147th Health Research Report 25 JAN 2013

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Health Research Report

147th Issue Date 25 JAN 2013

Compiled By Ralph Turchiano

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In This Issue:

1.      Fetal exposure to PVC plastic chemical linked to obesity in offspring

2.      Choline supplementation during pregnancy presents a new approach to schizophrenia prevention

3.      Could probiotics help HIV patients?

4.      Light exposure during pregnancy key to normal eye development

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

6.      Which nutritional factors help preserve muscle mass, strength and performance in seniors?

7.      Study suggests link between regular aspirin use, increased risk of age-related macular degeneration

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

9.      Eczema in infants linked to gut bacteria

10.  Harms from breast cancer screening outweigh benefits if death caused by treatment is included

11.  Common anti-fever medications pose kidney injury risk for children

Fetal exposure to PVC plastic chemical linked to obesity in offspring

UCI study identifies transgenerational effects of obesogen compound tributyltin

Irvine, Calif. — Exposing pregnant mice to low doses of the chemical tributyltin – which is used in marine hull paint and PVC plastic – can lead to obesity for multiple generations without subsequent exposure, a UC Irvine study has found.

After exposing pregnant mice to TBT in concentrations similar to those found in the environment, researchers saw increased body fat, liver fat and fat-specific gene expression in their “children,” “grandchildren” and “great-grandchildren” – none of which had been exposed to the chemical.

These findings suggest that early-life exposure to endocrine-disrupting compounds such as TBT can have permanent effects of fat accumulation without further exposure, said study leader Bruce Blumberg, UC Irvine professor of pharmaceutical sciences and developmental & cell biology. These effects appear to be inherited without DNA mutations occurring.

The study appears online Jan. 15 in Environmental Health Perspectives, a publication of the National Institute for Environmental Health Sciences.

Human exposure to TBT can occur through PVC plastic particles in dust and via leaching of the chemical and other related organotin compounds from PVC pipes and containers.

Significant levels of TBT have been reported in house dust – which is particularly relevant for young children who may spend significant time on floors and carpets. Some people are exposed by ingesting seafood contaminated with TBT, which has been used in marine hull paint and is pervasive in the environment.

Blumberg categorizes TBT as an obesogen, a class of chemicals that promote obesity by increasing the number of fat cells or the storage of fat in existing cells. He and his colleagues first identified the role of obesogens in a 2006 publication and showed in 2010 that TBT acts in part by modifying the fate of mesenchymal stem cells during development, predisposing them to become fat cells.

Choline supplementation during pregnancy presents a new approach to schizophrenia prevention

University of Colorado researchers study choline in infants

AURORA, Colo. (Jan. 15, 2013) — Choline, an essential nutrient similar to the B vitamin and found in foods such as liver, muscle meats, fish, nuts and eggs, when given as a dietary supplement in the last two trimesters of pregnancy and in early infancy, is showing a lower rate of physiological schizophrenic risk factors in infants 33 days old. The study breaks new ground both in its potentially therapeutic findings and in its strategy to target markers of schizophrenia long before the illness itself actually appears. Choline is also being studied for potential benefits in liver disease, including chronic hepatitis and cirrhosis, depression, memory loss, Alzheimer’s disease and dementia, and certain types of seizures.

Robert Freedman, MD, professor and chairman of the Department of Psychiatry, University of Colorado School of Medicine and one of the study’s authors and Editor of The American Journal of Psychiatry, points out, “Genes associated with schizophrenia are common, so prevention has to be applied to the entire population, and it has to be safe. Basic research indicates that choline supplementation during pregnancy facilitates cognitive functioning in offspring. Our finding that it ameliorates some of the pathophysiology associated with risk for schizophrenia now requires longer-term follow-up to assess whether it decreases risk for the later development of illness as well.”

Normally, the brain responds fully to an initial clicking sound but inhibits its response to a second click that follows immediately. In schizophrenia patients, deficient inhibition is common and is related to poor sensory filtering and familial transmission of schizophrenia risk. Since schizophrenia does not usually appear until adolescence, this trait—measurable in infancy—was chosen to represent the illness.

Half the healthy pregnant women in this study took 3,600 milligrams of phosphatidylcholine each morning and 2,700 milligrams each evening; the other half took placebo. After delivery, their infants received 100 milligrams of phosphatidylcholine per day or placebo. Eighty-six percent of infants exposed to pre- and postnatal choline supplementation, compared to 43% of unexposed infants, inhibited the response to repeated sounds, as measured with EEG sensors placed on the baby’s head during sleep.

