How you cope with stress may increase your risk for insomnia

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A new study is the first to identify specific coping behaviors through which stress exposure leads to the development of insomnia.

Results show that coping with a stressful event through behavioral disengagement -- giving up on dealing with the stress -- or by using alcohol or drugs each significantly mediated the relationship between stress exposure and insomnia development. Surprisingly, the coping technique of self-distraction -- such as going to the movies or watching TV -- also was a significant mediator between stress and incident insomnia. Furthermore, the study found that cognitive intrusion -- recurrent thoughts about the stressor -- was a significant and key mediator, accounting for 69 percent of the total effect of stress exposure on insomnia.

"Our study is among the first to show that it's not the number of stressors, but your reaction to them that determines the likelihood of experiencing insomnia," said lead author Vivek Pillai, PhD, research fellow at the Sleep Disorders & Research Center at Henry Ford Hospital in Detroit, Michigan. "While a stressful event can lead to a bad night of sleep, it's what you do in response to stress that can be the difference between a few bad nights and chronic insomnia."

Study results are published in the July 1 issue of the journal Sleep.

The study involved a community-based sample of 2,892 good sleepers with no lifetime history of insomnia. At baseline the participants reported the number of stressful life events that they had experienced in the past year, such as a divorce, serious illness, major financial problem, or the death of a spouse. They also reported the perceived severity and duration of each stressful event. Questionnaires also measured levels of cognitive intrusion and identified coping strategies in which participants engaged in the seven days following the stressful event. A follow-up assessment after one year identified participants with insomnia disorder, which was defined as having symptoms of insomnia occurring at least three nights per week for a duration of one month or longer with associated daytime impairment or distress. "This study is an important reminder that stressful events and other major life changes often cause insomnia," said American Academy of Sleep Medicine President Dr. Timothy Morgenthaler. "If you are feeling overwhelmed by events in your life, talk to you doctor about strategies to reduce your stress level and improve your sleep."

According to the authors, the study identified potential targets for therapeutic interventions to improve coping responses to stress and reduce the risk of insomnia. In particular, they noted that mindfulness-based therapies have shown considerable promise in suppressing cognitive intrusion and improving sleep.

"Though we may not be able to control external events, we can reduce their burden by staying away from certain maladaptive behaviors," said Pillai.

The American Academy of Sleep Medicine reports that short-term insomnia disorder lasting less than three months occurs in 15 to 20 percent of adults and is more prevalent in women than in men.

The research was performed under the supervision of Thomas Roth, PhD, and Christopher Drake, PhD, in the Sleep & Research Center at Henry Ford Hospital in Detroit. The study was supported by funding from the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH).

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Story Source:

The above story is based on materials provided by American Academy of Sleep Medicine. Note: Materials may be edited for content and length.

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Journal Reference:

1. Vivek Pillai, Thomas Roth, Heather M. Mullins, Christopher L. Drake. Moderators and Mediators of the Relationship Between Stress and Insomnia: Stressor Chronicity, Cognitive Intrusion, and Coping. SLEEP, 2014; DOI: 10.5665/sleep.3838

New insights on conditions for new blood vessel formation

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A new capillary sprouting off a blood vessel.

Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is essential to the body's development. As organs grow, vascular networks must grow with them to feed new cells and remove their waste. The same process, however, also plays a critical role in the onset and progression of many cancers, as it allows the rapid growth of tumors.

With lifesaving applications possible in both inhibiting and accelerating the creation of new blood vessels, a more fundamental understanding of what regulates angiogenesis is needed. Now, researchers at the University of Pennsylvania, Boston University and Harvard University have uncovered the existence of a threshold above which fluid flowing through blood vessel walls causes new capillaries to sprout.

This discovery could help pave the way for cancer-fighting drugs, treatments for the hardened blood vessels found in the cardiovascular disease arthrosclerosis or even growing synthetic organs in the lab.

