Gut Bacteria Can Cause, Predict and Prevent Rheumatoid Arthritis

  

Newswise, July 22, 2016— The bacteria in your gut do more than break down your food. They also can predict susceptibility to rheumatoid arthritis, suggests Veena Taneja, Ph.D., an immunologist at Mayo Clinic’s Center for Individualized Medicine. Dr. Taneja recently published two studies — one in Genome Medicine and one in Arthritis and Rheumatology — connecting the dots between gut microbiota and rheumatoid arthritis.

More than 1.5 million Americans have rheumatoid arthritis, a disorder that causes painful swelling in the joints. Scientists have a limited understanding of the processes that trigger the disease. Dr. Taneja and her team identified intestinal bacteria as a possible cause; their studies indicate that testing for specific microbiota in the gut can help physicians predict and prevent the onset of rheumatoid arthritis.

“These are exciting discoveries that we may be able to use to personalize treatment for patients,” Dr. Taneja says.

The paper published in Genome Medicine summarizes a study of rheumatoid arthritis patients, their relatives and a healthy control group. The study aimed to find a biomarker — or a substance that indicates a disease, condition or phenomena — that predicts susceptibility to rheumatoid arthritis. They noted that an abundance of certain rare bacterial lineages causes a microbial imbalance that is found in rheumatoid arthritis patients.

“Using genomic sequencing technology, we were able to pin down some gut microbes that were normally rare and of low abundance in healthy individuals, but expanded in patients with rheumatoid arthritis,” Dr. Taneja says.

Implications for predicting and preventing rheumatoid arthritis

After further research in mice and, eventually, humans, intestinal microbiota and metabolic signatures could help scientists build a predictive profile for who is likely to develop rheumatoid arthritis and the course the disease will take, Dr. Taneja says.

Based on mouse studies, researchers found an association between the gut microbe Collinsella and the arthritis phenotype. The presence of these bacteria may lead to new ways to diagnose patients and to reduce the imbalance that causes rheumatoid arthritis before or in its early stages, according to John Davis III, M.D., and Eric Matteson, M.D., Mayo Clinic rheumatologists and study co-authors. Continued research could lead to preventive treatments.

Possibility for more effective treatment with fewer side effects

The second paper, published in Arthritis and Rheumatology, explored another facet of gut bacteria. Dr. Taneja treated one group of arthritis-susceptible mice with a bacterium, Prevotella histicola, and compared that to a group that had no treatment. The study found that mice treated with the bacterium had decreased symptom frequency and severity, and fewer inflammatory conditions associated with rheumatoid arthritis. The treatment produced fewer side effects, such as weight gain and villous atrophy — a condition that prevents the gut from absorbing nutrients — that may be linked with other, more traditional treatments.

While human trials have not yet taken place, the mice’s immune systems and arthritis mimic humans, and shows promise for similar, positive effects. Since this bacterium is a part of healthy human gut, treatment is less likely to have side effects, says study co-author Joseph Murray, M.D., a Mayo Clinic gastroenterologist.

Rheumatoid arthritis is an autoimmune disorder; it occurs when the body mistakenly attacks itself. The body breaks down tissues around joints, causing swelling that can erode bone and deform the joints. The disease can damage other parts of the body, including the skin, eyes, heart, lung and blood vessels.

The study was funded by the Mayo Clinic Center for Individualized Medicine, which supports research that aims to find treatments compatible with a patient’s unique genetic structure. It also supports the transformation of research discoveries into practical applications for patient care.

Sac to the Future: Cellular Vessels Predict Likelihood of Developing Dementia

 Blood-based neuronally-derived exosomes carry tell-tale proteins that could help forecast transition from mild cognitive impairment to Alzheimer’s

disease

Newswise, July 8, 2016 — Researchers at University of California San Diego School of Medicine say tiny micro-vesicle structures used by neurons and other cells to transport materials internally or dispose of them externally carry tell-tale proteins that may help to predict the likelihood of mild cognitive impairment (MCI) developing into full-blown Alzheimer’s disease (AD).

The findings, published online this week in the journal Alzheimer’s & Dementia, represent a quicker and less invasive way to identify impending cognitive decline and begin treatment before progression to established, irreversible dementia.

“MCI is often a transitional stage between normal aging and dementia,” said senior author Robert A. Rissman, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, director of the Biomarker Core for the Alzheimer’s Disease Cooperative Study (ADCS) and director of the Neuropathology Core and Brain Bank for the UC San Diego Shiley-Marcos Alzheimer’s Disease Research Center.

