210CNO11JUl2015
CNO Report 210
Release Date 11 JUL 2015
Draft Report Compiled by
Ralph Turchiano
In this Issue:
1. Inactivity reduces people’s muscle strength
2. Omega-3 supplements and antioxidants may help with preclinical Alzheimer’s disease
3. Repeated courses of antibiotics may profoundly alter children’s development
4. Fundamental beliefs about atherosclerosis overturned
5. Nutritional supplement boosts muscle stamina in animal studies
6. Peppermint oil and cinnamon could help treat and heal chronic wounds
7. Targeting bacteria in the gut might help burn and trauma patients
8. Study finds vitamin A directs immune cells to the intestines
Public Release: 26-Jun-2015
Inactivity reduces people’s muscle strength
University of Copenhagen The Faculty of Health and Medical Sciences
New research reveals that it only takes two weeks of not using their legs for young people to lose a third of their muscular strength, leaving them on par with a person who is 40-50 years their senior. The Center for Healthy Aging and the Department of Biomedical Sciences at the University of Copenhagen conducted the research.
Time and again, we are told that we need to stay physically active and exercise daily. But how quickly do we actually lose our muscular strength and muscle mass if we go from being averagely active to being highly inactive? For example when we are injured, fall ill or simply take a very relaxing holiday. Researchers from the University of Copenhagen have examined what happens to the muscles in younger and older men after a period of high inactivity, by way of so-called immobilization with a leg pad.
Both older and younger people lose muscular strength
“Our experiments reveal that inactivity affects the muscular strength in young and older men equally. Having had one leg immobilized for two weeks, young people lose up to a third of their muscular strength, while older people lose approx. one fourth. A young man who is immobilized for two weeks loses muscular strength in his leg equivalent to ageing by 40 or 50 years,” says Andreas Vigelsoe, PhD at the Center for Healthy Aging and the Department of Biomedical Sciences at the University of Copenhagen.
Young people lose twice as much muscle mass
With age, our total muscle mass diminishes, which is why young men have approx. one kilogram more muscle mass in each leg than older men. Both groups lose muscle mass when immobilized for two weeks – young men lose 485 grams on average, while older men lose approx. 250 grams. The participants’ physical fitness was also reduced while their one leg was immobilized in a pad.
“The more muscle mass you have, the more you’ll lose. Which means that if you’re fit and become injured, you’ll most likely lose more muscle mass than someone who is unfit, over the same period of time. But even though older people lose less muscle mass and their level of fitness is reduced slightly less than in young people, the loss of muscle mass is presumably more critical for older people, because it is likely to have a greater impact on their general health and quality of life,” says Martin Gram, researcher at the Center for Healthy Aging and the Department of Biomedical Sciences, explains.
Cycling is not enough
After two weeks of immobilization, the participants bicycle-trained 3-4 times a week for six weeks.
“Unfortunately, bicycle-training is not enough for the participants to regain their original muscular strength. Cycling is, however, sufficient to help people regain lost muscle mass and reach their former fitness level. If you want to regain your muscular strength following a period of inactivity; you need to include weight training,” Andreas Vigelsoe states.
“It’s interesting that inactivity causes such rapid loss of muscle mass, in fact it’ll take you three times the amount of time you were inactive to regain the muscle mass that you’ve lost. This may be caused by the fact that when we’re inactive, it’s 24 hours a day,” Martin Gram concludes.
Public Release: 30-Jun-2015
Omega-3 supplements and antioxidants may help with preclinical Alzheimer’s disease
New research in The FASEB Journal suggests that clinical trials of omega-3 and antioxidant supplementation should be undertaken for people with Alzheimer’s disease with mild clinical impairment
Federation of American Societies for Experimental Biology
Here’s more evidence that fish oil supplementation and antioxidants might be beneficial for at least some people facing Alzheimer’s disease: A new report published in the July 2015 issue of The FASEB Journal describes the findings of a very small study in which people with mild clinical impairment, such as those in the very early stages of the disease, saw clearance of the hallmark amyloid-beta protein and reduced inflammation in neurological tissues. Although the findings involved just 12 patients over the course of 4 to 17 months, the findings suggest further clinical study of this relatively inexpensive and plentiful supplement should be conducted.
