Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits

Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking

Subtyping patients with heroin addiction at treatment entry: factor derived from the Self-Report Symptom Inventory (SCL-90)

<p>Abstract</p> <p>Background</p> <p>Addiction is a relapsing chronic condition in which psychiatric phenomena play a crucial role. Psychopathological symptoms in patients with heroin addiction are generally considered to be part of the drug addict's personality, or else to be related to the presence of psychiatric comorbidity, raising doubts about whether patients with long-term abuse of opioids actually possess specific psychopathological dimensions.</p> <p>Methods</p> <p>Using the Self-Report Symptom Inventory (SCL-90), we studied the psychopathological dimensions of 1,055 patients with heroin addiction (884 males and 171 females) aged between 16 and 59 years at the beginning of treatment, and their relationship to age, sex and duration of dependence.</p> <p>Results</p> <p>A total of 150 (14.2%) patients with heroin addiction showed depressive symptomatology characterised by feelings of worthlessness and being trapped or caught; 257 (24.4%) had somatisation symptoms, 205 (19.4%) interpersonal sensitivity and psychotic symptoms, 235 (22.3%) panic symptomatology, 208 (19.7%) violence and self-aggression. These dimensions were not correlated with sex or duration of dependence. Younger patients with heroin addiction were characterised by higher scores for violence-suicide, sensitivity and panic anxiety symptomatology. Older patients with heroin addiction showed higher scores for somatisation and worthlessness-being trapped symptomatology.</p> <p>Conclusions</p> <p>This study supports the hypothesis that mood, anxiety and impulse-control dysregulation are the core of the clinical phenomenology of addiction and should be incorporated into its nosology.</p

Screening of depression in adolescents through the Internet: Sensitivity and specificity of two screening questionnaires.

.001). The scores on both instruments were significantly increased in all subjects with a mood disorder, whether current or lifetime, except for lifetime minor depression. In the ROC analyses, high areas under the curve were found for the MDI (0.89) and CESD (0.90). The best cut-off point for the MDI was 19 (sensitivity: 90.48; specificity: 71.53), and for the CES-D it was 22 (sensitivity: 90.48; specificity: 74.31). We conclude that the MDI and CES-D are reliable and valid instruments that can be used for this screening

Reward-Related Dorsal Striatal Activity Differences between Former and Current Cocaine Dependent Individuals during an Interactive Competitive Game

Cocaine addiction is characterized by impulsivity, impaired social relationships, and abnormal mesocorticolimbic reward processing, but their interrelationships relative to stages of cocaine addiction are unclear. We assessed blood-oxygenation-level dependent (BOLD) signal in ventral and dorsal striatum during functional magnetic resonance imaging (fMRI) in current (CCD; n = 30) and former (FCD; n = 28) cocaine dependent subjects as well as healthy control (HC; n = 31) subjects while playing an interactive competitive Domino game involving risk-taking and reward/punishment processing. Out-of-scanner impulsivity-related measures were also collected. Although both FCD and CCD subjects scored significantly higher on impulsivity-related measures than did HC subjects, only FCD subjects had differences in striatal activation, specifically showing hypoactivation during their response to gains versus losses in right dorsal caudate, a brain region linked to habituation, cocaine craving and addiction maintenance. Right caudate activity in FCD subjects also correlated negatively with impulsivity-related measures of self-reported compulsivity and sensitivity to reward. These findings suggest that remitted cocaine dependence is associated with striatal dysfunction during social reward processing in a manner linked to compulsivity and reward sensitivity measures. Future research should investigate the extent to which such differences might reflect underlying vulnerabilities linked to cocaine-using propensities (e.g., relapses)

Emergency Portacaval Shunt Versus Rescue Portacaval Shunt in a Randomized Controlled Trial of Emergency Treatment of Acutely Bleeding Esophageal Varices in Cirrhosis—Part 3

Emergency treatment of bleeding esophageal varices in cirrhosis is of singular importance because of the high mortality rate. Emergency portacaval shunt is rarely used today because of the belief, unsubstantiated by long-term randomized trials, that it causes frequent portal-systemic encephalopathy and liver failure. Consequently, portacaval shunt has been relegated solely to salvage therapy when endoscopic and pharmacologic therapies have failed. Question: Is the regimen of endoscopic sclerotherapy with rescue portacaval shunt for failure to control bleeding varices superior to emergency portacaval shunt? A unique opportunity to answer this question was provided by a randomized controlled trial of endoscopic sclerotherapy versus emergency portacaval shunt conducted from 1988 to 2005. Unselected consecutive cirrhotic patients with acute bleeding esophageal varices were randomized to endoscopic sclerotherapy (n = 106) or emergency portacaval shunt (n = 105). Diagnostic workup was completed and treatment was initiated within 8 h. Failure of endoscopic sclerotherapy was defined by strict criteria and treated by rescue portacaval shunt (n = 50) whenever possible. Ninety-six percent of patients had more than 10 years of follow-up or until death. Comparison of emergency portacaval shunt and endoscopic sclerotherapy followed by rescue portacaval shunt showed the following differences in measurements of outcomes: (1) survival after 5 years (72% versus 22%), 10 years (46% versus 16%), and 15 years (46% versus 0%); (2) median post-shunt survival (6.18 versus 1.99 years); (3) mean requirements of packed red blood cell units (17.85 versus 27.80); (4) incidence of recurrent portal-systemic encephalopathy (15% versus 43%); (5) 5-year change in Child’s class showing improvement (59% versus 19%) or worsening (8% versus 44%); (6) mean quality of life points in which lower is better (13.89 versus 27.89); and (7) mean cost of care per year ($39,200 versus$216,700). These differences were highly significant in favor of emergency portacaval shunt (all p &lt; 0.001). Emergency portacaval shunt was strikingly superior to endoscopic sclerotherapy as well as to the combination of endoscopic sclerotherapy and rescue portacaval shunt in regard to all outcome measures, specifically bleeding control, survival, incidence of portal-systemic encephalopathy, improvement in liver function, quality of life, and cost of care. These results strongly support the use of emergency portacaval shunt as the first line of emergency treatment of bleeding esophageal varices in cirrhosis