“It’s associated with more minor cognitive impairment and carries an increased risk of developing Alzheimer’s dementia.”

MCI patients progress to AD at rates as high as 10 to 15 percent per year, prompting an increased emphasis upon diagnosing MCI early and developing treatments that can delay or prevent conversion to AD.

The need is underscored, write the authors, by the fact that clinical trials of treatments for established AD have thus far failed.

While clinically distinguishable from normal aging and AD, MCI remains nonetheless a complex condition with many and varied causes.

“That has prompted great interest in pinpointing underlying biomarkers that can predict the conversion from MCI to AD dementia,” said Rissman.

“Finding such biomarkers would also identify persons most likely to be responsive to preventive treatments.”

Currently, the accepted methods for diagnosing preclinical AD patients is to detect protein biomarkers found in cerebrospinal fluid (CSF), in combination with advanced neuroimaging and neuropsychological testing.

But CSF sampling involves an invasive, often painful, process. Neuroimaging is expensive. Neuropsychological testing is time-consuming and can often vary from visit to visit.

The new method described in the Alzheimer’s & Dementia study evaluated the potential of exosomes – extremely small vesicles or sacs found in most cell types, including neurons. Exosomes are thought to move materials inside cells and are used to dump cellular trash into the bloodstream for disposal.

In the case of disease, Rissman’s group predicted that neuronal derived exosomes (NDEs) would carry damaged or excess proteins and metabolites out of brain cells, among them amyloid and tau biomarker proteins that are strongly associated with AD.

The researchers harvested NDEs from human blood plasma of 60 patients who participated in an 18-month ADCS clinical trial that enrolled MCI patients only.

Some of these MCI patients converted to AD over the course of the study and some did not. Rissman’s lab also gathered samples from control patients and samples from known AD patients.

They enriched the NDE content of those originating from neurons. The samples represented patients with normal cognitive function, diagnoses of stable MCI and stable AD and patients who had recently transitioned from MCI to AD.

After characterizing NDEs by size, shape and concentration, the researchers compared that data with the different patient cohorts.

They found that NDEs carried targeted biomarker proteins, which have previously been found to predict development of AD up to 10 years before onset of clinical symptoms, and correctly distinguished 100 percent of patients with AD from normal cohorts.

Moreover, the researchers showed for the first time that plasma NDEs from AD and MCI patients may propagate tau tangles in the brains of normal mice similar to what is seen in human AD brains.

The fact that these NDEs could induce pathological-like structures in “naïve” mice (animals not previously subjected to experiments) suggests that the contents of NDEs are bioactive, said Rissman. It also suggests that released NDEs can be taken up by cells, raising the possibility of NDEs potential for drug delivery.

The development of blood-based biomarkers for AD (and other neurodegenerative diseases) diagnostics could significantly improve the effectiveness and reliability of patient care and future research, said the authors, who encouraged further studies to refine and validate the approach.

Co-authors include Charisse N. Winston, Bob C. Carter, Edward M. Rockenstein, Douglas Galasko and Eliezer Masliah, all at UC San Diego; and Edward J. Goetz and Johnny C. Akers, UC San Francisco.

Funding for this research came, in part, from the National Institutes of Health (grants AG04484, BX003040, AG0051839), the Alzheimer’s Association and the Alzheimer’s Art Quilt Initiative.

Genetic Risk Factors for Alzheimer’s Disease May Be Detectable Even in Young Adults

Newswise, July 8, 2016 – New research shows that a genetic risk score may detect those at higher risk for Alzheimer’s disease long before symptoms appear—even possibly in healthy young adults, according to a study published in the July 6, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“The stage of Alzheimer’s before symptoms show up is thought to last over a decade,” said Elizabeth C. Mormino, PhD, with Massachusetts General Hospital in Charlestown, Mass.

“Given that current clinical trials are testing whether therapies can slow memory and thinking decline among people at risk for the disease, it is critical to understand the influence of risk factors before symptoms are present.”

For the study, researchers calculated a polygenic risk score, or a numeric score based on whether or not a person has several high-risk gene variants, in 166 people with dementia and 1,026 without dementia.

Participants had an average age of 75. Scientists also looked for specific markers of Alzheimer’s disease. The markers included memory and thinking decline, clinical progression of the disease and the volume of the hippocampus (the memory center of the brain). 