Could probiotics help HIV patients?

Antiretroviral (ARV) drugs are the first line therapy for patients with HIV; however, ARV-treated, HIV-infected individuals still have a higher mortality rate than uninfected individuals. During the course of infection, HIV patients develop inflammation that damages the walls of the intestines, known as the gut mucosa, allowing intestinal microbes to escape and enter the blood stream to cause a life-threatening systemic infection. The health of the gut mucosa is significantly influenced by the complement of bacteria in the gut and there is mounting evidence that probiotic supplements benefit patients intestinal disorders, such as irritable bowel syndrome, C. difficile infection, and inflammatory bowel disease.

In this issue of the Journal of Clinical Investigation, researchers led by Jason Brenchley at the National Institute of Allergy and Infectious Disease, demonstrated that probiotic supplementation may also be beneficial for ARV-treated HIV patients. Brenchley and colleagues treated SIV-infected macaques (a model of human HIV-infection) with either ARV alone or ARV in combination with a mixture of probiotics. Macaques treated with probiotics had enhanced gastrointestinal immune function and decreased inflammation compared to macaques treated with ARV alone. In a companion article, Judith Aberg and colleagues at New York University School of Medicine discuss how these findings could benefit HIV patients.

Light exposure during pregnancy key to normal eye development

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.

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 · No comments

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

Which nutritional factors help preserve muscle mass, strength and performance in seniors?

January 18, 2013

New review by International Osteoporosis Foundation (IOF) Nutrition Working Group examines role of nutrition in sarcopenia, with focus on protein, vitamins D and B, and acid-based diet.

Sarcopenia, or the gradual loss of muscle mass, is a common consequence of ageing, and poses a significant risk factor for disability in older adults. As muscle strength plays an important role in the tendency to fall, sarcopenia leads to an increased risk of fractures and other injuries.

The International Osteoporosis Foundation (IOF) Nutrition Working Group has published a new review which identifies nutritional factors that contribute to loss of muscle mass, or conversely, are beneficial to the maintenance of muscle mass.  The Group reviewed evidence from worldwide studies on the role of nutrition in sarcopenia, specifically looking at protein, acid–base balance, vitamin D/calcium, and other minor nutrients like B vitamins.

“The most obvious intervention against sarcopenia is exercise in the form of resistance training,” said Professor Jean-Philippe Bonjour, co-author and Professor of Medicine at the Service of Bone Diseases, University of Geneva. “However, adequate nutritional intake and an optimal dietary acid-base balance are also very important elements of any strategy to preserve muscle mass and strength during ageing.”

The review discusses and identifies the following important nutritional factors that have been shown to be beneficial to the maintenance of muscle mass and the treatment and prevention of sarcopenia:

  • · Protein: Protein intake plays an integral part in muscle health. The authors propose an intake of 1.0–1.2 g/kg of body weight per day as optimal for skeletal muscle and bone health in elderly people without severely impaired renal function.
  • · Vitamin D:  As many studies indicate a role for vitamin D in the development and preservation of muscle mass and function, adequate vitamin D should be ensured through exposure to sunlight and/or supplementation if required. Vitamin D supplementation in seniors, and especially in institutionalized elderly, is recommended for optimal musculoskeletal health.
  • · Avoiding dietary acid loads: Excess intake of acid-producing nutrients (meat and cereal grains) in combination with low intake of alkalizing fruits and vegetables may have negative effects on musculoskeletal health. Modifying the diet to include more fruits and vegetables is likely to benefit both bones and muscles.

Emerging evidence also suggests that vitamin B12 and/or folic acid play a role in improving muscle function and strength.

As well, the Review discusses non-nutritional interventions such as hormones, and calls for more studies to identify the potential of antioxidants and anti-inflammatory compounds in the prevention of sarcopenia.

Dr. Ambrish Mithal, co-author and Chair and Head of Endocrinology and Diabetes division at Medanta, New Delhi underlined the need for further research in the field.  “Strategies to reduce the numbers of falls and fractures within our ageing populations must include measures to prevent sarcopenia. At present, the available evidence suggests that combining resistance training with optimal nutritional status has a synergistic affect in preventing and treating sarcopenia, “ said Mithal.

“We hope that further studies will shed light on other effective ways of preventing and treating this condition.”

Study suggests link between regular aspirin use, increased risk of age-related macular degeneration

CHICAGO – Regular aspirin use appears to be associated with an increased risk of neovascular age-related macular degeneration (AMD), which is a leading cause of blindness in older people, and it appears to be independent of a history of cardiovascular disease and smoking, according to a report published Online First by JAMA Internal Medicine, a JAMA Network publication.

