Posted on Leave a comment

Kids: Connection to nature lessens distress, hyperactivity and behavioral problems

City lifestyle has been criticised for being an important reason for children being disconnected from nature. This has led to an unhealthy lifestyle in regards to active play and eating habits. Even worse, many young children do not feel well psychologically — they are often stressed and depressed. 16 per cent of pre-schoolers in Hong Kong and up to 22% in China show signs of mental health problems.

Recent research shows that spending time in nature may bring many health benefits, and many environmental programmes around the world are trying to decrease ‘nature-deficit’ and ‘child-nature disconnectedness’ in order to improve children’s health. For example, the WHO, in order to monitor implementation of the Parma Declaration commitment to providing every child with access to “green spaces to play and undertake physical activity,” has set a 300-meter target. Interestingly, 90 per cent of the Hong Kong population lives within 400 metres of such areas. However, despite the extensive, adjacent greenness, families are not using these areas.

“We noticed a tendency where parents are avoiding nature. They perceive it as dirty and dangerous, and their children unfortunately pick up these attitudes. In addition, the green areas are often unwelcoming with signs like “Keep off the grass,” said Dr Tanja Sobko from the School of Biological Sciences of the University of Hong Kong. Until now, it has not been possible to measure connectedness to nature in preschool children, mostly due to the fact that they are too young to answer for themselves.

A new 16-item parent questionnaire (CNI-PPC) to measure “connectedness to nature’ in very young children has been developed by Dr Sobko and her collaborator Prof Gavin Brown, Director of the Quantitative Data Analysis and Research Unit at the University of Auckland. The questionnaire identified four areas that reflect the child-nature relationship: enjoyment of nature, empathy for nature, responsibility towards nature, and awareness of nature.

The study consisted of two parts: the initial interviews with the families and the subsequent development of the questionnaire. Altogether, 493 families with children aged between 2 and 5 have participated in the study. Finally the new questionnaire was tested against the Strengths and Difficulties Questionnaire, a well-established measurement of psychological well-being and children’s behaviour problems. The results revealed that parents who saw their child had a closer connection with nature had less distress, less hyperactivity, & fewer behavioural and emotional difficulties, and improved pro-social behaviour. Interestingly, children who took greater responsibility towards the nature had fewer peer difficulties. The results give a new possibility for investigating the link between the outdoor environment and well-being in pre-school children.

The study is part of Dr Sobko’s research-based programme Play&Grow, which is the first in Hong Kong to promote healthy eating and active playtime with preschool children by connecting them to nature. Launched 2016, it has so far included almost 1000 families from all over Hong Kong.

The findings have been published in multidisciplinary Open Access journal, PLOS ONE. The new scale has already attracted international attention and is being adopted by universities worldwide including Western Australia and Deakin Universities. In addition, the HKU-developed ‘Play&Grow’ programme is also on track to be conducted in Australia.

The next step is to further fine-tune future health promotion/disease prevention interventions, which Dr Sobko and the team are committed to. “We are grateful for the recognition of the Government, which has recently granted significant financial support to this important project,” said Dr Sobko. The new exciting extension of this work is to test the effect of the exposing children to nature and changes in their gut microbiota.

Story Source:

Materials provided by The University of Hong Kong. Note: Content may be edited for style and length.

Posted on Leave a comment

Better analysis of psychological flexibility

According to figures from NHS England, some 1.4 million people were referred for NHS mental health therapy during 2017. This does not take into account people who accessed mental health therapy from private sources.

Increasing numbers of people of all ages experiencing some form of psychological distress are well-documented and reported in the media. A key therapeutic resource for clinicians and their clients is Acceptance and Commitment Therapy (ACT), where difficult feelings are not eliminated but rather accepted by clients so that they can commit to move towards behaviour and goals in line with their chosen values.

A core element of ACT is psychological flexibility, which helps people get unstuck, deal with stress, improve wellbeing, but also build more meaningful lives around what it is they really value. To date, clinicians have had little scientific understanding of how the different component elements of psychological flexibility worked together to help cope with psychological distress. It appeared to be a ‘one size fits all’ construct, thereby limiting a clinician’s ability to tailor ACT to the individual needs of their clients.

New research from the University of Chichester, published in Behavior Modification, has for the first time analysed degrees of psychological flexibility and identified three distinct classes. It is thought that a knowledge of these classes among clinicians will help them to better tailor the ACT offered to their clients — with benefits not just for the client but for public health in general.

