Scientists Can Now Block Heroin, Morphine Addiction

In a major breakthrough, an international team of scientists has proven that addiction to morphine and heroin can be blocked, while at the same time increasing pain relief.

Photp: Jens Langner at http://commons.wikimedia.org/wiki/File:PET-image.jpg

Laboratory studies have shown that the drug (+)-naloxone (pronounced: PLUS nal-OX-own) will selectively block the immune-addiction response.The team from the University of Adelaide and University of Colorado has discovered the key mechanism in the body's immune system that amplifies addiction to opioid drugs.

The results -- which could eventually lead to new co-formulated drugs that assist patients with severe pain, as well as helping heroin users to kick the habit -- will be published August 16 in the Journal of Neuroscience.

"Our studies have shown conclusively that we can block addiction via the immune system of the brain, without targeting the brain's wiring," says the lead author of the study, Dr Mark Hutchinson, ARC Research Fellow in the University of Adelaide's School of Medical Sciences.

"Both the central nervous system and the immune system play important roles in creating addiction, but our studies have shown we only need to block the immune response in the brain to prevent cravings for opioid drugs."

The team has focused its research efforts on the immune receptor known as Toll-Like receptor 4 (TLR4).

"Opioid drugs such as morphine and heroin bind to TLR4 in a similar way to the normal immune response to bacteria. The problem is that TLR4 then acts as an amplifier for addiction," Dr Hutchinson says.

"The drug (+)-naloxone automatically shuts down the addiction. It shuts down the need to take opioids, it cuts out behaviours associated with addiction, and the neurochemistry in the brain changes -- dopamine, which is the chemical important for providing that sense of 'reward' from the drug, is no longer produced."

Senior author Professor Linda Watkins, from the Center for Neuroscience at the University of Colorado Boulder, says: "This work fundamentally changes what we understand about opioids, reward and addiction. We've suspected for some years that TLR4 may be the key to blocking opioid addiction, but now we have the proof.

"The drug that we've used to block addiction, (+)-naloxone, is a non-opioid mirror image drug that was created by Dr Kenner Rice in the 1970s. We believe this will prove extremely useful as a co-formulated drug with morphine, so that patients who require relief for severe pain will not become addicted but still receive pain relief. This has the potential to lead to major advances in patient and palliative care," Professor Watkins says.

The researchers say clinical trials may be possible within the next 18 months.

This study has been funded by the National Institute on Drug Abuse (NIDA) in the United States and the Australian Research Council (ARC).

Source: University of Adelaide (2012, August 14). Scientists can now block heroin, morphine addiction. ScienceDaily. Retrieved April 24, 2013, from http://www.sciencedaily.com­/releases/2012/08/120814213246.htm

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Half of Inhaled Soot Particles from Diesel Exhaust, Fires Gets Stuck in the Lungs

The exhaust from diesel-fueled vehicles, wood fires and coal-driven power stations contains small particles of soot that flow out into the atmosphere. The soot is a scourge for the climate but also for human health. Now for the first time, researchers have studied in detail how diesel soot gets stuck in the lungs. The results show that more than half of all inhaled soot particles remain in the body. (Credit: © Imagenatural / Fotolia)

The figure is higher than for most other types of particles. For example "only" 20 per cent of another type of particle from wood smoke and other biomass combustion gets stuck in the lungs. One explanation is that diesel soot is made up of smaller particles and can therefore penetrate deeper into the lungs, where it is deposited. The study was made on diesel particles (which mainly consist of soot) and was recently published in the Journal of Aerosol Science. Ten healthy people volunteered for the the study.

"Findings of this kind can be extremely useful both for researchers to determine what doses of soot we get into our lungs out of the amount we are exposed to, and to enable public authorities to establish well-founded limits for soot particles in outdoor air," says Jenny Rissler, researcher in aerosol technology at Lund University's Faculty of Engineering and responsible for publishing the study.

In population studies, other researchers have been able to observe that people who live in areas with high concentrations of particulates are more affected by both respiratory and cardiovascular diseases. But since there is no conclusive evidence that it is precisely the soot that is to blame, the authorities have so far not taken any decisions on guidelines.

"Currently there is no specific limit for soot particles in the air, despite the fact that soot in the air is linked to both lung cancer and other diseases," says Jenny Rissler.

