Potential new class of drugs blocks nerve cell death

Potential new class of drugs protects nerve cells in models of Parkinson's disease and amyotrophic lateral sclerosis Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures. Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in PNAS Early Edition. "We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need," says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies. About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3. "We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging," Pieper explains. "We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus." However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease. Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice. Of mice and worms In the ALS mouse model, a highly active variant of the original P7C3 molecule, known as P7C3A20, which the investigators synthesized, largely prevented death of the nerve cells within the spinal cord that are normally destroyed by this disease. The P7C3 molecule also worked, but was not as effective at protecting neurons in this model. As cell survival increased in the ALS model, coordination and strength of the mice improved as well. Mice that were given P7C3A20 were able to stay on a rotating rod much longer than untreated animals or animals that received the less active compounds. Animals receiving P7C3A20 also performed better in analysis of their walking gait, which typically worsens in these animals as the disease progresses. In PD, dopamine-producing neurons necessary for normal movement are gradually destroyed. In patients, loss of these brain cells leads to tremors, stiffness, and difficulty walking. The study again showed that P7C3 protects these neurons from cell death and the more active analogue, P7C3A20, provided even greater protection. The two compounds also potently blocked cell death of dopaminergic neurons in a C. elegans worm model of PD. Moreover, reduced cell death in this model was associated with improved movement in the worms. Healthy C. elegans worms have a very characteristic swimming motion. This movement is disrupted in the PD worm. Hector De Jesus-Cortes, a graduate student of neuroscience at UT Southwestern Medical Center and lead author of the Parkinson's study, videotaped and analyzed the PD worms' mobility with and without treatment. Normal swimming was almost completely preserved with P7C3A20, and was also fairly well preserved with P7C3. Tweaking the molecule The research team compared the activity of several new P7C3-related compounds that they synthesized, in both the hippocampal neurogenesis screen and the mouse model of PD. "Every variation of our P7C3 molecule that works in the neurogenesis assay also works in the PD model," Pieper says. "As we continue to refine the molecule, our hope is that the results from the neurogenesis assay will accurately predict the neuroprotective potency of the compound, and thus aid in more rapidly optimizing a new neuroprotective agent." Nursing CEUs The team plans to continue tweaking the structure of the P7C3 molecule to improve its neuroprotective ability while eliminating potential side effects. "Our hope is that this work will form the basis for designing a neuroprotective drug that could eventually help patients," Pieper says. ### Pieper and De Jesus-Cortes conducted the study with colleagues at UT Southwestern Medical Center, including Steven McKnight, Ph.D., chairman of biochemistry, and Joseph Ready, Ph.D., professor of biochemistry. The work was funded in part by grants from the National Institute for Mental Health.

Ready for Your Close-Up?

Caltech study shows that the distance at which facial photos are taken influences perception PASADENA, Calif.—As the saying goes, "A picture is worth a thousand words." For people in certain professions—acting, modeling, and even politics—this phrase rings particularly true. Previous studies have examined how our social judgments of pictures of people are influenced by factors such as whether the person is smiling or frowning, but until now one factor has never been investigated: the distance between the photographer and the subject. According to a new study by researchers at the California Institute of Technology (Caltech), this turns out to make a difference—close-up photo subjects, the study found, are judged to look less trustworthy, less competent, and less attractive. The new finding is described in this week's issue of the open-access journal PLoS One. Pietro Perona, the Allen E. Puckett Professor of Electrical Engineering at Caltech, came up with the initial idea for the study. Perona, an art history enthusiast, suspected that Renaissance portrait paintings often featured subtle geometric warping of faces to make the viewer feel closer or more distant to a subject. Perona wondered if the same sort of warping might affect photographic portraits—with a similar effect on their viewers—so he collaborated with Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology, and CNS graduate student Ronnie Bryan (PhD '12) to gather opinions on 36 photographs representing two different images of 18 individuals. One of each pair of images was taken at close range and the second at a distance of about seven feet. "It turns out that faces photographed quite close-up are geometrically warped, compared to photos taken at a larger distance," explains Bryan. "Of course, the close picture would also normally be larger, higher resolution and have different lighting—but we controlled for all of that in our study. What you're left with is a warping effect that is so subtle that nobody in our study actually noticed it. Nonetheless, it's a perceptual clue that influenced their judgments." That subtle distance warping, however, had a big effect: close-up photos made people look less trustworthy, according to study participants. The close-up photo subjects were also judged to look less attractive and competent. "This was a surprising, and surprisingly reliable, effect," says Adolphs. "We went through a bunch of experiments, some testing people in the lab, and some even over the Internet; we asked participants to rate trustworthiness of faces, and in some experiments we asked them to invest real money in unfamiliar people whose faces they saw as a direct measure of how much they trusted them." Alcoholism and Drug Abuse Counselors Continuing Education Across all of the studies, the researchers saw the same effect, Adolphs says: in photos taken from a distance of around two feet, a person looked untrustworthy, compared to photos taken seven feet away. These two distances were chosen by the researchers because one is within, and the other outside of, personal space—which on average is about three to four feet from the body. In some of the studies, the researchers digitally warped images of faces taken at a distance to artificially manipulate how trustworthy they would appear. "Once you know the relation between the distance warp and the trustworthiness judgment, you could manipulate photos of faces and change the perceived trustworthiness,'' notes Perona. He says that the group is now planning to build on these findings, using machine-vision techniques—technologies that can automatically analyze data in images. For example, one application would be for a computer program to have the ability to evaluate any face image in a magazine or on the Internet and to estimate the distance at which the photo was taken. "The work might also allow us to estimate the perceived trustworthiness of a particular face image," says Perona. "You could imagine that many people would be interested in such applications—particularly in the political arena." The study, "Perspective Distortion from Interpersonal Distance Is an Implicit Visual Cue for Social Judgments of Faces," was funded by grants from the National Institute of Mental Health and from the Gordon and Betty Moore Foundation. Written by Katie Neith

