Cells that alert nervous system to intestinal trouble could provide new target for gastrointestinal treatments — ScienceDaily

Specialized cells in the gut sense potentially noxious chemicals and trigger electrical impulses in nearby nerve fibers, according to a new study led by UC San Francisco scientists. “These cells are sensors, like a window looking into the contents of the gut,” said James Bayrer, MD, PhD, an assistant professor of pediatrics at UCSF and one of the lead authors of the paper.

Using gut-mimicking “organoids” grown from mouse stem cells, the researchers showed how cells in the intestinal lining called enterochromaffin (EC) cells alert the nervous system to signs of trouble in the gut, from bacterial products to inflammatory food molecules.

The authors of the new study — published online in Cell on June 22, 2017 — said that understanding the role of EC cells in how the gut reacts, and overreacts, to chemical irritants could provide new approaches for treating gastrointestinal disorders such as irritable bowel syndrome (IBS).

With over 100 times the surface area of our skin, the gut is the body’s largest surface exposed to external substances. Though EC cells make up only one percent of the gut’s lining, they produce 90 percent of the body’s serotonin, a key signaling molecule, so scientists have long been curious about their functions. Serotonin is best known for mediating mood through its actions in the brain, but it has a very different role in the gut, where it is involved in gut contractions and gastric discomfort.

“There are so few of these cells, but they seem so powerful,” said Holly Ingraham, PhD, a UCSF professor of cellular and molecular pharmacology and co-senior author of the new paper. “People are very interested in understanding what these cells do with all that serotonin.”

EC cells are interspersed among other cells that make up the lining of the intestinal tract, on the surface of tiny, fingerlike structures called villi that project into the gut’s inside space. Within the villi, underneath the EC cells and other cells, are nerve fibers which sense the movement and contents of the gut and contribute to intestinal pain and discomfort. But precisely how these nerve fibers communicate with EC cells has been unclear.

In their new study, the researchers showed that EC cells integrate information about chemical irritants, bacterial compounds, and stress hormones in the gut, then use serotonin to pass that information on to the neighboring nerve cells, from which electrical impulses may travel throughout the gut’s nervous system and ultimately to the brain.

“People had suspected such a role for EC cells before, but this study is exciting because for the first time it gives us a rigorous handle on exactly how the gut talks to the nervous system,” said David Julius, PhD, a professor and chair of UCSF’s Department of Physiology and the study’s other senior author.

Cells Are Electrically Excited by Irritants

The collaboration at the heart of the new study was an unusual one for Ingraham and Julius, who are married but usually take different paths in their research.

Julius’s lab, which is focused on learning how the body’s pain sensors work using natural products like chili peppers, horseradish and snake venom, became interested in this new research direction after discovering that cells sensitive to a painful spider toxin were highly prevalent in the gut. Nicholas Bellono, PhD, a postdoctoral researcher in the lab and the other lead author on the paper, became fascinated by the way the gut’s lining, called the epithelium, appears to sense and react to what’s inside it.

“The nervous system, the immune system, the vasculature, everything converges in the epithelium,” said Bellono. He took particular interest in EC cells, wondering if the serotonin they release activated adjacent nerve fibers.

When Julius mentioned Bellono’s new interest to Ingraham, she suggested that Bellono work with Bayrer, a gastroenterologist who was leading efforts in her lab to study gut disorders using intestinal organoids, small clumps of cells grown from stem cells that can serve as models of the gut. For Bellono and Bayrer, organoids made the EC cells much easier to work with. “You can look in the dish and there’s a little intestine in there — it’s totally wild,” said Bellono.

The team tested the cells’ reactions to dozens of different molecules and found that three classes of molecules caused a change in voltage across the cell’s membranes. Intriguingly, the three types of molecules that triggered EC cells — bacterial byproducts called volatile fatty acids; a class of hormones called catecholamines (including dopamine, epinephrine and norepinephrine) that can signal stress in the gut; and a dietary irritant called AITC, which is responsible for garlic’s pungent flavor — have all previously been linked to IBS.

When the EC cells are excited by any of these molecules, they release serotonin into synapses with the nearby nerve fibers, acting much like other sensory organs, from taste buds to odor receptors. In tissue samples taken from mice, the team showed that this serotonin release triggered electrical impulses in nerve fibers, indicating the signal could move quickly throughout the gut.

“They’re actually electrically excitable,” said Julius, who also holds the Morris Herzstein Chair in Molecular Biology and Medicine at UCSF. “They kind of behave like neurons.”

Signals Could Cause Both Pain and Pooping

The intestines are unique among our organs in that many of the nerve signals that control them come not from the brain but from a network of nerves within the gut sometimes called “the second brain,” which helps carry out much of the organ’s routine contractions and digestive activities without the intervention of the brain itself.