The research team found three classes of psychological flexibility: high, moderate and low. Those in the low psychological flexibility subgroup reported the highest levels of psychological distress, compared to the lowest levels of psychological distress reported by those in the high psychological flexibility subgroup. Clearly, the therapeutic requirements for those with high levels of psychological distress are very different to those at the other end of the spectrum — by providing information on classes of psychological flexibility, the research team have presented clinicians with invaluable diagnostic tools upon which to create more individual therapeutic solutions.

It is hoped that their findings will stimulate further, much-needed research on the subject.

The study was led by Dr Ian Tyndall and Dr Antonina Pereira from the Department of Psychology at the University of Chichester. Dr Tyndall commented: “Our study provides a clearer view to clinicians of the wider spectrum of psychological flexibility, which we hope will help them to facilitate greater change in their clients, in a way which is better tailored to their needs. With more and more people presenting with psychological distress, and seeking professional assistance with their conditions, it is important that the concept of psychological flexibility provides the necessary nuance to underpin successful therapy. Our study is an important addition to the literature, and we are looking forward to initiating further research in this area.”

The research team at the University of Chichester worked with colleagues from Coventry University, the University of Milano-Biccoca, Italy, Trinity College Dublin and Maynooth University, Ireland.

Story Source:

Materials provided by University of Chichester. Note: Content may be edited for style and length.

Posted on Leave a comment

Being HIV positive and staying on antiretroviral therapy in Africa

An international team of researchers have carried out a review of the evidence examining what influences people who are HIV positive to go to health services and then stay on antiretroviral drugs in Africa.

In a paper published in the Journal PLOS One the team, led by LSTM’s Professor Paul Garner, used advanced methods of thematic synthesis to examine over 59 studies carried out in Africa, extracting key messages from the qualitative research. Professor Garner said: “We wanted to bring together the mass of research exploring what influences people taking and continuing to take antiretroviral drugs. Much has been achieved by governments, donors, NGOs and the World Health Organization in ensuring that people have access to these life-saving treatments but our review offers — for the first time — a more comprehensive understanding of the influences to treatment seeking and adherence to help health workers design approaches to keep people on their meds.”

Looking at the evidence the team identified nine themes impacting on adherence and treatment seeking which they grouped under three main headings. The first of these was the acknowledgement that people who are HIV-Positive often must navigate the challenges presented by external issues such as poverty, unpredictable life events and stigma which can influence initiating and maintaining antiretroviral therapy (ART). Secondly, the health system is generally seen as punishing and uninviting, which can drive people out of care. Thirdly, long-term engagement requires adaptation and incorporation of ART into daily life, which is a process facilitated by factors including inherent self-efficacy, social responsibilities, previous HIV-related illness and emotional, practical or financial support.

Dr Ingrid Eshun-Wilson, lead author on the paper, who carried out the work whilst based at the Centre of Evidence-Based Healthcare, Stellenbosch University said: “The mix of all these factors happen over time, so there appears to be a tipping point when patients choose to either engage or disengage from care, with HIV-positive patients potentially cycling in and out of these care states in response to fluctuations in influences over time.”

The team hope that their work can contribute to the design of service delivery approaches, and informed thinking and action on the part of policy makers, providers, and society to understand what it is to be HIV-positive in Africa and how attitudes and the health service need to shift to help those with HIV lead ‘normal’ lives.

“Our review goes beyond presenting barriers and facilitators such as cost and distance from care, which are well known.” Continued Dr Eshun-Wilson: “We describe broadly how external influences and personal motivation interact and drive ART adherence and engagement decisions and presents a model for understanding why people do what they do.”

Story Source:

Materials provided by Liverpool School of Tropical Medicine. Note: Content may be edited for style and length.

Posted on Leave a comment

Parasites from patients with cerebral malaria stick preferentially in their brains

A team at LSTM with their collaborators in Malawi and Denmark have provided, for the first time, evidence which links the ability of red blood cells infected with the malaria parasite to bind to the cells lining the blood vessels of the brain, with the clinical syndrome cerebral malaria.

Cerebral malaria is a life-threatening complication of infection with the parasite Plasmodium falciparum. This complication is characterised by the parasite infected red blood cells accumulating in the brain and occurs in 1-2% of the over 200 million reported cases of malaria.