Policy Adjustment in a Dynamic Economic Game

Making sequential decisions to harvest rewards is a notoriously difficult problem. One difficulty is that the real world is not stationary and the reward expected from a contemplated action may depend in complex ways on the history of an animal's choices. Previous functional neuroimaging work combined with principled models has detected brain responses that correlate with computations thought to guide simple learning and action choice. Those works generally employed instrumental conditioning tasks with fixed action-reward contingencies. For real-world learning problems, the history of reward-harvesting choices can change the likelihood of rewards collected by the same choices in the near-term future. We used functional MRI to probe brain and behavioral responses in a continuous decision-making task where reward contingency is a function of both a subject's immediate choice and his choice history. In these more complex tasks, we demonstrated that a simple actor-critic model can account for both the subjects' behavioral and brain responses, and identified a reward prediction error signal in ventral striatal structures active during these non-stationary decision tasks. However, a sudden introduction of new reward structures engages more complex control circuitry in the prefrontal cortex (inferior frontal gyrus and anterior insula) and is not captured by a simple actor-critic model. Taken together, these results extend our knowledge of reward-learning signals into more complex, history-dependent choice tasks. They also highlight the important interplay between striatum and prefrontal cortex as decision-makers respond to the strategic demands imposed by non-stationary reward environments more reminiscent of real-world tasks

Lack of effect of high-protein vs. high-carbohydrate meal intake on stress-related mood and eating behavior

<p>Abstract</p> <p>Background</p> <p>Consumption of meals with different macronutrients, especially high in carbohydrates, may influence stress-related eating behavior. We aimed to investigate whether consumption of high-protein vs. high-carbohydrate meals influences stress-related mood, food reward, i.e. 'liking' and 'wanting', and post-meal energy intake.</p> <p>Methods</p> <p>Participants (n = 38, 19m/19f, age = 25 ± 9 y, BMI = 25.0 ± 3.3 kg/m²) came to the university four times, fasted, once for a stress session receiving a high-protein meal, once for a rest session receiving a high-protein meal, once for a stress session receiving a high-carbohydrate meal and once for a rest session receiving a high-carbohydrate meal (randomized cross-over design). The high-protein and high-carbohydrate test meals (energy percentage protein/carbohydrate/fat 65/5/30 vs. 6/64/30) matched for energy density (4 kJ/g) and daily energy requirements (30%). Stress was induced using an ego-threatening test. Pre- and post-meal 'liking' and 'wanting' (for bread, filling, drinks, dessert, snacks, stationery (non-food alternative as control)) was measured by means of a computer test. Following the post-meal 'wanting' measurement, participants received and consumed their wanted food items (post-meal energy intake). Appetite profile (visual analogue scales), mood state (Profile Of Mood State and State Trait Anxiety Inventory questionnaires), and post-meal energy intake were measured.</p> <p>Results</p> <p>Participants showed increased feelings of depression and anxiety during stress (P < 0.01). Consumption of the test meal decreased hunger, increased satiety, decreased 'liking' of bread and filling, and increased 'liking' of placebo and drinks (P < 0.0001). Food 'wanting' decreased pre- to post-meal (P < 0.0001). The high-protein vs. high-carbohydrate test meal induced lower subsequent 'wanting' and energy intake (1.7 ± 0.3 MJ vs. 2.5 ± 0.4 MJ) only in individuals characterized by disinhibited eating behavior (factor 2 Three Factor Eating Questionnaire, n = 16), during rest (P ≤ 0.01). This reduction in 'wanting' and energy intake following the high-protein meal disappeared during stress.</p> <p>Conclusions</p> <p>Consumption of a high-protein vs. high-carbohydrate meal appears to have limited impact on stress-related eating behavior. Only participants with high disinhibition showed decreased subsequent 'wanting' and energy intake during rest; this effect disappeared under stress. Acute stress overruled effects of consumption of high-protein foods.</p> <p>Trial registration</p> <p>The study was registered in the Dutch Trial Register (<a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2040">NTR1904</a>). The protocol described here in this study deviates from the trial protocol approved by the Medical Ethical Committee of the Maastricht University as it comprises only a part of the approved trial protocol.</p

Screening and early psychological intervention for depression in schools: systematic review and meta-analysis.

Abstract Depression in children and adolescents is considerably undertreated, and the school may be a good setting for identifying and treating depression. We conducted a meta-analysis of studies in which students were screened for depression, and those with depressive symptoms were treated with a psychological intervention. Only randomised controlled trials were included. Eight studies met the inclusion criteria. Five studies focused on younger children (7–14 years) and three studies were aimed at adolescents (12–19 years). In total 5803 students were screened, of whom 7.2% were included in the intervention studies (95% CI: 7.1–7.3). The ‘numbers-needed-to-screen’ was 31 (95% CI: 27–32), which means that 31 students had to be screened in order to generate one successfully treated case of depression. The effects of the psychological treatments at posttest were compared to control conditions in the 8 studies comprising 12 contrast groups, with a total of 413 students. The mean effect size was 0.55 (95% CI: 0.35– 0.76). There were not enough studies to examine whether specific psychotherapies were superior to other psychotherapies. Although the number of studies is small and their quality is limited, screening and early intervention at schools may be an effective strategy to reduce the burden of disease from depression in children and adolescents. More research on the (negative) effects of these interventions is needed

Pleosporales

One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae