Involvement of p38/NF-κB signaling pathway in the nucleus accumbens in the rewarding effects of morphine in rats

The nucleus accumbens (NAc) is one of the important brain regions for the acquisition of morphine-induced conditioned place preference (CPP), which is a valuable paradigm for detecting the rewarding effects of drugs. However, the underlying molecular mechanisms remain largely unknown. In the present study, we investigated the role of p38 and nuclear factor kappa B (NF-κB) in the NAc in the acquisition of morphine-induced CPP. The results showed that repeated morphine treatment induced the acquisition of CPP and increased the phosphorylation of p38, IκB-α and NF-κB p65 in the NAc. Microinjection of p38 inhibitor SB203580 into the NAc prior to the application of morphine prevented the acquisition of CPP and inhibited the activation of p38, IκB-α and NF-κB p65. Furthermore, pre-infusion of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, into the NAc blocked the CPP but also the phosphorylation of NF-κB p65 induced by morphine. It is concluded that the activation of p38/NF-κB p65 signaling pathway in the NAc plays a critical role in the morphine CPP.     

PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons

PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis,apoptosis,and nec roptosis,which simultaneously occur during the pathophysiological process of infectious and inflammatory diseases.Although our previous lite rature mining study suggested that PANoptosis might occur in neuronal ischemia/repe rfusion injury,little experimental research has been reported on the existence of PANoptosis.In this study,we used in vivo and in vitro retinal neuronal models of isch...     

An investigation of changes in children′s mental health in Wales between 2007/2008 and 2012/2013

Improving children’s mental wellbeing is a recognised public health priority, but evidence on recent trends is lacking. This study updates evidence on differences in child mental health since 2008 by comparing two nationally representative cohorts in Wales, UK. Parents of 4- to 12-year-old children completed the Strengths and Difficulties Questionnaire (SDQ). No significant differences were seen for younger girls between 2007/2008 and 2012/2013. There was a decrease in conduct, hyperactivity and total difficulties symptom scores and an increase in prosocial scores for boys and older girls. These findings suggest that rates of child mental health problems are stable or falling.     

PKC-β exacerbates in vitro brain barrier damage in hyperglycemic settings via regulation of RhoA/Rho-kinase/MLC2 pathway

Stroke patients with hyperglycemia (HG) develop higher volumes of brain edema emerging from disruption of blood–brain barrier (BBB). This study explored whether inductions of protein kinase C-β (PKC-β) and RhoA/Rho-kinase/myosin-regulatory light chain-2 (MLC2) pathway may account for HG-induced barrier damage using an in vitro model of human BBB comprising human brain microvascular endothelial cells (HBMEC) and astrocytes. Hyperglycemia (25 mmol/L D-glucose) markedly increased RhoA/Rho-kinase protein expressions (in-cell westerns), MLC2 phosphorylation (immunoblotting), and PKC-β (PepTag assay) and RhoA (Rhotekin-binding assay) activities in HBMEC while concurrently reducing the expression of tight junction protein occludin. Hyperglycemia-evoked in vitro barrier dysfunction, confirmed by decreases in transendothelial electrical resistance and concomitant increases in paracellular flux of Evan''s blue-labeled albumin, was accompanied by malformations of actin cytoskeleton and tight junctions. Suppression of RhoA and Rho-kinase activities by anti-RhoA immunoglobulin G (IgG) electroporation and Y-27632, respectively prevented morphologic changes and restored plasma membrane localization of occludin. Normalization of glucose levels and silencing PKC-β activity neutralized the effects of HG on occludin and RhoA/Rho-kinase/MLC2 expression, localization, and activity and consequently improved in vitro barrier integrity and function. These results suggest that HG-induced exacerbation of the BBB breakdown after an ischemic stroke is mediated in large part by activation of PKC-β.     

What is a clinically important level of improvement in symptoms of attention-deficit/hyperactivity disorder?