Researchers also looked at links between the risk score and hippocampus volume in 1,322 healthy, younger participants between the ages of 18 and 35.

The study found that within older people free of dementia, a higher polygenic risk score was associated with worse memory and smaller hippocampus at the start of the study, accounting for 2.3 percent of the total variance in memory and 2.0 percent of the variance in hippocampus volume.

Over the three years of the study, a higher score was also linked to greater longitudinal memory and executive function decline and clinical progression of the disease.

Finally, the risk score was associated with overall disease progression, with 15 of 194 participants that were cognitively normal at the start of the study developing mild cognitive impairment or Alzheimer’s disease, and 143 of 332 with mild cognitive impairment at the start of the study developing Alzheimer’s disease after three years. Each standard deviation increase in polygenic risk was associated with a 1.6 times increase in risk of clinical progression.

Within the younger group, a higher risk score was tied to smaller hippocampus volume. For the younger group, the risk score accounted for 0.2 percent of the difference in hippocampus volume between those with high and low risk scores.

“Our study was small and larger numbers of participants will need to be studied to confirm our findings,” said Mormino. “The goal of this type of research is to help physicians better identify those at high risk of dementia so that future preventative treatments may be used as early as possible.”

The study was supported by the National Institutes of Health.

To learn more about Alzheimer’s disease, please visit http://www.aan.com/patients.

The American Academy of Neurology, the world’s largest association of 30,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

Does Chronic Pain Run in Families?

 Genetics, Parenting, and Stress May All Play a Role

Newswise, July 8, 2016– Can an increased risk of chronic pain be transmitted from parents to children? Several factors may contribute, including genetics, effects on early development, social learning, and more according to a report in the journal PAIN®, the official publication of the International Association for the Study of Pain (IASP). The journal is published by Wolters Kluwer.

Amanda L. Stone of Vanderbilt University, in Nashville, Tenn., and Anna C. Wilson of Oregon Health & Science University, in Portland, Ore., present a conceptual model of transmission of chronic pain, including potential mechanisms and moderating factors.

The researchers write, "Such a framework highlights chronic pain as inherently familial and intergenerational, opening up avenues for new models of intervention and prevention that can be family-centered and include at-risk children."

Proposed Explanations for Familial Transmission of Chronic Pain Risk
Knowing that offspring of parents with chronic pain are at increased risk of developing chronic pain, as well as the adverse mental and physical health outcomes associated with chronic pain, Drs. Stone and Wilson developed an "integrative conceptual model" to explore possible explanations for this risk.

The researchers identify five "plausible mechanisms" to explain the transmission of chronic disease risk from parent to child:

• Genetics. Children of parents with chronic pain might be at increased genetic risk for sensory as well as psychological components of pain. Research suggests that genetic factors may account for roughly half of the risk of chronic pain in adults.

• Early Neurobiological Development. Having a parent with chronic pain may affect the features and functioning of the nervous system during critical periods in early development. For example, a baby's development might be affected by the mother's stress level or health behaviors during and after pregnancy.

• Pain-Specific Social Learning. Children may learn "maladaptive pain behaviors" from their parents, who may act in ways that reinforce those behaviors. Catastrophizing—exaggerated responses and worries about pain—might be one key factor.

• General Parenting and Health Habits. Chronic pain risk could be affected by parenting behaviors linked to adverse child outcomes—for example, permissive parenting or lack of consistency and warmth. The parents' physical activity level and other health habits might also play a role.

• Exposure to Stressful Environment. There may be adverse effects from growing up in stressful circumstances related to chronic pain—for example, financial problems or parents' inability to perform daily tasks.

The model also identifies some "moderators" that might explain when and under what circumstances children are at highest risk of developing chronic pain. These include chronic pain in the other parent; the timing, course, and location of the parent's pain; and the children's characteristics, including their personal temperament.

"The outlined mechanisms, moderators, and vulnerabilities likely interact over time to influence the development of chronic pain and related outcomes in offspring of parents with chronic pain," Drs. Stone and Wilson note.

They hope their model will provide a framework to guide future research—toward the goal of developing effective prevention and treatment approaches for children of parents with chronic pain.

Click here to read “Transmission of risk from parents with chronic pain to offspring: an integrative conceptual model.”

Role of Gender, Aging in Heart Failure Focus of Study

Newswise, July 8, 2016 — Why do women have lower rates of heart failure than men for most of their lives?

