Coenzyme Q10 helps veterans battle Gulf War illness symptoms

EEV: Requested Post from the CNO site:


Coenzyme Q10 helps veterans battle Gulf War illness symptoms

– CoQ10 is a fat-soluble antioxidant made by the body to support basic cell functions, including directly assisting mitochondrial energy production. Over a course of three and a half months, the veterans in the study received a pill form of either CoQ10 or a placebo. Researchers found 80 percent of those who received 100mg of CoQ10 had improvement in physical function. The degree of improvement correlated to the degree in which CoQ10 levels in the blood increased.
* Published in the Nov. 1 issue of Neural Computation Continue reading “Coenzyme Q10 helps veterans battle Gulf War illness symptoms”

How to erase a memory — and restore it

 
Researchers at the University of California, San Diego School of Medicine have erased and reactivated memories in rats, profoundly altering the animals’ reaction to past events.

 

The study, published in the June 1 advanced online issue of the journal Nature, is the first to show the ability to selectively remove a memory and predictably reactivate it by stimulating nerves in the brain at frequencies that are known to weaken and strengthen the connections between nerve cells, called synapses.

 

“We can form a memory, erase that memory and we can reactivate it, at will, by applying a stimulus that selectively strengthens or weakens synaptic connections,” said Roberto Malinow, MD, PhD, professor of neurosciences and senior author of the study. Continue reading “How to erase a memory — and restore it”

How computer-generated fake papers are flooding academia

More and more academic papers that are essentially gobbledegook are being written by computer programs – and accepted at conferences
'I've written five PhDs on Heidegger just this afternoon. What next?'
‘I’ve written five PhDs on Heidegger just this afternoon. What next?’ Photograph: Blutgruppe

Like all the best hoaxes, there was a serious point to be made. Three MIT graduate students wanted to expose how dodgy scientific conferences pestered researchers for papers, and accepted any old rubbish sent in, knowing that academics would stump up the hefty, till-ringing registration fees.

It took only a handful of days. The students wrote a simple computer program that churned out gobbledegook and presented it as an academic paper. They put their names on one of the papers, sent it to a conference, and promptly had it accepted. The sting, in 2005, revealed a farce that lay at the heart of science. Continue reading “How computer-generated fake papers are flooding academia”

175 Health Research Report 21 FEB 2014

 

                 HRR    

175

21 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:

Exercise may slow progression of retinal degeneration

Annual screening does not cut breast cancer deaths, suggests Canadian study

Could pizza herb prevent winter vomiting disease?

Prenatal vitamin A deficiency tied to postnatal asthma

Grape seed promise in fight against bowel cancer

Can citrus ward off your risk of stroke?

Natural compound attacks HER2 positive breast cancer cells

Probiotic treatment for vaginal thrush on the way

Garlic counteracts virulent bacteria

Thyroid cancer nearly triples; research blames “epidemic” on over diagnosis of harmless tumors

Exercise may slow progression of retinal degeneration

Animal study points to possible behavioral therapy for people with macular degeneration

Washington, DC — Moderate aerobic exercise helps to preserve the structure and function of nerve cells in the retina after damage, according to an animal study appearing February 12 in The Journal of Neuroscience. The findings suggest exercise may be able to slow the progression of retinal degenerative diseases. Continue reading “175 Health Research Report 21 FEB 2014”

The symphony of life, revealed

 

A new imaging technique captures the vibrations of proteins, tiny motions critical to human life

             IMAGE:   Using a new imaging technique they developed, scientists have managed to observe and document the vibrations of lysozyme, an antibacterial protein found in many animals. This graphic visualizes the vibrations…

Click here for more information.     

BUFFALO, N.Y. — Like the strings on a violin or the pipes of an organ, the proteins in the human body vibrate in different patterns, scientists have long suspected.

Now, a new study provides what researchers say is the first conclusive evidence that this is true.

Using a technique they developed based on terahertz near-field microscopy, scientists from the University at Buffalo and Hauptman-Woodward Medical Research Institute (HWI) have for the first time observed in detail the vibrations of lysozyme, an antibacterial protein found in many animals.

The team found that the vibrations, which were previously thought to dissipate quickly, actually persist in molecules like the “ringing of a bell,” said UB physics professor Andrea Markelz, PhD, wh0 led the study.

These tiny motions enable proteins to change shape quickly so they can readily bind to other proteins, a process that is necessary for the body to perform critical biological functions like absorbing oxygen, repairing cells and replicating DNA, Markelz said. Continue reading “The symphony of life, revealed”

Health Research Report #171 27 DEC 2013

Health Research Report

 #171

Latest Health Research Report Click Image for Report

27 DEC 2013 /  White paper draft

Compiled by Ralph Turchiano

 

 

In this issue:

1.       Research shows how household dogs protect against asthma and infection
2.       Pain drugs used in prostate gland removal linked to cancer outcome, Mayo Clinic-led study finds
3.       An apple a day keeps the doctor away
4.       Diet rich in tomatoes may lower breast cancer risk
5.       A new — and reversible — cause of aging
6.       Government’s voluntary approach to improving hospital food is not working, argues expert
7.       Research linking autism symptoms to gut microbes called ‘groundbreaking’
8.       Chewing Gum is Often the Culprit for Migraine Headaches in Teens
9.       Inosine treatment safely elevates urate levels in Parkinson’s disease patients
10.   Antioxidant drug knocks down multiple sclerosis-like disease in mice Continue reading “Health Research Report #171 27 DEC 2013”

Health Research Report #170 14 DEC 2013

Health Research Report

#170

Latest Health Research Report Click Image for Report
 

14 DEC 2013 /  White paper draft

Compiled by Ralph Turchiano

 

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

 

In this Issue:

1.       Evidence suggests that “healthy and overweight” is a myth
2.       Vitamin D Decreases Pain in Women with Type 2 Diabetes and Depression
3.       Estrogen: Not just produced by the ovaries
4.       Eating healthy vs. unhealthy diet costs about $1.50 more per day
5.       Progesterone changes may cause cognitive impairment of Alzheimer’s disease patients
6.       Does zinc supplementation reduce aluminum-induced neurotoxicity?
7.       Researchers see added nutritional benefits in organic milk
8.       You are what your father eats
9.       Long-term use of common heartburn and ulcer medications linked to vitamin B12 deficiency
10.   Gut microbes affect MicroRNA response to bacterial infection
11.   Low vitamin B12 levels increase the risk of fractures in older men
12.   Dietary amino acids relieve sleep problems after traumatic brain injury in animals
13.   Personal care products are possible sources of potentially harmful parabens for babies
14.   New study shows link between perfluorinated compounds and diabetes Continue reading “Health Research Report #170 14 DEC 2013”

Long-term use of common heartburn and ulcer medications linked to vitamin B12 deficiency

Contact: Cyrus Hedayati chedayati@golinharris.com 415-318-4377 Kaiser Permanente

OAKLAND, Calif. — Long-term use of commonly prescribed heartburn and ulcer medications is linked to a higher risk of vitamin B12 deficiency, according to a new study published in the Journal of the American Medical Association. Continue reading “Long-term use of common heartburn and ulcer medications linked to vitamin B12 deficiency”

LSUHSC research finds combo of plant nutrients killed 100% of sample breast cancer cells

Contact: Leslie Capo lcapo@lsuhsc.edu 504-568-4806 Louisiana State University Health Sciences Center

New Orleans, LA – A study led by Madhwa Raj, PhD, Research Professor in Obstetrics and Gynecology at LSU Health Sciences Center New Orleans and its Stanley S. Scott Cancer Center, has found that a super cocktail of six natural compounds in vegetables, fruits, spices and plant roots killed 100% of sample breast cancer cells without toxic side effects on normal cells. The results, which also revealed potential treatment target genes, are published in the November 2013 issue of The Journal of Cancer.

Continue reading “LSUHSC research finds combo of plant nutrients killed 100% of sample breast cancer cells”

Scientists report human dietary supplement cures lab animals infected with human intestinal parasite ( Hookworm )

Contact: Preeti Singh psingh@burnesscommunications.com 301-280-5722

Bridget DeSimone bdesimone@burnesscommunications.com 301-280-5735

Burness Communications

Preliminary success using ‘probiotics’ against hookworms raises hope for treating afflictions that burden 1.5 billion and cause stunting, development delays in children

WASHINGTON, D.C. (November 15, 2013) — Laboratory animals fed a modified version of a common human dietary supplement were completely cured of intestinal worms that belong to a family of parasites that currently infect 1.5 billion people, or almost one quarter of the world’s population, according to new research presented today at the annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH).

“We need to replicate the results in other animals and also in humans, but this is an important development in our effort to find a safe, affordable and effective way to confront a major global health problem,” said Raffi Aroian, PhD, principal investigator of a team of scientists at the University of California, San Diego who are seeking new treatments for a variety of parasitic worms known as “soil-transmitted helminths” or STHs.

While rarely fatal, STHs and other intestinal worms are leading contributors to disease in school-age children in low-income countries and are viewed by many experts as among the most burdensome of the world’s “neglected tropical diseases” or NTDs.

The study conducted by Aroian’s team focused on hookworms, common STHs that are found in soil that has been contaminated with human feces. Hookworms can linger in the intestines for years, where they feed on blood and tissue, robbing their hosts of iron and protein and interfering with absorption of critical nutrients. They frequently cause stunting and cognitive delays in infected children. They also can have long-term effects on educational achievement and productivity.

Currently, the only drugs available to treat hookworms in humans were originally developed to combat parasites that infect farm animals. Aroian said they are only partially effective against the range of intestinal parasites that infect humans. There is also evidence of reinfections occurring rapidly after treatment and low levels of efficacy in some places.

At the ASTMH meeting, Aroian’s colleague Yan Hu, PhD reported findings from a study in which hamsters were deliberately infected with hookworms. The hamsters were later divided into two groups. One group received a common strain of the bacteria Bacillus subtilis, which is often marketed as a “probiotic”—a dietary supplement consumed as a pill or added to food that is intended to promote digestive health. It also is the key ingredient in a popular Japanese fermented soybean dish called Natto. The other group received the same probiotic, except the researchers modified it to express a protein derived from a closely related bacterium, Bacillus thuringiensis or Bt, which is known to be safe in humans but potentially lethal to intestinal worms.

“Five days after we administered the bacteria, we examined the animals’ intestines,” Hu said. “We found no worms in the animals that received the modified probiotic, while those that did not receive the modified probiotic remained infected.”

Hu said the next step will be to conduct tests in different types of animals and against different types of STHs. If the probiotic continues to perform well against multiple intestinal parasites and is shown to be safe, then researchers would consider testing in humans, she said.

The research is supported by grants from the Bill & Melinda Gates Foundation and the National Institutes of Health.

“While the research has yet to move beyond tests in animals, the human health burden is so immense and the solutions so few that it’s gratifying to see progress being made toward finding new treatments for intestinal worm diseases,” said ASTMH President David H. Walker, MD. “It shows that new investments in neglected tropical diseases are inspiring creative solutions for the more than a billion people in need.”

Aroian said the overall goal of the work is to produce a treatment for intestinal worms that is safe, effective and affordable in the world’s poorest countries, where hookworms and other STHs do the most damage.  “This probiotic is a food-grade bacterial product that can be easily produced in large quantities in a simple fermenter, and it can be manufactured in a form that has a long shelf-life,” he said. “It could be well-suited to providing the cheap, mass treatment we need to substantially reduce the burden of this disease.”

Aroian said Bt is attractive because it is a well-understood, natural substance for controlling plant pests that is believed to be safe for animals and humans. It is frequently sprayed on organic crops and is mainly lethal to insects in their larva stage. Bt also is a bacteria used in genetically engineered corn and soybean to endow the crops with resistance to plant pests.

Aroian said that while the modified probiotic under development in his lab should be safe to consume, if it proves to be an effective intervention for intestinal worms it would be marketed as a treatment, not as a dietary supplement.

###

About the American Society of Tropical Medicine and Hygiene ASTMH, founded in 1903, is a worldwide organization of scientists, clinicians and program professionals whose mission is to promote global health through the prevention and control of infectious and other diseases that disproportionately afflict the global poor.

Compound derived from vegetables shields rodents from lethal radiation doses

Contact: Karen Mallet km463@georgetown.edu Georgetown University Medical Center

WASHINGTON — Georgetown University Medical Center researchers say a compound derived from cruciferous vegetable such as cabbage, cauliflower and broccoli protected rats and mice from lethal doses of radiation.

Their study, published today in the Proceedings of the National Academy of Sciences (PNAS) suggests the compound, already shown to be safe for humans, may protect normal tissues during radiation therapy for cancer treatment and prevent or mitigate sickness caused by radiation exposure.

The compound, known as DIM (3,3′-diindolylmethane), previously has been found to have cancer preventive properties.

“DIM has been studied as a cancer prevention agent for years, but this is the first indication that DIM can also act as a radiation protector,” says the study’s corresponding author, Eliot Rosen, MD, PhD, of Georgetown Lombardi Comprehensive Cancer Center.

For the study, the researchers irradiated rats with lethal doses of gamma ray radiation.  The animals were then treated with a daily injection of DIM for two weeks, starting 10 minutes after the radiation exposure.

The result was stunning, says Rosen, a professor of oncology, biochemistry and cell & molecular biology, and radiation medicine. “All of the untreated rats died, but well over half of the DIM-treated animals remained alive 30 days after the radiation exposure.”

Rosen adds that DIM also provided protection whether the first injection was administered 24 hours before or up to 24 hours after radiation exposure.

“We also showed that DIM protects the survival of lethally irradiated mice,” Rosen says. In addition, irradiated mice treated with DIM had less reduction in red blood cells, white blood cells and platelets — side effects often seen in patients undergoing radiation treatment for cancer.

Rosen says this study points to two potential uses of the compound. “DIM could protect normal tissues in patients receiving radiation therapy for cancer, but could also protect individuals from the lethal consequences of a nuclear disaster.”

Rosen and study co-authors Saijun Fan, PhD, and Milton Brown, MD, PhD, are co-inventors on a patent application that has been filed by Georgetown University related to the usage of DIM and DIM-related compounds as radioprotectors.

###

 

This work was supported by U.S. Public Health Service Grants (CA104546 and CA150646), a grant from the Center for Drug Discovery at Georgetown University, and other Georgetown funding.

About Georgetown University Medical Center

Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health).  GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.”  The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health

Obese stomachs tell us diets are doomed to fail

Public release date: 16-Sep-2013 [

Contact: Amanda Page amanda.page@adelaide.edu.au 61-882-225-644 University of Adelaide

The way the stomach detects and tells our brains how full we are becomes damaged in obese people but does not return to normal once they lose weight, according to new research from the University of Adelaide.

Researchers believe this could be a key reason why most people who lose weight on a diet eventually put that weight back on.

In laboratory studies, University of Adelaide PhD student Stephen Kentish investigated the impact of a high-fat diet on the gut’s ability to signal fullness, and whether those changes revert back to normal by losing weight.

The results, published in the International Journal of Obesity, show that the nerves in the stomach that signal fullness to the brain appear to be desensitized after long-term consumption of a high-fat diet.

“The stomach’s nerve response does not return to normal upon return to a normal diet.  This means you would need to eat more food before you felt the same degree of fullness as a healthy individual,” says study leader Associate Professor Amanda Page from the University’s Nerve-Gut Research Laboratory.

“A hormone in the body, leptin, known to regulate food intake, can also change the sensitivity of the nerves in the stomach that signal fullness.  In normal conditions, leptin acts to stop food intake.  However, in the stomach in high-fat diet induced obesity, leptin further desensitizes the nerves that detect fullness.

“These two mechanisms combined mean that obese people need to eat more to feel full, which in turn continues their cycle of obesity.”

Associate Professor Page says the results have “very strong implications for obese people, those trying to lose weight, and those who are trying to maintain their weight loss”.

“Unfortunately, our results show that the nerves in the stomach remain desensitized to fullness after weight loss has been achieved,” she says.

Associate Professor Page says they’re not yet sure whether this effect is permanent or just long-lasting.

“We know that only about 5% of people on diets are able to maintain their weight loss, and that most people who’ve been on a diet put all of that weight back on within two years,” she says.

“More research is needed to determine how long the effect lasts, and whether there is any way – chemical or otherwise – to trick the stomach into resetting itself to normal.”

###

This study has been funded by the National Health and Medical Research Council (NHMRC).

Media Contact:

Associate Professor Amanda Page Nerve-Gut Research Laboratory School of Medicine The University of Adelaide Phone: +61 8 8222 5644 amanda.page@adelaide.edu.au

Codeine could increase users’ sensitivity to pain

Contact: Paul Rolan paul.rolan@adelaide.edu.au 61-883-134-102 University of Adelaide

Using large and frequent doses of the pain-killer codeine may actually produce heightened sensitivity to pain, without the same level of relief offered by morphine, according to new research from the University of Adelaide.

Researchers in the Discipline of Pharmacology have conducted what is believed to be the world’s first experimental study comparing the pain relieving and pain worsening effects of both codeine and morphine.

The University’s Professor Paul Rolan, who is also a headache specialist at the Royal Adelaide Hospital, says codeine has been widely used as pain relief for more than 100 years but its effectiveness has not been tested in this way before.

“In the clinical setting, patients have complained that their headaches became worse after using regular codeine, not better,” Professor Rolan says.

“Codeine use is not controlled in the same way as morphine, and as it is the most widely used strong pain reliever medication in the world, we thought it was about time we looked into how effective it really is.”

In laboratory studies, University of Adelaide PhD student Jacinta Johnson found that codeine provided much less pain relief than morphine, but resulted in the same level of increased sensitivity to pain.

“Pain sensitivity is a major issue for users of opioid drugs because the more you take, the more the drug can increase your sensitivity to pain, so you may never quite get the level of relief you need.  In the long term it has the effect of worsening the problem rather than making it better.  We think that this is a particular problem in headache patients, who seem more sensitive to this effect,” Ms Johnson says.

“Both codeine and morphine are opioids but codeine is a kind of ‘Trojan horse’ drug – 10% of it is converted to morphine, which is how it helps to provide pain relief.  However, despite not offering the same level of pain relief, we found that codeine increased pain sensitivity just as much as morphine.”

Professor Rolan says while more research is needed, these laboratory findings suggest a potential problem for anyone suffering from chronic pain who needs ongoing medication.

“People who take codeine every now and then should have nothing to worry about, but heavy and ongoing codeine use could be detrimental for those patients who have chronic pain and headache,” Professor Rolan says.  “This can be a very difficult issue for many people experiencing pain, and it creates difficulties for clinicians who are trying to find strategies to improve people’s pain.”

Ms Johnson presented this research at the 2013 International Headache Congress in Boston, and her work is featured in this month’s issue of Neurology Reviews.

A clinical trial testing a new approach to treating codeine-related headache is now being run by Professor Rolan.

###

Media Contact:

Professor Paul Rolan Professor of Clinical Pharmacology The University of Adelaide Phone: +61 8 8313 4102 paul.rolan@adelaide.edu.au

Jacinta Johnson PhD student / Pharmacist School of Medical Sciences The University of Adelaide jacinta.johnson@adelaide.edu.au

Novel Chinese herbal medicine JSK improves spinal cord injury outcomes in rats

Contact: Daphne Watrin d.watrin@iospress.nl 31-206-883-355 IOS Press

Findings published in Restorative Neurology and Neuroscience

Amsterdam, NL, August 19, 2013 – A new study published in Restorative Neurology and Neuroscience demonstrates that Chinese herbal medicine Ji-Sui-Kang (JSK), given systemically for three weeks after injury in rats, improved locomotor function, reduced tissue damage, and preserved the structure of neural cells compared to control rats. The report also includes data showing that JSK may first act to reduce inflammation and cell apoptosis and death, and boost local oxygen supply while, later on, it appears to restore function and promote tissue regeneration.

Although Chinese herbal medicines have traditionally been used for a variety of ailments, the rationale for their use relies more on anecdotal evidence than the results of modern-day controlled experiments.

“A number of anecdotal reports from Chinese medicine practitioners indicate that treatment with a novel herbal formulation, JSK, for periods of one week or three months improved functional recovery,” explains co-lead investigator Shucui Jiang, MD, PhD, head of the Hamilton NeuroRestorative Group at McMaster University in Hamilton, Ontario, Canada. “Our present study provides an important and necessary foundation for further studies of JSK.”

In this study rats began JSK treatment immediately after undergoing spinal cord injury. Within 7 days, hindlimb locomotor function was significantly better in JSK-treated rats compared to those receiving only saline. JSK-treated rats continued to have better motor function than controls throughout the 21-day test period and treated animals appeared to support their weight better and have more coordinated movements.

When the investigators looked at histological samples of the spinal cord, they found that the architecture of the spinal cord was better preserved in JSK-treated animals and the size of the injured area was significantly smaller 7 days after injury. JSK-treated animals also showed more intact axons and myelin in the injured areas compared to controls. Other encouraging signs were less deposition of fibrinogen in the injured areas of JSK-treated animals, a decrease in pro-inflammatory COX-2 expression, and fewer cell deaths at the lesion site (as measured by caspase-3 staining).

JSK also increased the expression of growth associated protein 43 (GAP43), a marker of neuronal development and axonal regeneration, and neuroglobulin, a protein found in cerebral neurons that is thought to help neurons survive and recover after trauma. “Our data suggest that JSK may enhance tissue recovery by reducing cell growth inhibitors and by promoting the proliferation of cells within the injured spinal cord,” says co-lead investigator Michel P. Rathbone, MD, CHB, PhD, Professor, Division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Other findings suggest JSK might help protect against injury caused by damage to spinal cord blood vessels. For instance, JSK increased vascular endothelial growth factor (VEGF), a protein involved in the formation and growth of blood vessels, down-regulated clotting-associated genes, and promoted factors that contribute to vasodilation.

The authors say that JSK targets multiple biochemical and cellular pathways that may help protect against the primary traumatic injury as well as subsequent secondary injuries that evolve over time.

The authors do not disclose the complete herbal composition of JSK for proprietary reasons. Some of its ingredients include Ginseng, Rhizoma (chuan xiong), Glycyrrhizae Radix (gan cao), Paeoniae Alba Radix (bai shao) and Cinnamomi Cortex (rou gui).

Obesity kills more Americans than previously thought

Contact: Timothy S. Paul tp2111@columbia.edu 212-305-2676 Columbia University’s Mailman School of Public Health

1 in 5 Americans, Black and White, die from obesity — nearly 3 times previous estimates

Obesity is a lot more deadly than previously thought. Across recent decades, obesity accounted for 18 percent of deaths among Black and White Americans between the ages of 40 and 85, according to a study funded by the Robert Wood Johnson Foundation. This finding challenges the prevailing wisdom among scientists, which puts that portion at around 5%.

“Obesity has dramatically worse health consequences than some recent reports have led us to believe,” says first author Ryan Masters, PhD, who conducted the research as a Robert Wood Johnson Foundation Health & Society Scholar at Columbia University’s Mailman School of Public Health. “We expect that obesity will be responsible for an increasing share of deaths in the United States and perhaps even lead to declines in U.S. life expectancy.”

While there have been signs that obesity is in decline for some groups of young people, rates continue to be near historic highs. For the bulk of children and adults who are already obese, the condition will likely persist, wreaking damage over the course of their lives.

In older Americans, the rising toll of obesity is already evident. Dr. Masters and his colleagues documented its increasing effect on mortality in White men who died between the ages of 65 and 70 in the years 1986 to 2006. Grade one obesity (body mass index of 30 to less than 35) accounted for about 3.5% of deaths for those born between 1915 and 1919—a grouping known as a birth cohort. For those born 10 years later, it accounted for about 5% of deaths. Another 10 years later, it killed off upwards of 7%.

When the obesity epidemic hit in the 1980s, it hit across all age groups, so older Americans have lived through it for a relatively short period of time. But younger age groups will be exposed to the full brunt for much longer periods.

“A 5-year-old growing up today is living in an environment where obesity is much more the norm than was the case for a 5-year-old a generation or two ago. Drink sizes are bigger, clothes are bigger, and greater numbers of a child’s peers are obese,” explains co-author Bruce Link, PhD, professor of epidemiology and sociomedical sciences at Columbia University’s Mailman School of Public Health. “And once someone is obese, it is very difficult to undo. So it stands to reason that we won’t see the worst of the epidemic until the current generation of children grows old.”

A New Way of Looking at a Growing Problem

This study is the first to account for differences in age, birth cohort, sex, and race in analyzing Americans’ risk for death from obesity. “Past research in this area lumped together all Americans, but obesity prevalence and its effect on mortality differ substantially based on your race or ethnicity, how old you are, and when you were born,” says Dr. Masters. “It’s important for policy-makers to understand that different groups experience obesity in different ways.”

The researchers analyzed 19 waves of the National Health Interview Survey linked to individual mortality records in the National Death Index for the years 1986 to 2006, when the most recent data are available. They focused on ages 40 to 85 in order to exclude accidental deaths, homicides, and congenital conditions that are the leading causes of death for younger people. The study builds on earlier research by Dr. Masters that found, contrary to conventional wisdom, that risk for death from obesity increases with age. The new study is also influenced by previous work by co-authors Eric Reither, PhD, associate professor at Utah State University, and Claire Yang, PhD, associate professor at the University of North Carolina-Chapel Hill, which showed significant cohort differences in U.S. obesity rates.

Obesity’s Varying Effects by Sex and Race

In the groups studied, Black women had the highest risk of dying from obesity or being overweight at 27 percent, followed by White women at 21 percent. Obesity in Black women is nearly twice that of White women. White men fared better at 15%, and the lowest risk for dying from being obese was 5%, for Black men. While White men and Black men have similar rates of obesity, the effect of obesity on mortality is lower in Black men because it is “crowded out” by other risk factors, from high rates of cigarette smoking to challenging socioeconomic conditions. There were insufficient data to make estimates for Asians, Hispanics, and other groups due to the highly stratified nature of the methodology.

In sum, by using a new, more rigorous approach, the new research shows that obesity is far more consequential than previously recognized, that the impact of the epidemic is only beginning to be felt, and that some population groups are affected much more powerfully than others.

