234 CNO REPORT 27 AUG 2016



Release Date 27 AUG 2016

Draft Report Compiled by

Ralph Turchiano






In This Issue:

1.       An hour of moderate exercise a day enough to counter health risks from prolonged sitting

2.       Resveratrol appears to restore blood-brain barrier integrity in Alzheimer’s disease

3.       Ketone drink gives competitive cyclists a boost by altering their metabolism

4.       Fish oil vs. lard — why some fat can help or hinder your diet

5.       Omega-3 fatty acids from fish oil, may aid healing after heart attack

6.       Inosine treatment helps recovery of motor functions after brain injury

7.       Soy may help protect women with PCOS from diabetes, heart disease

8.       Helper molecule reverses degeneration of muscle in mouse model of tissue aging, wasting

9.       Fluoride consumption linked to diabetes using mathematical models

10.   New ‘food group’? Ketone esters improve endurance exercise and cognitive function

11.   Greater intake of dietary omega-3 fatty acids associated with lower risk of diabetic retinopathy

12.   Soluble corn fiber can help young women build bone, and older women preserve bone

13.   Stroke-like brain damage is reduced in mice injected with omega-3s

14.   Study validates new tool for diagnosing dehydration in children

15.   Essential oils could counter lung and liver ailments caused by air pollution

16.   Drinking green tea to prevent artery explosion

17.   How do antidepressants trigger fear and anxiety?

18.   Fish oil pills reverse the effects of a fatty diet


Public Release: 27-Jul-2016

An hour of moderate exercise a day enough to counter health risks from prolonged sitting

University of Cambridge

The health risks associated with sitting for eight or more hours a day – whether at work, home or commuting – can be eliminated with an hour or more of physical activity a day, according to a study from an international team of researchers.

Ever since a study back in 1953 discovered that London bus drivers were at greater risk of heart disease compared to bus conductors, scientists have found increasing evidence that lack of physical activity is a major risk factor for several diseases and for risk of early death. Recent estimates suggest that more than 5 million people die globally each year as a result of failing to meet recommended daily activity levels.

Studies in high-income countries have suggested that adults spend the majority of their waking hours sitting down. A typical day for many people is driving to work, sitting in an office, driving home and watching TV. Current physical activity guidelines recommend that adults do at least 150 minutes of moderate intensity exercise per week.

In an analysis published today in The Lancet that draws together a number of existing studies, an international team of researchers asked the question: if an individual is active enough, can this reduce, or even eliminate, the increased risk of early death associated with sitting down?

In total the researchers analysed 16 studies, which included data from more than one million men and women. The team grouped individuals into four quartiles depending on their level of moderate intensity physical activity, ranging from less than 5 minutes per day in the bottom group to over 60 minutes in the top. Moderate intensity exercise was defined as equating to walking at 3.5 miles/hour or cycling at 10 miles/hour, for example.

The researchers found that 60 to 75 minutes of moderate intensity exercise per day were sufficient to eliminate the increased risk of early death associated with sitting for over eight hours per day. However, as many as three out of four people in the study failed to reach this level of daily activity.

The greatest risk of early death was for those individuals who were physically inactive, regardless of the amount of time sitting – they were between 28% and 59% more likely to die early compared with those who were in the most active quartile – a similar risk to that associated with smoking and obesity. In other words, lack of physical activity is a greater health risk than prolonged sitting.

“There has been a lot of concern about the health risks associated with today’s more sedentary lifestyles,” says Professor Ulf Ekelund from the Medical Research Council Epidemiology Unit at the University of Cambridge. “Our message is a positive one: it is possible to reduce – or even eliminate – these risks if we are active enough, even without having to take up sports or go to the gym.

“For many people who commute to work and have office-based jobs, there is no way to escape sitting for prolonged periods of time. For these people in particular, we cannot stress enough the importance of getting exercise, whether it’s getting out for a walk at lunchtime, going for a run in the morning or cycling to work. An hour of physical activity per day is the ideal, but if this is unmanageable, then at least doing some exercise each day can help reduce the risk.”

The researchers acknowledge that there are limitations to the data analysed, which mainly came from participants aged 45 years and older and living in western Europe, the US and Australia. However, they believe that the strengths of the analysis outweigh these limitations. Most importantly, the researchers asked all included studies to reanalyse their data in a harmonized manner, an approach that has never before been adopted for a study of this size and therefore also provides much more robust effect estimates compared with previous studies.

Public Release: 27-Jul-2016

Resveratrol appears to restore blood-brain barrier integrity in Alzheimer’s disease

Georgetown University Medical Center

WASHINGTON — Resveratrol, given to Alzheimer’s patients, appears to restore the integrity of the blood-brain barrier, reducing the ability of harmful immune molecules secreted by immune cells to infiltrate from the body into brain tissues, say researchers at Georgetown University Medical Center. The reduction in neuronal inflammation slowed the cognitive decline of patients, compared to a matching group of placebo-treated patients with the disorder.

The laboratory data provide a more complete picture of results from a clinical trial studying resveratrol in Alzheimer’s disease that was first reported in 2015. The new findings will be presented at the Alzheimer’s Association International Conference 2016 in Toronto on July 27th.

The Alzheimer’s disease brain is damaged by inflammation, thought to be due to a reaction to the buildup of abnormal proteins, including Abeta40 and Abeta42, linked to destruction of neurons. Researchers believe that heightened inflammation — which was historically thought to come only from “resident” brain immune cells — worsens the disease. According to the researchers, this study suggests that some of the immune molecules that can cause inflammation in the blood can enter the brain through a leaky blood-brain barrier.

“These findings suggest that resveratrol imposes a kind of crowd control at the border of the brain. The agent seems to shut out unwanted immune molecules that can exacerbate brain inflammation and kill neurons,” says neurologist Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherapeutics Program. “These are very exciting findings because it shows that resveratrol engages the brain in a measurable way, and that the immune response to Alzheimer’s disease comes, in part, from outside the brain.”

Resveratrol is a naturally occurring compound found in foods such as red grapes, red wine, raspberries and dark chocolate. GUMC researchers, led by R. Scott Turner, MD, PhD, tested the substance in 119 patients, the largest nationwide phase II clinical trial to study high-dose pure synthetic (pharmaceutical-grade) resveratrol in individuals with mild to moderate Alzheimer’s. The study was published Sept. 11, 2015 in Neurology.

The new part of the resveratrol study examines specific molecules in the cerebrospinal fluid (CSF) taken from participants with biomarker-confirmed Alzheimer’s disease — 19 were given a placebo, and 19 treated daily for a year with resveratrol, equivalent to the amount found in about 1,000 bottles of red wine.

Previous studies with animals found that age-related diseases–including Alzheimer’s — can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake). The researchers studied resveratrol because it mimics the effects of caloric restriction by also activating proteins called sirtuins.