Popular HIV drug may cause memory declines

Johns Hopkins study suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain cells The way the body metabolizes a commonly prescribed anti-retroviral drug that is used long term by patients infected with HIV may contribute to cognitive impairment by damaging nerve cells, a new Johns Hopkins research suggests. Nearly 50 percent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities. It has long been assumed that the disease was causing the damage, but Hopkins researchers say the drug efavirenz may play a key role. People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades. Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain. Doctors have long believed that it might be possible to alleviate cognitive impairment associated with HIV by getting more drugs into the brain, but researchers say more caution is needed because there may be long-term effects of these drugs on the brain. "People with HIV infections can't stop taking anti-retroviral drugs. We know what happens then and it's not good," says Norman J. Haughey, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine. "But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV." For the study led by Haughey and described online in the Journal of Pharmacology and Experimental Therapeutics, researchers obtained samples of blood and cerebrospinal fluid from HIV-infected subjects enrolled in the NorthEastern AIDS Dementia study who were taking efavirenz. Researchers looked for levels of the drug and its various metabolites, which are substances created when efavirenz is broken down by the liver. Performing experiments on neurons cultured in the lab, the investigators examined the effects of 8-hydroxyefavirenz and other metabolites and found major structural changes when using low levels of 8-hydroxyefavirenz, including the loss of the important spines of the cells. Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons. The dendritic spine is the information processing point of a neuron, where synapses — the structures that allow communication among brain cells — are located. In the case of efavirenz, a minor modification in the drug's structure may be able block its toxic effects but not alter its ability to suppress the virus. Namandje N. Bumpus, Ph.D., one of the study's other authors, has found a way to modify the drug to prevent it from metabolizing into 8-hydroxyefavirenz while maintaining its effectiveness as a tool to suppress the HIV virus. "Finding and stating a problem is one thing, but it's another to be able to say we have found this problem and here is an easy fix," Haughey says. Haughey says studies like his serve as a reminder that while people infected with HIV are living longer than they were 20 years ago, there are significant problems associated with the drugs used to treat the infection. "Some people do seem to have this attitude that HIV is no longer a death sentence," he says. "But even with anti-retroviral treatments, people infected with HIV have shortened lifespans and the chance of cognitive decline is high. It's nothing you should treat lightly." HIV and AIDS CE Course ### The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA0017408), the National Institute of Mental Health (MH077543, MH075673 and MH71150), the National Institute on Aging (AG034849) and the National Institute of Neurological Disorders and Stroke (NS049465). Other Hopkins researchers involved in the study include Luis B. Tovar y Romo, Ph.D.; Lindsay B. Avery, Ph.D.; Ned Sacktor, M.D.; and Justin McArthur, M.B.B.S., M.P.H. For more information: http://www.hopkinsmedicine.org/neurology_neurosurgery/research/jhu_nimh/researchers

Mentally Ill Often Targets of Violence

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Suicide Now Kills More Americans Than Car Crashes: Study

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Suicide Now Kills More Americans Than Car Crashes: Prevention efforts lowered traffic fatalities, more attention needed for suicide, experts say ***************************************************** Suicide Prevention CE Course (7 hours) Description $ - For course pricing details, see our Pricing page by clicking on the "Pricing" tab This course is designed to help you: Increase awareness of suicide prevention methods Increase familiarity with broad based support systems Become familiar with strategies to reduce stigma Learn how to promote efforts to reduce efforts to lethal means of self harm. Identify at risk behavior Implement appropriate treatment and resources Develop and Promote Effective Clinical and Professional Practices CEU LPC, ceus mft, ceu’s for social workers, BBS approved, NBCC provider, nursing ceus, online ceus, ceus for MFTs, ce courses for counselors, Social Worker ceus, continuing education units for LPCs, MHC ceus, LCSW, ASW and MFT Intern ceus, Board approved ceus in many states, national board approval ceus, alcohol and drug abuse counselor ceus. See chart below for your state and license.