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Daniel Powers of the University of Texas at Austin and Andrew E. Burger of Utah State University also contributed to the paper.

The study, “The Impact of Obesity on U.S. Mortality Levels: The Importance of Age and Cohort Factors in Population Estimates,” was published online in the American Journal of Public Health.

BPA exposure disrupts human egg maturation

Contact: Tom Langford tlangford@partners.org 617-534-1605 Brigham and Women’s Hospital

Brigham and Women’s Hospital research could explain why some couples have trouble conceiving

             IMAGE:   Images of eggs examined in this study show a properly formed spindle structure with aligned chromosomes (image A) and eggs with spindles of various abnormal shapes and misaligned chromosomes after…

Click here for more information.     

Boston – As many as 20 percent of infertile couples in the United States have unexplained reasons for their infertility.  Now, new research led by Catherine Racowsky, PhD, director of the Assisted Reproductive Technologies Laboratory at Brigham and Women’s Hospital (BWH), shows that exposure to BPA (Bisphenol-A) could be a contributing factor as to why some infertile couples are having difficulty conceiving.   The study will be published online on July 31, 2013 in the journal Human Reproduction.

“To our knowledge, this is the first study that has shown that BPA has a direct effect on egg maturation in humans,” said Dr. Racowsky.  “Because exposure to BPA is so ubiquitous, patients and medical professionals should be aware that BPA may cause a significant disruption to the fundamentals of the human reproductive process and may play a role in unexplained infertility.”

The randomized trial examined 352 eggs from 121 consenting patients at a fertility clinic.  The eggs, which would have otherwise been discarded, were exposed to varying levels (20 ng/ml, 200 ng/ml and 20 µg/ml) of BPA in a laboratory setting.  An egg from each patient was not exposed to BPA and served as the control.  Researchers then examined the eggs and found that exposure to BPA caused:

  • A decrease in the percentage of eggs that matured.
  • An increase in the percentage of eggs that degenerated.
  • An increase in the percentage of eggs that underwent spontaneous activation, the abnormal process when an egg acts as though it has been fertilized, even though it has not been.

 

As the BPA dose increased, there was a decreased likelihood of maturity, an increased likelihood of degeneration and an increased likelihood of spontaneous activation.   Additionally, among the mature eggs, there was a significant trend toward a decreased incidence of bipolar spindles and aligned chromosomes with an increased dose of BPA.  Researchers note that these results are similar to the previous research examining the impact of BPA exposure on animal eggs.

Racowsky said, “Our data show that BPA exposure can dramatically inhibit egg maturation and adds to a growing body of evidence about the impact of BPA on human health.  I would encourage further research to gain a greater understanding of the role BPA plays in infertility.”

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This study was funded by the NIEHS Center Grant Pilot Project (P30-ES000002).  The full title of the paper is “Bisphenol-A and human oocyte maturation in vitro”.

Quants: the maths geniuses running Wall Street

Forget Gordon Gekko. Old-style City traders are being replaced by maths geniuses who use super-computers to beat the markets. But are ‘quants’ a force for good or evil?

Photo: Getty Images

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By Sarfraz Manzoor

7:00AM BST 23 Jul 2013

 

At seven minutes past one on the afternoon of Tuesday April 23 this year a tweet from the AP news agency in Washington was published. It read “Breaking: Two Explosions in the White House and Barack Obama is injured.” This was not true – the AP account had been hacked by a shady group of technology nerds calling themselves The Syrian Electronic Army – but within milliseconds the tweet had been noticed and flagged by trading computers on Wall Street.

Programmed to scan the internet for words or phrases that might effect stock markets, the unthinking machines had immediately seized upon the tweet, noted the proximity of the words “Obama”, “explosions” and “White House” and unleashed a torrent of trades. Within seconds, the Dow Jones had plunged 140 points and more than $200 billion of capital had been wiped out.

A few minutes later the report was exposed as a hoax and the markets quickly returned to their pre-tweet levels. But, to many, the idea that one fake tweet could have such an enormous impact on the financial markets was incredible. Who was running Wall Street? Humans or machines?

If you thought “humans”, you were woefully out of date. Over the past decade or so there has been a technological coup d’etat on the trading floor. The old “Masters of the Universe” – the Gordon Gekko types with their slicked-back hair and $5,000 suits – have been superseded by unbelievably powerful computers capable of analysing vast amounts of data and buying or selling shares in the blink of an eye. Today, if you visit a trading floor, instead of pumped-up men in loose ties screaming down the phone, you are more likely to see rows of studious-looking people (most of them still men) sitting in front of computer screens, quietly monitoring trades being carried out on their behalf by machines.

Around 70 per cent of the orders to buy or sell on Wall Street are now placed by software programs, and the studious-looking people, mathematical geniuses who are responsible for writing these programs, are the new “smartest guys in the room”. It is the age of the algorithm.

Mathematicians made their first forays into the financial world in the late Sixties. Edward Thorp, a professor of mathematics at the University of California, published a book in 1967 called Beat the Market in which he laid out what he claimed was a foolproof way of making money on the stock market, all based on a system he had previously devised to beat casinos at blackjack. The blackjack system had been so successful it had forced casinos to change their rules and Beat the Market – which had to do with selling stocks and bonds at one price and buying them back at a lower price – proved to be even more groundbreaking. In 1974, Thorp founded a hedge fund called Princeton/Newport Partners and proceeded to make a killing on the markets.

Edward Thorp, the mathematics professor who ‘beat the market’ (Time & Life Pictures/Getty Images)

At the same time, the job prospects for scientists had nosedived. Since the 1969 moon landing, the American government had cut funding for science programmes and diverted it to the war in Vietnam.

“A generation of physicists who had gone to graduate school left with their PhDs and entered a severely depressed job market,” explains James Owen Weatherall, author of The Physics of Finance. They had to earn a living somehow, and, seeing how much money that there was to be made on Wall Street, many decided to move into finance.

In Britain, the fall of the Soviet Union led to an influx of Warsaw Pact scientists. In both cases, these scientists brought with them a new methodology based on analysing data and also a faith that, using sufficient computing firepower, it was possible to predict the market. It was the start of a new discipline, quantitative analysis, and the most famous “quant” of all was a shambling donnish maths genius with a scraggly beard and aversion to socks called Jim Simons.

For those who know their physics, Simons is a living legend. A piece of mathematics he co-created, the Chern-Simons 3-form, is one of the most important elements of string theory, the so-called “theory of everything”. Highly academic, Simons never seemed the sort of person who would gravitate to the earthy environs of Wall Street. But in 1982, he founded an extraordinarily successful hedge fund management company, Renaissance Technologies, whose signature fund, Medallion, went on to earn an incredible 2,478.6 per cent return in its first 10 years, way above every other hedge fund on the planet, including George Soros’s Quantum Fund.

Physicist-turned-hedge fund mogul Jim Simons (AP)

Its success, based on a highly complex and secretive algorithm, continued in the Noughties and over the lifetime of the fund, Medallion’s returns have averaged 40 per cent a year, making Simons one of the richest men in the world with a net worth in excess of $10billion.

Of his 200 employees, ensconced in a fortress-like building in unfashionable Long Island, New York, a third have PhDs, not in finance, but in fields like physics, mathematics and statistics. Renaissance has been called “the best physics and mathematics department in the world” and, according to Weatherall, “avoids hiring anyone with even the slightest whiff of Wall Street bona fides. PhDs in finance need not apply; nor should traders who got their start at traditional investment banks or even other hedge funds. The secret to Simons’s success has been steering clear of the financial experts.”

Not surprisingly, old-style traders hate the quants. Not only have they pushed them off the top of the trading tree, there is also a basic clash of cultures. They are not flash and, invariably, rather awkward socially. As one anonymous software salesman who deals with hedge funds relates on a blog: “They don’t do small talk. When one of them picks me up from reception and we ride the elevator, I have learnt not to start chatting away about, say, the weather. They simply don’t seem to understand. They think you’re attempting to communicate something apparently important about meteorological conditions. Same thing with innocent jokes… blank stares.”

So what exactly do quantitative analysts do?

Patrick Boyle and Jesse McDougall run a hedge fund which they operate out of an Islington town house. Their offices are next to the sort of ethical café whose owners would probably be horrified at the rampant capitalism on display next door. When I meet them they are seated in a small room dominated by three computer screens. They start work at seven in the morning and end around 11 at night. “We have computer screens in our kitchen and living room,” says Boyle, 37. “So we can monitor the markets while having dinner and we can log in remotely if we are out in the evening.” He shows me a chart tracking his fund’s performance. The line doesn’t dip when the rest of the market dips and rises faster than the FTSE.

How do they do it?

“We do it with maths,” he says. “We buy stock market data and we analyse it. It’s like weather forecasting – we can say that there is a 65 per cent probability that the market will be up between open and close, so we are able to have better than 50 per cent odds on short-term movements and over time if you call short term well, you can make money.”

Who wrote the computer program they use? “I did,” says Boyle. How do you write something like that? “Slowly.”

The writing of the program may be slow but the speed of transactions is super fast. Some quants specialise in what is called High Frequency Trading (HFT), which involves large numbers of trades over very short periods of time. “In one millisecond the price could go up by one penny,” says McDougall. “You do it thousands of times on hundreds of shares and you make money.”

Boyle and McDougall’s hedge fund doesn’t do high frequency trades, so to find out more I meet Simon Jones, who was running the quants desk at a major bank up until a few months ago. He is 36 years old.

“The guys and women who worked with me were the best of the best. They came from all over the world: from India, Russia and China.” The job was intense and highly competitive. “Let’s say I have noticed that the moment the Dow goes up the FTSE goes up,” says Jones. “The first person to notice that and make a trade can make money but to do that means getting the data from New York to London and then getting my trading decision across the Atlantic and me buying my FTSE before anyone else does.”

In this game speed is critical and that has led to what has been dubbed an arms race between firms. It has got to a point where firms have actually started moving their servers nearer to an exchange to speed up connection times.

In 2010, a company called Spread Networks laid a new direct cable between New York and Chicago, going straight through the Allegheny mountains, which shaved a little bit more than 1,000th of a second off the transmission time between stock exchanges.

For the opportunity to use a similarly fast tube between New York and London, Jones’s old bank was asked to pay $50 million. “It would have given us an advantage over others of about a six thousandths of one second,” says Jones.

This focus on the shortest of short-term gains has vastly increased volatility. “Warren Buffett owns shares in Coca-Cola and when they go down he says ‘I’m holding on to them because I think they will go back up’,” says Jones. “But the HFT guy, all he cares about is the next millisecond. And when too many people start panicking about the next millisecond that’s when you have a crash.”

The perfect example of such a crash took place on May 6 2010. So many shares were traded that day that the online trading section of the New York Stock Exchange temporarily froze and between 2.30pm and 3pm the Dow Jones lost and then regained nearly $1 trillion. In what became known as the “Flash Crash”, shares in the management consultancy firm Accenture plummeted to a fraction above zero. Apple shares went up to $100,000.

“None of us knew what to do or what would happen next,” says Dave Lauer, a quant who was working on a HFT desk that day. “It was terrifying.”

For Lauer, the Flash Crash was a wake-up call. “I started to see how the race to be fastest had left things in a very fragile state,” he tells me. The following year his wife revealed she was pregnant which prompted him to make a big decision. “I remember thinking, ‘How will I explain to my future child what I do for a living?’” Lauer quit his job and last year told the Senate Banking committee that High Frequency Trading had brought the market to crisis point.

The Flash Crash was partly caused by the HFT strategy of “spoofing”; making bogus offers to buy or sell shares to flush out the intentions of rivals. On the day, an astonishing 19.4 billion shares were traded, more than were traded in the entirety of the Sixties, but hundreds of millions of them were never actually sold; they were merely held for a few thousandths of a second as traders tested the waters.

Isn’t there something wrong with a system that promotes so much volatility to the benefit of no one except a handful of hedge funds? Can it be a meaningful investment of time and technology? Warren Buffett’s business partner, Charlie Munger, has described High Frequency Trading as “basically evil”. “I think it is very stupid to allow a system to evolve where half of the trading is a bunch of short-term people trying to get information one millionth of a nanosecond ahead of somebody else,” he said earlier this year. “It’s legalised front-running.” HFT is certainly of no clear benefit to everyday investors – savers in pension funds and life policies.

The quants I meet don’t believe what they do is necessarily dangerous but they do voice some doubts.

“Some of the guys who come from pure science and maths backgrounds are used to solving a problem and it works,” Patrick Boyle says. “They think they can find a formula that will perfectly describe how the market moves. That is the philosopher’s stone – it is utterly impossible.” The danger is that in only seeing numbers and patterns the human dimension is forgotten.

After 16 years in the City, Simon Jones is now planning to go travelling. “A quant can earn up to seven figures,” he tells me, “but sometimes I do wonder whether I contributed positively to society.”

And what does he conclude? He pauses. “I was working with the best of the best,” he says. “My bank employed the brightest engineers, chemists and scientists – and we were all working together to get richer. The chemical and physics and health industries are worse off because of what we do because I tell you this: if there was a pay bonus structure similar to what we had in the City for curing cancer, we’d have found a cure for cancer.”

I find that sad and a little bit frightening. So, I ask, quants: good or bad? Jones looks at me and says, “Humans just found a new way of being greedy.”

 

 

Vitamin C Helps Control Gene Activity in Stem Cells

Vitamin C, in a natural source such as an orange and as a supplement. Vitamin C affects whether genes are switched on or off inside mouse stem cells, and may thereby play a previously unknown and fundamental role in helping to guide normal development in mice, humans and other animals. (Credit: © brozova / Fotolia)

July 1, 2013 — Vitamin C affects whether genes are switched on or off inside mouse stem cells, and may thereby play a previously unknown and fundamental role in helping to guide normal development in mice, humans and other animals, a scientific team led by UC San Francisco researchers has discovered.

The researchers found that vitamin C assists enzymes that play a crucial role in releasing the brakes that keep certain genes from becoming activated in the embryo soon after fertilization, when egg and sperm fuse.

The discovery might eventually lead to the use of vitamin C to improve results of in vitro fertilization, in which early embryos now are typically grown without the vitamin, and also to treat cancer, in which tumor cells abnormally engage or release these brakes on gene activation, the researchers concluded in a study published June 30, 2013 in the journal Nature.

In the near term, stem-cell scientists may begin incorporating vitamin C more systematically into their procedures for growing the most healthy and useful stem cells, according to UCSF stem-cell scientist Miguel Ramalho-Santos, PhD, who led the study. In fact, the unanticipated discovery emerged from an effort to compare different formulations of the growth medium, a kind of nutrient broth used to grow mouse embryonic stem cells in the lab.

Rather than building on any previous body of scientific work, the identification of the link between vitamin C and the activation of genes that should be turned on in early development was serendipitous, Ramalho-Santos said. “We bumped into this result,” he said.

Working in Ramalho-Santos’ lab, graduate student Kathryn Blaschke and postdoctoral fellow Kevin Ebata, PhD, were comparing different commercial growth media for mouse stem cells. The researchers began exploring how certain ingredients altered gene activity within the stem cells. Eventually they discovered that adding vitamin C led to increased activity of key enzymes that release the brakes that can prevent activation of an array of genes.

The brakes on gene activation that vitamin C helps release are molecules called methyl groups. These methyl groups are added to DNA at specific points along the genome to prevent specific genes from getting turned on.

During the development of multicellular organisms, humans among them, different patterns of methylation arise in different cells as methyl groups are biochemically attached to DNA at specific points along the genome during successive cell divisions. Normally this gradual methylation, a key part of the developmental program, is not reversible.

But after fertilization and during early development, a class of enzymes called “Tet” acts on a wide array of the methyl groups on the DNA to remove these brakes, so that genes can be activated as needed.

The UCSF researchers demonstrated that Tet enzymes require vitamin C for optimal activity as they act to remove the methyl groups from the DNA and to stimulate gene activity that more faithfully mimics in cultured stem cells what occurs at early stages of development in the mouse embryo.

“Potential roles for vitamin C in the clinic — including in embryo culture media used during in vitro fertilization, which currently do not contain vitamin C, and in cancers driven by aberrant DNA methylation — deserve exploration,” Ramalho-Santos, said.

In addition, scientists previously have found that many adult tissues also have stem cells, which can generate a variety of cell types found within a specific tissue. This raises the possibility that vitamin C might help maintain healthy stem cell populations in the adult, according to Ramalho-Santos.

“Although we did not in this paper address the function of Vitamin C in adult tissues, given the roles that Tet enzymes are now known to play in adult tissues, we anticipate that Vitamin C might also regulate Tet function in the adult,” Ramalho-Santos said. “This remains to be determined.”

Vitamin C already has become a popular supplement in recent decades, and potential health benefits of vitamin C supplementation continue to be investigated in clinical trials. It has been more than 80 years since vitamin C was first recognized as vital to prevent scurvy, a now rare connective-tissue disease caused by the failure of another enzyme that also relies on vitamin C.

The function of vitamin C as an antioxidant to prevent chemical damage is the likely reason why some commercial suppliers of growth media have included it in their products, Ramalho-Santos said, but other antioxidant molecules cannot replace Vitamin C in the enhancement of the activity of Tet enzymes.

Despite its importance, humans, unlike most animals and plants, cannot synthesize their own Vitamin C and must obtain it through their diet. The mouse makes vitamin C, but that fact does not diminish the expectation that the new findings will also apply to human development, according to Ramalho-Santos. Only adult liver cells in the mouse make vitamin C, he said.

Ramalho-Santos now aims to explore the newly discovered phenomenon in the living mouse. “The next step is to study vitamin C and gene expression in vivo,” he said.

 

http://www.sciencedaily.com/releases/2013/07/130701163755.htm

Study appears to overturn prevailing view of how the brain is wired

New research in rats shows how brain layers work

NEW YORK, NY (June 27, 2013) — A series of studies conducted by Randy Bruno, PhD, and Christine Constantinople, PhD, of Columbia University’s Department of Neuroscience, topples convention by showing that sensory information travels to two places at once: not only to the brain’s mid-layer (where most axons lead), but also directly to its deeper layers.  The study appears in the June 28, 2013, edition of the journal Science.

For decades, scientists have thought that sensory information is relayed from the skin, eyes, and ears to the thalamus and then processed in the six-layered cerebral cortex in serial fashion: first in the middle layer (layer 4), then in the upper layers (2 and 3), and finally in the deeper layers (5 and 6.) This model of signals moving through a layered “column” was largely based on anatomy, following the direction of axons—the wires of the nervous system.

“Our findings challenge dogma,” said Dr. Bruno, assistant professor of neuroscience and a faculty member at Columbia’s new Mortimer B. Zuckerman Mind Brain Behavior Institute and the Kavli Institute for Brain Science. “They open up a different way of thinking about how the cerebral cortex does what it does, which includes not only processing sight, sound, and touch but higher functions such as speech, decision-making, and abstract thought.”

The researchers used the well-understood sensory system of rat whiskers, which operate much like human fingers, providing tactile information about shape and texture. The system is ideal for studying the flow of sensory signals, said Dr. Bruno, because past research has mapped each whisker to a specific barrel-shaped cluster of neurons in the brain. “The wiring of these circuits is similar to those that process senses in other mammals, including humans,” said Dr. Bruno.

The study relied on a sensitive technique that allows researchers to monitor how signals move across synapses from one neuron to the next in a live animal. Using a glass micropipette with a tip only 1 micron wide (one-thousandth of a millimeter) filled with fluid that conducts nerve signals, the researchers recorded nerve impulses resulting from whisker stimulation in 176 neurons in the cortex and 76 neurons in the thalamus. The recordings showed that signals are relayed from the thalamus to layers 4 and 5 at the same time.  Although 80 percent of the thalamic axons went to layer 4, there was surprisingly robust signaling to the deeper layer.

To confirm that the deeper layer receives sensory information directly, the researchers used the local anesthetic lidocaine to block all signals from layer 4. Activity in the deeper layer remained unchanged.

“This was very surprising,” said Dr. Constantinople, currently a postdoctoral researcher at Princeton University’s Neuroscience Institute. “We expected activity in the lower layers to be turned off or very much diminished when we blocked layer 4. This raises a whole new set of questions about what the layers actually do.”

The study suggests that upper and lower layers of the cerebral cortex form separate circuits and play separate roles in processing sensory information. Researchers think that the deeper layers are evolutionarily older—they are found in reptiles, for example, while the upper and middle layers, appear in more evolved species and are thickest in humans.

One possibility, suggests Dr. Bruno, is that basic sensory processing is done in the lower layers: for example, visually tracking a tennis ball to coordinate the movement needed to make contact. Processing that involves integrating context or experience or that involves learning might be done in the upper layers. For example, watching where an opponent is hitting the ball and planning where to place the return shot.

“At this point, we still don’t know what, behaviorally, the different layers do,” said Dr. Bruno, whose lab is now focused on finding those answers.

Nobel-prize-winning neurobiologist Bert Sakmann, MD, PhD, of the Max Planck Institute in Germany, describes the study as “very convincing” and a game-changer. “For decades, the field has assumed, based largely on anatomy, that the work of the cortex begins in layer 4. Dr. Bruno has produced a technical masterpiece that firmly establishes two separate input streams to the cortex,” said Dr. Sakmann. “The prevailing view that the cortex is a collection of monolithic columns, handing off information to progressively higher modules, is an idea that will have to go.”

“Bruno’s work goes a long way toward overturning the conventional wisdom and provides new insight into the functional segregation of sensory input to the mammalian cerebral cortex, the region of the brain that processes our thoughts, decisions, and actions,” said Thomas Jessell, PhD, Claire Tow Professor of Motor Neuron Disorders in Neuroscience and a co-director of the Mortimer B. Zuckerman Mind Brain Behavior Institute and the Kavli Institute for Brain Science. “Developing a more refined understanding of cortical processing will take the combined efforts of anatomists, cell and molecular biologists, and animal behaviorists. The Zuckerman Institute, with its multidisciplinary faculty and broad mission, is ideally suited to building on Bruno’s fascinating work.”

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Funding for the study was provided by the National Institute of Neurological Disorders and Stroke (Grant # NS069679), the Rita Allen Foundation, and the Klingenstein Fund.

The authors declare no financial or other conflicts of interests.

About Columbia University

Among the world’s leading research universities, Columbia University in the City of New York continually seeks to advance the frontiers of scholarship and foster a campus community deeply engaged in understanding and confronting the complex issues of our time through teaching, research, patient care and public service. The University is comprised of 16 undergraduate, graduate and professional schools, and four affiliated colleges and seminaries in Northern Manhattan, as well as a wide array of research institutes and global centers located in major cities around the world. More than 40,000 accomplished students, award-winning faculty and professional staff define the University’s underlying values and commitment to pursuing new knowledge and educating informed, engaged citizens. Founded in 1754 as King’s College, Columbia is the fifth oldest institution of higher learning in the United States.

About Columbia University Medical Center

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.

Chemical in antibacterial soap fed to nursing rats harms offspring

Contact: Jenni Glenn Gingery
jgingery@endocrine.org
301-941-0240
The Endocrine Society

 

SAN FRANCISCO—- A mother’s exposure to triclocarban, a common antibacterial chemical, while nursing her babies shortens the life of her female offspring, a new study in rats finds. The results were presented Monday at The Endocrine Society’s 95th Annual Meeting in San Francisco.

Commonly used in antibacterial soap and other personal care products, triclocarban has the potential for a large portion of the public to be exposed to it, said the study’s lead author, Rebekah Kennedy, a graduate student in the Department of Public Health at the University of Tennessee, Knoxville.

“Our study provides supporting evidence for the potential adverse effects of triclocarban exposure during early life, specifically during the lactation period,” Kennedy said. “The results indicate that a mother’s long-term use of this compound might affect the early development of her offspring, at least according to our animal model.”

Past studies by the senior investigator, Jiangang Chen, PhD, an assistant professor at the University of Tennessee, showed that triclocarban enhances the growth of sex organs in the adult male rat. In this study, the researchers sought to learn if exposure to the same compound, either in the womb or during lactation, would affect rat pups.

Beginning on pregnancy day 5 and continuing until 21 days after giving birth, maternal rats continuously had free access to regular rat chow (the control rats) or chow supplemented with either 0.2 or 0.5 percent triclocarban. The doses found in the blood of maternal rats exposed to triclocarban correspond to blood levels of triclocarban in humans after a 15-minute whole-body shower using a bar soap containing 0.6 percent triclocarban, Chen said.

After birth, some littermates were moved to other groups so that each rat mother nursed two of her own pups and two pups from each of the other two groups. The offspring were weighed daily.

Body weight did not differ at birth among rat pups from the three groups, but by day 3, pups nursed by control rats were heavier than either triclocarban-exposed group, Kennedy reported. Pups nursed by rats that received 0.2 percent triclocarban were about half as heavy at weaning on day 21 as pups nursed by controls, and only 4 of 30 pups survived.

The investigators found that all pups nursed by the control rats survived until weaning, including those born to triclocarban-fed maternal rats but nursed by control rats. No pups nursed by rats that received the larger triclocarban dose, 0.5 percent, survived until day 6. Among pups nursed by rats that received the 0.2 percent dose of triclocarban, 57 percent reportedly lived to nine days after birth, and only 13% survived after weaning.

“Our data suggest that the critical exposure window affecting rat pup survival is related to lactation, as all pups raised by control rats survived regardless of triclocarban exposure status during gestation,” Kennedy said.

Although the researchers did not measure triclocarban levels in the offspring, they speculate that the chemical entered the gastrointestinal tract through the mother’s milk and affected the pups’ growth and development.

The National Institutes of Health’s National Institute of Environmental Health Sciences supported this research.

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Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology. Today, The Endocrine Society’s membership consists of over 16,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter.

Prenatal exposure to BPA affects fat tissues in sheep

Contact: Jenni Glenn Gingery
jgingery@endocrine.org
301-941-0240
The Endocrine Society

 

SAN FRANCISCO-— New research suggests that fetal exposure to the common environmental chemical bisphenol A, or BPA, causes increased inflammation in fat tissues after birth, which can lead to obesity and metabolic syndrome. Results of the animal study were presented Monday at The Endocrine Society’s 95th Annual Meeting in San Francisco.