In this new study, Moussa and Turner found that treated patients had a 50 percent reduction in matrix metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid. MMP-9 is decreased when sirtuin1 (SIRT1) is activated. High levels of MMP-9 cause a breakdown in the blood-brain barrier, allowing proteins and molecules from the body to enter the brain. Normally low MMP-9 levels maintain the barrier, say the researchers.

“These new findings are exciting because they increase our understanding of how resveratrol may be clinically beneficial to individuals with Alzheimer’s disease. In particular, they point to the important role of inflammation in the disease, and the potent anti-inflammatory effects of resveratrol,” says Turner, director of GUMC’s Memory Disorders Program and co-director of the Translational Neurotherapeutics Program.

They also found that resveratrol increased the level of molecules linked to a long-term beneficial or “adaptive” immune reaction, suggesting involvement of inflammatory cells that are resident in the brain, says Moussa. “This is the kind of immune response you want — it is there to remove and degrade neurotoxic proteins.”

“A puzzling finding from the resveratrol study (as well as immunotherapy strategies for Alzheimer’s under investigation) is the greater shrinkage of the brain found with treatment. These new findings support the notion that resveratrol decreases swelling that results from inflammation in Alzheimer’s brain,” says Turner. “This seemingly paradoxical effect is also found with many of the drugs that are beneficial for patients with multiple sclerosis — another brain disease characterized by excessive inflammation.”

Moussa says that resveratrol should be further tested in a phase III study, but the agent, by itself, is unlikely to be a complete treatment for Alzheimer’s. It does not inhibit destruction of brain neurons by tau, another protein aggregate involved in the disease, so a likely beneficial treatment would combine resveratrol with an agent that targets tau, he says.


Public Release: 27-Jul-2016

Ketone drink gives competitive cyclists a boost by altering their metabolism

Cell Press

A drink developed for soldiers to generate energy from ketones rather than carbs or fat allowed highly trained cyclists to add up to 400 meters of distance (2% increase) to their workouts , a small UK-led study reports July 27 in Cell Metabolism. The supplement, which will be commercially available within the year, works by temporarily switching the primary source of cellular energy from glucose or fat to ketones — molecules derived from fat that are known to be elevated in people consuming a low-carb, Atkins-like diet.

“It’s really interesting; with a single drink of nutritional ketone you can do the same exercise with completely different metabolism,” says Dr. Pete Cox, a clinician at the University of Oxford and first author on the paper. “Given the findings of this study, which challenges our fundamental understanding of human physiology, it will be tempting for many to focus on pursuing the endurance and sport-related avenues, but it would be a great shame if the metabolic basis of this work was not further explored.”

Ketosis is a way for humans to deal with starvation. Ketones are made in the liver from mobilized body fat, so when the body doesn’t get enough fuel from food, internal fat stores are broken down to make ketones that feed the brain. Normal metabolism is driven by the burning of carbs and fat obtained in a balanced diet.

The idea to develop a ketone food group came from the Defense Advanced Research Projects Agency (DARPA), the research branch of the United States army, who put out a $10 million call for the development of the most efficient food for soldiers to take onto a battlefield. One of the people to answer this call was University of Oxford biochemist Professor Kieran Clarke. With Dr. Richard Veech at the National Institutes of Health, she assembled a team who invented the ketone ester drink, and this paper is the first efficacy study to show that the exogenous ketone can improve performance for certain types of activities. (Safety studies have already been conducted, and the drink does not have any adverse effects.)

In a study of 39 cyclists, including some former Olympians, they found that the muscles use ketones when provided in the diet, and that this uptake increases in proportion to the intensity of exercise. In one experiment, the researchers gave the cyclists “energy drinks,” each infused with a different source of fuel — carbohydrates, fats, or ketones — and found that cyclists who had the ketone drink had the lowest levels of lactate, a byproduct of the body’s breakdown of glucose, which is often associated with muscular stress, or the achy, tired feeling felt after a strenuous workout. The observation could help explain why the high-performing cyclists on the ketone drink traveled an average of 400 meters farther over a half hour than those consuming the carbohydrate or fat drink.

“The ketone itself is inhibiting glycolysis, so that with the same exercise you’re preserving glycogen and producing much less lactic acid — this hasn’t been seen before,” Clarke says. “What may be happening is if you are doing something that isn’t a sprint, like going on a 26-mile run, you won’t hit the wall as quickly. Not only that, but it stops you from aching afterwards.”

While a good fit for marathon runners, the ketone drink is unlikely to help many Olympic athletes or sprinters, she says, because their exercise is primarily anaerobic, and the body needs oxygen to burn ketones. Clarke also cautions against drinking too much of the supplement, because while ketones become the primary metabolite, some glycolysis is also needed for them to have beneficial effects.

A University of Oxford spinout company, T?S® Ltd, will now develop and commercialize the ketone drink. Clarke says they are scaling up and are aiming to have the ketone food available for purchase by the end of the year. In the meantime, she and her group will continue to investigate the biology of this alternative metabolism in humans.

Public Release: 29-Jul-2016

Fish oil vs. lard — why some fat can help or hinder your diet


A diet high in saturated fat can make your brain struggle to control what you eat, says a new study in Frontiers in Cellular Neuroscience.

If people are looking to lose weight, stay clear of saturated fat. Consuming these types of fatty food affects a part of the brain called the hypothalamus, which helps regulate hunger.

The fat causes inflammation that impedes the brain to control the food intake. In other words, people struggle to control how much they eat, when to stop and what type of food to eat – symptoms seen in obesity.

The study found, through tests in rats, that a meal rich in saturated fat, reduces a person’s cognitive function that make it more difficult to control eating habits.

“These days, great attention is dedicated to the influence of the diet on people’s wellbeing. Although the effects of high fat diet on metabolism have been widely studied, little is known about the effects on the brain;” explained Professor Marianna Crispino and Professor Maria Pina Mollica from the University of Naples Federico II.

A diet rich in fat can take different forms and in fact, there are different types of fats. Saturated fats are found in lard, butter or fried food. Unsaturated fats are rich in food such as fish, avocado or olive oil.

Consuming fish oil instead of lard makes a significant difference. The research shows that brain function remains normal and manages to restrain from eating more than necessary.

“The difference was very clear and we were amazed to establish the impact of a fatty diet onto the brain. Our results suggest that being more aware about the type of fat consumed with the diet may reduce the risk of obesity and prevent several metabolic diseases”, concludes Professor Crispino.

Public Release: 1-Aug-2016

Omega-3 fatty acids from fish oil, may aid healing after heart attack

American Heart Association Rapid Access Journal Report

American Heart Association

DALLAS, August 1, 2016 — Giving heart attack patients a high dose of omega-3 fatty acids from fish oil, daily for six months after a heart attack improved the function of the heart and reduced scarring in the undamaged muscle, according to new research in the American Heart Association’s journal Circulation.

The heart’s shape and function can be altered after a heart attack, a condition known as post-heart attack remodeling and it is linked with poor patient outcomes and could lead to heart failure. Therapies that can improve healing of the heart or prevent adverse remodeling, remain scarce.

