Body

For the first time, researchers from Charité - Universitätsmedizin Berlin have shown that a unicellular parasite commonly found in the mouth plays a role in both severe tissue inflammation and tissue destruction. Most patients with severe and recurrent periodontitis (gum disease) showed an increased presence of the amoeba Entamoeba gingivalis inside their oral cavities. The effect of this amoeba is similar to that of Entamoeba histolytica, the parasite responsible for causing amebiasis. Once the parasite has invaded the gingival tissue, it feeds on its cells and causes tissue destruction. According to the researchers' findings, which have been published in the Journal of Dental Research*, the two amoebae show similar mechanisms of tissue invasion and elicit a similar immune response in the host.

Periodontitis, or gum disease, is an inflammation of the gums and supporting structures of the teeth. It is one of the most common chronic diseases in the world. In Germany, approximately 15 percent of people are affected by a particularly severe form of this disease. If left untreated, periodontitis will lead to tooth loss. The disease also increases the risk of arthritis, cardiovascular disease and cancer. In patients with periodontitis, a decrease in the diversity of the oral flora coincides with an increase in the frequency of E. gingivalis. A team of researchers, led by Prof. Dr. Arne Schäfer, Head of the Periodontology Research Unit at Charité's Institute of Dental and Craniofacial Sciences, was able to show that oral inflammation is associated with colonization by the oral parasite E. gingivalis.

Scientists have long been aware of the virulence potential of this genus of amoebae. The gastrointestinal parasite E. histolytica, for instance, causes a disease known as amebiasis, one of the most common causes of death from parasitic diseases worldwide. "We have shown that an amoeba like E. gingivalis, which colonizes the oral cavity, will invade the oral mucosa and destroy gingival tissue. This enables increased numbers of bacteria to invade the host tissue, which further exacerbates inflammation and tissue destruction," says Prof. Schäfer. The international team of researchers was the first to describe precise roles of E. gingivalis in the pathogenesis of inflammation. During their analysis of inflamed periodontal pockets, the researchers detected evidence of the amoeba in approximately 80 percent of patients with periodontitis, but in only 15 percent of healthy subjects. Their observations revealed that, after invading the gums, the parasites move within the tissue, feeding on and killing host cells. Cell culture experiments showed that infection with E. gingivalis slows the rate at which cells grow, eventually leading to cell death.

The researchers concluded that the amoeba's role in inflammation shows distinct parallels to the pathogenesis of amebiasis. "E. gingivalis actively contributes to cell destruction inside the gingival tissue and stimulates the same host immune response mechanisms as E. histolytica during its invasion of the intestinal mucosa," explains Prof. Schäfer. "This parasite, which is transmitted by simple droplet infection, is one potential cause of severe oral inflammation."

Treatment success is often short-lived in patients with periodontitis. This might be due to the high virulence potential of this previously unnoticed, yet extremely common amoeba. Summing up the results of the research, Prof. Schäfer says: "We identified one infectious parasite whose elimination could improve treatment effectiveness and long-term outcomes in patients with gum disease." He adds: "Current treatment concepts for periodontitis fail to consider the possibility of infection by this parasite or its successful elimination." A clinical trial is underway to determine the extent to which the elimination of this amoeba might improve treatment outcomes in patients with periodontitis.

JUPITER, Fla.-- April 14, 2020 -- Many cases of autism spectrum disorders (ASDs) may result from problems in immune cells that normally work to trim back unneeded brain connections in early life, suggests a new study led by scientists at Scripps Research.

The study, published Tuesday in Nature Communications, examined the effects of a set of gene mutations that account for a small percentage of autism disorders. These mutations are known to cause a general overproduction of many proteins in brain cells, but how that overproduction leads to autism behaviors has been a mystery.

The scientists found evidence that the most relevant effect of this protein overproduction occurs in brain-based immune cells called microglial cells. These cells normally prune unneeded brain connections, or synapses, as the brain develops in childhood.

Working in mice, the scientists determined that the protein overproduction impairs microglial cells in a way that hampers their synapse-pruning function, but only in males, leading to autism-like social behavior deficits.

The finding dovetails with the long-standing observation that autism disorders are four to five times more prevalent in males than females. It is also consistent with recent evidence that in people with ASDs, the brain commonly has a higher number of synapses than normal.

"Our study suggests that impairments in microglia play a key role in the development of autism behaviors, at least in some cases, and may help explain the higher prevalence of autism disorders in males," says study senior author Baoji Xu, PhD, professor in the Department of Neuroscience at Scripps Research. "That, in turn, suggests that microglia might be a good target for future drugs that prevent or treat autism spectrum disorders."

ASDs are found in an estimated 2.4 percent of boys and 0.5 percent of girls. They involve a variety of abnormalities including social skill deficits, repetitive behaviors, and hypersensitivities to sounds and light. Research suggests that these disorders are largely genetic but can be caused by abnormalities in a variety of different genes acting alone or in combination. To date, well over 100 gene mutations and variants have been linked to ASDs.