Found in plastic water bottles, older baby bottles and many other consumer products, BPA is a known hormone disrupter with estrogen-like properties. Prior research has linked BPA in both animals and humans to obesity and the metabolic syndrome, which is a cluster of metabolic risk factors that increase the chance of later developing diabetes, heart disease and stroke.

“This research is the first study to show that prenatal exposure to BPA increases postnatal fat tissue inflammation, a condition that underlies the onset of metabolic diseases such as obesity, diabetes and cardiovascular disease,” said the study’s lead author, Almudena Veiga-Lopez, DVM, PhD, a research investigator at the University of Michigan, Ann Arbor.

She said the study, which examines the effects of BPA on sheep, improves the understanding of how prenatal BPA exposure regulates the inflammatory response in offspring in the tissues that are relevant to development of metabolic disease. The study was conducted in the laboratory of Vasantha Padmanabhan, MS, PhD, Professor at the University of Michigan, Ann Arbor, with funding from the National Institutes of Health’s National Institutes of Environmental Health Sciences. Veiga-Lopez said sheep have similar body fat to that in humans, including visceral (deep belly) fat and subcutaneous fat, which is directly below the skin.

The researchers fed two groups of pregnant sheep corn oil, either with nothing added to it or with added BPA at a dose needed to achieve BPA levels similar to those seen in human cord blood in the umbilical cord blood of the sheep offspring. Of the female offspring from the sheep, half from each group were overfed at approximately 6 weeks of age. All female offspring then were divided into four groups of nine to 12 animals each: (1) non-BPA-exposed controls that received a normal diet, (2) BPA-exposed offspring that received a normal diet, (3) overfed, obese controls and (4) overfed, obese BPA-exposed offspring.

At 15 months of age, sheep underwent a glucose tolerance test, to measure their insulin and blood sugar levels. Seven months later, the researchers collected samples of the animals’ visceral and subcutaneous fat tissues to evaluate levels of two biological markers of inflammation. These biomarkers were CD68, a marker for inflammatory cells, and adiponectin, a molecule with a known role in the development of metabolic syndrome. When the adiponectin level decreases or CD68 expression increases, inflammation is worse, according to Veiga-Lopez.

Adiponectin was decreased and CD68 expression was raised in the visceral fat of both obese groups, and CD68 expression also was raised in the subcutaneous fat in normal weight, BPA-exposed female offspring, Veiga-Lopez reported. She said these results suggest that “prenatal BPA exposure and postnatal diet may interact to modulate inflammatory mechanisms in fat deposits.”

Both obese groups had hyperinsulinemia, or high insulin levels, a precursor to insulin resistance, which is a prediabetic state, Veiga-Lopez reported. However, she said prenatal exposure to BPA did not lead to insulin resistance in sheep, as was true in a previous mouse study. She speculated that the hyperinsulinemia in obese offspring stems from changes that occurred in the two inflammatory markers in the visceral fat deposit.

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Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology. Today, The Endocrine Society’s membership consists of over 16,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter.

Vitamin D supplementation may delay precocious puberty in girls

Contact: Jenni Glenn Gingery jgingery@endocrine.org 301-941-0240 The Endocrine Society

SAN FRANCISCO– Vitamin D supplementation may help delay early onset of puberty in girls, a new clinical study finds. The results were presented Monday at The Endocrine Society’s 95th Annual Meeting in San Francisco.

Among girls, puberty generally begins between the ages of 10 and 14. Boys undergo these changes later, usually between 12 to 16 years of age. Precocious puberty is diagnosed in girls when sexual development begins before the age of 8; in boys, it is diagnosed when these changes occur before age 9.

Recently, medical research has linked vitamin D deficiency to a number of diseases, including cancer, obesity and autoimmune disease. Low vitamin D levels have been found in girls with precocious puberty, as well, although the exact relationship between vitamin D deficiency and early development remains unclear.

To determine how low vitamin D deficiency is related to precocious puberty, investigators in the current study compared blood levels of the vitamin between girls with early and normal development.

They found that girls with precocious puberty were significantly more likely than those with age-appropriate development to have a severe vitamin D deficiency. Among the precocious puberty group, 44 percent had a severe deficiency in vitamin D, compared to 21 percent of the group with age-appropriate physical development.

Additionally, investigators examined the activity of neurons responsible for stimulating the release of a hormone that triggers the ovulation process.  Specifically, investigators used the neuron-stimulating compound called N-methyl-D-aspartate, or NMDA, to activate the neurons responsible for releasing gondadotropin-releasing hormone, or GnRH. They found that vitamin D was associated with a suppression of the NMDA-mediated neuronal activities on GnRH neurons.

“If we understand more about the action mechanism of vitamin D on GnRH neuronal activities, we can find a clue to control of precocious puberty using vitamin D or related molecules,” said study lead author Min Sun Kim, MD, PhD, assistant professor at Chonbuk National University Medical School in Jeonju, South Korea. “Our results suggest that vitamin D may inhibit early pubertal onset and/or the rapid progression of puberty, at least in part, through the suppression of NMDA-mediated GnRH neuronal excitation in humans.”

Study participants included 110 girls between the ages of 7 to 10 years. Seventy-five girls exhibited normal patterns of development, while 35 were classified as having precocious puberty. Investigators used the Tanner scale, which assesses human physical development, to differentiate normal versus precocious pubertal development.

According to Kim, more research, including studies in animal models, is necessary to confirm this project’s findings.

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Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology.  Today, The Endocrine Society’s membership consists of over 16,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter.

Short-term antidepressant use, stress, high-fat diet linked to long-term weight gain

Contact: Jenni Glenn Gingery jgingery@endocrine.org 301-941-0240 The Endocrine Society

SAN FRANCISCO—- Short-term use of antidepressants, combined with stress and a high-fat diet, is associated with long-term increases in body weight, a new animal study finds. The results were presented Sunday at The Endocrine Society’s 95th Annual Meeting in San Francisco.

“Our study suggests that short-term exposure to stress and antidepressants, rather than a high-calorie, high-fat diet alone, leads to long-term body weight gain, accompanied with increased bone and spleen weights,” said study lead author Suhyun Lee, a PhD candidate in the medical sciences at the John Curtin School of Medical Research at the Australian National University in Canberra, Australia.

Antidepressants are among the most prevalent medications today, accounting for millions of prescriptions each year. In the United States, physicians wrote more than 1.5 million prescriptions for antidepressants in 2009, while physicians in Australia wrote more than 12 million of these prescriptions in 2008.

At the same time, obesity rates are climbing in developed countries worldwide. Among adults in both the United States and Australia, two-thirds are overweight or obese. Being overweight or obese is a risk factor for many serious diseases, including heart disease, which is the leading cause of death among adults in the United States and Australia.

Unfortunately, weight gain is one of the main side effects associated with antidepressants. The amount of excess weight varies between patients, but some have reported increases as high as 7 percent of the amount they weighed at the start of their antidepressant treatment.

In this study, male rats treated with the antidepressant fluoxetine after induced stress had significantly increased body weight compared to control animals. In addition to greater overall body weight, animals in the antidepressant group also developed greater bone and spleen weights, compared to animals in the control group.

“These findings may implicate different pathophysiological mechanisms in stress and antidepressant related obesity when compared to obesity that is solely diet-induced,” Lee said.

During the follow-up, investigators also compared behavior between the drug and control groups. This comparison showed that the antidepressants reduced anxiety among the animals in response to induced stress. After the stressful periods, which involved physical restraint, the fluoxetine-treated animals exhibited significantly fewer symptoms of anxiety, compared to the control animals.

The study involved a two-week period of repeated restraint stress, combined with antidepressant treatment among one group of animals, and saline administration among the control group. After the two-week period, both groups of animals received a high-fat diet for 295 days.

The John Curtin School of Medical Research, Australian National University funded the study.

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Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology.  Today, The Endocrine Society’s membership consists of over 16,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter.

FDA – 2012 law now in effect which lifts conflict of interest restrictions on FDA advisory panels

Contact: Kathy Fackelmann kfackelmann@gwu.edu 202-994-8354 George Washington University School of Public Health and Health Services

Conflict-of-interest restrictions needed to ensure strong FDA review

Panel members with ties to industry might lead to approval of unsafe drugs, new analysis suggests

WASHINGTON, DC—A 2012 law that loosened conflict-of-interest restrictions for FDA advisory panels could weaken the agency’s review system and could allow more drugs with safety problems to gain market approval, says a new analysis published June 7 in Science by researchers at the George Washington  University School of Public Health and Health Services (SPHHS).

The 2012 legislation removed measures put in place by an earlier law passed in 2007, according to the report by Susan F. Wood, PhD, an associate professor of health policy at SPHHS and Jillian K. Mador, a medical student at the GW School of Medicine & Health Sciences (SMHS). The 2007 FDA Amendments Act put caps on the number of experts with conflict of interest who could serve on FDA advisory panels in order to ensure an impartial review of new drugs, the authors said.

They say there is good reason to worry about the revisions in the law that now allow FDA panels to have more members who report a conflict—such as consulting fees from drug companies.  The removal of the requirement for “caps” on advisory committee members with financial conflicts was seen as a top priority of the pharmaceutical industry during the 2012 passage of the FDA Safety and Innovation Act.

“Panels top-heavy with experts who have financial ties to industry might be more likely to dismiss or ignore scientific evidence of risks or other problems,” said Wood, who is a former FDA official and the lead author on the paper. “This analysis also suggests that loosening the restrictions could lead to an appearance of conflict—and to potentially biased recommendations for approval or disapproval of a FDA regulated product.”

The authors point to historical examples of cases in which loaded panels voted for drugs that were later found to have serious safety problems.

The 2012 law was passed after the drug industry complained that the conflict of interest restrictions slowed down the FDA approval process and made it hard to fill panel positions with qualified experts. But Wood and Mador looked at the evidence and concluded that there are plenty of scientists with expertise to fill these positions—without the ties to the industry.

The analysis goes on to say that the restrictions did not affect FDA’s productivity in the past and there is little reason to think that reinstituting the caps would slow down the process of bringing safe new drugs to market today.  The analysis also demonstrates that the caps have never been reached, so FDA had apparently been successful in identifying experts without financial conflicts.

The analysis concludes that the evidence does not support the decision to remove the caps on conflict of interest and points out that Congress will soon begin discussing reauthorization of the 2012 law which is revised every five years. The authors urge the scientific and medical community to weigh in early on those discussions in order to point out concerns—and to ensure that the FDA Advisory Committee and review process remains strong and effective.

Wood and Mador’s new analysis, “Uncapping Conflict of Interest,” appears in the June 7 issue of Science.

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About the George Washington University School of Public Health and Health Services:

Established in July 1997, the School of Public Health and Health Services brought together three longstanding university programs in the schools of medicine, business, and education and is now the only school of public health in the nation’s capital. Today, more than 1,100 students from nearly every U.S. state and more than 40 nations pursue undergraduate, graduate, and doctoral-level degrees in public health. http://sphhs.gwu.edu/

Tumors disable immune cells by using up sugar

Contact: Michael C. Purdy purdym@wustl.edu 314-286-0122 Washington University School of Medicine

Cancer cells’ appetite for sugar may have serious consequences for immune cell function, researchers at Washington University School of Medicine in St. Louis have learned.

The scientists found that when they kept sugar away from critical immune cells called T cells, the cells no longer produced interferon gamma, an inflammatory compound important for fighting tumors and some kinds of infection.

“T cells can get into tumors, but unfortunately they are often ineffective at killing the cancer cells,” said Erika Pearce, PhD, assistant professor of pathology and immunology. “Lack of the ability to make interferon gamma could be one reason why they fail to kill tumors. By understanding more about how sugar metabolism affects interferon production, we may be able to develop treatments that fight tumors by enhancing T cell function. ”

According to Pearce, inhibiting interferon gamma production also may help scientists treat autoimmune disorders in which T cells cause too much inflammation.

The results appear June 6 in Cell.

Pearce’s insights arose from her research into the metabolism of T cells.

Like most cells, T cells can make energy either by using an efficient process called oxidative phosphorylation or a less efficient pathway called aerobic glycolysis.

Cells normally make most of their energy via oxidative phosphorylation, but they need oxygen to do so. If oxygen runs short, most cells switch to aerobic glycolysis. Low sugar levels can force cells to use oxidative phosphorylation for their energy.

Scientists aren’t sure why, but many cells, including T cells, switch to aerobic glycolysis when they need to reproduce rapidly. T cells proliferate quickly as they begin to respond to invaders or tumors, and scientists have assumed their switch to aerobic glycolysis was essential for this replicative process.

For the new study, Chih-Hao Chang, PhD, a postdoctoral researcher in the Pearce lab and first author of the study, set up a system that allowed him to control the resources available to T cells in test tubes. Switching the sugars available to the cells let him force the cells to use either oxidative phosphorylation or aerobic glycolysis.

“The conventional view was that proliferating T cells needed to use glycolysis, ” Chang said. “We found that wasn’t true: they could also use oxidative phosphorylation to support proliferation.”

After proliferation starts, the T cells can sustain themselves with either energy-making process. But a problem arose when the scientists forced the T cells to switch from aerobic glycolysis to oxidative phosphorylation.

“The proteins involved in glycolysis don’t just disappear when glycolysis is turned off — they’re pretty stable proteins, so they can hang around in the cell and participate in other processes,” Pearce said. “In T cells this can be a problem since one of these proteins, GAPDH, can inhibit the production of interferon gamma.”

When the scientists put T cells in a dish with cancer cells, which regularly consume large amounts of sugar, the T cells’ ability to make inflammatory compounds was impaired. But when the researchers gave sugar directly to the T cells, production of those inflammatory compounds doubled.

“It’s like an on-off switch, and all we need to do to flip it is change the availability of sugar,” Pearce said. “T cells often can go everywhere — tumors, inflammation, infections — but sometimes they don’t do anything. If we can confirm that this same switch is involved in these failures in the body, we might be able to find a way to put the fight back into those T cells.”

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Funding from the National Institutes of Health (AI091965 and CA158823 to ELP and CA164062 to EJP), the Canadian Institute of Health Research (MOP-93799 to RGJ), the Arthritis Society of Canada (RGJ), the Dutch Organization for Scientific Research (GJWvdW), and the Emerald Foundation Young Investigator Award (ELP) supported this research.

Chang C-H, Curtis JD, Maggi Jr. LB, Faubert B, Villarino Av, O’Sullivan D, Huang S C-C, van der Windt GJW, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones G, and Pearce EL.Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell, online June 6, 2013. DOI 10.1016/

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Soda and illegal drugs cause similar damage to teeth

CHICAGO (May 28, 2013)—Addicted to soda? You may be shocked to learn that drinking large quantities of your favorite carbonated soda could be as damaging to your teeth as methamphetamine and crack cocaine use. The consumption of illegal drugs and abusive intake of soda can cause similar damage to your mouth through the process of tooth erosion, according to a case study published in the March/April 2013 issue of General Dentistry, the peer-reviewed clinical journal of the Academy of General Dentistry (AGD).

Tooth erosion occurs when acid wears away tooth enamel, which is the glossy, protective outside layer of the tooth. Without the protection of enamel, teeth are more susceptible to developing cavities, as well as becoming sensitive, cracked, and discolored.

The General Dentistry case study compared the damage in three individuals’ mouths—an admitted user of methamphetamine, a previous longtime user of cocaine, and an excessive diet soda drinker. Each participant admitted to having poor oral hygiene and not visiting a dentist on a regular basis. Researchers found the same type and severity of damage from tooth erosion in each participant’s mouth.

“Each person experienced severe tooth erosion caused by the high acid levels present in their ‘drug’ of choice—meth, crack, or soda,” says Mohamed A. Bassiouny, DMD, MSc, PhD, lead author of the study.

“The citric acid present in both regular and diet soda is known to have a high potential for causing tooth erosion,” says Dr. Bassiouny.

Similar to citric acid, the ingredients used in preparing methamphetamine can include extremely corrosive materials, such as battery acid, lantern fuel, and drain cleaner. Crack cocaine is highly acidic in nature, as well.

The individual who abused soda consumed 2 liters of diet soda daily for three to five years. Says Dr. Bassiouny, “The striking similarities found in this study should be a wake-up call to consumers who think that soda—even diet soda—is not harmful to their oral health.”

AGD Spokesperson Eugene Antenucci, DDS, FAGD, recommends that his patients minimize their intake of soda and drink more water. Additionally, he advises them to either chew sugar-free gum or rinse the mouth with water following consumption of soda. “Both tactics increase saliva flow, which naturally helps to return the acidity levels in the mouth to normal,” he says.

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Individuals had a 40 percent increased risk of pertussis for each additional acellular dose received (as compared to receipt of a DTwP dose) between ages 1-24 months

Contact: Vincent Staupe vstaupe@golinharris.com 415-318-4386 Kaiser Permanente

Whole-cell vaccine was more effective than acellular vaccine during California pertussis outbreak

OAKLAND, Calif., May 20, 2013 — Whole-cell pertussis vaccines were more effective at protecting against pertussis than acellular pertussis vaccines during a large recent outbreak, according to a new Kaiser Permanente study published in Pediatrics.

Whole-cell pertussis vaccines, also called DTwP, were available from the 1940s to 1990s, but were associated with safety concerns that ultimately led to the development of acellular pertussis vaccines, which are also called DTaP. By the late 1990s, the United States had switched from whole-cell to acellular vaccines for all five recommended infant and childhood doses.

The study, which followed the 2010-2011 pertussis outbreak in California, examined 10- to 17-year-olds who received the recommended four pertussis-containing vaccines. The researchers evaluated the risk of pertussis during the outbreak according to the number of whole-cell and/or acellular pertussis vaccines these participants had received as infants and toddlers.

Despite high levels of vaccine coverage, pertussis epidemics have arisen every three to five years since the 1980s, with progressively higher incidence rates over time. “Studies have suggested that protection following the acellular pertussis vaccine is less enduring than following the whole-cell pertussis vaccine,” said lead author Nicola Klein, MD, PhD, co-director of the Kaiser Permanente Vaccine Study Center and a pediatrician. “Although reasons for the recurrent pertussis outbreaks are complex, waning protection following five doses of acellular pertussis vaccine plays a central role, at least in recent epidemics.”

The study included 138 individuals with confirmed pertussis, 899 individuals who had a lab test indicating they did not have pertussis, and 54,339 individuals who were similar to those with confirmed pertussis on sex, race/ethnicity, medical clinic, and membership status.

Increased number of acellular doses from zero to four was significantly associated with an increasing percent of positive pertussis tests. On average, individuals had a 40 percent increased risk of pertussis for each additional acellular dose received (as compared to receipt of a DTwP dose) between ages 1-24 months.

Teenagers who were vaccinated with four doses of acellular vaccines were at almost six times higher risk of pertussis than were those who had received four doses of whole-cell vaccines. Persons who received mixed whole-cell and acellular vaccines had an intermediate level of risk between those who received all whole-cell or all acellular vaccines. Those who received mixed vaccines were at nearly four times higher risk of pertussis than were those who received all whole-cell vaccines.

Earlier studies by Kaiser Permanente have shown that protection from the fifth dose of acellular pertussis vaccine wanes substantially during the five years after vaccination among children 4 to 12 years of age who have only received the acellular vaccine. The current study included only individuals born in 1999 or earlier, for whom at least five years had passed since receipt of the fifth pertussis vaccine.

Since 2005, the Advisory Committee on Immunization Practices has recommended boosting with reduced antigen content acellular pertussis vaccine, also known as Tdap, for persons 11 years and older. The study found that a booster dose of Tdap did not overcome the advantage in protection from pertussis seen among those who had received four doses of the whole-cell vaccine.

“The results indicate that a booster dose of Tdap does not overcome the advantage in protection from pertussis afforded to those who previously received four doses of the whole-cell vaccine,” Dr. Klein said. “Despite this, boosting the newly emerging cohort of acellular pertussis vaccine-only teenagers with Tdap remains the best means currently available to help protect this group against disease.”

Studies demonstrate that whole-cell and acellular pertussis vaccines administered to infants trigger different immune responses that at least partially persist through the teenage years, but long-term clinical consequences of such differences have been unknown. The results of this study, the researchers said, suggest that variations in immune responses induced by primary immunization during infancy play a central role in protection from disease years later. Additionally, the study highlights the need for new pertussis vaccines that provide both an improved safety profile and long lasting immunity.

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Additional authors on the study include Joan Bartlett, MPH, MPP; Bruce Fireman, MA; Ali Rowhani-Rahbar, MD, MPH, PhD; and Roger Baxter, MD, of  Kaiser Permanente Division of Research in Northern California.

This research was supported by funding from Kaiser Permanente.

About the Kaiser Permanente Division of Research

The Kaiser Permanente Division of Research conducts, publishes and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and the society at large. It seeks to understand the determinants of illness and well-being and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 600-plus staff is working on more than 250 epidemiological and health services research projects. For more information, visit http://www.dor.kaiser.org.

About Kaiser Permanente

Kaiser Permanente is committed to helping shape the future of health care. We are recognized as one of America’s leading health care providers and not-for-profit health plans. Founded in 1945, our mission is to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve. We currently serve more than 9.1 million members in nine states and the District of Columbia. Care for members and patients is focused on their total health and guided by their personal physicians, specialists and team of caregivers. Our expert and caring medical teams are empowered and supported by industry-leading technology advances and tools for health promotion, disease prevention, state-of-the-art care delivery and world-class chronic disease management. Kaiser Permanente is dedicated to care innovations, clinical research, health education and the support of community health. For more information, go to: kp.org/newscenter.

Ginger compounds may be effective in treating asthma symptoms

Contact: Nathaniel Dunford ndunford@thoracic.org American Thoracic Society

ATS 2013, PHILADELPHIA ─ Gourmands and foodies everywhere have long recognized ginger as a great way to add a little peppery zing to both sweet and savory dishes; now, a study from researchers at Columbia University shows purified components of the spicy root also may have properties that help asthma patients breathe more easily.

The results of the study will be presented at the ATS 2013 International Conference.

Asthma is characterized by bronchoconstriction, a tightening of the bronchial tubes that carry air into and out of the lungs. Bronchodilating medications called beta-agonists (β-agonists) are among the most common types of asthma medications and work by relaxing the airway smooth muscle (ASM) tissues. This study looked at whether specific components of ginger could help enhance the relaxing effects of bronchodilators.

“Asthma has become more prevalent in recent years, but despite an improved understanding of what causes asthma and how it develops, during the past 40 years few new treatment agents have been approved for targeting asthma symptoms,” said lead author Elizabeth Townsend, PhD, post-doctoral research fellow in the Columbia University Department of Anesthesiology.  “In our study, we demonstrated that purified components of ginger can work synergistically with β-agonists to relax ASM.”

To conduct their study, the researchers took human ASM tissue samples and caused the samples to contract by exposing them to acetylcholine, a neurotransmitting compound that causes bronchoconstriction. Next, the researchers mixed the β-agonist isoproterenol with three separate components of ginger: 6-gingerol, 8-gingerol or 6-shogaol. Contracted tissue samples were exposed to each of these three mixtures as well as unadulterated isoproterenol and the relaxation responses were recorded and compared.

At the conclusion of their study, the researchers found that tissues treated with the combination of purified ginger components and isoproterenol exhibited significantly greater relaxation than those treated only with isoproterenol; of the three ginger components, 6-shogaol appeared most effective in increasing the relaxing effects of the β-agonist.

Once they were able to demonstrate that the ginger components enhanced the relaxing effects of the β-agonist, they turned their attention to learning why. First, the researchers wanted to determine if the ginger components might work by affecting an enzyme called phosphodiesterase4D (PDE4D). Previous studies have shown that PDE4D, which is found in the lungs, inhibits processes that otherwise help relax ASM and lessen inflammation. Using a technique called fluorescent polarization, they found that all three components significantly inhibited PDE4D.

Next, the study looked at F-actin filaments, a protein structure which previous studies have shown plays a role in the constriction of ASM, and found that 6-shogaol was effective in speedily dissolving these filaments.

“Taken together, these data show that ginger constituents 6-gingerol, 8-gingerol and 6-shogaol act synergistically with the β-agonist in relaxing ASM, indicating that these compounds may provide additional relief of asthma symptoms when used in combination with β-agonists,” Dr. Townsend noted.”By understanding the mechanisms by which these ginger compounds affect the airway, we can explore the use of these therapeutics in alleviating asthma symptoms.”

Dr. Townsend and her colleague, Dr. Charles Emala, hope future studies will enable them to gain a better understanding of the cellular mechanisms that facilitate ASM relaxation and to determine whether aerosol delivery of these purified constituents of ginger may have therapeutic benefit in asthma and other bronchoconstrictive diseases.

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* Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time.

Abstract 38824

Active Constituents Of Ginger Potentiate β-Agonist-Induced Relaxation Of Airway Smooth Muscle

Type: Scientific Abstract

Category: 03.10 – Smooth Muscle: Airway (RSF)

Authors: E.A. Townsend, Y. Zhang, C. Xu, R. Wakita, C. Emala; Columbia University – New York, NY/US

Abstract Body

Rationale: Asthma prevalence has steadily increased and is characterized by bronchoconstriction. Bronchodilators are the first-line therapy to reverse airway obstruction by relaxing airway smooth muscle (ASM). Asthma therapies include β-agonists that induce bronchodilation by activating adenylyl cyclase, increasing cAMP and activating protein kinase A. Despite improved understanding of the pathogenesis of asthma, few novel therapeutics have been approved for targeting asthma symptoms in the last 40 years. This highlights the need for new therapies that relax contracted airways while also augmenting traditional therapies. We demonstrated that purified components of ginger can relax ASM. By understanding the mechanisms by which these compounds exert their effects on the airway, we can explore the use of these phytotherapeutics in alleviating asthma symptoms. We hypothesized that unique chemical components of ginger have bronchorelaxant properties and work synergistically with β-agonist signaling to relax ASM.

