174 Health Research Report 07 FEB 2014

HRR

                     

174

07 FEB 2014 /  White paper draft

Compiled by Ralph Turchiano

 

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

In this issue:

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

Continue reading “174 Health Research Report 07 FEB 2014”

Navy Seeks To Map the Mind

May. 17, 2013 – 03:50PM
By Michael Peck

In some visions of the future, you’ll drive your car with little more than your mind. Electrodes on your head, you can climb into your car, think about how much you’d like a Big Mac, and let the car take you automatically to the nearest McDonald’s.

That’s one vision, at least — that of Navy Cdr. Joseph Cohn, program officer for the Office of Naval Research’s Neurocognitive Patterns project. This two-year joint effort between ONR, Brandeis University and Aptima aims to identify and capture neural patterns with enough accuracy to enable a machine to divine a user’s intentions from his brain activity. This could be useful for everything from driving a car to controlling a squadron of UAVs — and change how soldiers of the future train.

Brain-computer interface (BCI) technology has made great strides in recent years. Gamers can play video games with a BCI headset. Scientists at the University of Pittsburgh have trained a monkey to move a robotic arm by mental commands. DARPA’s Cognitive Technology Threat Warning System links cameras, neural sensors and a human operator so that an image of an object that triggers a threat neural pattern in the brain will be detected by the system.

But the high frontier of neuroscience still confronts the problem of mapping. Since the 1920s, scientists have been able to detect non-specific neural patterns. Yet among the mass of impulses that comprise the human brain, exactly which neural pattern corresponds to a desire to walk in the park versus a desire for a hamburger?

The ONR team is approaching this question on several levels. One way is to identify neural patterns and, perhaps more importantly, identify them in context. These patterns vary depending on external influences, from nighttime rhythms to the stress of being under fire.

There is also the computational and modeling level, where sensor data on a user’s neural pattern is combined with models so that a machine can determine what a user wants. Cohn likens it to a sports team.

“The way that folks become an expert team is not just to have a model of themselves, but models that represent the other people on their team,” he said. “They know how each member will behave.”

At the base of neuroscience is an attempt to decode the brain, Cohn said. This requires developing a grammar or lexicon that can represent how the brain attends to information, processes it, and acts upon it. “Part of doing this requires us to have the right tools in place for structuring and making sense of this data, and that’s really what we are trying to do in neurocognitive patterns.”

Cohn doesn’t expect the Neurocognitive Patterns project will accomplish all of this, but he hopes it will begin laying the foundation by identifying which neural patterns correspond to desired goals, such as driving to a specific destination. Phase I of the project saw pre-recorded neural patterns controlling an unmanned ground vehicle, while the second phase focuses on moving a prosthetic arm.

However, Cohn’s goal is more than just have a human think a series of instructions to be executed by a machine. If that were the case, he said, then “we have probably added to the workload, you might as well just use voice recognition software and have the person speak them.”

The true goal is to make a vehicle or a robot arm just another extension of the human body and brain. And in many ways, this is already how the brain works.

“If you use a sledgehammer long enough, you’re no longer clumsy with it,” said Cohn. “Your brain has internalized the dynamics of that sledgehammer, and it treats it like it’s just a new part of your arm. We’re taking advantage of the plasticity of the human brain to find another of communicating with our machines.”

http://www.defensenews.com/article/20130517/TSJ01/305170020/Navy-Seeks-Map-Mind?odyssey=mod|newswell|text|FRONTPAGE|p

No such thing as ‘junk RNA,’ say Pitt researchers

2009 study posted for filing

Contact: Anita Srikameswaran
SrikamAV@upmc.edu
412-578-9193
University of Pittsburgh Schools of the Health Sciences

PITTSBURGH, Oct. 12 – Tiny strands of RNA previously dismissed as cellular junk are actually very stable molecules that may play significant roles in cellular processes, according to researchers at the University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute (UPCI). The findings, published last week in the online version of the Journal of Virology, represent the first examination of very small RNA products termed unusually small RNAs (usRNAs). Further study of these usRNAs, which are present in the thousands but until now have been neglected, could lead to new types of biomarkers for diagnosis and prognosis, and new therapeutic targets.