First author on the paper, published recently in the journal EMBO Molecular Medicine, Dr Janet Storm, explained: “Very little is known about why this serious complication occurs in some children but not others. However, it is understood that infected red blood cells, presenting with a protein called P. falciparum erythrocyte membrane protein 1 (PfEMP1) on its surface bind to host cells lining the blood vessels in many organs, including the brain.”

A property of the PfEMP1 protein is its variability, which results in changes in the ability of infected red blood cells to bind to host cells in the brain. This has been suggested as the reason we only see cerebral malaria in some infected individuals, and if the infected red blood cells do not bind in the brain cerebral malaria cannot occur.

In their lab in at MLW in Malawi, the team utilised a flow-based adhesion assays to study the binding of infected red blood cells from children with cerebral or uncomplicated malaria to cells derived from human brain blood vessels. The team also used molecular techniques to study the PfEMP1 expressed by the infected red blood cells.

Results showed that binding of infected red blood cells from patients with cerebral malaria to the brain-derived cells was higher than that seen from patients with uncomplicated malaria. This suggests that in most cases P. falciparum avoids targeting the brain and that cerebral malaria only occurs when red blood cells express a subset of PfEMP1 proteins with particular adhesion phenotypes which allow for efficient binding to the cerebral blood vessels. Knowing that binding in the brain is a key feature of cerebral malaria allows researchers to focus their attention on developing new interventions for severe disease based on the interaction between infected red blood cells and the host cells lining the blood vessels in the brain.

Story Source:

Materials provided by Liverpool School of Tropical Medicine. Note: Content may be edited for style and length.

Posted on Leave a comment

Scope advance reveals first look through all cortical layers of awake brain

Just like doctors seek to scan deeper into the body with sonograms, CT and MRI, and astronomers seek to look farther out into the universe with space-based telescopes, adaptive optics and different wavelengths of light, neuroscientists pursue new ways to watch brain cells at work deep inside the brain. Three-photon microscopy recently emerged to give them a deeper look at brain cells than ever before. Now, based on a substantial refinement of the technology, scientists at MIT have conducted the first-ever study of stimulated neural activity in an awake mouse through every visual cortex layer and notably the mysterious “subplate” below.

“By optimizing the optical design and other features for parameters for making measurements in the live brain, we were able to actually make novel discoveries that were not possible before,” said co-corresponding author Mriganka Sur, Newton Professor of Neuroscience in the Picower Institute for Learning and Memory. The paper’s co-lead authors are postdocs Murat Yildirim and Hiroki Sugihara. The other corresponding author is Peter So, professor of mechanical engineering and biological engineering.

“The concept has existed, but the question was how do you make it work,” Sur said.

In the study, published in Nature Communications, the team showed that as mice watched visual stimuli, their human observers could measure patterns of activity among neurons in all six layers of visual cortex and the subplate, providing new data about their role in how mammals process vision. Moreover, through a series of careful experiments, the researchers were able to show that the light they sent in, as well as the light that came back out, neither damaged, nor even altered, the cells they measured.

In all, the paper describes a new three-photon microscope optimized to deliver rapid, short, low-power pulses of light capable of reaching deep targets without causing any functional disturbance or physical damage, and then to detect the resulting fluorescence emitted by cells with high efficiency to produce images with sharp resolution and a fast frame rate.

“We were motivated to show what we could do with three-photon microscope technology for an animal in an awake condition so we could ask important questions of neuroscience,” Yildirim said. “You could think you have the best microscope in the world, but until you ask those questions you don’t know what results you are going to get.”

Femtoseconds and nanojoules

The theory behind multi-photon microscopy dates back to the 1931 doctoral dissertation of Maria Goeppert-Mayer, whose work showed that a simultaneous combination of lower-energy photons could excite an atom or molecule to a higher energy state just like a single higher energetic photon could. In 1990 Cornell University scientists applied that insight to biological imaging in the two-photon microscope and again in 2013 with a three-photon scope. These allowed neuroscientists to see deeper into the brain because lower energy, higher wavelength photons are less susceptible than higher-energy, shorter-wavelength photons to being scattered by cellular molecules like lipids.

