and Nutrition Examination Survey, 2008-2011," the researchers concluded that prolonged use of HT is associated with higher muscle mass and a lower prevalence of sarcopenia in postmenopausal women.

"Although not all studies examining an association between hormone therapy and muscle mass have shown positive results, this large cross-sectional study demonstrated a relationship between extended use of hormone therapy and both greater muscle mass and lower risk of sarcopenia in women aged younger than 65 years and with a body mass index less than 25 kg/m2," says Dr. Stephanie Faubion, NAMS medical director. "The mechanism by which estrogen protects muscle mass remains unclear, and additional study is needed."

The discovery identifies an adaptation by cancer cells that facilitates their spreading to distant sites, and the potential for targeting these features to prevent or slow the progression of metastatic hormone receptor-positive breast cancer.

BOSTON - Hormone receptor-positive breast cancer can spread throughout the body via the bloodstream as circulating tumor cells, or CTCs, which eventually reach distal (remote) body sites to form metastatic tumors. An increase in ribosomes, the protein-making machinery found in every living cell, increases their potential to form metastasis, report investigators from Massachusetts General Hospital Cancer Center (MGH) and Harvard Medical School (HMS).

Their observation shows that a subpopulation of CTCs enriched from the blood of breast cancer patients have higher levels of ribosomal proteins (RP) and that their presence is associated with increased disease aggressiveness and poor clinical outcomes.

Importantly, the discovery also suggests that a combination of targeted therapies that disrupt the ribosome function and inhibit cancer cell growth slows the spread of breast cancer in a mouse model.

Their work is described in a first release paper published online in Science.

"The Haber/Maheswaran lab has been one of the pioneers in being able to isolate, analyze and now use CTCs that are derived from patient blood samples. They offer many advantages and opportunities for understanding the metastatic pathways that are involved in advanced breast cancer," says investigator Douglas S. Micalizzi, MD, PhD, from the MGH Cancer Center.

Micalizzi and graduate student Richard Ebright, who led the study, and their colleagues collected and analyzed CTCs from the blood of patients with metastatic hormone receptor-positive breast cancer and used cell lines generated from CTCs. They used CRISPR activation, a technique for studying the effect of gene activation, to screen the entire genome of the CTCs for genes that promote cancer spread.

They found that ribosomal proteins in general, and in particular one ribosomal protein, RPL15, promoted the spread of breast cancer and that patients with more aggressive breast cancer and worse survival tended to have CTCs with high levels of ribosomal proteins. In collaboration with the Vasudevan lab at MGH, they demonstrated that RPL15 alters the landscape of protein production within the CTCs.

Using a mouse model of metastatic breast cancer, the investigators tested the combination of targeted therapies consisting of an inhibitor of the ribosome and an inhibitor of cancer cell growth. They found that the combination had "dramatically increased efficacy" against RPL15 CTCs compared with other CTCs.These findings suggest that metastases might be slowed or prevented and warrants further investigation.

"These early results suggest that simultaneous therapeutic targeting of the cell translational machinery and cell proliferation pathways may merit investigation as a method to suppress an aggressive subset of CTCs that are characterized by high expression of RP genes," they write.

New Rochelle, NY, February 12, 2020--A new study has shown that gene therapy to treat one of the most common hereditary disorders, aldehyde dehydrogenase type 2 (ALDH2) deficiency, may prevent increased risk for esophageal cancer and osteoporosis associated with chronic alcohol exposure. The study, performed in a mouse model of ALDH2, is published in Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Click here to read the full-text article free on the Human Gene Therapy website through March 12, 2020.

Ronald Crystal, Matthew Greenblatt, Katie Stiles, and colleagues from Weill Cornell Medical College, The Rockefeller University, and Hospital for Special Surgery, New York, NY, coauthored the article entitled "Systemic Adeno-Associated Virus-Mediated Gene Therapy Prevents the Multiorgan Disorders Associated with Aldehyde Dehydrogenase 2 Deficiency and Chronic Ethanol Ingestion." The researchers delivered the ALDH2 gene to two mouse models of ALDH2 deficiency using an adeno-associated virus (AAV) vector. Some of the mice were then given ethanol in their drinking water over a 12-week period.

In ALDH2 deficiency, proper ethanol metabolism is not possible, and the systemic accumulation of acetaldehyde causes acute abnormalities as well as chronic disorders including esophageal damage that can lead to the development of esophageal cancer, and abnormalities in bone metabolism that can lead to osteoporosis. Compared to the non-ethanol drinking mice, the mice treated with gene therapy who ingested alcohol did not show signs of either the acute abnormalities or the chronic disorders normally associated with ethanol exposure in ALDH2 deficiency.

"This work by Dr. Crystal and his collaborators points to a new potential therapy for individuals with a particular genetic susceptibility to suffer long-term consequences of excessive drinking," says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA.