One set of autism-linked gene abnormalities--which include mutations in the genes PTEN, TSC1, TSC2, and FMR1--accounts for about 3 percent of ASD cases. The common effect of these abnormalities is to disrupt a pathway that normally regulates the level of protein production in cells, allowing protein production to rise.

Xu and his team sought to determine if there is a particular cell type in the brain that explains the connection between elevated protein production and ASD-like behaviors. They engineered mice to make--in just one cell type at a time--abnormally high levels of a protein-production factor called eIF4E. A high level of eIF4E is thought to be one of the common events that links PTEN, TSC1 and other autism mutations that increase protein production.

The team found that when high eIF4E levels occurred in microglial cells, the mice developed ASD-like abnormalities in social behavior, as well as cognitive deficits and repetitive behaviors. Curiously, although protein production rose in the microglial cells of both male and female mice, the ASD-type abnormalities occurred only in male mice.

The same behavioral abnormalities were not seen at all when the high eIF4E levels occurred in neurons or in helper cells called astrocytes, although mice whose neurons had high eIF4E levels showed more anxiety-like behaviors.

The researchers examined affected microglial cells for clues to how elevated protein synthesis in these cells could lead to ASD-like behavioral changes. They found that in young male mice, microglial cells in important brain regions, including the medial prefrontal cortex, the hippocampus and the striatum, were significantly larger and also more numerous, whereas in females these changes were much more subtle and transient.

Microglia during brain development normally prune synapses that are unused or otherwise unwanted. Xu and his colleagues found that in the male ASD-like mice with elevated microglial eIF4E, there were more synapses than normal, suggesting a pruning deficit--a pattern also thought to be widely present in people with autism.

The affected microglia in the mice showed gene activity patterns indicating an enhanced capacity to prune synapses. However, experiments also revealed that the cells lacked the usual motility, or movement ability, that would enable them to carry out their synapse pruning functions. Xu and his colleagues suspect that this reduction in microglial motility may be the most important factor, so that on balance the cells' synapse-pruning abilities are impaired, leading to ASD-like brain changes.

The researchers now are following up with studies to discover precisely why protein increases affect microglia in males so much more than in females. That discovery could prove to be an important piece of the puzzle of sex differences in autism--and could suggest new targets for autism treatments.

A team of researchers in Korea believes to have discovered a synthetic gold-based compound which may help patients with obesity. The team led by Sunoh Kim, Deok-Chun Yang at Bioresources and Technology and Kyung Hee University, South Korea, respectively, investigated the anti-lipid accumulation effect of spherical gold nanoparticles (10-20 nm in size) synthesized from Dendropanax morbifera Léveille - a shrub which is endemic to the Korean peninsula. The nanoparticles, dubbed D-AuNPs, were tested in both 3T3-L1 and HepG2 cell lines, which are two known candidates for studying obesity and related disease models.

Research into gold nanoparticles is increasingly gaining the attention of researchers due to a rare combination of their potential medicinal benefits and environmental friendly implications. The team introduced a cocktail of the synthetic compound into 3T3-L1 preadipocytes and HepG2 hepatocytes.

"We found that the gold nanoparticles were nontoxic to 3T3-L1 at concentrations up to 100 μg/ml and HepG2 at post-confluent and mature stages," says Kim. Additionally, the team found that adipogenesis, the process that is responsible for the formation of fat cells, was inhibited. This inhibition was also companied by reduced concentrations of key metabolites and downregulation of genetic expression of the key proteins required for adipogenesis.

"We hypothesize that Dendropanax contains a large amount of phenolic compounds that coats the surface of gold nanoparticles and has the ability to reduce the excess amount of lipid in both cell lines.," add Kim.

Having a general practitioner (GP) who is trained in motivational interviewing may reduce your risk of getting cardiovascular disease. But only if you do not already have diabetes or are at risk of developing it. This is shown by a new randomised study from Aarhus University.

More than half of all Danes above the age of 55 suffer some form of cardiovascular disease. Most often the disease is caused by atherosclerosis of the arteries in the heart and brain. A study from Aarhus University now shows that a motivational interview with a GP can have a preventative effect. The results have just been published in the scientific journal BJGP Open.

"Our study suggests that motivational interviewing could be a promising method for reducing cardiovascular disease. As the name suggests, the purpose of motivational interviewing is to motivate the person to change their lifestyle, for example by exercising more, switching to a healthier diet or quitting smoking," says Torsten Lauritzen from Aarhus University, who is behind the study.

Trained in motivation

The result derives from a survey which 175,000 patients aged 40-69 received from their general practitioner in connection with an initiative to fight diabetes. After completing the survey, each respondent could see whether he or she was at risk of having diabetes without knowing.

All the people in the risk group were encouraged to contact their own GP, and almost 26,000 of them did so. A A quarter of these GPs were randomised and trained to carry out motivational interviewing, while the others provided advice in the normal way. The GPs who were trained in motivational interviewing were able to schedule a longer interview with the patient of around half an hour, and to follow up on normal consultations as required.

