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In response to an increased awareness of sensitization issues with amide bond forming agents, a detailed toxicological analysis of this broad family of reagents was undertaken which led to a quantitative ranking of the sensitization potential of these commonly used compounds. This data enables occupational toxicologists to guide the safer use of these reagents in the laboratory, but it also provides an opportunity for chemists working on reaction development, optimization and scale‐up. To illustrate this, one of the strongest sensitizers, EDAC, is compared with the performance of one of the weakest, TCFH, showing the potential of this data for minimizing risks for researchers when using this family of reagents. [ABSTRACT FROM AUTHOR]

Neurons in the periaqueductal gray (PAG) integrate negative emotions with the autonomic, neuroendocrine, and immune systems to facilitate responses to threat. Modern functional track tracing in animals and optogenetic and chemogenetic techniques show that the PAG is a rich substrate for the integration of active and passive responses to threat. In humans, the same regions of the PAG that give rise to adaptive anger/fight, fear/panic, depression/shutdown, pain, and predatory behaviors in response to challenging situations or overwhelming threats can become activated pathologically, resulting in symptoms that resemble those of psychiatric disorders. This review coalesces human and animal studies to link PAG neuropathways to specific elements of psychiatric diagnoses. The insights gained from this overview may eventually lead to new therapeutic interventions. New animal/rodent data that utilize modern functional track tracing with optogenetics and designer receptors exclusively activated by designer drugs (DREADDS) technology show that the periaqueductal gray (PAG) is a rich substrate for the integration of active and passive responses to threat. Human data suggest that the PAG may be dysregulated in psychopathology that drives maladaptive behavior. The neural circuit that connects the frontal cortex, amygdala, PAG, and pons medulla is hypothesized to be a focal point for psychopathology where stress and threat converge to usurp decision making for stimulus-appropriate motivated behavior. [ABSTRACT FROM AUTHOR]

Paxilline indole diterpenes have been a subject of scientific inquiry for over 30 years due to their diverse biological activities and unique structural features. These efforts resulted in a multitude of synthetic approaches and a dozen completed synthesis. Here, we discuss our contributions to this area that culminated in an 11-step synthesis of (±)-emindole SB. [ABSTRACT FROM AUTHOR]

A synthetic approach to paxilline indole diterpenes is described. The route to the pentacyclic core relies on a new regioselective alkenylation of ketones and a tandem radical addition-aldol reaction sequence to access vicinal quaternary stereocenters. Emindole SB, the simplest member of the family, is synthesized in 11 steps from commercially available material to demonstrate the application of this approach. [ABSTRACT FROM AUTHOR]

Objective: Considering that epidemiological studies show that suicide rates in many countries are highest in the spring when vitamin D status is lowest, and that low vitamin D status can affect brain function, we sought to evaluate if a low level of 25-hydroxyvitamin D [25(OH)D] could be a predisposing factor for suicide. Method:We conducted a prospective, nested, case-control study using serum samples stored in the Department of Defense Serum Repository. Participants were previously deployed active duty US military personnel (2002-2008) who had a recent archived serum sample available for analysis. Vitamin D status was estimated by measuring 25(OH) D levels in serum samples drawn within 24 months of the suicide. Each verified suicide case (n = 495) was matched to a control (n = 495) by rank, age and sex. We calculated odds ratio of suicide associated with categorical levels (octiles) of 25(OH) D, adjusted by season of serum collection. Findings: More than 30% of all subjects had 25(OH)D values below 20 ng/mL. Although mean serum 25(OH)D concentrations did not differ between suicide cases and controls, risk estimates indicated that subjects in the lowest octile of season-adjusted 25(OH)D (<15.5 ng/mL) had the highest risk of suicide, with subjects in the subsequent higher octiles showing approximately the same level of decreased risk (combined odds ratio compared to lowest octile =0.49; 95% C.I.: 0.315-0.768). Conclusions: Low vitamin D status is common in active duty service members. The lowest 25(OH)D levels are associated with an increased risk for suicide. Future studies could determine if additional sunlight exposure and vitamin D supplementation might reduce suicide by increasing 25(OH) D levels. [ABSTRACT FROM AUTHOR]

Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism. [ABSTRACT FROM AUTHOR]

Objective: Alcoholism and aggression have each been associated with neurochemical measurements suggestive of decreased serotonin synaptic transmission. We measured densities of the serotonin transporter (SERT) in a moderate-sized sample of alcoholic patients who were assessed for aggressive characteristics. Methods: Thirty alcoholic inpatients and 18 healthy controls received a PET scan with [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile. The alcoholic inpatients were classified as aggressive or nonaggressive based on a comparison between the top third and bottom third scores on the Buss–Durkee Hostility Index. Results: Using a pixel-wise comparison, no brain region showed significant alterations in SERT binding among the 3 groups of subjects (aggressive alcoholic subjects, nonaggressive alcoholic subjects, and healthy controls) or between the combined alcoholic group and healthy controls. None of the clinical measures (including measures of aggression) correlated with SERT binding in the alcoholic subjects. Conclusion: Contrary to prior imaging reports using the nonselective ligand [123I] β-CIT, we found no significant alterations of SERT density in alcoholic patients. [ABSTRACT FROM AUTHOR]

