In September 2014, PharmaVoice ran a special edition on Data Management as a Key Business Driver. Target Health is pleased to announce that Dr. Jules Mitchel, President of Target Health, was quoted under the topic The Key to Regulatory Compliance. Dr. Mitchel was quoted as saying “When original data are captured through validated electronic systems, there is no need to perform source document verification (SDV).The key to regulatory compliance then becomes the availability of validated, independent, contemporaneous copies of source records, so that regulators can compare the data within the clinical trial database against original records at the clinical site. Data managers can now focus on whether the protocol is being followed, and whether data make sense and are consistent across sites.“

 

Birds of Central Park – Cormorant Taking in the Sun

20141006-13

 

Birds of Central Park – Migrating Birds Taking a Rest

20141006-14

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel orMs. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

Behavioral Variability Through Stochastic Choice and Learned Helplessness

20141006-9

In probability theory, a purely stochastic system is one whose state is non-deterministic (i.e., “random“) so that the subsequent state of the system is determined probabilistically. Any system or process that must be analyzed using probability theory is stochastic at least in part. 1) ___ systems and processes play a fundamental role in mathematical models of phenomena in many fields of science, engineering, and economics. Stochastic comes from the Greek word meaning “aim“. It also denotes a target stick; the pattern of arrows around a target stick stuck in a hillside is representative of what is stochastic. In competitive settings, rats can generate behavior that is effectively stochastic. Stochastic choice requires abandoning experience-based models by disengaging the anterior cingulate cortex (ACC). Noradrenergic input into ACC controls whether or not the model influences behavior. Behavioral choices that ignore prior experience promote exploration and unpredictability, but are seemingly at odds with the brain’s tendency to use 2)___ to optimize behavioral choice. Indeed, when faced with virtual competitors, primates resort to strategic counter-prediction rather than to stochastic choice. Rats also use history- and model-based strategies when faced with similar competitors but can switch to a “stochastic“ mode when challenged with a competitor that they cannot defeat by counter-prediction. In this mode, outcomes associated with an animal’s actions are ignored, and normal engagement of ACC is suppressed. Using circuit perturbations in transgenic rats, it was demonstrated that switching between strategic and stochastic behavioral modes is controlled by locus coeruleus input into ACC. These findings suggest that, under conditions of uncertainty about environmental rules, changes in noradrenergic input alter ACC output and prevent erroneous beliefs from guiding decisions, thus enabling behavioral variation.

 

Many of the choices we make are informed by experiences we’ve had in the 3) ___. But occasionally we’re better off abandoning those lessons and exploring a new situation unfettered by past experiences. The new studies look at how the brain generates strategic and random behavior, and how it switches between the two modes.

 

 

20141006-10

Many of the choices we make are informed by experiences we’ve had in the past. But occasionally we’re better off abandoning those lessons and exploring a new situation unfettered by past experiences. Scientists at the Howard Hughes Medical Institute’s Janelia Research Campus have shown that the brain can temporarily disconnect information about past experience from decision-making circuits, thereby triggering 4) ___ behavior.

 

In the study, rats playing a game for a food reward usually acted strategically, but switched to random behavior when they confronted a particularly unpredictable and hard-to-beat competitor. The animals sometimes got stuck in a random-behavior mode, but it was found that they could restore normal behavior by manipulating activity in a specific region of the brain. Because the behavior of animals stuck in this random mode bears some resemblance to that of patients affected by a psychological condition called learned helplessness, the findings may help explain that condition and suggest strategies for treating it. The authors published their findings in the September 25, 2012, issue of the journal Cell.

 