As coronavirus spreads across the globe via infected air travelers, authorities are attempting to contain the outbreak and avoid a pandemic. A study published in Risk Analysis analyzes the impact of implementing disease mitigation strategies at airports across the globe. The study finds that increasing traveler engagement with proper hand-hygiene at all airports has the potential to reduce the risk of a potential pandemic by 24-69 percent. The researchers also identified ten critical airports, central to the global air-transportation network, and if hand-washing mitigation strategies are implemented in just these ten locations, the pandemic risk can drop by up to 37 percent.

The study, "Hand-hygiene mitigation strategies against global disease spreading through the air transportation network," suggests that if increased hand-washing practices were instituted in ten key there would be a significant impact on decreasing the spread of viruses. These ten airports are not just locations that see large volumes of passengers, they also connect travelers with destinations in all parts of the world.

The airports include:

London Heathrow

Los Angeles International

John F. Kennedy

Charles de Gaulle

Dubai International

Frankfurt

Hong Kong International

Beijing Capital

San Francisco

Amsterdam Schiphol

"Airports, and airplanes, are highly infectious because they are close, confined areas with large, mobile populations," states Christos Nicolaides, Ph.D., lead author, University of Cyprus and Massachusetts Institute of Technology (MIT). "Viruses are spread through bodily fluids, so keeping hands clean at major transport hubs is central to control spread."

Airports also contain numerous highly contaminated surfaces that are frequently touched by travelers, including self-service check-in screens, gate bench armrests, water fountain buttons, door handles, seats and tray tables. In addition to increasing the frequency at which public areas are cleaned and sanitized, using proper coughing etiquette, wearing face masks and proper hand hygiene practices are the most common actions that can be adopted by air travelers.

Currently, analyses show that, at most, one in five people have clean hands at any given moment. If hand cleanliness at all airports increased from 20 percent to 30 percent, by increasing the capacity and/or awareness of hand-washing, the impact of a potential infectious disease would have a global impact that is 24 percent smaller. A cost-effective measure would be to adopt these practices at the top 10 influential airports, reducing the impact of the disease spreading to just 37 percent.

DALLAS, Feb. 12, 2020 -- Damaged small blood vessels in the eye may be a marker for increased stroke risk among people with diabetes, according to preliminary research to be presented at the American Stroke Association's International Stroke Conference 2020 - Feb. 19-21 in Los Angeles, a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Diabetic retinopathy, damage to small blood vessels of the eye, is a common complication of diabetes and can lead to blindness. It has also previously been linked with an increased risk of heart attack and heart attack deaths.

"A build-up of plaque in large arteries feeding the brain and the common heart arrhythmia atrial fibrillation, are the primary causes of ischemic (clot-caused) strokes. And, damage to small blood vessels also cause stroke and vascular dementia, so we thought that diabetic retinopathy might be an important biomarker of stroke risk for patients with diabetes," said Ka-Ho Wong, B.S., M.B.A., lead author of the study and clinical research coordinator and lab manager of the de Havenon Lab at the University of Utah Health Hospitals and Clinics in Salt Lake City, Utah.

Researchers followed 874 people with diabetes who developed diabetic retinopathy and 1,954 who did not. All of the patients (average age of 62; 62% male) are participating in ACCORD (Action to Control Cardiovascular Risk in Diabetes), a large trial to test whether intensive efforts to control blood sugar, reduce cholesterol and lower blood pressure can reduce the risk of heart disease in people with diabetes.

During a five-year follow-up, researchers found:

Overall, 117 patients had a stroke;

Diabetic retinopathy was more common in patients with stroke (41%) than those without (30%);

After adjusting for multiple stroke risk factors, those with diabetic retinopathy had a 60% higher risk of stroke than people with diabetes who did not have diabetic retinopathy; and

The heightened risk was found in all treatment groups.

"We were surprised that none of the ACCORD interventions (glucose, lipid and blood pressure control) decreased diabetic retinopathy and stroke risk, especially intense blood-pressure reduction, since a lot of microvascular diseases are caused by high blood pressure. This finding is in line with results from ACCORD, which showed no reduction in heart attacks," Wong said.

Despite the these findings, the researchers suggest that patients with diabetic retinopathy receive aggressive medical management to reduce stroke risk.

"It's important for everyone with diabetes to maintain good blood glucose control, and those with established diabetic retinopathy should pay particular attention to meeting all the stroke prevention guidelines that are established by the American Stroke Association," Wong said.

To reduce stroke risk, the American Stroke Association recommends a healthy lifestyle, which includes low salt intake; getting regular physical activity; maintaining a healthy weight; avoiding tobacco; managing stress; limiting alcohol intake to no more than one drink per day for women and two drinks per day for men; and taking medication as prescribed for high blood pressure, diabetes, high cholesterol and atrial fibrillation.

The study did not have information on the type (bleeding or blockage) or location of the strokes that occurred.

DALLAS, Feb. 12, 2020 -- Shingles, a viral infection caused by the chickenpox virus, is linked to an increased risk of stroke. A new study found that Zoster Vaccine Live, one type of shingles vaccination, may prevent some older adults from having a stroke, according to preliminary research to be presented at the American Stroke Association's International Stroke Conference 2020 - Feb. 19-21 in Los Angeles, a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

More than 99% of people aged 40 or older in the United States carry the dormant chickenpox virus, also known as the varicella-zoster virus. Shingles is a reactivation of the chicken pox virus and typically occurs after age 50. The risk of developing shingles, a painful condition that causes skin blisters and can have serious complications, increases with age and other health conditions.