In recent years, scientists have recognized the importance of small RNAs that generally contain more than 20 molecular units called nucleotides, said senior author Bino John, Ph.D., assistant professor, Department of Computational Biology, Pitt School of Medicine.

“But until we did our experiments, we didn’t realize that RNAs as small as 15 nucleotides, which we thought were simply cell waste, are surprisingly stable, and are repeatedly, reproducibly, and accurately produced across different tissue types.” Dr. John said. “We have dubbed these as usRNAs, and we have identified thousands of them, present in a diversity that far exceeds all other longer RNAs found in our study.”

The team’s experiments began with the observation that the Kaposi sarcoma-associated herpesvirus produces a usRNA that can control the production of a human protein. Detailed studies using both computational and experimental tools revealed a surprisingly large world of approximately 15 nucleotide-long usRNAs with intriguing characteristics. Many usRNAs interact with proteins already known to be involved in small RNA regulatory pathways. Some also share highly specific nucleotide patterns at one end. The researchers wrote that the existence of several different patterns in usRNAs reflects the diverse pathways in which the RNAs participate.

“These findings suggest that usRNAs are involved in biological processes, and we should investigate them further,” Dr. John noted. “They may be valuable tools to diagnose diseases, or perhaps they could present new drug targets.”

In addition to exploring biomarker potential, he and his colleagues plan to better characterize the various subclasses of usRNAs, identify their protein partners and study how they are made in the cell.

 

###

Co-authors of the paper include Zhihua Li, Ph.D., Sang Woo Kim, Ph.D., Yuefeng Lin, of the Department of Computational Biology; Patrick S. Moore, M.D., M.P.H, Department of Microbiology and Molecular Genetics and the Molecular Virology Program, UPCI; and Yuan Chang, M.D., Molecular Virology Program, UPCI.

This research was supported by grants from the National Institute of General Medicine Sciences and the National Cancer Institute, the American Cancer Society, the Pennsylvania Department of Health and the University of Pittsburgh.

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.

 

###

 

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.

Arsenic linked to cardiovascular disease at federally-approved levels for drinking water

2008 Study posted for filing

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

University of Pittsburgh mouse study published in Journal of Clinical Investigations

PITTSBURGH, Nov. 13 – When mice are exposed to arsenic at federally-approved levels for drinking water, pores in liver blood vessels close, potentially leading to cardiovascular disease, say University of Pittsburgh researchers in the Dec. 1 issue of the Journal of Clinical Investigation, available online Nov. 13. The study, while preliminary, also reveals how an enzyme linked to hypertension and atherosclerosis alters cells, and may call into question current Environmental Protection Agency standards that are based solely on risks for cancer.

In the study, Aaron Barchowsky, Ph.D., associate professor of environmental and occupational health at the University of Pittsburgh Graduate School of Public Health, and his research team looked at specialized cells in the liver called sinusoidal endothelial cells, which are tasked with removing wastes from blood and enabling nutrients to regulate metabolism. After exposing mice to 10 to 100 parts per billion (ppb) of arsenic over a two-week period, the cells were less able to remove damaged proteins from the blood and lost their characteristic pores or “windows,” severely compromising the cells’ ability to effectively exchange nutrients and waste. Dr. Barchowsky notes that despite their small size, mice are usually less sensitive to the effects of arsenic than people

The current EPA standard for arsenic in public water systems is 10 ppb, reduced from 50 ppb in 2006. The standard applies only to drinking water sources that serve more than 20 people.

“These results are important since this type of cellular dysfunction, over time, can impair the body’s ability to clear fats and waste proteins that build up in blood vessels and can lead to cardiovascular diseases such as hypertension and atherosclerosis,” said Dr. Barchowsky

According to Dr. Barchowsky, arsenic increased the activity of an enzyme called NADPH oxidase and the levels of oxidants it produces, compromising sinusoidal cell functions. Mice that lacked the enzyme did not have changes in liver blood vessels when exposed to arsenic and their cells were able to continue to function effectively.