Aspirin is one of the most widely used medications in the world and is commonly used in the prevention of cardiovascular disease, such as myocardial infarction (heart attack) and ischemic stroke. While a recent study suggested that regular aspirin use was associated with AMD, particularly the more visually devastating neovascular (wet) form, other studies have reported inconsistent findings. Smoking is also a preventable risk factor for AMD, the authors write in the study background.

Gerald Liew, Ph.D., of the University of Sydney, Australia, and colleagues examined whether regular aspirin use (defined as once or more per week in the past year) was associated with a higher risk of developing AMD by conducting a prospective analysis of data from an Australian study that included four examinations during a 15-year period. Of 2,389 participants, 257 individuals (10.8 percent) were regular aspirin users.

After the 15-year follow-up, 63 individuals (24.5 percent) developed incident neovascular AMD, according to the results.

“The cumulative incidence of neovascular AMD among nonregular aspirin users was 0.8 percent at five years, 1.6 percent at 10 years, and 3.7 percent at 15 years; among regular aspirin users, the cumulative incidence was 1.9 percent at five years, 7 percent at 10 years and 9.3 percent at 15 years, respectively,” the authors note. “Regular aspirin use was significantly associated with an increased incidence of neovascular AMD.”

The authors note that any decision concerning whether to stop aspirin therapy is “complex and needs to be individualized.”

“Currently, there is insufficient evidence to recommend changing clinical practice, except perhaps in patients with strong risk factors for neovascular AMD (e.g., existing late AMD in the fellow eye) in whom it may be appropriate to raise the potentially small risk of incident neovascular AMD with long-term aspirin therapy,” the authors conclude.

(JAMA Intern Med. Published online January 21, 2013. doi:10.1001/jamainternmed.2013.1583.)

Editor’s Note: This study was supported by project grants from the National Health & Medical Research Council Australia. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Commentary: Relationship of Aspirin Use with Age-Related Macular Degeneration

In an invited commentary, Sanjay Kaul, M.D., and George A. Diamond, M.D., of Cedars-Sinai Medical Center, Los Angeles, write: “This study has important strengths and limitations. It provides evidence from the largest prospective cohort with more than five years of longitudinal evaluation reported to date using objective and standardized ascertainment of AMD.”

“The key limitation is the nonrandomized design of the study with its potential for residual (unmeasured or unobserved) confounding that cannot be mitigated by multivariate logistic regression or propensity score analysis,” the authors continue.

“From a purely science-of-medicine perspective, the strength of evidence is not sufficiently robust to be clinically directive. These findings are, at best, hypothesis-generating that should await validation in prospective randomized studies before guiding clinical practice or patient behavior,” the authors conclude. “However, from an art-of-medicine perspective, based on the limited amount of available evidence, there are some courses of action available to the thoughtful clinician. In the absence of definitive evidence regarding whether limiting aspirin exposure mitigates AMD risk, one obvious course of action is to maintain the status quo.”

(JAMA Intern Med. Published online January 21, 2013. doi:10.1001/jamainternmed.2013.2530.)

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

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.

Eczema in infants linked to gut bacteria

Children with eczema have a more diverse set of bacteria in their guts than non affected children, finds a new study in BioMed Central’s open access journal BMC Microbiology. The types of bacteria present were also more typical of adult gut microbes than for toddlers without eczema.

Eczema is a chronic inflammation of the epidermis. The gut bacteria of children with or without eczema was examined when they were six and 18 months old. At six months all the infants had the same types of bacteria but by 18 months old the children with eczema had more of a type of bacteria normally associated with adults (Clostridium clusters IV and XIVa) while the healthy children had a greater amount of Bacteroidetes.

MSc Lotta Nylund from University of Turku, Finland, who led the project explained, “The composition of bacteria in a child’s gut depends on its environment and the food it eats. You would expect that as a child’s diet changes so will the bacteria present. The number of bifidobacteria naturally falls with age and in total we found 21 groups of bacteria which changed in this time period. However it is the early change towards adult-type bacteria which seems to be a risk factor for eczema.”

 

Harms from breast cancer screening outweigh benefits if death caused by treatment is included

 

Cancer expert remains to be convinced by breast screening review

Michael Baum, Professor emeritus of surgery at University College London says that, while deaths from breast cancer may be avoided, any benefit will be more than outweighed by deaths due to the long term adverse effects of treatment.