In an earlier study, we reported that some perpetrators of domestic violence evidenced exaggerated fear-related responses to the panicogenic agent sodium lactate. In the current study, we employed positron emission tomography (PET) to investigate our hypothesis that there are differences in the neural structures and/or pathways that mediate and control the expression of fear-induced aggression in perpetrators of domestic violence. Regional cerebral glucose metabolism was measured in eight male perpetrators of domestic violence who fulfilled DSM-III-R criteria for alcohol dependence (DV-ALC), 11 male participants who fulfilled DSM-III-R criteria for alcohol dependence and had no history of interpersonal aggression (ALC) and 10 healthy male participants who did not fulfill criteria for any DSM-III-R axis I diagnosis and had no history of interpersonal aggression (HCS). DV-ALC had a significantly lower mean glucose uptake in the right hypothalamus compared to ALC and HCS. Correlations were performed between measures of glucose utilization in the brain structures involved in fear-induced aggression. The comparison of DV-ALC to HCS and to ALC differed in six and seven comparisons, respectively, involving various cortical and subcortical structures. HCS and ALC differed between the left thalamus and the left posterior orbitofrontal cortex. These PET findings show that some perpetrators of domestic violence differ from control participants in showing lower metabolism in the right hypothalamus and decreased correlations between cortical and subcortical brain structures. A possible psychological covariate of these changes in regional activity might be fear-induced aggression, but this hypothesis should be examined in larger study groups that undergo provocation during imaging. [Copyright &y& Elsevier]

Perpetrators of domestic violence describe symptoms that are compatible with exaggerated autonomic arousal at the time of the domestic violence. This inappropriate arousal may be reflected in altered heart rate regulation. If heart rate is systematically regulated by vagal mechanisms, then increases in heart rate should correlate with decreases in cardiac vagal activity, as indexed by respiratory sinus arrhythmia (RSA). We hypothesized that perpetrators of domestic violence have an alteration in heart rate regulation. To test this hypothesis we compared the results of a postural shift performed on perpetrators, healthy volunteers, and nonviolent alcoholics. Results showed there were no significant differences in heart rate, RSA, or catecholamines. However, the significant inverse relationship between posture-elicited changes in RSA and heart rate present in the healthy volunteers was not found in perpetrators. These differences in the covariation between heart rate and RSA may represent differences in the neural regulation of heart rate and may be related to difficulties in controlling autonomic state. [ABSTRACT FROM AUTHOR]

Disturbances in central nervous system serotonin (5-HT) have been implicated in the pathophysiology of alcoholism. To test the hypothesis that increasing 5-HT function could promote treatment compliance, we randomized patients who had completed a 5-week inpatient treatment program for alcoholism to receive either buspirone or placebo for 1 year. Ten of the 49 patients remained in the study for the entire year. The days to relapse did not differ significantly between patients receiving buspirone or placebo. Regardless of the medication, late-onset alcoholics had a longer time to relapse than early-onset alcoholics. Cerebrospinal fluid showed that patients with high concentrations of both the 5-HT metabolite, 5-hydroxyindoleacetic acid, and the dopamine metabolite, homovanillic acid, were more likely to relapse, compared with patients with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid. [ABSTRACT FROM AUTHOR]

Chronic excessive alcohol consumption can significantly disturb the hypothalamic control of glucose metabolism; however, the mechanism and clinical significance of this disturbance are poorly understood. We used 2-deoxy-o-glucose (2-DG), which produces intracellular glucoprivation, to compare neurochemical, physiological, and behavioral responses to glucoprivic stress between alcoholics abstinent for 3 weeks and healthy volunteers. Twenty-six male alcoholics and 15 male healthy volunteers received intravenous infusions of placebo, 12.5 mg/kg, and 25.0 mg/kg of body weight of 2-DG over 30 min on three separate days, following a random-ordered, double-blind procedure. Minimal effects were obsewed following administration of the 12.5 mg/kg of body weight dose of 2-DG. Following 25.0 mg/kg, alcoholics showed both exaggerated ACTH and cortisol responses and greater increases in caloric intake when compared with controls. Although anxiety, desire to consume alcohol, plasma progesterone, and sympathetic and adrenal medullary activity all increased following 2-DG, these responses did not differ between alcoholics and controls. The present findings suggest certain specificity for the exaggerated hypothalamic and adrenocortical responses to mild glucoprivic stress in 3-week-abstinent alcoholics. [ABSTRACT FROM AUTHOR]

