Both Limited and Excess Sleep May Raise Diabetes Risk in Men

Study is the first to show opposite effects of lost sleep in healthy men and women

Newswise, June 30, 2016—Men who sleep either fewer or more hours than average may face a greater risk of developing diabetes, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

More than 29 million people nationwide have diabetes, according to the Endocrine Society’sEndocrine Facts and Figures Report. 

During the last 50 years, the average self-reported sleep duration for individuals has decreased by 1.5 to 2 hours, according to the study’s senior author, Femke Rutters, PhD, of the VU Medical Centre in Amsterdam, The Netherlands. The prevalence of diabetes has doubled in the same time period.

“In a group of nearly 800 healthy people, we observed sex-specific relationships between sleep duration and glucose metabolism,” said Rutters.

“In men, sleeping too much or too little was related to less responsiveness of the cells in the body to insulin, reducing glucose uptake and thus increasing the risk of developing diabetes in the future. In women, no such association was observed.”

The cross-sectional study examined the sleep duration and diabetes risk factors in 788 people. The researchers analyzed a subset of participants in the European Relationship between Insulin Sensitivity and Cardiovascular Disease (EGIR-RISC) study, who were healthy adults ranging in age from 30 to 60 years old. Study participants were recruited from 19 study centers in 14 European countries.

Researchers measured the participants’ sleep and physical activity using a single-axis accelerometer, a device to track movement.

To assess the risk for diabetes, researchers used a device called a hyperinsulinemic-euglycemic clamp to measure how effectively the body used the hormone insulin, which processes sugar in the bloodstream.

The study found that men who slept the least and the most were more likely to have an impaired ability to process sugar compared to men who slept an average amount, about seven hours. The men at either end of the spectrum had higher blood sugar levels than men who got the average amount of sleep.

Women who slept less or more than average, however, were more responsive to the hormone insulin than women who slept the average amount.

They also had enhanced function of beta cells – the cells in the pancreas that produce the hormone insulin. This suggests lost sleep may not put women at increased risk of developing diabetes.

The study is the first to show opposite effects of lost sleep on diabetes risk in men and women.

The authors theorized this may be a result of the study population being made up of healthy individuals, rather than those at risk of developing diabetes. The researchers also measured insulin sensitivity and sleep with more sensitive devices than past studies.

“Even when you are healthy, sleeping too much or too little can have detrimental effects on your health,” Rutters said. “This research shows how important sleep is to a key aspect of health – glucose metabolism.”

Key to Chronic Fatigue Syndrome Is in Your Gut, Not Head

Newswise, June 30, 2016— Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn’t alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journalMicrobiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

“Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn’t normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease,” said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper’s senior author.

“Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin.”

“In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease,” said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria.

Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn’s disease and ulcerative colitis.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

The study was funded by the National Institutes of Health.

New Pathway to Treat Heart Failure

 Researchers discover a new way to keep the heart pumping, which could lead to new drugs for heart disease

Newswise, June 30, 2016 — (PHILADELPHIA) -- About 5.7 million Americans have heart failure, half of whom will die from the disease within 5 years, according to the Centers for Disease Control and Prevention (CDC).

Two processes help drive the disease: a weakened heart muscle that is less able to pump, and the death of heart cells that irreparably damage the heart. Beta-blockers, commonly used to treat heart disease, work by blocking the beta-adrenergic receptors in the heart, saving heart cells from cell death. But beta-adrenergic receptors also help keep the heart pumping, a function that this medication also blocks.

Now, Jefferson researchers have discovered how to bypass this problem by tapping an alternate pathway that both blocks damage to the heart and helps it keep pumping.

The research, published online this week in theProceedings of the National Academy of Sciences USA (PNAS) offers the possibility of developing a new, and potentially more effective, class of heart-failure medications.

“There’s much more work to be done before this is ready for patients, but this is an excellent example of how a little curiosity in the basic research laboratory can lead to discoveries that have the potential to change the way we treat a very common and very deadly illness,” said senior author Jeffrey Benovic, Ph.D., Thomas Eakins Professor and Chair of the Department of Biochemistry and Molecular Biology at the Sidney Kimmel Medical College and Associate Director at the Sidney Kimmel Cancer Center at Thomas Jefferson University.

Of the beta-adrenergic receptors present in the heart, it is the beta1-adrenergic receptors that are primarily responsible for the heart’s contraction, or pumping action, and that are targeted by traditional beta-blockers.

 Dr. Benovic’s lab, however, had developed a series of molecules called pepducins that were derived from pieces of the beta2-adrenergic receptor, and which, they discovered, could selectively activate the very receptor they came from.

It was while former graduate student Richard Carr, in Dr. Benovic’s lab, was characterizing the properties of these pepducins that he noticed that the molecule shared similar characteristics to a common heart-failure medication called carvedilol.