A previous study found that omega-3 fatty acids from fish oil were associated with improved survival for heart attack patients, but the role of omega-3 fatty acids in improving the structure and tissue of the heart in patients receiving current guideline-based therapy after a heart attack was unknown.

In the new OMEGA-REMODEL randomized clinical trial, researchers found compared to those taking a placebo, patients taking a dose of 4 grams of omega-3 fatty acids daily for six months:

experienced a 5.8 percent reduction in left ventricular end-systolic volume index: a clinical marker that can predict patient outcome after a heart attack; and had a 5.6 percent reduction in a measurement of scarred connective tissue (fibrosis) formation in the non-damaged heart muscle.

“Heart failure is still a major problem after a heart attack despite all the therapy we have and the advances in interventional care,” said Raymond Y. Kwong, M.D., M.P.H., senior author of the study and director of Cardiac Magnetic Resonance Imaging, Brigham and Women’s Hospital and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts. “Our findings show that omega-3 fatty acids are a safe and effective treatment in improving cardiac remodeling, so it may be promising in reducing the incidence of heart failure or death, which are still major healthcare burdens to patients who suffer a heart attack.”

Researchers said these results suggests that omega-3 fatty acids allow the heart to contract better, and also reduces the fibrosis in the region that is not damaged.

The researchers also observed a reduction in biomarkers for inflammation, suggesting that omega-3 fatty acids have some anti-inflammatory properties.

The study involved 360 heart attack survivors, half were given a high dose omega-3 fatty acids and half placebo, beginning within a month of the heart attack. Because the study participants were given high doses of omega-3s in addition to their other medications, patients were under a physician’s care and observed for any potential adverse outcomes by study authors throughout the study.

The treatment was found to be safe and effective. Both groups received treatment based on guidelines issued by the American College of Cardiology Foundation and the American Heart Association. Blood tests were used to confirm that patients in the omega-3 fatty acids group were taking the treatment.

Public Release: 3-Aug-2016

Inosine treatment helps recovery of motor functions after brain injury

First study in primates shows promise reports restorative neurology and neuroscience

IOS Press

Brain tissue can die as the result of stroke, traumatic brain injury, or neurodegenerative disease. When the affected area includes the motor cortex, impairment of the fine motor control of the hand can result. In a new study published in Restorative Neurology and Neuroscience, researchers found that inosine, a naturally occurring purine nucleoside that is released by cells in response to metabolic stress, can help to restore motor control after brain injury.

Based on evidence from rodent studies, researchers used eight rhesus monkeys ranging in age from 5 to 10 years (approximately equivalent to humans from 15 to 30 years of age). All received medical examinations and motor skills were tested, including video recording of fine motor functions used to retrieve small food rewards. All monkeys were given initial MRI scans to ensure there were no hidden brain abnormalities.

Brain injuries were created in the area controlling each monkey’s favored hand. Four monkeys received inosine treatment, while four received a placebo. Research staff were not informed regarding which monkeys were included in the treatment vs placebo groups. Recovery of motor function was then measured for a period of 14 weeks after surgery.

While both the treated and placebo groups recovered significant function, three out of four of the treated monkeys were able to return to their pre-operative grasping methods. The placebo group developed a compensatory grasping method for retrieving food rewards unlike the original thumb-and-finger method.

“In the clinical context, the enhanced recovery of grasp pattern suggests that inosine facilitates greater recovery from this type of cortical injury and motor impairment,” explained lead investigator Tara L. Moore, PhD, of the Department of Anatomy & Neurobiology and the Department of Neurology, Boston University School of Medicine, Boston, MA, USA. “To our knowledge, this is the first study to demonstrate the positive effects of inosine for promoting recovery of function following cortical injury in a non-human primate.”

Inosine has also been administered in human clinical trials for multiple sclerosis and Parkinson’s disease and has been proven to be safe in doses up 3000 mg/day. Athletes have used inosine as a nutritional supplement for decades, and inosine supplements are widely available commercially. “Given the effectiveness of inosine in promoting cortical plasticity, axonal sprouting, and dendritic branching, the present evidence of efficacy after cortical injury in a non-human primate, combined with a long history of safe use, indicates a need for clinical trials with inosine after cortical injury and spinal cord injury,” noted Dr. Moore.

The study points to neural plasticity, whereby the brain essentially “re-wires” connections between neurons to reestablish control pathways, as a therapeutic target for the recovery of fine motor control and grasping ability. Further study of cortical tissue from these monkeys is currently being completed and may provide further insights into the mechanisms underlying recovery.

Public Release: 4-Aug-2016

Soy may help protect women with PCOS from diabetes, heart disease

Soy isoflavone supplements boosted markers of metabolic, cardiovascular health

The Endocrine Society

Washington, DC–Women who have polycystic ovary syndrome (PCOS)–a common cause of female infertility–may be able to improve their metabolic and cardiovascular health by consuming soy isoflavones, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

Soy isoflavones are naturally occurring plant-based estrogens found in the soybean plant. They are found in foods such as soy milk, as well as supplements.

The study examined how a diet containing soy isoflavones could benefit women with PCOS–a condition that affects an estimated 5 million to 6 million women in the United States.

Among the most common hormone disorders in women of reproductive age, PCOS occurs when a women’s body produces slightly higher amounts of testosterone and other androgen hormones–sex hormones typically associated with men, but also found in women–than normal. The resulting hormone imbalance can cause irregular or absent menstrual periods, infertility, weight gain, acne, excess hair on the face and body, or thinning hair on the scalp. Women who have PCOS also face a higher risk of developing other health problems, including diabetes and coronary heart disease.

“Our research found that women who have PCOS may benefit from incorporating soy isoflavones in their diets,” said the study’s first author, Zatollah Asemi, PhD, of Kashan University of Medical Sciences in Kashan, Iran. “In the first study to examine the connection, we found women who consumed soy isoflavones regularly saw improvement in biological markers that reflect how effectively the body utilizes insulin to process sugars and had reduced levels of harmful cholesterol.”

Seventy women who were between the ages of 18 and 40 and had PCOS participated in the prospective randomized double-blind, placebo-controlled clinical trial. The women were referred to the Kosar Clinic in Arak, Iran, between December 2015 and February 2016.

Half of the women were randomly assigned to take a daily 50 mg/d soy isoflavone supplement daily for 12 weeks. This amount is equivalent to the amount of soy isoflavones in 500 milliliters of soy milk. The other 35 participants received a placebo. Participants were instructed to maintain current levels of exercise and to avoid taking other nutritional supplements during the study.

Blood samples were taken from the women at the beginning and end of the study. The blood samples were analyzed to measure hormone and lipid levels, as well as biomarkers of insulin resistance and inflammation.

In comparison to the placebo group, women who received soy isoflavones had lower levels of circulating insulin in the blood and other biological markers associated with insulin resistance–a condition where the body doesn’t use insulin to process sugars effectively and that can lead to Type 2 diabetes. The researchers also found women who took soy isoflavone supplements tended to have lower levels of testosterone, harmful cholesterol known as LDL and triglycerides, or fats in the blood, than their counterparts who received the placebo.