In order to characterize changes in the presenting symptomatology and treatment of anorexia nervosa (AN), the hospital charts of 76 anorexia nervosa patients were reviewed form three time periods: (I) 1958–1962, (II) 1969–1972, and (III) 1978–1982. in period I, 92% of the patient were admitted to a medicines service, whereas in period III, 92% were admitted to psychiatry. Age of onset, percent mean weight for height upon admission, and reported frequencies of laxative use and vomiting showed no statistical differences among the periods. Length of hospital stay and weight gained during hospitalization increased significantly during period III, with similar stays occurring for both vomiters and restrictors. Between periods I and III the number of medical diagnostic studies decreased while the frequency of behavioral therapies and use of antidepressant medication increased. During the past 25 years, theories of etiology and approaches to treatment of anorexia nervosa have become increasingly psychiatric. We postulate that the apparent increasing incidence of AN may partially be attributable to an underdiagnosis of AN by medical services in the past. [ABSTRACT FROM AUTHOR]

Examines the central serotonergic functions in subgroups of alcoholics and in healthy comparison subjects. Effects of m-Chlorophenylpiperazine elicited subtype-related differential on alcoholics; Increase in plasma adrenocorticotropic hormone response in healthy individuals; Complexity of the biochemical events mediating clinical changes in schizophrenia.

Determines whether the addition of chloride to a lactate infusion would reduce the frequency of panic attacks. Induction of panic attacks by sodium lactate; Benzodiazepine binding to benzodiazepine-GABA-chloride ionophore modulation by chlorine; Blockage of lactate-induced sense of control loss by glucose in patients with panic attacks.

Covering: up to 2021 Rearranged indole diterpenes of the paxilline type comprise a large group of fungal metabolites that possess diverse structural features and potentially useful biological effects. The unique indoloterpenoid motif, which is common to all congeners, was first confirmed by crystallographic studies of paxilline. This family of natural products has fascinated organic chemists for the past four decades and has inspired numerous syntheses and synthetic approaches. The present review highlights efforts that have laid the foundation and introduced new directions to this field of natural product synthesis. The introduction includes a summary of biosynthetic considerations and biological activities, the main body of the manuscript provides a detailed discussion of selected syntheses, and the review concludes with a brief outlook on the future of the field. [ABSTRACT FROM AUTHOR]

The article presents a study which reveals that the combination of selective serotonin reuptake inhibitor (SSRI) to cognitive behavioral therapy (CBT) and alcohol counseling helps lessen anger and aggression in incidents of domestic violence related to alcoholism. The study uses the irritability subscale (IS) score to measure the primary outcome on the Modified Overt Aggression Scale (MOAS). It also presents the significant effect of fluoxetine than with placebo based on IS score analysis.

Investigates the validity of the Christian Orthodoxy Scale (COS) of Fullerton and Hunsberger for 125 male and 125 female college students in identifying their religious preference and in rating the importance of their religion. Allport and Ross's Religious Orientation Scale; Grouping by gender; Correlation between COS and Religious Orientation Scale.

The article comments on the ethical issues related to the administration of alcohol or alcohol cues to treatment-seeking alcoholics in a research setting for the development of medications. It discusses various issues, such as the benefits and risks for non-treatment-seeking alcoholics in abstinence-based studies, in the context of the U.S. National Advisory Council on Alcohol Abuse and Alcoholism's recommended council guidelines on ethyl alcohol administration in human experimentation.

Rationale: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. Objectives: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. Methods: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. Results: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. Conclusions: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. Clinical trial registration: NCT01631630 [ABSTRACT FROM AUTHOR]

Abstract This study was designed to examine and contrast cognitive effects (explicit memory and access to semantic knowledge) of the benzodiazepine Halcion (triazolam) in ten normal volunteers and ten cognitively unimpaired detoxified alcoholics. The two groups were indistinguishable from one another under placebo conditions on all measures of cognitive functioning. Under Halcion test conditions (0.375 mg PO), both groups were about equally impaired in their recall of to-be-remembered information. However, alcoholics, were more likely to recall information that they were not asked to remember (intrusion errors) on all measures of explicit remembering. Alcoholics also generated relatively uncommon (low frequency) responses from semantic memory, rather than common, categorically related associations in response to stimuli such as types of vegetables, flowers, and fruit following the administration of Halcion, but were not different from normal volunteers in the types of responses generated under placebo conditions. These findings suggest that a drug challenge that simulates many of the effects of acute alcohol administration induces alcoholics to think and remember differently (qualitatively) from normal volunteers. [ABSTRACT FROM AUTHOR]

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe—frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors. [ABSTRACT FROM AUTHOR]

Aims Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. Methods In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. Results Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. Conclusion We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. Short summary This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task. [ABSTRACT FROM AUTHOR]