The brain excels at integrating information from past experiences to guide decision-making in new situations. But in certain circumstances, random behavior may be preferable. An animal might have the best chance of avoiding a predator if it moves unpredictably, for example. And in a new environment, unrestricted exploration might make more sense than relying on an internal model developed elsewhere. Scientists have long speculated that the brain may have a way to switch off the influence of past experiences so that behavior can proceed randomly. Others argue that it’s inefficient, and that it would be at odds with what some people call one of the most central operating principles of the 5) ___ – to use our past experience and knowledge to optimize behavioral choices. The authors wanted to see if they could create a situation that would force animals to switch into this random mode of behavior. “We tried to create a setting that would push the need to create behavioral variability and unpredictability to its extreme,“ Karpova says. They did this by placing rats in a competitive setting in which a computer-simulated competitor determined which of two holes in a wall would provide a sugary reward. The virtual competitor, whose sophistication was varied by the experimenters, analyzed the rats’ behavior to predict their future choices. “We thought if we came up with very sophisticated competitors, then the animals would eventually be unable to figure out how to outcompete them, and be forced to either give up or switch into this [random] mode, if such a mode exists,“ Karpova says. And that’s exactly what happened: When faced with a weak competitor, the animals made strategic choices based on the outcomes of previous trials. But when a sophisticated competitor made strong predictions, the rats ignored past experience and made random selections in search of a reward. Now that they had evidence that the brain could generate both strategic and random 6) ___, the authors wanted to know how it switched between modes. Since that switch determines whether or not an animal’s internal model of the world influences its behavior, the scientists suspected it might involve a brain region called the anterior cingulate cortex, where that internal model is likely encoded. They found that they could cause animals to switch between random and strategic behavior by manipulating the level of a stress hormone called norepinephrine in the anterior cingulate cortex. Increasing norepinephrine in the region activated random behavior and suppressed the strategic mode. Inhibiting release of the hormone had the opposite effect. Karpova’s team observed that animals in their experiments sometimes continued to behave randomly, even when such behavior was no longer advantageous. “If all they’ve experienced is this really sophisticated competitor for several sessions that thwarts their attempts at strategic, model-based counter-prediction, they go into this [random mode], and they can get stuck in it for quite some time after that competitor is gone,“ she says. This, she says, resembles the condition of learnedhelplessness, in which strategic decision-making is impaired following an experience in which a person finds they are unable to control their environment.

 

The authors could release the animals from this “stuck“ state by suppressing the release of norepinephrine in the anterior cingulate cortex. “Just by manipulating a single neuromodulatory input into one brain area, you can dramatically enhance the strategic mode. The effect is strong enough to rescue animals out of the random mode and successfully transform them into strategic decision makers,“ Karpova says. “We think this might shed light on what has gone wrong in conditions such as learned helplessness, and possibly how we can help alleviate them.“ Karpova says that now that her team has uncovered a mechanism that switches the brain between random and strategic behavior, she would like to understand how those behaviors are controlled in more natural settings. “We normally try to use all of our knowledge to think strategically, but sometimes we still need to explore,“ she says. In most cases, that probably means brief bouts of random behavior during times when we are uncertain that past experience is relevant, followed by a return to more strategic behavior – a more subtle balance that Karpova intends to investigate at the level of changes in activity in individual neural circuits.

 

Learned helplessness experiments in classical conditioning started as research on digestion and almost by accident lead to a concept that has become a staple in behavioral theory. In 1967, while researching classical conditioning, another accidental discovery occurred. In the original experiments, dogs were placed in harnesses so that they could not escape and then were presented with small electric shocks (Overmier & Seligman, 1967; Seligman & Maier, 1967). After this experience, these dogs as well as dogs who had not undergone the original harness studies were placed in a shuttle box (see below) which consisted of two sides both with independent electric grids on the floor.

 

 