No wagging fingers

After eight years, figures were calculated for the number of deaths among the patients and the number who had developed cardiovascular diseases requiring hospitalisation. For patients with diabetes and a high risk of diabetes, no difference in the incidence of cardiovascular disease or mortality was found, regardless of whether they had one of the GPs who had been trained in motivational interviewing or not. The risk of cardiovascular disease was reduced by 13 per cent among the patients without diabetes who talked to a GP who had been trained in motivational interviewing, compared to the group of patients whose GP had not received the training.

"The results are probably due to the fact that the patients are controlled by their inner motivation, and that via the interviewing, patients are helped to take the decision to change and maintain a new lifestyle, instead of being told that 'you have to change your lifestyle'. The survey raises our awareness about how we talk to our patients and that this can have a preventative effect," says Torsten Lauritzen.

Previous studies have shown that motivational interviewing may have a beneficial short term effect in changing someone's weight, level of exercise or smoking habits. It has also been shown that motivational interviewing results in more satisfied patients and that the general practitioners who conduct the interviews assess them as being effective. However, none of the previous studies have shown whether motivational interviewing can affect morbidity or mortality several years later.

Background for the results:

The study is a register-based study. Of the 26,000 people who made an appointment with their GP, 1,615 were diagnosed with diabetes, while the message to 2,655 patients was that they had a high risk of diabetes. A total of 21,451 patients were told that they did not have diabetes or were not presently at risk of developing diabetes.

CLEMSON, South Carolina -- Scientists believe about 25 percent of the differences in human life span is determined by genetics -- with the rest determined by environmental and lifestyle factors. But they don't yet know all the genes that contribute to a long life.

A study published March 5, 2020, in PLOS Biology quantified variation in life span in the fruit fly genome, providing valuable insights for preserving health in elderly humans -- an ever-increasing segment of the population. The paper titled "Context-dependent genetic architecture of Drosophila life span" is the culmination of a decade of research by Clemson University geneticists Trudy Mackay and Robert Anholt.

It remains difficult to address the genetic basis for life span in humans, so researchers conduct their experiments with model systems. Mackay, the Self Family Endowed Chair of Human Genetics, is one of the world's leading experts on the Drosophila melanogaster model (aka the common fruit fly), which is an excellent model for comparative analysis of human disease and aging. About 70 percent of the fruit fly genome has a human counterpart.

"The fly lines are representative of a natural population and they are very diverse, with more than two million variants captured in these lines," said Mackay, who conducted the study using sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP).

In their experiment, Mackay and her team used the DGRP lines and an outbred population derived from these fly lines to examine variation in life span among male and female flies raised in three different temperature environments (18, 25 and 28 degrees Celsius).

In the process, they addressed which genes and variants are associated with increased life span and whether these genes and variants are the same in males and females and in different environments.

A variant, which is a change in a single DNA base of a person's DNA code, is introduced into a population as a mutation. The laws of natural selection indicate that variants with favorable characteristics will survive and be passed down to subsequent generations, while those with deleterious effects will not.

After conducting quantitative genetic analysis of life span and the micro-environmental variance of life span in the DGRP line, the researchers discovered that the genetic architecture of life span is context dependent. The same genes and variants had different effects in males and females and also different effects based on the temperature in which they were grown.

According to Mackay, understanding variants is much more complex than what the scientific community has previously believed, and emphasized that the male and female differences were particularly surprising.

"If average life span of a variant was increased in females, it was decreased in males," said Mackay, director of Clemson's Center for Human Genetics in Greenwood, South Carolina. "This is an example of what is called antagonistic pleiotropy, meaning the same variant has opposite effects on different traits. In this case it's the same trait, but its effects are opposite in males and females."

This is significant, Mackay said, because it has been predicted in theory that variants with opposite different effects in males and females would be maintained in natural populations and cause variation in life span. However, experimental examples of such variants have not been observed previously.

Mackay and her team had another major finding in their study. Of all the genes they identified as being associated with increased life span, 1,008 of them overlapped with genes previously identified as such by other researchers who had selected fruit flies for increased life span.

"We were very pleased to find out that even though life span is a very complicated trait caused by variation on a large number of loci, which is true for most complex traits, the number of loci that are in common is a totally finite number. So, we can imagine going on to the next stage and investigating one gene at a time and in combination," Mackay said.

ITHACA, N.Y. - A new study identifies some of the most critical genes that may drive a rare but deadly liver cancer, providing a road map for developing drugs that target those genes.

The cancer, fibrolamellar carcinoma, accounts for 1-5% of all liver cancers, and disproportionately affects children and young adults. By the time it is detected it has often already metastasized, leaving patients with a median one-year survival time.

The study provides the first picture of how the activity of the genome is rewired in this tumor. By understanding these inner workings, the researchers discovered a potentially effective drug-combination therapy.

"This work unveils concrete evidence-based therapy options that merit deeper investigation," said Praveen Sethupathy '03, associate professor of biomedical sciences at the College of Veterinary Medicine (CVM) and the paper's senior author. Timothy Dinh, a doctoral student in Sethupathy's lab, is first author of the study, "Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal candidate oncogenic pathways and therapeutic vulnerabilities," which appears April 14 in the journal Cell Reports.

