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07 FEB 2014 /  White paper draft

Compiled by Ralph Turchiano

 

•        Detailed research references and further affiliations on each article are posted at http://www.healthreserachreport.me .

In this issue:

1. Low Vitamin D Levels During Pregnancy May Increase Risk of Severe Preeclampsia
2. Certain probiotics could help women lose weight
3. Melatonin shows potential to slow tumor growth in certain breast cancers
4. Aspirin still overprescribed for stroke prevention in AF
5. New study suggests choline recommendations during pregnancy may be too low
6. Geranium extracts inhibit HIV-1
7. Blue light may fight fatigue around the clock
8. Are you Big Pharma’s new target market?
9. Simulated blindness can help revive hearing, researchers find
10. Toxin in seafood causes kidney damage in mice at levels considered safe for consumption
11. Huntington disease prevention trial shows creatine safe, suggests slowing of progression

Low Vitamin D Levels During Pregnancy May Increase Risk of Severe Preeclampsia

PITTSBURGH, Jan. 24, 2014 – Women who are deficient in vitamin D in the first 26 weeks of their pregnancy may be at risk of developing severe preeclampsia, a potentially life-threatening disorder diagnosed by an increase in blood pressure and protein in the urine, according to research by the University of Pittsburgh Graduate School of Public Health.

In one of the largest studies to date, researchers studied blood samples collected from 700 pregnant women who later developed preeclampsia in an effort to examine a woman’s vitamin D status during pregnancy and her risk of developing preeclampsia. The full study, funded by the National Institutes of Health (NIH), is available online in the journal Epidemiology, and will publish in the March print issue.

“For decades, vitamin D was known as a nutrient that was important only for bone health,” said lead author Lisa Bodnar, Ph.D., M.P.H., R.D., associate professor in Pitt Public Health’s Department of Epidemiology. “Over the past 10 to 15 years, scientists have learned that vitamin D has diverse functions in the body beyond maintaining the skeleton, including actions that may be important for maintaining a healthy pregnancy.”

Dr. Bodnar and her colleagues also studied blood samples from 3,000 mothers who did not develop preeclampsia. The samples were collected between 1959 and 1965 at 12 U.S. sites enrolled in the Collaborative Perinatal Project. The blood was well-preserved, and researchers were able to test for vitamin D levels decades later.

Scientists controlled for factors that could have affected a woman’s vitamin D status, including race, pre-pregnancy body mass index, number of previous pregnancies, smoking, diet, physical activity and sunlight exposure, which is the body’s primary source of vitamin D.

The researchers found that vitamin D sufficiency was associated with a 40 percent reduction in risk of severe preeclampsia. But there was no relationship between vitamin D and mild preeclampsia. The overall risk of severe preeclampsia in the women sampled was 0.6 percent, regardless of vitamin D status.

“Scientists believe that severe preeclampsia and mild preeclampsia have different root causes,” said senior author Mark A. Klebanoff, M.D., M.P.H., Center for Perinatal Research at The Research Institute at Nationwide Children’s Hospital and the Department of Pediatrics at The Ohio State University College of Medicine. “Severe preeclampsia poses much higher health risks to the mother and child, so linking it with a factor that we can easily treat, like vitamin D deficiency, holds great potential.”

“If our results hold true in a modern sample of pregnant women, then further exploring the role of vitamin D in reducing the risk of preeclampsia would be warranted,” said Dr. Bodnar. “Until then, women shouldn’t automatically take vitamin D supplements during pregnancy as a result of these findings.”

Additional co-authors include: Hyagriv N. Simhan, M.D., Janet M. Catov, Ph.D., James M. Roberts, M.D., and Jill C. Diesel, M.P.H., all of the University of Pittsburgh; and Robert W. Platt, Ph.D., of McGill University.

This research was supported by NIH grant HD 056999.

Certain probiotics could help women lose weight

Quebec City, January 28, 2014—Certain probiotics could help women lose weight and keep it off, according to a recent study published in the British Journal of Nutrition by a team of researchers headed by Université Laval Professor Angelo Tremblay.