20141006-11

What they discovered was a distinct difference between the dogs who had originally been harnessed and those who had not. For the latter, when a shock was presented, they almost immediately, after trying different methods of escape, jumped across the barrier to escape the uncomfortable shock. The previously harnessed dogs showed distress, as did the other digs, but unlike the other dogs, failed to escape the shock and ultimately laid down on the grid and whimpered (Seligman, 1975). These studies demonstrated that previous learning can result in a drastic change in behavior. When presented with a situation that allowed the dogs to control their experience, those who learned earlier that they had no control failed to escape the shock. Without this learning, escape was not only seen as a possibility, the behavior to escape was exercised in every case. In the study of psychological phenomenon of animals, the next logical step after a discovery such as this, was to determine its effect on humans. Experiments were designed presenting a loud irritating noise (rather than the original shock) to human subjects. In these experiments, subjects were presented with the noise and told that if they solved a puzzle the noise would turn off. By pressing a series of buttons, for example, one group learned that they had 7) ___ over their environment. A second group, however, were presented with puzzles that had no solutions, resulting in an inability to turn off the irritating noise. To test if their learning would generalize to other areas, these same subjects, as well as new subjects were then presented with similar situations but with new types of problems to solve. The problems in this phase were identical, so each group had an equal chance of solving the problems. Those who were able to control their environment before did as well as new subjects, however, those in the unsolvable condition before, did significantly worse. Like the dogs in the original experiments, the human subjects also inaccurately generalized their learned 8) ___ to a new situation. Several replications of these experiments support the idea that we can learn to be helpless in an environment that actually offers us control. This realization has since been applied to many aspects of human behavior, and does well to explain why people in certain situations accept their uncomfortable or negative situation despite the ability to change it. Since the original learned helplessness experiments, the phenomenon has been applied to several areas of human behavior, including (1) Depression; (2) elderly adults and old-age homes; (3) domestic violence and abusive relationships; and (4) drug abuse and addiction. Studies have found that a true inability to control the environment is not necessary for learned helplessness to occur. In fact, even when told there is nothing a person can do, he or she is more likely to not try or to try less diligently than those who were not given this advice. Like in many aspects of human behavior, perception is the key. The authors found that those who have experienced depression in the past are more likely to accept depression in their future and therefore less likely to attempt change. The same holds true for individuals in domestic violence situations. Those who have been unable to escape violent situations in their homes are much more likely to refuse help and accept future violence as inescapable. This is true even when presented with real options to avoid future violence. Many also argue that an inability to quit smoking is related, along with obvious chemical qualities, to the person’s perception of control. If a person witnesses others try and fail in their attempts to quit, they are less likely to try themselves. For those addicted to other substances, this phenomenon seems to hold true as well. The more you have witnessed failure either in yourself or others, the less likely you are to attempt change, even if the situation changes dramatically.

 

The feeling of helplessness or out of control in any situation is uncomfortable and can cause secondary feelings of stress, depression and anxiety. If such feelings continue to occur in response to any adverse environment, people can develop this condition of learned helplessness; however, overcoming learned helplessness can be overcome, so individuals can lead happier, more productive lives.

 

 

20141006-12

Psychologists Martin E.P. Seligman and Steven F. Maier observed the learned helplessness behavior while conducting a study on dogs they were conditioned to expect an electrical shock after hearing a tone.

 

After observing the amazing behavior, of learned helplessness, in the dogs, Seligman began to extend his research to behaviors in other animals as well as in humans. What he found is that some people react in the same way under repeated and difficult situations where there is a perceived lack of control. Like animals, some people simply give up in the face of adversity, or when they feel certain there is nothing they can do to change things or their outcomes. Learned helplessness is a fairly common behavior seen in abusive relationships. The abused individual believes that they are powerless to change their lives, and like the dogs, they make no attempt to remove themselves from the unpleasant conditions they are in. Children often show signs of learned helplessness in school. An often-used example refers to a child who performs poorly on math tests and assignments may begin to feel that nothing he does will have any effect on his math performance. If no type of intervention occurs, the child’s feeling of helplessness faced with any type of math-related task will carry over into adulthood.

 

Learned helplessness has been associated with depression, anxiety and certain phobias. When people feel a lack of control over their feelings and emotions, sometimes they quit trying to be anything different than depressed or anxious. Learned helplessness implies that the condition has control over the individual. When it comes to learned helplessness, the most important factor seems to be control. Humans need to feel they have some level of control over their 9) ___. When someone feels as though they have no control, the feeling comes from a perception and perceptions are formed as a result of sensory input from our experiences in the world. The good news is that because the feelings and behaviors associated with learned helplessness are the result of negative perceptions, they can be changed. Negative thinking may bring negative results because one’s thinking dictates who you are and where you’ll go. Changing perceptions involves changing thinking, but not just from negative to positive. It also requires changing the response to a stimulus from the one you have already learned (learned helplessness) by associating it with a new response. There are successful techniques that can help facilitate the development of new perceptions. One is called, Reframing. The success of reframing comes from the fact that reframing can be performed with language alone. Reframing, trains the part of the mind that causes a behavior (or response) a person doesn’t like, to one that is more appropriate. Reframing works best with a person who has learned helplessness. While learned helplessness is a behavioral response to certain perceptions we form about the world we live in, it is certainly not like a terminal illness. Learned helplessness is a behavioral response that can be changed through the use of techniques that work toward changing perceptions from old negative thought10) ___ to new positive affirmations. Sources: Howard Hughes Medical Institute; ScienceDaily.com; Wikipedia

 

ANSWERS: 1) Stochastic; 2) experience; 3) past; 4) random; 5) brain; 6) behavior; 7) control; 8) helplessness; 9) lives; 10) patterns