“There is growing interest in how adding soy to the diet can help address metabolic syndrome and related health conditions,” Asemi said. “Our findings indicate consuming soy isoflavone regularly may help women with PCOS improve their metabolic and cardiovascular health.”

Public Release: 9-Aug-2016

Helper molecule reverses degeneration of muscle in mouse model of tissue aging, wasting

Penn study illuminates role of essential compound in maintaining physical endurance, possible MD treatment

University of Pennsylvania School of Medicine



PHILADELPHIA – Maintaining proper levels of an essential helper molecule is crucial for optimal muscle function, according to a study led by Joseph Baur, PhD, an assistant professor of Physiology in the Perelman School of Medicine at the University of Pennsylvania. Some athletes are already taking supplements to increase synthesis of this compound, called NAD, with the hopes of reversing the natural decay associated with aging of the mitochondria, the cell’s powerhouses. However, this is the first study to directly investigate the consequences of NAD deficiency on muscle function. The Penn team published their findings this week in the cover article of Cell Metabolism.

Oversight of the natural products industry is much looser than that of regulated drugs, and supplements to boost NAD are available over the counter. “Finding out whether strategies to enhance the production of NAD will have any impact on muscle function in healthy individuals is a subject of much speculation,” Baur said. “However, answering this question will have to wait for controlled clinical trials.”

Baur and colleagues examined the role of NAD precursor molecules on mitochondria by specifically disrupting the “NAD salvage pathway,” in mouse skeletal muscle. This pathway consists of a series of enzymes that recycles building block molecules to make fresh NAD to power reactions throughout the cell, and especially within the mitochondria, the cell component that makes energy for the body from ingested food. Chemical reactions involving NAD are fundamental to metabolizing all fats and carbohydrates, yet NAD is degraded in response to such physiological stresses as DNA damage, and its concentration declines in several tissues over the natural course of aging.

Lead author David W. Frederick, PhD, a postdoctoral fellow in the Baur lab, and the team generated mice in which they could restrict the amount of NAD in specific tissues in order to simulate this aspect of normal aging in otherwise healthy mice. Surprisingly, young knockout mice were found to tolerate an 85 percent decline in intramuscular NAD content without losing spontaneous activity or treadmill endurance. However, when these same mice hit early adulthood (three to seven months of age), their muscles progressively weakened and their muscle fibers atrophied.

“Their muscle tissue looked like that of Duchene’s muscular dystrophy [DMD] patients,” Baur said. “The genes that were turned on and the presence of inflammatory immune cells in the muscles lacking NAD looked very similar to what we see in DMD.”

The team next sought to test whether a dietary NAD precursor might remedy the muscle pathology in the mice. The muscle decline was completely reversed by feeding the mice a form of vitamin B3, called nicotinamide riboside (NR), obtained from natural products company ChromaDex, a study collaborator.

“At first we were surprised by how rapidly NR was able to reactivate dormant mitochondria in muscle, despite being largely consumed by other cell types,” Frederick said. “It appears that a relatively small enhancement in muscle NAD can have profound functional consequences in this setting.”

Additionally, the team found that induced lifelong overexpression of Nampt, an enzyme important in making NAD, prevented the natural decline in NAD and partially preserved exercise capacity in aged mice. “This was supporting evidence that strategies to enhance muscle NAD synthesis might help to combat age-associated frailty,” says Frederick, emphasizing the need for more studies to confirm the long-term safety of such interventions.

Baur plans to follow up on the unexpected muscular dystrophy finding, asking if NAD is also depleted in some forms of dystrophy and if restoring NAD might help ameliorate certain features of the disease. Though the Baur lab previously found that enhanced NAD synthesis does not benefit muscle performance in young mice, these new findings suggest that it may be useful for combating age-related declines in muscle function.

Public Release: 17-Aug-2016

Fluoride consumption linked to diabetes using mathematical models

Regression analyses suggest association between increases in consumption of fluoridated water and type 2 diabetes

Case Western Reserve University

Water fluoridation prevents dental cavities, which are a costly public health concern. But despite the benefits supplemental water fluoridation remains a controversial subject. Some indicate it may cause long term health problems, but studies reporting side effects have been minimal or inconclusive. The long-term effects of ingested fluoride remain unclear.

A recent study published in the Journal of Water and Health examined links between water fluoridation and diabetes. Type 2 diabetes is a growing epidemic in the United States. Incidence rates have nearly quadrupled in the past 32 years and show no signs of stopping. According to the study, fluoridation with sodium fluoride could be a contributing factor to diabetes rates in the United States, as the chemical is a known preservative of blood glucose.

The sole author of the paper, Kyle Fluegge, PhD, performed the study as a post-doctoral fellow in the Department of Epidemiology and Biostatistics at Case Western Reserve University School of Medicine. Fluegge now serves as health economist in the Division of Disease Control for the New York City Department of Health and Mental Hygiene and co-director of the Institute of Health and Environmental Research in Cleveland, Ohio.

In the study, Fluegge used mathematical models to analyze publicly available data on fluoride water levels and diabetes incidence and prevalence rates across 22 states. He also included adjustments for obesity and physical inactivity collected from national telephone surveys to help rule out confounding factors. Two sets of regression analyses suggested that supplemental water fluoridation was significantly associated with increases in diabetes between 2005 and 2010.

“The models look at the outcomes of [diabetes] incidence and prevalence being predicted by both natural and added fluoride,” said Fluegge.

Fluegge reported that a one milligram increase in average county fluoride levels predicted a 0.17% increase in age-adjusted diabetes prevalence. Digging deeper revealed differences between the types of fluoride additives used by each region. The additives linked to diabetes in the analyses included sodium fluoride and sodium fluorosilicate. Fluorosilicic acid seemed to have an opposing effect and was associated with decreases in diabetes incidence and prevalence. Counties that relied on naturally occurring fluoride in their water and did not supplement with fluoride additives also had lower diabetes rates.

The positive association between fluoridation and diabetes was discovered when Fluegge adjusted fluoride exposure levels to account for estimated per capita tap water consumption.

“The models present an interesting conclusion that the association of water fluoridation to diabetes outcomes depends on the adjusted per capita consumption of tap water,” explained Fluegge. “Only using the concentration [of added fluoride] does not produce a similarly robust, consistent association.” For this reason, Fluegge adjusted his calculations to incorporate tap water consumption, instead of sticking to calculations that rely on “parts per million” measurements of fluoride in the water.

Fluegge used several estimations in his study, including calculations of county-level water fluoride levels; per capita county tap water consumption; and county measures of poverty, obesity and physical inactivity. Although he doesn’t suggest the study should trigger policy changes, he does indicate it should serve as a call for additional research on the important association between fluoridation and diabetes.

“This is an ecological study. This means it is not appropriate to apply these findings directly to individuals,” explained Fluegge. “These are population-level associations being made in the context of an exploratory inquiry. And water is not the only direct source of fluoride; there are many other food sources produced with fluoridated water.”