Studies have already demonstrated that the intestinal flora of obese individuals differs from that of thin people. That difference may be due to the fact that a diet high in fat and low in fiber promotes certain bacteria at the expense of others. Professor Tremblay and his team tried to determine if the consumption of probiotics could help reset the balance of the intestinal microbiota in favor of bacteria that promote a healthy weight.

To test their hypothesis, researchers recruited 125 overweight men and women. The subjects underwent a 12-week weight-loss diet, followed by a 12-week period aimed at maintaining body weight. Throughout the entire study, half the participants swallowed 2 pills daily containing probiotics from the Lactobacillus rhamnosus family, while the other half received a placebo.

After the 12-week diet period, researchers observed an average weight loss of 4.4 kg in women in the probiotic group and 2.6 kg in the placebo group. However, no differences in weight loss were observed among males in the two groups. “We don’t know why the probiotics didn’t have any effect on men. It may be a question of dosage, or the study period may have been too short,” says Professor Tremblay, who is also the Canada Research Chair in Environment and Energy Balance.

After the 12-week maintenance period, the weight of the women in the placebo group had remained stable but the probiotic group had continued to lose weight, for a total of 5.2 kg per person. In short, women consuming probiotics lost twice as much weight over the 24-week period of the study. Researchers also noted a drop in the appetite-regulating hormone leptin in this group, as well as a lower overall concentration of the intestinal bacteria related to obesity.

According to Angelo Tremblay, probiotics may act by altering the permeability of the intestinal wall. By keeping certain proinflammatory molecules from entering the bloodstream, they might help preventing the chain reaction that leads to glucose intolerance, type 2 diabetes, and obesity.

This study focused on only one strain of Lactobacillus rhamnosus, but Professor Tremblay believes that other probiotics found in dairy products could have a similar effect. He stresses, however, that the benefits of these bacteria are more likely to be observed in a favorable nutritional context that promotes low fat and adequate fiber intake.

Melatonin shows potential to slow tumor growth in certain breast cancers

DETROIT – An early stage study shows melatonin – a hormone that regulates the body’s sleep and awake cycles – may have the potential to help slow the growth of certain breast cancer tumors, according to researchers from Henry Ford Hospital in Detroit and Foundation for Research Support of the State of São Paulo.

The study, published online in the journal PLoS One, finds that melatonin may inhibit tumor growth and cell production, as well as block the formation of new blood vessels in ER-negative breast cancer models.

“These early stage research results with the melatonin drug in a triple-negative breast cancer animal models achieved in our lab has not been seen anywhere else,” says study co-author Adarsh Shankar, a research assistant in the Department of Radiology at Henry Ford Hospital.

“The key finding of the study is that we now know that we can trace this drug and its effect on tumor growth, which opens the door for more research on this topic.”

Melatonin is a hormone naturally produced by the brain’s pineal gland in response to darkness, and it is also available as a man-made supplement.

Because of melatonin’s suspected antioxidant properties, some believe it may suppress the growth of some types of cancer cells, especially when combined with certain anti-cancer drugs, according to the American Cancer Society.

A promising tactic in limiting cancer progression is controlling angiogenesis, the formation of new blood vessels. Once a tumor exceeds a few millimeters in diameter, hypoxia (lack of oxygen) triggers a cascade of events to allow angiogenesis and tumor progression.

To determine the therapeutic effectiveness of melatonin on tumor growth, the Henry Ford Hospital and Foundation for Research Support of the State of São Paulo researchers evaluated the action of melatonin on angiogenesis in ER-negative breast cancer in vitro and in vivo using cell and mouse models respectively.

The mice were randomly assigned to either the melatonin or control groups. The melatonin group received treatment each night for 21 days; melatonin was administered at pharmacologic concentration one hour before room lighting was switched off. Melatonin administered prior to the nocturnal is believed to be more effective because tissues are most sensitive to the hormone at this time.

At the end of the 21-day treatment, researchers used single photon emission computed tomography (SPECT) to determine whether melatonin therapy effectively decreased the size of implanted human triple negative breast cancer in the mouse models and if there was be any changes in the formation of new blood vessels.

