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Murail S.,KTH Royal Institute of Technology | Wallner B.,KTH Royal Institute of Technology | Trudell J.R.,Stanford University | Bertaccini E.,Stanford University | And 2 more authors.
Biophysical Journal | Year: 2011

Cys-loop receptors constitute a superfamily of ion channels gated by ligands such as acetylcholine, serotonin, glycine, and γ-aminobutyric acid. All of these receptors are thought to share structural characteristics, but due to high sequence variation and limited structure availability, our knowledge about allosteric binding sites is still limited. These sites are frequent targets of anesthetic and alcohol molecules, and are of high pharmacological importance. We used molecular simulations to study ethanol binding and equilibrium exchange for the homomeric α1 glycine receptor (GlyRα1), modeled on the structure of the Gloeobacter violaceus pentameric ligand-gated channel. Ethanol has a well-known potentiating effect and can be used in high concentrations. By performing two microsecond-scale simulations of GlyR with/without ethanol, we were able to observe spontaneous binding in cavities and equilibrium ligand exchange. Of interest, it appears that there are ethanol-binding sites both between and within the GlyR transmembrane subunits, with the intersubunit site having the highest occupancy and slowest exchange (∼200 ns). This model site involves several residues that were previously identified via mutations as being crucial for potentiation. Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors. © 2011 by the Biophysical Society.


Yoluk O.,KTH Royal Institute of Technology | Bromstrup T.,KTH Royal Institute of Technology | Bromstrup T.,University of Stockholm | Bertaccini E.J.,Palo Alto Veterans Affairs Health Care System | And 3 more authors.
Biophysical Journal | Year: 2013

Improving our understanding of the mechanisms and effects of anesthetics is a critically important part of neuroscience. The currently dominant theory is that anesthetics and similar molecules act by binding to Cys-loop receptors in the postsynaptic terminal of nerve cells and potentiate or inhibit their function. Although structures for some of the most important mammalian channels have still not been determined, a number of important results have been derived from work on homologous cationic channels in bacteria. However, partly due to the lack of a nervous system in bacteria, there are a number of questions about how these results relate to higher organisms. The recent determination of a structure of the eukaryotic chloride channel, GluCl, is an important step toward accurate modeling of mammalian channels, because it is more similar in function to human Cys-loop receptors such as GABAAR or GlyR. One potential issue with using GluCl to model other receptors is the presence of the large ligand ivermectin (IVM) positioned between all five subunits. Here, we have performed a series of microsecond molecular simulations to study how the dynamics and structure of GluCl change in the presence versus absence of IVM. When the ligand is removed, subunits move at least 2 Å closer to each other compared to simulations with IVM bound. In addition, the pore radius shrinks to 1.2 Å, all of which appears to support a model where IVM binding between subunits stabilizes an open state, and that the relaxed nonIVM conformations might be suitable for modeling other channels. Interestingly, the presence of IVM also has an effect on the structure of the important loop C located at the neurotransmitter-binding pocket, which might help shed light on its partial agonist behavior. © 2013 Biophysical Society.