Zinc deficiency is a frequent complication of alcohol abuse for multiple reasons including poor intake, increased excretion, internal redistribution and altered transporters. Zinc deficiency has been postulated to play a role in the development/progression of alcoholic liver disease (ALD). This study aimed to relate serum zinc levels with alcohol intake, serum albumin concentration and markers of inflammation and liver injury. One hundred and eight male and female very heavy drinking (≥10 drinks/day) individuals without clinical evidence of ALD were grouped by serum zinc concentration: normal-zinc group (zinc level≥71 μg/dl) included 67 patients, and low-zinc group (zinc level<71 μg/dl) included 41 patients. Data were collected on demographics, drinking history in last 90 days (heavy drinking days, HDD90 and total drinks, TD90), lifetime drinking history (LTDH) and clinical/ laboratory assessments. Our data show that in a very well-characterized, chronically heavy-drinking population without clinical evidence of liver disease, about 40% of subjects had low serum zinc levels. Frequency of heavy drinking days (HDD90) was significantly higher in the low-zinc group. Total drinks in past 90 days, LTDH and HDD90 showed significant associations with low zinc levels. The group with the low serum zinc had a higher aspartate aminotransferase/alanine aminotransferase ratio (good marker of alcoholic liver disease). Those in the low-zinc group had the lower albumin levels, a marker of hepatic synthetic function, and the highest C-reactive protein level, a biomarker of inflammation. [ABSTRACT FROM AUTHOR]

Aims: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. Methods: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. Results: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. Conclusion: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. Short summary: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task. [ABSTRACT FROM AUTHOR]

Background Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. Methods A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. Results Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. Conclusions The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program. [ABSTRACT FROM AUTHOR]

Background A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase ( FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder ( PTSD) and alcohol dependence ( AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses. Methods Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the National Institutes of Health Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid (eCB) levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSD symptom severity. Results FAAH C385A allele carriers showed a marked increase in serum anandamide levels at baseline and throughout the stress challenge procedure compared with C allele homozygotes, while levels of eCBs primarily metabolized through other enzymatic activity, such as 2-arachidonoylglycerol, did not differ between genotype groups. FAAH C385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAH C385A genotype were found at the level of clinical PTSD symptom severity, in particular in the arousal domain. Conclusions This is to our knowledge the first study showing that FAAH C385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the eCB pathway as a promising target for future antistress therapeutics. [ABSTRACT FROM AUTHOR]

Background Heavy alcohol consumption frequently causes liver inflammation/injury, and certain fatty acids ( FAs) may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking and the changes in the FA levels involved in the ω-6 (pro-inflammatory) and ω-3 (anti-inflammatory) state in alcohol-dependent ( AD) patients who had no clinical manifestations of liver injury. We aimed to identify sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. Methods A total of 114 heavy drinking AD female and male patients aged 21 to 65 years without clinical manifestations of liver injury, who were admitted to an alcohol dependence treatment program, were grouped by the alanine aminotransferase ( ALT) levels: ≤40 IU/l, as no liver injury ( GR.1), and >40 IU/l, as mild liver injury ( GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic panel, comprehensive FA panel, and drinking history data were evaluated. Results Elevated ALT and aspartate aminotransferase (AST) showed close association with markers of heavy alcohol intake. In the patients with mild biochemical liver injury ( GR.2), females showed significantly higher AST level than males. Significant association of AST and total drinks in past 90 days ( TD90) in females, and AST and heavy drinking days in past 90 days ( HDD90) in males was observed. The ω-6:ω-3 ratio showed a significant pro-inflammatory response only in females with mild liver injury ( GR.2) when adjusted by drinking history marker, TD90. Docosahexaenoic acid ( DHA) and eicosapentaenoic acid ( EPA) were increased in males with liver injury, while females did not show any comparable rise in EPA; and DHA levels were lower. Conclusions Measures of heavy drinking, TD90 and HDD90, predicted changes in liver injury. Changes in the ω-3 and ω-6 FA levels and the ω-6:ω-3 ratio showed a pro-inflammatory shift in patients with biochemical liver injury with a significant effect in females. Changes in FAs involved in the inflammatory state may represent one mechanism for liver inflammation/injury in response to heavy alcohol drinking. [ABSTRACT FROM AUTHOR]

Background: Post-traumatic stress disorder (PTSD) is often comorbid with alcohol dependence (AD), but little is known about the characteristics of AD treatment-seeking inpatients with PTSD. We examined differences between treatment-seeking alcohol dependent inpatients with and without comorbid PTSD. We hypothesized that those with AD and PTSD would have higher levels of: (1) alcohol use and AD severity; (2) anxiety and mood disorders; (3) neuroticism.Methods: Individuals (N=411, mean age=41.7±10.0years) with AD were monitored over 30days in a suburban inpatient alcohol treatment setting. Patients were evaluated to identify AD and comorbid PTSD, mood and anxiety disorders, alcohol use and dependence severity, personality, and aggression.Results: Those with PTSD (19% of the sample) did not differ in the amount of alcohol consumed, but had greater: (1) severity of AD (p=0.001, d=0.44); (2) diagnosis of anxiety (p=0.000, OR=3.64) and mood (p=0.000, OR=4.83) disorders; and (3) levels of neuroticism (p<0.001, d=0.67) and aggression (p<0.001, d=0.81).Conclusions: AD patients with comorbid PTSD present a more severe phenotype across AD severity, frequency of anxiety and mood disorders, and levels of neuroticism and aggression. This group may benefit from concurrent treatment of both AD and PTSD. Future research can investigate neuroticism as a potential treatment target. [ABSTRACT FROM AUTHOR]

Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder ( PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence ( AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm ( Trier/ CR), and a guided imagery ( Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/ CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/ CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving. [ABSTRACT FROM AUTHOR]

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans. [ABSTRACT FROM AUTHOR]

Senatorov et al. reveal a bilateral reduction in anterior insula volume, and bilateral increase in amygdala volume, in alcohol-dependent subjects compared to healthy controls. Post-mortem histological studies suggest that the lower anterior insula volumes may reflect a 60% reduction in von Economo neurons in subjects with a history of alcoholism.The insula, a structure involved in higher order representation of interoceptive states, has recently been implicated in drug craving and social stress. Here, we performed brain magnetic resonance imaging to measure volumes of the insula and amygdala, a structure with reciprocal insular connections, in 26 alcohol-dependent patients and 24 healthy volunteers (aged 22–56 years, nine females in each group). We used an established morphometry method to quantify total and regional insular volumes. Volumetric measurements of the amygdala were obtained using a model-based segmentation/registration tool. In alcohol-dependent patients, anterior insula volumes were bilaterally reduced compared to healthy volunteers (left by 10%, right by 11%, normalized to total brain volumes). Furthermore, alcohol-dependent patients, compared with healthy volunteers, had bilaterally increased amygdala volumes. The left amygdala was increased by 28% and the right by 29%, normalized to total brain volumes. Post-mortem studies of the anterior insula showed that the reduced anterior insular volume may be associated with a population of von Economo neurons, which were 60% diminished in subjects with a history of alcoholism (n = 6) as compared to subjects without a history of alcoholism (n = 6) (aged 32–56 years, all males). The pattern of neuroanatomical change observed in our alcohol-dependent patients might result in a loss of top-down control of amygdala function, potentially contributing to impaired social cognition as well as an inability to control negatively reinforced alcohol seeking and use. [ABSTRACT FROM AUTHOR]

Background Positively reinforcing properties of alcohol are in part mediated by activation of the ventral striatum ( VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone ( NTX) can block this cascade, but its ability to do so in treatment-seeking alcoholics has not been examined. Our objective was to study the effects of NTX on alcohol-induced VS activation and on amygdala response to affective stimuli in treatment-seeking alcohol-dependent inpatients. Methods Sixty-three treatment-seeking alcoholics were randomized to receive NTX (50 mg) or placebo ( PLC) daily. On Day 7, participants underwent an alcohol cue reactivity session, and craving was measured using the Penn Alcohol Craving Scale. On Day 9, participants received a saline infusion followed by an alcohol infusion and also viewed affective stimuli in a magnetic resonance scanner. Results Irrespective of medication treatment condition, the alcohol infusion did not activate the VS in the alcohol-dependent patients. Unexpectedly, VS activation was greater in NTX treated patients than in the PLC group. NTX treated patients also reported increased craving in response to alcohol cue exposure, and increased subjective response to alcohol ('high' and 'intoxicated') compared to PLC subjects. No significant effects of alcohol infusion on brain response to affective stimuli were in the NTX or PLC groups. Conclusions Unlike previous findings in social drinkers, a moderate level of intoxication did not activate the VS in treatment-seeking alcoholics. This is likely to reflect tolerance to the positively reinforcing properties of alcohol in this clinical population. Our findings may help explain the efficacy of NTX to reduce heavy drinking, but not to maintain abstinence. [ABSTRACT FROM AUTHOR]

Alcohol withdrawal is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity. [ABSTRACT FROM AUTHOR]

Background Liver inflammation in alcoholism has been hypothesized to influence the development of a neuroinflammatory process in the brain characterized by neurodegeneration and altered cognitive function. Monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2 ( MCP-1/ CCL2) elevations have been noted in the alcoholic brain at autopsy and may have a role in this process. Methods We studied cerebrospinal fluid ( CSF) levels of MCP-1 as well as interleukin-1 β and tumor necrosis factor- α in 13 healthy volunteers and 28 alcoholics during weeks 1 and 4 following detoxification. Serum liver enzymes were obtained as markers of alcohol-related liver inflammation. Results Compared to healthy volunteers, MCP-1 levels were significantly higher in alcoholics both on day 4 and day 25 ( p < 0.0001). Using multiple regression analysis, we found that MCP-1 concentrations were positively associated with the liver enzymes gamma glutamyltransferase ( GGT; p = 0.03) and aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/GOT; p = 0.004). Conclusions These preliminary findings are consistent with the hypothesis that neuroinflammation as indexed by CSF MCP-1 is associated with alcohol-induced liver inflammation, as defined by peripheral concentrations of GGT and AST/ GOT. [ABSTRACT FROM AUTHOR]