Additionally, tumor volume was measured each week and tumor tissue was analyzed at the end of treatment.

The study found that none of the treated mice showed any loss of weight and lethargy during the 21-day treatment; instead, most showed excessive movement but no irritability or aggressive behavior.

Those treated showed significantly smaller tumors after 21 days while the mean tumor volume increased significantly in the control group. And, there was less vascular growth in the tumors of the treated group.

Results were also replicated in cell models.

The study showed that melatonin administered at pharmacologic concentration was able to reduce ER-negative breast cancer cell viability in vitro.

These results suggest that melatonin has the potential as a therapeutic agent for breast cancer.

The study’s authors caution, however, that this research is still in its very early stages and results are not yet ready to be translated for patient use.

More basic research is needed on this topic – particularly on how melatonin acts on angiogenesis in various cancers – before clinical trials with humans can be planned.

Aspirin still overprescribed for stroke prevention in AF

Aspirin is still overprescribed for stroke prevention in atrial fibrillation despite the potential for dangerous side effects, according to research published today

Sophia Antipolis, 28 January 2014: Aspirin is still overprescribed for stroke prevention in atrial fibrillation (AF) despite the potential for dangerous side effects, according to research published today.

Professor Gregory Y.H. Lip, lead author of the European Society of Cardiology (ESC) study, said: “The perception that aspirin is a safe and effective drug for preventing strokes in AF needs to be dispelled. If anything, you could say that giving aspirin to patients with AF is harmful because it is minimally or not effective at stroke prevention, yet the risk of major bleeding or intracranial haemorrhage is not significantly different to well-managed oral anticoagulation.”

He added: “All the contemporary guidelines1 say that aspirin should not be used for the prevention of stroke in patients with AF. And yet our study shows that aspirin is still overprescribed in these patients.”

Stroke prevention is central to the management of patients with AF. As the most common cardiac rhythm disorder, AF occurs in 1.5-2% of the general population in the developed world and people over the age of 40 have a 1 in 4 lifetime risk of developing AF.2 Patients with AF have a five-fold risk of stroke, and when they do have strokes they lead to more death and disability.3

Prevention of strokes in patients with AF is based on identification of risk factors.2 Patients with no stroke risk factors (ie. CHA2DS2-VASc score of 0 in males or 1 in females) are considered ‘low risk’ and do not need any antithrombotic drugs. Patients with one or more risk factors should be offered effective stroke prevention, and thus be given an oral anticoagulant (warfarin or one of the novel oral anticoagulants). The use of aspirin, either alone or in combination with an oral anticoagulant, is not recommended.

The study published online today in the American Journal of Medicine provides the most up-to-date picture of European cardiologists’ prescribing of antithrombotic treatment, which includes oral anticoagulation therapy (warfarin and the novel oral anticoagulants) and antiplatelet drugs (mainly aspirin).4 The data are from the EORP Atrial Fibrillation General Pilot Registry of more than 3 100 patients in nine countries.5

Overall the study found that the use of oral anticoagulants has improved over the last decade since the last Euro Heart Survey was performed. Where oral anticoagulation was used, most patients (72%) were prescribed warfarin and just 8% were prescribed a new oral anticoagulant.

Professor Lip said: “Novel oral anticoagulant uptake is still a bit low, probably because of differences in regulatory approval, costs and access to drugs in different countries. But the main point is that overall oral anticoagulant uptake as a whole has improved in the last 10 years.”

Aspirin was commonly prescribed, either alone or in combination with an oral anticoagulant, when patients had myocardial infarction or coronary artery disease. The strongest reason to prescribe both drugs was coronary artery disease, which increased the use of combined therapy by more than eight-fold.

Professor Lip said: “Aspirin is still overused for stroke prevention in AF. ESC guidelines say concomitant aspirin should not be given to anticoagulated AF patients with stable vascular disease. The combination of drugs does not reduce cardiovascular events and stroke but does increase the risk of bleeding.”