“Prevention of mild cognitive impairment progression is one of the best hopes,” said Milan Fiala, M.D., Research Professor at the University of California’s Department of Surgery in Los Angeles. “In addition to physical and mental exercises recommended by experts, this study suggests that nutrition is equally important.”
To make their discovery, Fiala and colleagues investigated the effects of 4 to 17 months of supplementation with omega-3 fatty acids and antioxidants in 12 patients with minor cognitive impairment, 2 patients with pre-mild cognitive impairment, and 7 patients with Alzheimer disease. They measured the phagocytosis of amyloid-beta 1-42 by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 by enzyme immunoassay, and the cognitive status by MMSE. In patients with mild clinical impairment and pre-mild clinical impairment, phagocytosis of amyloid-beta by monocytes increased from 530 to 1306 mean fluorescence intensity units. The increase in patients with Alzheimer’s disease was not significant. The lipidic mediator resolvin D1, which stimulates amyloid-beta phagocytosis in vitro, increased in macrophages in 80 percent of patients with mild clinical impairment and pre-mild clinical impairment. The transcription of inflammatory genes’ mRNAs was increased in a subgroup of patients with low transcription at baseline, whereas it was not significantly changed in patients with high transcription at baseline.
“We’ve known for a long time that omega-3 fatty acids and some antioxidants can be beneficial to people with a wide range of health problems, as well as protective for healthy people,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Now, we know that the effects of these supplements may extend to Alzheimer’s disease as well. Although these supplements are considered to be generally safe and are very easy to obtain, full-scale clinical trials are necessary to verify the findings of this research and to identify who might benefit the most.”
Public Release: 30-Jun-2015
Repeated courses of antibiotics may profoundly alter children’s development
New study in mice from NYU Langone Medical Center finds multiple, long-lasting effects after several courses of antibiotics commonly used in children
NYU Langone Medical Center / New York University School of Medicine
June 30, 2015, NEW YORK — A new animal study by NYU Langone Medical Center researchers adds to growing evidence that multiple courses of commonly used antibiotics may have a significant impact on children’s development.
In the study, to be published online June 30 by the journal Nature Communications, female mice treated with two classes of widely used childhood antibiotics gained more weight and developed larger bones than untreated mice. Both of the antibiotics also disrupted the gut microbiome, the trillions of microbes that inhabit the intestinal tract.
Overall, the mice received three short courses of amoxicillin (a broad-spectrum antibiotic), tylosin (which isn’t used in children but represents another common antibiotic class called the macrolides, which is increasingly popular in pediatrics), or a mixture of both drugs. To mimic the effects of pediatric antibiotic use, the researchers gave the animals the same number of prescriptions and the same therapeutic dose that the average child receives in the first two years of life. A control group of mice received no drugs at all.
Martin Blaser, MD, the Muriel G. and George W. Singer Professor of Translational Medicine, director of the NYU Human Microbiome Program at NYU School of Medicine, and the study’s senior author, cautions that the study was limited to mice. Even so, he says the results agree with multiple other studies pointing toward significant effects on children exposed to antibiotics early in life, and he notes that the cumulative data could help shape guidelines governing the duration and type of pediatric prescriptions. “We have been using antibiotics as if there was no biological cost,” says Dr. Blaser. The average child in the United States, he says, receives 10 courses of the drugs by the age of 10.
The study supports previous research by Dr. Blaser’s group suggesting that antibiotic exposure during a critical window of early development disrupts the bacterial landscape of the gut and permanently reprograms the body’s metabolism, setting up a predisposition for obesity. The new study found that short, high-dose pulses of tylosin had the most pronounced and long-lasting effect on weight gain, while amoxicillin had the biggest effect on bone growth–a prerequisite for increased height.
Based on extensive DNA sequencing data, the study showed that both antibiotics also disrupted the gut microbiome. “They changed the ecology of the microbiome in terms of the richness of the organisms, the diversity, and also what we call the community structure, or the nature of its composition,” Dr. Blaser says. The drugs altered not only the bacterial species, but also the relative numbers of microbial genes linked to specific metabolic functions.