 

Martin Seligman, PhD (1942- Present)

20141006-7

Martin E. P. “Marty“ Seligman (born August 12, 1942) is an American psychologist, educator, and author of self-help books. His theory of learned helplessness is popular among scientific and clinical psychologists. According to Haggbloom et al.’s study of the most eminent psychologists of the 20th century, Seligman was the 13th most frequently cited psychologist in introductory psychology textbooks throughout the century, as well as the 31st most eminent overall. Seligman is the Zellerbach Family Professor of Psychology in the University of Pennsylvania’s Department of Psychology. He was previously the Director of the Clinical Training Program in the department. He is the director of the university’s Positive Psychology Center. Seligman was elected President of the American Psychological Association for 1998. He is the founding editor-in-chief of Prevention and Treatment Magazine (the APA electronic journal) and is on the board of advisers of Parents Magazine. Seligman has written about positive psychology topics such as The Optimistic Child, Child’s Play, Learned Optimism, Authentic Happiness, and Flourish.

 

Seligman was born in Albany, New York. He was educated at a public school and at The Albany Academy. He earned a BA in philosophy at Princeton University in 1964, graduating Summa Cum Laude. During his senior year, Seligman had to choose between three offers from various universities. They included a scholarship to study analytic philosophy at Oxford University, animal experimental psychology at the University of Pennsylvania and finally an offer to join Penn’s bridge team. Seligman chose to attend the University of Pennsylvania to study psychology. He earned his Ph.D. in psychology at University of Pennsylvania in 1967.

 

Seligman’s foundational experiments and theory of “learned helplessness“ began at University of Pennsylvania in 1967, as an extension of his interest in depression. Quite by accident, Seligman and colleagues discovered that the conditioning of dogs led to outcomes that were opposite to the predictions of B.F. Skinner’s behaviorism, then a leading psychological theory. Seligman developed the theory further, finding learned helplessness to be a psychological condition in which a human being or an animal has learned to act or behave helplessly in a particular situation – usually after experiencing some inability to avoid an adverse situation – even when it actually has the power to change its unpleasant or even harmful circumstance. Seligman saw a similarity with severely depressed patients, and argued that clinical depression and related mental illnesses result in part from a perceived absence of control over the outcome of a situation. In later years, alongside Abramson, Seligman reformulated his theory of learned helplessness to include attributional style. According to author Jane Mayer, Seligman gave a talk at the Navy SERE school in San Diego in 2002, which he said was a three-hour talk on helping US soldiers to resist torture, based on his understanding of learned helplessness.

 

Seligman worked with Christopher Peterson to create what they describe as a ?positive’ counterpart to the Diagnostic and Statistical Manual of Mental Disorders (DSM). While the DSM focuses on what can go wrong, Character Strengths and Virtues is designed to look at what can go right. In their research they looked across cultures and across millennia to attempt to distill a manageable list of virtues that have been highly valued from ancient China and India, through Greece and Rome, to contemporary Western cultures. Their list includes six character strengths: wisdom/knowledge, courage, humanity, justice, temperance, and transcendence. Each of these has three to five sub-entries; for instance, temperance includes forgiveness, humility, prudence, and self-regulation. The authors do not believe that there is a hierarchy for the six virtues; no one is more fundamental than or a precursor to the others. In July 2011, Seligman encouraged David Cameron to look into well-being as well as financial wealth in ways of assessing the prosperity of a nation. On July 6, 2011, Seligman appeared on Newsnight and was interviewed by Jeremy Paxman about his ideas and his interest in the concept of well-being. While presenting “Flourish“ to the Royal Society of Arts, Seligman articulated an account of the good life, which consisted of five elements under the acronym PERMA:

 

  1. Positive emotion – tunable by writing down, every day at bed time, three things that went well, and why
  2. Engagement – tunable by preferentially using one’s highest strengths to perform the tasks which one would perform anyway
  3. Relationships – tunable, but not in a way that can be explained briefly; listen to timestamp 15:12 and following of the audio
  4. Meaning – belonging to and serving something bigger than one’s self
  5. Achievement – determination is known to count for more than IQ

 

 