University of Guelph researchers have uncovered a possible clue – an actin binding protein called “CapZ” that also protects against heart attacks.

Now they’ll be studying how its levels are affected by gender and aging, backed by a prestigious Catalyst Grant from the Canadian Institutes of Health Research (CIHR).

Their research may lead to new therapeutic treatments for reducing heart problems and extending lives of both men and women.

“Age continues to be the largest independent risk factor for the development of heart failure,” said Glen Pyle, a professor in the Department of Biomedical Sciences in the Ontario Veterinary College and member of U of G’s Centre for Cardiovascular Investigations.

“With people living longer throughout the world, it’s expected that the rates of heart failure will rise dramatically.”

Pre-menopausal women are relatively protected against heart failure compared to men, Pyle said. But the gap starts to close after menopause; by age 80, women and men are at equal risk. No one knows exactly why.

It’s been speculated that estrogen plays a role, “but what are the hormonal changes doing to the cells in the heart? That is where we don’t know very much,” Pyle said.

“Once we figure it out, we can identify what is happening after menopause to make females more vulnerable to heart failure, and why they are protected earlier in life.”

Previously, Pyle found that hearts of aged male mice contain higher levels of CapZ than female mice of the same age. The males show signs of declining heart performance, but the females have normal function.

Pyle’s group has discovered that female mice somehow decrease CapZ levels to protect against cardiac dysfunction, while male mice are unable to do so.

Pyle and his research team genetically engineered male mice with decreased CapZ levels, and found it prevented heart failure.

“Even a small decrease – 20 per cent – offered protection,” he said.

“These results suggest that CapZ may be a viable target to protect hearts against the process of aging.”

He now plans to assess the impact of sex and aging on CapZ levels in the heart.

“We’ll be looking at how and when protein levels naturally change over time in both female and male mice,” said Pyle, who has studied CapZ for nearly 20 years.

They will need to study mice much older than those typically used in research – two and three years of age, the equivalent of 70 and 90 years in humans.

Nurturing lab mice to that age takes time and resources. That is why the $150,000 CIHR Catalyst Grant is critical, Pyle said. The funding comes from CIHR’s Institute of Cancer Research, Institute of Genetics, Institute of Infection and Immunity, and Institute of Gender and Health.

“We plan to age the female mice longer, to three years — the equivalent of 90 years in humans — to see when they get to the point where they lose the CapZ protection,” he said.

This is important because menopause duration varies in women, and it takes time for the heart to change. “We often do not see an effect in women until they are in their 60s or 70s,” Pyle said.

Pyle will work with postdoctoral researcher Ilka Lorenzen-Schmidt on the project, which he called “unique research and in an under-examined field.”

“The relative lack of research using female subjects is finally being recognized as a significant issue in medicine, and aging populations worldwide are creating the potential for a heart failure epidemic,” he said.

“This work will advance our understanding of the influence of both gender and aging on heart function, and tackle two emerging problems at the same time.”

The GW Cancer Center Joins Nearly 1,000 Local and National Organizations to Increase Colorectal Cancer Screening Rates Nationwide

Newswise, July 8, 2016 —George Washington University (GW) Cancer Center has joined with nearly 1,000 local and national organizations to support the 80% by 2018 initiative, led by the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), and the National Colorectal Cancer Roundtable (NCCRT), an organization co-founded by ACS and CDC. The 80% by 2018 initiative represents a shared goal to have 80 percent of adults age 50 and over regularly screened for colorectal cancer by 2018.

Colorectal cancer is the nation’s second-leading cause of cancer-related deaths when men and women are combined; however, it is one of only a few cancers that can be prevented. Through proper colorectal cancer screening, doctors can find and remove hidden growths (called “polyps”) in the colon before they become cancerous. Removing polyps can prevent cancer altogether.

“Our support of the 80% by 2018 initiative represents a continuation and recognition of our work in comprehensive cancer control,” said Mandi Pratt-Chapman, associate center director for patient-centered initiatives and health equity for the GW Cancer Center. “We are committed to spreading the word about the importance of regular colorectal cancer screening and supporting the great work of the NCCRT.”

The GW Cancer Center is committed to increasing colorectal cancer screening and has expertise in colorectal cancer information and research.

The GW Cancer Center contributed to the ACS Colorectal Cancer Survivorship Care Guidelines and recently launched a new colorectal cancer survivorship module in its popular e-learning series for primary care providers.