But Jenny Rissler thinks that in the future, limits on soot levels will also be set, with reference to the WHO's recent reclassification of diesel exhaust from "probably carcinogenic" to "carcinogenic."

Soot particles are not only connected to effects on health but may also contribute to a warmer climate. Paradoxically, other types of aerosol particles can partly be desirable, insofar as they have a cooling effect on the climate and thereby mitigate the warming effect of carbon dioxide.

"Soot particles are black and absorbs light, thus producing a warming effect. So it could be a double advantage to reduce it," she observes.

Jenny Rissler will next be studying individual variations in lung deposition and exposing cells to soot. She is also in the process of further developing methods to measure the surface area of the particles, as this has shown to be an important indicator of their harmfulness.

Background: Every time we breathe, we inhale tiny airborne particles, so-called aerosol particles. Some occur naturally, while others are the result of human activity. Soot mainly belongs in the latter category, as a by-product of combustion from power stations to small-scale wood fires and decorative candles. Another common source of soot is the exhaust from diesel engines, even though modern diesel cars have considerably reduced emissions thanks to efficient filters.

The EU will be tightening rules on emissions for heavy duty diesel vehicles in 2014.

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The above story is reprinted from materials provided byLund University.

Jenny Rissler, Erik Swietlicki, Agneta Bengtsson, Christoffer Boman, Joakim Pagels, Thomas Sandström, Anders Blomberg, Jakob Löndahl. Experimental determination of deposition of diesel exhaust particles in the human respiratory tract. Journal of Aerosol Science, 2012; 48: 18 DOI: 10.1016/j.jaerosci.2012.01.005

Lund University (2012, June 27). Half of inhaled soot particles from diesel exhaust, fires gets stuck in the lungs. ScienceDaily. Retrieved April 15, 2013, from http://www.sciencedaily.com­/releases/2012/06/120627092016.htm

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How stress can boost the immune system

The study's findings provide a thorough overview of how a triad of stress hormones affects the main cell subpopulations of the immune system. They also offer the prospect of, someday, being able to manipulate stress-hormone levels to improve patients' recovery from surgery or wounds or their responses to vaccines.

You've heard it a thousand times: Stress is bad for you. And it's certainly true that chronic stress, lasting weeks and months, has deleterious effects including, notably, suppression of the immune response. But short-term stress -- the fight-or-flight response, a mobilization of bodily resources lasting minutes or hours in response to immediate threats -- stimulates immune activity, said lead author Firdaus Dhabhar, PhD, an associate professor of psychiatry and behavioral sciences and member of the Stanford Institute for Immunity, Transplantation and Infection.

And that's a good thing. The immune system is crucial for wound healing and preventing or fighting infection, and both wounds and infections are common risks during chases, escapes and combat.

Working with colleagues at Stanford and two other universities in a study published online June 22 inPsychoneuroendocrinology, Dhabhar showed that subjecting laboratory rats to mild stress caused a massive mobilization of several key types of immune cells into the bloodstream and then onto destinations including the skin and other tissues. This large-scale migration of immune cells, which took place over a time course of two hours, was comparable to the mustering of troops in a crisis, Dhabhar said. He and colleagues had previously shown that a similar immune-cell redistribution in patients experiencing the short-term stress of surgery predicts enhanced postoperative recovery.

In the new study, the investigators were able to show that the massive redistribution of immune cells throughout the body was orchestrated by three hormones released by the adrenal glands, in different amounts and at different times, in response to the stress-inducing event. These hormones are the brain's call-to-arms to the rest of the body, Dhabhar said.

"Mother Nature gave us the fight-or-flight stress response to help us, not to kill us," said Dhabhar, who has been conducting experiments for well over a decade on the effects of the major stress hormones on the immune system. Last summer, Dhabhar received the International Society for Psychoneuroendocrinology's Curt. P. Richter Award for his work in this area, culminating in the new study.

The findings paint a clearer picture of exactly how the mind influences immune activity. "An impala's immune system has no way of knowing that a lion is lurking in the grass and is about to pounce, but its brain does," Dhabhar said. In such situations, it benefits lion and impala alike when pathogen-fighting immune cells are in positions of readiness in such places as the skin and mucous membranes, which are at high risk for damage and consequent infection.