They sent the pepducin to their colleague Dr. Douglas Tilley, Ph.D., at Temple University who tested how heart cells responded to the molecule. “He was blown away by what he saw,” said Dr. Benovic.

When Dr. Tilley pulsed the heart cells with the pepducin, the cells started to beat more forcefully.

“We didn’t expect that this would happen,” said Dr. Benovic.

The pepducin they were using was specific for the beta2-adrenergic receptor pathway, and didn’t have any effect on the beta1 receptors. The researchers had demonstrated for the first time that contraction of heart muscle cells could be triggered via the beta2-adrenergic receptor, using this novel pepducin.

Through further biochemical analysis the researchers showed that the pepducin activated the ability of the beta2-adrenergic receptor to interact with a secondary signaling molecule called beta-arrestin and that it was this interaction that promoted the heart cells to beat.

In addition, the pepducin only activated the beta2 receptor to 40 or 50 percent. By tinkering with the pepducin molecules, said Benovic, “we think we can get full activation.”

The next steps, said Dr. Benovic, are to design a better version of the pepducin. In addition, Dr. Benovic and colleagues plan to screen existing small molecules, or drugs, to see if one can mimic the action of the pepducin.

They also plan to study the structure of the pepducin and the beta2 receptors to gain better insight into the design of more effective pepducin-like molecules.

“If we find or design a compound that works like this pepducin, it wouldn’t necessarily cure heart disease, but it would give doctors another tool to help bolster a failing heart,” says Benovic.

This research was supported by National Institutes of Health awards R37 GM047417, R01 GM068857, P01 HL114471, R01 HL105414, RO1 HL074854, P01 HL075443, P01 HL091799 and T32 GM100836. The authors report no conflicts of interest.

Two-in-One Approach Could Help Keep Brain Cancer in Check

Newswise, June 30, 2016 — A “combined therapy” approach to treating the most common form of brain cancer could prove promising, scientists say.

Glioblastoma is not only the most common form of brain cancer, it’s also the most deadly. It affects people from around 40 years of age, and most people live for less than 2 years after aggressive therapy. “This is a devastating disease,” says Simona Parrinello of the MRC’s Clinical Sciences Centre, who led the research.

New treatments are urgently needed, and in a study published today in eLife, the team shows that targetting just one protein has two effects, it both halts the division of the cancer cells, and stops these cells from spreading through normal tissue, a two-in-one approach.

“Current treatments often fail because the tumours spread throughout the brain, and so can’t be fully removed by surgery. If we can target this spread, it may be possible to make therapies more effective. When we target this one protein we block two key features of the tumour: its ability to divide and its ability to invade. It could be a combined therapy in one,” says Parrinello.

Scientists are not clear exactly how the cancer cells invade the brain in patients with this condition, though they know that one key route is through the space that surrounds blood vessels.

It is also known that it’s a critical subset of cancer cells that appears to favour this route. These are called “glioblastoma stem-like cells”, or GSCs, because they behave in a similar way to stem cells in the developing and adult brain.

GSCs are particularly resistant to chemotherapy and radiotherapy. Scientists believe that this, and their ability to invade, could mean it’s these cells that are responsible for the regular recurrence of glioblastoma after initial treatment.

In this study, Parrinello’s team used a cutting-edge technique called intravital imaging, to watch GSC invasion within the normal brain in real time.

Using this technique, the team discovered that when healthy cells first develop non-cancerous mutations, blood vessels within the brain keep them in a compartment so that they cannot spread and cause damage.

They found that the vessels do this by producing a protein, called ephrin-B2, which appears to immobilise the cells and hold them in place. However, when cells become cancerous GSCs, they are able to override this anti-invasion signal, and escape the compartment.

Crucially, Parrinello showed that the GSCs do this by producing their own ephrin-B2, which makes them insensitive to the ephrin-B2 already on the blood vessels.

The study also shows that a positive feedback effect comes into play along with the raised levels of ephrin-B2. At high levels, the protein appears to act as a signal, telling the GSCs to divide.

The team tried blocking ephrin-B2 using mouse models created with tumour cells from patients with the condition, a “gold standard” test for potential treatments in people.

They found that the tumour cells were unable to divide and spread through the brain. This resulted in tumours shrinking in size and the mice outliving those that did not receive the treatment, with some tumours disappearing completely. 

Parrinello says it is exciting that one treatment targets two key traits of a tumour.

“The ephrin-B2 system is complex, but in this case it works in our favour. By blocking one molecule we affect two key aspects of the tumour,” says Parrinello.

“In addition, because ephrin-B2 levels are much higher in tumour cells relative to normal cells, blocking this protein should have minimal side-effects”.