In addition to being found in food like processed beverages or produce exposed to specific pesticides, fluoride is found naturally in water in the form of calcium fluoride. Supplemental fluoride was first added to community water supplies in the 1940s.

Said Fluegge, “The models indicate that natural environmental fluoride has a protective effect from diabetes. Unfortunately, natural fluoride is not universally present in the water supply.”

Residents can learn more about fluoride levels in their communities through the Centers for Disease Control My Water’s Fluoride database.

Public Release: 17-Aug-2016

New ‘food group’? Ketone esters improve endurance exercise and cognitive function

New research in The FASEB Journal suggests that adding a ketone ester to a rat’s diet increased treadmill run times, faster maze-solving, and increased energy levels in the heart

Federation of American Societies for Experimental Biology

New research published online in The FASEB Journal shows that in rats, a substance called a ketone ester significantly increase exercise endurance, cognitive function and energy levels in the heart at high workloads. Ketone esters are small organic chemicals that provide energy for the heart, brain and skeletal muscle in a highly efficient way, but are typically produced by the body only during periods of food scarcity and are not naturally present in typical modern diets.

“The dramatic improvements in exercise performance and cognitive function will no doubt interest athletes and professional sports teams worldwide. Our hope, however, is that ketone ester supplementation will also hold benefits for people who are suffering from debilitating metabolic and neurological diseases by improving energy availability,” said Andrew J. Murray, Ph.D., a researcher involved in the work from the Department of Physiology, Development and Neuroscience at the University of Cambridge, in Cambridge, England. “Further research into the potential benefits of ketone ester for human health is vital, and only just beginning.”

To make this discovery, Murray and colleagues fed three different diets to rats for five days. A third of the calories in the diets were from a novel ketone ester, or fat, or carbohydrate. To test endurance, the rats ran on a treadmill. To test memory, the rats had to complete a maze. The researchers found that the ketone ester-fed rats ran farther and completed the maze faster and more accurately than rats on the carb or fat diets. Additional work described in the study shows that the ketone ester diet also improved energy production in the heart itself.


“These endogenous compounds have long been known in the metabolism field but here one is being used exogeneously,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. “This may be a new horizon on the energy balance sheet in certain nutrional or physiological situations”

Public Release: 18-Aug-2016

Greater intake of dietary omega-3 fatty acids associated with lower risk of diabetic retinopathy

The JAMA Network Journals

In middle-aged and older individuals with type 2 diabetes, intake of at least 500 mg/d of dietary long-chain ω-3 polyunsaturated fatty acids, easily achievable with 2 weekly servings of oily fish, was associated with a decreased risk of sight-threatening diabetic retinopathy, according to a study published online by JAMA Ophthalmology.

The increasing prevalence of type 2 diabetes mellitus, coupled with an increased lifespan, has resulted in a steady rise of disability in older individuals with diabetes. A major concern for this population group is diabetic retinopathy (DR), a leading global cause of vision loss. Given the economic and societal burden of DR, developing effective strategies to prevent or at least delay its onset is a major public health issue. The retina is rich in long-chain ω-3 polyunsaturated fatty acids (LCω3PUFAs). Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking.

Aleix Sala-Vila, D.Pharm., Ph.D., of the Lipid Clinic, Barcelona, and colleagues conducted a prospective study within the randomized clinical trial Prevencion con Dieta Mediterranea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3,614 individuals age 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3,482 participants (48 percent men; average age 67 years). Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention was assessed by a validated food-frequency questionnaire.

Of the participants, a total of 2,611 (75 percent) met the target LCω3PUFA recommendation. During a median follow-up of 6 years, incident DR was diagnosed in 69 of the study participants. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (500 mg/d or greater) compared with those not fulfilling this recommendation (less than 500 mg/d) showed a 48 percent relatively reduced risk of incident sight-threatening DR.

“Our findings, which are consistent with the current model of the pathogenesis of DR and data from experimental models, add to the notion of fish-derived LCω3PUFA as a healthy fat,” the authors write.

(JAMA Ophthalmol. Published online August 18, 2016.doi:10.1001/jamaophthalmol.2016.2906; this study is available pre-embargo at the For The Media website.)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Commentary: Eat Your Fish or Go for Nuts

The PREDIMED study provides food for thought for those who wish to fight the complications of diabetes by clever eating, writes Michael Larsen, M.D., D.M.Sc., of Rigshospitalet-Glostrup and University of Copenhagen, Glostrup, Denmark, in an accompanying commentary.

“It seems a safe bet now to spread one’s food intake to include the gifts of our oceans and forests, while we consider how they can be protected for future generations and wait for large and ambitious studies of the effects of diet on diabetic retinopathy. The success of such studies in age-related macular degeneration shows that solid scientific information is worth waiting and working for.”

(JAMA Ophthalmol. Published online August 18, 2016.doi:10.1001/jamaophthalmol.2016.2942; this commentary is available pre-embargo at the For The Media website.)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.


Media Advisory: To contact Aleix Sala-Vila, D.Pharm., Ph.D., email asala@clinic.ub.es. To contact commentary author Michael Larsen, M.D., D.M.Sc., email miclar01@regionh.dk.

Public Release: 22-Aug-2016

Soluble corn fiber can help young women build bone, and older women preserve bone

Purdue University

WEST LAFAYETTE, Ind. — Supplementing with soluble corn fiber at two critical times in a woman’s life – adolescence and post-menopause – can help build and retain calcium in bone, according to new research from Purdue University.

“We are looking deeper in the gut to build healthy bone in girls and help older women retain strong bones during an age when they are susceptible to fractures,” said Connie Weaver, distinguished professor and head of nutrition science. “Soluble corn fiber, a prebiotic, helps the body better utilize calcium during both adolescence and post-menopause. The gut microbiome is the new frontier in health.”

The post-menopause findings are published in the American Journal of Clinical Nutrition, and the adolescent findings are published in Journal of Nutrition. The studies are funded by Tate & Lyle Ingredients America LLC. Weaver serves on the scientific advisory board for Pharmative LLC.

A prebiotic fiber passes through the gut for the microbes in the lower gut to digest. Here is where Weaver found that soluble corn fiber is broken down into short chain fatty acids to aid in bone health.

In the post-menopausal study, calcium retention was measured in 14 women by using an isotope to measure the excretion of 41Ca to measure bone loss. The women consumed 0 grams, 10 grams or 20 grams of this nondigestible carbohydrate each day for 50 days. Bone calcium retention was improved by 4.8 percent and 7 percent for those who consumed 10 grams and 20 grams, respectively. These amounts of soluble corn fiber would be found in supplement form.

“If projected out for a year, this would equal and counter the average rate of bone loss in a post-menopausal woman,” said Weaver, an expert in mineral bioavailability, calcium metabolism, botanicals and bone health.

The calcium 41 technology, an isotope measure to trace calcium deposits through accelerator mass spectrometry in the Purdue Rare Isotope Measurement Laboratory (PRIME Lab), can measure atomic quantities. In the adolescent study, 44Ca and 43Ca were used.