Methods and Results: Epithelial-denuded human ASM tissue (deidentified; exempt from Columbia’s IRB) was contracted with acetylcholine in organ baths. ASM tissues were then relaxed dose-dependently with β-agonist, isoproterenol (100 pM – 10 μM, half-log increments). The tissues were treated concurrently at 300 pM isoproterenol with vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 μM). Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-shogaol showed the largest leftward shift in the EC50 for isoproterenol. Purified phosphodiesterase 4D enzyme, the prominent isoform in the lung, was used to assess PDE inhibitory action of the ginger constituents using fluorescent polarization analyses. 6-gingerol, 8-gingerol, and 6-shogaol (100 μM, 15 min) significantly inhibited PDE4D compared to vehicle control (0.2% DMSO), the PDE4-selective inhibitor, rolipram (10 μM) and non-selective PDE inhibitor, IBMX (250 μM) were used as positive controls. β-agonist induced depolymerization of actin via a PKA-HSP20-dependent pathway contributes to ASM relaxation. In primary human ASM cells transiently transfected with RFP-actin, treatment with 6-gingerol, 8-gingerol, or 6-shogaol showed acute (within seconds) dissolution of F-actin filaments. This was not due to PKA phosphorylation of HSP20.

Conclusions: Taken together, these data show synergistic effects of ginger constituents 6-gingerol, 8-gingerol, and 6-shogaol with β-agonist in relaxing ASM. This may be attributed to increased cAMP due to PDE4D inhibitory activity. Additionally, these compounds stimulate actin depolymerization through a novel PKA-independent pathway, providing another pathway for potentiation with β-agonists. These compounds may provide additional relief of asthma symptoms when used in combination with β2-agonists and highlight novel use of phytotherapeutics in the treatment of obstructive lung disease.

Over-diagnosis and over-treatment of depression is common in the US

Contact: Natalie Wood-Wright nwoodwri@jhsph.edu 410-614-6029 Johns Hopkins University Bloomberg School of Public Health

Americans are over-diagnosed and over-treated for depression, according to a new study conducted at the Johns Hopkins Bloomberg School of Public Health. The study examines adults with clinician-identified depression and individuals who experienced major depressive episodes within a 12-month period. It found that when assessed for major depressive episodes using a structured interview, only 38.4 percent of adults with clinician-identified depression met the 12-month criteria for depression, despite the majority of participants being prescribed and using psychiatric medications. The results are featured in the April 2013 issue of Psychotherapy and Psychosomatics.

“Depression over-diagnosis and over-treatment is common in the U.S. and frankly the numbers are staggering,” said Ramin J. Mojtabai, PhD, author of the study and an associate professor with the Bloomberg School’s Department of Mental Health. “Among study participants who were 65 years old or older with clinician-identified depression, 6 out of every 7 did not meet the 12-month major-depressive-episodes criteria. While participants who did not meet the criteria used significantly fewer services and treatment contacts, the majority of both groups used prescription psychiatric medication.”

Using a sample of 5,639 participants from the 2009-2010 United States National Survey of Drug Use and Health, Mojtabai assessed clinician-identified depression based on questions about conditions that the participants were told they had by a doctor or other medical professional in the past 12 months. The study indicates that even among participants without a lifetime history of major or minor depression, a majority reported having taken prescription psychiatric medications.

“A number of factors likely contribute to the high false-positive rate of depression diagnosis in community settings, including the relatively low prevalence of depression in these settings, clinicians’ uncertainty about the diagnostic criteria and the ambiguity regarding sub-threshold syndromes,” said Mojtabai. “Previous evidence has highlighted the under-diagnosis and under-treatment of major depression in community settings.  The new data suggest that the under-diagnosis and under-treatment of many who are in need of treatment occurs in conjunction with the over-diagnosis and over-treatment of others who do not need such treatment. There is a need for improved targeting of diagnosis and treatment of depression and other mental disorders in these settings.”

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“Clinician-Identified Depression in Community Settings: Concordance with Structured-Interview Diagnoses,” was written by Ramin J. Mojtabai.

Mild iodine deficiency in womb associated with lower scores on children’s literacy tests

Contact: Jenni Glenn Gingery jgingery@endo-society.org 301-941-0240 The Endocrine Society

Changes in mother’s diet, supplements may prevent long-term neurological impairment

Chevy Chase, MD––Children who did not receive enough iodine in the womb performed worse on literacy tests as 9-year-olds than their peers, according to a recent study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).

Iodine is absorbed from food and plays a key role in brain development. Even mild deficiency during pregnancy can harm the baby’s neurological development.

“Our research found children may continue to experience the effects of insufficient iodine for years after birth,” said the study’s lead author, Kristen L. Hynes, PhD, of the Menzies Research Institute at the University of Tasmania in Australia. “Although the participants’ diet was fortified with iodine during childhood, later supplementation was not enough to reverse the impact of the deficiency during the mother’s pregnancy.”

The longitudinal study examined standardized test scores of 228 children whose mothers attended The Royal Hobart Hospital’s antenatal clinics in Tasmania between 1999 and 2001. The children were born during a period of mild iodine deficiency in the population. Conditions were reversed when bread manufacturers began using iodized salt in October 2001 as part of a voluntary iodine fortification program.

The study found inadequate iodine exposure during pregnancy was associated with lasting effects. As 9-year-olds, the children who received insufficient iodine in the womb had lower scores on standardized literacy tests, particularly in spelling. However, inadequate iodine exposure was not associated with lower scores on math tests. Researchers theorize iodine deficiency may take more of a toll on the development of auditory pathways and, consequently, auditory working memory and so had more of an impact on students’ spelling ability than their mathematical reasoning ability.

“Fortunately, iodine deficiency during pregnancy and the resulting neurological impact is preventable,” Hynes said. “Pregnant women should follow public health guidelines and take daily dietary supplements containing iodine. Public health supplementation programs also can play a key role in monitoring how much iodine the population is receiving and acting to ensure at-risk groups receive enough iodine in the diet.”

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The Endocrine Society’s clinical practice guidelines on managing thyroid dysfunction during pregnancy and postpartum, including iodine supplementation, are available at http://www.endo-society.org/guidelines/upload/Thyroid-Exec-Summ.pdf.

Other researchers working on the study include: P. Otahal, I. Hay and J. Burgess of the University of Tasmania.

The article, “Mild Iodine Deficiency During Pregnancy is Associated with Reduced Educational Outcomes in the Offspring: 9-Year Follow-Up of the Gestational Iodine Cohort,” appears in the May 2013 issue of JCEM.

Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology.  Today, The Endocrine Society’s membership consists of over 16,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at http://www.endo-society.org. Follow us on Twitter at https://twitter.com/#!/EndoMedia.

Gold Nanoparticles Accelerate Aging : “found in everyday items such as personal care products”

Nanoparticles Found in Everyday Items Can Inhibit Fat Storage: Gold Nanoparticles Accelerate Aging

New research reveals that pure gold nanoparticles found in everyday items such as personal care products, as well as drug delivery, MRI contrast agents and solar cells can inhibit adipose (fat) storage and lead to accelerated aging and wrinkling, slowed wound healing and the onset of diabetes. (Credit: © Sandor Kacso / Fotolia)

Apr. 18, 2013 — New research reveals that pure gold nanoparticles found in everyday items such as personal care products, as well as drug delivery, MRI contrast agents and solar cells can inhibit adipose (fat) storage and lead to accelerated aging and wrinkling, slowed wound healing and the onset of diabetes. The researchers, led by Tatsiana Mironava, a visiting assistant professor in the Department of Chemical and Molecular Engineering at Stony Brook University, detail their research in the journal Nanotoxicology.

Together with co-author Dr. Marcia Simon, Professor of Oral Biology and Pathology at Stony Brook University, and Director of the University’s Living Skin Bank, a world-class facility that has developed skin tissue for burn victims and various wound therapies, the researchers tested the impact of nanoparticles in vitro on multiple types of cells, including adipose (fat) tissue, to determine whether their basic functions were disrupted when exposed to very low doses of nanoparticles. Subcutaneous adipose tissue acts as insulation from heat and cold, functions as a reserve of nutrients, and is found around internal organs for padding, in yellow bone marrow and in breast tissue.

They discovered that the human adipose-derived stromal cells — a type of adult stem cells — were penetrated by the gold nanoparticles almost instantly and that the particles accumulated in the cells with no obvious pathway for elimination. The presence of the particles disrupted multiple cell functions, such as movement; replication (cell division); and collagen contraction; processes that are essential in wound healing.

According to the researchers, the most disturbing finding was that the particles interfered with genetic regulation, RNA expression and inhibited the ability to differentiate into mature adipocytes or fat cells. “Reductions caused by gold nanoparticles can result in systemic changes to the body,” said Professor Mironava. “Since they have been considered inert and essentially harmless, it was assumed that pure gold nanoparticles would also be safe. Evidence to the contrary is beginning to emerge.”

This study is also the first to demonstrate the impact of nanoparticles on adult stem cells, which are the cells our body uses for continual organ regeneration. It revealed that adipose derived stromal cells involved in regeneration of multiple organs, including skin, nerve, bone, and hair, ignored appropriate cues and failed to differentiate when exposed to nanoparticles. The presence of gold nanoparticles also reduced adiponectin, a protein involved in regulating glucose levels and fatty acid breakdown, which helps to regulate metabolism.

“We have learned that careful consideration and the choice of size, concentration and the duration of the clinical application of gold nanoparticles is warranted,” said Professor Mironava. “The good news is that when the nanoparticles were removed, normal functions were eventually restored.”

“Nanotechnology is continuing to be at the cutting edge of science research and has opened new doors in energy and materials science,” said co-author, Miriam Rafailovich, PhD, Chief Scientist of the Advanced Energy Center and Distinguished Professor of Materials Science and Engineering at Stony Brook. “Progress comes with social responsibility and ensuring that new technologies are environmentally sustainable. These results are very relevant to achieving these goals.”

The research, funded by the National Science Foundation Materials Research Science and Engineering Centers (MRSEC) and Polymer Programs, was a collaboration of Stony Brook University and New York State Stem Cell Science (NYSTEM). The paper was also co-authored by Michael Hadjiargyrou, Professor and Chairperson, Department of Life Sciences at New York Institute of Technology (NYIT) and former Professor in the Department of Biomedical Engineering at Stony Brook.

http://www.sciencedaily.com/releases/2013/04/130418162138.htm

 

Researchers abuzz over caffeine as cancer-cell killer

UAlberta research team uses caffeine and fruit flies to pinpoint genetic pathways that guide DNA repair in cancer cells.

Posted by News Staff  April 17, 2013

Before-and-after images showing how a caffeine-laden diet causes a fruit fly's eye to become disfigured. The fly had a genetic mutation making it super-sensitive to caffeine.                                     Images showing the normal eye of a fruit fly (left), versus the disfigured eye of a fruit fly fed with a caffeine-supplemented diet. The fly had a genetic mutation that made it super-sensitive to the stimulant.

(Edmonton) Researchers from the University of Alberta are abuzz after using fruit flies to find new ways of taking advantage of caffeine’s lethal effects on cancer cells—results that could one day be used to advance cancer therapies for people.

Previous research has established that caffeine interferes with processes in cancer cells that control DNA repair, a finding that has generated interest in using the stimulant as a chemotherapy treatment. But given the toxic nature of caffeine at high doses, researchers from the faculties of medicine and dentistry and science instead opted to use it to identify genes and pathways responsible for DNA repair.

“The problem in using caffeine directly is that the levels you would need to completely inhibit the pathway involved in this DNA repair process would kill you,” said Shelagh Campbell, co-principal investigator. “We’ve come at it from a different angle to find ways to take advantage of this caffeine sensitivity.”

Lead authors Ran Zhuo and Xiao Li, both PhD candidates, found that fruit flies with a mutant gene called melanoma antigen gene, or MAGE, appeared normal when fed a regular diet but died when fed food supplemented with caffeine.

On closer inspection, the researchers found that the mutant flies’ cells were super-sensitive to caffeine, with the drug triggering “cell suicide” called apoptosis. Flies fed the caffeine-laden diet developed grossly disfigured eyes.

Through this work, the research team identified three genes responsible for a multi-protein complex, called SMC5/SMC6/MAGE, which regulates DNA repair and the control of cell division. Neither process works properly in cancer cells.

Co-principal investigator Rachel Wevrick explains that this finding is significant because it means that scientists one day could be able to take advantage of cancer-cell sensitivity to caffeine by developing targeted treatments for cancers with specific genetic changes. Their results were published in the March issue of the peer-reviewed journal PLOS One.

“Unless you actually know what it is those proteins are doing in the first place to make a cell a cancer cell instead of a normal cell, it’s hard to know what to do with that information,” she says. “You need to know which genes and proteins are the really bad actors, how these proteins work and which of them work in a pathway you know something about where you can actually tailor a treatment around that information.”

Along with Wevrick and Campbell as lead investigators, the project also included biological sciences professor Kirst King-Jones and medical geneticist Sarah Hughes. It’s the type of research-intensive environment that benefits students who gain experience working with peers as part of a team, Wevrick says.

“The U of A has a reputation for co-operation, and that’s not the case everywhere. People here are very willing to share their results and their successes, and work together.”

The research was funded by the Cancer Research Society, the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

Drug treatment corrects autism symptoms in mouse model : suramin

Contact: Debra Kain ddkain@ucsd.edu 619-543-6163 University of California – San Diego

An old drug gives hope for new treatment in autism

Autism results from abnormal cell communication. Testing a new theory, researchers at the University of California, San Diego School of Medicine have used a newly discovered function of an old drug to restore cell communications in a mouse model of autism, reversing symptoms of the devastating disorder.

The findings are published in the March 13, 2013 issue of the journal PLOS ONE.

“Our (cell danger) theory suggests that autism happens because cells get stuck in a defensive metabolic mode and fail to talk to each other normally, which can interfere with brain development and function,” said Robert Naviaux, MD, PhD, professor of medicine and co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego. “We used a class of drugs that has been around for almost a century to treat other diseases to block the ‘danger’ signal in a mouse model, allowing cells to return to normal metabolism and restore cell communication.”

“Of course, correcting abnormalities in a mouse is a long way from a cure for humans,” said Naviaux, “but we are encouraged enough to test this approach in a small clinical trial of children with autism spectrum disorder in the coming year. This trial is still in the early stages of development. We think this approach – called antipurinergic therapy or APT – offers a fresh and exciting new path that could lead to development of a new class of drugs to treat autism.”

Autism spectrum disorders (ASDs) are complex disorders defined by abnormalities in the development of language, social and repetitive behaviors. Hundreds of different genetic and environment factors are known to confer risk.  In this study, nearly a dozen UC San Diego scientists from different disciplines collaborated to find a unifying mechanism that explains autism.  Their work is the result of one of just three international “Trailblazer” awards given by the group Autism Speaks in 2011.

Describing a completely new theory for the origin and treatment of autism using APT, Naviaux and colleagues introduce the concept that a large majority of both genetic and environmental causes for autism act by producing a sustained cell danger response – the metabolic state underlying innate immunity and inflammation.

“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated,” Naviaux explained.  “This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.”

Since mitochondria – the so-called “power plants” of the cell – play a central role in both infectious and non-infectious cellular stress, innate immunity and inflammation, Naviaux and colleagues searched for a signaling system in the body that was both linked to mitochondria and critical for innate immunity.  They found it in extracellular nucleotides like adenosine triphosphate (ATP) and other mitokines – signaling molecules made by distressed mitochondria. These mitokines have separate metabolic functions outside of the cell where they bind to and regulate receptors present on every cell of the body.  Fifteen types of purinergic receptors are known to be stimulated by these extracellular nucleotides, and the receptors are known to control a broad range of biological characteristics with relevance to autism.

The researchers tested suramin – a well-known inhibitor of purinergic signaling used medically for the treatment of African sleeping sickness since shortly after it was synthesized in 1916 – in mice.  They found that this APT mediator corrected autism-like symptoms in the animal model, even if the treatment was started well after the onset of symptoms.  The drug restored 17 types of multi-symptom abnormalities including normalizing brain synapse structure, cell-to-cell signaling, social behavior, motor coordination and normalizing mitochondrial metabolism.

“The striking effectiveness shown in this study using APT to ‘reprogram’ the cell danger response and reduce inflammation showcases an opportunity to develop a completely new class of anti-inflammatory drugs to treat autism and several other disorders,” Naviaux said.

###

Additional contributors to the study include Zarazuela Zolkipli, Lin Wang, Tomohiro Nakayama, Jane C. Naviaux, Thuy P. Le, Michael Schuchbauer, Mihael Rogac, Qingbo Tang, Laura L. Dugan, and Susan B. Powell.

Funding for the project was provided by Autism Speaks, the UCSD Christini Fund, the Jane Botsford-Johnson Foundation, the Wright Family Foundation, the Lennox Foundation, the Larry L. Hillblom Foundation, the Gerber Foundation, and Hailey’s Wish Foundation.

Nanoparticles loaded with bee venom kill HIV

 

March 7, 2013
By Julia Evangelou Strait

Joshua L. Hood, MD, PhD

Nanoparticles (purple) carrying melittin (green) fuse with HIV (small circles with spiked outer ring), destroying the virus’s protective envelope. Molecular bumpers (small red ovals) prevent the nanoparticles from harming the body’s normal cells, which are much larger in size.

Article Body 2010

Nanoparticles carrying a toxin found in bee venom can destroy human immunodeficiency virus (HIV) while leaving surrounding cells unharmed, researchers at Washington University School of Medicine in St. Louis have shown. The finding is an important step toward developing a vaginal gel that may prevent the spread of HIV, the virus that causes AIDS.

“Our hope is that in places where HIV is running rampant, people could use this gel as a preventive measure to stop the initial infection,” says Joshua L. Hood, MD, PhD, a research instructor in medicine.

The study appears in the current issue of Antiviral Therapy.

Bee venom contains a potent toxin called melittin that can poke holes in the protective envelope that surrounds HIV, and other viruses. Large amounts of free melittin can cause a lot of damage. Indeed, in addition to anti-viral therapy, the paper’s senior author, Samuel A. Wickline, MD, the J. Russell Hornsby Professor of Biomedical Sciences, has shown melittin-loaded nanoparticles to be effective in killing tumor cells.

The new study shows that melittin loaded onto these nanoparticles does not harm normal cells. That’s because Hood added protective bumpers to the nanoparticle surface. When the nanoparticles come into contact with normal cells, which are much larger in size, the particles simply bounce off. HIV, on the other hand, is even smaller than the nanoparticle, so HIV fits between the bumpers and makes contact with the surface of the nanoparticle, where the bee toxin awaits.

“Melittin on the nanoparticles fuses with the viral envelope,” Hood says. “The melittin forms little pore-like attack complexes and ruptures the envelope, stripping it off the virus.”

According to Hood, an advantage of this approach is that the nanoparticle attacks an essential part of the virus’ structure. In contrast, most anti-HIV drugs inhibit the virus’s ability to replicate. But this anti-replication strategy does nothing to stop initial infection, and some strains of the virus have found ways around these drugs and reproduce anyway.

“We are attacking an inherent physical property of HIV,” Hood says. “Theoretically, there isn’t any way for the virus to adapt to that. The virus has to have a protective coat, a double-layered membrane that covers the virus.”

Beyond prevention in the form of a vaginal gel, Hood also sees potential for using nanoparticles with melittin as therapy for existing HIV infections, especially those that are drug-resistant. The nanoparticles could be injected intravenously and, in theory, would be able to clear HIV from the blood stream.

“The basic particle that we are using in these experiments was developed many years ago as an artificial blood product,” Hood says. “It didn’t work very well for delivering oxygen, but it circulates safely in the body and gives us a nice platform that we can adapt to fight different kinds of infections.”

Since melittin attacks double-layered membranes indiscriminately, this concept is not limited to HIV. Many viruses, including hepatitis B and C, rely on the same kind of protective envelope and would be vulnerable to melittin-loaded nanoparticles.

While this particular paper does not address contraception, Hood says the gel easily could be adapted to target sperm as well as HIV. But in some cases people may only want the HIV protection.

“We also are looking at this for couples where only one of the partners has HIV, and they want to have a baby,” Hood says. “These particles by themselves are actually very safe for sperm, for the same reason they are safe for vaginal cells.”

While this work was done in cells in a laboratory environment, Hood and his colleagues say the nanoparticles are easy to manufacture in large enough quantities to supply them for future clinical trials.

 


Hood JL, Jallouck AP, Campbell N, Ratner L, Wickline SA. Cytolytic nanoparticles attenuate HIV-1 infectivity. Antiviral Therapy. Vol. 19: 95 – 103. 2013

This work was supported by the Bill & Melinda Gates Foundation Grand Challenges Explorations grant number OPP1024642 ‘Fusogenic nanoparticles for combined anti-HIV/contraception.’

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

BPA may affect the developing brain by disrupting gene regulation

Contact: Rachel Harrison rachel.harrison@duke.edu 919-419-5069 Duke University Medical Center

             IMAGE:   Exposure to BPA may disrupt development of the central nervous system by slowing down the removal of chloride from neurons. As an organism matures and the brain develops, chloride levels…

Click here for more information.     

DURHAM, N.C. — Environmental exposure to bisphenol A (BPA), a widespread chemical found in plastics and resins, may suppress a gene vital to nerve cell function and to the development of the central nervous system, according to a study led by researchers at Duke Medicine.

The researchers published their findings – which were observed in cortical neurons of mice, rats and humans – in the journal Proceedings of the National Academy of Sciences on Feb. 25, 2013.

“Our study found that BPA may impair the development of the central nervous system, and raises the question as to whether exposure could predispose animals and humans to neurodevelopmental disorders,” said lead author Wolfgang Liedtke, M.D., PhD, associate professor of medicine/neurology and neurobiology at Duke.

BPA, a molecule that mimics estrogen and interferes with the body’s endocrine system, can be found in a wide variety of manufactured products, including thermal printer paper, some plastic water bottles and the lining of metal cans. The chemical can be ingested if it seeps into the contents of food and beverage containers.

Research in animals has raised concerns that exposure to BPA may cause health problems such as behavioral issues, endocrine and reproductive disorders, obesity, cancer and immune system disorders. Some studies suggest that infants and young children may be the most vulnerable to the effects of BPA, which led the U.S. Food and Drug Administration to ban the use of the chemical in baby bottles and cups in July 2012.

While BPA has been shown to affect the developing nervous system, little is understood as to how this occurs. The research team developed a series of experiments in rodent and human nerve cells to learn how BPA induces changes that disrupt gene regulation.

During early development of neurons, high levels of chloride are present in the cells. These levels drop as neurons mature, thanks to a chloride transporter protein called KCC2, which churns chloride ions out of the cells. If the level of chloride within neurons remains elevated, it can damage neural circuits and compromise a developing nerve cell’s ability to migrate to its proper position in the brain.

Exposing neurons to minute amounts of BPA alters the chloride levels inside the cells by somehow shutting down the Kcc2 gene, which makes the KCC2 protein, thereby delaying the removal of chloride from neurons.

MECP2, another protein important for normal brain function, was found to be a possible culprit behind this change. When exposed to BPA, MECP2 is more abundant and binds to the Kcc2 gene at a higher rate, which might help to shut it down. This could contribute to problems in the developing brain due to a delay in chloride being removed.

These findings raise the question of whether BPA could contribute to neurodevelopmental disorders such as Rett syndrome, a severe autism spectrum disorder that is only found in girls and is characterized by mutations in the gene that produces MECP2.

While both male and female neurons were affected by BPA in the studies, female neurons were more susceptible to the chemical’s toxicity. Further research will dig deeper into the sex-specific effects of BPA exposure and whether certain sex hormone receptors are involved in BPA’s effect on KCC2.

“Our findings improve our understanding of how environmental exposure to BPA can affect the regulation of the Kcc2 gene. However, we expect future studies to focus on what targets aside from Kcc2 are affected by BPA,” Liedtke said. “This is a chapter in an ongoing story.”

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In addition to Liedtke, study authors include Michele Yeo and Ken Berglund of the Liedtke Lab in the Division of Neurology at Duke Medicine; Michael Hanna, Maria D. Torres and Jorge Busciglio of the University of California, Irvine; Junjie U. Guo and Yuan Gao of the Lieber Institute for Brain Development and Johns Hopkins University in Baltimore, Md.; and Jaya Kittur, Joel Abramowitz and Lutz Birnbaumer of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.

The research received funding from Duke University, the Klingenstein Fund, the National Institutes of Health (R21NS066307, HD38466 and AG16573), and intramural funds from the National Institute of Environmental Health Sciences

Is There a Link Between Coffee Drinking and Mortality?

Contact: Vicki Cohn, (914) 740-2156, vcohn@liebertpub.com

New Rochelle, NY, February 19, 2013–A large study of nearly half a million older adults followed for about 12 years revealed a clear trend: as coffee drinking increased, the risk of death decreased. Study author Neal Freedman, PhD, MPH, National Cancer Institute, discusses the significance of these findings and the potential links between coffee drinking, caffeine consumption, and various specific causes of disease in an interview in Journal of Caffeine Research, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available on the Journal of Caffeine Research website.

Epidemiology of Caffeine Consumption and Association of Coffee Drinking with Total and Cause-specific Mortality” presents an in-depth interview exploring the many factors that could contribute to the association between coffee, disease, and mortality.

Dr. Freedman examines the relationship between coffee drinking and behaviors such as smoking and alcohol abuse, the physiological effects of caffeine on blood pressure and cardiac function, and the importance of differentiating between the effects of coffee and caffeine.

“Given the near-universal daily consumption of caffeine, Dr. Freedman‘s research underscores the urgent need for randomized controlled trials to identify which components of coffee and other caffeine beverages benefit or harm consumers, under what circumstances, and in relation to which health outcomes,” says Jack E. James, PhD, Editor-in-Chief of Journal of Caffeine Research.