Another worrying finding was that oral anticoagulants were underprescribed in elderly patients, with aspirin alone more commonly prescribed. Professor Lip said: “Elderly patients are at the highest risk for stroke and yet they are given aspirin which is not recommended and potentially harmful. There is a perception that elderly patients do not do well on anticoagulation. But a number of studies now, including BAFTA,6 have shown that in elderly patients warfarin is far superior to aspirin in preventing stroke.”

Patients with paroxysmal AF were less likely to receive oral anticoagulation compared to patients with permanent AF. Professor Lip said: “Cardiologists are continuing to underprescribe anticoagulation in paroxysmal AF and the belief that these patients are at less risk is another myth. ESC guidelines say that AF patients with stroke risk factors should receive oral anticoagulation irrespective of the type of AF.”

Professor Lip concluded: “Our study of antithrombotic prescribing by cardiologists reveals a positive trend of increasing oral anticoagulant use. But worrying misconceptions and practices remain regarding aspirin, treatment of the elderly and paroxysmal AF.”

New study suggests choline recommendations during pregnancy may be too low

National Birth Defects Prevention Month underscores need for higher choline intake

Park Ridge, Ill. (January 30, 2014) – Recent research published in the American Journal of Clinical Nutrition (AJCN) found that during pregnancy, and particularly during the third trimester, large amounts of choline may be needed to support fetal development. Conclusions of the research revealed that current recommendations may be too low.¹ Choline deficiency in pregnant women may result in elevated levels of homocysteine, potentially resulting in birth defects.

January is National Birth Defects Prevention Month, and according to the National Birth Defects Prevention Network (NBDPN), every 4½ minutes a baby is born with a birth defect such as spina bifida.² This study adds to the growing body of evidence demonstrating that adequate maternal choline intake is vital to a healthy pregnancy.

Choline Needed for Healthy Fetal Growth Choline is an essential nutrient that is required to make phosphatidylcholine, a component of all cell membranes. Researchers evaluated pregnant and non-pregnant women who were all given a controlled diet that provided 380 milligrams/day (mg/d) of choline, primarily from eggs. The women were then randomly assigned to receive choline supplements of 100 or 550 mg/d. The study found that there is an increased fetal demand for phosphatidylcholine during pregnancy, much of it being transferred to the developing fetus.

“The methodology we employed in this study helped us clearly see changes in choline metabolism during pregnancy,” says Dr. Marie Caudill, professor in the Division of Nutritional Sciences at Cornell University and lead investigator of this study. “The results are very meaningful because they demonstrate the substantial demand for choline during pregnancy and may call for an increase in the amount of choline recommended in the diets of expecting mothers.”

Additional Benefits of Choline There is a significant body of research demonstrating the vital role choline plays in the diets of pregnant and breastfeeding women.

• Choline has been shown to play an important role in fetal and infant brain development, affecting the areas of the brain responsible for memory and life-long learning ability.³
• Moreover, research shows that choline may help prevent neural tube defects. Compared with women who get sufficient choline in their diets, women with diets low in choline have four times greater risk of having babies with neural tube defects such as spina bifida.⁴

Eggs Are a Simple Way to Add Choline to the Diet Research shows that nine out of 10 Americans don’t get enough choline.⁵ With numerous implications for health, increasing choline intake can be as easy as incorporating eggs into a healthy diet. Egg yolks are an excellent source of choline, providing about 125 mg, or roughly one-quarter of the recommended daily amount. “As one of the most convenient and low-cost food sources of choline, eggs are a food that I commonly encourage pregnant and breastfeeding women to consume,” says pediatric physician assistant Chris Barry, PA-C, MMSc. “Eggs are all-natural, packed with a number of nutrients and a delicious addition to a healthy diet.” For those looking to add more choline to their diet, Barry suggests simple, nutritious recipes like this Microwave Mexican Omelet or Easy Hardboiled Eggs.

For more information on the health benefits of eggs, materials on the nutritional importance of choline or recipes, visit EggNutritionCenter.org, CholineInfo.org and IncredibleEgg.org.

Geranium extracts inhibit HIV-1

Neuherberg, Germany, 30 January 2014. Extracts of the geranium plant Pelargonium sidoides inactivate human immunodeficiency virus type 1 (HIV-1) and prevent the virus from invading human cells. In the current issue of “PLOS ONE”, scientists from the Helmholtz Zentrum München report that these extracts represent a potential new class of anti-HIV-1 agents for the treatment of AIDS.