So it makes perfect evolutionary sense that predator/prey activity and other situations in nature, such as dominance challenges and sexual approaches, trigger stress hormones. "You don't want to keep your immune system on high alert at all times," Dhabhar said. "So nature uses the brain, the organ most capable of detecting an approaching challenge, to signal that detection to the rest of the body by directing the release of stress hormones. Without them, a lion couldn't kill, and an impala couldn't escape." The stress hormones not only energize the animals' bodies -- they can run faster, jump higher, bite harder -- but, it turns out, also mobilize the immune troops to prepare for looming trouble.

The response occurs across the animal kingdom, he added. You see pretty much the same pattern of hormone release in a fish that has been picked up out of the water.

The experiments in this study were performed on rats, which Dhabhar subjected to mild stress by confining them (gently, and with full ventilation) in transparent Plexiglas enclosures to induce stress. He drew blood several times over a two-hour period and, for each time point, measured levels of three major hormones -- norepinephrine, epinephrine and corticosterone (the rat analog of cortisol in humans) -- as well as of several distinct immune-cell types in the blood.

What he saw was a pattern of carefully choreographed changes in blood levels of the three hormones along with the movement of many different subsets of immune cells from reservoirs such as the spleen and bone marrow into the blood and, finally, to various "front line" organs.

To show that specific hormones were responsible for movements of specific cell types, Dhabhar administered the three hormones, separately or in various combinations, to rats whose adrenal glands had been removed so they couldn't generate their own stress hormones. When the researchers mimicked the pattern of stress-hormone release previously observed in the confined rats, the same immune-cell migration patterns emerged in the rats without adrenal glands. Placebo treatment produced no such effect.

The general pattern, Dhabhar said, was that norepinephrine is released early and is primarily involved in mobilizing all major immune-cell types -- monocytes, neutrophils and lymphocytes -- into the blood. Epinephrine, also released early, mobilized monocytes and neutrophils into the blood, while nudging lymphocytes out into "battlefield" destinations such as skin. And corticosterone, released somewhat later, caused virtually all immune cell types to head out of circulation to the "battlefields."

The overall effect of these movements is to bolster immune readiness. A study published by Dhabhar and his colleagues in 2009 in the Journal of Bone and Joint Surgery assessed patients' recovery from surgery as a function of their immune-cell redistribution patterns during the stress of the operation. Those patients in whom the stress of surgery mobilized immune-cell redistributions similar to those seen in the confined rats in the new study did significantly better afterward than patients whose stress hormones less adequately guided immune cells to appropriate destinations.

The mechanisms Dhabhar has delineated could lead to medical applications, such as administering low doses of stress hormones or drugs that mimic or antagonize them in order to optimize patients' immune readiness for procedures such as surgery or vaccination. "More study will be required including in human subjects, which we hope to conduct, before these applications can be attempted," Dhabhar said. Closer at hand is the monitoring of patients' stress-hormone levels and immune-cell distribution patterns during surgery to assess their surgical prognosis, or during immunization to predict vaccine effectiveness.

The study was funded by the John D. & Catherine T. MacArthur Foundation, the Dana Foundation, the DeWitt Wallace Foundation, the Carl & Elizabeth Naumann Fund and the National Institutes of Health. The medical school's Department of Psychiatry and Behavioral Sciences also supported this work. Dhabhar's co-authors were statistician Eric Neri at Stanford, and neuroendocrinologists at Ohio State University and Rockefeller University.

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The above story is reprinted from materials provided byStanford University Medical Center. The original article was written by Bruce Goldman.

Stanford University Medical Center (2012, June 21). How stress can boost immune system.ScienceDaily. Retrieved April 15, 2013, from http://www.sciencedaily.com­/releases/2012/06/120621223525.htm

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Heart attack risk differs between men and women

Findings on coronary CT angiography (CTA), a noninvasive test to assess the coronary arteries for blockages, show different risk scenarios for men and women, according to a study presented today at the Radiological Society of North America (RSNA). 

Coronary artery disease (CAD) is a narrowing of the blood vessels that supply blood and oxygen to the heart. It is caused by a build-up of fat and other substances that form plaque on vessel walls. According to the Centers for Disease Control and Prevention, heart disease is the leading cause of death for both men and women in the U.S. 