 

About the Journal Journal of Caffeine Research: The International Multidisciplinary Journal of Caffeine Science is a quarterly journal published in print and online that covers the effects of caffeine on a wide range of diseases and conditions, including mood disorders, neurological disorders, cognitive performance, cardiovascular disease, and sports performance. The Journal explores all aspects of caffeine science including the biochemistry of caffeine; its actions on the human body; benefits, dangers, and contraindications; and caffeine addiction and withdrawal, across all stages of the human life span from prenatal exposure to end-of-life. Complete tables of content and a sample issue may be viewed on the Journal of Caffeine Research website.

About the Publisher Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Breastfeeding Medicine, Journal of Medicinal Food, and Journal of Child and Adolescent Psychopharmacology. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry’s most widely read publication worldwide. A complete list of the firm’s 70 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.

Silibinin, found in milk thistle, protects against UV-induced skin cancer

 

By Garth Sundem in In the Lab · January 30, 2013 ·

 

Agarwal.Preferred.Pic

Rajesh Agarwal, PhD, shows that silibinin, found in milk thistle, protects against UVB damage and kills cells damaged by UVA — but is not at all toxic in healthy cells.

A pair of University of Colorado Cancer Center studies published this month show that the milk thistle extract, silibinin, kills skin cells mutated by UVA radiation and protects against damage by UVB radiation – thus protecting against UV-induced skin cancer and photo-aging.

“When you have a cell affected by UV radiation, you either want to repair it or kill it so that it cannot go on to cause cancer. We show that silibinin does both,” says Rajesh Agarwal, PhD, co-program leader of Cancer Prevention and Control  at the CU Cancer Center and professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences.

The first study, published in the journal Photochemistry and Photobiology worked with human skin cells subjected to UVA radiation, which makes up about 95 percent of the sun’s radiation that reaches Earth. The Agarwal Lab treated these UVA-affected cells with silibinin. With silibinin, the rate at which these damaged cells died increased dramatically.

“When you take human skin cells – keratinocytes – and treat them with silibinin, nothing happens. It’s not toxic. But when you damage these cells with UVA radiation, treatment with silibinin kills the cells,” Agarwal says, thus removing the mutated cells that can cause skin cancer and photo-aging.

Specifically, the study shows that pretreatment with silibinin resulted in higher release of reactive oxygen species (ROS) within the UVA-exposed cells, leading to higher rates of cell death.

The second study, published this month by the same authors in the journal Molecular Carcinogenesis shows that instead of beneficially killing cells damaged by UVA radiation, treatment with silibinin protects human skill cells from damage by UVB radiation, which makes up about 5 percent of the sun’s radiation reaching Earth.

Again, remember Agarwal’s suggestion that the prevention of UV-induced skin cancer can happen in two ways: by protecting against DNA damage or by killing cells with damaged DNA. With UVA, silibinin kills; with UVB, it protects, in this case by increasing cells’ expression of the protein interleukin-12, which works to quickly repair damaged cells.

“It has been 20 years of work with this compound, silibinin,” Agarwal says. “We first noticed its effectiveness in treating both skin and solid cancers, and we now have a much more complete picture of the mechanisms that allow this compound to work.”

Agarwal and colleagues continue to test the effectiveness of silibinin in cancer prevention and treatment in cell lines and mouse models, and are working toward human trials of silibinin-based therapeutics.

Silibinin and skin cancer chemoprevention studies in the Agarwal Lab are supported by NCI R01 grant CA140368.

Beta carotene may protect people with common genetic risk factor for type-2 diabetes

Contact: Bruce Goldman goldmanb@stanford.edu 650-725-2106 Stanford University Medical Center

STANFORD, Calif. — Stanford University School of Medicine investigators have found that for people harboring a genetic predisposition that is prevalent among Americans, beta carotene, which the body converts to a close cousin of vitamin A, may lower the risk for the most common form of diabetes, while gamma tocopherol, the major form of vitamin E in the American diet, may increase risk for the disease.

The scientists used a “big data” approach to hunt down interactions between gene variants previously associated with increased risk for type-2 diabetes and blood levels of substances previously implicated in type-2 diabetes risk. In people carrying a double dose of one such predisposing gene variant, the researchers pinpointed a highly statistically significant inverse association of beta carotene blood levels with type-2 diabetes risk, along with a suspiciously high positive association of gamma tocopherol with risk for the disease.

“Type-2 diabetes affects about 15 percent of the world’s population, and the numbers are increasing,” said Atul Butte, MD, PhD, associate professor of systems medicine in pediatrics. “Government health authorities estimate that one-third of all children born in the United States since the year 2000 will get this disease at some point in their lives, possibly knocking decades off their life expectancies.”

Butte is the senior author of the new study, which will be published online Jan. 22 in Human Genetics. The first author, Chirag Patel, PhD, is a former graduate student in Butte’s lab and now a postdoctoral scholar at the Stanford Prevention Research Center.

The findings point the way to further experiments that could establish whether beta carotene and gamma tocopherol are, respectively, protective and harmful themselves, or merely “markers” whose blood levels dovetail with the presence or absence of some other substance, process or defect that is a true causal factor.

Moreover, the fact that both beta carotene and gamma tocopherol interact with the same gene variant to influence diabetes risk, albeit in opposite directions, suggests that the protein the gene called, SLC30A4, codes for may play a crucial role in the disease. Indeed, that protein is relatively abundant in insulin-producing islet cells of the pancreas, where it aids the transport of zinc into those cells. This, in turn, triggers the release of insulin, whose adequate secretion by the pancreas and efficient uptake in muscle, liver and fat tissue counters the dangerous buildup of glucose in the blood and, in the long run, the onset of type-2 diabetes.

The genomes of some 50 to 60 percent of the U.S. population carry two copies of that very gene variant, which previous studies have shown to confer a slightly increased risk of contracting type-2 diabetes. This variant was one of 18, each found by other researchers to have a mild association with type-2 diabetes risk, that the Butte team incorporated into its analysis.

These gene/disease connections had been identified via so-called “genome-wide association studies,” or GWAS. In such analyses, the genomes of large numbers of people with a disease are compared with those of people without it to see if certain versions of any gene variants occur with substantially greater frequency in one group than in the other.

The most well-studied gene variations are substitutions of one type of chemical unit of DNA for another one at a single position along the genome. “It’s like a single-letter spelling change,” said Butte. “‘Grey’ versus ‘gray’ may not matter much, if at all. But when ‘grey’ turns into ‘grew,’ you might have some serious semantic issues.” The genome contains millions of spots at which such differences occur, so advanced statistical techniques must be employed to screen out “frequency differences” between the “diseased” and “healthy” groups that are, at bottom, the mere results of blind chance.

“While plenty of genetic risk factors for type-2 diabetes have been found,” said Butte, “none of them taken alone, and not even all of them taken together, comes close to accounting for the prevalence of type-2 diabetes.” But genes don’t act in a vacuum, he added. (If food is hard to find, nobody gets fat, obesity predisposition or not.)

A few years ago, Butte and his associates designed an approach analogous to the GWAS: the EWAS, or environment-wide association study. Unlike the genome, which is huge but finite (about 3 billion chemical units long), the environment contains an infinite number of substances, from dietary micronutrients to synthetic pollutants, to which a person might be exposed over a lifetime. But increasing numbers of exposures are being cataloged by investigators — including, for example, scientists at the federal Centers for Disease Control and Prevention who conduct massive biennial screenings to collect data that can guide public-health policy decisions. This ongoing endeavor, called the National Health and Nutrition Examination Survey, involves a detailed analysis of substances in blood drawn from thousands of volunteers along with their heights, weights, blood pressures, fasting blood-glucose levels and other indicators of their medical status.

In 2010, Patel, Butte and their colleagues published the results of the first-ever EWAS, in which they combed large public databases to compare people with or without high blood-glucose levels — a defining marker of type-2 diabetes — in pursuit of differences between the two groups’ exposures to myriad environmental substances. The analysis fingered five substances, including both beta carotene, found in carrots and many other vegetables, and gamma tocopherol, which is relatively abundant in vegetable fats such as soybean, corn and canola oils and margarine.

The Stanford investigators learned that the NHANES contained data on numerous individuals’ environmental exposures and, for many of the same individuals, their genomic compositions. This enabled the researchers to perform a novel study pairing each of the 18 type-2-diabetes-implicated gene variants with each of the five suspect environmental substances to see how, for individuals carrying a particular gene variant, different blood levels of a given substance correlated with those individuals’ blood-glucose levels.

None of the genetic factors studied in isolation had shown a particularly impressive impact on type-2 diabetes risk. But when they were paired off one by one with the environmental factors, a couple of statistically robust results jumped out. First, for those carrying two copies of the variant in SLC30A4, higher beta-carotene levels correlated with lower blood-glucose levels. “This vitamin was already known as being ‘good’ with respect to type-2 diabetes, so it was no surprise that we saw it, too,” said Butte. “But it was reassuring, as it suggested we were doing things right, and interesting to find it paired with SLC30A4.”

The second finding was at once novel and disconcerting. High blood levels of gamma tocopherol appeared to be associated with increased risk for the disease.

The Butte lab is now gearing up to perform studies in which purified beta carotene and gamma tocopherol will be fed to lab mice. This may show whether those substances themselves are critical to preventing or accelerating the onset of type-2 diabetes. It also may throw light on precisely how these substances affect the production or performance of the protein for which the implicated gene codes.

“We can’t say, based on just this study, that ‘vitamin E is bad for you,'” said Patel. He noted that blood levels of alpha tocopherol — another form of vitamin E that predominates in most supplements — showed no deleterious interaction with the predisposing gene variant in the new study.

But maybe it can’t hurt to eat a few more carrots.

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Other co-authors were John Ioannidis, MD, PhD, professor of medicine and of health research and policy; former staff bioinformatician Rong Chen, PhD; and research associate Keiichi Kodama, MD, PhD.

The Lucile Packard Foundation for Children’s Health, National Library of Medicine, National Institute of General Medical Sciences and other National Institutes of Health agencies funded the study.

Information about the medical school’s Department of Pediatrics, which also supported this work, is available at http://pediatrics.stanford.edu.

The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.

Print media contact: Bruce Goldman (650) 725-2106 (goldmanb@stanford.edu)

Broadcast media contact: M.A. Malone at (650) 723-6912 (mamalone@stanford.edu)

As colorectal cancer gets more aggressive, treatment with grape seed extract is even more effective

By Garth Sundem in In the Lab · January 16, 2013 ·

Derry

Molly Derry, PhD candidate at the University of Colorado Cancer Center

When the going gets tough, grape seed extract gets going: A University of Colorado Cancer Center study recently published in the journal Cancer Letters shows that the more advanced are colorectal cancer cells, the more GSE inhibits their growth and survival. On the other end of the disease spectrum, GSE leaves healthy cells alone entirely.

“We’ve known for quite a while that the bioactive compounds in grape seed extract selectively target many types of cancer cells. This study shows that many of the same mutations that allow colorectal cancer cells to metastasize and survive traditional therapies make them especially sensitive to treatment with GSE,” says Molly Derry, doctoral candidate in the lab of Rajesh Agarwal, PhD, investigator at the CU Cancer Center and professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences.

Derry notes this is an especially important finding in light of increasing colorectal cancer rates (due in part to increasingly high-fat diets and sedentary lifestyles) and a low screening rate; that means 60 percent of patients diagnosed have already reached the advanced stage of the disease.

“Finding a way to selectively target advanced colorectal cancer cells could have major clinical importance,” Derry says.

The group performed their experiments on colorectal cancer cell lines representing various stages of the disease. Whereas it generally takes much more chemotherapy to kill a stage IV cancer cell than a stage II cancer cell, Derry saw that the reverse was true with grape seed extract.

“It required less than half the concentration of GSE to suppress cell growth and kill 50 percent of stage IV cells than it did to achieve similar results in the stage II cells,” Derry says.

The group also discovered a likely mechanism of GSE’s preferential targeting of advanced colorectal cancer cells: when cancer cells were treated with antioxidants the GSE induced cell death was reversed and so Derry and colleagues consider it likely that GSE targets colorectal cancer through inducing oxidative stress that leads to the programmed cell death known as apoptosis.

“A colorectal cancer cell can have upwards of 11,000 genetic mutations – differences from the DNA in healthy cells. Traditional chemotherapies may only target a specific mutation and as cancer progresses more mutations occur. These changes can result in cancer that is resistance to chemotherapy. In contrast, the many bioactive compounds of GSE are able to target multiple mutations. The more mutations a cancer presents, the more effective GSE is in targeting them,” Derry says.

The Agarwal Lab continues its preclinical work studying the effectiveness and action of dietary compounds against cancer and encourages further exploration of their findings in clinical settings.

Study supported in part by NIH R01 AT003623 and NCI R01 CA112304

About the author: Garth Sundem

In addition to writing for the University of Colorado Cancer Center, Garth is the author of the books The Geeks’ Guide to World Domination, Brain Candy, and Geek Logik. Contact him at garth.sundem [at] ucdenver.edu.

Light exposure during pregnancy key to normal eye development

Contact: Nick Miller nicholas.miller@cchmc.org 513-803-6035 Cincinnati Children’s Hospital Medical Center

Contact: Jason Bardi jason.bardi@ucsf.edu 415-502-4608 University of California, San Francisco

CINCINNATI – New research in Nature concludes the eye – which depends on light to see – also needs light to develop normally during pregnancy.

Scientists say the unexpected finding offers a new basic understanding of fetal eye development and ocular diseases caused by vascular disorders – in particular one called retinopathy of prematurity that can blind premature infants. The research, led by scientists at Cincinnati Children’s Hospital Medical Center and the University of California, San Francisco (UCSF), appears online Jan. 16 ahead of print publication.

“This fundamentally changes our understanding of how the retina develops,” says study co-author Richard Lang, PhD, a researcher in the Division of Pediatric Ophthalmology at Cincinnati Children’s Hospital Medical Center. “We have identified a light-response pathway that controls the number of retinal neurons. This has downstream effects on developing vasculature in the eye and is important because several major eye diseases are vascular diseases.”

Lang is a principal investigator on the ongoing research along with project collaborator, David Copenhagen, PhD, a scientist in the departments of Ophthalmology and Physiology at UCSF. The scientists say their current study, conducted in mouse models, includes several unexpected findings.

“Several stages of mouse eye development occur after birth,” says Copenhagen. “Because of this, we had always assumed that if light played a role in the development of the eye, it would also happen only after birth.”

But researchers in the current study found that activation of the newly described light-response pathway must happen during pregnancy to activate the carefully choreographed program that produces a healthy eye. Specifically, they say it is important for a sufficient number of photons to enter the mother’s body by late gestation, or about 16 days into a mouse pregnancy.

Researchers were also surprised to learn that photons of light activate a protein called melanopsin directly in the fetus – not the mother – to help initiate normal development of blood vessels and retinal neurons in the eye.

One purpose of the light-response pathway is to suppress the number of blood vessels that form in the retina. These vessels are critical to retinal neurons, which require large amounts of oxygen to form and to function. When retinopathy of prematurity occurs in infants, retinal vessels grow almost unchecked. This continued expansion puts intense pressure on the developing eye and in extreme cases causes severe damage and blindness.

The research team led by Lang and Copenhagen conducted several experiments in laboratory mouse models that allowed them to identify the light-response pathway’s specific components and function.

Mice were reared in the dark and in a normal day-night cycle beginning at late gestation to observe the comparative effects on vascular development of the eye. The researchers verified the function of the light response pathway by mutating an opsin gene in mice called Opn4 that produces melanopsin, in essence preventing activation of the photo pigment.

Both mice reared under dark conditions from late gestation, and those with mutated Opn4, exhibited nearly identical promiscuous expansion of hyaloid vessels and abnormal retinal vascular growth. The unchecked vascular growth was driven by the protein vascular endothelial growth factor (Vegfa). When the light response pathway is properly engaged, it modulates Vegfa to help prevent promiscuous vascular growth, according to researchers.

The melanopsin protein is present in both mice and humans during pregnancy. Lang said the research team is continuing to study how the light-response pathway might influence the susceptibility of pre-term infants to retinopathy of prematurity and also be related to other diseases of the eye.

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First author on the study was Sujata Rao, PhD, a member of Lang’s laboratory team. Funding support for the research came in part from the National Institutes of Health (NIH AR-47363) and the Abrahamson Pediatric Eye Institute at Cincinnati Children’s.

About Cincinnati Children’s:

Cincinnati Children’s Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report‘s 2012 Best Children’s Hospitals ranking. It is ranked #1 for neonatology and in the top 10 for all pediatric specialties. Cincinnati Children’s is one of the top two recipients of pediatric research grants from the National Institutes of Health and a research affiliate of the University of Cincinnati College of Medicine. It is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at www.cincinnatichildrens.org.

About UCSF:

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. http://www.ucsf.edu

High fiber diet prevents prostate cancer progression

 

By Garth Sundem in In the Lab · January 9, 2013 ·

 

Komal Raina, PhD, shows that prostate cancers in mice fed a high-fiber diet fail to progress.

A high-fiber diet may have the clinical potential to control the progression of prostate cancer in patients diagnosed in early stages of the disease.

The rate of prostate cancer occurrence in Asian cultures is similar to the rate in Western cultures, but in the West, prostate cancer tends to progress, whereas in Asian cultures it does not. Why? A University of Colorado Cancer Center study published in the January 2013 issue of the journal Cancer Prevention Research shows that the answer may be a high-fiber diet.

The study compared mice fed with of inositol hexaphosphate (IP6), a major component of high-fiber diets, to control mice that were not. Then the study used MRI to monitor the progression of prostate cancer in these models.

“The study’s results were really rather profound. We saw dramatically reduced tumor volumes, primarily due to the anti-angiogenic effects of IP6,” says Komal Raina, PhD, research instructor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, working in the lab of CU Cancer Center investigator and School of Pharmacy faculty member, Rajesh Agarwal, PhD.

Basically, feeding with the active ingredient of a high-fiber diet kept prostate tumors from making the new blood vessels they needed to supply themselves with energy. Without this energy, prostate cancer couldn’t grow. Likewise, treatment with IP6 slowed the rate at which prostate cancers metabolized glucose.

Possible mechanisms for the effect of IP6 against metabolism include a reduction in a protein called GLUT-4, which is instrumental in transporting glucose.

“Researchers have long been looking for genetic variations between Asian and Western peoples that could explain the difference in prostate cancer progression rates, but now it seems as if the difference may not be genetic but dietary. Asian cultures get IP6 whereas Western cultures generally do not,” Raina says.

The research provides the cover image of this month’s issue of the journal.

Support provided in part by NCI RO1grant CA116636, the NCI Cancer Center P30 CA046934, and the NCRR CTSA UL1 RR025780

Metformin leads to an accumulation of AMP, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of cyclic AMP and protein kinase activity: WOOPS

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine

Most-used diabetes drug works in different way than previously thought

Findings could lead to diabetes treatments with less side effects

PHILADELPHIA – A team, led by senior author Morris J. Birnbaum, MD, PhD, the Willard and Rhoda Ware Professor of Medicine, with the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, found that the diabetes drug metformin works in a different way than previously understood. Their research in mice found that metformin suppresses the liver hormone glucagon’s ability to generate an important signaling molecule, pointing to new drug targets. The findings were published online this week in Nature.

For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin, the most frequently prescribed drug for type 2 diabetes. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.

“Overall, metformin lowers blood glucose by decreasing liver production of glucose,” says Birnbaum. “But we didn’t really know how the drug accomplished that.”

Imperfectly Understood

Despite metformin’s success, its mechanism of action remained imperfectly understood. About a decade ago, researchers suggested that metformin reduces glucose synthesis by activating the enzyme AMPK. But this understanding was challenged by genetic experiments in 2010 by collaborators on the present Nature study. Coauthors Marc Foretz and Benoit Viollet from Inserm, CNRS, and Université Paris Descartes, Paris, found that the livers of mice without AMPK still responded to metformin, indicating that blood glucose levels were being controlled outside of the AMPK pathway.

Taking another look at how glucose is regulated normally, the team knew that when there is no food intake and glucose decreases, glucagon is secreted from the pancreas to signal the liver to produce glucose. They then asked if metformin works by stopping the glucagon cascade.

The Nature study describes a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. The team showed that metformin leads to the accumulation of AMP in mice, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of cyclic AMP and protein kinase activity, eventually blocking glucagon-dependent glucose output from liver cells.

From this new understanding of metformin’s action, Birnbaum and colleagues surmise that adenylate cyclase could be a new drug target by mimicking the way in which it is inhibited by metformin. This strategy would bypass metformin’s affect on a cell’s mitochondria to make energy, and possibility avoid the adverse side effects experienced by many people who take metformin, perhaps even working for those patients resistant to metformin.

###

Co-authors are Russell A. Miller and Qingwei Chu from Penn, and Jianxin Xie from Cell Signaling Technology, Mass.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (RO1 DK56886, PO1 DK49210, F32 DK079572); the Association pour l’Etude des Diabètes et des Maladies Métaboliques; the Programme National de Recherche sur le Diabète; and the Institut Benjamin Delessert.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

Chromium picolinate may lessen inflammation in diabetic nephropathy

Contact: Donna Krupa DKrupa@the-aps.org 301-634-7209 American Physiological Society

Supplement linked to decreased protein in the urine of diabetic mice

Bethesda, Md. (September 22, 2010) – Taking chromium picolinate may help lessen inflammation associated with diabetic nephropathy (kidney disease), say researchers at the Medical College of Georgia in Augusta. In a study comparing diabetic mice treated with chromium picolinate with those that received placebo, the researchers found that mice who received the supplement had lower levels of albuminuria (protein in the urine), an indication of kidney disease.

The Study

To arrive at their conclusions, the researchers compared three groups of mice, one lean, healthy group and two groups genetically engineered to be obese and have diabetes. When the mice were 6 weeks old, the researchers separated them according to treatment plan. The healthy mice and one group of diabetic mice, the untreated diabetic group, were fed a regular rodent diet. The remaining group, the treated diabetic group, were fed a diet enriched with chromium picolinate.

Over the course of 6 months, the researchers measured glycemic control and albuminuria in all three groups. The untreated diabetic mice excreted nearly 10 times more albumin than the db/m mice, which was to be expected. However, the treated diabetic mice, who were fed the diet with chromium picolinate, excreted about half as much albumin compared to their untreated diabetic counterparts.

At the end of 6 months, the mice were euthanized and the researchers studied tissue samples from the mice’s kidneys. They found that the untreated diabetic mice had marked immunostaining for interleukin 6 (IL-6) and interleukin 17 (IL-17), two cytokines associated with inflammation. These mice also had moderate immunostaining for indolamine 2,3-dioxygenase (IDO), an immunoregulatory enzyme that modulates the production of IL-6 and IL-17. However, the treated diabetic mice had intense immunostaining for IDO but reduced IL-6 and IL-17 compared to the untreated diabetic group. The implication is that the chromium picolinate may have reduced inflammation in the treated diabetic group by affecting IDO, IL-6, and IL-7.

Mahmood Mozaffari, DMD, PhD, professor in the Medical College of Georgia Department of Oral Biology and lead author of the study, noted that the results are preliminary and that further studies are necessary to tease out the effects of chromium picolinate. He is particularly interested in the relationship between IDO and chromium picolinate because IDO is involved in the metabolism of tryptophan, an amino acid, and one of the by-products of that metabolism is picolinic acid.

“This clearly raises an important question for us as to whether our observations are related to the provision of picolinic acid from the chromium picolinate or whether the formulation [chromium picolinate], in and of itself, is mediating the effects.”

###

 

NOTE TO EDITORS: Dr. Mozaffari discussed the study at the 2010 American Physiological Society conference, Inflammation, Immunity, and Cardiovascular Disease, in Westminster Colorado. To arrange an interview with him, please contact Donna Krupa at 301.634.7209 or dkrupa@the-aps.org.

Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (www.The-APS.org/press) has been an integral part of this discovery process since it was established in 1887.

Repeated antibiotic use alters gut’s composition of beneficial microbes, Stanford study shows

2010 study posted for filing

 

Contact: Bruce Goldman goldmanb@stanford.edu 650-725-2106 Stanford University Medical Center

STANFORD, Calif. – Repeated use of an antibiotic that is considered generally benign, because users seldom incur obvious side effects, induces cumulative and persistent changes in the composition of the beneficial microbial species inhabiting the human gut, researchers at the Stanford University School of Medicine have found.

By a conservative estimate, something like 1,000 different varieties of microbes coexist harmoniously within a typical healthy person’s gut, said David Relman, MD, professor of medicine and of microbiology and immunology at the medical school and chief of the infectious diseases division at the Veterans Affairs Palo Alto Health Care System. Relman is the senior author of a paper, which will appear online Sept. 13 in Proceedings of the National Academy of Sciences.

The study examined the effects of ciprofloxacin (trade name Cipro), an antibiotic that is widely prescribed for intestinal, urinary and a variety of systemic infections. In an earlier, short-term study, Relman’s group had concluded that people’s intestinal microbial communities seem to bounce back reasonably well within weeks after a five-day regimen of ciprofloxacin. This new study involved two courses of antibiotic administration, six months apart, and it revealed more-subtle, long-term effects of ciprofloxacin use – such as the replacement of multiple resident bacterial species by other, closely related varieties and the occasional complete eradication of a species.

The infrequent occurrence of easily visible side effects such as bloating and diarrhea from ciprofloxacin use has given rise to an assumption that the drug spares most beneficial gut-dwelling bacteria. Overall similarities between pre-regimen gut bacterial strains and their post-regimen replacements explain why such side effects aren’t typically seen after ciprofloxacin use. Still, the more nuanced differences between the pre-existing communities and those that appear in the wake of this repeated disturbance present a new set of problems, said Relman, who is also the Thomas C. and Joan M. Merigan Professor at the medical school. A bacterial species whose presence was lost or diminished may have been performing a valuable job – for example, secreting a protein that’s toxic to a particular pathogen – that is shirked by its replacement. The abandoned function might not be noticed until, perhaps, years later when the pathogen in question invaded the person’s gut.