He estimates that, for every 10, 000 women invited for screening, three to four breast cancer deaths are avoided at the cost of 2.72 to 9.25 deaths from the long term toxicity of radiotherapy.

These figures contrast with an independent report on breast cancer screening, led by Sir Michael Marmot and published in November last year. Marmot and his committee were charged with asking whether the screening programme should continue, and if so, what women should be told about the risks of overdiagnosis.

They concluded that screening should continue because it prevented 43 deaths from breast cancer for every 10,000 women invited for screening.

The downside was an estimated 19% rate of overdiagnosis: 129 of the 681 cancers detected in those 10,000 women would have done them no harm during their lifetime. However, those women would have undergone unnecessary treatment, including surgery, radiotherapy and chemotherapy.

But despite this higher than previous estimate of overdiagnosis, they concluded that the breast screening programme should continue.

The report also judged that screening reduces the risk of dying from breast cancer by 20%. But Professor Baum disputes these figures, saying the analysis takes no account of improvements in treatment since these trials were done, which will reduce the benefits of screening. Nor does it make use of more recent observational data.

With these data included, estimated rates of overdiagnosis as a result of screening increase to up to 50%, he argues.

This is important because it can change the decisions women make when invited for screening. In a study also published today, researchers at the University of Sydney explored attitudes to screening in a sample of 50 women. Many of the women were surprised when they were told about overdiagnosis and most said they would attend screening if overdiagnosis rates were 30% or lower, but a rate of 50% made most of them reconsider.

An accompanying editorial points out that the harms of screening will reduce as more effective diagnostic processes develop to inform less harmful and more personalised treatments. In the meantime, it says women need up to date and transparent information about the benefits and harms of screening to help them make informed choices.

Common anti-fever medications pose kidney injury risk for children

Sick children, especially those with some dehydration from flu or other illnesses, risk significant kidney injury if given drugs such as ibuprofen and naproxen, Indiana University School of Medicine researchers said Friday.

In an article published online Jan. 25 by the Journal of Pediatrics, Jason Misurac, M.D., and colleagues from IU and Butler University reported that nearly 3 percent of cases of pediatric acute kidney injury over a decade could be traced directly to having taken the common nonsteroidal anti-inflammatory drugs, or NSAIDs.

Although relatively few in terms of percentage of total kidney damage cases, the children with problems associated with NSAIDs included four young patients who needed dialysis, and at least seven who may have suffered permanent kidney damage, the researchers said.

“These cases, including some in which patients’ kidney function will need to be monitored for years, as well as the cost of treatment, are quite significant, especially when you consider that alternatives are available and acute kidney injury from NSAIDs is avoidable,” Dr. Misurac, a fellow in pediatric nephrology, said.

Although such drugs have been linked to kidney damage in small, anecdotal reports, the study reported Thursday is believed to be the first large-scale study of the incidence and impact of acute kidney injury caused by NSAIDs.

The research team evaluated medical records at Riley Hospital for Children at IU Health in Indianapolis from January 1999 through June 2010 and found 1,015 cases in which patients had been treated for acute kidney injury from any cause.

After excluding cases in which the acute kidney injuries could possibly be explained by other factors, such as diseases affecting kidney function, the researchers found 27 cases, or 2.7 percent, in which the only factors were the administration of NSAIDs. In nearly all cases, the NSAIDs were administered before the children were admitted to the hospital. Because many of the 1,015 cases involved multiple potential causes of acute kidney injury, the researchers said the 27 cases are likely an underestimate of the number of cases in which NSAIDs contributed to the kidney damage.

Among the researchers’ findings:

  • Most of the children had been treated with recommended dosages.
  • All of the children under the age of 5 needed to undergo dialysis temporarily, were more likely than the older children to be placed in an intensive care unit and needed longer hospital stays.
  • The average cost for hospital and kidney specialist fees in the 27 cases was nearly $13,500, and the costs were much higher for younger children. At least $375,000 was spent on the NSAID-associated kidney injury cases at Riley Hospital over the study period, the researchers said, but billing data for other specialists were not available in the database, suggesting that the actual costs were likely much higher.

NSAIDs affect kidney function by restricting blood flow to the blood-filtering components of the kidneys, which suggests the risks from the drugs are greater among children who are dehydrated due to the effects of their illness, such as vomiting or diarrhea, Dr. Misurac said.

Fever is normal during an infection and not in itself dangerous, he noted, so “one alternative to NSAIDs would be acetaminophen, but another alternative would be no medication at all, at least for a while, to let the body fight the infection.”