Thirty-one girls either consumed 0 grams, 10 grams or 20 grams of soluble corn fiber carbohydrate each day for three weeks while maintaining their regular diets. Both 10 grams and 20 grams led to improved calcium absorption by 12 percent for female adolescents, which would build 1.8 percent more skeleton a year.

In both studies, gastrointestinal symptoms were minimal and the same for the control groups, as well as in those who consumed soluble corn fiber.

“Most studies looking at benefits from soluble corn fiber are trying to solve digestion problems, and we are the first to determine that this relationship of feeding certain kind of fiber can alter the gut microbiome in ways that can enhance health,” Weaver said. “We found this prebiotic can help healthy people use minerals better to support bone health.”

Calcium is considered a shortfall nutrient, and few people meet the recommended intake of 1,300 milligrams of calcium for healthy bone mass.

“The finding doesn’t mean we should diminish our recommendation to drink milk and follow a well-balanced diet. This is a strategy to better utilize your minerals for those not consuming the whole recommendation of dairy,” Weaver said. “Calcium alone suppresses bone loss, but it doesn’t enhance bone formation. These fibers enhance bone formation, so they are doing something more than enhancing calcium absorption.”

Weaver’s team is looking into the mechanisms of how soluble corn fiber boosts calcium absorption and retention, as well as if the prebiotic fiber benefits the body in other ways.

Weaver is a member of the National Academy of Medicine and deputy director of the National Institutes of Health-funded Indiana Clinical and Translational Science Institute. She also is director of Purdue’s Women’s Global Health Institute.

In 2011 she was appointed to the Institute of Medicine’s Food and Nutrition Board, and in 2005 she was appointed to the U.S. Dietary Guidelines Advisory Committee. She also served on the National Academy of Sciences Food and Nutrition Board Panel to develop new requirement recommendations for calcium and related minerals. Her lab’s previous work identified these optimal calcium levels for healthy bone growth during puberty to prevent osteoporosis later in life.

Public Release: 22-Aug-2016

Stroke-like brain damage is reduced in mice injected with omega-3s

Emulsion containing omega-3 triglyceride DHA also improved brain function

Columbia University Medical Center

New York, NY, August 22, 2016–Researchers from Columbia University Medical Center (CUMC) found that omega-3 fatty acids reduced brain damage in a neonatal mouse model of stroke.

Findings from the study were published recently in PLOS ONE.

The researchers treated 10-day-old mice that had incurred hypoxic-ischemic brain injury (caused by a decrease in blood flow and oxygen to the brain, as occurs during a stroke) with a fat emulsion containing either DHA or EPA–omega-3 fatty acids that are found in certain foods and in supplements. The researchers evaluated the mice’s neurological function 24 hours and 8 to 9 weeks after the brain injury.

EPA and DHA are bioactive omega-3 fatty acids that are found in oils extracted from cold-water fish. The CUMC researchers and other scientists have shown that these fish-oil fatty acids protect organs and cells in numerous ways after oxygen deprivation, reducing inflammation and cell death.

At 24 hours, mice treated with DHA, but not EPA, had a significant reduction in brain injury. In the following weeks, the DHA group also had significantly better results in multiple brain functions compared to the EPA-treated mice and untreated (control) mice.

The researchers also discovered that these mice had increased concentrations of DHA in their brain mitochondria, energy-producing structures in cells that can be injured by free radicals when blood flow is restored to the brain after a stroke. This process, known as reperfusion injury, is a common cause of brain damage following the oxygen and nutrient deprivation that occurs after a stroke.

“Our findings suggest that injecting the omega-3 fatty acid DHA after a stroke-like event has the ability to protect brain mitochondria against the damaging effects of free radicals,” said senior co-author, Vadim S. Ten, MD, PhD, associate professor of pediatrics at CUMC.

Interruption of blood flow and oxygen supply to the brain during or shortly after birth is a major cause of brain damage in newborns, causing life-long neurological impairments in more than 25 percent of those affected. Many of the pathways involved in this type of brain damage are similar to those in an adult stroke.

“Clinical trials are needed to determine if administering lipid emulsions containing DHA shortly after a stroke-like brain injury offers the same neuroprotective effects in babies and adults, as seen in mice. If successful, such trials could lead to the development of a novel therapy for stroke in newborns, children, and adults, addressing a major medical need,” said senior co-author Richard J. Deckelbaum, MD, CM, the Robert R. Williams Professor of Nutrition (in Pediatrics) and Professor of Epidemiology and director of the Institute of Nutrition at CUMC.

Funding for the study was provided by the National Heart, Lung, and Blood Institute (grants R01 HL040404, and P01GM095467) and the National Institute of Neurological Disorders and Stroke (RO1 NS 088197).

The authors declare no conflicts of interest.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

The Institute of Human Nutrition (IHN) provides outstanding academic, professional education and training programs in human nutrition, and conducts basic science and translational research on the role of nutrition in human health. IHN programs include projects, symposia and other initiatives for health practitioners, scientists, policy makers, educators, and individuals that advance understanding of the importance of nutrition for individuals and populations worldwide.

Public Release: 22-Aug-2016

Study validates new tool for diagnosing dehydration in children

Brown University

PROVIDENCE, R.I. [Brown University] –To properly treat young children with severe diarrhea, caregivers in clinics long on patients and short on resources need a quick and accurate way to assess the severity of dehydration. After a study testing it with nearly 500 children in Bangladesh, the four-symptom “DHAKA” score is now the most tested method.

“The DHAKA score now has better evidence for its performance in assessing dehydration in a specifically low-income country setting than any other scale,” said Dr. Adam Levine, associate professor of emergency medicine in the Warren Alpert Medical School of Brown University and lead author of the study in The Lancet Global Health. “Looking at it from an evidence-based medicine point of view, it is better than anything else out there.”

In a side-by-side comparison, the study showed that DHAKA, which stands for Dehydration: Assess Kids Accurately, was a significantly better predictor of dehydration severity in children under age five than the current standard, the World Health Organization’s Integrated Management of Childhood Illness (IMCI) guidelines.

Continuous improvement of diagnostic methods is vital, explained Levine, who is also a physician in the Lifespan health system, because in hospitals and clinics where intravenous fluids and beds are in limited supply, it’s imperative that those treatment resources be provided only to severely dehydrated children. Children with moderate dehydration can be rehydrated orally. Moreover, mistaken overtreatment with IV fluids of only somewhat or non-dehydrated children can result in seizures or difficulty breathing.

A validated score

Levine and colleagues including a team at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, derived the DHAKA score in 2014 by analyzing the cases of 770 children with diarrhea due to cholera and other serious intestinal infections. The researchers statistically determined which clinical signs at intake best predicted dehydration severity. They found four such symptoms that a nurse or doctor could observe within two minutes to make an accurate diagnosis:

·         General appearance: Is the child restless or irritable, or lethargic or unconscious?

