Health Research Report

162nd Issue Date 23 AUG 2013

Compiled By Ralph Turchiano

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In This Issue:

1.   Sugar is toxic to mice in ‘safe’ doses

2.   DHA-enriched formula in infancy linked to positive cognitive outcomes in childhood

3.   Meal Timing Can Significantly Improve Fertility in Women with Polycystic Ovaries

4.   6 months of fish oil reverses liver disease in children with intestinal failure, study shows

5.   Watermelon juice relieves post-exercise muscle soreness

6.   Celery, artichokes contain flavonoids that kill human pancreatic cancer cells

7.   Hitting the gym may help men avoid diet-induced erectile dysfunction

Sugar is toxic to mice in ‘safe’ doses

New test hints 3 sodas daily hurt lifespan, reproduction

SALT LAKE CITY, Aug. 13, 2013 – When mice ate a diet of 25 percent extra sugar – the mouse equivalent of a healthy human diet plus three cans of soda daily – females died at twice the normal rate and males were a quarter less likely to hold territory and reproduce, according to a toxicity test developed at the University of Utah.

“Our results provide evidence that added sugar consumed at concentrations currently considered safe exerts dramatic adverse impacts on mammalian health,” the researchers say in a study set for online publication Tuesday, Aug. 13 in the journal Nature Communications.

“This demonstrates the adverse effects of added sugars at human-relevant levels,” says University of Utah biology professor Wayne Potts, the study’s senior author. He says previous studies using other tests fed mice large doses of sugar disproportionate to the amount people consume in sweetened beverages, baked goods and candy.

“I have reduced refined sugar intake and encouraged my family to do the same,” he adds, noting that the new test showed that the 25 percent “added-sugar” diet – 12.5 percent dextrose (the industrial name for glucose) and 12.5 percent fructose – was just as harmful to the health of mice as being the inbred offspring of first cousins.

Even though the mice didn’t become obese and showed few metabolic symptoms, the sensitive test showed “they died more often and tended to have fewer babies,” says the study’s first author, James Ruff, who recently earned his Ph.D. at the University of Utah. “We have shown that levels of sugar that people typically consume – and that are considered safe by regulatory agencies – impair the health of mice.”

The new toxicity test placed groups of mice in room-sized pens nicknamed “mouse barns” with multiple nest boxes – a much more realistic environment than small cages, allowing the mice to compete more naturally for mates and desirable territories, and thereby revealing subtle toxic effects on their performance, Potts says.

“This is a sensitive test for health and vigor declines,” he says, noting that in a previous study, he used the same test to show how inbreeding hurt the health of mice.

“One advantage of this assay is we get the same readout no matter if we are testing inbreeding or added sugar,” Potts says. “The mice tell us the level of health degradation is almost identical” from added-sugar and from cousin-level inbreeding.

The study says the need for a sensitive toxicity test exists not only for components of our diet, but “is particularly strong for both pharmaceutical science, where 73 percent of drugs that pass preclinical trials fail due to safety concerns, and for toxicology, where shockingly few compounds receive critical or long-term toxicity testing.”

The study was funded by the National Institutes of Health and the National Science Foundation.

A Mouse Diet Equal to What a Quarter of Americans Eat

The experimental diet in the study provided 25 percent of calories from added sugar – half fructose and half glucose – no matter how many calories the mice ate. Both high-fructose corn syrup and table sugar (sucrose) are half fructose and half glucose.

Potts says the National Research Council recommends that for people, no more than 25 percent of calories should be from “added sugar,” which means “they don’t count what’s naturally in an apple, banana, potato or other nonprocessed food. … The dose we selected is consumed by 13 percent to 25 percent of Americans.”

The diet fed to the mice with the 25 percent sugar-added diet is equivalent to the diet of a person who drinks three cans daily of sweetened soda pop “plus a perfectly healthy, no-sugar-added diet,” Potts says.

Ruff notes that sugar consumption in the American diet has increased 50 percent since the 1970s, accompanied by a dramatic increase in metabolic diseases such as diabetes, obesity, fatty liver and cardiovascular disease.