Sur and So’s labs at MIT have joined in pushing the frontiers of multiphoton microscopy. In the new study they show they’ve now taken it far enough to study live neural activity. To do that, the team sought to refine many different parameters of both the laser light and the scope optics, based on meticulous measurements of properties of the brain tissue they were imaging. For instance, they not only measured the energy at which cells started to show overt damage (about 10 nanojoules), but also measured the power at which cells would start to behave differently, thereby producing data influenced by the measurement (2 to 5 nanojoules). With precision and purpose to deliver lower energy levels, the scientists optimized the scope to emit incredibly short pulses of light lasting for a “pulse width” of only 40 femtoseconds, or quadrillionths of a second, and painstakingly arranged the optics to maximize the collection of the light that molecules, excited by the incoming laser energy, would emit back.

Unprecedented neuroscience

After carefully validating that the optimized three-photon scope’s measurements agreed with those of two-photon scopes (in shallower layers of the cortex) and electrophysiology (which can go deeper, but blindly), the team set out to do some unprecedented neuroscience — direct visual observation of neural activity in all cortical layers of awake, behaving animals.

In the lab they showed mice some grating patterns in 12 different rotated orientations and two directions of motion across a screen. With their optimized three-photon scope, they watched neurons in each layer of the cortex — going more than a millimeter deep — to see how the cells reacted to this standard visual input. They could see the activity of the cells because they had engineered them to glow upon elevated calcium activity, using a label called GCaMP6s. They could see other tissues like blood vessels and white matter via a phenomenon called “third harmonic generation.”

With the capability to see the deepest layers they observed that layer 5 neurons are “broadly” tuned for orientation, meaning they respond to a wide variety of orientations, rather than just one or 2 specific ones. Layer 5 neurons also had more spontaneous activity than cells in other layers and more connections to deeper parts of the brain. Meanwhile, layer 6 neurons had somewhat sharper orientation tuning than neurons in other layers, meaning they are more specific in their response to distinct orientations.

Subplate surprise

Their most surprising finding was that the subplate, a thin layer of mostly neural “white-matter” fibers, was home to a population of neurons with patterns of activity that were weakly and broadly tuned to the visual input. The finding was revelatory, the researchers said, in that many neuroscientists believed that subplate neurons were mostly only active during development. The layer is also too thin, Yildirim said, to be measured with electrophysiology.

“So far, subplate neurons in the mature brain have not been studied at all due to the technical challenges of imaging these cells in vivo,” the researchers wrote.

Sugihara recalled the first time Yildirim showed him that subplate neurons were active in the mature mice. “What are they doing there?” he recalled asking in surprise.

Now they are continuing to use their new scope to answer that question.

The National Institutes of Health, the National Science Foundation, a Picower Institute Engineering Collaboration Grant and the Massachusetts Life Sciences Initiative supported the research.

Posted on Leave a comment

Ultra-sturdy bones, with a surprising origin, suggest new osteoporosis approach

A handful of brain cells deep in the brain may play a surprising role in controlling women’s bone density, according to new research by UC San Francisco and UCLA scientists.

In a study published January 11, 2019 in Nature Communications, researchers showed that blocking a particular set of signals from these cells causes female (but not male) mice to build extraordinarily strong bones and maintain them into old age, raising hopes for new approaches to preventing or treating osteoporosis in older women.

“Our collaborators who study bone for a living said they’d never seen bone this strong,” said study senior author Holly Ingraham, PhD. “Our current understanding of how the body controls bone growth can’t explain this, which suggests we may have uncovered a completely new pathway that could be used to improve bone strength in older women and others with fragile bones.”

More than 200 million people worldwide suffer from osteoporosis, a weakening of the bones to the point where falls or even minor stresses like bending over or coughing can trigger fractures. In healthy individuals, bone tissue is constantly being recycled — old bone tissue is broken down and replaced by new bone. As we age, this cycle tilts in favor of bone loss, causing our bones to become increasingly porous and fragile.

Women are at particularly high risk of osteoporosis after menopause (nearly one in three post-menopausal women in the U.S. and Europe suffer from weakened bones) because of declining levels of the sex hormone estrogen, which normally promotes bone growth.

Estrogen plays many roles in the female body, particularly in the regulation of reproduction, but its function in the brain is still poorly understood. The Ingraham lab has long sought to understand how estrogen’s signaling in the brain impacts the female metabolism at different life stages, including how estrogen-sensitive neurons in a brain region called the hypothalamus balance energetic demands needed for survival or reproduction.