Background Childhood trauma has been linked with a number of negative outcomes later in life, including alcohol dependence ( AD). Previous studies have suggested a mediating role for neuroticism in the relationship between childhood trauma and psychopathology. In this study, we investigate the prevalence of multiple types of childhood trauma in treatment-seeking alcohol-dependent patients, and the associations between childhood trauma and AD severity using multiple mediation analysis. Methods The prevalence of 5 types of childhood trauma-emotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglect-was assessed in treatment-seeking alcohol-dependent patients ( n = 280) and healthy controls ( n = 137) using the Childhood Trauma Questionnaire. Multiple mediation analyses were used to model associations between childhood trauma measures and alcohol-related outcomes, primarily the severity of AD in the alcohol-dependent sample. Results Childhood trauma was significantly more prevalent and more severe in the alcohol-dependent subjects. In addition, childhood trauma was found to influence AD severity, an effect that was mediated by neuroticism. When individual trauma types were examined, emotional abuse was found to be the primary predictor of AD severity, both directly and through the mediating effects of the impulsivity subfacet of neuroticism. Physical abuse also had a moderate direct effect on AD severity. Mediation analysis did not reveal any association between childhood trauma and Alcohol Use Disorders Identification Test score in the nondependent control sample. Conclusions Childhood trauma is highly prevalent in treatment-seeking alcoholics and may play a significant role in the development and severity of AD through an internalizing pathway involving negative affect. Our findings suggest that alcoholics with a history of childhood emotional abuse may be particularly vulnerable to severe dependence. [ABSTRACT FROM AUTHOR]

ABSTRACT Studies have shown that various brain structure abnormalities are associated with chronic alcohol abuse and impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric magnetic resonance imaging (MRI) to compare the volumes of different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs). Caucasian men ( n = 54), ages 24-55, who had participated in National Institutes of Alcohol Abuse and Alcoholism treatment programs, were grouped together as IPV-ADs ( n = 27), non-violent ADs ( n = 14) and HCs ( n = 13). The MRI scan was performed at least 3 weeks from the participant's last alcohol use. T1-weighted images were used to measure the volumes of intracranial space, gray and white matter, orbitofrontal cortex, medial prefrontal cortex, lateral prefrontal cortex, and six subcortical structures. Results revealed that IPV-ADs, compared with non-violent ADs and HCs, had a significant volume reduction in the right amygdala. No significant volumetric difference was found in other structures. This finding suggests that structural deficits in the right amygdala may underlie impulsive types of aggression often seen in alcohol-dependent patients with a history of IPV. It adds to a growing literature suggesting that there are fundamental differences between alcohol-dependent patients with and without IPV. [ABSTRACT FROM AUTHOR]

Background This study examined the prevalence of single- and multiple-type childhood trauma exposure ( CTE) among alcoholic patients undergoing inpatient detoxification and treatment. The relationships between various types of CTE and lifetime psychiatric comorbidities and suicide attempts were also explored. Methods A total of 196 alcoholic inpatients were assessed by Structured Clinical Interview for DSM-IV Axis I Disorders and Childhood Trauma Questionnaire ( CTQ) for CTE history. Results The overall prevalence of CTE in the entire sample was high (55.1%). Specifically, the prevalence of emotional abuse was 21.4%, physical abuse 31.1%, sexual abuse 24.0%, emotional neglect 20.4%, and physical neglect 19.9%. Regarding multiple types of CTE, 31.7 and 18.9% reported at least 2 and at least 3 CTE types, respectively. Strikingly, among those with at least 1 positive CTQ category, more than half reported 2 or more CTE types. A history of emotional abuse increased the risk of mood disorder, in particular major depressive disorder, as well as posttraumatic stress disorder ( PTSD). Physical abuse contributed to the prediction of suicide attempts, while sexual abuse was associated with a diagnosis of anxiety disorder, PTSD, and multiple comobidities (e.g., anxiety and mood disorder). The number of reported CTE types or the total score of the CTQ predicted an increased risk of having single or multiple psychiatric comorbidities as well as suicide attempts. Conclusions We observed high rates of a broad range of CTE types and a trend for CTE-specific enhancement of risk for various psychiatric outcomes among alcoholic inpatients. Of note, a dose-response relationship between number of CTE types and risk of psychiatric comorbidities as well as suicide attempts was found. We suggest a wide range of CTE should be included when exploring the effects of CTE or developing prevention and treatment strategies among alcoholic subjects. [ABSTRACT FROM AUTHOR]