OBJECTIVE: To compare the desired and actual reduction in scores on a parent reported behaviour rating scale in a naturalistic sample of children and adolescents who had been treated with psychostimulant medication, referenced to global ratings of treatment benefit. METHOD: Forty-five parents reporting poor global response to psychostimulant treatment, 44 reporting moderate response, and 49 reporting a high response retrospectively completed Conners rating scales describing their child prior to treatment, the child currently, and how the parent hoped the child would be following treatment. RESULTS: Percentage actual improvement in behaviour rating scales from baseline ranged from around 25% for the poor responders to above 50% for the high responders. Desired improvement was above 50%, with no significant difference between the groups on level of expectation. CONCLUSIONS: Percentage cut points used to indicate clinical improvement reported in previous controlled trials of psychostimulant medication are probably too low, and could lead to an overestimate of treatment effect. Expectation of treatment benefit is unlikely to contribute to variation in treatment response.     

Exploration of dimensions of psychopathology in neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder

Previous studies have suggested that schizophrenic psychopathology segregates into three orthogonal dimensions, viz., psychosis, negative and disorganization. Most of these reports were based on studies on medicated patients with varying degrees of chronicity. The present study aimed at exploring the dimensionality of psychopathology rated on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in a sample of 43 neuroleptic-na?ve patients with recent-onset schizophrenia/schizophreniform disorder. Principal Components Analysis (PCA) of SANS and SAPS global ratings, excluding inattention but including inappropriate affect as a separate global rating, revealed that the symptoms segregated into three dimensions, viz., negative (affective flattening, alogia, avolition anhedonia and inappropriate affect), psychosis (delusions and hallucinations) and disorganization (positive formal thought disorder and bizarre behavior). Cumulatively these three dimensions explained 74.07% of the variance. The results suggest that the three dimensions of schizophrenic psychopathology are valid even in neuroleptic-na?ve, recent-onset patients with schizophrenia/schizophreniform disorder. PCA of the SANS and SAPS individual items revealed similar findings, but psychotic symptoms loaded under two components, thus yielding a four-factor solution; however, this observation needs to be confirmed in a larger sample of neuroleptic-na?ve schizophrenic patients.     

Clinical value of C-reactive protein/albumin ratio in Guillain-Barré syndrome

Neurological Sciences - Respiratory failure in patients with Guillain-Barré syndrome (GBS) can lead to serious complications and dysfunctions, emphasizing the importance of early detection....     

Cytoarchitectural organization of the parabrachial/Kölliker-Fuse complex in man

While the parabrachial/K?lliker-Fuse complex has been described in a variety of animal species it has not been characterized in human brainstem. In the present study we investigated fetal and infant brainstems, focusing particularly on the dorsolateral part of the pontine tegmentum, with the aim of defining the precise cytoarchitecture of the medial parabrachial, lateral parabrachial, and K?lliker-Fuse nuclei in man, and analyzing the developmental stages of this complex. In serial sections of 28 human brainstems of subjects aged between 32 gestational weeks and 1 year we made a morphologic and morphometric analysis of the shape and size of the parabrachial/K?lliker-Fuse complex. We observed a homogeneous morphology in all cases, which enabled us to define the structure of the three nuclei. The features of the parabrachial nuclei are largely consistent with those reported in experimental studies. However, the K?lliker-Fuse nucleus appears to be more developed in human beings than in other animal species, showing a greater extension and a more complex structure. The neuronal maturation of these nuclei was seen to occur between the 35th and the 36th gestational weeks.     

The characteristics of unacceptable/taboo thoughts in obsessive–compulsive disorder

Background

In the quest to unravel the heterogeneity of obsessive–compulsive disorder (OCD), an increasing number of factor analytic studies are recognising unacceptable/taboo thoughts as one of the symptom dimensions of OCD.

Aims

This study aims to examine the characteristics associated with unacceptable/taboo thoughts.

Methods

Using the Yale–Brown Obsessive–Compulsive Scale Symptom Checklist (YBOCS-SC) with 154 individuals with OCD, obsessive–compulsive symptoms were subjected to principal components analysis. The characteristics associated with the resulting symptom dimensions were then assessed using logistic and linear regression techniques.