“Our findings raise some concerns about whether current EPA-developed standards can effectively protect against cardiovascular risks posed by arsenic in drinking water,” said Dr. Barchowsky. “We are especially concerned about water from individual wells in small, rural and semi-rural communities that are exempt from the EPA requirement and often contain levels of arsenic that exceed the EPA limit.

Next phases of the research will focus on further understanding how arsenic increases the production of oxidants by NADPH oxidase and determining effective preventative measures to lessen the impact of arsenic and other environmental exposures on the function of the endothelial cells. Additional studies will investigate the relationship between arsenic’s effects on liver blood vessels and metabolism and disease-related changes in other blood vessels in the body.

Arsenic is a naturally occurring mineral primarily found in groundwater. Drinking high levels of arsenic over many years has been linked to increased risks for lung, bladder and skin cancers, as well as heart disease, diabetes and neurological damage.

 

###

The study was funded by the National Institute of Environmental Health Sciences, the National Heart, Lung, and Blood Institute, the Environmental Protection Agency and the University of Pittsburgh. Co-authors include Adam Straub, Ph.D., Katherine Clark, Mark Ross, Ashwin Chandra, Song Li, M.D., Ph.D., Xiang Gao, Ph.D., Patrick Pagano, Ph.D., and Donna Stolz, Ph.D., all with the University of Pittsburgh.

UCLA/Pitt scientists uncover virus with potential to stop pimples in their tracks

Contact: Elaine Schmidt eschmidt@mednet.ucla.edu 310-794-2272 University of California – Los Angeles Health Sciences

Going viral to kill zits

Watch out, acne.  Doctors soon may have a new weapon against zits:  a harmless virus living on our skin that naturally seeks out and kills the bacteria that cause pimples.

The Sept. 25 online edition of the American Society for Microbiology’s mBio publishes the findings by scientists at UCLA and the University of Pittsburgh.

“Acne affects millions of people, yet we have few treatments that are both safe and effective,” said principal investigator Dr. Robert Modlin, chief of dermatology and professor of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA.  “Harnessing a virus that naturally preys on the bacteria that causes pimples could offer a promising new tool against the physical and emotional scars of severe acne.”

The scientists looked at two little microbes that share a big name:  Propionibacterium acnes, a bacterium thriving in our pores that can trigger acne; and P. acnes phages, a family of viruses that live on human skin.  The viruses are harmless to humans, but programmed to infect and kill the aforementioned P. acnes bacteria.

When P. acnes bacteria aggravate the immune system, it causes the swollen, red bumps associated with acne.  Most effective treatments work by reducing the number of P. acnes bacteria on the skin.

“We know that sex hormones, facial oil and the immune system play a role in causing acne, however, a lot of research implicates P. acnes as an important trigger,” explained first author Laura Marinelli, a UCLA postdoctoral researcher in Modlin’s laboratory.  “Sometimes they set off an inflammatory response that contributes to the development of acne.”

Using over-the-counter pore cleansing strips from the drugstore, the researchers lifted acne bacteria and the P. acnes viruses from the noses of both pimply and clear-skinned volunteers.

When the team sequenced the bacteriophages’ genomes, they discovered that the viruses possess multiple features – such as small size, limited diversity and the broad ability to kill their hosts – that make them ideal candidates for the development of a new anti-acne therapy.

“Our findings provide valuable insights into acne and the bacterium that causes it,” observed corresponding author Graham Hatfull, Eberly Family Professor of Biotechnology, professor of biological sciences at the University of Pittsburgh and a Howard Hughes Medical Institute researcher.  “The lack of genetic diversity among the phages that attack the acne bacterium implies that viral-based strategies may help control this distressing skin disorder.”