Researchers at the Medical University of South Carolina analyzed the results of coronary CTA on 480 patients, mean age 55, with acute chest pain. Approximately 65 percent of the patients were women, and 35 percent were men. The possibility of acute coronary syndrome was ruled out for each of the patients. 

Using coronary CTA, the researchers were able to determine the number of vessel segments with plaque, the severity of the blockage and the composition of the plaque. 

"The latest CT scanners are able to produce images that allow us to determine whether the plaque is calcified, non-calcified or mixed," said John W. Nance Jr., M.D., currently a radiology resident at Johns Hopkins Hospital in Baltimore, Md. 

By comparing the coronary CTA results with outcome data over a 12.8-month follow-up period, the researchers were able to correlate the extent, severity and type of plaque build-up with the occurrence of major adverse cardiac events, such as a heart attack or coronary bypass surgery. The statistical analysis tested all plaques combined (calcified, non-calcified and mixed) and each individual plaque type separately. 

"We found that the risks for cardiovascular events associated with plaque were significantly different between women and men," Dr. Nance said. 

Within the follow-up period, 70 of the patients experienced major adverse cardiac events, such as death, heart attack, unstable angina or revascularization. In total, 87 major adverse cardiac events occurred among the patients during the follow-up period. 

When the outcome data were correlated with the CTA combined plaque findings, the results indicated that women with a large amount of plaque build-up and extensive atherosclerosis are at significantly greater cardiovascular risk than men. 

Specifically, the risk for major adverse cardiac events was significantly higher in women than in men when extensive plaque of any kind was present or when more than four artery segments were narrowed. 

"This research tells us that extensive coronary plaque is more worrisome in women than the equivalent amount in men," Dr. Nance said. 

However, when analyzing risk factors associated with the presence of individual types of plaque, the risk for major adverse cardiac events was greater in men, compared to women, when their artery segments contained non-calcified plaque. 

Dr. Nance said the new data suggested that the atherosclerotic process, or hardening of the arteries, is not necessarily linear and that more research is needed to better understand the disease. 

"Our research confirms that coronary CTA provides excellent prognostic information that helps identify risk, but there are gender differences that need to be considered," Dr. Nance said.  

Source: Radiological Society of North America [November 30, 2011]

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Study debunks stereotype that men think about sex all day long

Men may think about sex more often than women do, but a new study suggests that men also think about other biological needs, such as eating and sleep, more frequently than women do, as well. 

And the research discredits the persistent stereotype that men think about sex every seven seconds, which would amount to more than 8,000 thoughts about sex in 16 waking hours. In the study, the median number of young men's thought about sex stood at almost 19 times per day. Young women in the study reported a median of nearly 10 thoughts about sex per day. 

As a group, the men also thought about food almost 18 times per day and sleep almost 11 times per day, compared to women's median number of thoughts about eating and sleep, at nearly 15 times and about 8 1/2 times, respectively. 

The college-student participants carried a golf tally counter to track their thoughts about either eating, sleep or sex every day for a week. Each student was assigned to just one type of thought to record. Before receiving the tally counter, they had completed a number of questionnaires and were asked to estimate how often they had daily thoughts about eating, sleeping and sex. 

Overall, a participant's comfort with sexuality was the best predictor for which person would have the most frequent daily thoughts about sex. 

"If you had to know one thing about a person to best predict how often they would be thinking about sex, you'd be better off knowing their emotional orientation toward sexuality, as opposed to knowing whether they were male or female," said Terri Fisher, professor of psychology at Ohio State University's Mansfield campus and lead author of the study. "Frequency of thinking about sex is related to variables beyond one's biological sex." 

Correcting this stereotype about men's sexual thoughts is important, Fisher noted. 

"It's amazing the way people will spout off these fake statistics that men think about sex nearly constantly and so much more often than women do," she said. "When a man hears a statement like that, he might think there's something wrong with him because he's not spending that much time thinking about sexuality, and when women hear about this, if they spend significant time thinking about sex they might think there's something wrong with them." 

The study appears online and is scheduled for publication in the January issue of the Journal of Sex Research. 

The study involved 163 female and 120 male college students between the ages of 18 and 25 who were enrolled in a psychology research participation program. Of those, 59 were randomly assigned to track thoughts about food, 61 about sleep and 163 about sex. Most students were white and self-identified as heterosexual. The college-student sample made it comparable to previous research and involved an age group at which gender differences in sexuality are likely at their peak. 

