bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of α5 Subunit‐Containing GABAA Receptors Alters Alcohol Drinking by Rhesus Monkeys
Authors: Rüedi‐Bettschen Daniela , Rowlett James K. , Rallapalli Sundari , Clayton Terry , Cook James M. , Platt Donna M. 
Published: November 2012

BackgroundAlcohol's ability to potentiate the activity of γ‐aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse‐related effects and that subtype‐selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5GABAA receptor ligands to alter selectively the reinforcing effects of alcohol.MethodsTwo groups of rhesus monkeys were trained to orally self‐administer alcohol or sucrose under fixed‐ratio schedules and limited daily access conditions. In addition, following daily self‐administration sessions, the behavior of each monkey was scored for both species‐typical and drug‐induced behaviors.ResultsConcentrations of 1 to 6% alcohol maintained self‐administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self‐administration. The α5GABAA receptor agonist QH‐ii‐066 enhanced and the α5GABAA receptor inverse agonist L‐655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5GABAA receptor antagonist XLi‐093. However, L‐655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect.ConclusionsThese findings suggest a prominent and specific role for α5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.
Commentary on Marczinski and Colleagues: Mixing an Energy Drink with an Alcoholic Beverage Increases Motivation for More Alcohol in College Students
Authors: Griffin William C. 
Published: November 2012

BackgroundThis commentary discusses the study by Marczinski and colleagues in which they used an alcohol priming procedure to examine the effects of an alcohol/energy drink mixture on the priming effect.MethodsThe significance of the main findings from this study and new avenues of investigation are discussed.ResultsUsing an alcohol priming paradigm, Marczinski and colleagues report that an alcohol/energy drink combination (AmED) prolongs the desire‐to‐drink rating compared with alcohol alone.ConclusionsThe results of this laboratory study add to the growing body of literature that the intoxicating effects of AmED are different than the intoxication by alcohol alone.
Differences in onset of disease and severity of psychopathology between toxoplasmosis‐related and toxoplasmosis‐unrelated schizophrenia
Authors: Holub D. , Flegr J. , Dragomirecká E. , Rodriguez M. , Preiss M. , Novák T. , Čermák J. , Horáček J. , Kodym P. , Libiger J. , Höschl C. , Motlová L. B. 
Published: November 2012

ObjectiveToxoplasmosis is a lifelong parasitic disease that appears to be associated to schizophrenia. However, no distinguishing attributes in Toxoplasma‐infected schizophrenia patients have been described as yet.MethodWe searched for differences in symptom profile, cognitive performance and treatment response between 194 Toxoplasma‐free and 57 (22.7%) Toxoplasma‐infected schizophrenia patients treated in Prague Psychiatric Centre between 2000 and 2010.ResultsInfected and non‐infected patients differed in severity of symptoms (P = 0.032) measured with the Positive and Negative Symptom Scale (PANSS). Infected patients scored higher in positive subscale of PANSS, but not in the general and negative subscales. Infected men scored higher also in Total PANSS score, and negative, reality distortion, disorganisation and cognitive scores. Higher PANSS scores of positive, negative and disorganised psychopathology were associated with the lower titres of anti‐Toxoplasma antibodies suggesting that psychopathology deteriorates with duration of parasitic infection. Infected patients remained about 33 days longer in hospital during their last admission than uninfected ones (P = 0.003). Schizophrenia started approximately 1 year earlier in infected men and about 3 years later in infected women, no such difference was observed in uninfected subjects.ConclusionLatent toxoplasmosis in schizophrenia may lead to more severe positive psychopathology and perhaps less favourable course of schizophrenia.
Haemophagocytic lymphohistiocytosis in a patient with severe burns
Authors: Porter J. R. S. , Handy J. , Yarranton H. , Gurney S. 
Published: November 2012

SummaryRecently, increasing attention has been drawn to haemophagocytic lymphohistiocytosis as a potentially under‐diagnosed condition in critically ill patients with severe sepsis. It is thought to be caused by a highly stimulated, but ineffective, immune system. We report the case of a patient suffering from major burns who, despite extensive investigations showing the absence of concurrent sepsis or infection, developed haemophagocytic lymphohistiocytosis refractory to treatment. We believe that this is the first report suggestive of haemophagocytic lymphohistiocytosis triggered by a burns injury.
Efficacy and safety of ribavirin plus pegylated interferon alfa in geriatric patients with chronic hepatitis C
Authors: Hu C.‐C. , Lin C.‐L. , Kuo Y.‐L. , Chien C.‐H. , Chen S.‐W. , Yen C.‐L. , Lin C.‐Y. , Chien R.‐N. 
Published: November 2012