Their new study began when Stephanie Correa, PhD, then an Ingraham lab postdoctoral researcher and now an assistant professor at UCLA, found that genetically deleting the estrogen receptor protein in hypothalamic neurons caused mutant animals to gain a little weight, and also to become less active. Correa expected to find that the animals had put on extra fat or gained lean muscle, but these did not explain the difference. To find the source of the extra weight, she decided to use an extra-sensitive laboratory technique that could also reveal changes in bone density. To her surprise, she discovered that her heavy mice were truly just big-boned: the animals’ bone mass had increased by as much as 800 percent.

“I was immediately struck by the size of the effect. The two groups didn’t overlap at all, which I had never seen,” Correa said. “We knew right away it was a game changer and a new, exciting direction with potential applications for improving women’s health.”

The mutant animals’ extra-dense bones also proved to be super-strong. When collaborators such as UCSF’s Aaron Fields, PhD, an assistant professor in the Department of Orthopedic Surgery, tested the mechanical strength of these bones by crushing them, his equipment almost failed, Ingraham says.

After Correa moved to UCLA, Ingraham lab postdoctoral fellows Candice Herber, PhD, and William Krause, PhD, spearheaded a series of experiments that zeroed in on a specific population of just a few hundred estrogen-sensitive brain cells — located in a region of the hypothalamus called the arcuate nucleus — which appeared to be responsible for these dramatic increases in bone density. The authors hypothesized that estrogen must normally signal these neurons to shift energy away from bone growth, but that deleting the estrogen receptors had reversed that shift.

Notably, interfering with arcuate estrogen signaling in male mice appeared to have no effect. “Most neuroscientists limit studies to male mice, and few study estrogen, which may explain why this had never been seen before,” Ingraham said. “I’ve always been interested in how sex hormones make male and female brains different, and this is a really wonderful example of how dramatic those differences can be.”

Further experiments showed that Ingraham and Correa’s mutant animals maintained their enhanced bone density well into old age. Normal female mice begin to lose significant bone mass by 20 weeks of age, but mutant animals maintained elevated bone mass well into their second year of life, quite an old age by mouse standards.

Remarkably, Herber and Krause were even able to reverse existing bone degeneration in an experimental model of osteoporosis. In female mice that had already lost more than 70 percent of their bone density due to experimentally lowered blood estrogen, deletion of arcuate estrogen receptors caused bone density to rebound by 50 percent in a matter of weeks.

These results highlight the opposite roles played by estrogen in the blood, where it promotes bone stability, and in the hypothalamus, where it appears to restrain bone formation, Ingraham said. “We hypothesize that after puberty the estrogen system in the female brain actively shifts resources away from bone growth and towards things like reproduction, which could contribute to women’s higher risk of weakened bones as we age.”

The dramatic pattern of enhanced bone growth seen in the current study is unlike anything in the scientific literature, the researchers say, suggesting that Correa’s fortuitous discovery may have uncovered a totally novel biological pathway by which the brain regulates bone density. Ingraham and colleagues are now investigating exactly how this brain-bone communication happens, and whether drugs could be developed to boost bone strength in post-menopausal women without potentially dangerous effects of estrogen replacement therapy.

“This new pathway holds great promise because it allows the body to shift new bone formation into overdrive,” Correa said.

“I’m in the clouds about this result,” Ingraham added. “If our next experiments show that the brain releases a novel circulating factor that triggers enhanced bone growth, we might have a real chance of developing a drug that counteracts osteoporosis.”

Posted on Leave a comment

VAT fat may cause pathogenic obesity

Type-2 (adult-onset) diabetes and other diseases related to the obesity epidemic depend on how the body stores excess energy, according to evolutionary biologist Mary Jane West-Eberhard, emeritus scientist at the Smithsonian Tropical Research Institute. In the Proceedings of the National Academy of Sciences, she describes her theory about fat inside the abdominal cavity — visceral adipose tissue or VAT — the “VAT prioritization hypothesis.”

More than 300 million people are affected by obesity-associated diabetes. Heart disease is a major killer. Both involve chronic inflammation.

“Pathogenic obesity is an advantageous process gone awry,” said West-Eberhard. “Very early in life the body makes decisions about where to store fat. It makes sense for poorly nourished fetuses to invest in VAT rather than in fat under the skin because VAT evolved to protect us from infections, but this choice sets us up for disaster if we have access to too many calories later in life.”