Whilst an important discovery, the scientists expect that it will be many years before this treatment is ready to be tested in people.

 In this study, they explored one particular sub-type of glioblastoma. Parrinello now plans to investigate how other subtypes respond, and whether other signalling molecules play a similar role to ephrin-B2.

Earlier this year, Parrinello won a ‘Programme Foundation Award’ grant from Cancer Research UK worth £1.5 million. Her Cell Interactions and Cancer group has also been awarded a grant from MRC Technology, which will allow the team to explore how this treatment might be used alongside existing approaches such as chemotherapy and surgery.

In this study, the CSC scientists worked with colleague Vincenzo De Paola to set up the technique for intravital imaging of the tumour cells, with Steven Pollard from the MRC Centre for Regenerative Medicine in Edinburgh, who supplied patient cells, and with Jorge Martinez-Torrecuadrada from the Centro Nacional de Investigaciones Oncologicas in Madrid who developed the molecule that blocks ephrin-B2. Federico Roncaroli of the University of Manchester provided and analysed human tumour material. Paul Bertone from the European Bioinformatics Institute in Cambridge assisted with the bioinformatics analysis of the results. 

Soaring Temperatures Pose Threat to Children, Elderly

Newswise, June 24, 2016 — The searing, record-setting temperatures in the West and Southwest United States flared a warning that extreme heat could be commonplace across much of the country this summer.

“Any extremes in weather can be inherently dangerous, but the initial heat waves every summer can be particularly perilous to those who are most vulnerable to heat-related illnesses, including children, the elderly and those with chronic medical conditions,” said Dr. Jennifer Caudle, a family physician and an assistant professor at the Rowan UniversitySchool of Osteopathic Medicine.

Most individuals can adjust to changes in temperature, a process called acclimatization, within five to seven days, but for some the process can take up to two weeks, Dr. Caudle explained.

“When the weather changes quickly, such as with a sudden heat wave, our bodies race to help maintain a normal body temperature by adjusting blood flow and sweating,” she said.

“The bodies of infants and the elderly aren’t able to make those changes as easily as healthy adults, leaving them at higher risk for serious illness and even death.”

A study by the U.S. Centers for Disease Control and Prevention (CDC) found that hot weather causes, on average, 658 deaths in the United States each year.

Interestingly, the results of the study indicated that most of the deaths occurred in the home and the vast majority of times those homes had no air conditioning. Already this year a number of deaths have been attributed to the heat in the West and Southwest United States.

“Many older individuals have medical conditions or live in situations that make them more likely to succumb to the heat,” Dr. Caudle noted.

 “Aside from their bodies’ inability to adjust quickly to changing temperatures, older individuals are less likely to sense and respond to changes in temperature and can have a diminished thirst reflex that keeps them from drinking adequate amounts of liquid. They may also have safety and financial concerns that keep them behind closed windows without fans or air conditioners.”

Dr. Caudle also emphasized that it is never o.k. to leave a child alone in a parked car, not even for a minute. Temperatures inside a parked car increase rapidly, as much as 20 degrees in just 10 minutes and can rise nearly 30 degrees within 20 minutes. Tragically, at least 15 children across the country have died already this year from the heat when left in parked cars.

“If you find a child asleep in a parked car, don’t assume that child is merely napping,” she said.

“Lethargy and confusion are signs of heat exhaustion or heat stroke, and are urgent medical conditions. Remove the child from the car and call 911 immediately. A high body temperature in a child could lead to permanent brain and organ damage.”

Dr. Caudle offered these hot-weather safety tips:

Children
• Never leave children unattended in a parked vehicle or near any pool or body of water for any amount of time.
• Avoid outdoor activities during the hours (10 a.m. to 3 p.m.) when the sun is hottest.
• Wear and re-apply sunscreen frequently.
• Children dehydrate faster than adults and should drink plenty of water during hot weather.

Elderly
• Check on elderly relatives and neighbors twice daily during hot weather.
• Make sure older individuals are appropriately dressed in loose, lightweight clothing.
• Encourage non-caffeine fluids and make sure they are within easy reach. Avoid overly sugary drinks or alcoholic drinks because these can make dehydration worse.
• If safety or finances keep older individuals behind closed doors without air conditioning, offer to take them to an air-conditioned environment like a mall or library.

Heat-related illnesses
• Heat cramps are spasms of the large muscles of the abdomen or legs accompanied by excessive perspiration. Move this person to a cool area to rest and to drink plenty of caffeine free, non alcoholic liquids.
• Heat exhaustion causes heavy perspiration, dizziness, weakness and nausea. Treat heat exhaustion with rest, drinks of cool water every 10 or 15 minutes and by applying cool, wet cloths directly to the skin. Seek immediate medical help if symptoms don’t improve quickly or if they suddenly worsen.
• Heat stroke causes many of the symptoms of heat exhaustion, without the perspiration. In fact, skin is often red and hot. Other symptoms include fainting, staggering or acting in a strange or confused manner. Heat stroke is a life threatening condition. Call 911 or emergency services for immediate help.