While the study’s findings shouldn’t be interpreted to mean that ciprofloxacin is dangerous and should be avoided, Relman said, they do raise questions about possible long-term effects of antibiotic administration, in addition to concerns about spurring the evolution of drug-resistant organisms. The new findings underscore the desirability of finding ways to pinpoint not just which bacteria have been lost or whose numbers were diminished by an antibiotic, but also which important beneficial functions performed by the patient’s gut microbial community as a whole have been impaired – such as signaling cells of the intestinal lining, which are constantly turning over, to maintain an appropriate barrier against ingested toxic compounds, or secreting anti-inflammatory substances that may prevent allergic or autoimmune diseases.

For this study, the Stanford scientists collected more than 50 stool samples from each of three healthy adult females over a period of 10 months. Then they used advanced, molecular techniques to count the number of different microbial species represented in each sample, as well as relative population sizes of the different species in that sample.

Twice during this 10-month period, the researchers perturbed their subjects’ gut ecosystems by giving them five-day courses of ciprofloxacin at a standard dose. During the first course, overall bacterial populations in each subject – which had previously waxed and waned but, on the whole, been quite stable – plummeted and remained depressed for about a week. Roughly one-third to one-half of the resident species’ populations declined, with some disappearing entirely. A few originally less-abundant species grew in number, as they filled in the ecological niche abandoned by bugs adversely affected by the drug.

Within a week after the first course’s completion, two of the three subjects’ internal microbial ecosystems had largely returned to a state fairly similar to that before the regimen, as measured by the broad classes to which the microbial constituents belonged. One subject’s overall ecosystem, however, still had not recovered even by that rough measure a full six months later.

The second course of antibiotic administration produced a stronger effect. “Even the one subject whose gut bacterial community fully recovered after the first ciprofloxacin course experienced an incomplete recovery after the second one,” said Relman. The communities in the other two subjects partially recovered from the second course, but never returned to their original state. In essence, each subject’s community of gut-dwelling microbes shifted to a new, “alternative” state and remained in that state for at least two months after the second antibiotic course had been completed. Thus, all three subjects experienced significant and lasting changes in the specific membership of their internal microbial communities at the end of the 10-month study period.

“Ecologists have found that an ecosystem, such as a wildlife refuge, that is quite capable of rebounding from even huge occasional perturbations – forest fire, volcanic eruption, pests – may yet be undone by too rapid a series of such perturbations,” said Les Dethlefsen, PhD, a research scientist in Relman’s lab and the study’s first author. “In the same way, recurring antibiotic use may produce a cumulative effect on our internal microbial ecosystems with potentially debilitating, if as yet unpredictable, consequences.”

“It’s as if your beneficial bacteria ‘remember’ the bad things done to them in the past,” said Relman. “Clinical signs and symptoms may be the last thing to show up.”

The precise counts of gut-dwelling microbes in this study were made possible by a new technique, pioneered in recent years by Relman and others. The older method – growing the microbes in culture – simply doesn’t work for many species and, even when it does, rare species are often swamped by more common ones and don’t get counted. The new technique reads short, telltale DNA snippets that distinguish microbes both from human cells and one from another. This allowed the Stanford researchers to assess both the total number of different microbial varieties and the relative size of each variety’s population.

Similar techniques now make it possible to assess, before and after antibiotic administration, the abundance in a patient’s gut of microbial genes known to code for important functions performed by one or more members of the patient’s gut community, Relman said. In the future, if it becomes known that a key function has been impaired, clinicians might perhaps restore that function by prescribing specific probiotics or nutrients that encourage the return of appropriate beneficial bugs.

###

The research was supported by a National Institutes of Health Pioneer Award and by the Doris Duke Charitable Foundation. More information about the Departments of Medicine and of Microbiology and Immunology, which also supported the research, is available at http://medicine.stanford.edu and http://microimmuno.stanford.edu.

The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.

Grapefruit’s bitter taste holds a sweet promise for diabetes therapy

2010 study posted for filing

Contact: Jen Laloup jlaloup@plos.org 415-624-1220 Public Library of Science

Naringenin, an antioxidant derived from the bitter flavor of grapefruits and other citrus fruits, may cause the liver to break down fat while increasing insulin sensitivity, a process that naturally occurs during long periods of fasting.

A team of researchers from the Hebrew University of Jerusalem and Massachusetts General Hospital (MGH) report that naringenin activates a family of small proteins, called nuclear receptors, causing the liver to break down fatty acids. In fact, the compound seems to mimic the actions of other drugs, such as the lipid-lowering Fenofibrate and the anti-diabetic Rosiglitazone, offering the advantages of both. If the results of this study extend to human patients, this dietary supplement could become a staple in the treatment of hyperlipidemia, type-2 diabetes, and perhaps metabolic syndrome. The report appears in this week issue of the online journal PLoS ONE.

“It is a fascinating find,” says Yaakov Nahmias, PhD, of the Hebrew University of Jerusalem the paper’s senior author. “We show the mechanism by which naringenin increases two important pharmaceutical targets, PPARα and PPARγ, while blocking a third, LXRα. The results are similar to those induced by long periods of fasting”.

The liver is the main organ responsible for the regulation of carbohydrate and lipid levels in the blood. Following a meal, the blood is flushed with sugars, which activate LXRα, causing the liver to create fatty acids for long-term storage. During fasting, the process is reversed; fatty acids are released by fat cells, activate PPARα in the liver, and are broken down to ketones.  A similar process, involving PPARγ, increases sensitivity to insulin.

“It is a process which is similar to the Atkins diet, without many of the side effects,” says Martin L. Yarmush, MD, PhD, director of the MGH Center for Engineering in Medicine and one of the paper’s authors.

“The liver behaves as if fasting, breaking down fatty acids instead of carbohydrates.” Yarmush is the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School.

“Dual PPARα and PPARγ agonists, like naringenin, were long sought after by the pharmaceutical industry,” says Nahmias, “but their development was plagued by safety concerns. Remarkably, naringenin is a dietary supplement with a clear safety record. Evidence suggests it might actually protect the liver from damage.”

Grapefruit’s bitter taste is caused the presence of the flavonoid naringin, which is broken down in the gut into naringenin. Earlier evidence has shown the compound has cholesterol lowering properties and may ameliorate some of the symptoms associated with diabetes. The researchers demonstrated that the compound activates PPARα and PPARγ by dramatically increasing the levels of a co-activator peptide of both, called PGC1α. At the same time, naringenin bound directly to LXRα, blocking its activation. These effects culminated with increased fatty acid oxidation and the inhibition of vLDL (‘bad cholesterol’) production.

###

 

Additional co-authors of the PLoS ONE paper are Jonathan Goldwasser, PhD, Eric Yang, PhD, MGH; Pazit Cohen, PhD, Hebrew University; and Patrick Balaguer, PhD, INSERM Univ. Montpellier France. The work was supported by grants from the National Institutes of Health (NIH) and European Research Council (ERC).

Citation: Goldwasser J, Cohen PY, Yang E, Balaguer P, Yarmush ML, et al. (2010) Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARa, PPARc and LXRa. PLoS ONE 5(8): e12399. doi:10.1371/journal.pone.0012399

Competing Interests: The authors have declared that no competing interests exist.

Funding: This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K01DK080241), a European Research Council starting grant (TMIHCV 242699), and the Harvard Clinical Nutrition Research Center (P30-DK040561). Resources were provided by the BioMEMS Resource Center (P41 EB-002503), Shriners Burns Hospital, and the Alexander Silberman Institute of Life Sciences. The funders had no role in study design, data collection and analysis,decision to publish, or preparation of the manuscript.

PLEASE LINK TO THE SCIENTIFIC ARTICLE IN ONLINE VERSIONS OF YOUR REPORT (URL goes live after the embargo ends): http://dx.plos.org/10.1371/journal.pone.0012399

FOR A PRESS-ONLY PREVIEW OF THE FULL ARTICLE, VISIT THE FOLLOWING URL: http://www.plos.org/press/pone-05-08-nahmias.pdf

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87th Health Research Report 19 AUG 2010 – Reconstruction

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Health Research Report

87th Issue 19 AUG 2010

Compiled By Ralph Turchiano

www.vit.bz

www.youtube.com/vhfilm 

www.facebook.com/engineeringevil

www.engineeringevil.com  

www.healthresearchreport.me 

120922_0002

Editors Top Five:

 

  1. SCIENTISTS TARGET POSSIBLE CAUSE OF ONE FORM OF BOWEL DISEASE
  2. Pancreatic cancers use fructose, common in the Western diet, to fuel their growth
  3. Acetaminophen tied to childhood wheezing and allergies
  4. FDA moves to withdraw unproven blood pressure drug
  5. After Avandia: Does the FDA Have a Drug Problem?

In this issue:

1. At Two Years, Low-carb Diet Beats Low-Fat for HDL-Cholesterol Levels

2. Drug Trials Funded by Industry More Likely to Report Positive Outcomes

3. Certain meat components may increase bladder cancer risk

4. Mind over matter? The psychology of healing

5. Exercise and caloric restriction rejuvenate synapses in lab mice

6. SCIENTISTS TARGET POSSIBLE CAUSE OF ONE FORM OF BOWEL DISEASE

7. Research shows what you say about others says a lot about you

8. SCIENTISTS TARGET POSSIBLE CAUSE OF ONE FORM OF BOWEL DISEASE

9. Disrupted circadian rhythm may cause triglycerides to rise

10. Oral contraceptive use associated with increased risk of breast cancer

11. Sperm may be harmed by exposure to BPA, study suggests

12. Homes of the poor and the affluent both have high levels of endocrine disruptors

13. Acetaminophen tied to childhood wheezing and allergies

14. Surgery better than radiation, hormone treatments for some prostate cancer, study shows

15. Free statins with fast food could neutralize heart risk, scientists say

16. FDA moves to withdraw unproven blood pressure drug

17. After Avandia: Does the FDA Have a Drug Problem?

Public release date: 2-Aug-2010

At Two Years, Low-carb Diet Beats Low-Fat for HDL-Cholesterol Levels

Previous studies comparing low-carbohydrate and low-fat diets have not included comprehensive behavioral treatment. Researchers sought to evaluate the long-term effects of a low-carbohydrate versus a low-fat diet when combined with a comprehensive lifestyle modification program. Three hundred and seven patients were randomly assigned to either a low-carbohydrate (n=153) or low-fat (n=154) diet with behavior treatment. Weight at two years was the primary outcome, but other effects were measured throughout the study period. At three, six, and 12 months, patients were evaluated for weight, serum lipid concentrations, blood pressure, urinary ketones, bone mineral density, and body composition. The researchers found no differences in weight, body composition, or bone mineral density between the two groups at any point during the study. At two years, both groups had lost a clinically significant amount of weight (about 7 percent of body weight), showing that successful weight loss can be achieved with either approach when coupled with a behavioral modification program. However, the low-carbohydrate diet produced a greater increase in plasma HDL cholesterol concentration than did the low-fat diet at all assessments points during the two-year study.

Public release date: 2-Aug-2010

Drug Trials Funded by Industry More Likely to Report Positive Outcomes

Clinicaltrials.gov is a publicly available database that provides details of clinical trials. Researchers studied 546 drug trials listed at clinicaltrials.gov to determine if funding source was associated with published outcomes. Of the trials studied, 346 (63 percent) were primarily funded by industry, 74 (14 percent) by government, and 126 (23 percent) by nonprofit or nonfederal organizations. The researchers found that industry-funded trials reported positive outcomes in 85.4 percent of publications, compared with 50 percent for government-funded trials and 71.9 percent for organization-funded trials. Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding. In addition, industry-funded trials were less likely to be published within two years of completion than were trials with other funding sources.

Public release date: 2-Aug-2010

Certain meat components may increase bladder cancer risk

A new study suggests that consuming specific compounds in meat related to processing methods may be associated with an increased risk of developing bladder cancer. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings may be relevant for understanding the role of dietary exposures in cancer risk.

Eating red and processed meats has been linked to an increased risk of developing several different types of cancer. Animal studies have identified a number of compounds in meat that might account for this association. These include heterocyclic amines, polycyclic aromatic hydrocarbons, and N-nitroso compounds. Nitrate and nitrite are added to processed meats and are known precursors to N-nitroso compounds.

Amanda J. Cross, PhD, of the National Cancer Institute in Rockville and colleagues conducted one of the first prospective studies – the NIH-AARP Diet and Health Study—to assess the relationship between intake of these meat-related compounds and the risk of developing bladder cancer. They used information gathered through questionnaires to assess the types of meat consumed as well as how meat was prepared and cooked to estimate the intake of these meat-related compounds.

The investigators had information from approximately 300,000 men and women aged 50 to 71 years from eight US states. At the start of the study (1995 to 1996), all participants completed lifestyle and dietary questionnaires about their usual consumption of foods and drinks. The participants were followed for up to eight years, during which time 854 people were diagnosed with bladder cancer.

People whose diets had the highest amount of total dietary nitrite (from all sources and not just from meat), as well as those whose diets had the highest amount of nitrate plus nitrite from processed meats had a 28 percent to 29 percent increased risk of developing bladder cancer compared with those who consumed the lowest amount of these compounds. This association between nitrate/nitrite consumption and bladder cancer risk may explain why other studies have observed an association between processed meats and increased bladder cancer risk.

“Our findings highlight the importance of studying meat-related compounds to better understand the association between meat and cancer risk,” said Dr. Cross. “Comprehensive epidemiologic data on meat-related exposures and bladder cancer are lacking; our findings should be followed up in other prospective studies,” she added.

 

Public release date: 2-Aug-2010

Mind over matter? The psychology of healing

People suffering from diabetes-related foot ulcers show different rates of healing according to the way they cope and their psychological state of mind, according to new research by a health psychologist at The University of Nottingham.

The large study published in the journal Diabetologia this month has shown that the way patients cope with the condition and their levels of depression, affect how the wound heals or worsens.

The work by Professor Kavita Vedhara from the University’s Institute of Work, Health and Organisations, has sparked a follow-on project to develop psychological treatments to reduce depression in sufferers and help them cope more effectively with this debilitating and potentially life-threatening condition.

Foot ulcers are open sores which form when a minor skin injury fails to heal because of microvascular and metabolic dysfunction caused by diabetes. Up to fifteen per cent of people with diabetes, both Type 1 and Type 2, develop foot or leg ulcers with many suffering depression and poorer quality of life as a result.

The increased morbidity and mortality caused by the condition are estimated to cost UK health services £220 million per year. The costs are exacerbated by slow healing rates with two thirds of ulcers remaining unhealed after 20 weeks of treatment. The five year amputation and death rates among patients are 19 per cent and 44 per cent respectively. Ulcers account for around four out of five lower leg amputations and half of diabetes-related hospital admissions.

During the five-year study 93 patients (68 men and 25 women) with diabetic foot ulcers were recruited from specialist podiatry clinics across the UK. Clinical and demographic determinants of healing; psychological distress, coping style and levels of cortisol (a stress hormone) in saliva were assessed and recorded at the start of a 24 week monitoring period. The size of each patient’s ulcer was also measured at the start, and then at 6, 12 and 24 weeks to record the extent of healing or otherwise of the ulcer.

The results of the research showed that the likelihood of the ulcer healing over a 24 week period was predicted by how individual’s coped. Surprisingly perhaps, patients who showed a ‘confrontational’ way of coping (a style characterised by a desire to take control) with the ulcer and its treatment were less likely to have a healed ulcer at the end of the 24 week period.

Professor Vedhara said: “My colleagues and I believe that this confrontational approach may, inadvertently, be unhelpful in this context because these ulcers take a long time to heal. As a result, individuals with confrontational coping may experience distress and frustration because their attempts to take control do not result in rapid improvements.”

A secondary analysis of each patient examined the relationship of psycho-social factors with the change in the size of the ulcer over the observation period. Whereas the first analysis showed that only confrontation coping, not anxiety or depression, was a significant predictor of healing, the second showed that depression was a significant predictor in how the size of the ulcer changed over time, with patients with clinical depression showing smaller changes in ulcer size over time i.e., they showed less improvement or healing.

Public release date: 2-Aug-2010

Exercise and caloric restriction rejuvenate synapses in lab mice

Finding may illuminate a reason for the beneficial effects of these regimens on aging

CAMBRIDGE, Mass. — Harvard University researchers have uncovered a mechanism through which caloric restriction and exercise delay some of the debilitating effects of aging by rejuvenating connections between nerves and the muscles that they control.

The research, conducted in the labs of Joshua Sanes and Jeff Lichtman and described this week in the journal Proceedings of the National Academy of Sciences, begins to explain prior findings that exercise and restricted-calorie diets help to stave off the mental and physical degeneration of aging.

“Caloric restriction and exercise have numerous, dramatic effects on our mental acuity and motor ability,” says Sanes, a professor of molecular and cellular biology and director of the Center for Brain Science at Harvard. “This research gives us a hint that the way these extremely powerful lifestyle factors act is by attenuating or reversing the decline in our synapses.”

Sanes says their research, conducted with mice genetically engineered so their nerve cells glow in fluorescent colors, shows some of the debilitation of aging is caused by deterioration of connections that nerves make with the muscles they control, structures called neuromuscular junctions. These microscopic links are remarkably similar to the synapses that connect neurons to form information-processing circuits in the brain.

In a healthy neuromuscular synapse, nerve endings and their receptors on muscle fibers are almost a perfect match, like two hands placed together, finger to finger, palm to palm. This lineup ensures maximum efficiency in transmitting the nerve’s signal from the brain to the muscle, which is what makes it contract during movement.

As people age, however, the neuromuscular synapses can deteriorate in several ways. Nerves can shrink, failing to cover the muscle’s receptors completely. The resulting interference with transmission of nerve impulses to the muscles can result in wasting and eventually even death of muscle fibers. This muscle wasting, called sarcopenia, is a common and significant clinical problem in the elderly.

The new work showed that mice on a restricted-calorie diet largely avoid that age-related deterioration of their neuromuscular junctions, while those on a one-month exercise regimen when already elderly partially reverse the damage.

“With calorie restriction, we saw reversal of all aspects of the synapse disassembly. With exercise, we saw a reversal of most, but not all,” Sanes says.

Because of the study’s structure — mice were on calorie-restricted diets for their whole lives, while those that exercised did so for just a month late in life — Sanes cautions against drawing conclusions about the effectiveness of exercise versus calorie restriction. He notes that longer periods of exercise might have more profound effects, a possibility he and Lichtman are now testing.

Though much of Sanes and Lichtman’s work focuses on brain synapses, both have investigated neuromuscular synapses for many years. Neuromuscular junctions are large enough to be viewed by light microscopy, and can be a jumping-off point for brain study, highlighting areas of inquiry and potential techniques.

“These findings in neuromuscular synapses make us curious to know whether similar effects might occur in brain synapses,” Sanes says.

While the changes to the synapses through caloric restriction and exercise were clear in the images the researchers obtained, Sanes cautioned that their work was structural, not functional, and they have not yet tested how well the synapses worked.

Public release date: 2-Aug-2010

SCIENTISTS TARGET POSSIBLE CAUSE OF ONE FORM OF BOWEL DISEASE

COLUMBUS, Ohio – A possible cause of irritable bowel syndrome has been traced to a small piece of RNA that blocks a substance protecting the colon membrane, leading to hostile conditions that can produce diarrhea, bloating and chronic abdominal pain.

New research shows that this RNA segment sends signals that stop the activity of the gene that produces glutamine, an amino acid. Previous research has linked a shortage of glutamine in the gut with the seepage of toxins and bacteria through the intestinal wall, irritating nerves and creating disease symptoms.

Scientists say that trying to generate glutamine in the disordered bowel by silencing this RNA segment could open up a whole new way of thinking about treating the diarrhea-predominant type of irritable bowel syndrome (IBS). In the meantime, they are making plans to conduct a clinical trial to see if glutamine supplements could also reduce common IBS symptoms.

This form of the disorder is characterized by diarrhea and bloating as well as chronic abdominal pain that is difficult to treat. About a third of IBS patients have the diarrhea-predominant type, another third experience consistent constipation, and the rest experience alternating bouts of diarrhea and constipation.

“We treat the disorder, but we still don’t understand it completely. We often have to use multiple therapies to attack the symptoms, but the pain is by far the most difficult to treat. For some patients, the pain responds only to escalating doses of narcotics or tricyclic antidepressants.”

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In the Ohio State University study, researchers observed that in human tissue samples, the presence of this small piece of RNA was associated with reduced activity by the gene that produces glutamine. Lower levels of glutamine were seen only in tissue samples from patients with the diarrhea-predominant type of IBS.

A group of these patients also had a condition called increased intestinal permeability, which allows toxins and bacteria into the colon that typically can’t get in. The resulting irritation to nerves in the colon is believed to contribute to diarrhea and abdominal pain. The finding suggests that the glutamine deficiency is connected to the increased intestinal permeability, which dramatically increases the likelihood that diarrhea-predominant IBS symptoms will follow.

The researchers say that manipulating that tiny piece of RNA, known as microRNA-29a, has potential as a novel treatment for IBS. “We’ve known about characteristics of this disease, but we didn’t know the reasons behind them. This study helps us connect everything together. Maybe if we can modulate the microRNA, we can heal the disease. That is our whole hypothesis,” said QiQi Zhou, assistant professor of internal medicine at Ohio State and lead author of the study.

The research is published in a recent issue of the journal Gut.

While testing the effectiveness of glutamine supplementation in IBS patients could lead to a viable treatment for symptoms, the researchers say it is important to continue to pursue the underlying cause of IBS.

“We treat the disorder, but we still don’t understand it completely,” said study senior co-author G. Nicholas Verne, professor of internal medicine and director of the Division of Gastroenterology, Hepatology and Nutrition at Ohio State. “We often have to use multiple therapies to attack the symptoms, but the pain is by far the most difficult to treat. For some patients, the pain responds only to escalating doses of narcotics or tricyclic antidepressants.

“That’s why if we had a specific target for an underlying structural defect, we could try to resolve that defect as a much more effective way to reduce the symptoms.”

Zhou, Verne and colleagues are the first group of scientists to report on a link between microRNAs, glutamine deficiency and IBS. Most studies of microRNAs have identified their role in the development of cancer.

RNA in cells is responsible for using instructions carried in the DNA to make proteins, but microRNAs are small segments of RNA that, when they become overactive themselves, can block the protein-building process. Each microRNA can target numerous genes, but Zhou concentrated on microRNA-29a and its connection to the production of glutamine in this study because of glutamine’s established connection to intestinal permeability.

The researchers collected intestinal tissue and blood samples from three groups: IBS patients with increased intestinal permeability, IBS patients with normal intestinal permeability and control participants with no bowel disease.

The samples showed that microRNA-29a levels were four times higher in the tissues of IBS patients with increased intestinal permeability than were levels seen in IBS patients with normal intestinal permeability conditions and in participants with no bowel disease.

The scientists further tested this relationship by manipulating the microRNA-29a in experiments. When the microRNA-29a levels were driven up, the function of the gene that produces glutamine was prevented and intestinal membrane permeability increased, as well. When the microRNA-29a was artificially silenced, gene function was active, glutamine was produced and the intestinal membrane permeability was closer to normal.

“We’ve only tested the one target gene, and we’ve shown that when the gene activity is low, or the gene is not expressed, that’s when disease characteristics come into play,” Zhou said. “But there still may be other target genes related to this process.”

The study also sought to determine how much related genetic information was contained in blood microvesicles, which are tiny blood vessel membrane fragments. Because the heightened expression of microRNA-29a was also detected in microvesicles from IBS patients with increased permeability in this study, the scientists believe a specially handled blood sample could provide as much disease information as a tissue sample for diagnostic purposes.

This work was supported by the National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs.

Co-authors, both from Ohio State, include Wiley Souba, dean of the College of Medicine; and Carlo Croce, professor and chair of the Department of Molecular Virology, Immunology and Medical Genetics. Verne and Zhou also are affiliated with the Cincinnati VA Medical Center Research Service.

 

Public release date: 2-Aug-2010

Research shows what you say about others says a lot about you

How positively you see others is linked to how happy, kind-hearted and emotionally stable you are, according to new research by a Wake Forest University psychology professor.

“Your perceptions of others reveal so much about your own personality,” says Dustin Wood, assistant professor of psychology at Wake Forest and lead author of the study, about his findings. By asking study participants to each rate positive and negative characteristics of just three people, the researchers were able to find out important information about the rater’s well-being, mental health, social attitudes and how they were judged by others.

The study appears in the July issue of the Journal of Personality and Social Psychology. Peter Harms at the University of Nebraska and Simine Vazire of Washington University in St. Louis co-authored the study.

The researchers found a person’s tendency to describe others in positive terms is an important indicator of the positivity of the person’s own personality traits. They discovered particularly strong associations between positively judging others and how enthusiastic, happy, kind-hearted, courteous, emotionally stable and capable the person describes oneself and is described by others.

“Seeing others positively reveals our own positive traits,” Wood says.

The study also found that how positively you see other people shows how satisfied you are with your own life, and how much you are liked by others.

In contrast, negative perceptions of others are linked to higher levels of narcissism and antisocial behavior. “A huge suite of negative personality traits are associated with viewing others negatively,” Wood says. “The simple tendency to see people negatively indicates a greater likelihood of depression and various personality disorders.” Given that negative perceptions of others may underlie several personality disorders, finding techniques to get people to see others more positively could promote the cessation of behavior patterns associated with several different personality disorders simultaneously, Wood says.

This research suggests that when you ask someone to rate the personality of a particular coworker or acquaintance, you may learn as much about the rater providing the personality description as the person they are describing. The level of negativity the rater uses in describing the other person may indeed indicate that the other person has negative characteristics, but may also be a tip off that the rater is unhappy, disagreeable, neurotic—or has other negative personality traits.

Raters in the study consisted of friends rating one another, college freshmen rating others they knew in their dormitories, and fraternity and sorority members rating others in their organization. In all samples, participants rated real people and the positivity of their ratings were found to be associated with the participant’s own characteristics.

By evaluating the raters and how they evaluated their peers again one year later, Wood found compelling evidence that how positively we tend to perceive others in our social environment is a highly stable trait that does not change substantially over time.