The researchers used a mouse supply company that makes specialized diets for research. Chow for the mice was a highly nutritious wheat-corn-soybean mix with vitamins and minerals. For experimental mice, glucose and fructose amounting to 25 percent of calories was included in the chow. For control mice, corn starch was used as a carbohydrate in place of the added sugars.

House Mice Behaving Naturally

Mice often live in homes with people, so “mice happen to be an excellent mammal to model human dietary issues because they’ve been living on the same diet as we have ever since the agricultural revolution 10,000 years ago,” Potts says.

Mice typically used in labs come from strains bred in captivity for decades. They lack the territoriality shown by wild mice. So the study used mice descended from wild house mice that were “outbred” to prevent inbreeding typical of lab mice.

“They are highly competitive over food, nesting sites and territories,” he says. “This competition demands high performance from their bodies, so if there is a defect in any physiological systems, they tend to do more poorly during high competition.”

So Potts’ new test – named the Organismal Performance Assay, or OPA – uses mice “in a more natural ecological context” more likely to reveal toxic effects of whatever is being tested, he says.

“When you look at a mouse in a cage, it’s like trying to evaluate the performance of a car by turning it on in a garage,” Ruff says. “If it doesn’t turn on, you’ve got a problem. But just because it does turn on, doesn’t mean you don’t have a problem. To really test it, you take it out on the road.”

A big room was divided into 11 “mouse barns” used for the new test. Six were used in the study. Each “barn” was a 377-square-foot enclosure ringed by 3-foot walls.

Each mouse barn was divided by wire mesh fencing into six sections or “territories,” but the mice could climb easily over the mesh. Within each of the six sections was a nest box, a feeding station and drinking water.

Four of the six sections in each barn were “optimal,” more desirable territories because the nest boxes were opaque plastic storage bins, which mice entered via 2-inch holes at the bottom. Each bin had four nesting cages in it, and an enclosed feeder.

The two other sections were “suboptimal” territories with open planter trays instead of enclosed bins. Female mice had to nest communally in the trays.

Running the Experiment

The mice in the experiment began with 156 “founders” that were bred in Potts’ colony, weaned at four weeks, and then assigned either to the added-sugar diet or the control diet, with half the males and half the females on each diet.

The mice stayed in cages with siblings of the same sex (to prevent reproduction) for 26 weeks while they were fed these diets. Then the mice were placed in the mouse barns to live, compete with each other and breed for 32 more weeks. They all received the same added-sugar diet while in the mouse barns, so the study only tested for differences caused by the mice eating different diets for the previous 26 weeks.

The founder mice had implanted microchips, like those put in pets. Microchip readers were placed near the feeding stations to record which mice fed where and for how long. A male was considered dominant if he made more than 75 percent of the visits by males to a given feeding station. In reality, the dominant males made almost 100 percent of male visits to the feeder in the desirable territory they dominated.

With the 156 founder mice (58 male, 98 female), the researchers ran the experiment six times, with an average of 26 mice per experiment: eight to 10 males (competing for six territories, four desirable and two suboptimal) and 14 to 18 females.

The Findings: Added Sugar Impairs Mouse Lifespan and Reproduction

• After 32 weeks in mouse barns, 35 percent of the females fed extra sugar died, twice the 17 percent death rate for female control mice. There was no difference in the 55 percent death among males who did and did not get added sugar. Ruff says males have much higher death rates than females in natural settings because they compete for territory, “but there’s no relation to sugar.”
• Males on the added-sugar diet acquired and held 26 percent fewer territories than males on the control diet: control males occupied 47 percent of the territories while sugar-added mice controlled less than 36 percent. Male mice shared the remaining 17 percent of territories.
• Males on the added-sugar diet produced 25 percent fewer offspring than control males, as determined by genetic analysis of the offspring. The sugar-added females had higher reproduction rates than controls initially – likely because the sugar gave them extra energy to handle the burden of pregnancy – but then had lower reproductive rates as the study progressed, partly because they had higher death rates linked to sugar.

The researchers studied another group of mice for metabolic changes. The only differences were minor: cholesterol was elevated in sugar-fed mice, and the ability to clear glucose from the blood was impaired in female sugar-fed mice. The study found no difference between mice on a regular diet and mice with the 25 percent sugar-added diet when it came to obesity, fasting insulin levels, fasting glucose or fasting triglycerides.