20141006-8

Is happiness overrated? Martin Seligman now thinks so, which may seem like an odd position for the founder of the positive psychology movement. As president of the American Psychological Association in the late 1990s, he criticized his colleagues for focusing relentlessly on mental illness and other problems. He prodded them to study life’s joys, and wrote a best seller in 2002 titled “Authentic Happiness.“ But now he regrets that title. As the investigation of happiness proceeded, Dr. Seligman began seeing certain limitations of the concept. Why did couples go on having children even though the data clearly showed that parents are less happy than childless couples? Why did billionaires desperately seek more money even when there was nothing they wanted to do with it? And why did some people keep joylessly playing bridge? Dr. Seligman, an avid player himself, kept noticing them at tournaments. They never smiled, not even when they won. They didn’t play to make money or make friends. They didn’t savor that feeling of total engagement in a task that psychologists call flow. They didn’t take aesthetic satisfaction in playing a hand cleverly and “winning pretty.“ They were quite willing to win ugly, sometimes even when that meant cheating. “They wanted to win for its own sake, even if it brought no positive emotion,“ says Dr. Seligman. “They were like hedge fund managers who just want to accumulate money and toys for their own sake. Watching them play, seeing them cheat, it kept hitting me that accomplishment is a human desiderata in itself.“ This feeling of accomplishment contributes to what the ancient Greeks called eudaimonia, which roughly translates to “well-being“ or “flourishing,“ a concept that Dr. Seligman has borrowed for the title of his new book, “Flourish.“

 

The positive psychology movement has inspired efforts around the world to survey people’s state of mind, like a new project in Britain to measure what David Cameron, the prime minister, calls GWB, for general well-being. Dr. Seligman says he’s glad to see governments measuring more than just the G.D.P., but he’s concerned that these surveys mainly ask people about their “life satisfaction.“ In theory, life satisfaction might include the various elements of well-being. But in practice, Dr. Seligman says, people’s answers to that question are largely – more than 70% – determined by how they’re feeling at the moment of the survey, not how they judge their lives over all. “Life satisfaction essentially measures cheerful moods, so it is not entitled to a central place in any theory that aims to be more than a happiology,“ he writes in “Flourish.“ By that standard, he notes, a government could improve its numbers just by handing out the kind of euphoriant drugs that Aldous Huxley described in “Brave New World.“

 

So what should be measured instead? The best gauge so far of flourishing, Dr. Seligman says, comes from a study of 23 European countries by Felicia Huppert and Timothy So of the University of Cambridge. Besides asking respondents about their moods, the researchers asked about their relationships with others and their sense that they were accomplishing something worthwhile. Denmark and Switzerland ranked highest in Europe, with more than a quarter of their citizens meeting the definition of flourishing. Near the bottom, with fewer than 10% flourishing, were France, Hungary, Portugal and Russia. There’s no direct comparison available with the United States, although some other researchers say that Americans would do fairly well because of their sense of accomplishment. The economist Arthur Brooks notes that 51% of Americans say they’re very satisfied with their jobs, which is a higher percentage than in any European country except Denmark, Switzerland and Austria. In his 2008 book, “Gross National Happiness,“ Dr. Brooks argues that what’s crucial to well-being is not how cheerful you feel, not how much money you make, but rather the meaning you find in life and your sense of “earned success“ – the belief that you have created value in your life or others’ lives. “People find meaning in providing unconditional love for children,“ writes Dr. Brooks, who is now president of the American Enterprise Institute. “Paradoxically, your happiness is raised by the very fact that you are willing to have your happiness lowered through years of dirty diapers, tantrums and backtalk. Willingness to accept unhappiness from children is a source of happiness.“ Some happiness researchers have suggested that parents delude themselves about the joys of children: They focus on the golden moments and forget the more frequent travails. But Dr. Seligman says that parents are wisely looking for more than happy feelings. “If we just wanted positive emotions, our species would have died out a long time ago,“ he says. “We have children to pursue other elements of well-being. We want meaning in life. We want relationships.“

 