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

Choline supplementation during pregnancy presents a new approach to schizophrenia prevention

Contact: Jackie Brinkman jackie.brinkman@ucdenver.edu 303-724-1525 University of Colorado Denver

University of Colorado researchers study choline in infants

AURORA, Colo.  (Jan. 15, 2013) — Choline, an essential nutrient similar to the B vitamin and found in foods such as liver, muscle meats, fish, nuts and eggs, when given as a dietary supplement in the last two trimesters of pregnancy and in early infancy, is showing a lower rate of physiological schizophrenic risk factors in infants 33 days old. The study breaks new ground both in its potentially therapeutic findings and in its strategy to target markers of schizophrenia long before the illness itself actually appears. Choline is also being studied for potential benefits in liver disease, including chronic hepatitis and cirrhosis,  depression, memory loss, Alzheimer’s disease and dementia, and certain types of seizures.

Robert Freedman, MD, professor and chairman of the Department of Psychiatry, University of Colorado School of Medicine and  one of the study’s authors and Editor of The American Journal of Psychiatry, points out, “Genes associated with schizophrenia are common, so prevention has to be applied to the entire population, and it has to be safe. Basic research indicates that choline supplementation during pregnancy facilitates cognitive functioning in offspring. Our finding that it ameliorates some of the pathophysiology associated with risk for schizophrenia now requires longer-term follow-up to assess whether it decreases risk for the later development of illness as well.”

Normally, the brain responds fully to an initial clicking sound but inhibits its response to a second click that follows immediately. In schizophrenia patients, deficient inhibition is common and is related to poor sensory filtering and familial transmission of schizophrenia risk. Since schizophrenia does not usually appear until adolescence, this trait—measurable in infancy—was chosen to represent the illness.

Half the healthy pregnant women in this study took 3,600 milligrams of phosphatidylcholine each morning and 2,700 milligrams each evening; the other half took placebo. After delivery, their infants received 100 milligrams of phosphatidylcholine per day or placebo. Eighty-six percent of infants exposed to pre- and postnatal choline supplementation, compared to 43% of unexposed infants, inhibited the response to repeated sounds, as measured with EEG sensors placed on the baby’s head during sleep.

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The study will be published online by The American Journal of Psychiatry (AJP) at AJP in Advance, its online-ahead-of-print website. The research was funded by the Institute for Children’s Mental Disorders, the Anschutz Family Foundation, and the National Institute of Mental Health.

The American Journal of Psychiatry is the official journal of the American Psychiatric Association, a national medical specialty society whose physician members specialize in the diagnosis, treatment, prevention, and research of mental illnesses including substance use disorders. Visit the APA at www.psychiatry.org and www.HealthyMinds.org.

Faculty at the University of Colorado School of Medicine work to advance science and improve care. These faculty members include physicians, educators and scientists at University of Colorado Hospital, Children’s Hospital Colorado, Denver Health, National Jewish Health, and the Denver Veterans Affairs Medical Center. Degrees offered by the CU Denver School of Medicine include doctor of medicine, doctor of physical therapy, and masters of physician assistant studies.  The School is located on the University of Colorado’s Anschutz Medical Campus, one of four campuses in the University of Colorado system. For additional news and information, please visit our online newsroom.

Why Antidepressants Don’t Live Up to the Hype

2009 report posted for filing

By John Cloud Wednesday, May 06, 2009

 

In the ’90s, Americans grew fond of the idea that you can fix depression simply by taking a pill – most famously fluoxetine (better known as Prozac), though fluoxetine is just one of at least seven selective serotonin reuptake inhibitors (SSRIs) that have been prescribed to treat hundreds of millions of people around the world.

 

 

But in the past few years, researchers have challenged the effectiveness of Prozac and other SSRIs in several studies. For instance, a review published in the Journal of Affective Disorders in February attributed 68% of the benefit from antidepressants to the placebo effect. Likewise, a paper published in PLoS Medicine a year earlier suggested that widely used SSRIs, including Prozac, Effexor and Paxil, offer no clinically significant benefit over placebos for patients with moderate or severe depression. Meanwhile, pharmaceutical companies maintain that their research shows that SSRIs are powerful weapons against depression. (Here’s a helpful blog post that summarizes the debate.)