News Article | November 25, 2016
Site: www.biosciencetechnology.com

The amount of a particular chemical in a particular part of your brain predicts your ability to simultaneously hang onto several bits of information in your working memory, a Stanford University School of Medicine scientist and his University of California-Davis collaborators have learned. The discovery helps to clarify at least one aspect of the brain’s mysterious ways, and could someday help guide therapies for those whose working memory could stand improvement. Working memory is the brain function that lets you carry on a phone conversation while adding three numbers in your head and remembering that you need to steer the car onto the freeway exit in about two minutes — all this time not forgetting who you’re talking to. Like a computer’s RAM, working memory serves as a buffer where information, derived from the senses or retrieved from long-term memory, can be temporarily placed so the conscious brain can process it. It’s tied to assessments of cognitive capacity such as IQ, and to real-world outcomes such as academic performance. As most people eventually find out, working memory declines with age. “Deficits in working memory also characterize various neuropsychiatric conditions and are particularly evident in schizophrenia,” said Jong Yoon, M.D., an assistant professor of psychiatry and behavioral sciences at Stanford and a psychiatrist at the Palo Alto Veterans Affairs Health Care System who sees numerous patients with this disorder. Yoon is the lead author of the study, published Nov. 16 in the Journal of Neuroscience. The study teases apart three key components of working memory and shows that one component, but not the other two, is tied to the amount of a chemical called GABA in a brain area known as the dorsolateral prefrontal cortex, or DLPFC. Richard Maddock, M.D., a professor of psychiatry at UCD, is senior author of the study. This component, referred to as load, is a measure of the number of separate bits of information a person’s working memory can store at the same time. A second component, maintenance, denotes how long information can be stored in working memory before it’s lost. A third, distraction resistance, gauges how well an individual’s working memory holds onto information in the face of interfering stimuli. The DLPFC, a broad swath of neural tissue on the forebrain surface, has been shown in animal studies and in observations of brain-damaged patients to be integral to high-level executive functions in the brain, such as planning, prioritizing and avoiding distractions. It has likewise been strongly implicated in working memory. The DLPFC orchestrates activity in numerous distant centers throughout the brain, including the visual cortex, which is located near the brain’s surface but in the hindbrain. “No previous study has ever pinpointed GABA’s link with working memory in humans,” said Yoon. “Working memory is a complex process, requiring coordinated activity in centers throughout the brain. Yet, remarkably, the amount of this one chemical in a single part of the brain accounts for close to one-third of the variance in individuals’ load capacity.” In the study, 23 healthy participants ages 19-32 were subjected to batteries of tests of working memory. Yoon reasoned that different components of working memory would involve different neurotransmitter inputs. So he devised working-memory tests that separated the measurement of load, maintenance and distraction resistance. Participants repeated several related tasks. In the simplest, they were shown a drawing of a face and then, after a two-second delay, shown a second face and asked whether it was the same as or different from the first one. Variations of this task — initially presenting two faces instead of just one; lengthening the intervening delay; or displaying a different, irrelevant face between the initial and final displays — tested load, maintenance and distraction resistance, respectively. The investigators compared individuals’ error rates on the simple version of the task with outcomes on tasks taxing one or another working-memory component more heavily. The smaller the deterioration in performance on a test of a particular working-memory component, the greater the individual’s capacity regarding that component was judged to be. Using an advanced imaging method, the scientists measured GABA levels in the DLPFC and, for comparison, in the visual cortex. GABA, secreted by nerve cells, is an inhibitory neurotransmitter: Its uptake by other nerve cells inhibits their firing. Yoon and his associates also measured levels of an excitatory neurotransmitter, glutamate. By far the two most abundant neurotransmitters in the brain, GABA and glutamate are considered to be that organ’s stop and go signals. Individuals with higher levels of GABA in their DLPFC performed better on tests of their load capacity — the ability to juggle more bits of information — the researchers found. In contrast, no significant association emerged linking GABA levels in the DLPFC to maintenance or to distraction resistance, or tying participants’ load capacity to GABA levels in the visual cortex. Nor did imaging reveal any connection between performance on tests of load capacity and levels of glutamate in the DLPFC. Schizophrenic patients, Yoon said, are known to be deficient in an enzyme essential to GABA production. So, drugs that boost GABA levels or function in the brain might prove helpful in restoring their impaired working memory. He plans to test this hypothesis.