About Rowan University
Rowan University offers bachelor’s through doctoral programs to 16,100 students through its campuses in Glassboro, Camden and Stratford, New Jersey. In the past four years, Rowan created a School of Biomedical Sciences & Health Professions; opened the Camden-based Cooper Medical School of Rowan University; and incorporated the School of Osteopathic Medicine and the Graduate School of Biomedical Sciences, making Rowan only the second university in the nation to grant both M.D. and D.O. medical degrees. Rowan is collaborating with Rutgers-Camden to create degree programs to meet the growing need for medical services in the City of Camden. One of only three state-designated public research institutions in New Jersey, Rowan comprises the University's William G. Rohrer College of Business, the Henry M. Rowan College of Engineering and colleges of Communication & Creative Arts, Education, Humanities & Social Sciences, Performing Arts, and Science & Mathematics and the Division of Global Learning & Partnerships, as well as the medical schools.

Diabetes Raises Risk of Heart Attack Death by 50 Percent

Newswise, June 24, 2016 — Having diabetes increases the risk of dying from the effects of a heart attack by around 50 per cent, according to a widespread study.

Researchers at the University of Leeds tracked 700,000 people who had been admitted to hospital with a heart attack between January 2003 and June 2013.

Of these, 121,000 had diabetes.

After stripping out the effects of age, sex, any other illnesses and differences in the emergency medical treatment received, the team found stark differences in survival rates.

People with diabetes were 56 per cent more likely to have died if they had experienced a ST elevation myocardial infarction (STEMI) heart attack - in which the coronary artery is completely blocked - than those without the condition.

They were 39 per cent more likely to have died if they had a non-ST elevation myocardial infarction (NSTEMI) heart attack - in which the artery is partially blocked - than those without diabetes.

Lead researcher Dr Chris Gale, Consultant Cardiologist and Associate Professor in the university's School of Medicine, said: "These results provide robust evidence that diabetes is a significant long-term population burden among patients who have had a heart attack.

"Although these days people are more likely than ever to survive a heart attack, we need to place greater focus on the long-term effects of diabetes in heart attack survivors.

"The partnership between cardiologists, GPs and diabetologists needs to be strengthened and we need to make sure we are using established medications as effectively as possible among high-risk individuals."

He added that the next step in their research would be finding out exactly what it is about having diabetes that increases the risk of death following heart attack.

Dr Mike Knapton, Associate Medical Director at the British Heart Foundation, which funded the study said: "We knew that following a heart attack, you are less likely to survive if you also have diabetes.

"However, we did not know if this observation was due to having diabetes or having other conditions which are commonly seen in people with diabetes.

"This paper is the first to conclusively show that the adverse effect on survival is linked to having diabetes, rather than other conditions people with diabetes may suffer from.

"This research highlights the need to find new ways to prevent coronary heart disease in people with diabetes and develop new treatments to improve survival after a heart attack.

"The British Heart Foundation is committed to funding research in this area.

"We are currently funding researchers in Leeds to find new ways of keeping blood vessels healthy in people with diabetes in the fight for every heartbeat."

Dr Anna Morris, Head of Research Funding at Diabetes UK, said: "While researchers tackle this issue, we know that managing diabetes effectively can reduce the risk of developing cardiovascular disease.

"This includes eating healthily, keeping active and taking medications as prescribed by your doctor.

"It's essential that people with diabetes get the support they need to do this effectively, and that we continue to fund research across the UK aimed at preventing the onset of complications in the first place."

The study is published in the Journal of Epidemiology and Community Health.

Understanding How Chemical Changes in the Brain Affect Alzheimer's Disease

Newswise, June 24, 2016 — A new study from Western University is helping to explain why the long-term use of common anticholinergic drugs used to treat conditions like allergies and overactive bladder lead to an increased risk of developing dementia later in life. The findings show that long-term suppression of the neurotransmitter acetylcholine - a target for anticholinergic drugs - results in dementia-like changes in the brain.

"There have been several epidemiological studies showing that people who use these drugs for a long period of time increase their risk of developing dementia," said Marco Prado, PhD, a Scientist at the Robarts Research Institute and Professor in the departments of Physiology and Pharmacology and Anatomy & Cell Biology at Western's Schulich School of Medicine & Dentistry. "So the question we asked is 'why?'"

For this study, published in the journalCerebral Cortex, the researchers used genetically modified mouse models to block acetylcholine in order to mimic the action of the drugs in the brain. Neurons that use acetylcholine are known to be affected in Alzheimer's disease; and the researchers were able to show a causal relationship between blocking acetylcholine and Alzheimer's-like pathology in mice.