The study used a Cornell-developed technique, chromatin run-on sequencing (ChRO-Seq), which provides a snapshot of transcription across a sample's entire genome. The technique - developed by study co-author Charles Danko, an assistant professor at Cornell's Baker Institute for Animal Health and CVM - allowed the researchers to determine which regions of the DNA might be specifically activated in fibrolamellar carcinoma compared to healthy liver tissue, and even compared to every other cancer type for which similar data is publicly available.

DNA is mostly comprised of regions that do not code for genes, called "noncoding DNA," which includes genetic elements known as enhancers that act as adjustable switches to dial nearby genes up or down. The researchers used the ChRO-Seq technique to identify dense and highly active clusters of these enhancers, known as super enhancers.

"It has been recently demonstrated that genes that are near super enhancers are particularly critical to driving the behavior of those cells," Sethupathy said. The group identified approximately 15 genes very strongly associated with super enhancers that are specific to fibrolamellar carcinoma tissue.

These particular genes were strongly implicated in the MAPK signaling pathway, which is known to become unusually active in other types of cancer as well and leads to uncontrolled cell proliferation, a cancer hallmark. At around the same time, study co-author John Scott, professor of pharmacology at the University of Washington, and his colleagues had independently used a biochemical approach that also implicated the MAPK pathway in fibrolamellar carcinoma. The two groups joined forces.

"The exciting part is that there are already Food and Drug Administration (FDA)-approved drugs for other cancers like melanoma that target the MAPK pathway," Sethupathy said. The team developed a cell model of fibrolamellar carcinoma, which allowed them to test how these drugs fared as a potential treatment for the cancer. They found that the drugs did disrupt the ability of the tumor cells to survive, but only at concentrations that were too high to give to patients.

"These findings were consistent with the burgeoning idea in the field that fibrolamellar carcinoma tumor cells exhibit a high level of intrinsic drug resistance," Sethupathy said.

The team decided to revisit the list of fibrolamellar carcinoma super enhancer genes. Two genes in particular (SLC16A14 and CA12) drew their attention.

When the researchers administered an inhibitor of SLC16A14, most of the tumor cells died. Treatment with an inhibitor of CA12 combined with lower doses of the FDA-approved MAPK inhibitor also showed very promising results.

Said Sethupathy: "We're excited not only by the finding of a possible combination therapy strategy [a CA12 inhibitor with a MAPK inhibitor], but also by the discovery of the cancer-promoting potential for a previously poorly characterized gene, SLC16A14, that may turn out to be an important key to unlock therapies for fibrolamellar carcinoma."

The group plans to use more mouse models to further test the combination therapy and investigate more closely the functions of SLC16A14. Validation of these findings is the next step toward the ultimate goal of designing clinical trials.

Aggressive social distancing policies being used to slow the spread of the novel coronavirus COVID-19 are hammering the U.S. economy, but an analysis by University of Wyoming researchers suggests that these measures are economically justified.

The potential benefits of social distancing in saving lives far outweigh the projected damage to the economy, according to the economists from the Department of Economics in the UW College of Business. The team's research, which has received widespread attention in national and international media outlets, will appear in the Journal of Benefit Cost Analysis.

"Our benefit-cost analysis shows that the extensive social distancing measures being adopted in the U.S. likely do not constitute an overreaction," says Assistant Professor Linda Thunstrom, lead author of the article. "Social distancing saves lives but comes at large costs to society due to reduced economic activity. Still, based on our benchmark assumptions, the economic benefits of lives saved substantially outweigh the value of the projected losses to the U.S. economy."

In fact, assuming that social distancing measures are adopted widely enough to substantially reduce contacts among individuals, the benefits of those policies will outweigh the economic costs by $5.2 trillion, the economists found.

Joining Thunstrom in conducting the analysis were Assistant Professor Stephen Newbold, Professors David Finnoff and Jason Shogren, and graduate student Madison Ashworth. The team used the most up-to-date information on disease spread and effects on economic activity to conduct the analysis.

"It should be possible to conduct a more detailed analysis after more data are available," Newbold says. "But a rapid assessment, based on the best currently available information, adds much-needed rigor to the public discussion about the policy response to this outbreak."

Attempts to slow the rate of COVID-19 infections have led many governments around the world to issue unprecedented public policies and guidelines to increase social distance within and across countries. Those measures include closing schools and businesses, imposing broad travel restrictions, and urging citizens to avoid gatherings of 10 or more people.

A recent forecast by Goldman Sachs predicts that these actions will cause the nation's gross domestic product to shrink by more than 6 percent this year, even with substantial government stimulus efforts. Already, the country is seeing declines in economic activity and dramatic increases in unemployment, with a particular impact on vulnerable low-income workers.

The UW economists' analysis takes into account the potential impact of COVID-19 on the U.S. health care system. Based on previous studies by other researchers, they estimate that the current social distancing measures across the country will reduce the average contact rate among individuals by 38 percent, which reduces the peak of the infection curve by more than half. This would help to avoid overwhelming the health care system and keep the mortality rate lower than the worst-case scenarios.

The economists note that their analysis doesn't examine the impacts of social distancing policies on specific segments of the U.S. population.