Scientists from the Helmholtz Zentrum München demonstrate that root extracts of the medicinal plant Pelargonium sidoides (PS) contain compounds that attack HIV-1 particles and prevent virus replication. A team spearheaded by Dr. Markus Helfer and Prof. Dr. Ruth Brack-Werner from the Institute of Virology and Prof. Dr. Philippe Schmitt-Kopplin from the Analytical BioGeoChemistry research unit (BGC) performed a detailed investigation of the effects of PS extracts on HIV-1 infection of cultured cells. They demonstrated that PS extracts protect blood and immune cells from infection by HIV-1, the most widespread type of HIV. PS extracts block attachment of virus particles to host cells and thus effectively prevent the virus from invading cells. Chemical analyses revealed that the antiviral effect of the PS extracts is mediated by polyphenols. Polyphenol mixtures isolated from PS extracts retain high anti-HIV-1 activity but are even less toxic for cells than the crude extract.

Safety of PS-extracts has been established in several clinical trials. In Germany PS extracts are licensed as a herbal medicine and used to reduce symptoms of acute bronchitis. Research group leader Brack-Werner says, “PS-extracts are a very promising lead for the development of the first scientifically validated phytomedicine against HIV-1. PS extracts attack HIV-1 with a mode-of-action that is different from all anti-HIV-1 drugs in clinical use. Therefore a PS-based phytomedicine may be a valuable supplement for established anti-HIV therapies. Furthermore, PS extracts are attractive candidates for increasing anti-HIV-1 therapy options in resource-limited settings, since they are easy to produce and do not require refrigeration. The results of our study and the proven safety of PS extracts encourages their testing in HIV-1 infected individuals as next step.”

According to the World Health Organisation (WHO), more than 35 million people in the world are infected with HIV, the majority with HIV-1. Without treatment, HIV destroys the immune system and causes the acquired immunodeficiency syndrome (AIDS), which is a life-threatening disease. HIV/AIDS is one of the 10 leading causes of death worldwide.

The goal of research at the Helmholtz Zentrum München is to develop new approaches to diagnosing, treating and preventing common diseases. In the interest of translational research, the acquired knowledge is to be applied to humans as quickly as possible in order to provide concrete benefits for society.

Blue light may fight fatigue around the clock

Researchers find blue light exposure may be a countermeasure for fatigue, during the day and night

Boston, MA– Researchers from Brigham and Women’s Hospital (BWH) have found that exposure to short wavelength, or blue light, during the biological day directly and immediately improves alertness and performance. These findings are published in the February issue of Sleep.

“Our previous research has shown that blue light is able to improve alertness during the night, but our new data demonstrates that these effects also extend to daytime light exposure,” said Shadab Rahman, PhD, a researcher in BWH’s Division of Sleep Medicine and lead author of this study. “These findings demonstrate that prolonged blue light exposure during the day has an an alerting effect.”

In order to determine which wavelengths of light were most effective in warding off fatigue, the BWH researchers teamed with George Brainard, PhD, a professor of neurology at Thomas Jefferson University, who developed the specialized light equipment used in the study. Researcherscompared the effects of blue light with exposure to an equal amount of green light on alertness and performance in 16 study participants for 6.5 hours over a day. Participants then rated how sleepy they felt, had their reaction times measured and wore electrodes to assess changes in brain activity patterns during the light exposure.

The researchers found that participants exposed to blue light consistently rated themselves as less sleepy, had quicker reaction times and fewer lapses of attention during the performance tests compared to those who were exposed to green light. They also showed changes in brain activity patterns that indicated a more alert state.

“These results contribute to our understanding of how light impacts the brain and open up a new range of possibilities for using light to improve human alertness, productivity and safety,” explained Steven Lockley, PhD, neuroscientist at BWH and senior investigator of the study. “While helping to improve alertness in night workers has obvious safety benefits, day shift workers may also benefit from better quality lighting that would not only help them see better but also make them more alert.”