Feeling Guilty Versus Feeling Angry – Who Can Tell the Difference?

When you rear-end the car in front of you at a stoplight, you may feel a mix of different emotions such as anger, anxiety, and guilt. The person whose car you rear-ended may feel angered and frustrated by your carelessness, but it’s unlikely that he’ll feel much guilt. The ability to identify and distinguish between negative emotions helps us address the problem that led to those emotions in the first place. But while some people can tell the difference between feeling angry and guilty, others may not be able to separate the two. Distinguishing between anger and frustration is even harder. In a study forthcoming in Psychological Science, a journal of the Association for Psychological Science, psychological scientist Emre Demiralp of the University of Michigan and his colleagues hypothesized that clinically depressed people would be less able to discriminate between different types of negative emotions compared to healthy individuals. Clinically depressed people often experience feelings of sadness, anger, fear, or frustration that interfere with everyday life. “It is difficult to improve your life without knowing whether you are sad or angry about some aspect of it,” says Demiralp. “For example, imagine not having a gauge independently indicating the gasoline level of your car. It would be challenging to know when to stop for gas. We wanted to investigate whether people with clinical depression had emotional gauges that were informative and whether they experienced emotions with the same level of specificity and differentiation as healthy people.” The researchers recruited 106 people between the ages of 18 and 40 to participate in their study. Half of the participants were diagnosed with clinical depression and half were not. Over the course of seven to eight days, they carried a Palm Pilot, which prompted them to record emotions at 56 random times during the day. To report their emotions, they marked the degree to which they felt seven negative emotions (sad, anxious, angry, frustrated, ashamed, disgusted, and guilty) and four positive emotions (happy, excited, alert, and active) on a scale from one to four. Demiralp and his colleagues looked at participants’ tendency to give multiple emotions (e.g., disgusted and frustrated) similar rankings at a given point in time. According to their methodology, the more two emotions were reported together the less the person differentiated between these emotions. The researchers found that clinically depressed people had less differentiated negative emotions than those who were healthy, supporting their hypothesis. Notably, they did not find the same difference between groups for positive emotions—people with and without diagnosed clinical depression were equally able to differentiate between positive emotions. It is possible that people who are clinically depressed differentiate more between positive emotions as a coping mechanism. Demiralp and his colleagues argue that the procedure used in the study to record emotions may be particularly useful in studying the emotional experience of clinically depressed people, paving the way for more treatment and therapy options in the future. “Our results suggest that being specific about your negative emotions might be good for you”, says Demiralp. “It might be best to avoid thinking that you are feeling generally bad or unpleasant. Be specific. Is it anger, shame, guilt or some other emotion? This can help you circumvent it and improve your life. It is one of our overarching goals to investigate approaches for facilitating this kind of emotional intelligence at a large scale in the population.” *** This research was supported by NIMH grants MH60655 to John Jonides, MH59259 to Ian H. Gotlib, and F32 MH091831 to Renee J. Thompson, SNF Fellowship PA001/117473 to Susanne Jaeggi, and fellowships SFRH/BPD/35953/2007 from Fundação para a Ciência e a Tecnologia and Wi3496/41 from the Deutsche Forschungsgemeinschaft awarded to Jutta Mata. Jutta Mata is now at the University of Basel, Switzerland LPCC Continuing Education ### For more information about this study, please contact: Emre Demiralp at emredemi@umich.edu. The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "Feeling Blue or Turquoise? Emotional Differentiation in Major Depressive Disorder" and access to other Psychological Science research findings, please contact Anna Mikulak at 202-293-9300 or amikulak@psychologicalscience.org.