The team thinks the nerve signals that originate with the EC cells can affect both networks, causing involuntary gut contractions or, if the signals reach the brain, what Ingraham described as a “gut ache.”

“Just like when we taste something foul and we try to get rid of it” through gagging, the gut may react to the foul “taste” of bacterial or irritating molecules by trying to push them out the other end, said Bayrer. “This could be a way of the gut sensing which populations of bacteria are around.”

The next step, said the researchers, is to study EC cells in organoids grown from human cells. Because mice and humans have different diets, our EC cells could be sensitive to entirely different molecules.

Targeting Cells Could Help Treat Irritable Bowel Syndrome

Though triggering the gut to push out unwanted chemicals and microbes is normally healthy, overreactions by EC cells and the nerve networks they trigger may cause problems like IBS. The team hopes that understanding what leads these cells to react to food and bacteria will aid the search for drugs that will prevent them from overreacting, perhaps by blocking the proteins that sense these molecules in the first place.

Intriguingly, clinicians already use SSRI’s (Selective Serotonin Reuptake Inhibitors), which affect serotonin levels, to treat IBS, suggesting there may be a link between the disease and the serotonin system. Bayrer, a pediatric gastroenterologist who works with children with IBS, hopes understanding EC cells and other gut sensors will help researchers understand and improve such treatments.

Optimized immunizations reliably elicit protective antibodies in preclinical study, marking an important milestone on the way to an effective HIV vaccine — ScienceDaily

For decades, HIV has successfully evaded all efforts to create an effective vaccine but researchers at The Scripps Research Institute (TSRI) and the La Jolla Institute for Allergy and Immunology (LJI) are steadily inching closer. Their latest study, published in the current issue of Immunity, demonstrates that optimizing the mode and timing of vaccine delivery is crucial to inducing a protective immune response in a preclinical model.

More than any other factors, administering the vaccine candidate subcutaneously and increasing the time intervals between immunizations improved the efficacy of the experimental vaccine and reliably induced neutralizing antibodies. Neutralizing antibodies are a key component of an effective immune response. They latch onto and inactive invading viruses before they can gain a foothold in the body and have been notoriously difficult to generate for HIV.

“This study is an important staging point on the long journey toward an HIV vaccine,” says TSRI Professor Dennis R. Burton, Ph.D, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI. “The vaccine candidates we worked with here are probably the most promising prototypes out there, and one will go into people in 2018,” says Burton.

“There had been a lot of big question marks and this study was designed to get as many answers as possible before we go into human clinical trials,” adds senior co-author Shane Crotty, Ph.D., a professor in LJI’s Division of Vaccine Discovery. “We are confident that our results will be predictive going forward.”

HIV has faded from the headlines, mainly because the development of antiretroviral drugs has turned AIDS into a chronic, manageable disease. Yet, only about half of the roughly 36.7 million people currently infected with HIV worldwide are able to get the medicines they need to control the virus. At the same time, the rate of new infections has remained stubbornly high, emphasizing the need for a preventive vaccine.

The latest findings are the culmination of years of collaborative and painstaking research by a dozen research teams centered around the development, improvement, and study of artificial protein trimers that faithfully mimic a protein spike found on the viral surface. At the core of this effort is the CHAVI-ID immunogen working group, comprised of TSRI’s own William R. Schief, Ph.D., Andrew B. Ward, Ph.D., Ian A. Wilson, D.Phil. and Richard T. Wyatt, Ph.D., in addition to Crotty and Burton. This group of laboratories in collaboration with Darrell J. Irvine, Ph.D., professor at MIT, and Rogier W. Sanders, Ph.D., professor at the University of Amsterdam, provided the cutting-edge immunogens tested in the study.

The recombinant trimers, or SOSIPs as they are called, were unreliable in earlier, smaller studies conducted in non-human primates. Non-human primates, and especially rhesus macaques, are considered the most appropriate pre-clinical model for HIV vaccine studies, because their immune system most closely resembles that of humans.

“The animals’ immune responses, although the right kind, weren’t very robust and a few didn’t respond at all,” explains Colin Havenar-Daughton, Ph.D., a scientific associate in the Crotty lab. “That caused significant concern that the immunogen wouldn’t consistently trigger an effective immune response in all individuals in a human clinical trial.”

In an effort to reliably induce a neutralizing antibody response, the collaborators tested multiple variations of the trimers and immunization protocols side-by-side to determine the best strategy going forward. Crotty and Burton and their colleagues teamed up with Professor Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, who coordinated the immunizations.