"It stands to reason that the most vulnerable groups in society will be the hardest hit. For example, the service industry will be disproportionately affected by these policies, which will lead to mass layoffs of low-income workers," the researchers wrote. "It also is likely that the most economically disadvantaged groups will suffer the most severe adverse health consequences from COVID-19."

In theory, the disparate impact of the epidemic and social distancing measures could be addressed "with appropriate redistributions of resources," they wrote.

The analysis also doesn't consider how the current social distancing measures might affect the probability of a second wave of COVID-19 infections. "Instead, we implicitly assume that aggressive social distancing measures buy enough time to develop and distribute cost-effective COVID-19 treatments or vaccines, should a second wave occur," the economists wrote.

In the end, it is in the nation's interest to better prepare for outbreaks such as COVID-19, they say.

"Our analysis suggests that the aggressive social distancing policies currently promoted in the U.S. probably are justified, given that no good contingency plans were in place for an epidemic of this magnitude," they wrote. "But the costs and consequences will be painful. To avoid these in the future, there are likely large social benefits to ensuring that we are better prepared for the next pandemic."

In an article posted online April 13, 2020 in the journal Brain, Behavior, and Immunity, a trio of researchers at University of California San Diego School of Medicine suggest that in the aftermath of the novel coronavirus pandemic, a host of neuropsychiatric challenges may remain -- or emerge -- for those recovering from COVID-19 infections.

"Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients," the authors warn.

"Our article seeks to bring the medical community's attention to the need for monitoring and investigations to mitigate such outcomes, not to cause panic among individuals whose lives are already greatly affected by this pandemic."

Encephalopathy is a broad term for any insult that alters brain function or structure, and therefore one's mental status. Demyelination is loss of the protective myelin sheathing of nerve cells, resulting in neurological problems.

"COVID-19 is a significant psychological stressor, both for individuals and communities," said senior author Suzi Hong, PhD, associate professor in the departments of Psychiatry and Family Medicine and Public Health at UC San Diego School of Medicine. "There are fears of illness, death and uncertainty of the future. This pandemic is a potential source of direct and vicarious traumatization for everyone."

But less attention, wrote Hong and co-authors Emily Troyer, MD, and Jordan Kohn, PhD, has been focused on the impact the virus itself may have on the human central nervous system (CNS) and related neuropsychiatric outcomes. The authors noted that studies of past respiratory viral pandemics indicate diverse types of neuropsychiatric symptoms can arise, including increased incidence of insomnia, anxiety, depression, mania, suicidality, and delirium, which followed influenza pandemics in the 18th and 19th centuries.

"Encephalitis lethargica is an inflammatory disorder of the CNS marked by hypersomnolence (abnormal sleepiness), psychosis, catatonia, and Parkinsonism. Incidence increased around the time of the 1918 pandemic," said the authors.

During more recent viral outbreaks, such as SARS-CoV-1 in 2003, H1N1 in 2009, and MERS-CoV in 2012, there were subsequent reports of higher rates of narcolepsy, seizures, encephalitis (brain inflammation), Guillain-Barre syndrome and other neuromuscular and demyelinating conditions.

"Reports are already surfacing of acute CNS-associated symptoms in individuals affected by COVID-19," said Hong, including greater stroke incidence in severely infected patients in Wuhan, China, along with delirium and loss of smell and taste senses. (A survey of UC San Diego Health patients treated for COVID-19, published April 12, 2020 issue of International Forum of Allergy & Rhinology, described the first empirical findings strongly associating sensory loss with COVID-19. The loss was temporary, said the authors, with taste and smell returning within two to four weeks of infection.)

Hong, Troyer and Kohn say the neuropsychiatric consequences of the current novel coronavirus pandemic are not yet known, but likely will be significant and last for years. They said emerging evidence suggests the biomedical community should begin monitoring for symptoms of neuropsychiatric conditions and the neuroimmune status of persons exposed to SARS-CoV-2, the virus that causes COVID-19.

"We will need to do this at different points in their lives, for years to come, to fully appreciate this pandemic's effects on neuropsychiatric outcomes for differing age groups, and how to better prepare for pandemics to come," Hong said.

New Rochelle, NY, April 14, 2020--A new study examined the knowledge and attitudes of anesthesiologists regarding the strategies used to treat suspected or confirmed COVID-19 patients needing to be operated on or cared for after surgery in an intensive care unit. The majority of the anesthesiology specialists and residents expressed the correct attitudes toward airway management, according to the study published in Surgical Infections, a peer-reviewed journal from Mary Ann Liebert, Inc. Click here to read the full-text article free on the Surgical Infections website through May 14, 2020.

The study evaluated anesthesiology specialists and residents at various health institutions in Turkey and was coauthored by Burhan Dost and colleagues from the Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey. The provision of theoretical and practical training can help ensure the safety of both patients and healthcare workers and prevent panic. The authors recommended that anesthesiologists who perform emergency operations on COVID-19 patients outside the intensive care units should follow easy-to-understand algorithms to ensure safety.

"This article underscores that surgeons and anesthesiologists must adopt new behavior patterns in the management of surgical and intensive care unit patients with ventilation support measures to avoid the transmission of infection to other patients and to the healthcare staff," says Surgical Infections Editor-in-Chief Donald E. Fry, MD, Northwestern University Feinberg School of Medicine, Chicago, IL.