 

 

Now a major new study suggests that both critics and proponents might be right about SSRIs: the drugs can work, but they appear to work best for only a subset of depressed patients – those with a limited range of psychological problems. People whose depression is compounded with, say, substance abuse or a personality disorder may not get much help from SSRIs – which is unfortunate for the 45% to 60% of patients in the U.S. who have been diagnosed with a common mental disorder like depression and also meet the criteria for at least one other disorder, like substance abuse. (Multiple diagnoses are known in medical parlance as comorbidities.)

 

 

The new study, published online in April by the American Journal of Psychiatry, was conducted using data from a large, government-funded trial called Sequenced Treatment Alternatives to Relieve Depression, which usually goes by the moniker STAR*D. The STAR*D project, which collected data from 2001 to 2004 at 41 U.S. psychiatric facilities, was one of the most ambitious efforts ever to understand how best to treat people with major depression. STAR*D participants comprise a powerful research sample because they are highly representative of all depressed Americans. Very few depressed people were excluded from STAR*D; only women who were pregnant, those with seizure disorders and a few others with acute conditions were kept out. All other psychiatric and medical comorbidities were allowed.

 

 

The authors of the new paper, a team of 11 researchers led by University of Pittsburgh professor of epidemiology Stephen Wisniewski, were curious how the STAR*D group would compare with a typical group of patients selected for a run-of-the-mill drug-company trial for a new antidepressant – the very trials on which the Food and Drug Administration bases its decisions regarding new drug approval. Drawing on their own experiences in helping to conduct such trials, which have far more stringent inclusion criteria than the STAR*D group, Wisniewski and his team divided the STAR*D patients into two groups – an “efficacy” sample of patients who would normally be included in a typical Phase III clinical trial for a new antidepressant and a “nonefficacy” sample of patients who would normally be rejected.

 

 

Depressed STAR*D patients who were classified for inclusion had no more than one general medical condition (like, say, heart disease) and no more than one additional primary psychiatric disorder besides depression. All patients with multiple comorbidities – along with anyone whose depression had lasted more than two years – were excluded. Once the authors crunched all the numbers, they found that only 22% of STAR*D patients met entry criteria for a conventional antidepressant trial.

 

 

All the STAR*D patients were taking citalopram, an SSRI marketed in North America as Celexa. Not surprisingly, those who met standard inclusion criteria for a clinical trial had significantly better outcomes on the drug. In the efficacy group, 52% responded to Celexa vs. 40% of the nonefficacy group. Patients in the latter group also took longer to respond and had to be readmitted to psychiatric settings more often. “Thus,” the authors conclude, “current efficacy trials suggest a more optimistic outcome than is likely in practice, and the duration of adequate treatment suggested by data from efficacy trials may be too short.”

 

 

To bolster their findings, the authors cite a smaller 2002 study that arrived at similar results: in that paper, published in the American Journal of Psychiatry, Dr. Mark Zimmerman of Brown University and his colleagues found that of 315 patients with major depressive disorder who sought care, only 29, or 9.2%, met typical criteria for an efficacy trial. Similarly, psychologist Ronald Kessler of Harvard co-authored a 2003 paper in the Journal of the American Medical Association that concluded that most “real world” patients with major depression would be excluded from clinical trials because of comorbidities.

 

 

Such findings help explain why antidepressants haven’t quite lived up to their promise. But the University of Pittsburgh’s Wisniewski, the lead author of the new study, cautions against interpreting the results as an indictment against greedy drug companies eager to exclude difficult patients in order to show better results. “If the population in a [clinical] trial were more representative, that would come at a cost,” he says. Researchers expect a certain number of bad reactions during clinical trials; some of these reactions can cause serious medical problems. If patients enter a trial with multiple complications – if they are, say, not only depressed, but also cocaine-addicted, hypertensive and diabetic – you dramatically increase the chances of adverse side effects. “That’s why trials to determine efficacy are done on a relatively homogeneous population,” Wisniewski says.

 

 

That’s understandable, but the new study does shed light on the limitations of antidepressants. Conducting clinical trials with representative samples would undoubtedly be more complex – and expensive – since patients with multiple risk factors would have to be monitored more carefully. But for a future generation of antidepressants to be truly effective for most patients, more-inclusive trials may be the best answer.

 

http://www.time.com/time/health/article/0,8599,1895672,00.html

People with depression often excluded from clinical studies of antidepressants?

2009 report posted for filing

Contact: Clare Collins
CollCX@upmc.edu
412-647-3555
University of Pittsburgh Schools of the Health Sciences

Are we cherry picking participants for studies of antidepressants?