SummaryBackgroundLimited data are available on the efficacy and safety of antiviral therapy in geriatric patients with chronic hepatitis C virus (HCV) infection.AimTo evaluate the efficacy and safety of pegylated interferon (pegIFN) plus ribavirin (RBV) therapy in geriatric HCV‐infected patients.MethodsNinety‐one geriatric patients (age ≥65 years; the elderly group) with HCV infection and 91 gender‐ and HCV genotype‐matched middle‐aged patients (age 50–64 years; the younger group) were assigned to receive weekly pegIFN injection plus weight‐based oral RBV for 24 weeks. The on‐ and off‐treatment virological responses were evaluated for treatment efficacy.ResultsIn intention‐to‐treat analysis, the sustained virological response (SVR) rate was substantially decreased in the elderly patients (elderly group vs. younger group, 40.7% vs. 61.5%, respectively; P = 0.005). The SVR rate was significantly lower in geriatric patients than in middle‐aged patients with HCV genotype non‐1 (54.3% vs. 82.9%; P = 0.01), but the difference was not significant with HCV genotype 1 (32.1% vs. 48.2%; P = 0.083). Furthermore, the older patients infected with HCV genotype non‐1 who achieved a rapid virological response had a similar SVR rate to that of the younger patients. The withdrawal rate was 13.2% in the elderly group and 7.7% in the younger group.ConclusionsCompared with middle‐aged patients, the therapeutic efficacy of pegylated interferon plus ribavirin therapy is lower in hepatitis C virus‐infected geriatric patients with an acceptable withdrawal rate. Considering prolonged lifespan in geriatric patients, we recommend treating geriatric hepatitis C virus‐infected patients who have significant hepatic fibrosis and no other health problems.
Population pharmacokinetics of abacavir in infants, toddlers and children
Authors: Zhao Wei , Piana Chiara , Danhof Meindert , Burger David , Della Pasqua Oscar , Jacqz‐Aigrain Evelyne 
Published: November 2012

AimsTo characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations.MethodsAbacavir concentration data from three clinical studies in human immunodeficiency virus‐infected children (n = 69) were used for model building. The children received either a weight‐normalized dose of 16 mg kg−1 day−1 or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria.ResultsA two‐compartmental model with first‐order absorption and first‐order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady‐state maximal plasma concentration and area under the concentration–time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l−1 and 6.1 mg h l−1 for toddlers and infants, and 3.6 mg l−1 and 8.7 mg h l−1 for children, respectively. Model‐based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling.ConclusionsThe disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny.
Establishing a body awareness group for adults with learning disabilities
Authors: Rubbert Stefanie , Bisnauth Radha , Offen Liz 
Published: November 2012

Accessible Summary

We held a group for people with Learning Disabilities who were overweight and unhappy about being so.

The group ran for 9 weeks. It lasted 2 h and four adults came to the group.

The group talked about how they felt about their bodies, why they ate and why it is sometimes hard to choose healthy food over unhealthy food. It helped people learn to accept their body size and shape.

SummaryThe Clinical Psychology Service and the Dietetic and Nutrition Service for People with Learning Disabilities in Birmingham shared concerns about the effectiveness of services offered to service users who were overweight. In an effort to gain more understanding of the issues from a service user perspective and to ultimately provide more effective services, a body awareness group was established, structured according to the ‘Health at Every Size’ model. Four adults with learning disabilities attended a total of nine sessions held once a week for a period of 2 h. Topics were presented to the group in the form of group discussions or group activities, which included: personal and social attributions towards body shape and size; self‐esteem; physical eating vs. emotional eating; relationship with food (e.g. understanding of choosing junk food over healthier options); negative messages people tell themselves about eating and factors that prevent people from engaging in a healthier lifestyle. This study aims to report the process of designing and facilitating the ‘Body Awareness Group’ and to critically review observations and findings in an effort to gain greater understanding of the role of food in this context.
Brain Maturation and Risky Behavior: The Promise and the Challenges of Neuroimaging‐Based Accounts
Authors: Bjork James M. , Lynne‐Landsman Sarah D. , Sirocco Karen , Boyce Cheryl A. 
Published: November 2012