“Our test shows an adverse outcome from the added-sugar diet that couldn’t be detected by conventional tests,” Potts says.

Human-made toxic substances in the environment potentially affect all of us, and more are continually discovered, Potts says.

“You have to ask why we didn’t discover them 20 years ago,” he adds. “The answer is that until now, we haven’t had a functional, broad and sensitive test to screen the potential toxic substances that are being released into the environment or in our drugs or our food supply.”

DHA-enriched formula in infancy linked to positive cognitive outcomes in childhood

LAWRENCE – University of Kansas scientists have found that infants who were fed formula enriched with long-chain polyunsaturated fatty acids (LCPUFA) from birth to 12 months scored significantly better than a control group on several measures of intelligence conducted between the ages of three to six years.

Specifically, the children showed accelerated development on detailed tasks involving pattern discrimination, rule-learning and inhibition between the ages of three to five years of age as well as better performance on two widely-used standardized tests of intelligence: the Peabody Picture Vocabulary Test at age five and the Weschler Primary Preschool Scales of Intelligence at age six.

“These results support the contention that studies of nutrition and cognition should include more comprehensive and sensitive assessments that are administered multiple times through early childhood,” said John Colombo, study director and KU professor of psychology.

The results of LCPUFA supplementation studies have been mixed according to Colombo, a neuroscientist who specializes in the measurement of early neurocognitive development, but many of those studies have relied mainly on children’s performance on the Bayley Scales of Infant Development at 18 months.

In the randomized, double-blind study, 81 infants were fed one of four formulas from birth to 12 months; three with varying levels of two LCPUFAs (DHA and ARA) and one formula with no LCPUFA. Beginning at 18 months, the children were tested every six months until six years of age on age-appropriate standardized and specific cognitive tests.

At 18 months the children did not perform any better on standardized tests of performance and intelligence, but by age three study directors Colombo and Susan E. Carlson, A. J. Rice Professor of Dietetics and Nutrition at KUMC, began to see significant differences in the performance of children who were fed the enriched formulas on finer-grained, laboratory-based measures of several aspects of cognitive function.

DHA or docosahexaenoic acid is an essential long-chain fatty acid that affects brain and eye development, and babies derive it from their mothers before birth and up to age two. But the American diet is often deficient in DHA sources such as fish.

ARA or arachidonic acid is another LCPUFA that is present in breast milk and commercial formula.

The study was designed to examine the effects of postnatal DHA at levels that have been found to vary across the world, said study co-director Carlson.

The results on the children’s development from the first 12 months of this study were published in Pediatric Research in 2011, and showed improved attention and lower heart rate in infants supplemented with any level of LCPUFA. Colombo and Carlson’s earlier work and collaborations influenced infant formula manufacturers to begin adding DHA in 2001.

The study was published ahead of print in the June 2013 issue of the American Journal of Clinical Nutrition.

Meal Timing Can Significantly Improve Fertility in Women with Polycystic OvariesTuesday,

August 13, 2013

Managing insulin levels through meal timing boosts ovulation and decreases testosterone, says TAU researcher

Polycystic Ovarian Syndrome (PCOS), a common disorder that impairs fertility by impacting menstruation, ovulation, hormones, and more, is closely related to insulin levels. Women with the disorder are typically “insulin resistant” — their bodies produce an overabundance of insulin to deliver glucose from the blood into the muscles. The excess makes its way to the ovaries, where it stimulates the production of testosterone, thereby impairing fertility.

Now Prof. Daniela Jakubowicz of Tel Aviv University‘s Sackler Faculty of Medicine and the Diabetes Unit at Wolfson Medical Center has found a natural way to help women of normal weight who suffer from PCOS manage their glucose and insulin levels to improve overall fertility. And she says it’s all in the timing.

The goal of her maintenance meal plan, based on the body’s 24 hour metabolic cycle, is not weight loss but insulin management. Women with PCOS who increased their calorie intake at breakfast, including high protein and carbohydrate content, and reduced their calorie intake through the rest of the day, saw a reduction in insulin resistance. This led to lower levels of testosterone and dramatic increase in the ovulation frequency — measures that have a direct impact on fertility, notes Prof. Jakubowicz.