Public release date: 2-Aug-2010

 

Pancreatic cancers use fructose, common in the Western diet, to fuel their growth

Pancreatic cancers use the sugar fructose, very common in the Western diet, to activate a key cellular pathway that drives cell division, helping the cancer to grow more quickly, a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center has found.

Although it’s widely known that cancers use glucose, a simple sugar, to fuel their growth, this is the first time a link has been shown between fructose and cancer proliferation, said Dr. Anthony Heaney, an associate professor of medicine and neurosurgery, a Jonsson Cancer Center researcher and senior author of the study.

“The bottom line is the modern diet contains a lot of refined sugar including fructose and it’s a hidden danger implicated in a lot of modern diseases, such as obesity, diabetes and fatty liver,” said Heaney, who also serves as director of the Pituitary Tumor and Neuroendocrine Program at UCLA. “In this study, we show that cancers can use fructose just as readily as glucose to fuel their growth.”

The study appeared in the Aug. 1 issue of the peer-reviewed journal Cancer Research.

The source of fructose in the Western diet is high fructose corn syrup (HFCS), a corn-based sweetener that has been on the market since about 1970. HFCS accounts for more than 40 percent of the caloric sweeteners added to foods and beverages, and it is the sole sweetener used in American soft drinks.

Between 1970 and 1990, the consumption of HFCS in the U.S. has increased over 1,000 percent, according to an article in the April 2004 issue of the American Journal of Clinical Nutrition. Food companies use HFCS – a mixture of fructose and glucose – because it’s inexpensive, easy to transport and keeps foods moist. And because it is so sweet, it’s cost effective for companies to use small quantities of HCFS in place of more expensive sweeteners or flavorings.

In his study, Heaney and his team took pancreatic tumors from patients and cultured and grew the malignant cells in Petri dishes. They then added glucose to one set of cells and fructose to another. Using mass spectrometry, they were able to follow the carbon-labeled sugars in the cells to determine what exactly they were being used for and how.

Heaney found that the pancreatic cancer cells could easily distinguish between glucose and fructose even though they are very similar structurally, and contrary to conventional wisdom, the cancer cells metabolized the sugars in very different ways. In the case of fructose, the pancreatic cancer cells used the sugar in the transketolase-driven non-oxidative pentose phosphate pathway to generate nucleic acids, the building blocks of RNA and DNA, which the cancer cells need to divide and proliferate.

“Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose,” the study states. “However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters … These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients, given dietary refined fructose consumption.”

As in anti-smoking campaigns, a federal effort should be launched to reduce refined fructose intake, Heaney said.

“I think this paper has a lot of public health implications,” Heaney said. “Hopefully, at the federal level there will be some effort to step back on the amount of HFCS in our diets.”

Heaney said that while this study was done in pancreatic cancer, these finding may not be unique to that cancer type.

Going forward, Heaney and his team are exploring whether it’s possible to block the uptake of fructose in the cancer cells with a small molecule, taking away one of the fuels they need to grow. The work is being done in cell lines and in mice, Heaney said.

Public release date: 3-Aug-2010

Disrupted circadian rhythm may cause triglycerides to rise

When the circadian rhythm gets thrown off, it could come with an unexpected side effect: high triglycerides. The discovery, based on studies in mice with a “broken clock,” helps to explain the normal rise and fall in triglycerides, which happens at about the same time each day, according to researchers who report their findings in the August issue of Cell Metabolism, a Cell Press publication.

“We show that the normal up and down [of triglycerides] is lost in clock mutants,” said M. Mahmood Hussain of SUNY Downstate Medical Center. “They have high triglycerides all the time.” An elevated triglyceride level is a risk factor for atherosclerosis and heart disease.

Several biological, physiological, and behavioral activities show a characteristic recurrence with 24-hour intervals attuned to sunrise and sunset, the researchers explained. That circadian rhythm is driven by the interaction of so-called clock genes.

In normal mice, plasma triglycerides double or triple over the course of the day, reaching their lowest point at night when the nocturnal animals eat and are most active, the new report shows. In clock mutants, triglyceride levels don’t change; rather, they stay high all the time.

The researchers delved further into the mechanism linking the animal’s internal clocks to triglycerides. They found that a core component of the circadian circuitry—a protein known as CLOCK—controls levels of another protein (called microsomal triglyceride transfer protein, or MTP) that helps to ferry triglycerides through the bloodstream. That control takes place via yet another transcription factor.

“Metabolic syndrome and obesity are major metabolic disorders characterized by high plasma lipid concentrations,” the researchers conclude. “Plasma lipids are tightly controlled by mechanisms regulating their production and clearance. Here, we show that light-entrained mechanisms involving clock genes also play a role in regulating plasma triglyceride.”

If the findings in mice can be extrapolated to humans, it suggests that the effects of drugs designed to lower triglyceride levels by acting on MTP might depend on when they are taken each day, the researchers said.

“The dose needed may vary depending on the time of day,” Hussain said. “Now we can start to think about [the role of] drug timing in controlling disease states.”

The findings also suggest that activities that disrupt the circadian rhythm—staying up until 2:00 a.m. or traveling overseas—might come with real consequences for lipid metabolism, he added.

 

 

Public release date: 3-Aug-2010

Oral contraceptive use associated with increased risk of breast cancer

(Boston) – Investigators from the Slone Epidemiology Center at Boston University School of Medicine (BUSM) have reported that African American women who use oral contraceptives have a greater likelihood of developing breast cancer than nonusers. The study results, recently published on-line in Cancer Epidemiology Biomarkers and Prevention, were based on data from the Black Women’s Health Study (BWHS), a large follow-up study of 59,000 African American women from across the U.S. conducted by investigators at the Slone Epidemiology Center since 1995.

The investigators followed 53,848 participants in the BWHS for 12 years, during which time 789 cases of breast cancer developed on which information on receptor status was obtained. The incidence of estrogen receptor negative cancer was 65 percent greater among women who had ever used oral contraceptives than among nonusers.

According to the BUSM researchers, the increase in risk was greatest for women who had used oral contraceptives within the previous five years and whose use had lasted 10 or more years, and the increase was greater for estrogen receptor negative than for estrogen receptor positive breast cancer. Estrogen receptor positive tumors have a better prognosis than estrogen receptor negative breast cancers.

Lead investigator Lynn Rosenberg, PhD, an associate director of the Slone Epidemiology Center and professor of epidemiology at BUSM, points out- that oral contraceptive formulations have changed over time, making it relevant to assess the effects of more recent formulations on breast cancer risk. “Some past studies found a stronger association with estrogen receptor negative breast cancer. This was the first assessment of the effect of oral contraceptive use on the incidence of breast cancer classified by receptor status among African American women,” said Rosenberg who is also the principal investigator of the BWHS. “A mechanism to explain an adverse influence of oral contraceptives on development of estrogen receptor negative breast cancer is currently unknown,” she added.

Public release date: 3-Aug-2010

Sperm may be harmed by exposure to BPA, study suggests

ANN ARBOR, Mich.—In one of the first human studies of its kind, researchers have found that urinary concentrations of the controversial chemical Bisphenol A, or BPA, may be related to decreased sperm quality and sperm concentration.

However, the researchers are quick to point out that these results are preliminary and more study is needed. Several studies have documented adverse effects of BPA on semen in rodents, but none are known to have reported similar relationships in humans.

BPA is a common chemical that’s stirred much controversy in the media lately over its safety. Critics say that BPA mimics the body’s own hormones and may lead to negative health effects. BPA is most commonly used to make plastics and epoxy resins used in food and beverage cans, and people are exposed primarily through diet, although other routes are possible. More than 6 billion pounds of BPA are produced annually.

The new study suggests that more research should focus on BPA and health effects in adults, says John Meeker, assistant professor of Environmental Health Sciences at the University of Michigan School of Public Health.

Meeker is the lead author on the study, along with Russ Hauser, the Frederick Lee Hisaw Professor of Reproductive Physiology at Harvard School of Public Health. Colleagues at Massachusetts General Hospital and the U.S. Centers for Disease Control and Prevention also contributed to the research.

“Much of the focus for BPA is on the exposures in utero or in early life, which is of course extremely important, but this suggests exposure may also be a concern for adults,” Meeker said. “Research should focus on impacts of exposure throughout multiple life stages.” Meeker and Hauser recruited 190 men through a fertility clinic. All gave spot urine samples and sperm samples the same day. Subsequently, 78 of the men gave one or two additional urine samples a month apart. Researchers detected BPA in 89 percent of the urine samples.

Researchers measured sperm concentration, sperm motility, sperm shape and DNA damage in the sperm cell.

“We found that if we compare somebody in the top quartile of exposure with the lowest quartile of exposure, sperm concentration was on average about 23 percent lower in men with the highest BPA,” Meeker said.

 

Results also suggested a 10 percent increase in sperm DNA damage.

The results are consistent with a previous study by Meeker and Hauser suggesting that certain hormones, specifically FSH (follicle-stimulating hormone) and Inhibin B, are elevated or decreased in relation to BPA, respectively, a pattern consistent with low sperm production and development.

Meeker stressed that further study is necessary due to the study’s relatively small sample size and design.

“The study from which these data came is currently in progress,” Hauser said. “With a larger sample size and enhanced study design, we will be able to more definitively investigate this preliminary association in the near future.”

The University of Michigan School of Public Health has been promoting health and preventing disease since 1941, and is ranked among the top five public health schools in the nation. Whether making new discoveries in the lab or researching and educating in the field, SPH faculty, students, and alumni are deployed around the globe to promote and protect our health.

 

Public release date: 4-Aug-2010

 

Homes of the poor and the affluent both have high levels of endocrine disruptors

Homes in low-income and affluent communities in California both had similarly high levels of endocrine disruptors, and the levels were higher in indoor air than outdoor air, according to a new study believed to be the first that paired indoor and outdoor air samples for such wide range (104) of these substances. The study appears in ACS’ Environmental Science & Technology, a semi-monthly journal.

Ruthann Rudel and colleagues note concern about the reproductive and other health effects of endocrine disrupting compounds (EDCs), which are found in many products used in the home. Examples include phthalates, which are found in vinyl and other plastics, and polychlorinated biphenyls (PCBs), which are found in older paints, electrical equipment, and building materials. EDCs also are among the ingredients in some pesticides, fragrances, and other materials.

The scientists analyzed indoor and outdoor air samples as well as house dust in homes from two different communities in the San Francisco Bay area for the presence of 104 compounds, including 70 suspected EDCs. The sampling, which took place in 2006, included 40 homes in Richmond, Calif., an urban, industrial, low-income area, and 10 homes in Bolinas, Calif., an affluent, coastal community. Levels were generally higher indoors than outdoors — 32 of the compounds occurred in higher concentrations indoors and only 2 were higher outdoors. The scientists expressed surprise at finding higher concentrations of some phthalates outdoors near urban homes contributing to higher indoor levels as well, but concluded that EDCs “are ubiquitously common across socioeconomic groups.”

Public Release: 5-Aug-2010

Surgery better than radiation, hormone treatments for some prostate cancer, study shows

 

Surgery for localized prostate cancer offers a significantly higher survival rate than either external-beam radiation or hormonal therapies, according to a new study led by researchers at UCSF.

The differences among therapies were more prominent at higher levels of cancer risk, and suggest, the researchers say, that in many cases surgery should play a greater role in treatment strategies for patients with prostate cancer that is likely to recur or spread.

The study is available online in the journal “Cancer,” the journal of the American Cancer Society,

Most previous reports comparing treatment outcomes among different treatment options have looked only at PSA responses to treatment, rather than at the more important long-term survival outcomes, according to the researchers. Measuring levels of PSA, or prostate-specific antigen, in the blood, is intended to help determine whether prostate cancer has recurred or spread, although in many cases a rising PSA level does not necessarily mean the cancer will progress.

Roughly one man in six will be diagnosed with prostate cancer, which is the second leading cause of cancer death in American men, according to the American Cancer Society.

“Despite the high incidence of prostate cancer, there is relatively little high-quality evidence on which to base current treatments for localized disease,” said Matthew R. Cooperberg, MD, MPH, lead investigator of the study and a prostate cancer specialist in the UCSF Department of Urology and the UCSF Helen Diller Family Comprehensive Cancer Center.

“These therapies can all have significant side effects, so it’s important to understand which treatment alternatives are most effective. In current practice, likelihood of undergoing surgery falls progressively with increasing levels of risk, which may be exactly contrary to what the treatment pattern should be,” he said.

Researchers found that the risk for cancer-specific mortality was more than three times higher in patients who received hormone therapy versus radical prostatectomy (surgical removal of the prostate) and more than twice as high in patients who received external-beam radiation therapy versus prostatectomy.

For men at low levels of risk, prostate cancer mortality was very uncommon, and differences among the treatment options were small. The survival differences increased substantially for men at intermediate and high risk, according to the analysis, with the greatest relative benefit for surgery seen for men at higher levels of risk.

The American Urological Association’s clinical practice guidelines for localized prostate cancer treatments include active surveillance, radical prostatectomy, external-beam radiation therapy, and brachytherapy (radiotherapy delivered via radioactive seeds), but draw no conclusions about the relative efficacy of each.

Androgen-deprivation therapy, which suppresses the production of male sex hormones, is not endorsed by the American Urological Association clinical practice guidelines for localized prostate cancer, due to inadequate evidence regarding outcomes, yet it is commonly used in practice, the researchers state.

“This is a clear signal to the physician community that prostatectomy should be considered for men with higher-risk prostate cancer. In many cases, surgery would be part of a multimodal treatment approach, including adjuvant radiation or systemic treatments based on the pathology and early PSA response,” added Peter R. Carroll, MD, MPH, chair of the UCSF Department of Urology and leader of the Prostate Program at the UCSF Helen Diller Family Comprehensive Cancer Center. Carroll is senior author on the paper.

Because no adequate randomized trials have compared active treatments for localized prostate cancer, the authors analyzed risk-adjusted, cancer-specific mortality outcomes among men who underwent radical prostatectomy, external-beam radiation therapy, or primary androgen deprivation.

The research team analyzed data from 7,538 men with localized disease from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry, a national disease registry comprising men from 40 urologic practice sites from across the country. The team then compared outcomes across treatments after adjusting for risk and age. In total, 266 men died of prostate cancer during follow-up.

Co-authors of the paper are Andrew J. Vickers, PhD, of the Memorial Sloan-Kettering Cancer Center; Jeanette M. Broering, RN, MS, MPH, of the UCSF Department of Urology and the UCSF Helen Diller Family Comprehensive Cancer Center; and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) Investigators.

 

Public release date: 12-Aug-2010

Free statins with fast food could neutralize heart risk, scientists say

Fast food outlets could provide statin drugs free of charge so that customers can neutralize the heart disease dangers of fatty food, researchers at Imperial College London suggest in a new study published this week

Fast food outlets could provide statin drugs free of charge so that customers can neutralise the heart disease dangers of fatty food, researchers at Imperial College London suggest in a new study published this week.

Statins reduce the amount of unhealthy “LDL” cholesterol in the blood. A wealth of trial data has proven them to be highly effective at lowering a person’s heart attack risk.

In a paper published in the Sunday 15 August issue of the American Journal of Cardiology, Dr Darrel Francis and colleagues calculate that the reduction in cardiovascular risk offered by a statin is enough to offset the increase in heart attack risk from eating a cheeseburger and a milkshake.

Dr Francis, from the National Heart and Lung Institute at Imperial College London, who is the senior author of the study, said: “Statins don’t cut out all of the unhealthy effects of burgers and fries. It’s better to avoid fatty food altogether. But we’ve worked out that in terms of your likelihood of having a heart attack, taking a statin can reduce your risk to more or less the same degree as a fast food meal increases it.”

One statin, simvastatin, is already available in low doses (10mg) over the counter at pharmacies without a prescription. Other statins are so far only prescribed by doctors, and limited by cost to patients at particular risk of heart attack or stroke. However, the cost of the tablets has fallen sharply in recent years (from ~£40/month to ~£1.50/month), such that the cost to the NHS of seeing a doctor is much greater than the cost of the tablet.

“It’s ironic that people are free to take as many unhealthy condiments in fast food outlets as they like, but statins, which are beneficial to heart health, have to be prescribed,” Dr Francis said.

Statins have among the best safety profiles of any medication. A very small proportion of regular statin users experience significant side effects, with problems in the liver and kidneys reported in between 1 in 1,000 and 1 in 10,000 people.

“Everybody knows that fast food is bad for you, but people continue to eat it because it tastes good. We’re genetically programmed to prefer high-calorie foods, and sadly fast food chains will continue to sell unhealthy foods because it earns them a living.

“It makes sense to make risk-reducing supplements available just as easily as the unhealthy condiments that are provided free of charge. It would cost less than 5p per customer – not much different to a sachet of ketchup.

“When people engage in risky behaviours like driving or smoking, they’re encouraged to take measures that minimise their risk, like wearing a seatbelt or choosing cigarettes with filters. Taking a statin is a rational way of lowering some of the risks of eating a fatty meal.”

Studies have shown a clear link between total fat intake and blood cholesterol, which is strongly linked to heart disease. Recent evidence suggests that trans fats, which are found in high levels in fast food, are the component of the Western diet that is most dangerous in terms of heart disease risk.

Dr Francis and his colleagues used data from a previous large cohort study to quantify how a person’s heart attack risk increases with their daily intake of total fat and trans fat. He compared this with the decrease in risk from various statins, based on a meta-analysis of seven randomised controlled trials.

The results showed that most statin regimes are able to compensate for the relative risk increase from eating a cheeseburger and a small milkshake.

The researchers note that studies should be conducted to assess the potential risks of allowing people to take statins freely, without medical supervision. They suggest that a warning on the packet should emphasise that no tablet can substitute for a healthy diet, and advise people to consult their doctor for more advice.

 

Ralph’s Note – Enough Said

 

 

Public release date: 12-Aug-2010

Acetaminophen tied to childhood wheezing and allergies

NEW YORK (Reuters Health) – A pair of studies suggests that the common painkiller acetaminophen — better known as Tylenol in the U.S. — may be fueling a worldwide increase in asthma.

According to one study out Thursday, acetaminophen could be responsible for as many as four in 10 cases of wheezing and severe asthma in teens.

While no one knows if the drug causes asthma by itself, another report — published along with the first study — shows for the first time that many toddlers took acetaminophen before they developed asthma symptoms such as wheezing.

“We have confirmed that acetaminophen use comes first, so a causal link is increasingly likely,” said Dr. Alemayehu Amberbir, of Addis Ababa University in Ethiopia and the University of Nottingham in the UK.

But large-scale clinical tests are necessary before anyone cleans out their medicine cabinet, stressed Amberbir, whose findings are published in the American Journal of Respiratory and Critical Care Medicine.

His team followed more than 1,000 Ethiopian babies over three years. When the toddlers turned one, the researchers asked the mothers if their babies had breathing problems, and how much acetaminophen they had used.

About eight percent of the kids began to wheeze between ages one and three. Those who had been given acetaminophen during their first year — before they had breathing trouble — had up to seven times the odds of developing wheezing.

That increase held even after adjusting for fever and coughs, which in principle could have triggered both the wheezing and the use of painkillers.

“What we have is further information and a stronger association between the use of acetaminophen and asthma,” said Dr. Dipak Kanabar, who has written guidelines on painkillers, but wasn’t involved in the new studies.

But Kanabar, a consultant pediatrician at Evelina Children’s Hospital in London, cautioned that parents’ recall isn’t always accurate, which could have influenced the findings.

“We have to be careful when we give advice to parents to stress that these studies do not mean that giving acetaminophen will necessarily result in their child developing asthma,” he said.

But if the link turns out to be real, it could have a major impact on public health, according to another report in the American Journal of Respiratory and Critical Care Medicine.

In that study, based on more than 320,000 teens from 50 countries, 11 percent of the children had breathing trouble — only slightly more than the percentage of American children who have asthma.

Those teens who took acetaminophen at least once a month — one third overall, and more than four in 10 Americans — doubled their odds of wheezing.

They were also more likely to have allergic nasal congestion and the skin condition eczema, Dr. Richard W. Beasley, of the Medical Research Institute of New Zealand, and colleagues report.

The researchers estimate that acetaminophen could potentially be responsible for up to four in 10 of all asthma symptoms, including severe ones such as waking up gasping for air once a week or more.

McNeil Consumer Healthcare, the Johnson & Johnson subsidiary that sells Tylenol, said in a comment their product “has over 50 years of clinical history to support its safety and efficacy.”

“The well-documented safety profile for acetaminophen makes it the preferred pain reliever for asthma sufferers,” the company told Reuters Health in an e-mail. The company said there are no gold-standard clinical trials showing “a causal link between acetaminophen and asthma.”

However, Kanabar found in his review of the medical literature that ibuprofen — another painkiller, sometimes sold as Advil — seemed to trigger less wheezing than acetaminophen.

Ibuprofen, however, is not recommended in people with asthma, Kanabar said, and that most doctors favor Tylenol.

Aspirin, another common painkiller, is generally discouraged in children because it can cause short-term breathing problems and other rare side effects.

According to Kanabar, dropping painkillers entirely is probably a bad idea, and might cause a child to feel worse and drink less liquid, which could slow recovery.

So which painkiller should a parent choose if their child has a headache or a fever — Tylenol or ibuprofen?

At this point, said Kanabar, “you could go for either.”

SOURCE: http://link.reuters.com/sej74n American Journal of Respiratory and Critical Care Medicine, online

Public release date: 16-Aug-2010

FDA moves to withdraw unproven blood pressure drug

By MATTHEW PERRONE, AP Business Writer Matthew Perrone, Ap Business Writer

WASHINGTON – Federal health regulators are pushing to withdraw a blood pressure drug that has been on the market for 14 years in spite of the manufacturer’s failure to submit evidence that it actually helps patients.

The Food and Drug Administration approved Shire Laboratories’ drug ProAmatine in 1996 based on promising early results in treating low blood pressure. But the company has never conducted a mandatory follow-up study to actually prove the long-term benefits of the drug.

 

In letter to the company posted online Monday, the FDA proposes withdrawing the drug from the market and gives Shire an opportunity to schedule a hearing to discuss the matter. The letter marks the first time the FDA has threatened to pull a drug off the market due to missing follow-up data, though it has long held that power.

“This proposal is necessitated by Shire’s failure to conduct postmarketing clinical trials that verify and describe the clinical benefit” of ProAmatine, the agency states.

Calls placed to Dublin, Ireland-based Shire seeking comment were not returned Monday afternoon.

Copies of the letter were also sent to five generic drugmakers who manufacture the drug, including Mylan Pharmaceuticals and Sandoz Inc. Those generic products would also be subject to a market withdrawal, unless their manufacturers complete the study requested by the FDA.

Roughly 100,000 U.S. patients received prescriptions for ProAmatine or generic versions last year, according to the FDA. The drug is approved to treat orthostatic hypotension, a type of low blood pressure that causes patients to become dizzy or faint when standing upright.

The letter does not cite any safety or effectiveness problems with the drug, and suggests the action is primarily aimed at enforcing drug approval regulations that have not always been enforced.

ProAmatine is part of a family of heart drugs that help stimulate dangerously low blood pressure. Several companies sell generic versions of the drug phenylephrine, which is used off-label to treat the condition.

For nearly 20 years, the FDA has granted accelerated approval to drugs based on so-called surrogate endpoints, or initial measures that suggest the drug will make real improvements in patient health. In cancer drugs, for example, tumor shrinkage is considered a predictor of increased survival.

Drugmakers favor the program because it helps them get products to market sooner.

But the program has not escaped criticism from government watchdogs.

Last fall the Government Accountability Office issued a report saying the FDA should do more to track whether drugs approved based on preliminary results actually live up to their promise.

The report singled out ProAmatine as a particularly egregious example of missing follow-up data. The government watchdog said that ProAmatine has generated more than $257 million in sales even though “the clinical benefit of the drug has never been established.”

According to the GAO, the FDA has never once pulled a drug off the market due to missing or unimpressive follow-up data.

The GAO’s September 2009 report found that the FDA had requested 144 follow-up studies for drugs since 1992. Of those about 64 percent had been completed and more than one-third were still pending

 

Thursday, Aug. 12, 2010

After Avandia: Does the FDA Have a Drug Problem?

By Massimo Calabresi with Alice Park

Five days before a 2007 article in the New England Journal of Medicine showed that the diabetes drug Avandia was linked to a 43% increase in heart attacks compared with other medications or placebos, a group of scientists and executives from the drug’s maker, GlaxoSmithKline (GSK), gathered in a conference room at the offices of the Food and Drug Administration in White Oak, Md. The GSK goal: to convince regulators that the evidence that the company’s $3 billion-a-year blockbuster drug caused heart problems was inconclusive. To do that, the GSK officials focused not on heart-attack data but on a broader, less well defined category of heart problems called myocardial ischemia. The most recent studies of Avandia, the GSK officials told the FDA, had “yielded information that is inconsistent with an increased risk of myocardial ischemic events,” according to sealed court proceedings obtained by TIME.

What GSK didn’t tell the FDA was that on May 14, 2007, two days before the White Oak meeting, GSK’s Global Safety Board had noted that a new assessment of Avandia studies “strengthens the [cardiac-risk] signal observed in the [previous] analysis.” Or that eight days earlier, the company’s head of research and development, Moncef Slaoui, had sent an e-mail to its chief medical officer saying Avandia patients showed an “increased risk of ischemic event ranging from 30% to 43%!” Or that the day before the meeting, the company had produced a preliminary draft report that showed patients on Avandia had a 46% greater likelihood of heart attack than those in a control group.

But the mixed-evidence argument GSK presented to the FDA worked. After months of deliberation, the agency decided to keep the drug on the market — a move worth billions of dollars to GSK but that also may have put millions of patients at risk.