Researchers study obesity from different perspectives, but West-Eberhard took a broader look to ask how the body makes decisions about where to deposit fat and why.

“Trying to understand diseases related to obesity without understanding the abdominal structures that become obese is like trying to understand circulatory diseases without knowing the functions of the heart,” West-Eberhard said.

Visceral fat is nature’s super band-aid. Sometimes called “the abdominal policeman,” a VAT-rich structure called the omentum, a loosely hanging fold of the membrane lining the abdominal cavity, sticks to wounds, foreign objects such as shrapnel and infection sites like a bandage full of antibiotics. In fact, surgeons sometimes use pieces of omentum to control severe postoperative infections. VAT surrounds the small intestine, defending the body from ingested pathogens and toxins.

“The fact that visceral fat tissue evolved to fight visceral infections provides a causal hypothesis for how high fructose sweeteners and saturated fats contribute to chronic diseases such as type 2 diabetes,” West-Eberhard said. “They influence which bacteria grow inside the intestines [called the microbiome], making the intestinal walls more permeable and releasing more toxins into the bloodstream, stimulating the visceral immune system and potentially leading to chronic inflammatory disease.”

In the past, the role of visceral fat as part of the immune system may have been more widely important than it is today because starvation and infections were more common. West-Eberhard proposes that in fetuses subject to nutritional stress, more energy may be stored as fat around the abdominal organs rather than as fat under the skin (subcutaneous fat or SAT). She notes that childhood catch-up growth, a better predictor of obesity-associated disease than low birth weight, may be a sign of the mistake the body has made as it assigns energy to VAT producing the apple shape of abdominal obesity, rather than the pear shape of lower body fat distributed in the hips, buttocks or thighs or more evenly under the skin.

In overweight individuals, a dangerous feedback loop may develop: increased VAT leads to increased chronic inflammation, which, in turn, leads to increased insulin resistance leading to further VAT storage and increased susceptibility to disease. Eventually, the ability to produce insulin is reduced and these individuals may need injected insulin to control type-2 (adult onset) diabetes.

“I think the combination of malnutrition early in life coupled with modern diets of saturated and trans-fats and high-fructose foods available on a global scale is leading to a situation that is toxic for individuals in many different cultures.” West-Eberhard said. “People’s body shape — apple versus pear — is based on the way their bodies allocate fat. Even in ancient societies, poor nutrition leading to investment in VAT contributed to apple-shaped bodies, versus more ‘beautiful,’ voluptuous, pear-shaped bodies associated with SAT fat storage by better-nourished babies. Social upheaval (war, conquest and disease) would have favored flexibility in fat allocation because social rank and food availability would occasionally have changed.”

In the future, she hopes to see more research revealing fetal cues that turn on VAT storage, the development of the visceral immune system, the role of the omentum, disease-resistance in obese individuals and the capabilities of people of different geographic and ethnic origins to allocate fat differently.

Story Source:

Materials provided by Smithsonian Tropical Research Institute. Note: Content may be edited for style and length.

Posted on Leave a comment

Activated PMN exosomes are pathogenic entities that cause destruction in the COPD lung

University of Alabama at Birmingham researchers have found a novel, previously unreported pathogenic entity that is a fundamental link between chronic inflammation and tissue destruction in the lungs of patients with chronic obstructive pulmonary disease, or COPD. COPD is the fourth-leading cause of death in the world.

This pathogenic entity — exosomes from activated polymorphonuclear leukocytes, or PMNs — caused COPD damage when the small, subcellular particles, collected from purified PMNs, were instilled into the lungs of healthy mice. Remarkably, the UAB researchers also collected exosomes from the lung fluids of human patients with COPD and the lung fluids of neonatal ICU babies with the lung disease bronchopulmonary dysplasia; when those human-derived exosomes were instilled into the lungs of healthy mice, they also caused COPD lung damage. Damage was primarily from PMN-derived exosomes from the human lungs.

“This report seems to provide the first evidence of the capability of a defined non-infectious subcellular entity to recapitulate disease phenotype when transferred from human to mouse,” said J. Edwin Blalock, Ph.D., professor of pulmonary, allergy and critical care medicine in the UAB Department of Medicine. “I think this could be a very profound discovery. A lot of what we have found here will apply in other tissues, depending on the disease.”