He likens this broad shift to a country in which the majority of residents are farmers who produce food and then suddenly shift to become merchants focused on trade. “We see a fundamental shift in the economy of the microbial genes that are present,” Dr. Blaser says, but he stresses that the full implications within the microbiome are still unclear.
Tylosin, the collaborators found, had a much bigger impact on the maturity of the microbiome compared with amoxicillin. “We also see that the effect is cumulative,” says lead coauthor Laura M. Cox, PhD, an adjunct instructor in the Department of Medicine at NYU School of Medicine. “So the number of courses of antibiotics matters,” she says. “We get a little interruption of the maturation process after the second course of antibiotics, and then we have even more interruption after three courses.”
Furthermore, the study suggested that antibiotic-exposed microbiomes may be less adaptable to environmental changes. When the researchers moved the young mice to a high-fat diet on day 41, for example, the microbiomes of the control mice all shifted within a single day to adapt to the new conditions. Among the mice on amoxicillin, some microbiomes shifted in one day, while others took two weeks to make the transition. “In the tylosin-treated mice, some of the microbiomes didn’t adapt to high-fat diets until months later,” Dr. Cox says.
Taken together, the researchers say the more pronounced effects of tylosin on weight gain and microbiome disruption are especially worrisome, given the increasing popularity of macrolide antibiotic prescriptions for children. The accumulating evidence, they stress, highlights the need for better awareness of the potential downsides of antibiotic overuse.
Public Release: 6-Jul-2015
Fundamental beliefs about atherosclerosis overturned
Complications of artery-hardening condition are No. 1 killer worldwide
University of Virginia Health System
Doctors’ efforts to battle the dangerous atherosclerotic plaques that build up in our arteries and cause heart attacks and strokes are built on several false beliefs about the fundamental composition and formation of the plaques, new research from the University of Virginia School of Medicine shows. These new discoveries will force researchers to reassess their approaches to developing treatments and discard some of their basic assumptions about atherosclerosis, commonly known as hardening of the arteries.
“The leading cause of death worldwide is complications of atherosclerosis, and the most common end-stage disease is when an atherosclerotic plaque ruptures. If this occurs in one of your large coronary arteries, it’s a catastrophic event,” said Gary K. Owens, PhD, of UVA’s Robert M. Berne Cardiovascular Research Center. “Once a plaque ruptures, it can induce formation of a large clot that can block blood flow to the downstream regions. This is what causes most heart attacks. The clot can also dislodge and cause a stroke if it lodges in a blood vessel in the brain. As such, understanding what controls the stability of plaques is extremely important. “
Until now, doctors have believed that smooth muscle cells – the cells that help blood vessels contract and dilate – were the good guys in the body’s battle against atherosclerotic plaque. They were thought to migrate from their normal location in the blood vessel wall into the developing atherosclerotic plaque, where they would attempt to wall off the accumulating fats, dying cells and other nasty components of the plaque. The dogma has been that the more smooth muscle cells in that wall — particularly in the innermost layer referred to as the “fibrous cap” — the more stable the plaque is and the less danger it poses.
UVA’s research reveals those notions are woefully incomplete at best. Scientists have grossly misjudged the number of smooth muscle cells inside the plaques, the work shows, suggesting the cells are not just involved in forming a barrier so much as contributing to the plaque itself. “We suspected there was a small number of smooth muscle cells we were failing to identify using the typical immunostaining detection methods. It wasn’t a small number. It was 82 percent,” Owens said. “Eighty-two percent of the smooth muscle cells within advanced atherosclerotic lesions cannot be identified using the typical methodology since the lesion cells down-regulate smooth muscle cell markers. As such, we have grossly underestimated how many smooth muscle cells are in the lesion.”
Suddenly, the role of smooth muscle cells is much more complex, much less black-and-white. Are they good or bad? Should treatments try to encourage more? It’s no longer that simple, and the problem is made all the more complicated by the fact that some smooth muscle cells were being misidentified as immune cells called macrophages, while some macrophage-derived cells were masquerading as smooth muscle cells. It’s very confusing, even for scientists, and it has led to what Owens called “complete ambiguity as to which cell is which within the lesion.” (The research also shows other subsets of smooth muscle cells were transitioning to cells resembling stem cells and myofibroblasts.)