"We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer's pathology," said Prado.

Prado and his partner Dr. Vania Prado, DDS, PhD, along with PhD candidates Ben Kolisnyk and Mohammed Al-Onaizi, have shown that blocking acetylcholine-mediated signals in neurons causes a change in approximately 10 per cent of the Messenger RNAs in a region of the brain responsible for declarative memory.

Messenger RNA encodes for specific amino acids which are the building blocks for proteins and several of the changes they uncovered in the brains of mutant mice are similar to those observed in Alzheimer's disease.

"We demonstrated that in order to keep neurons healthy you need acetylcholine," said Prado. "So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer's disease."

Importantly, by targeting one of the messenger RNA pathways they uncovered, the researchers improved pathology in the mutant mice.

The study, conducted at Western's Robarts Research Institute, used human tissue samples to validate the mouse data and mouse models to show not only the physical changes in the brain, but also behavioral and memory changes.

The researchers were able to show that long-term suppression of acetylcholine caused brain cell to die and as a consequence decrease memory in the aging mice.

"When the mutant mice were old, memory tasks they mastered at young age were almost impossible for them, whereas normal mice still performed well," said Kolisnyk.

The researchers hope their findings will have an impact on reducing the burden of dementia by providing new ways to reverse the loss of acetylcholine.

The researchers were supported by CIHR, Brain Canada and NSERC and the work was done in collaboration with researchers at the UCL Institute of Neurology, The Hebrew University of Jerusalem and McMaster University.

New Clues to COPD Linked to Proteostasis Imbalance Caused by Cigarette Smoke

Newswise, June 23, 2016 — Few threats to public health are as perilous as cigarette smoking, with more than 435,000 Americans dying each year of tobacco-related pulmonary illnesses such as chronic obstructive pulmonary disease (COPD).

COPD ranks as the third-leading cause of tobacco-related morbidity and mortality worldwide in 2012 and the global cost of illness related to COPD is expected to rise to $4.8 trillion by 2030, yet there are currently no effective medical treatments to cure COPD or stop its progression.

Since the identification of factors contributing to the development of COPD is crucial for developing new treatments, a team of scientists including Anna Blumental-Perry, PhD, from the department of surgery, and Xing-Huang Gao, PhD, from the department of genetics and genome sciences, at Case Western Reserve University School of Medicine embarked on a study to examine COPD development at the cellular level.

Specifically, Blumental-Perry and her team sought to better understand the mechanisms of a relatively new scientific concept – the smoke induced collapse of protein homeostasis and its contribution to age-dependent onset of COPD. Knowing that upon inhalation of cigarette smoke (CS), the free radicals in it can reach the interior of lung cells where they react with a wide variety of cell proteins and affect their functions, the scientists formed the hypothesis that CS-free radicals can interfere with proper folding of the proteins within the cell.

The scientists’ findings, recently published inThe Journal of Biological Chemistry, demonstrated that free radicals—small, unstable molecules present in CS—can reach the endoplasmic reticulum, a cellular organelle that is critical in manufacturing and transporting fats, steroids, hormones and various proteins, and alter its function by oxidizing and damaging its most abundant and crucial to protein folding chaperone, Protein Disulfide Isomerase (PDI).

Determining that PDI is a critical factor in the development of COPD, the researchers identified for the first time how cells adapt to the presence of less functional PDI, which is by increasing the levels of it through a novel mechanism at the protein synthesis level, as opposed to the level of gene transcription. Since adaptation wears off with age, the researchers have now identified one of the first clues to age-dependency in COPD onset.

“Understanding the mechanisms of the collapse of protein homeostasis in COPD allows us to focus on maintaining functional levels of PDI. This could improve outcomes for the many patients with COPD as well as potentially giving us clues to improve health with aging.” said Blumental-Perry. “

We discovered that PDI is a critical new factor in the pathogenesis of COPD, and that protein collapse in COPD is age dependent and unpredictable. Based on these fascinating findings, we plan to conduct future research targeting failed adaptive systems in an effort to maintain functional levels of PDI, and prevent it from acquisitions of ‘bad’ functions – discoveries that could ultimately help us to identify new therapeutic approaches for COPD.”

This research was supported by Flight Attendants Medical Research Institute Young Clinical Investigator Award 092207; National Institute of Health grants 5P20GM103542 from the National Center for Research Resources; COBRE in Oxidants, Redox Balance and Stress Signaling; CO6 RR015455; R37-DK60596 and R01-DK53307.

For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.