·         Breathing: Is it normal or deep?

·         Skin pinch: After a pinch, does skin snap right back or respond slowly, or very slowly?

·         Tears: Does the child produce a normal volume, less than normal or none at all?

When applied retrospectively to the patients, the DHAKA score showed significant accuracy, sensitivity and specificity in identifying which child had no dehydration, moderate dehydration or severe dehydration. The definitive measure is made by comparing a child’s weight at intake and after full rehydration.

In the new study, Levine and his team returned to Dhaka in 2015 to validate the score by testing its predictive value with an entirely new population of 496 patients. This was a crucial step to determine whether the method would work for any group of patients, not just the ones from whom it was derived. Nurses employed both the DHAKA score and IMCI algorithm when new patients arrived.

DHAKA performed well. Each additional point on the 0 to 12 scale predicted a 0.6 percent increase in dehydration and a 1.4-fold increase in the odds of some or severe dehydration. On a statistical measure of accuracy where 0.5 is no better than chance and 1 is perfect, DHAKA rated 0.82 while IMCI rated 0.76.

“Not only is this the first score to be derived and validated in a low-income country setting, but the DHAKA study is also the largest study ever of dehydration assessment of kids anywhere,” Levine said. “If you take the derivation and validation studies together with more than 1,200 children, that’s more than all of the children who have been involved in every other study of every other dehydration scale ever assessed in the developing or the developed world.”

Levine plans one more set of tests that he expects will be necessary before DHAKA can earn the WHO’s endorsement as a new diagnostic standard for use in clinics in resource-limited settings. Next spring, as cholera makes its grim annual return to Bangladesh, he plans to test it in rural clinics where the question will be whether DHAKA is easy enough to use accurately when there isn’t the same degree of training and experience as at the center in Dhaka.

Public Release: 23-Aug-2016

Essential oils could counter lung and liver ailments caused by air pollution

Extracts from plants such as cloves, aniseed, fennel and ylang-ylang studied


Certain ingredients in essential oils made from plants such as cloves, anise, fennel and ylang-ylang could serve as a natural treatment of lung and liver conditions caused by air pollution. This is according to Miriana Kfoury of the Unité de Chimie Environnementale et Interactions sur le Vivant, Université du Littoral Côte d’Opale in France and the Lebanese University in Lebanon. She is the lead author of a study in Springer’s journal Environmental Chemistry Letters. It is the first of its kind to evaluate the value of using certain essential oil compounds to treat inflammation caused by the fine particles that are typical of hazy, polluted air, and that are known to be carcinogenic.

Plants naturally contain various essential oils that are made up of different compounds. Some of these have been found to have antioxidant value, and to also be able to fight inflammation. A group of organic compounds called phenylpropanoids are found in the essential oils of some plants, and show promise as possible anti-inflammatory substances. Among these are trans-anethole (a flavor component of anise and fennel), estragole (found in basil), eugenol (which occurs in clove bud oil) and isoeugenol (contained in ylang ylang).

Kfoury and her collaborators first collected air pollutant samples containing fine particles in Beirut, Lebanon. In laboratory tests, the samples were then introduced to human cell cultures of normal bronchial epithelial cells (BEAS-2B) and cancer derived hepatic cells (HepG2). The fine particle matter was found to induce inflammation in the cells – these started to secrete the pro-inflammatory cytokines IL-6 and IL-8 (substances that are secreted during infections and tissue damage). Cytokin levels normally increase when the body’s immune system is fighting a specific infection.

Next, the researchers established that the trans-anethole, estragole, eugenol and isoeugenol all have so-called cytotoxicity, which means that they could cause cell death at relatively high concentrations. In this evaluation, they were able to determine the level of cytotoxicity of these oil compounds. This was important in order to establish the maximum dose to be selected in the next step, namely the assessment for anti-inflammatory properties. In the second round of tests, the four compounds were introduced to the combination of cell lines and air pollutants to see whether these could protect liver and lung cells damaged by fine particle air pollutants. It was found that the essential oil compounds tested decrease the levels of the two types of cytokines in the samples. The levels of cytokine IL-6 decreased up to 96 percent, and the levels of cytokine IL-8 by 87 percent.

“The findings provide the first evidence that natural essential oil components counteract the inflammatory effects of particulate matter, such as that contained in polluted air,” says Kfoury.

Public Release: 23-Aug-2016

Drinking green tea to prevent artery explosion

Kyoto University shows polyphenol intake reduces abdominal aneurysm expansion in rats

Kyoto University

Kyoto, Japan — Japan’s favorite beverage might be offering more than just a relaxing tea break.

According to new research, green tea could prevent a deadly condition in the body’s main artery. A Kyoto University team has found that abdominal aortic aneurysm — a condition in which the main artery becomes overstretched and bloated — developed less frequently in rats that drank green tea polyphenol, a major component of green tea.

Without treatment, abdominal aortic aneurysms eventually rupture and lead to death 50% of the time.

“Abdominal aortic aneurysms often go unnoticed because there are no symptoms until they burst,” says Kenji Minakata, an author of the study. “If a patient is lucky and bloating is found before rupture, it needs to be treated surgically, such as by transplanting an artificial blood vessel or inserting a stent graft. At the moment there are no pharmacological treatments.”

Recent research has pointed to a host of health benefits from drinking green tea, including the prevention of cancer, cardiovascular disease, inflammation, and oxidation.

“The type of polyphenol found in green tea has recently been shown to regenerate elastin, an essential protein that gives the artery its stretchy, yet study, texture,” explains lead author Shuji Setozaki. “Considering that abdominal arterial aneurysms are caused by inflammation and the degradation of elastin components in the arterial wall, we thought drinking green tea may show promise for treatment.”

In the study, the team treated rats with enzymes that induce abdominal aortic aneurysm, and found that the condition developed less in rats that drank green tea polyphenol. They also saw less inflammation and more elastin production, protecting the artery from rupture.

“Japanese people have the longest lifespan in the world, and studies show that 80% of the population drink green tea on a daily basis,” says co-author Hidetoshi Masumoto. “We believe daily intake of green tea should be considered as a new preventative strategy for abdominal aortic aneurysm; the focus of future studies will be to investigate optimal doses.”

Public Release: 24-Aug-2016

How do antidepressants trigger fear and anxiety?

UNC School of Medicine researchers map the anxiety circuit in the brain and use a compound to limit fearful behavior — an acute side effect of commonly prescribed SSRI antidepressants

University of North Carolina Health Care

CHAPEL HILL, NC – More than 100 million people worldwide take selective serotonin reuptake inhibitors (SSRIs), such as Prozac and Zoloft, to treat depression, anxiety and related conditions, but these drugs have a common and mysterious side effect: they can worsen anxiety in the first few weeks of use, which leads many patients to stop treatment. Scientists at the University of North Carolina (UNC) School of Medicine have mapped out a serotonin-driven anxiety circuit that may explain this side effect and lead to treatments to eliminate it.