Results

Unacceptable/taboo thoughts comprised of sexual, religious and impulsive aggressive obsessions, and mental rituals. Higher scores on an unacceptable/taboo thoughts symptom dimension were predicted by higher Y-BOCS obsession subscores, Y-BOCS time preoccupied by obsessions scores, Y-BOCS distress due to obsessions scores, importance of control of thought ratings, male gender, and having had treatment prior to entering into the study. Unacceptable/taboo thoughts were also predicted by greater levels of hostility, and a past history of non-alcohol substance dependence.

Conclusions

An unacceptable/taboo thought symptom dimension of OCD is supported by a unique set of associated characteristics that should be considered in the assessment and treatment of individuals with these symptoms.     

Effects of nerve growth factor on the expression of caspase-12 of nerve cells in cerebral ischemia/reperfusion area

INTRODUCTIONApoptosis plays a key role in cerebral ischemia/reperfusion injury [1-5].Recently, researches suggest that stress of endoplasmic reticulumcan mediate apoptosis [6-12]; especially, stress apoptosis of endoplas-mic reticulum mediated by caspase-…     

Time-dependent changes of glial fibriliary acidic protein and cytosolic phospholipase A2 in hippocampal area of focal cerebral ischemia/reperfusion in rats

INTRODUCTIONAfter onset of focal cerebral ischemia, corresponding reaction be-tween neuroglial cells and neurons in brain tissue is the hot topic atpresent. Interaction between astrocyte and neuron may two-dimen-sionally influence on ischemic injury; howe…     

Investigating the role of Ca2+/calmodulin-dependent protein kinaseⅡin the survival of retinal ganglion cells

Retinal ganglion cells(RGCs)are the sole output neurons of the retina that project long axons and transmit visual information to the brain.The degeneration of RGCs leads to irreversible vision loss in a variety of pathological states,including excitotoxicity,traum atic nerve injury,and glaucoma.     

The effect of N-octyl-β-valienamine on β-glucosidase activity in tissues of normal mice

Gaucher disease (GD), mainly caused by a defect of acid β-glucosidase (β-Glu), is the most common sphingolipidosis. We have previously shown that a carbohydrate mimic N-octyl-β-valienamine (NOV), an inhibitor of β-Glu, could increase the protein level and enzyme activity of various mutant β-Glu in cultured GD fibroblasts, suggesting that NOV acted as a pharmacological chaperone to accelerate transport and maturation of this mutant enzymes. In the present study, the NOV effect was evaluated for β-Glu activity, tissue distribution and adverse effects in normal mice. We measured the β-Glu activity in tissues of normal mice which received water containing increasing concentrations of NOV ad libitum for 1 week. Fluid intake and body weight were measured periodically throughout the study. Measurement of tissue NOV concentration, blood chemistry and urinalysis were performed at the end of the study. The results showed that NOV had no impact on the body weight but fluid intake in the 10 mM NOV group mice decreased and there was a moderate increase in blood urea nitrogen (BUN). No other adverse effect was observed during this experiment. Tissue NOV concentration increased in all tissues examined with increasing NOV doses. No inhibitory effect of NOV on β-Glu was observed. Furthermore, NOV increased the β-Glu activity in the liver, spleen, muscle and cerebellum of the mice significantly. This study on NOV showed its oral availability and wide tissue distribution, including the brain and its lack of acute toxicity. These characteristics of NOV would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations and selected mutations.     