“Phages are programmed to target and kill specific bacteria, so P. acnes phages will attack only P. acnes bacteria, but not others like E. coli,” added Marinelli.  “This trait suggests that they offer strong potential for targeted therapeutic use.”

Acne affects nearly 90 percent of Americans at some point in their lives, yet scientists know little about what causes the disorder and have made narrow progress in developing new strategies for treating it.  Dermatologists’ arsenal of anti-acne tools — benzoyl peroxide, antibiotics and Accutane – hasn’t expanded in decades.

“Antibiotics such as tetracycline are so widely used that many acne strains have developed resistance, and drugs like Accutane, while effective, can produce risky side effects, limiting their use,” explained coauthor Dr. Jenny Kim, director of the UCLA Clinic for Acne, Rosacea and Aesthetics.  “Acne can dramatically disfigure people and undermine their self-esteem, especially in teens.  We can change patients’ lives with treatment.  It’s time we identified a new way to safely treat the common disorder.”

The research team plans to isolate the active protein from the P. acnes virus and test whether it is as effective as the whole virus in killing acne bacteria. If laboratory testing proves successful, the researchers will study the compound’s safety and effectiveness in combating acne in people.

###

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR060382, R01 AR053542 and F32AR060655) at the National Institutes of Health in Bethesda, Md.

Additional coauthors included Sorel Fitz-Gibbon, Megan Inkeles, Shawn Cokus, Matteo Pellegrini and Jeffrey F. Miller, all of UCLA; former UCLA researchers Clarmyra Hayes and Anya Loncaric, now of the California Institute of Technology and Solta Medical, respectively; and  Charles Bowman, Daniel Russell and Deborah Jacobs-Sera of the University of Pittsburgh.

The Clinic for Acne, Rosacea and Aesthetics at the UCLA Division of Dermatology at the David Geffen School of Medicine offers comprehensive care for acne and rosacea, as well as the scarring and discoloration that can result from these conditions.  The clinic’s goal is to educate the public and help patients develop habits leading to healthy skin.  Current research projects include studying the effect of Vitamin-D on immune response to acne, the effect of Omega-3 fatty acids on acne and its treatment, and the use of a mobile device application for acne management.  To schedule an appointment, call (310) 825-6911

Plant antioxidant may protect against radiation exposure: Acetyl Resveratrol

2008 study posted for filing

Contact: Coutney McCrimmon
McCrimmonCP@upmc.edu
412-647-3555
University of Pittsburgh Schools of the Health Sciences

PITTSBURGH, Sept. 23 – Resveratrol, the natural antioxidant commonly found in red wine and many plants, may offer protection against radiation exposure, according to a study by the University of Pittsburgh School of Medicine. When altered with acetyl, resveratrol administered before radiation exposure proved to protect cells from radiation in mouse models. The results of the research will be presented during the American Society for Therapeutic Radiology and Oncology’s (ASTRO) 50th Annual Meeting in Boston.

The study, led by Joel Greenberger, M.D., professor and chairman of the Department of Radiation Oncology at the University of Pittsburgh School of Medicine, is overseen by Pitt’s Center for Medical Countermeasures Against Radiation. The center is dedicated to identifying and developing small molecule radiation protectors and mitigators that easily can be accessed and administered in the event of a large-scale radiological or nuclear emergency.

“New, small molecules with radioprotective capacity will be required for treatment in case of radiation spills or even as countermeasures against radiological terrorism,” said Dr. Greenberger. “Small molecules which can be easily stored, transported and administered are optimal for this, and so far acetylated resveratrol fits these requirements well.”

“Currently there are no drugs on the market that protect against or counteract radiation exposure,” he added. “Our goal is to develop treatments for the general population that are effective and non-toxic.”

Dr. Greenberger and his team are conducting further studies to determine whether acetylated resveratrol eventually can be translated into clinical use as a radioprotective agent. In 2004, this same team of researchers identified the drug JP4-039, which can be delivered directly to the mitochondria, the energy producing areas of cells. When this occurs, the drug assists the mitochondria in combating radiation-induced cell death.