The research was led by postdoctoral fellow Peter Galie of the Department of Bioengineering in Penn's School of Engineering and Applied Science and Christopher Chen, then a professor of bioengineering at Penn who is now at Boston University and an associate faculty member of the Wyss Institute for Biologically Inspired Engineering at Harvard University. They collaborated with Duc-Huy Nguyen, Colin Choi and Daniel Cohen, all members of Chen's lab, and professor Paul Janmey, also of the Department of Bioengineering, as well as the Department of Physiology in Penn's Perelman School of Medicine.

Their study was published in the Proceedings of the National Academy of Sciences.

The team's experiments incorporated "blood-vessel-on-a-chip" devices, which use microfluidic technology to simulate processes that normally occur deep within tissues. They found that cells lining each artificial vessel sprouted to form new vessels once the force exerted by fluid flow through the vessel exceeded a certain threshold.

"These findings suggest that our blood vessels can sense when blood flow exceeds their carrying capacity and respond by producing additional vessels on demand," Chen explained. "Perhaps we could one day take advantage of this response to enhance vessel regrowth where the need is critical, such as after a heart attack."

During their experiments, the researchers controlled the fluid flow within the artificial vessel, and ultimately where new vessels would sprout, by changing the shape and orientation of thin needles deployed within a collagen gel containing each vessel. Using a mathematical model, they predicted the exact spots along the vessel where force exceeded the sprouting threshold, thereby pinpointing the location where new vessels would form.

Now the researchers aim to advance new experiments designed to figure out how cells sense this mechanical threshold.

"The logical next step is to determine the molecular mechanism behind this phenomenon," said Galie, "what proteins are involved and how might they be targeted in new drug therapies."

Their work was funded by the National Institutes of Health and the University of Pennsylvania's Center for Engineering Cells and Regeneration, where Chen was the founding director.

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Story Source:

The above story is based on materials provided by University of Pennsylvania. Note: Materials may be edited for content and length.

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Journal Reference:

1. P. A. Galie, D.-H. T. Nguyen, C. K. Choi, D. M. Cohen, P. A. Janmey, C. S. Chen. Fluid shear stress threshold regulates angiogenic sprouting. Proceedings of the National Academy of Sciences, 2014; 111 (22): 7968 DOI: 10.1073/pnas.1310842111

Fotos de família

Biological signal processing: Body cells -- instrumentalists in a symphony orchestra

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Like an isolated note in a symphony orchestra, an isolated signal in the cell is of subordinate importance.

Every organism has one aim: to survive. Its body cells all work in concert to keep it alive. They do so through finely tuned means of communication. Together with cooperation partners from Berlin and Cambridge, scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have now successfully revealed for the first time the laws by which cells translate signals from their surroundings into internal signals. Like an isolated note in a symphony orchestra, an isolated signal in the cell is of subordinate importance. "What is important is the relative variation of intensity and frequency at which the signals are transmitted from the cell membrane into the cell," says Dr. Alexander Skupin, who led the studies at LCSB. The research group published their results now in the scientific journal Science Signaling.

The instruments in an orchestra produce signals -- musical notes -- by causing the air to vibrate. Inside a cell, calcium ions carry signals. When a piece of information from the environment -- say a biological messenger -- meets the outer envelope of the cell, calcium ions are released inside the cell. There, they control various adaptation processes. "At first sight, there is no simple pattern to the ion impulses," Skupin explains; "yet they still culminate in a meaningful response inside the cell, like the activation of a specific gene, for instance."

In order to determine the laws underlying this phenomenon, the researchers studied human kidney cells and rat liver cells using a combination of imaging technologies and mathematical methods. They discovered that the intensity and frequency of calcium impulses undergo extreme variation -- both cell-internally and cell-to-cell. Accordingly, the information they convey cannot be interpreted by analyzing isolated signals alone. "It's like in an orchestra, where studying an isolated note on its own allows no inference of the melody," Skupin continues the musical analogy. "You have to hear how the frequency and volume of all instruments vary and produce the melody. Then you gain an impression of the musical piece."