Brooks J.O.,University of California at Los Angeles | Bearden C.E.,University of California at Los Angeles | Hoblyn J.C.,Palo Alto Veterans Affairs Health Care System | Woodard S.A.,Palo Alto Veterans Affairs Health Care System | And 2 more authors.
Bipolar Disorders | Year: 2010

Objective: Reports of sustained attention deficits in the euthymic phase of bipolar disorder have been variable, and have yet to be related to cerebral metabolism. In the present study, we evaluated relationships between cognitive performance deficits and resting cerebral metabolism in euthymic older adults with bipolar disorder.Methods: Sixteen older (mean age 58.7 years) euthymic outpatients with bipolar disorder (10 type I, 6 type II; 44% female) and 11 age-matched healthy controls received resting positron emission tomography with 18fluorodeoxyglucose and, within 10 days, the Conners' Continuous Performance Test-II, a commonly used measure of sustained attention and inhibitory control.Results: Bipolar disorder patients had significantly more omission errors (z = 2.53, p = 0.01) and a trend toward more commission errors (z = 1.83, p < 0.07) than healthy controls. Relative to healthy controls, among bipolar disorder subjects commission errors were more strongly related to inferior frontal gyrus [Brodmann area (BA) 45/47] hypometabolism and paralimbic hypermetabolism. In bipolar disorder subjects, relative to controls, omission errors were more strongly related to dorsolateral prefrontal (BA 9/10) hypometabolism and greater paralimbic, insula, and cingulate hypermetabolism.Conclusions: In older adults with bipolar disorder, even during euthymia, resting-state corticolimbic dysregulation was related to sustained attention deficits and inhibitory control, which could reflect the cumulative impact of repeated affective episodes upon cerebral metabolism and neurocognitive performance. The relative contributions of aging and recurrent affective episodes to these differences in bipolar disorder patients remain to be established. © 2010 John Wiley and Sons A/S.


Brooks III J.O.,University of California at Los Angeles | Hoblyn J.C.,Palo Alto Veterans Affairs Health Care System | Ketter T.A.,Stanford University
Psychiatry Research - Neuroimaging | Year: 2010

Findings from previous research on the neural substrates of mania have been variable, in part because of heterogeneity of techniques and patients. Though some findings have been replicated, the constellation of neurophysiological changes has not been demonstrated simultaneously. We sought to determine resting state cerebral metabolic changes associated with relatively severe acute mania. Resting positron emission tomography with 18fluorodeoxyglucose was performed in bipolar disorder patients with severe mania and in healthy controls. Statistical parametric mapping was used to determine regions of differential metabolism. Relative to controls, bipolar disorder patients with mania exhibited significantly decreased cerebral metabolism in both the dorsolateral prefrontal regions and the precuneus. Conversely, manic patients exhibited significant hypermetabolism in the parahippocampal complex, temporal lobe, anterior cingulate, and subgenual prefrontal cortex compared with controls. These results demonstrate simultaneous resting limbic/paralimbic hypermetabolism and prefrontal hypometabolism during mania. The findings support the hypothesis of corticolimbic dysregulation as a crucial contributor to the pathophysiology of bipolar disorder. © 2009 Elsevier Ireland Ltd.