Memory Loss Caused by West Nile Virus Explained

Study identifies targets for prevention, treatment

Newswise, June 23, 2016— Every year as mosquito season arrives, so does West Nile virus, causing fever in thousands of people nationwide and life-threatening brain infections in an unlucky few. About half the people who survive that infection – West Nile encephalitis – are left with permanent neurological deficits such as memory loss.

New research shows that these long-term neurological problems may be due to the patient’s own immune system destroying parts of their neurons, which suggests that intervening in the immune response may help prevent brain damage or help patients recover.

The study is published June 22 in Nature.

Since 1999, when West Nile arrived in the Western Hemisphere via an infected flamingo in the Bronx Zoo, the virus has spread throughout the Americas, infecting millions of people.

Ten thousand West Nile survivors are living with long-term neurological problems such as fatigue, weakness, difficulty walking and memory loss, and the number goes up by about a thousand every year following mosquito season. There is no vaccine or specific treatment for West Nile infection.

“When I talk with other doctors about West Nile patients with these persistent neurological deficits, many say, ‘The virus in their brains must have killed neurons, and there’s nothing we can do about it,’” said Robyn Klein, MD, PhD, a professor of medicine and the study’s senior author.

“My thinking has been, if we can determine what triggers this brain damage, maybe we can prevent this from happening or stop it afterwards.’”

Klein, postdoctoral researcher Michael Vasek, PhD, and colleagues developed a mouse model of West Nile encephalitis by injecting a weakened strain of the virus directly on top of the mouse hippocampus, a region of the brain important for memory.

A month after the mice had recovered from the infection, the researchers tested the animals’ ability to navigate a maze.

Much like West Nile survivors who cannot navigate their neighborhood, the infected mice could not remember how to navigate the maze. But contrary to conventional wisdom, their hippocampal neurons hadn’t been killed by the virus.

Instead, the researchers found that microglial cells, a kind of immune cell that lives in the brain, were clustered around the neurons at the site of infection and were highly activated – “on fire,” as Klein put it.

Moreover, levels of an immune protein called complement were high in the brains of mice with memory loss. Neurons make connections to each other at junctions called synapses, allowing information to be passed from cell to cell. During normal brain development, many more synapses are formed than needed and only those that are strengthened should persist. Complement tags the weak synapses to be removed, and activated microglia destroy them.

In the mice with memory loss, viral infection seems to have sent this system into overdrive, leading to the destruction of needed synapses. Synapses must be formed or strengthened for learning and memory to occur.

While the neurons near the activated microglia were still alive, they were lacking synapses. The more synapses that were destroyed, the worse the mouse’s memory problems.

“There’s never been any model of cognitive dysfunction due to brain infection that shows that eliminating synapses without loss of neurons could cause these symptoms,” said Klein, who is also a professor of pathology and immunology, and of neurosciences.

“It’s really a paradigm-shifting idea that a viral infection can do this. It also makes us wonder whether these mechanisms are involved in other diseases associated with memory loss.”

Healthy people create new synapses throughout life as they learn new things. West Nile survivors, however, may be unable to grow new synapses to replace the ones lost during their bouts of encephalitis.

“The microglia remain activated long after the virus is cleared, and this may be preventing the synapses from recovering,” Klein said. “But that gives us hope that we can develop interventions directed at the immune response. We think we can treat this. And that’s what we’re trying to do.” 

New Heart Failure Therapy Could Prevent Substantial Number of Deaths, Study Finds

Newswise, June 23, 2016— A UCLA-led study estimates that almost 28,500 deaths could be prevented each year in the U.S. through use of a new FDA-approved class of cardiovascular medication that helps reduce mortality in patients diagnosed with heart failure and reduced ejection fraction, the percentage of blood pumped from the heart with each contraction.

Previous studies have demonstrated that ‘angiotensin receptor neprilysin inhibitor’ (ARNI) therapy using a new class of medication (generic name: sacubitril and valsartan) reduces mortality in patients with heart failure and reduced ejection fraction.

The therapy works by enhancing the body’s protective hormonal systems while simultaneously inhibiting the overactive hormones that harm the heart.

In this study, researchers wanted to quantify the number of deaths that could be prevented or postponed with ARNI therapy. Researchers conducted the study by analyzing published data of patients who were eligible for the therapy, estimates of the number of people in the U.S. diagnosed with heart failure and reduced ejection fraction, and the numbers needed to treat with the medication to avert death.

More than 2.7 million patients in the United States have been diagnosed with heart failure and reduced ejection fraction. Of these patients, 84 percent (almost 2.3 million) are potential candidates for ARNI therapy. This study showed that, if ARNI therapy were comprehensively applied to eligible patients, it could potentially prevent 28,484 deaths each year.