Now, for the first time, the researchers have managed to gain such an impression of the whole by listening in on the cells' communications. They discovered that the plethora of calcium impulses vary relatively to one another in a specific relationship: A stimulus from outside does not lead to an absolute increase in calcium impulses, but instead to a change in the frequency at which they occur -- in the concert hall, the notes of the instruments rise and fall in symphony. "This pattern is the actual signal that leads to a response in the cells," Skupin says. "With our analyses, we have rendered it interpretable."

"The results are of great importance for analyzing diseases," says Director of LCSB Prof. Dr. Rudi Balling. "We know that, in Parkinson's disease, the calcium balance in the nerve cells is disrupted, and suspect that errant communications between the cells could play a role in the onset of neurodegenerative diseases. With the discovery of the fundamental laws of these communications, as Alexander Skupin, his team and our cooperation partners have now achieved, we are set to take a major step forward in the analysis of Parkinson's disease."

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Story Source:

The above story is based on materials provided by University of Luxembourg. Note: Materials may be edited for content and length.

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Journal Reference:

1. K. Thurley, S. C. Tovey, G. Moenke, V. L. Prince, A. Meena, A. P. Thomas, A. Skupin, C. W. Taylor, M. Falcke. Reliable Encoding of Stimulus Intensities Within Random Sequences of Intracellular Ca2 Spikes. Science Signaling, 2014; 7 (331): ra59 DOI: 10.1126/scisignal.2005237

Explaining 'healthy' obesity

 

July 3, 2014

Cell Press

Up to one-quarter of individuals currently labeled as obese are actually metabolically healthy. Though obesity is a major risk factor for diabetes, the two conditions aren't always linked. A new study sheds light on a possible explanation, revealing that high levels of a molecule HO-1 are linked to poor metabolic health and an increased risk of type 2 diabetes in obese humans. HO-1 blockers could represent a promising new strategy for the treatment of metabolic disease.

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Up to one-quarter of individuals currently labeled as obese are actually metabolically healthy and do not have a high risk of developing type 2 diabetes. Though obesity is a major risk factor for diabetes, the two conditions aren't always linked. A study published by Cell Press July 3rd in the journal Cell sheds light on a possible explanation, revealing that high levels of a molecule called heme oxygenase-1 (HO-1) are linked to poor metabolic health and an increased risk of type 2 diabetes in obese humans. Moreover, HO-1 inhibition improves metabolic health in obese mice, suggesting that HO-1 blockers could represent a promising new strategy for the treatment of metabolic disease.

"The results indicate that HO-1 is in fact necessary for the development of metabolic disease and call for a re-evaluation of numerous findings in the field," says senior study author Harald Esterbauer of the Medical University of Vienna. "The study also reveals HO-1 as a candidate biomarker for the stratification of metabolically healthy and unhealthy obesity and provides a framework for selective, personalized therapy."

The factors that determine whether obesity leads to poor metabolic health have been unclear, but the evidence suggests that a maladaptive immune response called metabolic inflammation plays an important role. However, studies examining the relationship between a supposedly anti-inflammatory molecule called HO-1 and metabolic disease have produced conflicting results.

To address this question, Esterbauer teamed up with senior study author J. Andrew Pospisilik of the Max Planck Institute of Immunobiology and Epigenetics. In contrast to past findings, they found higher levels of HO-1 in liver and fat biopsies from obese, insulin-resistant humans compared with obese, metabolically healthy individuals. When the researchers deleted the HO-1 gene in immune cells called macrophages, molecular signs of inflammation decreased in mice, suggesting that HO-1 actually promotes inflammation, contrary to widespread belief. Moreover, deletion of the HO-1 gene specifically in the liver or macrophages of mice fed a high-fat diet led to better liver function and an increase in insulin sensitivity -- a clear sign of improved metabolic health.

"Our findings show that HO-1 is among the strongest predictors of metabolically unhealthy obesity in humans, and it could have a high prognostic value for detecting disease onset," Pospisilik says. "This could allow clinicians to use targeted interventions to prevent disease progression specifically in obese individuals who show early signs of type 2 diabetes."