The research has been published in Clinical Science and was recently presented at the Endocrine Society’s annual meeting in June. It was conducted in collaboration with Dr. Julio Wainstein of TAU and Wolfson Medical Center and Dr. Maayan Barnea and Prof. Oren Froy of the Hebrew University of Jerusalem.

Managing insulin to increase ovulation

Many of the treatment options for PCOS are exclusively for obese women, Prof. Jakubowicz explains. Doctors often suggest weight loss to manage insulin levels, or prescribe medications that are used to improve the insulin levels of overweight patients. But many women who suffer from PCOS maintain a normal weight — and they are looking for ways to improve their chances of conceiving and giving birth to a healthy baby.

In a recent study, Prof. Jakubowicz and her fellow researchers confirmed that a low-calorie weight-loss plan focusing on larger breakfasts and smaller dinners also lowers insulin, glucose, and triglycerides levels. This finding inspired them to test whether a similar meal plan could be an effective therapeutic option for women with PCOS.

Sixty women suffering from PCOS with a normal body mass index (BMI) were randomly assigned to one of two 1,800 calorie maintenance diets with identical foods. The first group ate a 983 calorie breakfast, a 645 calorie lunch, and a 190 calorie dinner. The second group had a 190 calorie breakfast, a 645 calorie lunch, and 983 calorie dinner. After 90 days, the researchers tested participants in each group for insulin, glucose, and testosterone levels as well as ovulation and menstruation.

As expected, neither group experienced a change in BMI, but other measures differed dramatically. While participants in the “big dinner” group maintained consistently high levels of insulin and testosterone throughout the study, those in the “big breakfast” group experienced a 56 percent decrease in insulin resistance and a 50 percent decrease in testosterone. This reduction of insulin and testosterone levels led to a 50 percent rise in ovulation rate, indicated by a rise in progesterone, by the end of the study.

A natural therapy

According to Prof. Jakubowicz, these results suggest that meal timing — specifically a meal plan that calls for the majority of daily calories to be consumed at breakfast and a reduction of calories throughout the day — could help women with PCOS manage their condition naturally, providing new hope for those who have found no solutions to their fertility issues, she says. PCOS not only inhibits natural fertilization, but impacts the effectiveness of in vitro fertilization treatments and increases the rate of miscarriage.

And beyond matters of fertility, this method could mitigate other symptoms associated with the disorder, including unwanted body hair, oily hair, hair loss, and acne. Moreover, it could protect against developing type-2 diabetes.

6 months of fish oil reverses liver disease in children with intestinal failure, study shows

Children who suffer from intestinal failure, most often caused by a shortened or dysfunctional bowel, are unable to consume food orally. Instead, a nutritional cocktail of sugar, protein and fat made from soybean oil is injected through a small tube in their vein.

For these children, the intravenous nutrition serves as a bridge to bowel adaptation, a process by which the intestine recovers and improves its capacity to absorb nutrition. But the soybean oil, which provides essential fatty acids and calories, has been associated with a potentially lethal complication known as intestinal failure–associated liver disease, which may require a liver and/or intestinal transplant. Such a transplant can prevent death, but the five-year post-transplant survival rate is only 50 percent.

Previous studies have shown that replacing soybean oil with fish oil in intravenous nutrition can reverse intestinal failure–associated liver disease. However, the necessary duration of fish oil treatment had not been established in medical studies.

Now, a clinical trial conducted at the Children’s Discovery and Innovation Institute at Mattel Children’s Hospital UCLA has found that, compared with soybean oil, a limited duration (24 weeks) of fish oil is safe and effective in reversing liver disease in children with intestinal failure who require intravenous nutrition. The researchers believe that fish oil may also decrease the need for liver and/or intestinal transplants — and mortality — associated with this disease.

The researchers’ study, “Six Months of Intravenous Fish Oil Reverses Pediatric Intestinal Failure Associated Liver Disease,” is published online in the Journal of Parenteral and Enteral Nutrition.

“With this particular study, we set out to determine if a finite period of six months of intravenous fish oil could safely reverse liver damage in these children, and we have had some promising results,” said lead author Dr. Kara Calkins, an assistant professor in the department of pediatrics in the division of neonatology and developmental biology at UCLA. “But because intravenous fish oil is not yet approved by the Food and Drug Administration and is much more costly than soybean oil, it is typically not covered by insurance. As a result, this oil is considered experimental and is currently available only under special protocols. If it proves safe and effective for patients, we hope it would eventually be available for wider use.”