Researcher Laura S. Shankman, a PhD student in the Owens lab, was able to overcome the limitations of the traditional methodology for detecting smooth muscle cells in the plaque. Her approach was to genetically tag smooth muscle cells early in their development, so she could follow them and their descendants even if they changed their stripes. “This allowed us to mark smooth muscle cells when we were confident that they were actually smooth muscle cells,” she said. “Then we let the atherosclerosis develop and progress [in mice] in order to see where those cells were later in disease.”
Further, Shankman identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when she genetically knocked out Klf4 selectively in smooth muscle cells, the atherosclerotic plaques shrank dramatically and exhibited features indicating they were more stable — the ideal therapeutic goal for treating the disease in people. Of major interest, loss of Klf4 in smooth muscle cells did not reduce the number of these cells in lesions but resulted in them undergoing transitions in their functional properties that appear to be beneficial in disease pathogenesis. That is, it switched them from being “bad” guys to “good” guys.
Taken together, Shankman’s findings raise many critical questions about previous studies built on techniques that failed to assess the composition of the lesions accurately. Moreover, her studies are the first to indicate that therapies targeted at controlling the properties of smooth muscle cells within lesions may be highly effective in treating a disease that is the leading cause of death worldwide.
The discoveries have been outlined in a paper published online by the journal Nature Medicine: http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3866.html
Public Release: 7-Jul-2015
Nutritional supplement boosts muscle stamina in animal studies
Duke University Medical Center
DURHAM, N.C. – The benefits of exercise are well known, but physical fitness becomes increasingly difficult as people age or develop ailments, creating a downward spiral into poor health.
Now researchers at Duke Medicine report there may be a way to improve exercise tolerance and, by extension, its positive effects.
Reporting in the July 7 issue of the journal Cell Metabolism, the research team describes a small molecule and its metabolic pathway that work together to optimize energy use in exercising muscles. In mouse studies, animals that received a nutrient supplement that increased activity of this pathway ran longer and farther than those that were not supplemented.
“We don’t know yet if these results will hold true in humans,” said senior author Deborah Muoio, Ph.D, director of basic research at the Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center.
“Exercise intolerance becomes a problem when reduced strength and stamina prevent normal, routine activities such as mowing the lawn or climbing stairs, or when physical activity causes extreme discomfort,” Muoio said. “So finding ways to optimize exercise could have tremendous impact to improve overall health.”
Muoio and colleagues focused on a metabolic enzyme called carnitine acetyltransferase, or CrAT, which uses the micronutrient carnitine to boost the energy economy within mitochondria, the tiny engines of cells. CrAT has been known for many years, but its role in exercise was unknown.
The Duke researchers engineered mice that lack the gene encoding CrAT, specifically in skeletal muscle, and evaluated their ability to perform exercise. The CrAT-deficient mice were compared against a control group of mice that were identical, except they had the CrAT gene.
As suspected, mice that lacked the CrAT gene tired earlier during various exercise tests because their muscles had more difficulty meeting the energy demands of the activity.
The researchers then introduced a carnitine supplement. Exercise tolerance improved only in animals with normal CrAT activity in muscle. Muoio said these results strongly imply that carnitine and the CrAT enzyme work together to optimize muscle energy metabolism during exercise.
“We were actually quite surprised that carnitine supplementation proved beneficial in young, healthy mice because our presumption was that carnitine availability was not a limiting factor under these circumstances,” Muoio said. “We don’t know yet if these results will hold true in humans.”
Muoio said the findings suggest that CrAT and the metabolite it produces help the mitochondrial engines respond more efficiently when muscles transition from a low to higher work rate, and vice versa. She said more research is needed to fully understand how this system improves energy economy during exercise.
“Responses to any given exercise regimen or intervention can vary tremendously among individuals, which means that both genetic and environmental factors influence exercise-induced improvements in physical fitness and overall health,” Muoio said. “Nutrition is one of those factors, and we are interested in identifying nutritional strategies to augment the positive effects of physical activity. Our recent studies suggest that the CrAT enzyme might be targetable through such strategies.”