The design of the study was largely guided by what the collaborators had learned in a previous study via fine needling sampling of the lymph nodes, where the scientists observed follicular helper T cells help direct the maturation steps of antibody-producing B cells. Administering the vaccine subcutaneously versus the more conventional intramuscular route, and spacing the injection at 8 weeks instead of the more common 4-6 weeks, reliably induced a strong functional immune response in all animals.

Using an osmotic pump to slowly release the vaccine over a period of two weeks resulted in the highest neutralizing antibody titers ever measured following SOSIP immunizations in non-human primates. While osmotic pumps are not a practical way to deliver vaccines, they illustrate an important point. “Depending on how we gave the vaccine, there was a bigger difference due to immunization route than we would have predicted,” says Matthias Pauthner, a graduate student in Burton’s lab and the study’s co-lead author. “We can help translate what we know now into the clinic.”

First randomized controlled trial of deep brain stimulation for chronic pain shows promise — ScienceDaily

Deep brain stimulation (DBS) of the ventral striatum/anterior limb of the internal capsule is safe and feasible in addressing the affective component of pain in patients with post-stroke pain syndrome.

Cleveland Clinic investigators reported findings from the first prospective, randomized, controlled trial of DBS for neuropathic pain in a presentation at the 2017 annual scientific meeting of the American Association of Neurological Surgeons. The study was also published in the May 2017 issue of Annals of Neurology.

“We showed that active versus sham DBS of the ventral striatum/anterior limb of the internal capsule produced significant improvements in multiple outcome measures associated with the affective sphere of chronic pain,” says lead investigator Andre Machado, MD, PhD, Chairman of Cleveland Clinic’s Neurological Institute. “This trial represents a paradigm shift in chronic pain management in that it targeted neurostimulation to brain structures related to the affective, rather than sensory, sphere of chronic pain.”

Dr. Machado sees that as the investigation’s key point of distinction, since previous studies of DBS and other forms of neurostimulation for pain have focused nearly exclusively on modulation of pain transmission and pain amplitude.

“In this study, we departed from an analgesia-based approach and focused on neural networks related to control of emotion and behavior,” he explains, “based on our hypothesis that modulating the affective sphere of pain would improve quality of life or relieve pain-related disability, with or without attenuation of pain intensity.”

To test that hypothesis, Dr. Machado and his team designed their investigator-initiated study as a six-month, randomized, double-blind, placebo-controlled, crossover trial.

They enrolled 10 Cleveland Clinic patients with longstanding post-stroke pain syndrome who had hemibody pain and anesthesia dolorosa secondary to a contralateral lesion. “We chose post-stroke pain syndrome because it is associated with severe, refractory pain and patients with this syndrome are in need of therapies to alleviate suffering and disability,” said Dr. Machado. “Because these patients have complete or near-complete damage to the sensory-discriminative pathways, they also provided a unique model for studying the effects of neuromodulation specifically on brain networks related to emotion and behavior control.”

All patients underwent bilateral implantation of electrode array leads through the anterior limb of the internal capsule (ALIC) into the ventral striatum (VS). Surgical targeting was based on the investigators’ experience with DBS for obsessive-compulsive disorder (OCD) and treatment-resistant depression. “We targeted the VS/ALIC because of its well-established role in controlling emotion and behavior and the documented safety of DBS in this brain region for treating OCD and treatment-resistant depression,” said Dr. Machado.

One month after implantation, patients were randomized to active DBS or sham for three months and then crossed over to the other arm for another three months. After this blinded phase, patients underwent an 18-month open stimulation phase.

The study was negative for its primary and secondary end point, with no significant difference seen in pain-related disability on the PDI between active and sham treatment during the blinded stimulation phase. However, significant differences in favor of active DBS were seen in multiple outcomes associated with the affective dimension of chronic pain.

“Although the primary end point was not achieved, the efficacy of DBS was manifested by significant improvements in indices of the affective component of pain, such as depression, anxiety and quality of life,” Dr. Machado observes. “These improvements — achieved without significant reductions in the amplitude of pain — corroborate our hypothesis and suggest that DBS of the VS/ALIC specifically modulated the affective sphere of pain in patients with post-stroke pain syndrome.”

The findings suggest that analgesia may not be the appropriate treatment goal in central pain syndromes, said Dr. Machado. “We contend that neuromodulation therapies should focus on reducing pain-related suffering or disability rather than pain intensity,” he says. “We propose a shift in surgical targeting away from neural networks underlying the sensory-discriminative domain toward the networks that mediate the affective-motivational sphere of chronic pain.”

He adds that his team’s future work will involve analyzing functional neuroimaging and neurophysiological data obtained during this study to develop objective biomarkers that could help improve patient selection. These data will also be used to examine the neural substrates underlying how DBS impacts the affective aspect of pain.