Background: Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought. Methods: Platelet monoamine oxidase B (MAO-B) protein was quantitated in 2 populations of subjects who had histories of different levels of alcohol consumption. Levels were assayed by immunoblotting or by ELISA. The development and evaluation of the new ELISA-based measure of platelet MAO-B protein levels is described. Results: One subject population constituted a nontreatment-seeking, cross-sectional subject sample, and the other population was a longitudinally followed, hospitalized group of subjects. An algorithm combining measures of platelet MAO-B protein with the plasma levels of carbohydrate-deficient transferrin (CDT) and with liver enzymes (aspartate aminotransferase or γ-glutamyltransferase [GGT]) can detect hazardous/harmful alcohol use (HHAU) with the highest sensitivity and specificity in the cross-sectional nontreatment-seeking population. In the treatment-seeking population, low MAO-B protein levels at admission are associated with heavy drinking prior to admission, and these protein levels increase over a period of abstinence from alcohol. Conclusions: The platelet MAO-B protein measurement is particularly effective for male alcohol consumers. The combined use of MAO-B protein measures together with measures of CDT and GGT does, however, improve the diagnostic utility of both markers for ascertaining HHAU in women. Furthermore, measurement of changes in platelet MAO-B protein levels during treatment for alcohol dependence may help monitor the success of the treatment program. [ABSTRACT FROM AUTHOR]

Background: Episodes of explosive rage and violence comprise a symptom complex which can have a devastating effect on a person's life. In the community this behavior is seen as workplace violence, domestic abuse and road rage, while in the clinical setting, this behavior is rarely mentioned by patients, despite evidence that it can signify an important biological disorder that may afflict more than three percent of the population. Discussion: Patients are often reluctant to seek help for episodic attacks of rage, especially attacks which are accompanied by physical violence. Although, in the past, clinicians have had few treatment options to offer, recent neuroscience advances have created new possibilities to understand and help patients with this neglected problem. No formal medical guidelines for treating violence exist; however, many patients can be helped by diagnosis, referral and treatment. Treatment can include pharmaceuticals and nutrients, as well as referral for anger management or behavioral therapy. Summary: The astute clinician has an opportunity to positively impact an important problem through the diagnosis and treatment of patients with symptoms of intermittent explosive disorder. [ABSTRACT FROM AUTHOR]

Modulation of alcohol craving induced by challenge stimuli may predict the efficacy of new pharmacotherapies for alcoholism. We evaluated two pharmacological challenges, the α2-adrenergic antagonist yohimbine, which reinstates alcohol seeking in rats, and the serotonergic compound meta-chlorophenylpiperazine (mCPP), previously reported to increase alcohol craving in alcoholics. To assess the predictive validity of this approach, the approved alcoholism medication acamprosate was evaluated for its ability to modulate challenge-induced cravings. A total of 35 treatment seeking alcohol dependent inpatients in early abstinence were randomized to placebo or acamprosate (2997 mg daily). Following two weeks of medication, subjects underwent three challenge sessions with yohimbine, mCPP or saline infusion under double blind conditions, carried out in counterbalanced order, and separated by at least 5 days. Ratings of cravings and anxiety, as well as biochemical measures were obtained. In all, 25 subjects completed all three sessions and were included in the analysis. Cravings were modestly, but significantly higher following both yohimbine and mCPP challenge compared with saline infusion. The mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. There was a significant correlation between craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. Both yohimbine and mCPP challenges lead to elevated alcohol craving in a clinical population of alcoholics, and these cravings correlate with alcoholism severity. Under the experimental conditions used, alcohol cravings induced by these two stimuli are not sensitive to acamprosate at clinically used doses. [ABSTRACT FROM AUTHOR]

Abstract: Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential. [ABSTRACT FROM AUTHOR]

Medications which influence monoaminergic neurotransmission can also have an effect on glucose regulation. In order to better understand the role of central monoaminergic neurotransmission in blood glucose homeostasis, we explored the relation between blood glucose and cerebrospinal fluid metabolite concentrations of monoaminergic neurotransmitters. Under stringently controlled resting conditions, we measured fasting blood glucose and performed lumbar punctures on 41 healthy participants. Peripheral blood glucose concentrations were significantly correlated with the cerebrospinal fluid concentrations of the dopamine metabolite, homovanillic acid and the noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglycol. These correlations may represent a homeostatic relation between brain neurotransmitter activity and blood glucose. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

: Background.Aortomyoplasty (AMP), a procedure in which the latissimus dorsi muscle (LDM) is wrapped around the aorta and stimulated during diastole, is a potential method of chronic counterpulsation. Counterpulsation by the intraaortic balloon pump (IABP) is a proven treatment for ischemic coronary syndrome and heart failure but cannot be used chronically. This study examined the long-term potential of a unique AMP configuration and compared its performance to the IABP.: Materials and methods.AMP was done using a wringer configuration (AMP-W) in nine dogs. Six and 12 months later, acute hemodynamic augmentation was evaluated by measuring differences in mean diastolic aortic pressure (mDAP), peak left ventricular pressure (pLVP), and the endocardial viability ratio (EVR) between stimulated and unstimulated beats.: Results.The diastolic augmentation obtained by AMP-W at 6 months and by AMP-W and IABP at 12 months was statistically significant. Additionally, the enhancements in EVR (16.1 ± 4.3%), mDAP (8.6 ± 2.5%), and pLVP (−1.8 ± 1.0%) at 6 months were similar to those in EVR (19.1 ± 5.2%), mDAP (13.1 ± 3.6%), and pLVP (−0.8 ± 1.3%) at 12 months. Most importantly, the augmentation obtained by AMP-W at 12 months was similar to that of the IABP: EVR (17.1 ± 5.9%), mDAP (13.4 ± 6.7%), and pLVP (−1.5 ± 0.8%).: Conclusions.AMP-W is a safe, robust procedure, capable of providing counterpulsation equivalent to the IABP, 12 months following surgery. The potential for AMP-W to offer chronic counterpulsation and to benefit the ischemic heart should be investigated further. [Copyright &y& Elsevier]