AbstractEmerging brain‐imaging findings suggest that developmental differences in the structure and activity of brain regions involved in motivation and behavior control may contribute to risky behavior in adolescence. Adolescence may be characterized by robust motivational neurocircuitry that is relatively unhindered by developing cognitive control neurocircuitry. However, how developmental differences in brain structure or function depend on task features or other experimental contexts, or whether observed differences are functionally relevant for real‐world risky behavior, is not well understood. The challenge of attributing adolescent risk taking to developmental patterns of brain morphology and brain activity underscores the need for future research sensitive to development and the contexts of adolescence.
Differential effect of hyperglycaemia on the immune response in an experimental model of diabetes in BALB/cByJ and C57Bl/6J mice: participation of oxidative stress
Authors: Rubinstein M R , Genaro A M , Wald M R 
Published: November 2012

SummaryDiabetes is associated with an increased risk of death from infectious disease. Hyperglycaemia has been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. However, experimental evidence indicates individual susceptibility to develop complications of diabetes. In this context, the aim of this work was to study the immune response in a streptozotocin-induced type 1 diabetes in two mouse strains: BALB/cByJ and C57Bl/6J. The participation of hyperglycaemia and oxidative stress was also analysed. Diabetic BALB/cByJ mice showed a decrease in both the in-vivo and in-vitro immune responses, whereas diabetic C57Bl/6J mice had higher blood glucose but exhibited no impairment of the immune response. The influence of hyperglycaemia over the immune response was evaluated by preincubation of lymphocytes from normal mice in a high glucose-containing medium. T and B cells from BALB/cByJ mice showed a decrease in cell viability and mitogen-stimulated proliferation and an increase in apoptosis induction. An increase in oxidative stress was implicated in this deleterious effect. These parameters were not affected in the T and B lymphocytes from C57Bl/6J mice. In conclusion, BALB/cByJ mice were sensitive to the deleterious effect of hyperglycaemia, while C57BL/6J were resistant. Although an extrapolation of these results to clinical conditions must be handled with caution, these results highlight the need to contemplate the genetic background to establish models to study the deleterious effect of diabetes in order to understand phenotypical variations that are of clinical importance in the treatment of patients.
Human leucocyte antigen-Bw4 and Gag-specific T cell responses are associated with slow disease progression in HIV-1B-infected anti-retroviral therapy-naive Chinese
Authors: Li W-H , Li C-Y , Yang H-B , Zhang H-P , Zhang X , Kong L-S , Xu X-N , Lu S-C , Yan H-P 
Published: November 2012

Summary
In China, the majority of human immunodeficiency virus (HIV) infections are predominately subtype B. It is important to characterize the HIV-1 subtype B-specific and its T cell response within the Chinese population, with the aim of identifying protective correlates of immunity to control HIV-1 infections. In this study, we performed a comprehensive analysis looking into the magnitude/strength of T cell responses directed at the Gag protein of the HIV-1 subtype B, one of the most conserved HIV-1 proteins. The study group consisted of anti-retroviral native and chronic HIV-1 subtype B-infected individuals. We used enzyme-linked immunospot (ELISPOT) assay to quantify the total T cell responses to HIV-1 Gag at the single peptide level. Twenty-eight (38%) peptides were recognized in 24 (82·8%) individuals. The p24 was identified as the most frequently recognized subunit protein with the greatest T cell response in the test, which correlated positively with CD4+ T cell count and inversely with viral load (VL). At the level of the human leucocyte antigen (HLA) supertypes, we detected the highest levels and a significant correlation with both the CD4+ T cell count and the VL with Gag T cell responses in Bw4/Bw4. These findings demonstrate that (i) the HIV-1B Gag p24-specific immune responses play an important role in controlling viral replication and slowing clinical progression; and (ii) HLA-Bw4/Bw4 allele has stronger T cell responses, which is associated with slow clinical progression in Chinese HIV patients.
Experimental models to investigate the function of dendritic cell subsets: challenges and implications
Authors: Hancock D G , Guy T V , Shklovskaya E , Fazekas de St Groth B 
Published: November 2012

