Promising results of the chaperone effect caused by iminosugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease

Gaucher disease is an autosomal recessive disorder. It is characterized by the accumulation of glucosylceramide in lysosomes of mononuclear phagocyte system, attributable to acid β-glucosidase deficiency. The main consequences of this disease are hepatosplenomegaly, skeletal lesions and, sometimes, neurological manifestations. At sub-inhibitory concentrations, several competitive inhibitors act as chemical chaperones by inducing protein stabilization and increasing enzymatic activity. Here we tested two iminosugars (NB-DNJ and NN-DNJ) and four aminocyclitols with distinct degrees of lipophilicity as pharmacological chaperones for glucocerebrosidase (GBA). We report an increase in the activity of GBA using NN-DNJ, NB-DNJ and aminocyclitol 1 in stably transfected cell lines, and an increment with NN-DNJ and aminocyclitol 4 in patient fibroblasts. These results on specific mutations validate the use of chemical chaperones as a therapeutic approach for Gaucher disease. However, the development and analysis of new compounds is required in order to find more effective therapeutic agents that are active on a broader range of mutations.     

Chronic fatigue syndrome and personality: A case-control study using the alternative five factor model

Neuroticism is the personality dimension most frequently associated with chronic fatigue syndrome (CFS). Most studies have also shown that CFS patients are less extraverted than non-CFS patients, but results have been inconsistent, possibly because the facets of the extraversion dimension have not been separately analyzed. This study has the following aims: to assess the personality profile of adults with CFS using the Alternative Five-Factor Model (AFFM), which considers Activity and Sociability as two separate factors of Extraversion, and to test the discriminant validity of a measure of the AFFM, the Zuckerman–Kuhlman Personality Questionnaire, in differentiating CFS subjects from normal-range matched controls. The CFS sample consisted of 132 consecutive patients referred for persistent fatigue or pain to the Department of Medicine of a university hospital. These were compared with 132 matched normal population controls. Significantly lower levels of Activity and significantly higher levels of Neuroticism-Anxiety best discriminated CFS patients from controls. The results are consistent with existing data on the relationship between Neuroticism and CFS, and clarify the relationship between Extraversion and CFS by providing new data on the relationship of Activity to CFS.     

Cell types and coincident synapses in the ellipsoid body of Drosophila

Cellular ultrastructures for signal integration are unknown in any nervous system. The ellipsoid body (EB) of the Drosophila brain is thought to control locomotion upon integration of various modalities of sensory signals with the animal internal status. However, the expected excitatory and inhibitory input convergence that virtually all brain centres exhibit is not yet described in the EB. Based on the EB expression domains of genetic constructs from the choline acetyl transferase (Cha), glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) genes, we identified a new set of neurons with the characteristic ring‐shaped morphology (R neurons) which are presumably cholinergic, in addition to the existing GABA‐expressing neurons. The R1 morphological subtype is represented in the Cha‐ and TH‐expressing classes. In addition, using transmission electron microscopy, we identified a novel type of synapse in the EB, which exhibits the precise array of two independent active zones over the same postsynaptic dendritic domain, that we named ‘agora’. This array is compatible with a coincidence detector role, and represents ~8% of all EB synapses in Drosophila. Presumably excitatory R neurons contribute to coincident synapses. Functional silencing of EB neurons by driving genetically tetanus toxin expression either reduces walking speed or alters movement orientation depending on the targeted R neuron subset, thus revealing functional specialisations in the EB for locomotion control.     

Neuroticism and impulsivity: Their hierarchical organization in the personality characterization of drug-dependent patients from a decision tree learning perspective

Objective

Neuroticism and impulsivity are the personality variables most consistently associated with drug-dependent patients. To date, no data mining procedures have been applied to explore the differential role of personality variables in this population.

Methods

The personality profile of 336 drug-dependent patients was compared with that of a sample of community participants in the context of a decision tree learning approach using the Alternative Five Factor Model. The resulting discriminant model was cross-validated.

Results

Neuroticism and impulsivity were the most relevant variables in the resulting model, but their association appeared to be hierarchically organized. In the personality characterization of these patients, neuroticism became the main discriminant dimension, whereas impulsivity played a differential role, explained by means of an interaction effect. Decision tree learning models appear to be a heuristic theoretical and empirical approximation to the study of relevant variables, such as personality traits, in drug-dependency research.     

Differences in the association between childhood trauma history and borderline personality disorder or attention deficit/hyperactivity disorder diagnoses in adulthood

European Archives of Psychiatry and Clinical Neuroscience - Common environmental etiological factors between borderline personality disorder (BPD) and attention deficit/hyperactivity disorder...     

甘草泻心汤治疗溃疡性结肠炎机制及临床研究进展

溃疡性结肠炎（UC）是一种慢性、非特异性炎症性肠病,病因与环境、遗传、感染和肠道微生物等多种因素相关。甘草泻心汤出自《伤寒论》,由炙甘草、黄芩、黄连、干姜、人参、半夏、大枣组成,具有调和寒热,消痞止利的功效。现代研究发现,甘草泻心汤单独或联合西药治疗UC具有显著疗效,其作用机制包括调节炎症因子、保护肠道黏膜和改善肠道菌群。通过查阅相关文献,对近年来甘草泻心汤及其单体治疗UC的相关机制与临床研究进行梳理与总结,以期为中医及中西医结合治疗UC提供理论依据并拓展治疗思路。     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

Two different maturational stages of natural killer lymphocytes in human newborn infants.

The objective of this study was to assess the basis for the diminished natural killer (NK) lymphocyte activity of neonates. We found either severely reduced (63% of 68 neonates) or normal (similar to healthy adult) levels of NK activity. The percentages of cord blood mononuclear cells from the two groups of infants that expressed CD16, a differentiation antigen found in NK cells, were similar and within the range found in peripheral blood mononuclear cells of adults. However, infants with low NK activity had reduced numbers of cells in the CD16+56+ subpopulation, whereas the number of these effector cells present in cord blood mononuclear cells from infants with normal NK activity was within the range found in adults. Recombinant interleukin-2, but not recombinant interferon-gamma, normalized the low NK activity of infants in a dose- and time-dependent manner. Analysis of the pattern of target cell susceptibility to lysis, together with the CD16+CD3- phenotype of the precursor and effector lymphocytes, demonstrated that the induced cytotoxicity was mediated by NK cells. In contrast, NK cells from infants with normal cytotoxic levels exhibited a functional response to interleukin-2 and interferon-gamma similar to that of adults. Our results indicate that NK cells in human neonates go through two different maturational stages.     

Acute renal failure in a neonate due to pelviureteric candidal bezoars successfully treated with long-term systemic fluconazole

Systemic candidiasis with renal involvement is a rare but well-recognized complication during intensive care treatment in very-low-birth-weight infants. We report a term neonate who developed anuria associated with bilateral bezoar formation in the renal pelvis and candidemia. The treatment consisted of placement of a nephrostomy tube in the left kidney, short-term irrigation with amphotericin B and iv, and later, oral administration of fluconazole.