Before the thought-tracking began, the participants completed a number of questionnaires. These included a sexual opinion survey to measure a positive or negative emotional orientation toward sexuality (erotophilia vs. erotophobia); a sociosexual orientation inventory measuring attitudes about sex and tracking sexual behavior and levels of desire; a social desirability scale to measure respondents' tendency to try to appear socially acceptable; and an eating habits questionnaire and sleepiness scale. They also were asked to estimate how many times in an average day that they thought about sleeping, eating and sex. 

Researchers then gave each student a tally counter device and told those assigned to the sexual thoughts condition to click the device to maintain a count their of thoughts about sex. They were told to count a thought about any aspect of sex: sexual activity of any kind, fantasies and erotic images, sexual memories and any arousing stimuli. 

Others were instructed to use the device to record thoughts about eating that included food, hunger, cravings, snacking or cooking, and thoughts about sleep that included dreaming, sleeping, napping, going to bed or needing rest. 

The questions about food and sleep were designed to mask the true intent of the study's focus on thoughts about sex, Fisher said. However, the results about these additional thoughts provided important information about differences in thinking among males and females. 

"Since we looked at those other types of need-related thoughts, we found that it appears that there's not just a sex difference with regard to thoughts about sex, but also with regard to thoughts about sleep and food," she said. "That's very significant. This suggests males might be having more of these thoughts than women are or they have an easier time identifying the thoughts. It's difficult to know, but what is clear is it's not uniquely sex that they're spending more time thinking about, but other issues related to their biological needs, as well." 

And when all of those thoughts were taken into account in the statistical analysis, the difference between men and women in their average number of daily thoughts about sex wasn't considered any larger than the gender differences between thoughts about sleep or thoughts about food. 

In raw numbers, male participants recorded between one and 388 daily thoughts about sex, compared to the range of female thoughts about sex of between one and 140 times per day. 

"For women, that's a broader range than many people would have expected. And there were no women who reported zero thoughts per day. So women are also thinking about sexuality," Fisher said. 

The questionnaire data offered some additional clues about the influences on sexual thoughts. When all participants were analyzed together, those measuring the highest in erotophilia – or comfort with their sexuality – were the most likely to think more frequently about sex. 

But when the analysis considered males and females separately, no single variable – erotophilia score, unrestrictive attitudes about sex or a lack of desire to be socially acceptable – could be defined as a predictor of how often men think about sex. 

But for women, the erotophilia score remained a good predictor of more frequent sexual thoughts. On the other hand, women who scored high on the desire to be socially acceptable were more likely to think less frequently about sex. 

"People who always give socially desirable responses to questions are perhaps holding back and trying to manage the impression they make on others," Fisher explained. "In this case, we're seeing that women who are more concerned with the impression they're making tend to report fewer sexual thoughts, and that's because thinking about sexuality is not consistent with typical expectations for women." 

The participants' estimates about how often they thought each day about eating, sleeping and sex were all much lower than the actual number of thoughts they recorded. This suggested to Fisher that previous research in this area – especially on thoughts about sex – was weak because almost all previous studies were based on participants' retrospective estimates about how often they thought about sex. 

"There's really no good reason that our society should have believed that men are thinking so much more about sex than women. Even the research that had been done previously doesn't support the stereotype that men are thinking about sex every seven seconds," she said. 

Fisher conducted the research with undergraduate Ohio State-Mansfield students Zachary Moore and Mary-Jo Pittenger. Both have since graduated. 

Source: Ohio State University [November 28, 2011]

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Study IDs new genetic links to impulsivity, alcohol problems in men

Being impulsive can lead us to say things we regret, buy things we really don't need, engage in behaviors that are risky and even develop troublesome addictions. But are different kinds of hastiness and rashness embedded in our DNA? A new study suggests the answer is yes -- especially if you're a man. 

The research, led by University of Nebraska-Lincoln assistant professor of psychology Scott Stoltenberg, found links between impulsivity and a rarely researched gene called NRXN3. The gene plays an important role in brain development and in how neurons function. 

The newly discovered connection, which was more prevalent among men than women in the study, may help explain certain inclinations toward alcohol or drug dependence, Stoltenberg said. 

"Impulsivity is an important underlying mechanism in addiction," he said. "Our finding that NRXN3 is part of the causal pathway toward addiction is an important step in identifying the underlying genetic architecture of this key personality trait." 