In observing people’s need for accomplishment, Dr. Seligman says, he’s reminded of his early experiments that famously identified the concept of “learned helplessness.“ He found that when animals or people were given a series of arbitrary punishments or rewards, they stopped trying to do anything constructive. “We found that even when good things occurred that weren’t earned, like nickels coming out of slot machines, it did not increase people’s well-being,“ he said. “It produced helplessness. People gave up and became passive.“ To avoid that sort of malaise, Dr. Seligman recommends looking at the basic elements of well-being, identifying which ones matter most to you, setting goals and monitoring progress. Simply keeping track of how much time you spend daily pursuing each goal can make a difference, he says, because it’s easy to see discrepancies between your goals and what you do. You might also start to question some of your goals and activities, the way that Dr. Seligman occasionally wonders why he spends so much time playing bridge. It’s brought him some clear achievements – including a second-place finish in the North American pairs championship – but he doesn’t pretend that bridge provides any meaning in life. He says he plays for another element of well-being, the feeling of engagement. “I go into flow playing bridge,“ he writes, “but after a long tournament, when I look in the mirror, I worry that I am merely fidgeting until I die.“ Is playing bridge for the feeling of flow any more worthwhile than playing it just to win? Dr. Seligman doesn’t want to judge. “My view of positive psychology is that it describes rather than prescribes what human beings do,“ he says. “I don’t want to mess with people’s values. I’m not saying it’s a good or a bad thing to want to win for its own sake. I’m just describing what lots of people do. One’s job as a therapist is not to change what people value, but given what they value, to make them better at it.“

 

HHS Releases 13th Report on Carcinogens

 

Government studies and oversight are key to our survival as a species. The private sector has no incentive, other than for moral and ethical reasons, to self-police. In the short term, morality and ethics often take a back seat.

 

Four substances have been added in the U.S. Department of Health and Human Services 13th Report on Carcinogens, a science-based document that identifies chemical, biological, and physical agents that are considered cancer hazards for people living in the United States. Ortho-toluidine, used to make rubber chemicals, pesticides, and dyes, has been reevaluated and is now listed as a known human carcinogen. Three substances have been added as reasonably anticipated to be human carcinogens. These include 1-bromopropane, used as a cleaning solvent and spray adhesive; cumene, used to make phenol and acetone, and also found in fuel products and tobacco smoke; and the wood preservative mixture pentachlorophenol.

 

The Report on Carcinogens is a congressionally mandated report prepared for the HHS Secretary by NTP. The report identifies agents, substances, mixtures, or exposures in two categories: known to be a human carcinogen and reasonably anticipated to be a human carcinogen. A listing in the report indicates a cancer hazard, but does not by itself mean that a substance will cause cancer. Many factors, including the amount and duration of exposure, and an individual’s susceptibility to a substance, can affect whether a person will develop cancer.

 

ONE SUBSTANCE ADDED AS A KNOWN HUMAN CARCINOGEN

 

Since 1983, ortho-toluidine has been listed in the Report on Carcinogens as reasonably anticipated to be a human carcinogen. However, new cancer studies led NTP to reevaluate and reclassify ortho-toluidine, and it is now added to the category of known-to-be a human carcinogen, based on studies in humans showing it causes urinary bladder cancer. Ortho-toluidine is a synthetic chemical produced in other countries and imported into the United States by several companies in high volumes. It is primarily used to make rubber chemicals, pesticides, and dyes. It is also used in some consumer and medical products. People are mainly exposed through the workplace, by skin contact and/or inhalation when using ortho-toluidine. People can also be exposed outside the workplace through sources such as tobacco smoke.

 

THREE SUBSTANCES ADDED TO THE NEW REPORT AS REASONABLY ANTICIPATED TO BE A HUMAN CARCINOGEN

 

The chemical 1-bromopropane is a colorless to pale yellow liquid used as a solvent in many commercial industries. It is used as a cleaner for optics, electronics, and metals, as well as a solvent for aerosol-applied adhesives such as those used in foam cushion manufacturing. It is also used in dry cleaning and in solvent sprays for aircraft maintenance. Workers in certain occupations may be more exposed to 1-bromopropane than the general population. No human studies were identified that evaluated the relationship between human cancer and exposure specifically to 1-bromopropane. However, inhalation exposure to 1-bromopropane in rodents caused tumors in several organs, including the skin, lungs, and large intestine.

 

Cumene is a flammable and volatile liquid with a gasoline-like odor. It is a natural component of coal tar and petroleum, and is found in tobacco smoke. It is used primarily to make acetone and phenol. People are mainly exposed to cumene through the environment and in workplaces that use or produce cumene. It can be found in emissions from petroleum products. Inhalation exposure to cumene caused lung tumors in male and female mice, and liver tumors in female mice. No human studies were identified that looked at the relationship between human cancer and exposure specifically to cumene.