Researchers note that the next big challenge is to figure out how to deliver better lighting. While natural light is ideal, many people do not have access to daylight in their schools, homes or work places. In addition to improvements in daylight access, the advent of new, more controllable lighting technologies may help enable researchers to develop ‘smart’ lighting systems designed to maximize the beneficial effects of light for human health, productivity and safety.

Are you Big Pharma’s new target market?

Taking a cue from Apple and Coca-Cola, pharmaceutical firms are humanizing their brands

Version française

Montreal, February 4, 2014 — By 2018, it is estimated that the global pharmaceutical market will be worth more than $1.3 trillion USD. To corner their share of profits, established drug companies have to fight fierce competition from generic products, adhere to stringent government regulations and sway a consumer base that is better informed than ever before.

New research from Concordia University’s John Molson School of Business shows that Big Pharma has begun these efforts by embracing “brand personality,” a marketing strategy traditionally employed by consumer-focused companies like Apple, Coca-Cola and Harley-Davidson.

By imbuing their brands with human characteristics, pharmaceutical companies can boost sales by developing direct relationships with their consumers. The result: patients are more likely to ask their physician to prescribe specific brand-name medication.

“Brand personalities can transform products from being merely functional to having emotional value in the eyes of the consumer,” says marketing professor Lea Katsanis, a co-author of the study that recently appeared in the Journal of Consumer Marketing.

“Pharmaceutical companies give their brands personality traits by relying on physical attributes, practical functions, user imagery and usage contexts. As a result, brand names like Viagra, Lipitor and Prozac become shorthand for the drugs themselves.”

To carry out the study, Katsanis and co-author Erica Leonard, a recent graduate of Concordia’s Master of Science in Marketing program, used an online survey to poll a total of 483 U.S. respondents. They rated 15 well-known prescription medications based on 22 different personality traits, such as dependability, optimism, anxiousness and elegance. The study included blockbuster drugs from Big Pharma companies such as Pfizer, Eli Lilly and GlaxoSmithKline.

The results show that prescription drug brand personality, as perceived by consumers, has two distinct dimensions: competence and innovativeness.

Consumers typically applied terms such as dependable, reliable, responsible, successful, stable, practical and solution-oriented” to branded drugs, thus showing a preference for overall competence. Words like unique, innovative and original related to the “innovativeness” of the drug in question.

“Our findings can help marketers better understand how competing brands are positioned and act accordingly to ensure their products remain distinctive. One way of achieving this could be to appropriately focus more on either the competence or innovativeness dimensions,” says Katsanis.

“From a consumer perspective, prescription drug brand personality may make health-related issues more approachable and less intimidating, facilitating physician-patient interactions by making patients more familiar with the medications used to treat what ails them.”

Simulated blindness can help revive hearing, researchers find

Minimizing a person’s sight for as little as a week may help improve the brain’s ability to process hearing, neuroscientists have found.

Hey-Kyoung Lee, an associate professor of neuroscience and researcher at the Mind/Brain Institute at the Johns Hopkins University, along with biologist Patrick Kanold at the University of Maryland, College Park, are co- authors on a paper in the journal Neuron, which examines the relationship between vision and hearing in the brain.

Music experts often cite blind musicians Stevie Wonder and Ray Charles as examples of how a lack of sight can heighten or enhance hearing. Scientists, however, did not fully understand just how that happened until now.

In experiments using mice, Lee, Kanold, and other researchers from the two universities, were able to uncover how the neural connections in the area of the brain that manages vision and hearing work together to support each sense. These findings could help those experiencing hearing loss regain more use of that sense.

“In my opinion, the coolest aspect of our work is that the loss of one sense – vision – can augment the processing of the remaining sense, in this case, hearing, by altering the brain circuit, which is not easily done in adults,” Lee said.

“By temporarily preventing vision, we may be able to engage the adult brain to now change the circuit to better process sound, which can be helpful for recovering sound perception in patients with cochlear implants for example,” she said.

In their experiments, the researchers placed healthy adult mice in a darkened environment to simulate blindness for about a week and monitored their response to certain sounds. Those responses and brain activity were then compared to a second group of mice that were in a traditional, naturally lit environment.