In addition to its provider education work, the GW Cancer Center created a social media toolkit to promote colorectal cancer screening in tandem with the launch of the “80% by 2018 Communications Guidebook: Effective Messaging to Reach the Unscreened.” GW Cancer Center staff have also presented about evaluating colorectal cancer social media campaigns as part of ongoing technical assistance efforts to cancer control professionals. The Center is also an active member of the Comprehensive Cancer Control National Partnership’s Colorectal Cancer Screening Workgroup.

Part of the 80% by 2018 goal is to leverage the energy of multiple and diverse partners to empower communities, patients and providers to increase screening rates.

The 80% by 2018 initiative consists of health care providers, health systems, communities, businesses, community health centers, government, non-profit organizations and patient advocacy groups who are committed to getting more people screened for colorectal cancer to prevent more cancers and save lives.

For more information or to learn about the 80% by 2018 pledge, visit http://nccrt.org/tools/80-percent-by-2018/.

Scientific Breakthrough May Limit Damage Caused by Heart Attacks

Research identifies master controller of blood vessel growth in the heart

Paramedic Brett Schneider uses iTREAT to consult with Andrew Southerland, MD, a stroke expert at the University of Virginia Health System.

Newswise, July 1, 2016— A research advance from the Sanford Burnham Prebys Medical Discovery Institute (SBP) and Stanford University could lead to new drugs that minimize the damage caused by heart attacks.

The discovery, published today in Nature Communications, reveals a key control point in the formation of new blood vessels in the heart, and offers a novel approach to treat heart disease patients.

“We found that a protein called RBPJ serves as the master controller of genes that regulate blood vessel growth in the adult heart,” said Mark Mercola, Ph.D., professor in SBP’s Development, Aging, and Regeneration Program and jointly appointed as professor of medicine at Stanford University, senior author of the study.

“RBPJ acts as a brake on the formation of new blood vessels. Our findings suggest that drugs designed to block RBPJ may promote new blood supplies and improve heart attack outcomes.”

In the US, someone has a heart attack every 34 seconds. The ensuing loss of heart muscle, if it affects a large enough area, can severely reduce the heart’s pumping capacity, which causes labored breathing and makes day-to-day tasks difficult. This condition, called heart failure, arises within five years in at least one in four heart attack patients.

The reason heart muscle dies in a heart attack is that it becomes starved of oxygen—a heart attack is caused by blockage of an artery supplying the heart. If heart muscle had an alternative blood supply, more muscle would remain intact, and heart function would be preserved.

Many researchers have therefore been searching for ways to promote the formation of additional blood vessels in the heart.

“Studies in animals have shown that having more blood vessels in the heart reduces the damage caused by ischemic injuries, but clinical trials of previous therapies haven’t succeeded,” said Ramon Díaz-Trelles, Ph.D., staff scientist at SBP and lead author of the study.

“The likely reason they have failed is that these studies have evaluated single growth factors, but in fact building blood vessels requires the coordinated activity of numerous factors. Our data show that RBPJ controls the production of these factors in response to the demand for oxygen.

“We used mice that lack RBPJ to show that it plays a novel role in myocardial blood vessel formation (angiogenesis)—it acts as a master controller, repressing the genes needed to create new vessels,” added Diaz-Trelles.

“What’s remarkable is that removing RBPJ in the heart muscle did not cause adverse effects—the heart remained structurally and functionally normal in mice without it, even into old age.”

“RBPJ is a promising therapeutic target. It’s druggable, and our findings suggest that blocking it could benefit patients with cardiovascular disease at risk of a heart attack. It may also be relevant to other diseases,” commented Pilar Ruiz-Lozano, Ph.D., associate professor of pediatrics at Stanford and adjunct professor at SBP, co-senior author.

“Inhibitors of RBPJ might also be used to treat peripheral artery disease, and activators might be beneficial in cancer by inhibiting tumor angiogenesis.”

This research was performed in collaboration with scientists at Stanford University, Washington University in St. Louis, and the University of California, San Diego. Funding was provided by the National Institutes of Health, the Sanford Children’s Health Center, the American Heart Association, the Burroughs Wellcome Fund, the California Institute for Regenerative Medicine, the Italian Ministry of Research and Education, and the Italian Society of Cardiology.

About SBP
Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children’s diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

About Stanford
The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visithttp://www.med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Lucile Packard Children’s Hospital Stanford. For information about all three, please visithttp://www.med.stanford.edu.