“These findings support the timely implementation of ARNI therapy into routine clinical practice because this will have substantial impact on population health for patients with heart failure,” said the study’s lead author, Dr. Gregg Fonarow, the Eliot Corday Chair in Cardiovascular Medicine and Science, director of the Ahmanson–UCLA Cardiomyopathy Center and co-chief of the UCLA Division of Cardiology.

In addition to Fonarow, authors included Dr. Adrian Hernandez of Duke; Dr. Scott Solomon of Brigham and Women’s; and Dr. Clyde Yancy of Northwestern.

 Fonarow has received research grants from the National Institutes of Health and consulting fees from Amgen, Janssen, Medtronic and Novartis. Hernandez received research support from Amgen, AstraZeneca, Merck and Novartis and honoraria from Amgen, Luitpold, Merck and Novartis. Solomon received research grants from Novartis to Brigham and Women’s Hospital and consulting fees from Novartis, Amgen and Bayer.

Mayo Clinic Study Shows Increase in Parkinson’s Disease Over 30 Years

Newswise, June 22, 2016--The incidence of Parkinson’s disease and parkinsonism increased significantly in 30 years from 1976 to 2005, Mayo Clinic researchers reported today in a study in JAMA Neurology. This trend was noted in particular for men age 70 and older. According to the researchers, this is the first study to suggest such an increasing trend.

The study shows that men of all ages had a 17 percent higher risk of developing parkinsonism and 24 percent higher risk of developing Parkinson’s disease for every 10 calendar years.

The study also showed that men 70 and older had an even greater increase — a 24 percent higher risk of developing parkinsonism and 35 percent higher risk of developing Parkinson’s disease for every 10 calendar years.

Using the Rochester Epidemiology Project, Mayo Clinic researchers were able to look at the complete medical records — from birth to death — of anyone in Olmsted County, Minnesota, who received at least one of the diagnoses related to parkinsonism.

The records were reviewed by a movement disorders specialist to confirm the diagnosis and to classify different types of parkinsonism, including the most common type, Parkinson’s disease.

“We have reasons to believe that this is a real trend,” says Rodolfo Savica, M.D., Ph.D., lead author and neurologist at Mayo Clinic. “The trend is probably not caused merely by changes in people’s awareness or changes in medical practice over time. We have evidence to suggest that there has been a genuine increase in the risk of Parkinson’s disease.

”The researchers point to environmental and lifestyle changes as potential causes for the increase.

“There has been a dramatic change in exposure to some risk factors in the United States,” Dr. Savica says.

“We know that environmental agents like pesticides or smoking or other agents in the environment have changed in the last 70 years or so. Changes in exposure to a number of risk factors may have caused Parkinson’s disease to rise.”

The study, based on almost 1,000 patients affected by parkinsonism, is the first to consider long-term trends in risk over 30 years. It also provides evidence contrary to two previous U.S. studies and one Canadian study that showed no trend, and particularly contrary to three United Kingdom studies that suggested a possible decline in the occurrence of Parkinson’s disease over time.

The Mayo Clinic study also revealed a possible higher incidence of both parkinsonism and Parkinson’s disease in men and women born from 1915 to 1924.

“This observation is important because the persons born in that particular decade may have been exposed to some environmental or other factors during their intrauterine life or early after birth that increased the risk,” Dr. Savica says. “We need to confirm this hypothesis.

”Parkinsonism is the umbrella term that includes Parkinson’s disease but also may include other disorders. The diagnosis of parkinsonism requires the presence of slowness of movement and at least one other symptom — a tremor while at rest, muscle rigidity or a tendency to fall. Parkinson’s disease is defined as having the manifestations of parkinsonism but without any other known causes, and it is the most common type of parkinsonism.

The researchers urged caution in interpreting the trends, which may be from an increased awareness of symptoms and improved access to care. In the study’s earlier years, for example, patients with cancer or severe cardiac disease may not have been diagnosed with parkinsonism or Parkinson’s disease if doctors did not consider their movement disorder to be important in their care.

“Parkinson’s disease is an important disease and a cause of disability, especially in older ages, and we don’t want to have people untreated for a condition that is treatable just because they have four or five other diseases that are more prominent,” Dr. Savica says.

The observation that the time trends were more evident in men than in women may support a genuine trend in incidence. Recognition of symptoms in the context of multiple illnesses should have changed similarly over time in men and women, the study notes. Thus, if the trend was not genuine it should have been similar in men and women.

Parkinsonism and Parkinson’s disease tend to affect more men than women in general. But Dr. Savica also notes that the increase was more dramatic in men, but the study also showed a similar trend in women — an increase in Parkinson’s disease in women 70 years of age and older. However, the trend in women did not reach statistical significance.

“Differences in men and women may be important in understanding the environmental causes of Parkinson’s disease,” Dr. Savica says.

If the trend of increasing incidence rates is genuine, and can be replicated in other populations, it has major implications for finding the causes of Parkinson’s disease and for public health, the researchers note.