Clinical trials and additional animal studies are underway to define the role of CrAT in muscle energy metabolism. Muoio said the short-term goal is to determine whether carnitine supplementation enhances the benefits of exercise training in older individuals at risk of metabolic disease.
Long-term plans include efforts to identify other genes and metabolic pathways that influence individual responses to exercise intervention, with the goal of developing personalized programs to optimize the health benefits gained by physical activity.
“This work is not meant to imply that everyone should be taking carnitine supplements,” Muoio said. “We need to consider underlying genetics, lifestyle factors and acquired conditions.”
Public Release: 8-Jul-2015
Peppermint oil and cinnamon could help treat and heal chronic wounds
American Chemical Society
Infectious colonies of bacteria called biofilms that develop on chronic wounds and medical devices can cause serious health problems and are tough to treat. But now scientists have found a way to package antimicrobial compounds from peppermint and cinnamon in tiny capsules that can both kill biofilms and actively promote healing. The researchers say the new material, reported in the journal ACS Nano, could be used as a topical antibacterial treatment and disinfectant.
Many bacteria clump together in sticky plaques in a way that makes them difficult to eliminate with traditional antibiotics. Doctors sometimes recommend cutting out infected tissues. This approach is costly, however, and because it’s invasive, many patients opt out of treatment altogether. Essential oils and other natural compounds have emerged recently as alternative substances that can get rid of pathogenic bacteria, but researchers have had a hard time translating their antibacterial activity into treatments. Vincent M. Rotello and colleagues wanted to address this challenge.
The researchers packaged peppermint oil and cinnamaldehyde, the compound in cinnamon responsible for its flavor and aroma, into silica nanoparticles. The microcapsule treatment was effective against four different types of bacteria, including one antibiotic-resistant strain. It also promoted the growth of fibroblasts, a cell type that is important in wound healing.
Public Release: 8-Jul-2015
Targeting bacteria in the gut might help burn and trauma patients
PLOS ONE study finds that severe burns dramatically alter bacteria populations
Loyola University Health System
MAYWOOD, Ill. (July 8, 2015) – A study published in PLOS ONE has found that burn patients experience dramatic changes in the 100 trillion bacteria inside the gastrointestinal tract.
Loyola University Chicago Health Sciences Division scientists found that in patients who had suffered severe burns, there was a huge increase in Enterobacteriaceae, a family of potentially harmful bacteria. There was a corresponding decrease in beneficial bacteria that normally keep harmful bacteria in check.
The findings suggest that burn patients might benefit from treatment with probiotics (live beneficial bacteria). The findings also might apply to other trauma patients, including patients who have suffered traumatic brain injuries, said senior author Mashkoor Choudhry, PhD.
In healthy individuals, the gastrointestinal tract contains more than 100 trillion bacteria, called the microbiome, that live symbiotically and provide numerous benefits. If this healthy balance is disrupted, a state called dysbiosis occurs. Dysbiosis has been linked to many conditions, including inflammatory bowel disease, obesity, rheumatoid arthritis and diabetes.
Dr. Choudhry and colleagues examined fecal samples from four severely burned patients who were treated in the Burn Center of Loyola University Medical Center. The samples were taken 5 to 17 days after the burn injuries occurred. The microbiomes of these patients were compared with the microbiomes of a control group of eight patients who had suffered only minor burns.
In the severely burned patients, Enterobacteriaceae accounted for an average of 31.9 percent of bacteria in the gut microbiome. By comparison, Enterobacteriaceae accounted for only 0.5 percent of the microbiome in patients who had suffered minor burns. Enterobacteriaceae is a family of bacteria that includes pathological bacteria such as E. coli and Salmonella.
Dr. Choudhry said such imbalances of bacteria may contribute to sepsis or other infectious complications that cause 75 percent of all deaths in patients with severe burns. The imbalance could compromise the walls of the gastrointestinal tract, enabling harmful bacteria to leak out of the gut and into the bloodstream. Dr. Choudhry is planning further studies to confirm this hypothesis.