"One in three people who have had chickenpox develop shingles in their lifetime," said Quanhe Yang, Ph.D., lead study author and senior scientist at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. "The Zoster Vaccine Live helps to prevent shingles and reduces the risk for shingles by about 51%. But its effect declines with increased age, about 64% in people 60-69 years, about 41% for ages 70-79 years and about 18% in those 80 years or older."

To help determine if the shingles vaccine reduces the risk of stroke, Yang and colleagues reviewed the Medicare health records of more than one million Medicare fee-for-service beneficiaries age 66 or older who had no history of stroke and who were vaccinated with the Zoster Vaccine Live between 2008 and 2014, and followed them for an average of almost four years. That group was matched with the same number of Medicare fee-for-service beneficiaries who did not receive the shingles vaccine with the same four-year follow-up. To examine the effect of the vaccine on risk of stroke, researchers controlled for age, gender, race, medications and co-existing health conditions.

Researchers found:

Receiving the shingles vaccine lowered the risk of stroke by about 16%, lowered the risk of ischemic (clot-caused) stroke by about 18% and lowered the risk of hemorrhagic (bleeding) stroke by about 12%;

The vaccine's protection was strongest among people ages 66 to 79 years; and

Among those under the age of 80 years, the shingles vaccine reduced the risk of stroke by nearly 20% and in those older than 80, reduced the risk by about 10%.

"The reason for increased risk of stroke after a shingles infection may be due to inflammation caused by the virus," according to Yang.

"Approximately one million people in the United States get shingles each year, yet there is a vaccine to help prevent it," said Yang. "Our study results may encourage people ages 50 and older to follow the recommendation and get vaccinated against shingles. You are reducing the risk of shingles, and at the same time you may be reducing your risk of stroke."

This study was conducted when the only shingles vaccine was Zoster Vaccine Live (available since 2006). The newest shingles vaccine, Adjuvanted, Non-Live Recombinant Shingles Vaccine (available since 2017), confers even greater protection and is now the preferred vaccine recommended by the CDC's Advisory Committee on Immunization Practices. Two doses of Adjuvanted, Non-Live Recombinant Shingles Vaccine is more than 90% effective at preventing shingles and is recommended for adults age 50 and older.

Future studies are needed to confirm the link between Zoster Vaccine Live and stroke and to determine any association between Adjuvanted, Non-Live Recombinant Shingles Vaccine and risk for stroke.

DALLAS, Feb. 12, 2020 -- Regularly golfing - at least once per month - was found to lower the risk of death among older adults, according to preliminary research to be presented at the American Stroke Association's International Stroke Conference 2020 - Feb. 19-21 in Los Angeles, a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Golf, a sport played by approximately 25 million Americans, can provide benefits such as stress reduction and regular exercise. Due to its social nature and controlled pace, people often maintain motivation and the ability to continue playing the sport even in older age and after suffering heart attack or stroke.

"Our study is perhaps the first of its kind to evaluate the long-term health benefits of golf, particularly one of the most popular sports among older people in many countries," said Adnan Qureshi, M.D., lead author and executive director of the Zeenat Qureshi Stroke Institutes and professor of neurology at the University of Missouri in Columbia, Missouri. "The U.S. Department of Health and Human Services Physical Activity Guidelines for Americans does not yet include golf in the list of recommended physical activities. Therefore, we are hopeful our research findings could help to expand the options for adults to include golf."

Researchers analyzed data from the Cardiovascular Health Study, a population-based observational study of risk factors for heart disease and stroke in adults 65 and older. Starting in 1989 and continuing through 1999, participants had extensive annual clinical exams and clinic visits every six months for the 10-year period. Once clinic visits ended, patients were contacted by phone to determine any occurrences of heart attack and stroke events. Patients who played golf at least once a month were considered regular golfers.

Out of almost 5,900 participants, average age 72, researchers identified 384 golfers (41.9% men). During follow-up, 8.1% of the golfers had suffered strokes and 9.8% of the golfers had heart attacks. When comparing death rates among golfers and non-golfers, researchers found a significantly lower rate of death among golfers compared to non-golfers, 15.1% compared to 24.6%, respectively.

"While walking and low intensity jogging may be comparable exercise, they lack the competitive excitement of golf," Qureshi said. "Regular exercise, exposure to a less polluted environment and social interactions provided by golf are all positive for health. Another positive is that older adults can continue to play golf, unlike other more strenuous sports such as football, boxing and tennis. Additional positive aspects are stress relief and relaxation, which golf appears better suited for than other sports."

While researchers were unable to determine if golfing had a direct impact on lowering the risk of heart attack or stroke, they are currently performing additional analyses to identify what other health conditions may benefit from regularly playing golf. They also did not specify whether the golfers walked or rode in a golf cart. Researchers are currently performing additional analyses to determine whether gender and race of golfers has any effect on their findings.