New strategy could uncover genes at the root of psychiatric illnesses

 

July 3, 2014

Cell Press

Understanding the basis of psychiatric disorders has been extremely challenging because there are many genetic variants that may increase risk but are insufficient to cause disease. Now investigators describe a strategy that may help reveal how such 'subthreshold' genetic risks interact with other risk factors or environmental exposures to affect the development of the nervous system. Their research pinpoints a genetic variant that may predispose individuals to schizophrenia.

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Yoon et al. use modeling in iPSCs and mice to examine the functional effects of 15q11.2 CNVs, a known risk factor for several neuropsychiatric disorders including schizophrenia. Their analysis highlights defects in adherens junctions and polarity in neural stem cells associated with haploinsufficiency of the cytoskeletal regulator CYFIP1. The cover image was created using images of neural rosettes derived from human iPSCs with and without a 15q11.2 microdeletion (round circles) and images of radial glial cells in the developing mouse cortex (thin filaments), and it is inspired by July 4th fireworks.

 

Understanding the basis of psychiatric disorders has been extremely challenging because there are many genetic variants that may increase risk but are insufficient to cause disease. Now investigators reporting in the July 3rd issue of the Cell Press journal Cell Stem Cell describe a strategy that may help reveal how such "subthreshold" genetic risks interact with other risk factors or environmental exposures to affect the development of the nervous system. Their research pinpoints a genetic variant that may predispose individuals to schizophrenia.

The work takes advantage of a recently developed technology that allows skin cells from patients to be reprogrammed into induced pluripotent stem cells (iPSCs) that can then generate any cell type in the body. Through this technology, scientists obtained stem cells from individuals with a genetic abnormality that confers increased susceptibility to schizophrenia, and they observed deficits during nerve development that could be traced to a specific gene called CYFIP1, which helps maintain a nerve cell's structure. The team then blocked the expression of this gene in developing mouse embryos and noticed defects in the formation of the cerebral cortex, a brain region that plays an important role in consciousness.

Next, the scientists turned to human genetic studies to see how CYFIP might interact with other factors. They found that mutations in two genes within a cellular pathway linked to CYFIP1 led to a significantly increased risk of schizophrenia. The findings support the theory that multiple factors within the same pathway may interact to affect one's risk for psychiatric disorders.

"We were able to use a set of cutting-edge tools to gain insight into a critical cellular process for normal brain development, the dysregulation of which may be a manifestation of a genetic predisposition for schizophrenia," says senior author Dr. Guo-li Ming, of Johns Hopkins University School of Medicine. The researchers' strategy -- generating disease-specific nerve cells, identifying a causative gene for developmental defects, validating the gene-specific defect in animal models, and then investigating interactions with other genes both in animal models and in humans -- represents a promising new approach for understanding the mechanisms underlying some of the most intractable psychiatric illnesses.

The work also highlights the promise of iPSC technology as a discovery tool in understanding and treating human disorders. "Despite an enormous amount of time and resources devoted to producing solid, reproducible results in animal models, far too often, results from preclinical trials deviate from our expectations," says co-author Dr. Hongjun Song. "The lack of access to disease-relevant human cell types has been a missing link in our current drug discovery process, which has now been resolved through advances in cellular reprogramming."

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Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.

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Journal Reference:

1. Ki-Jun Yoon, Ha Nam Nguyen, Gianluca Ursini, Fengyu Zhang, Nam-Shik Kim, Zhexing Wen, Georgia Makri, David Nauen, Joo Heon Shin, Youngbin Park, Raeeun Chung, Eva Pekle, Ce Zhang, Maxwell Towe, Syed Mohammed Qasim Hussaini, Yohan Lee, Dan Rujescu, David St. Clair, Joel E. Kleinman, Thomas M. Hyde, Gregory Krauss, Kimberly M. Christian, Judith L. Rapoport, Daniel R. Weinberger, Hongjun Song, Guo-li Ming. Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity. Cell Stem Cell, 2014; 15 (1): 79 DOI: 10.1016/j.stem.2014.05.003

Genetic link to autism found, known as CHD8 mutation

 

July 3, 2014

University of Washington - Health Sciences/UW News, Community Relations & Marketing

In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. This is the first time researchers have shown a definitive cause of autism to a genetic mutation. Previously identified genetic events like Fragile X, which account for a greater number of autism cases, are associated with other impairments, such as intellectual disability, more than autism.