A burn or other traumatic injury appears to start a vicious cycle: In response to the injury, the body’s immune system mounts an inflammatory response. This causes an imbalance in the microbiome, further boosting the inflammatory response and triggering an even greater imbalance in the microbiome, said Richard Kennedy, PhD, a co-author of the study.
Dr. Choudhry said further research would be needed to determine whether administration of probiotics could restore a healthy microbiome and reduce the risk of sepsis and other infectious complications.
Public Release: 9-Jul-2015
Study finds vitamin A directs immune cells to the intestines
Purdue University
WEST LAFAYETTE, Ind. — A key set of immune cells that protect the body from infection would be lost without directions provided by vitamin A, according to a recent study.
A team of researchers from Purdue University found retinoic acid, a metabolite that comes from digested vitamin A, is necessary for two of the three types of innate immune cells that reside in the intestine to find their proper place.
“It is known that vitamin A deficiencies lead to increased susceptibility to disease and low concentrations of immune cells in the mucosal barrier that lines the intestines,” said Chang Kim, the professor and section head of microbiology and immunology in Purdue’s College of Veterinary Medicine who led the research. “We wanted to find the specific role the vitamin plays in the immune system and how it influences the cells and biological processes. The more we understand the details of how the immune system works, the better we will be able to design treatments for infection, and autoimmune and inflammatory diseases.”
Within the immune system there are two categories of cells that work together to rid the body of infection: innate immune cells, the innate lymphoid cells and leukocytes that are fast acting and immediately present to eliminate infection; and adaptive immune cells, the T-cells and B-cells that arrive later, but are specific to the pathogen and more effective at killing or neutralizing it.
All innate immune cells are produced in the bone marrow, but eventually populate other areas of the body. Innate lymphoid cells, which include the group studied by Kim, are present in barrier tissues. While it is known that innate lymphoid cells are concentrated in the intestines, it has been unknown how these cells find their way there, Kim said.
Innate lymphoid cells first gather in the lymph nodes before traveling to their final destination, and this is where retinoic acid acts upon two of the three subsets destined for the intestines. Kim and his team found that retinoic acid activates specific receptors in the cells that act as homing devices for the intestines. As the innate immune cells then travel through the circulatory system, the receptors grab onto and bind to molecules in the intestines and keep the cells in place, he said.
“It is important that these cells be concentrated in mucosal barrier tissues, as opposed to scattered throughout the body, because these tissues are the point of entry for many infections from bacteria, viruses and parasites,” Kim said. “Now that we have established the system of migration for these cells, we can play with it a little and see what changes the behavior and function of the cells.”
A paper detailing the results of the study, which was performed using both cell cultures and mice, will be published in the July 21 issue of the journal Immunity and is currently available online.
In addition to Kim, co-authors of the paper include Myung H. Kim, a graduate student in the Department of Comparative Pathobiology, and Elizabeth J. Taparowsky, a professor of biological sciences.
In a healthy system, these innate immune cells reside under the epithelial cell barrier that lines the intestine. When a pathogen arrives and penetrates the epithelial barrier, innate immune cells are already there, lying in wait. Innate immune cells sound the alarm for the broader immune response and attack the pathogen to keep it from penetrating farther into the tissue or reaching the bloodstream, Kim said.
In earlier work Kim found that vitamin A also regulates the migration of T-cells.
“It is interesting that both innate and adaptive immune cells share a vitamin A-regulated pathway for migration,” he said. “However, there are distinct differences and programs that regulate the migration of the different types of cells and even subsets within them.”
This is not the only vitamin known to regulate the migration of immune cells. Vitamin D has been shown to work in a similar way to guide immune cells to the skin, Kim said.
“We all know that what we eat significantly affects our overall health and immunity,” he said. “While there are other important regulators of immune system function, the role vitamins play is significant. How this works on a molecular level is a growing field of study.”
Foods rich in vitamin A include sweet potatoes, carrots, pumpkin, spinach, mango, cantaloupe and apricots, according to the U.S. Department of Health and Human Services.
Kim next plans to study in greater detail the molecular pathways involved in the migration of innate lymphoid cells to the intestine and other organs.