News Article | November 1, 2016
Site: www.eurekalert.org

PISCATAWAY, NJ - Young adults with symptoms of alcohol dependence may see health effects late in life--even decades after conquering their problem drinking, according to a study in the November 2016 issue of the Journal of Studies on Alcohol and Drugs. Researchers found that, of 664 U.S. male veterans, those who had symptoms of alcohol dependence for at least five years in young adulthood generally had poorer physical and mental health by the time they were in their 60s. And that was true even if they'd gotten control over their drinking problems by the age of 30. The findings are surprising, said lead researcher Randy Haber, Ph.D., of the Palo Alto Veterans Affairs Health Care System, in Menlo Park, Calif. It's clear that people's lives improve when alcohol dependence goes into remission, Haber pointed out, but it is not clear whether there are hidden consequences that remain after heavy drinking has ceased. For instance, evidence shows that both brain and body are affected by excessive drinking, but we don't know how long these effects last. The new findings suggest that years of alcohol dependence during young adulthood result in silent but "permanent" injuries that, in later life, appear to result in serious health problems, according to Haber. The findings are based on men taking part in a larger study of Vietnam-era veterans. Haber's team focused on 368 men who did not report any symptoms of alcohol dependence at any point in adulthood, 221 who had at least three symptoms of dependence in young adulthood and middle-age and 75 who had symptoms in early adulthood but not after the age of 30. Overall, the study found that men who had alcohol dependence symptoms for at least five years in early adulthood scored lower on standard measures of both physical and mental health once they'd reached their 60s. For example, those with alcohol dependence in young adulthood had, on average, three medical conditions in later life whereas those without this history reported two. In addition, their scores on a depression scale were about twice as high. Most important, these effects were seen even among men who'd been free of dependence symptoms for several decades. The reasons are unclear. But, Haber said, other studies have shown that chronic drinking may injure parts of the brain involved in emotional regulation, self-control and decision making. It's possible, he noted, that years of alcohol exposure in early adulthood could have lasting effects on those brain areas. Still, Haber stressed that this study is reporting "averages" and not what any one person is destined for. He said that people who not only quit problem drinking but also turn their lifestyle around--eating well, not smoking and just generally "taking care of themselves"--will likely see health benefits that last into late life. Plus, he said, there is a "whole body of literature" showing that when people with alcohol dependence go into recovery, their lives improve in almost every area. "If you have entered (alcohol dependence) recovery, keep going," Haber said. "Live your life to its fullest." Haber, J. R., Harris-Olenak, B., Burroughs, T., & Jacob, T. (November 2016). Residual effects: Young adult diagnostic drinking predicts late-life health outcomes. Journal of Studies on Alcohol and Drugs, 77(6), 859-867. To arrange an interview with Randy Haber, Ph.D., please contact Michael Hill-Jackson at the VA Office of Public Affairs at 650-444-7380 or michael.hill-jackson@va.gov. The Journal of Studies on Alcohol and Drugs is published by the Center of Alcohol Studies at Rutgers, The State University of New Jersey. It is the oldest substance-related journal published in the United States. To learn about education and training opportunities for addiction counselors and others at the Rutgers Center of Alcohol Studies, please visit AlcoholStudiesEd.rutgers.edu.


Metcalf R.A.,Stanford University | Bashey S.,Stanford University | Wysong A.,Stanford University | Kim J.,Stanford University | And 3 more authors.
American Journal of Surgical Pathology | Year: 2013

Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients. Copyright © 2013 by Lippincott Williams & Wilkins.


Haber J.R.,Palo Alto Veterans Affairs Health Care System | Grant J.D.,University of Washington | Jacob T.,Palo Alto Veterans Affairs Health Care System | Koenig L.B.,Kutztown University of Pennsylvania | Heath A.,University of Washington
Journal of Studies on Alcohol and Drugs | Year: 2012

Objective: The alcoholism research literature has long reported a significant, reliable, and inverse association between alcohol use disorders and religion/spirituality (R/S), and this is also evident in the period of highest risk-adolescence and young adulthood. In the treatment area, both clinical and mutual-help programs for alcohol use disorders often include a spiritual component, and outcome studies validate the efficacy of such programs. Even so, the alcoholism-R/S relationship is little understood. Method: The current study examined data from an existing sample of 4,002 female adolescents/young adults and their families. Data analyses examined five demographic, nine R/S, and eight risk-factor variables as predictors of five alcohol milestones: initial drink, first intoxication, regular use, heavy consumption, and alcohol dependence. Results: Results affirmed the known association between alcoholism risk factors and alcohol use milestones and also found moderate to strong associations between most R/S variables and these risk factors and milestones. A multivariate model simultaneously examining both sets of variables found that specific risk factors and specific R/S variables remained significant predictors of alcohol use milestones after accounting for all other variables. Mediation and moderation tests did not find evidence that R/S accounted for or qualified the relationship between alcohol risk factors and alcohol milestones. Conclusions: This study confirmed the multidimensional role of R/S influences within the etiological network of alcoholism risk and protective factors in adolescents/young adults and found R/S dimensions to be independent and substantial infl uences on alcohol use disorders rather than mediators or moderators of other risks.