Researchers trying to turn off a gene that allows cancers to spread have made a surprising U-turn. By making the gene overactive and functional in the hearts of mice, they have triggered heart cell regeneration. Since adult hearts cannot usually repair themselves once damaged, harnessing the power of this gene represents major progress towards the first curative treatment for heart disease.

"This is really exciting because scientists have been trying to make heart cells proliferate for a long time. None of the current heart disease treatments are able to reverse degeneration of the heart tissue - they only slow progression of the disease. Now we've found a way to do it in a mouse model," said Dr Catherine Wilson, a researcher in the University of Cambridge's Department of Pharmacology, who led the study.

The cell cycle - through which cells make copies of themselves - is tightly controlled in mammalian cells. Cancer develops when cells start to replicate themselves uncontrollably, and the Myc gene plays a key role in the process. Myc is known to be overactive in the vast majority of cancers, so targeting this gene is one of the highest priorities in cancer research. Much recent research has focused on trying to take control of Myc as a means of cancer therapy.

When the researchers made Myc overactive in a mouse model, they saw its cancerous effects in organs including the liver and lungs: huge amount of cells started replicating over the course of a few days. But in the heart, nothing much happened.

They found that Myc-driven activity in heart muscle cells is critically dependent on the level of another protein called Cyclin T1, made by a gene called Ccnt1, within the cells. When the Ccnt1 and Myc genes are expressed together, the heart switches into a regenerative state and its cells start to replicate. The results are published today in the journal Nature Communications.

"When these two genes were overexpressed together in the heart muscle cells of adult mice we saw extensive cell replication, leading to a large increase in the number of heart muscle cells," said Wilson.

Heart failure affects around 23 million people worldwide each year, and there is currently no cure. After a heart attack, an adult human heart can lose up to one billion heart muscle cells - called cardiomyocytes. Unlike many other organs in the body, the adult heart can't regenerate itself, so these cells are never replaced. Their loss reduces the strength of the heart and causes scar formation, heart failure and ultimately death.

Using a next generation sequencing technology called ChIP, the researchers were able to watch the action of Myc in the heart cells. Myc produces a protein - called a transcription factor - that binds to the DNA in specific cells and activates gene expression. But despite the protein binding successfully, the heart cells didn't start to replicate themselves because the protein could not activate gene expression. Another protein vital to gene expression, Cyclin T1, was deficient in the heart. Adding it to the cells with the overactive Myc caused the cells to start proliferating.

"None of the current treatment options can reverse the degeneration of heart tissue. The inability of the heart to regenerate itself is a significant unmet clinical need," said Wilson. "We found that even when Myc is switched on in a heart, the other tools aren't there to make it work, which may be one of the reasons heart cancer is so extremely rare. Now we know what's missing, we can add it and make the cells replicate."

As the world's population grows and the prevalence of heart failure increases, the cost of patient care is anticipated to increase dramatically. The researchers hope to develop their finding into a genetic therapy for the treatment of heart disease. "We want to use short-term, switchable technologies to turn on Myc and Cyclin T1 in the heart. That way we won't leave any genetic footprint that might inadvertently lead to cancer formation," said Wilson.

April 14, 2020--Clinicians grappling with the pharmacologic management of COPD in patients complaining of exercise intolerance or dyspnea now have new guidance. The American Thoracic Society has published an official clinical practice guideline in which a panel of experts strongly recommended LABA/LAMA combination therapy over LABA or LAMA alone. The complete guideline detailing all the recommendations was posted online ahead of print in the American Journal of Respiratory and Critical Care Medicine.

Pharmacologic management of COPD is focused on improving patients' quality of life while reducing the frequency of exacerbations. In this new clinical practice guideline, an expert panel addressed six "emerging questions around COPD management that were not covered in the previous guideline published in 2011," noted Shawn Aaron, MD, co-chair of the guideline committee and professor/senior Scientist at The Ottawa Hospital Research Institute and The University of Ottawa.

"The panel's priority was to formulate questions that were of significant clinical importance to both health care providers and patients," added Linda Nici, MD, co-chair of the guideline committee and professor of medicine at Brown University and Chief of Pulmonary/Critical Care at the Providence VAMC. "This clinical practice guideline is the most rigorous, outcome-driven distillation of the scientific literature to date."

The following is a summary of the recommendations, which were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE):

Among patients with COPD who complain of dyspnea or exercise intolerance, we recommend LABA/LAMA combination therapy over LABA or LAMA monotherapy (strong recommendation, moderate certainty evidence).

Among patients with COPD who complain of dyspnea or exercise intolerance despite dual therapy with a LABA/LAMA, we suggest the use of triple therapy with ICS/LABA/LAMA compared to dual therapy with a LABA/ LAMA in those patients with a history of 1 or more exacerbations in the past year requiring antibiotics or oral steroids or hospitalization (conditional recommendation, moderate certainty evidence).