Other diseases marked by immune cell inflammation and tissue destruction include heart attacks, metastatic cancer and chronic kidney disease. The activated PMN exosomes may also contribute to lung damage in other lung diseases that have excessive PMN-driven inflammation, such as cystic fibrosis. The study is reported in the journal Cell.

“These findings highlight a novel role of the innate immune response in chronic lung diseases and could be used for the development of new diagnostics and therapeutics for COPD and possibly cystic fibrosis,” said James Kiley, Ph.D., director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.

Background

COPD, a smoking-associated disease, is marked by PMN-driven inflammation in the lungs. Damage to the lung tissue leads to airway obstruction, shortness of breath and respiratory failure. PMN immune cells, also known as neutrophils, are part of the body’s white blood cell defense against infections and tissue damage. They comprise 60 percent of the body’s white blood cells, or about 2.5 billion PMNs in each pint of blood. PMNs are voracious eaters of microbes or damaged human cells after activation by a signal of infection.

All cells shed exosomes. These tiny extracellular membrane-bound vesicles can be mediators of cell-to-cell communication, and they can ferry a diverse cargo of proteins, lipids and nucleic acids from cell to cell. The UAB research focused on a recently found third role for exosomes — the ability to harbor protease enzymes.

Activated PMNs are known to release neutrophil elastase, or NE, a protease that can degrade type I collagen and elastin. The collagen and elastin proteins help form the extracellular matrix that glues cells together. In the lungs, the extracellular matrix and lung cells are sheets of tissue that help form the tiny alveoli, where the lung exchanges oxygen and carbon dioxide. In COPD, the damaged alveoli enlarge, reducing oxygen exchange and forcing the heart to pump harder to push blood through the lungs.

NE and other proteases from PMNs can attack microbes. Healthy lungs are protected by anti-proteases that can inhibit the proteases. Normally, NE is inhibited by a robust barrier of alpha1-antitrypsin in the lung.

The research

Blalock and fellow researchers investigated whether NE might exist in an exosomal form and whether such exosomes might bypass alpha1-antitrypsin inhibition to contribute to inflammatory lung disease.

They found that exosomes from quiescent PMNs did not cause COPD when transferred to healthy mice. In contrast, exosomes from activated PMNs did cause COPD, as measured by histologic changes of the alveoli, increased pulmonary resistance and enlargement of the right heart ventricle that pumps blood to the lung.

The activated PMN exosomes were covered with enzymatically active surface-bound NE, while quiescent PMN exosomes had none. This surface NE was resistant to alpha1-antitrypsin inhibition; the exosomes from activated PMNs degraded collagen, they caused emphysema when put into mouse lungs, and they carried the PMN cell-surface markers CD63 and CD66b that identify them as coming from PMNs. Human COPD lung-derived exosomes carrying those PMN cell-surface markers conferred COPD to mice.

A very large dose of purified NE — enough to overwhelm the alpha1-antitrypsin barrier — can cause alveolar enlargement in mice. Because the exosome-bound NE was protected against apha1-antitrypsin inhibition, researchers found that the dose of activated PMN exosomes needed to cause the same damage as purified NE was 10,000 times less.

The activated PMN exosomes had another cause for their aggressive proteolysis — they carried integrin Mac-1 on their surface. Integrin Mac-1 allowed the exosomes to bind directly to collagen fibrils, a second mechanism besides protected NE for why the proteolytic exosomes exert an outsized degradative capacity in relation to their size and protease load.

“This investigation reveals an entirely unappreciated aspect of the interplay between inflammation, proteolysis and matrix remodeling with far-reaching implications for future research,” Blalock said. “Our report significantly expands the biological repertoire of the exosome, demonstrating potent biological effects of these particles ex cellula.”

Looking ahead

The study also suggests therapeutic strategies to interrupt pathogenic aspects of PMN exosome function: 1) disrupting the ionic binding of the NE to the exosome, to dislodge the NE and make it susceptible to alpha1-antitrypsin; 2) inhibiting the exosomal integrin Mac-1 to block collagen binding; and 3) directly inhibiting the exosomal NE with small-molecule compounds.

Blalock is also interested in another big question — exosome activity in healthy smokers.

“Only one in seven or one in eight smokers gets COPD,” he said. “It would be an amazing outcome if we found activated PMN exosomes in a subpopulation of people who smoke.” Those people could then be warned of the risk they faced.

This Cell study took six years of work.