For the study, researchers measured impulsivity levels in nearly 450 participants -- 65 percent women, 35 percent men -- via a wide range of tests. Then, they compared those results with DNA samples from each participant. They found that impulsivity was significantly higher in those who regularly used tobacco or who had alcohol or drug problems. 

The results, interestingly, also came down along gender lines. In men, two connections clearly emerged; first, between a particular form of the NRXN3 gene and attentional impulsivity, and second, between another NRXN3 variant and alcohol problems. The connections for women, meanwhile, were much weaker. 

Stoltenberg said the gender-specific results are a rich area for further study. 

"We can't really say what causes these patterns of association to be different in men and women. But our findings will be critical as we continue to improve our understanding of the pathways from specific genes to health-risk behaviors," he said. 

The researchers were interested in impulsivity because the trait can predispose people to any number of behavioral problems -- addictions, behavior control, failing to plan ahead or think through consequences of actions -- and settled on the role of NXRN3 from previous, recent studies. 

While the results add important new evidence to the genetic role in impulsivity and, in turn, its role in substance abuse, researchers were careful to not claim a perfect cause-and-effect relationship. Impulsivity may interact with sensitivity to alcohol, for one example, or anxiety, for another, to create complex pathways to substance use problems in both men and women. 

"If you're working to explain how genes are associated with something like (substance) dependence, you have to connect a lot of dots," Stoltenberg said. "There's a big gap between genes and a substance use disorder. Impulsivity is one factor to such problems -- not the only factor." 

Source: University of Nebraska-Lincoln [November 16, 2011]

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Low risk? Women and young men responsible for large portion of heart attacks

In a contemporary cohort of acute heart attack patients, 70 percent of the patients were unaware they had coronary heart disease (CHD) prior to the event and 60 percent of those patients were women or young men. However, these two subgroups are less likely to qualify for aggressive preventive therapy and, therefore, do not receive preventive medications that could reduce the heart attack risk, according to a study being presented at the American Heart Association (AHA) scientific sessions in Orlando, Fla., on Nov. 16. 

"For those patients with known coronary disease, the evidence and guidelines are fairly clear about the benefit of aggressive medical therapy, including an aspirin and statin, regardless of your age or gender," says Michael Miedema, MD, a cardiology fellow at the University of Minnesota working in collaboration with researchers at the Minneapolis Heart Institute® at Abbott Northwestern Hospital in Minneapolis. "However, for patients without known coronary disease, the optimal approach is much less clear. We currently only treat high-risk patients but our data show that women and young males, who rarely qualify as high risk, make up a substantial portion of the current heart attack population." 

The researchers assessed the Minneapolis Heart Institute's Level One heart attack program to better understand the presence of premature CHD in patients without a prior history of CHD presenting to their facility with ST-elevation myocardial infarction (STEMI), or an acute heart attack. 

From March 2003 to January 2010, 3,038 patients were evaluated, and 70.3 percent did not have previously diagnosed CHD prior to their heart attack and 41.7 percent qualified as premature. Despite similar rates of high cholesterol, patients with premature disease (men 55 years or younger, women 65 years or younger) were approximately half as likely to be on a statin prior to their heart attack (10.45 vs. 19.4 percent). Aspirin and combination therapy were being used significantly less often as well. 

The Framingham Risk Score is the most commonly used risk calculator, using the patient's age, gender and risk factors such as cholesterol and blood pressure to determine the potential risk for a cardiac event. However, Miedema suggests that the Framingham Risk Score is heavily weighted toward age and gender. 

"If you're an older male, you're much more likely to qualify for preventive therapy while females and younger males often do not meet criteria despite similar risk factors," Miedema says. "While older males are still the most likely group to have heart attacks, we have shown that women and patients with premature disease make up a substantial portion of the heart attacks we are seeing and very few of these patients are on the medications which research has shown to prevent heart attacks. Better methods of risk assessment could potentially allow us to target more people truly at high risk for an event and avoid excessive treatment of those who are low risk." 

Based on the study findings, the study authors concluded without improved preventive care strategies, the possibility of further decreasing the rate of STEMIs in the United States may be "challenging."  

Source: Minneapolis Heart Institute Foundation [November 16, 2011]

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