For the study, intravenous soybean oil was replaced with intravenous fish oil in 10 patients between the ages of 2 weeks and 18 years who had advanced intestinal failure–associated liver disease and who were at high risk for death and/or transplant. The researchers compared these subjects with 20 historical controls who had received soybean oil.

Results showed that the children receiving fish oil had a much higher rate of reversal of liver disease than those who received the standard soybean oil. In fact, after 17 weeks of fish oil, nearly 80 percent of patients experienced a reversal of their liver disease, while only 5 percent of the soybean patients saw a reversal.

The next phase of research will involve following children for up to five years after they stop fish oil to determine if their liver disease returns and if transplant rates are truly decreased, the study authors said.

“We are also trying to better understand how fish oil reverses this disease by investigating changes in proteins and genes in the blood and liver,” Calkins said. “These studies will provide the scientific and medical community with a better understanding of this disease and how intravenous fish oil works.”

For Isabella Piscione, who was one of the first patients at UCLA to receive the fish oil treatment under compassionate use, her outcome with the treatment paved the way for researchers to establish the six-month protocol. Because of multiple surgeries due to an obstruction in her intestines, Isabella was left with only 10 centimeters of intestine. She depended on intravenous nutrition for survival, which unfortunately resulted in liver damage.

When Isabella started the fish oil treatment, she was just over 6 months old and was listed for a liver and bowel transplant. Within a month of starting the treatment, her condition started to improve. By six months, her liver had healed, and she no longer needed a transplant.

“We cried tears of joy each week that we saw her getting better and better,” said her father, Laureano Piscione. “She is a success story.”

Watermelon juice relieves post-exercise muscle soreness

Watermelon juice’s reputation among athletes is getting scientific support in a new study, which found that juice from the summer favorite fruit can relieve post-exercise muscle soreness. The report in ACS’ Journal of Agricultural and Food Chemistry attributes watermelon’s effects to the amino acid L-citrulline.

Encarna Aguayo and colleagues cite past research on watermelon juice’s antioxidant properties and its potential to increase muscle protein and enhance athletic performance. But scientists had yet to explore the effectiveness of watermelon juice drinks enriched in L-citrulline. Aguayo’s team set out to fill that gap in knowledge.

They tested natural watermelon juice, watermelon juice enriched in L-citrulline and a control drink containing no L-citrulline on volunteers an hour before exercise. Both the natural juice and the enriched juice relieved muscle soreness in the volunteers. L-citrulline in the natural juice (unpasteurized), however, seemed to be more bioavailable — in a form the body could better use, the study found.

Celery, artichokes contain flavonoids that kill human pancreatic cancer cells

URBANA, Ill. – Celery, artichokes, and herbs, especially Mexican oregano, all contain apigenin and luteolin, flavonoids that kill human pancreatic cancer cells in the lab by inhibiting an important enzyme, according to two new University of Illinois studies.

“Apigenin alone induced cell death in two aggressive human pancreatic cancer cell lines. But we received the best results when we pre-treated cancer cells with apigenin for 24 hours, then applied the chemotherapeutic drug gemcitabine for 36 hours,” said Elvira de Mejia, a U of I professor of food chemistry and food toxicology.

The trick seemed to be using the flavonoids as a pre-treatment instead of applying them and the chemotherapeutic drug simultaneously, said Jodee Johnson, a doctoral student in de Mejia’s lab who has since graduated.

“Even though the topic is still controversial, our study indicated that taking antioxidant supplements on the same day as chemotherapeutic drugs may negate the effect of those drugs,” she said.

“That happens because flavonoids can act as antioxidants. One of the ways that chemotherapeutic drugs kill cells is based on their pro-oxidant activity, meaning that flavonoids and chemotherapeutic drugs may compete with each other when they’re introduced at the same time,” she explained.

Pancreatic cancer is a very aggressive cancer, and there are few early symptoms, meaning that the disease is often not found before it has spread. Ultimately the goal is to develop a cure, but prolonging the lives of patients would be a significant development, Johnson added.