Posted on Leave a comment

New leukemia drug is more effective and easier to use

A landmark study co-authored by a Loyola Medicine oncologist has found that a newer targeted drug is significantly more effective than standard therapy for treating elderly patients with chronic lymphocytic leukemia (CLL).

The drug, ibrutinib, attacks cancer cells without damaging normal cells, thus causing fewer side effects. The drug is taken as a pill once a day — much more convenient than the standard treatment requiring the patient to come in three times a month for infusions and an injection.

“Ibrutinib should become the new standard of care,” said Loyola oncologist Scott Smith, MD, PhD, one of the senior authors of the study, which was published in The New England Journal of Medicine.

In 2016, the U.S. Food and Drug Administration approved ibrutinib (brand name, Imbruvica) for treatment of CLL.

Dr. Smith is a professor in the division of ematology/oncology, department of medicine of Loyola Medicine and Loyola University Chicago Stritch School of Medicine. He was executive officer of the Alliance for Clinical Trials in Oncology, which coordinated the study, and was responsible for the execution of the study.

CLL, a disease of the immune system, is the most common form of leukemia in adults. It affects mainly older adults, with the average age of diagnosis around 70. The risk is higher in men.

Until now, the standard treatment has been a combination of a chemotherapy drug (bendamustine) that kills cancer cells and an immunotherapy drug (rituximab) that suppresses the immune system.

The study enrolled 547 CLL patients (67 percent male) at 219 centers in the United States and Canada. All were older than 65, with a median age of 71. Researchers randomly assigned patients to receive one of three regimens: the standard treatment of bendamustine plus rituximab; ibrutinib alone; or ibrutinib plus rituximab. After two years, 87 percent of patients receiving ibrutinib alone were alive without any disease progression, compared with 74 percent of patients who received bendamustine plus rituximab. There was no significant difference between patients receiving ibrutinib alone and those receiving ibrutinib plus rituximab.

About 17 percent of patients who received ibrutinib alone experienced an irregular heartbeat called atrial fibrillation. But overall, the drug caused fewer side effects than the standard treatment, Dr. Smith said.

Additional studies of ibrutinib are underway in CLL patients younger than age 65, Dr. Smith said.

Story Source:

Materials provided by Loyola University Health System. Note: Content may be edited for style and length.

Posted on Leave a comment

VLC Media Player 3.0.6 (32-bit)

VLC Media Player (formerly VideoLAN Client) is a highly portable free multimedia player for various audio and video formats, including MPEG-1, MPEG-2, MPEG-4, DivX, MP3, and OGG, as well as for DVDs, VCDs, and various streaming protocols. It also can be used as a server for unicast or multicast streams in IPv4 or IPv6 on a high-bandwidth network.

With a new audio core, hardware decoding and encoding, port to mobile platforms, preparation for Ultra-HD video and a special care to support more formats, 2.1 is a major upgrade for VLC 2019 latest.

Rincewind has a new rendering pipeline for audio, with better effiency, volume and device management, to improve VLC audio support. It supports many new devices inputs, formats, metadata and improves most of the current ones, preparing for the next-gen codecs.

VLC Media Player Features:

  • 8K support (hardware decoding is on by default)
  • Chromecast/Google Cast support
  • HDR and 10 bit video
  • HMDI Audio passthrough
  • Network browsing for NAS systems
  • 360 video and 3D audio
  • Modifying subtitle size live
  • Drag and drop support
  • HD DVD support
  • Rewritten video output core and modules, allowing blending in GPU.
  • Shader support in the OpenGL output, for conversion, including 10bits.
  • Video outputs for Windows 8 and 7, Android, iOS and OS/2.
  • Debanding, grain, denoising and anti-flickering filters.
  • Deinterlacing filter, including an Inverse Telecine algorithm.
  • Resamplers for higher quality audio.
  • Dynamic range compressor and karaoke filters.
  • Simplification of the audio core for faster processing.
  • Audio outputs for iOS, Android and OS/2.
  • Multi-threaded decoding for H.264, MPEG-4/Xvid and WebM.
  • Support for 10bits codecs, WMV image and some other codecs.
  • Rewritten support for images, including jpeg, png, xcf, bmp etc.
  • Important changes in RealVideo and Real Format support.
  • CrystalHD cards and Android OpenMAX support for hardware decoding.
  • And many more features…

Also Available: Download VLC Media Player for Mac