People with depression often excluded from clinical studies and tend not to fare as well as study participants

PITTSBURGH, April 28 – Findings from clinical studies used to gain Food and Drug Administration approval of common antidepressants are not applicable to most patients with depression, according to a report led by the University of Pittsburgh Graduate School of Public Health. Published in the May issue of the American Journal of Psychiatry, the study suggests only a small percentage of people with depression qualify for these studies, and those who do not qualify are often treated with the same medications but may suffer poorer clinical outcomes.

A part of the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project – the largest study of the treatment of depression conducted in the United States – researchers compared symptoms and outcomes in depressed patients who met phase III study inclusion criteria to those who did not. Phase III studies for antidepressants determine the effectiveness of the drug in comparison to a placebo. The inclusion criteria for these studies are not standardized nor subject to federal guidelines, resulting in some variation from study to study in the profile of eligible patients. Typically excluded are patients with milder forms of depression, who might be more likely to respond to a placebo drug, and those who may have chronic depression or psychiatric and medical co-morbidities – additional illnesses or conditions.

After assessing 2,855 patients treated with citalopram, a commonly prescribed selective serotonin reuptake inhibitor for mood disorders, study authors concluded that fewer than one in four, or 22.2 percent, of the patients met the usual criteria for inclusion in phase III antidepressant trials.

“Only a small percentage of depressed patients in our study would have qualified for inclusion in phase III efficacy trials of depression drugs,” said study lead author, Stephen Wisniewski, Ph.D., professor of epidemiology and co-director of the Epidemiology Data Center, University of Pittsburgh Graduate School of Public Health. “This raises major concerns about whether results from traditional phase III studies can be generalized to most people with depression, who also often suffer from anxiety, substance abuse and other medical and psychiatric problems.”

When Dr. Wisniewski and colleagues further assessed how well patients did on treatment, they found that those who met the eligibility criteria for phase III trials had better outcomes, including higher remission rates, less severe side effects and serious adverse events. The depression remission rate in the patients who met the criteria was 34.4 percent, compared to only 24.7 percent in the ineligible group. Additionally, the drug response rate also was higher in the eligible group – 51.6 percent compared to 39.1 percent of the ineligible group.

“Results from research studies suggest more optimistic outcomes than may exist for real-world patients receiving treatment for depression,” said Dr. Wisniewski. Although phase III eligibility criteria could be changed to include a broader population of patients, Dr. Wisniewski cautions that this could come at the cost of more serious side effects in patients who have co-morbidities and are generally sicker. These patients may not be able to safely tolerate the drugs being tested. Instead, he suggests medical care providers who treat patients with depression use their professional judgment by noting that most phase III findings are based on patients who may be very different than those under their care.

 

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The study was funded by the National Institute for Mental Health. Co-authors include A. John Rush, M.D., National University of Singapore; Diane Warden, Ph.D., M.B.A., and Madhukar Trivedi, M.D., University of Texas Southwestern Medical Center; Andrew Nierenberg, M.D., and Maurizio Fava, M.D., Harvard Medical School; Bradley Gaynes, M.D., M.P.H., University of North Caroline School of Medicine; James Luther, M.A., University of Pennsylvania School of Medicine; Patrick McGrath, M.D., Columbia University Medical Center; Philip Lavori, Ph.D., Stanford University School of Medicine; and Michael Thase, M.D., University of Pittsburgh School of Medicine.

Creatine aids women rapidly with major depression

Muscle-building supplement vastly improves reponse time, quality of recovery

(SALT LAKE CITY)—Women battling stubborn major depression may have a surprising new ally in their fight—the muscle-building dietary supplement creatine.

In a new proof-of-concept study, researchers from three South Korean universities and the University of Utah report that women with major depressive disorder (MDD) who augmented their daily antidepressant with 5 grams of creatine responded twice as fast and experienced remission of the illness at twice the rate of women who took the antidepressant alone. The study, published Aug. 3, 2012, in the American Journal of Psychiatry online, means that taking creatine under a doctor’s supervision could provide a relatively inexpensive way for women who haven’t responded well to SSRI (selective serotonin reuptake inhibitor) antidepressants to improve their treatment outcomes.

“If we can get people to feel better more quickly, they’re more likely to stay with treatment and, ultimately, have better outcomes,” says Perry F. Renshaw, M.D., Ph.D., M.B.A, USTAR professor of psychiatry at the U of U medical school and senior author on the study.

If these initial study results are borne out by further, larger trials, the benefits of taking creatine could directly affect many Utahns. The depression incidence in Utah is estimated to be 25 percent higher than the rest of the nation, meaning the state has an even larger proportion of people with the disease. This also brings a huge economic cost to both the state and individuals.