The team also plans to initiate a multicenter study to confirm these findings elsewhere and potentially expand the study population to include patients with other types of chronic pain. “We believe the present findings justify further investigation of this treatment approach,” said Dr. Machado.

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People who go to bed late have less control over OCD symptoms — ScienceDaily

A late bedtime is associated with lower perceived control of obsessive thoughts, according to new research from Binghamton University, State University of New York.

Binghamton University Professor of Psychology Meredith E. Coles and former graduate student Jessica Schubert (now at University of Michigan Medical School) monitored twenty individuals diagnosed with OCD and ten individuals endorsing subthreshold OCD symptoms during one week of sleep. Participants completed sleep diaries and daily ratings of perceived degree of control over obsessive thoughts and ritualized behaviors. The researchers found that previous night’s bedtime significantly predicted participants’ perceived ability to control their obsessive thoughts and compulsive behavior on the subsequent day.

“We’re really interested in how this kind of unusual timing of sleep might affect cognitive functioning,” said Schubert. “One possibility is impulse control. It might be that something about shifting the timing of your sleep might reduce your ability to control your thoughts and your behaviors, so it might make it more likely that you’re going to have a hard time dismissing intrusive thoughts characteristic of obsessions, and it might make it more difficult for you to refrain from compulsive behaviors that are designed to reduce the anxiety caused by obsessive thoughts.”

On average participants in the study went to bed around 12:30 at night. Patients who met criteria for delayed sleep phase disorder, about 40% of the sample, went to bed around 3 a.m.

“I always knew you were supposed to get eight hours of sleep, but I was never told it matters when you do it,” said Coles. “It’s been striking to me that this difference seems to be very specific to the circadian component of when you sleep. That we find that there are specific negative consequences of sleeping at the wrong times, that’s something to educate the public about.”

The researchers are interested in exploring this phenomenon further. Coles plans on collecting pilot data using lightboxes to shift people’s bedtimes. “It’s one of our first efforts to actually shift their bedtimes and see if it reduces their OCD symptoms, and if this improves their ability to resist those intrusive thoughts and not develop compulsions in response to them.”

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Physical activity counseling affects parents and get children to move — ScienceDaily

Parents can affect their children’s physical activity behavior. A unique finding of the study was that especially the parents who have previously provided only little support for their children’s physical activity can make changes that have a positive effect on the daily physical activity of the children.

A research conducted at the University of Jyväskylä in 2011-2013 supports the understanding that parents can affect their children’s physical activity behavior. A unique finding of the study was that especially the parents who have previously provided only little support for their children’s physical activity can make changes that have a positive effect on the daily physical activity of the children.

A remarkable proportion of children move too little from the perspective of their growth and development. Home environment, especially parents, are known to play a key role in the birth of physical activity habits. Physical activity-related parenting practices are known to be very stable and difficult to intervene.

The study reveals that physical activity counseling can have an effect on the parenting practices and, consequently, children’s daily physical activity. In particular, the parents providing little support for their children’s daily physical activity can make behavior changes that increase the children’s physical activity.

“During the six-month counseling period, the parents who tended to provide scarcely support for their children’s daily physical activity remarkably increased the level of support. Correspondingly, the level of their children’s physical activity increased by almost one third compared to the children of control group families,” says Postdoctoral Researcher Arto Laukkanen from the University of Jyväskylä.

Parenting practices that support children’s physical activity can be divided into three categories: being physically active with the children, having an encouraging atmosphere for physical activity and supporting children’s physical activity directly or indirectly, such as taking children to parks or hobbies and paying the costs.

“Home environment that respects child-oriented practices and provides freedom and stimuli for physical activity has been found to associate with the creation of sustained physical activity habits. In the present study, we encouraged parents, at least when with the children, to favor walking instead of driving, taking the stairs instead of the elevator and going outdoors at least once a weekend,” Laukkanen explains.

“As a rule of thumb, we used an idea that children are physically active for about an hour at school or daycare, and the recommended another physically active hour should accumulate during the leisure time,” he continues.

Permanent changes are challenging — also in parenting

Although the results were encouraging, physical activity-related parenting practices, as well as the level of children’s physical activity, returned to the baseline level after the six-month counseling period. Therefore, it should be investigated in further studies how the parenting practices could become a more lasting part of parenting. The physical activity habits of new families should be paid attention to in a very early phase, and their development should be supported continuously.

The research was published in the distinguished journal Research Quarterly for Exercise and Sport on 6 June 2017.

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ABT Ballerina Isabella Boylston Shares a Photo Diary From the Vail International Dance Festival