It is the fourth leading cause of cancer-related deaths, with a five-year survival rate of only 6 percent, she said.

The scientists found that apigenin inhibited an enzyme called glycogen synthase kinase-3β (GSK-3β), which led to a decrease in the production of anti-apoptotic genes in the pancreatic cancer cells. Apoptosis means that the cancer cell self-destructs because its DNA has been damaged.

In one of the cancer cell lines, the percentage of cells undergoing apoptosis went from 8.4 percent in cells that had not been treated with the flavonoid to 43.8 percent in cells that had been treated with a 50-micromolar dose. In this case, no chemotherapy drug had been added.

Treatment with the flavonoid also modified gene expression. “Certain genes associated with pro-inflammatory cytokines were highly upregulated,” de Mejia said.

According to Johnson, the scientists’ in vitro study in Molecular Nutrition and Food Research is the first to show that apigenin treatment can lead to an increase in interleukin 17s in pancreatic cells, showing its potential relevance in anti-pancreatic cancer activity.

Pancreatic cancer patients would probably not be able to eat enough flavonoid-rich foods to raise blood plasma levels of the flavonoid to an effective level. But scientists could design drugs that would achieve those concentrations, de Mejia said.

And prevention of this frightening disease is another story. “If you eat a lot of fruits and vegetables throughout your life, you’ll have chronic exposure to these bioactive flavonoids, which would certainly help to reduce the risk of cancer,” she noted.

Hitting the gym may help men avoid diet-induced erectile dysfunction

Bethesda, Md. (Aug. 20, 2013)—Obesity continues to plague the U.S. and now extends to much of the rest of the world. One probable reason for this growing health problem is more people worldwide eating the so-called Western diet, which contains high levels of saturated fat, omega-6 polyunsaturated fatty acids (the type of fat found in vegetable oil), and added sugar. Researchers have long known that this pattern of consumption, as well as the weight gain it often causes, contributes to a wide range of other health problems including erectile dysfunction and heart disease. Other than changing eating patterns, researchers haven’t discovered an effective way to avoid these problems.

Searching for a solution, Christopher Wingard and his colleagues at East Carolina University used rats put on a “junk food” diet to test the effects of aerobic exercise. They found that exercise effectively improved both erectile dysfunction and the function of vessels that supply blood to the heart.

The article is entitled “Exercise Prevents Western-Diet Associated Erectile Dysfunction and Coronary Artery Endothelial Dysfunction: Response to Acute Apocynin and Sepiapterin Treatment.” It appears in the online edition of the American Journal of Physiology: Regulatory, Integrative, and Comparative Physiology, published by the American Physiological Society. The article is online at http://bit.ly/13jYpED.

Methodology

For 12 weeks, the researchers fed a group of rats chow that reflected the Western diet, high in sugar and with nearly half its calories from fat. Another group of rats ate a healthy standard rat chow instead. Half of the animals in each group exercised five days a week, running intervals on a treadmill.

At the end of the 12 weeks, anesthetized animals’ erectile function was assessed by electrically stimulating the cavernosal nerve, which causes an increase in penile blood flow and produces an erection. The researchers also examined the rats’ coronary arteries to see how they too responded to agents that would relax them and maintain blood flow to the heart, an indicator of heart health.

Results

The findings showed that rats who ate the Western diet but stayed sedentary developed erectile dysfunction and poorly relaxing coronary arteries. However, those who ate the diet but exercised were able to stave off these problems.

Animals who ate the healthy chow were largely able to avoid both erectile dysfunction and coronary artery dysfunction.

Importance of the Findings

These findings may suggest that exercise could be a potent tool for fighting the adverse effects of the Western diet as long as the subjects remained very active over the course of consuming this type of diet, the authors say. Whether exercise would still be effective in reversing any vascular problems after a lifetime of consuming a Western diet is still unknown.

“The finding that exercise prevents Western diet-associated erectile dysfunction and coronary artery disease progression translates to an intensively active lifestyle throughout the duration of the ‘junk food’ diet,” the authors say. “It remains to be seen if a moderately active lifestyle, or an active lifestyle initiated after a prolonged duration of a sedentary lifestyle combined with a ‘junk food’ diet is effective at reversing functional impairment.”

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