The researchers found a change in the brain circuitry for the mice that experienced simulated blindness, specifically in the area of the brain that processes sound, called the primary auditory cortex. The primary auditory cortex allows conscious perception of pitch and loudness.

“Our result would say that not having vision allows you to hear softer sounds and better discriminate pitch,” said Lee, an expert on how the brain processes vision. “If you ever had to hear a familiar piece of music with a loud background noise, you would have noticed that sometimes it seems the beat or the melody is different, because some of the notes are lost with the background. Our work would suggest that if you don’t have vision you can now rescue these ‘lost’ notes to now appreciate the music as is.”

The researchers concluded that a certain set of connectors in the primary sensory areas of the brain, called thalamocortical inputs, are less flexible in humans later in life. When another sense also impaired, however, those connectors can be reactivated to support the sense that is lagging.

The University of Maryland’s Kanold, whose expertise is in how the brain processes sound, is hopeful that the study’s findings will apply to humans.

“We don’t know how many days a human would have to be in the dark to get this effect, and whether they would be willing to do that,” Kanold said. “But there might be a way to use multi-sensory training to correct some sensory processing problems in humans.”

Presently, the changes uncovered by the group are reversible, meaning the mice that experienced simulated blindness eventually reverted to normal hearing after a few weeks in a normal light-dark environment. In the next phase of their five-year study, Lee and Kanold plan to look for ways to make the sensory improvements permanent. The pair also said they will look beyond individual neurons to study broader changes in the way the brain processes sounds.

Toxin in seafood causes kidney damage in mice at levels considered safe for consumption

FDA may need to reconsider what levels of domoic acid in shellfish and fish are safe

Washington, DC (February 6, 2014) — A chemical that can accumulate in seafood and is known to cause brain damage is also toxic to the kidneys, but at much lower concentrations. The findings, which come from a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN), suggest that officials may need to reconsider what levels of the toxin are safe for human consumption.

The world’s oceans contain algae that produce certain chemicals that can be harmful to humans and other living creatures. Many of these chemicals are considered neurotoxins because they cause damage to the brain. The neurotoxin domoic acid, also called “Amnesic Shellfish Poisoning,” is a very stable, heat resistant toxin that is becoming more prominent in coastal regions, likely due to environmental changes. It can accumulate in mussels, clams, scallops, and fish, and the FDA has set a legal limit of domoic acid in seafood based primarily on its adverse neurological effects.

Because domoic acid is cleared from the body by the kidneys, P. Darwin Bell, PhD, Jason Funk, PhD (Medical University of South Carolina), and their colleagues looked to see if the toxin might also have detrimental effects on these organs. By giving mice varying doses of domoic acid and the assessing animals’ kidney health, the team found that the kidney is much more sensitive to this toxin than the brain.

“We have found that domoic acid damages kidneys at concentrations that are 100 times lower than what causes neurological effects,” said Dr. Bell. “This means that humans who consume seafood may be at an increased risk of kidney damage possibly leading to kidney failure and dialysis.”

While the findings need to be verified in humans, the researchers would like to see increased awareness and monitoring of domoic acid levels in all seafood. They say that the FDA may also need to reconsider the legal limit of domoic acid in food due to its kidney toxicity.

Highlights

• Domoic acid accumulates in seafood and is toxic to the brain
• The toxin damages kidneys at concentrations that are 100 times lower than what causes neurological effects.

Huntington disease prevention trial shows creatine safe, suggests slowing of progression

Novel study design allows participation of at-risk individuals who do not want to know their genetic status

The first clinical trial of a drug intended to delay the onset of symptoms of Huntington disease (HD) reveals that high-dose treatment with the nutritional supplement creatine was safe and well tolerated by most study participants. In addition, neuroimaging showed a treatment-associated slowing of regional brain atrophy, evidence that creatine might slow the progression of presymptomatic HD. The Massachusetts General Hospital (MGH) study also utilized a novel design that allowed participants – all of whom were at genetic risk for the neurodegenerative disorder – to enroll without having to learn whether or not they carried the mutation that causes HD.