The spatial patterns of β/A4 deposit subtypes in Alzheimer's disease

Summary The spatial patterns of diffuse, primitive, classic (cored) and compact (burnt-out) subtypes of /A4 deposits were studied in coronal sections of the frontal lobe and hippocampus, including the adjacent gyri, in nine cases of Alzheimer's disease (AD). If the more mature deposits were derived from the diffuse deposits then there should be a close association between their spatial patterns in a brain region. In the majority of tissues examined, all deposit subtypes occurred in clusters which varied in dimension from 200 to 6400 m. In many tissues, the clusters appeared to be regularly spaced parallel to the pia or alveus. The mean dimension of the primitive deposit clusters was greater than those of the diffuse, classic and compact types. In about 60% of cortical tissues examined, the clusters of primitive and diffuse deposits were not in phase, i.e. they alternated along the cortical strip. Clusters of classic deposits appeared to be distributed independently of the diffuse deposit clusters. Cluster size of the primitive deposits was positively correlated with the density of the primitive deposits in a tissue but no such relationship could be detected for the diffuse deposits. This study suggested that there was a complex relationship between the clusters of the different subtypes of /A4 deposits. If the diffuse deposits do give rise to the primitive and classic varieties then factors unrelated to the initial deposition of /A4 in the form of diffuse plaques were important in the formation of the mature deposits.Supported in part by the Alzheimer's disease Society of the UK     

The spatial patterns of β/A4 deposit subtypes in Down's syndrome

The spatial patterns of diffuse, primitive and classic /A4 deposits were studied in coronal sections of the hippocampus and adjacent gyri in 11 cases of Down's syndrome (DS) varying in age from 38 to 67 years. The objectives of the study were first, to compare the spatial patterns of /A4 deposits revealed in DS with those reported in cases of Alzheimer's disease (AD) and second, to study how the spatial patterns of /A4 deposits may develop in the tissue. The spatial patterns revealed in DS exhibited a number of similarities with those reported in AD: (1) the range and frequency of the different types of spatial pattern revealed were similar, (2) /A4 deposits occurred in clusters and in many cortical tissues, the clusters were distributed in a regular pattern parallel to the pia, (3) the clusters of diffuse and primitive /A4 deposits occurred in an alternating pattern along the cortex, and (4) the clusters of classic /A4 deposits were not correlated with the clusters of the diffuse and primitive deposits. Primitive deposits may develop from the diffuse deposits in regions of the cortex where extracellular paired helical filaments were formed. However, clusters of the classic /A4 deposits, which are formed in older cases, appear to develop independently of the diffuse and primitive deposits.Supported in part by the Alzheimer's Disease Society, UK     

Altered immunoreactivity of HPC-1/syntaxin 1A in proliferated nerve fibers in the human aganglionic colon of hirschsprung’s disease

To clarify the pathogenesis of excessive proliferation of extrinsic nerve fibers in the aganglionic colon of patients with Hirschsprung’s disease (HD), we immunohistochemically determined the role that exocytosis-related proteins play in the regulation of exocytosis using the antibody to HPC-1/syntaxin 1A, an exocytosis-related protein. Localization of exocytosis-related proteins (HPC-1/syntaxin 1A, N-ethylmalemide-sensitive fusion protein (NSF), soluble NSF attachment protein (SNAP), synaptotagmin, synaptobrevin, and synaptosome-associated protein 25 (SNAP-25)) was determined in surgical specimens obtained from normal proximal and aganglionic distal segments of the colon of 7 infant patients with HD. In the normal ganglionic colon, Auerbach’s plexus, Meisner’s plexus, nerve fibers in the muscle layer, and ganglion cells were immunopositive for all six kinds of antisera. In the aganglionic segments, numerous proliferated nerve fibers and hypertrophied nerve bundles were detected in the submucosal layer and myenteric layer by NSF, SNAP, synaptotagmin, synaptobrevin, and SNAP-25. However, HPC-1/syntaxin 1A was not recognized in the proliferated nerve fibers of the submucosal layer or the hypertrophied nerve bundles of the aganglionic segment. These findings show that immunoreactivity of HPC-1/syntaxin 1A was decreased in the affected bowel segments of patients with HD and may be related to the pathogenesis of extrinsic nerve-fiber proliferation in the aganglionic colon of HD.     

Focusing on the protective effects of metallothionein-Ⅰ/Ⅱ in cerebral ischemia

正Ischemic stroke is a leading cause of death and has a remarkable social and economical impact,which rises with the increasing age of the industrial population.Unfortunately,treatment strategies for cerebral ischemia still remain very limited.Acute reperfusion therapies with either systemic thrombolysis using rt-PA