SummaryThe dendritic cell (DC) lineage is remarkably heterogeneous. It has been postulated that specialized DC subsets have evolved in order to select and support the multitude of possible T cell differentiation pathways. However, defining the function of individual DC subsets has proven remarkably difficult, and DC subset control of key T cell fates such as tolerance, T helper cell commitment and regulatory T cell induction is still not well understood. While the difficulty in assigning unique functions to particular DC subsets may be due to sharing of functions, it may also reflect a lack of appropriate physiological in-vivo models for studying DC function. In this paper we review the limitations associated with many of the current DC models and highlight some of the underlying difficulties involved in studying the function of murine DC subsets.
Acquired auditory agnosia in childhood and normal sleep electroencephalography subsequently diagnosed as Landau–Kleffner syndrome: a report of three cases
Authors: VAN BOGAERT PATRICK , KING MARY D , PAQUIER PHILIPPE , WETZBURGER CATHERINE , LABASSE CATHERINE , DUBRU JEAN‐MARIE , DEONNA THIERRY 
Published: November 2012

Aim We report three cases of Landau–Kleffner syndrome (LKS) in children (two females, one male) in whom diagnosis was delayed because the sleep electroencephalography (EEG) was initially normal.Method Case histories including EEG, positron emission tomography findings, and long‐term outcome were reviewed.Results Auditory agnosia occurred between the age of 2 years and 3 years 6 months, after a period of normal language development. Initial awake and sleep EEG, recorded weeks to months after the onset of language regression, during a nap period in two cases and during a full night of sleep in the third case, was normal. Repeat EEG between 2 months and 2 years later showed epileptiform discharges during wakefulness and strongly activated by sleep, with a pattern of continuous spike‐waves during slow‐wave sleep in two patients. Patients were diagnosed with LKS and treated with various antiepileptic regimens, including corticosteroids. One patient in whom EEG became normal on hydrocortisone is making significant recovery. The other two patients did not exhibit a sustained response to treatment and remained severely impaired.Interpretation Sleep EEG may be normal in the early phase of acquired auditory agnosia. EEG should be repeated frequently in individuals in whom a firm clinical diagnosis is made to facilitate early treatment.
Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences
Authors: Labate Angelo , Tarantino Patrizia , Viri Maurizio , Mumoli Laura , Gagliardi Monica , Romeo Antonino , Zara Federico , Annesi Grazia , Gambardella Antonio 
Published: November 2012

SummaryHeterozygous mutations of PRRT2, which encodes proline‐rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6–44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD—mental retardation, episodic ataxia, and absences—who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.
Fluvastatin inhibits the induction of inducible nitric oxide synthase, an inflammatory biomarker, in hepatocytes
Authors: Tokuhara Katsuji , Habara Kozo , Oishi Masaharu , Miki Hirokazu , Tanaka Yoshito , Kaibori Masaki , Nishizawa Mikio , Okumura Tadayoshi , Kwon A‐Hon 
Published: November 2012

AimStatins (3‐hydroxy‐3‐methylglutaryl coenzyme A [HMG‐CoA] reductase inhibitors), which were originally designed to lower plasma cholesterol levels, are increasingly recognized as anti‐inflammatory agents. In the inflamed liver, pro‐inflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS). Overproduction of NO by iNOS has been implicated as a factor in liver injury. We examined pro‐inflammatory cytokine‐stimulated hepatocytes as a simple in vitro injury model to determine liver‐protective effects of statins. We hypothesized that statins are involved in the downregulation of iNOS, resulting in decreased hepatic inflammation.MethodsHepatocytes were isolated from rats by collagenase perfusion and centrifugation. Primary cultured hepatocytes were treated with interleukin (IL)‐1β in the presence or absence of fluvastatin. The induction of iNOS and its signaling pathway were analyzed.ResultsIL‐1β produced increased levels of NO. This effect was inhibited by fluvastatin, which exerted its maximal effects at 100 μM. Fluvastatin decreased the levels of iNOS protein and its mRNA expression. Fluvastatin had no effects on IκB degradation and nuclear factor‐κB activation. However, fluvastatin inhibited the upregulation of type I IL‐1 receptor mRNA and protein expression. Transfection experiments demonstrated that fluvastatin suppressed iNOS induction by the inhibition of promoter transactivation and mRNA stabilization. Fluvastatin reduced the expression of an iNOS gene antisense‐transcript, which is involved in iNOS mRNA stability.ConclusionResults indicate that fluvastatin inhibits the induction of iNOS at both transcriptional and post‐transcriptional steps, leading to the prevention of NO production. Fluvastatin may provide therapeutic potential in iNOS induction involved in various liver injuries.