From a research perspective, the trend should prompt studies to identify environmental or lifestyle changes during the study subjects’ lifespan. Environmental or lifestyle factors could include smoking, pesticide use, head trauma, coffee consumption and other factors.

Study co-authors are Brandon Grossardt, M.S.; James Bower, M.D.; Eric Ahlskog, M.D., Ph.D.; and senior author Walter Rocca, M.D., M.P.H., all of Mayo Clinic.

The study was supported by an award from the National Institute on Aging of the National Institutes of Health (grant AG 034676) and by the Mayo Foundation for Medical Education and Research.

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About Mayo Clinic

Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www.mayoclinic.org/about-mayo-clinic and http://www.newsnetwork.mayoclinic.org/.

Getting a Better Handle on Hispanics’ Health

Newswise, June 22, 2016– Politicians, marketers and media moguls pay serious attention to this country’s Hispanic residents.

The medical community is starting to do so, too.

“Despite its size, this segment of the population has until very recently been somewhat ignored by health care providers and researchers,” said Carlos J. Rodriguez, M.D., an associate professor of medicine and epidemiology at Wake Forest Baptist Medical Center.

“That’s unfortunate, because Hispanics’ health is vital to the public health of the nation.”

The more than 55 million Hispanics – defined by the U.S. Census Bureau as individuals “of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin regardless of race” – currently living in the United States account for 17 percent of the total population and constitute the nation’s largest racial or ethnic minority.

To illustrate: Garcia, Rodriguez, Martinez and Hernandez are among the 15 most common surnames in this country.

While there are still “traditional” concentrations of Puerto Ricans in the New York area, Cuban-Americans in South Florida and people of Mexican heritage in the Southwest and California, the geographical distribution of the Hispanic population has changed dramatically in recent years. Hispanics now represent at least 9 percent of the population in 24 states and the District of Columbia. As for the future, the Census Bureau projects that by 2060 Hispanics – or, as some prefer, Latinos – will number 119 million, or 28 percent of the national total.

But whether the goal is getting votes, selling products, attracting audiences or tracking health trends, treating the Hispanic population as a single, homogenous community can be hazardous to success.

“Hispanics are a diverse ethnic population, varying in race, national origin, immigration status and a wide range of cultural and socioeconomic factors,” said Rodriguez, who was born in the Dominican Republic and grew up in New York City. “The diversity among U.S. Hispanics presents many challenges.”

In medicine, those challenges include overcoming some major gaps in research data.

“An incomplete understanding of Hispanic populations in academic research has produced a lack of comprehensive data addressing Hispanic health,” Rodriguez said.

“Many surveys have examined Hispanics as an aggregate group without identifying their background or origin, and while there is a greater availability of data on Mexican-Americans, which may simply reflect their larger numerical presence within the United States, it may not be appropriate to extrapolate that data to other Hispanic groups.”

A National Institutes of Health-funded initiative called the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is filling in some of those gaps.

The largest study of Hispanic health ever conducted in the United States, it enrolled more than 16,000 adults living in San Diego, Chicago, Miami, and the Bronx, New York, who self-identified as being of Cuban, Dominican, Mexican, Puerto Rican, Central American or South American origin.

 It has found, for example, that the percentage of people with asthma ranged from 7.4 percent among those of Mexican ancestry to 35.8 percent among those of Puerto Rican descent and that the percentage of individuals with high blood pressure ranged from 20.3 among those with South American heritage to 32.2 percent among those with Cuban origins.

Rodriguez, a cardiologist who also holds a master’s degree in public health, has analyzed data collected by HCHS/SOL to investigate heart disease and stroke among Hispanics, a high-risk population for these disorders.
Among his findings in a 2015 study were that nearly half of Hispanic adults with high cholesterol were unaware of it and that less than one-third of those who were aware received treatment.

A study published in April of this year indicated that Hispanics had higher rates of a potentially serious heart-pumping problem than other populations but that fewer than 5 percent of those with the condition knew they had it.

“Lack of awareness is a problem with roots at different levels for Hispanics, including access to care and patient-provider difficulties such as language barriers or cultural insensitivity that may contribute to these gaps,” Rodriguez said. “That needs to change, since awareness is the first step in prevention.”

Rodriguez also was the lead author of a 2014 science advisory from the American Heart Association that provided a comprehensive overview of cardiovascular disease and stroke among Hispanics and recommended specific, culturally appropriate strategies that health care providers, researchers and policymakers could use to improve heart health and treatment in the both the Hispanic population at large and in subgroups by country of origin.

“Given the number of Hispanics in the United States, it’s critical that we pay more attention to these individuals,” Rodriguez said. “No population can be left behind if we are to improve the health of the entire country.”