New national strategy paves way for reducing suicide deaths

Today on World Suicide Prevention Day, the National Action Alliance for Suicide Prevention (Action Alliance) released an ambitious national strategy to reduce the number of deaths by suicide. The strategy was called for by Health and Human Services (HHS) Secretary Kathleen Sebelius and former Department of Defense Secretary Robert Gates when they launched the Action Alliance on Sept. 10, 2010. The 2012 National Strategy for Suicide Prevention, a report from the U.S. Surgeon General and the Action Alliance, details 13 goals and 60 objectives for reducing suicides over the next 10 years. The Action Alliance, co-chaired by Gordon Smith, chief executive of the National Association of Broadcasters, and Army Secretary John McHugh, highlights four immediate priorities to reduce the number of suicides: integrating suicide prevention into health care policies; encouraging the transformation of health care systems to prevent suicide; changing the way the public talks about suicide and suicide prevention; and improving the quality of data on suicidal behaviors to develop increasingly effective prevention efforts. The Obama Administration also announced a series of activities that will help prevent suicide: •Secretary Sebelius announced $55.6 million in new grants for national, state, tribal, campus and community suicide prevention programs made possible under the Garrett Lee Smith Memorial Act and partially funded by the Prevention and Public Health Fund under the Affordable Care Act, the health care law enacted in 2010. •The Department of Veterans Affairs (VA) launched, Stand by Them: Help a Veteran, a joint VA-Department of Defense (DoD) outreach campaign that includes a new public service announcement, Side by Side, designed to help prevent suicide among veterans and servicemembers and focuses on the important role family and community play in supporting Veterans in crisis. Throughout September and beyond, VA and DoD are urging community-based organizations, Veterans Service Organizations, health care providers, private companies and other government agencies to connect Veterans and Service members in need of assistance to the Veterans Crisis Line ( 1-800-273-8255 , press 1). Additionally, as directed by President Obama’s Mental Health Executive Order issued August 31st, VA is also increasing the workforce of the Crisis Line by 50% and hiring 1,600 new mental health professionals. “Our message today is one of hope,” Secretary Sebelius said. “The national strategy will bring together the nation’s resources, both public and private, in an organized effort to provide life saving services and improve the ability of individuals, friends and family members to recognize the warning signs of despair and take action to save lives.” “By implementing this plan, we will engage diverse sectors of our communities, from health care systems and policy-makers to the media and public,” said Gordon Smith, a former U.S. senator from Oregon. “It will take all of our efforts to win this fight against suicide that touches so many American lives.” VA Deputy Secretary W. Scott Gould said, “All of us working together - friends, family, neighbors, the public and the private sector - can make a difference for Service members and Veterans transitioning back into their communities. Recognizing the warning signs of suicide and knowing where to turn for help will save lives.” Army Secretary McHugh commented on the impact of suicide on the military community in particular. “Suicide is one of the most challenging issues we face,” he said. “In the Army, suicide prevention requires soldiers to look out for fellow soldiers. We must foster an environment that encourages people in need to seek help and be supported.” Suicide is a public health issue that results in an average of 100 American deaths each day, more than double the average number of homicides. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), more that 8 million adults in the United States had serious thoughts of suicide within the past 12 months. The first National Strategy for Suicide Prevention was launched in 2001 by then-Surgeon General David Satcher. The progress achieved over the years, the significant advances in knowledge, research and practice of preventing suicide, and public comment informed the development of the new Strategy by the Action Alliance. Since the development of the first strategy, more than 100 best practices in suicide prevention are now documented and form the foundation of the new strategy. “The latest research shows that suicide is preventable, suicidal behaviors are treatable, and the support of families, friends, and colleagues are critical protective factors. Suicide prevention needs to be addressed in the comprehensive, coordinated way outlined in the national strategy,” said Surgeon General Regina M. Benjamin. Dr. Benjamin also released a new public service announcement promoting the national suicide prevention line –1-800-273-TALK(8255). The Action Alliance is composed of approximately 200 public- and private- sector organizations united by a common vision of a nation free from the tragic experience of suicide. One of the private sector partners, Facebook is supporting the strategy by harnessing the power of social networking and crisis support to help prevent suicides across the nation. "All too often, people in crisis do not know how—or who—to ask for help,” said Facebook’s Global VP for Public Policy, Marne Levine. “At Facebook, we have a unique opportunity to provide the right resources to our users in distress, when and where they need them most. By enabling connection to trained and caring professionals around the world, we can do our part to let users know help is available. Through a concerted and coordinated effort on the part of private industry, government, and concerned family and friends, we can make a real difference in preventing suicide and saving lives." A new service offered by Facebook enables users to report a suicidal comment they see posted by a friend to Facebook using either the Report Suicidal Content link or the report links found throughout the site. The person who posted the suicidal comment will then immediately receive an email from Facebook encouraging him or her to call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255) or to click on a link to begin a confidential chat session with a crisis worker. Additionally, •If you are concerned about yourself or someone you care about, call the National Suicide Prevention Lifeline 24/7 for free, confidential help ( 1-800-273-8255 ). •To view or order printed copies of the National Strategy for Suicide Prevention and other materials, visit www.samhsa.gov/NSSP. •To learn more about suicide prevention, visit www.sprc.org. •To view the U.S. Surgeon General’s new “Everyone Plays A Role” PSA, visit http://www.surgeongeneral.gov/ •To view the Department of Veterans Affairs new “Side by Side” PSA, visit http://www.veteranscrisisline.net/materials/spmsupport/files/side-by-side-SD-eng-60-cc.wmv -------------------------------------------------------------------------------- SAMHSA is a public health agency within the Department of Health and Human Services. Its mission is to reduce the impact of substance abuse and mental illness on America’s communities.