 

###

The abstract, “Acetylated resveratrol: A new small molecule radioprotector,” will be presented at a poster discussion session at 5 p.m., Tuesday, Sept. 23.

The study was funded by a $10 million grant from the National Institute of Allergy and Infectious Diseases to establish the Center for Medical Countermeasures Against Radiation at the University of Pittsburgh.

The University of Pittsburgh School of Medicine is one of the nation’s leading medical schools, renowned for its curriculum that emphasizes both the science and humanity of medicine and its remarkable growth in National Institutes of Health (NIH) grant support, which has more than doubled since 1998. For fiscal year 2006, the University ranked sixth out of more than 3,000 entities receiving NIH support with respect to the research grants awarded to its faculty. As one of the university’s six Schools of the Health Sciences, the School of Medicine is the academic partner to the University of Pittsburgh Medical Center. Their combined mission is to train tomorrow’s health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care.

Researchers discover mechanism related to negative emotions of cocaine withdrawal

Contact: Eric Sorensen
eric.sorensen@wsu.edu
206-799-9186
Washington State University

Emotional ‘brakes’ stay on after cocaine wears off

PULLMAN, Wash.—Washington State University researchers have found a cellular mechanism that contributes to the lack of motivation and negative emotions of a cocaine addict going through withdrawal. Their discovery, published in the latest Proceedings of the National Academy of Sciences, offers a deeper look into the cellular and behavioral implications of addiction.

Bradley Winters, lead author of the PNAS paper and a freshly minted WSU doctor of neuroscience, says he, his major advisor Yan Dong, and colleagues at WSU, the University of Pittsburgh and the European Neuroscience Institute focused on cells that produce a signaling molecule called cannabinoid receptor 1, or CB1. Its main function is regulating the communication between nerve cells related to the functions like memory, motor control, perception, mood and appetite. Those same functions are affected by THC, the cannabinoid in its namesake cannabis, or marijuana.

“These receptors are not here just to make marijuana fun,” says Winters. “Their main function is changes in how nerve cells communicate with each other.”

The researchers studied the CB1 cells by producing a line of mice in which the cells that make CB1 were labeled fluorescently. The researchers could then identify the cells and target them with glass pipettes 1/100th the width of a human hair and record electrical currents they use to communicate with other nerve cells.

The CB1 cells act like brakes, slowing down activity in a brain region called the nucleus accumbens, which governs emotion and motivation.

“Cocaine causes profound cellular changes in the nucleus accumbens, but no one has ever looked at this type of cell, and these cells are important because they help organize the output,” says Winters.

The researchers found that cocaine increases the excitability of the CB1 cells, in effect stepping on the brakes of emotion and motivation. When an addict is high on cocaine, the brakes are struggling to slow things down. The problem is, they stay on even when the cocaine has worn off.

“As you do cocaine, it speeds everything up, pushing you to a highly rewarding emotional state,” says Winters. “It is kind of like going down a steep hill so you have to start riding that brake really hard. But then after the cocaine wears off and the hill levels out, you’re still riding that brake just as hard. Now you’re going down a regular, low-grade hill but you’re going 2 mph because your foot is still jammed on the brake.”

The result is a drag on the emotions and motivation of an addict in withdrawal — a drag that could be linked to sluggish activation of the nucleus accumbens.

“That state is like, ‘I feel terrible and I don’t want to do anything,'” says Winters. “You have the high and the crashing low and this low that you feel is what brings you back to the drug because you want to feel better and the drug is the only thing you feel motivation for.”

EPA pesticide exposure test too short, overlooks long term effects: EPA only test Pesticides health effects over 4 days

Contact: Morgan Kelly mekelly@pitt.edu 412-624-4356 University of Pittsburgh

Pitt research suggests EPA pesticide exposure test too short, overlooks long term effects

PITTSBURGH—The four-day testing period the U.S. Environmental Protection Agency (EPA) commonly uses to determine safe levels of pesticide exposure for humans and animals could fail to account for the toxins’ long-term effects, University of Pittsburgh researchers report in the September edition of Environmental Toxicology and Chemistry.