According to numbers recently compiled at the U of U, the state of Utah paid an estimated $214 million in depression-related Medicaid and disability insurance in 2008. Add the costs of inpatient and outpatient treatment, medication, and lost productivity in the workplace, and the total price of depression in Utah reached $1.3 billion in 2008, according to the U estimate. With those large numbers, any treatment that improves outcomes not only could ease the life of thousands of Utah women but also would save millions of dollars.

“There has been a misunderstanding of how crippling and common this disease is in Utah,” says Renshaw, who’s also medical director of the Mental Illness Research, Education and Clinical Center at the Salt Lake City Veterans Affairs Health Care System. “It begs that we understand it better than we do.”

Creatine is an amino acid made in the human liver, kidneys, and pancreas. It also is found in meat and fish. Inside the body it is converted into phosphocreatine and stored in muscle. During high-intensity exercise, phosphocreatine is converted into ATP, an important energy source for cells. For this reason, creatine has become a popular supplement among bodybuilders and athletes who are trying to add muscle mass or improve athletic ability.

How creatine works against depression is not precisely known, but Renshaw and his colleagues suggest that the pro-energetic effect of creatine supplementation, including the making of more phosphocreatine, may contribute to the earlier and greater response to antidepressants.

The eight-week study included 52 South Korean women, ages 19-65, with major depressive disorder. All the women took the antidepressant Lexapro (escitalopram) during the trial. Twenty-five of the women received creatine with the Lexapro and 27 were given a placebo.  Neither the study participants nor the researchers knew who received creatine or placebo. Eight women in the creatine group and five in the placebo group did not finish the trial, leaving a total of 39 participants.

Participants were interviewed at the start of the trial to establish baselines for their depression, and then were checked at two, four, and eight weeks to see how they’d responded to Lexapro plus creatine or Lexapro and a placebo. The researchers used three measures to check the severity of depression, with the primary outcomes being measured by the Hamilton Depression Rating Scale (HDRS), a widely accepted test.

The group that received creatine showed significantly higher improvement rates on the HDRS at two and four weeks (32 percent and 68 percent) compared to the placebo group (3.7 percent and 29 percent). At the end of eight weeks, half of those in the creatine group showed no signs of depression compared with one-quarter in the placebo group. There were no significant adverse side effects associated with creatine.

Antidepressants typically don’t start to work until four to six weeks. But research shows that the sooner an antidepressant begins to work, the better the treatment outcome, and that’s why Renshaw and his colleagues are excited about the results of this first study. “Getting people to feel better faster is the Holy Grail of treating depression,” he says.

Study co-author Tae-Suk Kim, M.D., Ph.D., associate professor of psychiatry at the Catholic University of Korea College of Medicine and visiting associate professor of psychiatry at the U of U, already is recommending creatine for some of his female depression patients.

In prior studies, creatine had been shown to be effective only in female rats. But that shouldn’t rule out testing the supplement in men as well, according to Renshaw.

U of U researchers expect soon to begin another trial to test creatine in adolescent and college-age females who have not responded to SSRI medications. Principal investigator Douglas G. Kondo, M.D., assistant professor of psychiatry, says he is looking for 40 females between the ages of 13-21. Recruitment of participants will begin as soon as the U of U Institutional Review Board approves the study, which is expected in early July.

After the initial eight weeks of treatment, study participants will be offered a six-month extension of close supervision and monitoring by the research team and board-certified child, adolescent, and adult psychiatrist at no charge.

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Those interested in joining the study can call (801) 587-1549; visit the study Web site www.UtahBrain.org; or email Doug.Kondo@hsc.utah.edu.

The first authors on the study are In Kyoon Loo, M.D., Ph.D., professor of the Seoul National University College of Medicine and College of Natural Sciences, Seoul, South Korea, and USTAR research associate professor of psychiatry at the U of U, and Sujung Yoon, M.D., Ph.D., associate professor of psychiatry at the Catholic University of Korea College of Medicine, Seoul, and visiting associate professor of psychiatry at the U of U.

Other authors include Jaeuk Hwang M.D., Ph.D., of the Soonchunhyang University College of Medicine, Seoul; Wangyoun Won, M.D., Catholic University of Korea College of Medicine, Seoul; Jieun E. Kim, M.D., Ph.D., Ewha Womans University Graduate School, Seoul; Sujin Bae, Ph.D., Seoul National University College of Natural Sciences