— Aims: In this study we explored the relationship between alcohol and carbohydrate consumption in long-term abstinent alcoholics. Methods: We employed an established laboratory paradigm which allowed us to stimulate and measure dietary intake. 2-Deoxy-d-glucose (2-DG) is a glucose analogue that causes an intracellular energy deprivation resulting in exaggerated food consumption and a compensatory metabolic response to raise blood glucose. Using a double-blind design, we gave an infusion of 25 mg/kg 2-DG or placebo to 20 long-term abstinent alcoholics and 19 healthy volunteers. Results: There were no baseline differences in any dietary, behavioural or biochemical variables. As expected, 2-DG increased caloric consumption and blood glucose levels in a time-dependent fashion. There were no differences in food consumption between the alcoholics and the healthy volunteers following the 2-DG stimulus. However, the alcoholic group had a significantly blunted response in blood glucose. Conclusions: The origin of this atypical blood glucose response may antedate the onset of alcoholism, or it may be secondary to alcohol-related damage that persists beyond 6 months. Previous accounts of increased sweet consumption in alcoholics were not substantiated, although they may be present in the peri-withdrawal period. [ABSTRACT FROM PUBLISHER]

Background: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long-term sober alcoholics. Methods: To characterize HPA axis function in long-term sober alcoholics, we used a challenge paradigm with 2-deoxy-d-glucose (2-DG). An infusion of 2-DG (a nonmetabolizable glucose analog) induces a well-characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2-DG on 19 healthy volunteers and 20 community-living alcoholics who had been abstinent more than 6 months. Results: In contrast to the previous study, long-term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2-DG. Conclusions: Previously observed abnormalities in cortisol regulation in 3-week-sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long-term abstinence has been achieved. [ABSTRACT FROM AUTHOR]

Describes a stimulator that allows arbitrary pulse patterns to be sent to three isolated, bipolar electrodes, which allows selective stimulation of latissimus dorsi muscle (LDM). Methodology used in study; Design of the programmable multichannel stimulator; Discussion on results of study.

Background: Elevated levels of corticotrophin-releasing hormone in the cortical-hippocampal-amygdala pathway increase fear and anxiety, which are components of defensive and violent behaviors. Prostaglandins E2 and F2α, which increase corticotrophin-releasing hormone RNA expression in this pathway, are reduced by dietary intakes of omega-3 fats. Methods: Among 21 perpetrators of domestic violence, cerebrospinal fluid and plasma were assessed for corticotrophin-releasing hormone and fatty acid compositions, respectively. Results: Lower plasma docosahexaenoic acid (wt% fatty acids) alone predicted greater cerebrospinal fluid corticotrophin-releasing hormone (pg/mL), in exponential (r = -.67, p < .006) and linear regressions (r = -0.68, p < .003 excluding four subjects with the highest docosahexaenate levels). Conclusions: In this small observational study, low plasma docosahexaenoic acid levels were correlated to higher cerebrospinal fluid corticotrophin-releasing hormone levels. Placebo controlled trials can determine if dietary omega-3 fatty acids can reduce excessive corticotrophin-releasing hormone levels in psychiatric illnesses. [Copyright &y& Elsevier]

Background: Episodes of explosive rage and violence comprise a symptom complex which can have a devastating effect on a person's life. In the community this behavior is seen as workplace violence, domestic abuse and road rage, while in the clinical setting, this behavior is rarely mentioned by patients, despite evidence that it can signify an important biological disorder that may afflict more than three percent of the population.Discussion: Patients are often reluctant to seek help for episodic attacks of rage, especially attacks which are accompanied by physical violence. Although, in the past, clinicians have had few treatment options to offer, recent neuroscience advances have created new possibilities to understand and help patients with this neglected problem. No formal medical guidelines for treating violence exist; however, many patients can be helped by diagnosis, referral and treatment. Treatment can include pharmaceuticals and nutrients, as well as referral for anger management or behavioral therapy.Summary: The astute clinician has an opportunity to positively impact an important problem through the diagnosis and treatment of patients with symptoms of intermittent explosive disorder. [ABSTRACT FROM AUTHOR]