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To confirm the findings, researchers worked with scientists at Duke University who do zebra fish modeling.

In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. The results are being published in Cell magazine July 3, 2014: "Disruptive CHD8 Mutations Define a Subtype of Autism in Early Development."

"We finally got a clear cut case of an autism specific gene," said Raphael Bernier, the lead author, and UW associate professor in the Department of Psychiatry and Behavioral Sciences and the clinical director of the Autism Center at Seattle Children's.

Bernier said people with a mutation in the CHD8 gene have a very "strong likelihood" that they will have autism marked by gastrointestinal disorders, a larger head and wide set eyes.

In their study of 6,176 children with autism spectrum disorder, researchers found 15 had a CHD8 mutation and all these cases had similar characteristics in appearance and issues with sleep disturbance and gastrointestinal problems.

Bernier and his team interviewed all 15 cases with CHD8 mutations.

To confirm the findings, researchers worked with scientists at Duke University who do zebra fish modeling. The researchers disrupted the CHD8 gene in the fish and the fish developed large heads and wide set eyes. They then fed the fish fluorescent pellets and found that the fish had problems discarding food waste and were constipated.

Bernier said this is the first time researchers have shown a definitive cause of autism to a genetic mutation. Previously identified genetic events like Fragile X, which account for a greater number of autism cases, are associated with other impairments, such as intellectual disability, more than autism. Although less than half a percent of all kids will have this kind of autism related to the CHD8 mutation, Bernier said there are lots of implications from this study.

"This will be a game changer in the way scientists are researching autism," he said.

The results could lead the way to a "genetics-first approach" that could uncover hundreds more genetic mutations and lead to genetic testing. Genetic testing could be offered to families as a way of guiding them on what to expect and how to care for their child. Currently, autism is diagnosed based on behavior, said Bernier.

In the short term, Bernier said, clinicians can pay attention to the small population with this CHD8 mutation and provide targeted treatment.

Researchers say autism has currently been linked to different types of genetic events. The most commonly researched genetic events associated with autism are chromosomal re-arrangements, called "copy number variations," in which a chunk of chromosome is copied or deleted. But no one rearrangement affects more than 1 percent of all autism cases. While these copy number events are associated with autism, they do not have a definitive link, or as they say among researchers, a "strong penetrance."

Then there are genetic mutations in which a gene has been disrupted and is not creating the kind of protein it should create. The CHD8 gene mutation is the first gene mutation to show a very strong penetrance linked to a certain subtype of autism.

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Story Source:

The above story is based on materials provided by University of Washington - Health Sciences/UW News, Community Relations & Marketing. Note: Materials may be edited for content and length.

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Journal Reference:

1. Raphael Bernier, Christelle Golzio, Bo Xiong, Holly A. Stessman, Bradley P. Coe, Osnat Penn, Kali Witherspoon, Jennifer Gerdts, Carl Baker, Anneke T. Vulto-van Silfhout, Janneke H. Schuurs-Hoeijmakers, Marco Fichera, Paolo Bosco, Serafino Buono, Antonino Alberti, Pinella Failla, Hilde Peeters, Jean Steyaert, Lisenka E.L.M. Vissers, Ludmila Francescatto, Heather C. Mefford, Jill A. Rosenfeld, Trygve Bakken, Brian J. O’Roak, Matthew Pawlus, Randall Moon, Jay Shendure, David G. Amaral, Ed Lein, Julia Rankin, Corrado Romano, Bert B.A. de Vries, Nicholas Katsanis, Evan E. Eichler. Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development. Cell, 2014; DOI: 10.1016/j.cell.2014.06.017

Host genetics can contribute to lung damage in severe tuberculosis

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Schematic illustration of a hypothetical model to explain the high and low involvement of the P2X7R during severe and mild TB.