The team found that the highly toxic pesticide endosulfan—a neurotoxin banned in several nations but still used extensively in U.S. agriculture—can exhibit a “lag effect” with the fallout from exposure not surfacing until after direct contact has ended. Lead author Devin Jones, a recent Pitt biological sciences graduate, conducted the experiment under Rick Relyea, an associate professor of biological sciences in Pitt’s School of Arts and Sciences, with collaboration from Pitt post-doctoral researcher John Hammond. The paper is available on Pitt’s Web site at www.pitt.edu/news2009/Endosulfan.pdf

The team exposed nine species of frog and toad tadpoles to endosulfan levels “expected and found in nature” for the EPA’s required four-day period, then moved the tadpoles to clean water for an additional four days, Jones reported. Although endosulfan was ultimately toxic to all species, three species of tadpole showed no significant sensitivity to the chemical until after they were transferred to fresh water. Within four days of being moved, up to 97 percent of leopard frog tadpoles perished along with up to 50 percent of spring peeper and American toad tadpoles.

Of most concern, explained Relyea, is that tadpoles and other amphibians are famously sensitive to pollutants and considered an environmental indicator species. The EPA does not require testing on amphibians to determine pesticide safety, but Relyea previously found that endosulfan is 1,000-times more lethal to amphibians than other pesticides. Yet, he said, if the powerful insecticide cannot kill one the world’s most susceptible species in four days, then the four-day test period may not adequately gauge the long-term effects on larger, less-sensitive species.

“When a pesticide’s toxic effect takes more than four days to appear, it raises serious concerns about making regulatory decisions based on standard four-day tests for any organism,” Relyea said. “For most pesticides, we assume that animals will die during the period of exposure, but we do not expect substantial death after the exposure has ended. Even if EPA regulations required testing on amphibians, our research demonstrates that the standard four-day toxicity test would have dramatically underestimated the lethal impact of endosulfan on even this notably sensitive species.”

Andrew Blaustein, a professor in Oregon State University’s nationally ranked Department of Zoology, who is familiar with the Pitt study, said the results raise concerns about standards for other chemicals and the delayed dangers that might be overlooked. Some of the frog eggs the Pitt team used had been collected by Blaustein’s students for an earlier unrelated experiment, but he had no direct role in the current research.

“The results are somewhat alarming because standards for assessing the impacts of contaminants are usually based on short-term studies that may be insufficient in revealing the true impact,” Blaustein said. “The implications of this study go beyond a single pesticide and its effect on amphibians. Many other animals and humans may indeed be affected similarly.”

Tadpoles in the Pitt project spent four days in 0.5 liters of water containing endosulfan concentrations of 2, 6, 7, 35, 60, and 296 parts-per-billion (ppb), levels consistent with those found in nature. The team cites estimates from Australia—where endosulfan is widely used—that the pesticide can reach 700 ppb when sprayed as close as 10 meters from the ponds amphibians typically call home and 4 ppb when sprayed within 200 meters. The EPA estimates that surface drinking water can have chronic endosulfan levels of 0.5 to 1.5 ppb and acute concentrations of 4.5 to 23.9 ppb.

Leopard frogs, spring peepers, and American toads fared well during the experiment’s first four days, but once they were in clean water, the death rate spiked for animals previously exposed to 35 and 60 ppb. Although the other six species did not experience the lag effect, the initial doses of endosulfan were still devastating at very low concentrations. Grey and Pacific tree frogs, Western toads, and Cascades frogs began dying in large numbers from doses as low as 7 ppb, while the same amount killed all green frog and bullfrog tadpoles.

The endosulfan findings build on a 10-year effort by Relyea to understand the potential links between the global decline in amphibians, routine pesticide use, and the possible threat to humans in the future.