In patients with COPD who are taking triple therapy (ICS/LABA/LAMA), we suggest that the ICS can be withdrawn, if the patient has had no exacerbations in the past year (conditional recommendation, moderate certainty evidence).

We do not make a recommendation for or against ICS as an additive therapy to long-acting bronchodilators in patients with COPD and blood eosinophilia, except for those patients with a history of blood eosinophilia and one or more exacerbations in the past year in whom we suggest ICS as an additive therapy (conditional recommendation, moderate certainty evidence).

In COPD patients with a history of severe and frequent exacerbations despite otherwise optimal therapy, we suggest against using maintenance oral corticosteroid therapy (conditional recommendation, low certainty evidence).

In individuals with COPD, who experience advanced refractory dyspnea despite otherwise optimal therapy, we suggest that opioid-based therapy be considered for dyspnea management, within a personalized shared decision-making approach (conditional recommendation, very low certainty evidence).

Contributors to the guideline included expert clinicians and researchers with experience in COPD.

The ATS has published nearly 20 clinical practice guidelines on various conditions, ranging from allergy and asthma to TB and other pulmonary infections. For ATS guideline implementation tools and derivatives, go here.

CHICAGO--April 14, 2020--Women with Polycystic Ovary Syndrome (PCOS) should consider adopting a mindful yoga practice to help ease symptoms and improve androgen levels. Researchers found a one-hour mindful yoga class, done three times a week, reduced testosterone levels by 29% over a three-month period.

Other androgen levels, like DHEA, were also reduced, and depression and anxiety levels improved by 55% and 21%, respectively, according to the study in The Journal of the American Osteopathic Association.

"There are effective pharmacologic options for managing PCOS. However, they come with the potential for some significant side effects," says Diana Speelman, PhD, Associate Professor of Biochemistry at Lake Erie College of Osteopathic Medicine and lead author on this study.

"Mindful yoga appears to be a promising option for treating PCOS in a way that can improve several aspects of the disorder."

PCOS is a common hormonal disorder that affects reproductive, metabolic and psychological health. It is estimated PCOS affects between 5 and 15% of reproductive-age women, and it is the most common cause of anovulatory infertility.

Women with PCOS may experience irregular menstrual cycles, hirsutism, acne, male-pattern hair loss, subfertility and higher incidence of miscarriage. Reducing androgen levels, including testosterone and DHEA, is key to managing these symptoms. Weight loss, where appropriate, can also help in the management of symptoms.

Researchers recruited women with PCOS aged 22-43 and randomly assigned them into a group, either with no intervention or one in which they would participate in mindful yoga practice for three months. The latter group was given a course in practicing mindfulness one week before beginning the 3-month mindful yoga practice.

Mindful yoga sessions were an hour long and took place three times a week, over three months. The benefits of improved androgen levels, as well as reduced depression and anxiety, occurred in the absence of weight loss.

Some participants also reported fewer acne breakouts and improved menstrual regularity, following the mindful yoga intervention.

"Yoga has so many benefits," says Speelman. "One of its best qualities is that it is accessible to such a wide array of ages and fitness levels."

The novel coronavirus that has infected more than one million people globally (at time of publication) is not just a physical health threat.

A first-of-its-kind study published in Frontiers in Psychiatry found that more than a third of medical staff responding to the outbreak during its peak in China suffered from insomnia.

The healthcare workers who experienced sleeplessness were also more likely to feel depressed, anxious and have stress-based trauma, according to the paper.

"Typically, stress-related insomnia is transient and persists for only a few days," said Dr. Bin Zhang, a professor at Southern Medical University in Guangzhou, China, and co-author of the paper. "But if the COVID-19 outbreak continues, the insomnia may gradually become chronic insomnia in the clinical setting."

The results are based on a series of self-administered questionnaires conducted online between January 29 and February 3 at the peak of the COVID-19 epidemic in China. Researchers used the WeChat social media platform to gather answers from 1,563 participants in the medical field.

Of that number, 564 people, or 36.1 percent, had insomnia symptoms. The authors of the current study note that the statistic is consistent with previous research conducted on the psychological effects of the 2002 outbreak of SARS, a related coronavirus that also causes severe respiratory distress. For example, 37 percent of nurses who worked with SARS patients experienced insomnia.

The insomnia group in the current paper experienced significantly higher levels of depression than the non-insomnia group, 87.1 percent versus 31 percent, especially in moderate (22.9 percent versus 2.8 percent) and severe (16.7 percent versus 1.8 percent) cases. The percentages and differences between the groups was similar for anxiety and trauma as well.

The team also identified certain factors that were correlated with insomnia.

"The most important factor was having very strong uncertainty regarding effective disease control among medical staff," Zhang noted. Strong uncertainty was 3.3 times higher for those exhibiting insomnia than not.

Staff with less education were also prone to the sleep disorder. Specifically, researchers found the risk of insomnia among medical staff with a high school education or below was 2.69 times higher than those with a doctoral degree. They speculated that less education led to more outcome-based fear.

The authors note that healthcare workers were also under incredible stress in general. They were in close contact with infected patients who could pass on the disease to them. They were worried about infecting their own family and friends. Medical staff had to wear a full array of personal protective equipment (PPE) for more than 12 hours at a time, often without being able to take a break because they risked infection by removing PPE.