 

Pentachlorophenol and by-products of its synthesis are complex mixtures of chemicals used as wood preservatives. Because virtually everyone who is exposed to pentachlorophenol is also exposed to its synthesis by-products, they were evaluated together. In the United States, pentachlorophenol has been regulated since the 1980s as a restricted-use pesticide. It is used industrially for treating utility poles, wood pilings, fence posts, and lumber or timber for construction. Most exposure has occurred in settings where workers treat lumber or come in contact with treated lumber. People may also be exposed to this mixture from breathing contaminated air or dust, or from contact with contaminated soil. Exposure to this mixture was associated with an increased risk of non-Hodgkin lymphoma in studies in humans. It also caused tumors in the liver and other organs in mice.

 

The Report on Carcinogens, 13th Edition, is prepared by the National Toxicology Program (NTP). NTP is a federal, interagency program, headquartered at the NIEHS, whose goal is to safeguard the public by identifying substances in the environment that may affect human health.

 

Genome-Wide Analysis of the Heritability of Amyotrophic Lateral Sclerosis

 

Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations. As a result, a study published in JAMA Neurology (2014;71:1123-1134) was performed to estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.

 

For the study, the genome-wide complex trait analysis algorithm was applied to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website. The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d’Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland. For the main outcomes, a linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred (not inbred) individuals. Variance measures were used to estimate heritability.

 

Based on the meta -analysis, which is based on genome-wide genotyping data, the overall heritability of ALS was estimated to be approximately 21.0%, indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, 17 regions of the genome that display significantly high heritability estimates were identified. Eleven of these regions represent novel candidate regions for ALS risk.

 

The authors concluded that the heritability of ALS was significantly higher than previously reported and that there are multiple, novel genomic regions that may contain causative risk variants that influence susceptibility to ALS.

 

FDA Grants to Stimulate Drug, Device Development for Rare Diseases

 

A disease or condition is considered rare if it affects less than 200,000 persons in the United States. There are about 7,000 rare diseases and conditions, according to the National Institutes of Health. In total, nearly 30 million Americans suffer from at least one rare disease.

 

The FDA has awarded 15 grants totaling more than $19 million to boost the development of medical device, drug, and biological products for patients with rare diseases, with at least a quarter of the funding going to studies focused solely on pediatrics. The FDA awards grants for clinical studies on safety and/or effectiveness of products that could either result in, or substantially contribute to, approval of the products.

 

The program is administered through the FDA’s Orphan Products Grants Program. This program was created by the Orphan Drug Act, passed in 1983, to promote the development of products for rare diseases. Since its inception, the program has given more than $330 million to fund more than 530 new clinical studies on developing treatments for rare diseases and has been used to bring more than 50 products to marketing approval. A panel of independent experts with experience in the disease-related fields reviewed the grant applications and made recommendations to the FDA.

 

The 2014 grant recipients are:

 

  1. Denise Adams, Cincinnati Children’s Hospital Medical Center (Cincinnati, Ohio), Phase 2 Study of Vincristine vs. Sirolimus for the Treatment of High Risk Kaposiform Hemangioendothelioma–$1.6 million over four years
  2. Mitesh Borad, Mayo Clinic Arizona (Scottsdale, Ariz.), Phase 1 Study of VSV-hIFN-B for the Treatment of Hepatocellular Carcinoma– approximately $600,000 over three years
  3. Andrew Brenner, University of Texas Health Center San Antonio (San Antonio, Texas), Phase 2 Study of TH-302 for the Treatment of Glioblastoma– approximately $1.6 million over four years
  4. Kelly Dooley, The Johns Hopkins University (Baltimore, Md.), Phase 2 Study of PA-824 for the Treatment of Pulmonary Tuberculosis– $1.6 million over four years
  5. Donald Durden, University of California San Diego (San Diego, Calif.), Phase 2 Study of Poly-ICLC for the Treatment of Pediatric Low Grade Gliomas– $1.6 million over four years
  6. Alfred Lane, Stanford University (Stanford, Calif.), Phase 2 Study of Sildenafil for the Treatment of Lymphatic Malformations– approximately $1.6 million over four years
  7. Dung Le, The Johns Hopkins University (Baltimore, Md.), Phase 2 Study of Folfirinox followed by Ipilimumab/GVAX for the Treatment of Pancreatic Cancer– $1.6 million over four years
  8. Phillip Low, Mayo Clinic Rochester (Rochester, Minn.), Phase 1 Study of Intrathecal Autologous Mesenchymal Stem Cell Therapy for the Treatment of Multiple System Atrophy–$600,000 over three years
  9. Guido Magni, River Vision Development Corporation (New York, N.Y.), Phase 2 Study of RV001 for the Treatment of Thyroid Eye Disease–$1.2 million over three years
  10. Michael Portman, Seattle Children’s Hospital (Seattle, Wash.), Phase 3 Study of Triiodothyronine Supplementation for the Treatment of Young Infants After Cardiopulmonary Bypass– approximately $1.6 million over four years
  11. Jana Portnow, City of Hope Beckman Research Institute (Duarte, Calif.), Phase 1 Study of Neural Stem Cells & 5-FC/Leucovorin for the Treatment of Recurrent High Grade Gliomas–$600,000 over three years
  12. Scott Rollins, Selexys Pharmaceuticals Corporation (Oklahoma City, Okla.), Phase 2 Study of SelG1 for the Treatment of Sickle Cell Disease– $1.6 million over four years
  13. Beena Sood, Wayne State University (Detroit, Mich.), Phase 1/2 Study of Aerosolized Survanta for the Treatment of Neonatal Respiratory Distress Syndrome– approximately $1.4 million over four years
  14. Warren Stern, Aesrx, LLC (Newton, Mass.), Phase 2 Study of Aes103 (5-HMF) for the Treatment of Stable Sickle Cell Disease–approximately $1.6 million over four years
  15. Pamela Zeitlin, The Johns Hopkins University (Baltimore, Md.), Phase 2 Study of Digitoxin for the Treatment of Cystic Fibrosis– approximately $290,000 for one year

 

When Your Spouse/Partner Takes Over the Kitchen

 

Jules Mitchel Goes Paleo with Filet Mignon

20141006-1

This steak was so tender, you could easily cut it with a fork.  ©Joyce Hays, Target Health Inc.

 

Ingredients (for two people)

 

2 Center-cut fillet mignon, 1.5 inches thick. Buy the best

 

Here’s the Rub

 

1/2 teaspoon garlic powder

1/2 teaspoon onion powder

Pinch black pepper (or grind to your taste)

Add any other spice you like

 

Rub Directions

 

In a small bowl, mix the spices together.

Now, rub both sides of the steaks with the rub and leave in for 60 minutes

 

Cooking the Steaks

 

2 Center-cut fillet mignon, 1.5 inches thick

Canola oil (enough to thinly cover pan

1/2 teaspoon garlic powder

1/2 teaspoon onion powder

Pinch black pepper (grind to your taste)

Cabernet (not cooking wine) 2 splashes

 

Cooking Directions

 

Use a fry pan that’s deep enough to hold all the ingredients.

 

Add the canola oil to thinly cover the bottom of the pan

 

Turn heat to medium and add the spices, above, stirring as you add. Now, add 2 splashes of the cabernet and stir. We used the same cab we planned to be drinking with the steak.

 

Now, turn heat up to sizzle. Then add the steaks. Cook the first side well, then turn over. Either watch the steaks like a hawk, or cover and cook for 3 to 5 minutes, depending on how you like your steak. We like rare to medium rare.

 

Serve right away with any type of sauce you like for steak.

20141006-2

We started out with freshly made, buttery soft, mozzarella, sliced and served on plump ripe beefsteak tomatoes, garnished with tender basil sprouts. (3 pieces each). Luscious. He said he liked this even better than the fillet mignon. ©Joyce Hays, Target Health Inc.

 

20141006-3

Delicious Mushroom/Wine sauce for the fillet mignon – ©Joyce Hays, Target Health Inc.

 

20141006-4

Just before adding the Mushroom/wine sauce. ©Joyce Hays, Target Health Inc.

 

20141006-5

By the time we were finished, nothing was left. ©Joyce Hays, Target Health Inc.

 

20141006-6

I found regular bottles of Hall Cab. This was a meal to remember, and we lost weight the following morning. (no dessert) – ©Joyce Hays, Target Health Inc.

 

Fall was in the air this past Saturday night, here in the Big Apple, when temperatures fell into the 50’s and then 48 degrees.  We’re tired of summer and welcome some crisp cold Autumn weather. We’re not talking about the play we saw this weekend because we didn’t like it. Since, we’re patrons of the theater club that produced it, we’re not going to name it or the play, but we were disappointed. We’re big contributors to the arts because we believe that a city without culture is a city without a soul.

 

From Our Table to Yours!

 

Bon Appetit!