“More than 90 percent of those in the United States who know they are at risk for HD because of their family history have abstained from genetic testing, often because they fear discrimination or don’t want to face the stress and anxiety of knowing they are destined to develop such a devastating disease,” says H. Diana Rosas, MD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead and corresponding author of the paper that will appear in the March 11 issue of Neurology and has been released online. “Many of these individuals would still like to help find treatments, and this trial design allows them to participate while respecting their autonomy, their right not to know their personal genetic information.”

Among the ways that the mutated form of the huntingtin protein damages brain cells is by interfering with cellular energy production, leading to a depletion of ATP, the molecule that powers most biological processes. Known to help restore ATP and maintain cellular energy, creatine is being investigated to treat a number of neurological conditions – including Parkinson disease, amyotrophic lateral sclerosis and spinal cord injury. Studies in mouse models of HD showed that creatine raises brain ATP levels and protects against neurodegeneration. Previous clinical trials of creatine in symptomatic HD patients have been limited in scale, involved daily doses of 10 grams or less, and did not provide evidence of potential efficacy. Based on the results of a pilot study at MGH that evaluated doses as high as 40 grams, participants in the current study received doses of up to 30 grams daily.

The phase II PRECREST trial enrolled 64 adult participants – 19 who knew they carried the mutated form of the HD gene and 45 with a 50 percent risk of having inherited the HD mutation. Genetic testing, results of which were made available only to the study statistician and not to study staff or participants, confirmed the genetic status of those who had previously been tested and revealed an additional 26 presymptomatic carriers of the mutated gene, for a total of 47 participants with presymptomatic HD and 17 controls.

For the first 6 months of the trial, participants were randomized into two groups, regardless of gene status. One group received twice-daily oral doses of creatine, up to a maximum of 30 grams per day, the other received placebo. After that first phase, all participants received creatine for an additional 12 months. Participants were assessed at regular study visits for adverse effects, and dosage levels were adjusted, if necessary, to reduce unpleasant side effects. Additional tests – cognitive assessments, measurement of blood markers and MRI brain scans – were conducted at the trial’s outset, at 6 months and at the end of the study period.

During the first phase of the trial more than three-quarters of those randomized to creatine tolerated a daily dose of 15 grams or more, and more than two -thirds tolerated the full 30-gram dose. Throughout the entire trial, a total of 15 participants – including several who knew they carried the HD mutation – discontinued taking creatine because of gastrointestinal discomfort, the taste of the drug, inconvenience, or the stress of being constantly reminded of their HD risk. Other than occasional diarrhea and nausea, few adverse events were associated with creatine.

In participants who carried the HD mutation, the MRI scans taken at the outset of the trial had revealed significant atrophy in regions of the cerebral cortex and basal ganglia known to be affected by the disease. Followup MRI scans at six months showed a slower rate of atrophy in participants taking creatine compared to those on placebo. At the end of the second phase, the rate of brain atrophy had also slowed in presymptomatic participants that started taking creatine after 6 months on placebo.

In addition to suggesting that creatine could slow the progression of HD, these results also imply that neuroimaging may provide a useful biomarker of disease modification in studies of other potential treatments. While participants with the mutation had performed less well than controls on the cognitive tests at the study outset, creatine treatment had no significant effect on those measures, possibly because the tests were not sensitive enough to detect subtle changes that might occur during such a brief time period, the authors note.

“The results of this trial suggest that the prevention or delay of HD symptoms is feasible, that at-risk individuals can participate in clinical trials – even if they do not want to learn their genetic status – and that useful biomarkers can be developed to help assess therapeutic benefits,” says senior author Steven Hersch, MD, PhD, of MGH-MIND. “In addition, we believe our study design sets an important precedent for other genetic diseases and will help inform discussions of how clinical research can coexist with deep concerns about genetic privacy and patient autonomy.”

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These reports are done with the appreciation of all the Doctors, Scientist, and other Medical Researchers who sacrificed their time and effort. In order to give people the ability to empower themselves. Without the base aspirations for fame, or fortune. Just honorable people, doing honorable things.