"Under these dangerous conditions, medical staff become mentally and physically exhausted, and therefore experience an increased risk of insomnia due to high stress," they wrote.

The paper highlights some strategies for mitigating sleep disorders, including Cognitive Behavioral Therapy for Insomnia (CBTI), which includes sleep hygiene education, relaxation therapy, stimulation control, sleep restriction and cognitive therapy. The investigators also suggest health officials screen medical staff based on the risk factors their research identified.

"A longitudinal study to track the changes of insomnia symptoms is needed among medical staff, especially when the death of medical staff during COVID-19 will be officially announced and updated," Zhang said of future research goals.

Oxford, April 14, 2020 - Liver cancer is the fourth most common cause of cancer death worldwide and is growing rapidly due to the "diabesity pandemic." A new study reported in the Journal of Hepatology, published by Elsevier, provides strong evidence that voluntary exercise could help prevent the most common type of liver cancer, hepatocellular carcinoma, and identifies the molecular signaling pathways involved.

Fatty liver disease is common with obesity and diabetes and contributes to rapidly increasing rates of liver cancer throughout the world. More than 800,000 people worldwide are diagnosed with this cancer each year. It is also a leading cause of cancer deaths, accounting globally for more than 700,000 deaths each year.

"As yet there are very few effective therapies for liver cancer (the death rate approximates the incidence), so approaches to prevent liver cancer are greatly needed," explained lead investigator Geoffrey C. Farrell, MD, Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia. "Some population data suggest that persons who exercise regularly are less likely to develop liver cancer but, studies addressing whether this has a real biological basis, and, if so, identifying the molecular mechanism that produces such a protective effect, are few and the findings have been inconclusive."

Investigators studied whether exercise reduces the development of liver cancer in obese/diabetic mice. Mice genetically driven to eat so that they become obese and develop type 2 diabetes as young adults were injected early in life with a low dose of a cancer-causing agent. Half of the mice were allowed regular access to a running wheel; the other half were not and remained sedentary. The mice ran up to 40 kilometers a day as measured by rotations of the exercise wheel. This slowed down the weight gain for three months, but at the end of six months of experiments even the exercising mice were obese. At six months, most of the sedentary mice had liver cancer while none of the exercising mice had developed it.

This research shows that exercise can stop development of liver cancer in mice that have fatty liver disease related to obesity and type 2 diabetes. Specifically, while nearly all obese mice injected with a low dose of a cancer-causing agent developed liver cancer within six months, mice that regularly exercised failed to do so. They were completely protected against liver cancer development in the timeframe of these experiments. Weight control did not mitigate the development of liver cancer.

Investigators also carried out detailed mechanistic studies that partly clarified how exercise can prevent liver cancer. They showed that the beneficial effects of voluntary exercise were exerted via molecular signaling pathways, two of which were identified as tumor suppressor gene p53 and the stress-activated protein kinase JNK1.

The investigators first demonstrated JNK1 activation to be a key factor that can be "switched off" by exercise and proved its involvement by separate studies in obese mice lacking JNK1. They also demonstrated that activated p53, known as "guardian of the cell" and "policeman of the oncogenes," is important for regulation of the cell cycle inhibitor, p27, thereby stopping the persistent growth of altered cells destined to become cancerous.

"Exercise has already been shown to improve some outcomes for patients with cirrhosis. If the present studies in an animal model that closely resembles humans with fatty liver disease can be replicated in patients, it is likely that exercise could delay onset of liver cancer and mitigate its severity, if not completely prevent it - thereby greatly improving patient outcomes," commented Dr. Farrell. "Also, knowing the molecular pathways involved points to ways that drugs or pharmaconutrients could be employed to harness the powerful protective effect of exercise to lower risk of liver cancer in overweight people with diabetes."

Findings of a new study led by Prof. XU Guowang from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences and Prof. YANG Chunzhang from the National Cancer Institute shed light on the selective therapeutics for IDH1-mutated glioma by targeting glutathione synthesis pathway.

The study was published in Proceedings of the National Academy of Sciences on Apr. 14.
Glioma is the most common type of primary brain tumors. Isocitrate dehydrogenase I (IDH1) mutation is a cancer-associated mutation highly prevalent in patients with glioma.

Although the oncogenic role of IDH1 mutation has been shown in several human solid tumors, selective therapeutics for IDH1-mutated malignancies remain unavailable.

The researchers demonstrated that glutathione de novo synthesis plays an essential role in IDH1-mutated cancer cells. Glutathione synthesis was controlled by a transcription factor NF-E2-related factor 2 (Nrf2), which governs the gene expressions for antioxidative pathway.

"Our in vitro findings suggest that the disruption of Nrf2-driven glutathione synthesis pathway establishes synergistic lethality with a neomorphic IDH1 mutation, " said Prof. XU.

Triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor. "Triptolide exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Furthermore, we studied the anticancer mechanism of triptolide." YANG said.

Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species (ROS) derived from IDH1 mutant neomorphic activity.

The study highlights triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.