Such examples of the drug industry’s outmaneuvering FDA regulators are disturbingly common, say both scientists and policymakers who follow drug approval and safety monitoring. More than 140 million Americans take at least one prescription drug in any given month, and they rely on the FDA to ensure those drugs are safe. That trust, the story of Avandia illustrates, is a gamble. In July, an FDA advisory group conducted the second hearing on the drug’s safety since its 1999 approval and again concluded that the evidence against the drug was insufficient to pull it from the market. The group instead recommended additional warnings and restrictions on Avandia’s use. In the coming weeks, the FDA will decide whether to take that advice or withdraw Avandia from the market

 

Gaming the System

Over the past two decades, as drug after drug has been recalled after winning FDA approval, it has been hard not to wonder if FDA regulators have been captured by the drug industry. FDA critics and industry monitors charge that the drug-approval process is too easy for pharmaceutical companies to game. It is in some ways an unsurprising development. The FDA serves a public insatiably hungry for new medicines. Yet the agency does not have responsibility for performing safety testing. It relies on drug companies to perform all premarket testing on drugs for safety and efficacy. And it relies on industry “user fees” for 65% of its budget for postmarket monitoring of the drugs it approves, thanks to a 1992 law designed to speed treatments to patients. “The FDA’s relationship with the drug industry [is] too cozy,” says Senator Chuck Grassley of Iowa.

Federal studies reveal that the FDA doesn’t have a complete or accurate list of prescription drugs on the market and is missing or has incomplete information on one-third of the drug-safety and efficacy trials under way. Over the past three years, the inspector general at the Department of Health and Human Services found that the FDA had inspected only 1% of clinical-trial sites from 2000 to 2005 and lacked financial disclosure data for clinical investigators in half of all industry drug reviews.

 

The results of this broken system may prove criminal as well as fatal. In June, FDA whistle-blower Dr. David Graham published an article suggesting that Avandia caused 47,000 more diabetics to suffer heart failure, stroke or death than would have been the case if they had taken an alternative. The risk is especially troubling given that diabetics are already more vulnerable to heart disease because of their condition. Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug. Equally alarming is the revelation that the FDA knew of the dangers months before it informed the public. Now the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandia’s heart risks, deputy FDA commissioner Dr. Joshua Sharfstein tells TIME. At the least, the story of Avandia shows how drug companies use uncertainty to their advantage — at a risk to public health.

Risk and Reward

In November 1998, SmithKline Beecham (SB), which more than a year later would merge with Glaxo Wellcome to become GlaxoSmithKline, presented the FDA with an impressive application to market Avandia: dozens of boxes, each containing eight volumes the size of the New York City phone book, filled with trial data and chemical analyses. Avandia, or rosiglitazone, was only the second in a new class of antidiabetes drugs that was showing promise in helping Type 2 patients keep their blood sugar in check. But the first product, troglitazone, or Rezulin, was also causing a troubling amount of liver damage, so doctors and patients were eager for a safer alternative. Aware of this, FDA officials put Avandia on a six-month fast track to approval. As the FDA’s medical, statistical and pharmacological reviewers went through the mountain of documents, they soon found the same thing: Avandia users experienced more cardiovascular issues, including a rise in bad cholesterol (or LDL) and lipids, than those taking other antidiabetes medications or a placebo. But detailed though the pages of data provided by SB were, they didn’t show this danger of heart problems with certainty.

In public, SB executives defended the safety of their drug. At an April 1999 FDA public hearing featuring outside experts charged with recommending whether to approve Avandia, SB’s head of research and development, Dr. Tadataka Yamada, maintained that Avandia had a “risk-neutral lipid profile” and “cardiovascular safety … comparable to placebo and active comparators.” FDA scientists disagreed. Concerned about the boost in LDL, FDA pharmacologists recommended against approving the drug. Dr. Robert Misbin, the FDA’s medical officer, said he would support approval only if the company committed to a thorough safety trial that would include monitoring for cardiovascular risks.

The hearing committee, three of whose eight voting members had declared financial conflicts of interest in the case, debated the heart issue and eventually recommended that the FDA approve the drug. (TIME requested the forms that waived the conflicts of interest; an FDA official declined to release them and said none of the conflicts involved a relationship with SB.) Then came the horse trading. After outside experts weigh in on a new drug, but before it receives final approval from the agency, the FDA and the drugmaker negotiate which tests the company will perform once large numbers of people are taking it on the open market.

On May 5, 1999, SB sent its proposal for testing Avandia to the FDA. The company didn’t want to do a long-term safety test at all. Less than a week later, in a letter to his superior, Misbin threatened to withdraw his approval recommendation, saying the risk of heart disease may be increased by treatment with Avandia and accusing SB of attempting to divert attention from dangers that Avandia might pose to patients, according to parts of the letter read to TIME.

Then, right at the May 25 deadline for FDA approval, SB made an offer to focus its testing on the drug’s ability, as compared with competitor drugs, to lower blood sugar. It was a side step from the question the agency wanted to answer about the drug’s safety. Instead of focusing on finding out if Avandia posed a heart risk, SmithKline Beecham was going to run a trial its sales representatives could use to promote the drug. “It was really a marketing study,” says Misbin now. But later that day, Dr. John Jenkins, the FDA’s director for new drugs, accepted SB’s proposal for testing the drug on the market and approved Avandia for sale. By agreeing to the company’s version of the postmarket trial, scientists say, the FDA abdicated its responsibility to collect reliable data on Avandia’s safety.

Even with the FDA’s help, the company had its hands full. In 1999, Dr. John Buse of the University of North Carolina at Chapel Hill, a diabetes expert, using slides that SB officials had presented at their approval hearing, did his own calculations based on the data. In speeches, he highlighted the fact that Avandia users experienced a more than fourfold rise in cholesterol compared with those taking a placebo. Because elevated cholesterol levels are a risk factor for heart disease, Buse wrote to the FDA commissioner, warning that Avandia could cause “adverse cardiac outcomes.” In March 2000, officials with the newly merged GlaxoSmithKline got a copy of the letter and, Buse tells TIME, contacted his boss, accusing Buse of being a liar and being for sale, and saying he needed to be muzzled. The company’s stock had dropped, and “they threatened to sue me for something like $4 billion, which was the loss of the company’s valuation,” he says.

In the meantime, the company took measures to promote Avandia. In 2001, GSK worked on an article, later published in the American Heart Association’s journal Circulation by Dr. Steven Haffner of the University of Texas Health Science Center at San Antonio, arguing that the class of drugs that includes Avandia could significantly reduce cardiovascular risk factors in animals. At meetings with doctors in 2001, GSK sales representatives denied Avandia had cardiac side effects, prompting the FDA to issue a public letter of warning against the company.

Keeping the Public in the Dark

By 2004, Avandia sales were earning GSK more than $1.5 billion a year in the U.S. alone. But as more people went on the drug, the picture on cardiovascular risk began to get clearer. GSK began a review of the drug’s heart risks, and in 2005 and 2006 the company produced internal analyses showing 29% and 31% jumps in negative heart events. On May 9, 2006, the company provided these results to the FDA. The agency didn’t immediately release those studies to the public, because its officials “didn’t necessarily agree with some of the methodology used,” says Dr. Janet Woodcock, head of the FDA Center for Drug Evaluation and Research. Instead, the FDA put its own statistician on the job. Just before Christmas that year, Misbin looked at the statistician’s spreadsheet and found that “in virtually every trial, there were more cardiac events with Avandia than with the comparator,” Misbin says. He was convinced enough to call his uncle, who was on Avandia, and advise him to ask his doctor to switch him to another drug.

It was seven years after the drug was approved, and the dangers of Avandia had still not been made sufficiently clear to the public. The FDA was sitting on the new analyses, and GSK, the FDA discovered during an investigation by its inspections unit in the fall of 2007, had failed to report clinical data and other material from 15 tests of Avandia by the end of 2006, according to a March 25, 2008, warning letter to the company. With the company and the FDA maintaining tight control over the full database of information on Avandia’s effectiveness and safety, there was little independent scientists could do to assuage their growing concerns about the drug.

Then came a bit of legal serendipity. As part of a settlement with the state of New York over GSK’s nondisclosure of possible heightened suicide risk among teenagers taking its antidepressant Paxil, the company agreed to put all its recent clinical studies on a website. Aware of the growing concerns among clinicians about the risks posed by Avandia, in April 2007, Cleveland Clinic cardiologist Dr. Steven Nissen Googled the site and downloaded all of the available Avandia trials. After analyzing the 42 trials, he wrote up his findings and in May submitted them to the New England Journal of Medicine. He had found what GSK and the FDA already knew: a 43% higher rate of cardiac events among Avandia patients compared with those taking other drugs or placebos.

By chance, the New England Journal of Medicine chose as a prepublication reviewer of the Nissen article Haffner, the University of Texas doctor who was the lead author on the 2001 paper that had suggested that Avandia’s class of drug could decrease cardiovascular risk. He faxed a copy of Nissen’s article directly to GSK. Now GSK faced the threat of broad public awareness of the hazards of its drug. So with the clock ticking until Nissen’s article was to be published on May 21, 2007, GSK harvested data on cardiac events from the recently completed efficacy trial Jenkins had signed off on back in 1999. Because the trial had been designed to show efficacy, not safety, its cardiac data were inconclusive.

As it prepared for the pivotal May 16, 2007, meeting in White Oak with FDA regulators, GSK came up with an additional counterattack to Nissen’s study. Unlike the FDA, European regulators had insisted on a long-term cardiac-safety study, called RECORD, when they approved the drug. So GSK argued that the only prudent approach would be to let the RECORD trial run to completion in 2009 to reach a definitive answer on cardiovascular risk. To top agency officials, it seemed like a reasonable solution at the time. But three years and hundreds of millions of dollars in Avandia sales later, it turns out the RECORD trial may not be as reliable a study of cardiac risk as agency officials had hoped.

Regulator, Regulate Thyself

By 2008, after the painkiller Vioxx and the cholesterol-lowering medication Baycol were pulled from the market because of side effects and complications, House and Senate overseers both began investigations of the drug-approval process and the relationship between the drug industry and its federal minders. The Senate Finance Committee concluded in January 2010, after a two-year review, that GSK failed to promptly alert the FDA about Avandia’s drug risks. In response, FDA commissioner Dr. Margaret Hamburg initiated another review of whether to keep Avandia on the market. As part of that review, FDA investigator Dr. Thomas Marciniak presented a devastating report on RECORD’s shortcomings, detailing how the RECORD study minimized Avandia’s heart risks: one death among the drug takers, for example, was missing from the final tally, and discrepancies in some cardiovascular data favored Avandia by a ratio of 4 to 1. The congressional investigation also uncovered e-mails indicating that GSK executives had managed to persuade the trial’s supposedly independent steering committee to publish interim results that demonstrated how inconclusive the heart risk was. The trial’s design, Marciniak found, was “completely inappropriate and biased.”

For its part, GSK insists the drug is indeed safe and says it has played fair with the data. It lists multiple studies that are inconclusive or show no increase in heart risk for Avandia. It says it has disciplined the sales representatives who triggered the FDA admonition; it updated its report on Avandia tests after the FDA’s 2008 warning letter. “GSK continues to stand behind Avandia,” says spokesman Kevin Colgan. “The facts will support our position.” Using the most powerful argument of all, GSK says diabetics desperately want and need drugs to lower their blood-sugar levels. All of this persuaded the FDA advisory group this July to narrowly vote not to pull Avandia off the market, citing a lack of strong evidence that it should be withdrawn. Eleven years after the drug was approved, neither GSK nor the FDA could yet prove Avandia was safe.

GSK certainly had reason to dispel the uncertainty if it could. In 2001, it ran a calculation of what the “net sales downside” would be if the cardiovascular “safety issue intensifies” and found that for 2002-04, potential lost revenue amounted to $600 million, according to the civil-court proceedings obtained by TIME. GSK reported a 10% drop in profits for the fourth quarter of 2007, partly as a consequence of a drop in Avandia sales following the publication of the Nissen article. Now GSK has other financial concerns. In March the company put aside $3.5 billion for “legal and other disputes.” In May it paid $60 million to settle 700 Avandia civil cases; in July it reportedly offered to pay $460 million to settle civil cases claiming the drug caused heart attacks. GSK declines to discuss the costs of — or anything else about — the investigation the FDA is undertaking against it.

That investigation may indicate that change is coming to the FDA. Government and independent watchdogs say the agency has made some progress. In 2009, government auditors found that the FDA had begun to bolster the role of drug-safety monitors. The Health and Human Services inspector general said last March that the FDA has boosted its prescription database of postmarket reports.

But none of that addresses the issue at the heart of the Avandia case. Science is often inconclusive, and the FDA rightly argues that surveys like Nissen’s are sometimes wrong. Where the FDA fell down on Avandia was in allowing GSK to perpetuate the uncertainty about safety rather than clarify it. In 2007, the FDA gained new powers to require postmarket safety trials, but FDA leaders admit they’re still learning how to use them. Grassley wants to give FDA safety monitors even more power, and former FDA chief Mark McClellan says the agency should use newly computerized medical records to track safety data in near real time.

But with the FDA ever more dependent on industry user fees, and with new drug-safety concerns emerging year after year, it will take more than faster data retrieval to restore the reputation of an agency that was once synonymous with trust in the public mind. The FDA will have to start forcing companies to be transparent and call them out on it when they’re not. Says the medical reviewer Misbin: “Companies are always going to present their best face. It’s our job to say no.” In that sense, the FDA just needs to perform the task it was charged with more than 100 years ago: protecting the public interest by keeping industry honest

Ralph’s Note – Thank you Time Magazine….

 

________________________________

 

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.

Early life exposure to BPA may affect testis function in adulthood

2010 study posted for filing

 

Exposure to environmental levels of the industrial chemical bisphenol A, or BPA, in the womb and early life may cause long-lasting harm to testicular function, according to a new study conducted in animals. The results are being presented Monday at The Endocrine Society’s 92nd Annual Meeting in San Diego.

 

“We are seeing changes in the testis function of rats after exposure to BPA levels that are lower than what the Food and Drug Administration and Environmental Protection Agency consider safe exposure levels for humans,” said Benson Akingbemi, PhD, the study’s lead author and an associate professor at Auburn (Ala.) University. “This is concerning because large segments of the population, including pregnant and nursing mothers, are exposed to this chemical.”

 

Many hard plastic bottles and canned food liners contain BPA, as do some dental sealants. BPA acts in a similar manner as the female sex hormone estrogen and has been linked to female infertility. This chemical is present in placenta and is able to pass from a mother into her breast milk. In their study of the male, Akingbemi and colleagues saw harmful effects of BPA at the cellular level, specifically in Leydig cells. These cells in the testis secrete testosterone, the main sex hormone that supports male fertility. After birth, Leydig cells gradually acquire the capacity for testosterone secretion, Akingbemi explained.

 

The process of testosterone secretion was decreased in male offspring of female rats that received BPA during pregnancy and while nursing. The mothers were fed BPA in olive oil at a dose of either 2.5 or 25 micrograms of BPA per kilogram of body weight. Akingbemi said this is below the daily upper limit of safe exposure for humans, which federal guidelines currently put at 50 micrograms per kilogram of body weight. A control group of pregnant rats received olive oil without BPA. Male offspring, after weaning at 21 days of age, received no further exposure to BPA.

 

Using a combination of analytical methods, the investigators studied the development of Leydig cells in male offspring. The capacity for testosterone secretion was assessed at 21, 35 and 90 days of age. The amount of testosterone secreted per Leydig cell was found to be much lower in male offspring after early-life exposure to BPA than in offspring from control unexposed animals.

 

“Although BPA exposure stopped at 21 days of age, BPA’s effects on Leydig cells, which were seen immediately at the end of exposure and at 35 days, remained apparent until 90 days of age, when the rats reached adulthood,” Akingbemi said. “Therefore, the early life period is a sensitive window of exposure to BPA and exposure at this time may affect testis function into adulthood.”

Early life exposure to BPA may affect testis function in adulthood

2010  study posted for filing

Contact: Aaron Lohr alohr@endo-society.org 240-482-1380 The Endocrine Society

Exposure to environmental levels of the industrial chemical bisphenol A, or BPA, in the womb and early life may cause long-lasting harm to testicular function, according to a new study conducted in animals. The results are being presented Monday at The Endocrine Society’s 92nd Annual Meeting in San Diego.

“We are seeing changes in the testis function of rats after exposure to BPA levels that are lower than what the Food and Drug Administration and Environmental Protection Agency consider safe exposure levels for humans,” said Benson Akingbemi, PhD, the study’s lead author and an associate professor at Auburn (Ala.) University. “This is concerning because large segments of the population, including pregnant and nursing mothers, are exposed to this chemical.”

Many hard plastic bottles and canned food liners contain BPA, as do some dental sealants. BPA acts in a similar manner as the female sex hormone estrogen and has been linked to female infertility. This chemical is present in placenta and is able to pass from a mother into her breast milk. In their study of the male, Akingbemi and colleagues saw harmful effects of BPA at the cellular level, specifically in Leydig cells. These cells in the testis secrete testosterone, the main sex hormone that supports male fertility. After birth, Leydig cells gradually acquire the capacity for testosterone secretion, Akingbemi explained.

The process of testosterone secretion was decreased in male offspring of female rats that received BPA during pregnancy and while nursing. The mothers were fed BPA in olive oil at a dose of either 2.5 or 25 micrograms of BPA per kilogram of body weight. Akingbemi said this is below the daily upper limit of safe exposure for humans, which federal guidelines currently put at 50 micrograms per kilogram of body weight. A control group of pregnant rats received olive oil without BPA. Male offspring, after weaning at 21 days of age, received no further exposure to BPA.

Using a combination of analytical methods, the investigators studied the development of Leydig cells in male offspring. The capacity for testosterone secretion was assessed at 21, 35 and 90 days of age. The amount of testosterone secreted per Leydig cell was found to be much lower in male offspring after early-life exposure to BPA than in offspring from control unexposed animals.

“Although BPA exposure stopped at 21 days of age, BPA’s effects on Leydig cells, which were seen immediately at the end of exposure and at 35 days, remained apparent until 90 days of age, when the rats reached adulthood,” Akingbemi said. “Therefore, the early life period is a sensitive window of exposure to BPA and exposure at this time may affect testis function into adulthood.”

###

Funding from this study came in part from the Graduate Research Scholars Program of Alabama EPSCoR (Experimental Program to Stimulate Competitive Research), Tuscaloosa, Ala., and the National Institute of Environmental Health Sciences.

Scripps Research Institute scientists describe elusive replication machinery of flu viruses

Contact: Jann Coury
jcoury@scripps.edu
858-784-8245
Scripps Research Institute

IMAGE:The new Scripps Research Institute study shows flu virus proteins in the act of self-replication. Shown here is the influenza virus, which encapsidates its RNA genome (green) with a viral…

Click here for more information. 

LA JOLLA, CA – November 22, 2012 – Scientists at The Scripps Research Institute (TSRI) have made a major advance in understanding how flu viruses replicate within infected cells. The researchers used cutting-edge molecular biology and electron-microscopy techniques to “see” one of influenza’s essential protein complexes in unprecedented detail. The images generated in the study show flu virus proteins in the act of self-replication, highlighting the virus’s vulnerabilities that are sure to be of interest to drug developers.

The report, which appears online in Science Express on November 22, 2012, focuses on influenza’s ribonucleoprotein (RNP). RNPs contain the virus’s genetic material plus the special enzyme that the virus needs to make copies of itself.

“Structural studies in this area had stalled because of the technical obstacles involved, and so this is a welcome advance,” said Ian A. Wilson, the Hansen Professor of Structural Biology at TSRI and senior author of the report with TSRI Professors of Cell Biology Bridget Carragher and Clint Potter. “The data from this study give us a much clearer picture of the flu virus replication machinery.”

Unveiling the Mystery of RNPs

At the core of any influenza virus lie eight RNPs, tiny molecular machines that are vital to the virus’s ability to survive and spread in its hosts. Each RNP contains a segment—usually a single protein-coding gene—of the RNA-based viral genome. This viral RNA segment is coated with protective viral nucleoproteins and has a structure that resembles a twisted loop of chain. The free ends of this twisted loop are held by a flu-virus polymerase enzyme, which handles the two central tasks of viral reproduction: making new viral genomic RNA, and making the RNA gene-transcripts that will become new viral proteins.

Aside from its importance in ordinary infections, the flu polymerase contains some of the key “species barriers” that keep, for example, avian flu viruses from infecting mammals. Mutations at key points on the enzyme have enabled the virus to infect new species in the past. Thus researchers are eager to know the precise details of how the flu polymerase and the rest of the RNP interact.

Getting those details has been a real challenge. One reason is that flu RNPs are complex assemblies that are hard to produce efficiently in the lab. Flu polymerase genes are particularly resistant to being expressed in test cells, and their protein products exist in three separate pieces, or subunits, that have to somehow self-assemble. Until now, the only flu RNPs that have been reproduced in the laboratory are shortened versions whose structures aren’t quite the same as those of native flu RNPs. Researchers also are limited in how much virus they can use for such studies.

The team nevertheless managed to develop a test-cell expression system that produced all of the protein and RNA components needed to make full-length flu RNPs. “We were able to get the cells to assemble these components properly so that we had working, self-replicating RNPs,” said Robert N. Kirchdoerfer, a first author of the study. Kirchdoerfer was a PhD candidate in the Wilson laboratory during the study, and is now a postdoctoral research associate in the laboratory of TSRI Professor Erica Ollmann Saphire.

Kirchdoerfer eventually purified enough of these flu RNPs for electron microscope analysis at TSRI’s Automated Molecular Imaging Group, which is run jointly by Carragher and Potter.

Never Seen Before

The imaging group’s innovations enable researchers to analyze molecular samples more easily, in less time, and often with less starting material. “We were able, for example, to automatically collect data for several days in a row, which is unusual in electron microscopy work,” said Arne Moeller, a postdoctoral research associate at the imaging group who was the other first author of the study.

Electron microscopes make high-resolution images of their tiny targets by hitting them with electrons rather than photons of light. The images revealed numerous well-defined RNP complexes. To Moeller and his colleagues’ surprise, many of these appeared to have new, partial RNPs growing out of them. “They were branching—this was very exciting,” he said.

“Essentially these were snapshots of flu RNPs being replicated, which had never been seen before,” said Kirchdoerfer. These and other data, built up from images of tens of thousands of individual RNPs, allowed the team to put together the most complete model yet for flu-RNP structure and functions. The model includes details of how the viral polymerase binds to its RNA, how it accomplishes the tricky task of viral gene transcription, and how a separate copy of the viral polymerase assists in carrying out RNP replication. “We’re now able to take a lot of what we knew before about flu virus RNP and map it onto specific parts of the RNP structure,” said Kirchdoerfer.

The new flu RNP model highlights some viral weak points. One is a shape-change that a polymerase subunit—which grabs viral RNA and feeds it to the polymerase’s active site on a second subunit—has to undergo during viral gene transcription. Another is key interaction between the polymerase and viral nucleoproteins. Flu RNPs are long and flexible, curving and bending in electron microscope images; and thus the structural model remains only modestly fine-grained. “You wouldn’t be able to design drugs based on this model alone,” said Kirchdoerfer, “but we now have a much better idea of how flu RNPs work, and that does suggest some possibilities for better flu drugs.”

 

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The study, “Organization of the Influenza Virus Replication Machinery,” was funded in part by grants from the National Institutes of Health (AI058113, GM095573) and the Joint Center for Innovation in Membrane Protein Production for Structure Determination (P50GM073197). TSRI’s Automated Molecular Imaging Group includes the National Resource for Automated Molecular Microscopy, which is supported by the National Institutes of Health’s National Center for Research Resources (2P41RR017573-11) and the National Institute of General Medical Sciences Biomedical Technology Resource Centers (9 P41 GM103310-11).

Common antidepressant drugs linked to lactation difficulties in moms

2010 study posted for filing

Contact: Aaron Lohr alohr@endo-society.org 240-482-1380 The Endocrine Society

According to a new study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM), women taking commonly used forms of antidepressant drugs may experience delayed lactation after giving birth and may need additional support to achieve their breastfeeding goals.

Breastfeeding benefits both infants and mothers in many ways as breast milk is easy to digest and contains antibodies that can protect infants from bacterial and viral infections. The World Health Organization recommends that infants should be exclusively breastfed for the first six months of life. This new study shows that certain common antidepressant drugs may be linked to a common difficulty experienced by new mothers known as delayed secretory activation, defined as a delay in the initiation of full milk secretion.

“The breasts are serotonin-regulated glands, meaning the breasts’ ability to secrete milk at the right time is closely related to the body’s production and regulation of the hormone serotonin,” said Nelson Horseman, PhD, of the University of Cincinnati and co-author of the study. “Common antidepressant drugs like fluoxetine, sertraline and paroxetine are known as selective serotonin reuptake inhibitor (SSRI) drugs and while they can affect mood, emotion and sleep they may also impact serotonin regulation in the breast, placing new mothers at greater risk of a delay in the establishment of a full milk supply.”

In this study, researchers examined the effects of SSRI drugs on lactation using laboratory studies of human and animal cell lines and genetically modified mice. Furthermore, an observational study evaluated the impact of SSRI drugs on the onset of milk production in postpartum women. In this study of 431 postpartum women, median onset of lactation was 85.8 hours postpartum for the SSRI-treated mothers and 69.1 hours for mothers not treated with SSRI drugs. Researchers commonly define delayed secretory activation as occurring later than 72 hours postpartum.

“SSRI drugs are very helpful medications for many moms, so understanding and ameliorating difficulties moms experience can help them achieve their goals for breastfeeding their babies,” said Horseman. “More human research is needed before we can make specific recommendations regarding SSRI use during breastfeeding.”

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Other researchers working on the study include: Aaron Marshall, Laura Hernandez and Karen Gregerson of the University of Cincinnati in Ohio; Laurie Nommsen-Rivers of Cincinnati Children’s Hospital Medical Center in Ohio; Kathryn Dewey of the University of California at Davis; and Caroline Chantry of the University of California Davis Medical Center in Sacramento.

The article, “Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution,” will appear in the February 2010 issue of JCEM.

Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology. Today, The Endocrine Society’s membership consists of over 14,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied, and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at www.endo-society.org.