A second paper by Relyea and Jones also in the current Environmental Toxicology and Chemistry expands on one of Relyea’s most notable investigations, a series of findings published in Ecological Applications in 2005 indicating that the popular weed-killer Roundup® is “extremely lethal” to amphibians in concentrations found in the environment. The latest work determined the toxicity of Roundup Original Max for a wider group of larval amphibians, including nine frog and toad species and four salamander species. The report is available on Pitt’s Web site at www.pitt.edu/news2009/Roundup.pdf

In November 2008, Relyea reported in Oecologia that the world’s 10 most popular pesticides—which have been detected in nature—combine to create “cocktails of contaminants” that can destroy amphibian populations, even if the concentration of each individual chemical is within levels considered safe to humans and animals. The mixture killed 99 percent of leopard frog tadpoles and endosulfan alone killed 84 percent.

A month earlier, Relyea published a paper in Ecological Applications reporting that gradual amounts of malathion—the most popular insecticide in the United States—too small to directly kill developing leopard frog tadpoles instead sparked a biological chain reaction that deprived them of their primary food source. As a result, nearly half the tadpoles in the experiment did not reach maturity and would have died in nature

Repost at request

Study reveals ‘huffing’ household chemicals connected to teen suicide

Contact: Dave Brendsel dbrendse@du.edu 303-871-2775 University of Denver

Girls who ‘huff’ are at higher risk of suicidal thoughts and behaviors

DENVER— With suicide as the third leading cause of death among adolescents in the United States, a new University of Denver (DU) study reveals inhaling or “huffing” vapors of common household goods, such as glue or nail polish, are associated with increased suicidal thoughts and attempts.

Of the study’s participants, 33 percent reported having inhaled volatile solvents, 25 percent had attempted suicide, and 58 percent reported suicidal thoughts.

Stacey Freedenthal and Jeffrey M. Jenson of DU’s Graduate School of Social Work joined researchers from Chapel Hill and the University of Pittsburgh in a study of 723 incarcerated youth. “Inhalant Use and Suicidality among Incarcerated Youth” appeared in the September 2007 issue of the academic journal Drug and Alcohol Dependence. The study was the first work to categorize both levels of severity of inhalant use and gender in relation to suicidal ideas and suicide attempts.

The investigators found a significant increase in suicidal thoughts and attempts with higher use of volatile solvents. Researchers did not determine which problem came first, the huffing or the suicidal behavior, but showed that the two are undeniably connected, even when accounting for numerous other factors. Freedenthal warns parents to be aware of the possibility of suicidal thoughts in children who have been caught inhaling household chemicals.

“Inhalant use has many serious, physiological consequences, including death,” says Freedenthal. “Now we are learning ever more strongly that they are also linked to suicidal thoughts and behaviors.”

The study found the correlation between huffing and suicidality greater in girls than boys. More than 80 percent of girls who abused inhalants revealed a history of suicide attempts, while less than 60 percent of boys showed the same history. The study also indicated that suicidal thoughts were much higher for girls than boys. Suicidal thoughts and attempts were considered two separate constructs, since thoughts do not always lead to attempts, and attempts are not always preceded by much thought.

The study involved 723 participants incarcerated by the Missouri Division of Youth Services, 629 boys and 94 girls at an average age of 15. Participants were asked if they huffed any of the 35 common household substances, such as paint, paint thinner, shoe polish, spot remover, floor polish, kerosene, gasoline, antifreeze, permanent markers, nail polish remover, mothballs, waxes, lighter fluid, and others.

###

The University of Denver (www.du.edu), the oldest private university in the Rocky Mountain region, enrolls approximately 11,117 students in its undergraduate and graduate programs. The Carnegie Foundation classifies the University of Denver as a Research University with high research activity.

Total undergraduate enrollment for fall 2007 is 5,311, including 1,140 first-time, first-year students, compared to 1,142 last year. Graduate enrollment is 5,806

*Reposted for Filing