Purpose: Obesity presents many challenges to the anesthesiologist, including poorly fitting blood pressure (BP) cuffs due to the conical shape of the upper arm. The aim of this study was to determine the accuracy of noninvasive BP readings, obtained from a noninvasive BP cuff using various cuff locations and wrapping techniques, compared with invasive intra-arterial BP readings. Methods: Thirty American Society of Anesthesiologists physical status I-III obese (body mass index > 30 kg·m−2) individuals undergoing non-cardiac surgery were enrolled in this observational study. Serial oscillometric noninvasive BP (NIBP) measurements were taken in the patients’ forearm and upper arm with two different wrapping formations (one following the contour of the upper arm, the other keeping cuff edges parallel). These NIBP measurements were compared with invasive arterial blood pressure (ABP) measurements taken from the ipsilateral radial artery. The precision and bias of the NIBP and ABP measurements were determined using Bland-Altman analysis. Analysis of variance and Welch’s t test were used to determine between-group differences in bias. Results: There was poor agreement between the ABP measurements and all types of NIBP measurements. Each of our study participants had a least one NIBP parameter (mean arterial pressure, systolic BP, or diastolic BP) that was > 10 mmHg different than the corresponding ABP parameter. Upper arm BP measurements showed a statistically insignificant trend toward underestimating ABP. For all cuff positions and wrapping techniques, systolic BP offered the best agreement between NIBP and ABP measurements. Conclusions: All the forms of NIBP cuff orientation studied had unacceptable precision and bias compared with invasive ABP measurements. When patient and/or surgical conditions necessitate accurate BP monitoring, direct arterial measurement should be considered over NIBP measurements in obese patients. © 2015, Canadian Anesthesiologists' Society.


News Article | November 2, 2016
Site: www.sciencedaily.com

Young adults with symptoms of alcohol dependence may see health effects late in life -- even decades after conquering their problem drinking, according to a study in the November 2016 issue of the Journal of Studies on Alcohol and Drugs. Researchers found that, of 664 U.S. male veterans, those who had symptoms of alcohol dependence for at least five years in young adulthood generally had poorer physical and mental health by the time they were in their 60s. And that was true even if they'd gotten control over their drinking problems by the age of 30. The findings are surprising, said lead researcher Randy Haber, Ph.D., of the Palo Alto Veterans Affairs Health Care System, in Menlo Park, Calif. It's clear that people's lives improve when alcohol dependence goes into remission, Haber pointed out, but it is not clear whether there are hidden consequences that remain after heavy drinking has ceased. For instance, evidence shows that both brain and body are affected by excessive drinking, but we don't know how long these effects last. The new findings suggest that years of alcohol dependence during young adulthood result in silent but "permanent" injuries that, in later life, appear to result in serious health problems, according to Haber. The findings are based on men taking part in a larger study of Vietnam-era veterans. Haber's team focused on 368 men who did not report any symptoms of alcohol dependence at any point in adulthood, 221 who had at least three symptoms of dependence in young adulthood and middle-age and 75 who had symptoms in early adulthood but not after the age of 30. Overall, the study found that men who had alcohol dependence symptoms for at least five years in early adulthood scored lower on standard measures of both physical and mental health once they'd reached their 60s. For example, those with alcohol dependence in young adulthood had, on average, three medical conditions in later life whereas those without this history reported two. In addition, their scores on a depression scale were about twice as high. Most important, these effects were seen even among men who'd been free of dependence symptoms for several decades. The reasons are unclear. But, Haber said, other studies have shown that chronic drinking may injure parts of the brain involved in emotional regulation, self-control and decision making. It's possible, he noted, that years of alcohol exposure in early adulthood could have lasting effects on those brain areas. Still, Haber stressed that this study is reporting "averages" and not what any one person is destined for. He said that people who not only quit problem drinking but also turn their lifestyle around -- eating well, not smoking and just generally "taking care of themselves" -- will likely see health benefits that last into late life. Plus, he said, there is a "whole body of literature" showing that when people with alcohol dependence go into recovery, their lives improve in almost every area. "If you have entered (alcohol dependence) recovery, keep going," Haber said. "Live your life to its fullest."

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