A third of the global population is infected with the bacterial pathogen, a mycobacterium, that causes tuberculosis (TB). Most carriers control the infection and are asymptomatic, but severe forms of the disease (more common in children and immune-compromised adults, and often caused by particularly aggressive -- or hypervirulent -- mycobacterial strains) kill over a million people every year. An article published on July 3rd in PLOS Pathogens now identifies a factor made by the host that exacerbates lung damage in severe TB. The results also suggest why gene mutations that render the factor inactive are common.

To understand the mechanisms underlying aggressive TB, Elena Lasunskaia from the Universidade Estadual do Norte Fluminense, Rio de Janeiro, Maria Regina D'Império-Lima from the Universidade de São Paulo, Brazil, and colleagues studied mouse models which recapitulate the symptoms of severe pulmonary TB in humans. Like human patients, mice infected with two different hypervirulent mycobacterial strains develop necrotic lesions in the lung, that is, areas of dead cells that break open and release their contents. The necrotic debris contains molecules that promote an influx of immune cells from the host, and the resulting local inflammation causes further damage to the lung tissue.

One of the contents of necrotic debris is the energy-storage molecule ATP, and when it is found outside cells, it is known to stimulate immune cells through the binding to the P2X7 receptor (P2X7R). The researchers asked whether this molecular pathway plays a role in the severe forms of TB that are associated with lung necrosis. They studied mice that were lacking P2X7R and found that those mice survived otherwise deadly infections with either of the two hypervirulent mycobacterial strains.

A more detailed analysis suggested that P2X7R has a dual role in the development of aggressive TB. First, it appears to facilitate the dissemination of hypervirulent mycobacteria by killing infected immune cells but releasing their content, namely viable mycobacteria that have survived the process. Second, P2X7R also seems to contribute to lung inflammation and damage by promoting widespread tissue destruction.

The better outcomes in mice without P2X7R were only seen after infection with hypervirulent mycobacteria. When the researchers infected mice with a less aggressive TB strain, they found that P2X7R actually helped to control this infection. In this case, P2X7R-mediated stimulation of infected immune cells did not result in the cell death and release of viable mycobacteria, and so actually contained the infection rather than spreading it.

The observed opposite effects of P2X7R on lung infection with hypervirulent and less aggressive mycobacterial strains, respectively, could explain an epidemiological puzzle: P2X7R loss-of-function alleles (that is defective variants of the P2X7R gene) are common in humans despite the fact that they are linked to a higher risk of developing pulmonary TB. Based on their results, the researchers suggest that such variants might increase the risk of mild TB but reduce the risk of severe TB. This, they say "could explain why evolutionary pressure has maintained these gene polymorphisms at high rates in the human population."

They also state that their study "provides a perspective for the development of new therapeutic approaches in which drugs designed to inhibit P2X7R are used to ameliorate the outcomes of aggressive forms of TB."

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Story Source:

The above story is based on materials provided by PLOS. Note: Materials may be edited for content and length.

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Journal Reference:

1. Eduardo P. Amaral, Simone C. M. Ribeiro, Verônica R. Lanes, Fabrício M. Almeida, Marcelle R. M. de Andrade, Caio Cesar Barbosa Bomfim, Érika M. Salles, Karina R. Bortoluci, Robson Coutinho-Silva, Mario H. Hirata, José M. Alvarez, Elena B. Lasunskaia, Maria Regina D'Império-Lima. Pulmonary Infection with Hypervirulent Mycobacteria Reveals a Crucial Role for the P2X7 Receptor in Aggressive Forms of Tuberculosis. PLoS Pathogens, 2014; 10 (7): e1004188 DOI: 10.1371/journal.ppat.1004188