“The hope is that we’ll be able to identify a drug that inhibits this circuit and that people could take for just the first few weeks of SSRI use to get over that hump,” said senior investigator Thomas L. Kash, PhD, the John Andrews Distinguished Professor of Alcohol Studies in the UNC School of Medicine’s department of pharmacology. “More generally, this finding gives us a deeper understanding of the brain networks that drive anxiety and fear behavior in mammals.”

The new study, published in Nature, counters the popular view of serotonin as a neurotransmitter that promotes only good feelings. SSRIs, which are taken by about one in 10 people in the United States and about one in four women in their 40s and 50s, are thought to improve mood by boosting serotonin activity in the brain. There are brain circuits through which serotonin does seem to improve mood, and some studies have linked depression to abnormally low levels of serotonin. But the short-lived promotion of anxiety in many patients on SSRIs – even suicidal thinking, particularly in younger people – has long hinted that serotonin can have negative effects on mood, depending on the precise brain circuit where it acts.

In the Nature study, for which co-authors were UNC postdoctoral researcher Catherine A. Marcinkiewcz, PhD, and UNC graduate student Christopher M. Mazzone, the researchers used an array of sophisticated methods, including advanced optogenetic and chemogenetic tools, to trace a serotonin-activated pathway in the brains of mice, a pathway that drives anxious behavior.

The team first demonstrated that a mild shock to the paws of mice – a standard method for evoking fear and anxiety behaviors – activates serotonin-producing neurons in the dorsal raphe nucleus (DRN), a brainstem region known to be involved in mood and depression. These DRN serotonin neurons project to a brain region that is called the bed nucleus of the stria terminalis (BNST) and has been shown in previous studies to have a role in serotonin’s negative mood effects in rodents. Artificially increasing the activity of the DRN-to-BNST neurons enhanced anxiety-like behaviors in the mice.

UNC scientists found that the serotonin output from the DRN neurons activates their target neurons in the BNST through a specific subset of serotonin receptors, known as 2C receptors. These serotonin-activated BNST neurons then tamp down the activity of another family of BNST neurons, which, in turn, project to the ventral tegmental area (VTA) and lateral hypothalamus (LH) – key nodes in the brain’s reward, motivation and alertness networks.

The pathways from BNST to VTA and LH have been reported in previous studies to improve mood and relieve anxiety. Researchers confirmed that artificially driving the activity of these pathways has the effect of reducing foot-shock-induced fear and anxiety behaviors in the mice. By contrast, the silencing of these pathways by serotonin-activated BNST neurons effectively allows the anxiety level to rise.

Examining the impact of SSRIs, the scientists exposed 2C-receptor BNST neurons to fluoxetine (Prozac), which like other SSRIs gives a boost to serotonin levels wherever the neurotransmitter is at work. This turned out to increase the 2C-receptor neurons’ inhibitory effect on the neighboring VTA- and LH-projecting neurons, worsening fear and anxiety behavior in mice.

How can this effect be blocked? Kash and his team observed that the anxiety-mediating BNST neurons expressed the stress-signaling molecule corticotropin releasing factor (CRF). When they added a compound to block CRF activity, they witnessed that fearful behaviors – which had been triggered by fluoxetine – were greatly reduced.

One of the next steps is to confirm that this serotonin-sensitive DRN-to-BNST anxiety circuit exists in humans as well. “It’s logical that it would,” Kash said, “since we know SSRIs can induce anxiety in people, and the pathways in these brain regions tend to be very similar in mice and humans.”

Another next step will be to test drugs – ideally FDA-approved for various conditions – for their ability to alter this anxiety circuit and thereby block SSRIs’ anxiety-inducing effect. In principle, a CRF-blocker might work. For years, pharmaceutical companies have been trying to develop CRF blockers to treat depression, anxiety and addiction. In practice, Kash said, CRF blockers haven’t yet had success in clinical trials, so an FDA-approved one is probably still years away at least.

“Other researchers are working to develop better CRF-inhibiting compounds, so that’s one potential direction to take, but there are others,” Kash said. “We’re now looking at the various proteins expressed by these BNST neurons, and we’re hoping to identify a receptor that is already targeted by established drugs. One of them might be useful for people as they start taking SSRIs.”


Other authors of the study were Giuseppe D’Agostino, PhD, research fellow at the University of Aberdeen; Lindsay R. Halladay, PhD, research fellow at the National Institutes of Health; J. Andrew Hardaway, postdoctoral fellow in the Kash Lab; Jeffrey F. DiBerto, research technician in the Kash Lab; Todd E. Thiele, PhD, professor of psychology at UNC; Montserrat Navarro, PhD, associate research professor of psychology and neuroscience at UNC; Nathan Burnham, graduate student in the Thiele Lab; Lora K. Heisler, PhD, chair of human nutrition at the University of Aberdeen; Claudia Cristiano, PhD, research fellow in the Heisler Lab; Cayce E. Dorrier, undergraduate research assistant in the Kash Lab; Gregory J. Tipton, research specialist at the UNC Center for Alcohol Studies; Charu Ramakrishnan, lab manager for Deisseroth Lab; Tamas Kozicz, MD, PhD, associate professor of anatomy at Tulane University; Karl Deisseroth, MD, PhD, professor of bioengineering, and psychiatry and behavioral sciences at Stanford University; Zoe A. McElligott, PhD, assistant professor of psychiatry at UNC; and Andrew Holmes, PhD, senior investigator at the National Institute on Alcohol Abuse and Alcoholism.

Public Release: 24-Aug-2016

Fish oil pills reverse the effects of a fatty diet

Scientists have found that fish oil supplements can reverse the effects of a high fat diet according to a study published in the Journal of Physiology

The Physiological Society

Scientists have found that fish oil supplements can reverse the effects of a high fat diet according to a study published in the Journal of Physiology.

The research from the University of São Paulo shows that giving mice supplement of fish oil prevents or reverses the harmful effects of a high fat diet. This further demonstrates the beneficial properties of fish oil pills, suggesting that they could be effective in preventing obesity and type-2 diabetes in humans.

Fish oil pills are a popular dietary supplement as they have many perceived benefits. A high-fat diet can lead to insulin resistance, weight gain and increased cholesterol, which can lead to obesity and type-2 diabetes. This research reports, for the first time, that consumption of fish oil can prevent and counter the negative effects of a high-fat diet.

The researchers fed mice that had been administered fish oil a high-fat diet for 4 weeks. They then collected and analysed their body fat samples and compared them to mice on a high-fat diet that had not been consuming fish oil. Factors that affect metabolism, fat deposits and insulin resistance were measured.

Professor Maria Isabel Alonso-Vale, Assistant Professor in the Department of Biological Sciences at the Federal University of São Paulo and lead investigator of the study explained, ‘Our research suggests that fish oil supplements may be used in addition to other strategies as a preventative measure for insulin resistance and obesity.’

She added, ‘However, it is important to note that this research has been performed in mice which may not translate to humans. More research will need to be done so we can have a better understanding of the effect of fish oil in humans.’