N-valproyl-L-tryptophan for CNS-targeting: synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug

A new aminoacidic derivative of valproic acid (VPA) has been synthesized and characterized by analytical and spectral data. The rationale for the preparation of such potential antiepileptic agent is based on the observation that chemical combination of the anticonvulsant pharmacophore, VPA with essential aminoacids could afford more effective and less toxic actives. The synthesis, characterization, physico-chemical parameters functional for crossing Blood Brain Barrier of N-valproyl-L-tryptophan (4) are reported. The Log D (pH7.4) (0.3) indicates that (4) is adequate to cross biological membranes. Its chemical and enzymatic stability were assessed. The experiments indicate high stability of compound (4) at pH conditions of physiological fluids. Moreover, both in plasma and in cerebral enzymatic environments compound (4) doesn't undergo cleavage after 24 h. The anticonvulsant activity of the new compound was assessed against epileptic burst discharges evoked in vitro in rat hippocampal slices (Seizure like events - SLEs) and compared with that of the widely used VPA. Compound (4), even at the lower tested concentration, when compared to VPA, showed an improved protective effect against hippocampal seizures. The collected data suggest that compound (4) could be considered a very valuable candidate for subsequent in vivo evaluation as new potential antiepileptic drug.     

HIV-associated immune activation: from bench to bedside

HIV infection is associated with a state of chronic, generalized immune activation that has been shown in many studies to be a key predictor of progression to AIDS. Consistent with this model, nonpathogenic SIV infections of natural hosts, such as the sooty mangabeys, are characterized by low levels of immune activation during the chronic phase of infection. The molecular, cellular, and pathophysiological mechanisms underlying the HIV-associated immune activation are complex and still poorly understood. There is, however, growing consensus that both viral and host factors contribute to this phenotype, with emphasis on the role played by the mucosal immune dysfunction (and consequent microbial translocation) as well as the pattern of in vivo-infected CD4(+) T cells. The observation that antiretroviral therapy (ART)-induced suppression of HIV replication does not fully resolve immune activation provided the rationale for a number of exploratory studies of potential immune modulatory treatments to be used in HIV-infected individuals in addition to standard ART. This review provides an update on the causes and consequences of the HIV-associated immune activation, and a summary of the immune modulatory approaches that are currently under clinical investigation.     

Left coronary artery stenosis with post-stenotic aneurysm after arterial switch operation before and after coronary revascularisation surgery

We report the case of a child with severe and atypical stenosis of the left main coronary artery, which occurred late after arterial switch operation for transposition of the great arteries. Cardiac computed tomography accurately defined the lesion, showing the presence of post-stenotic dilation, guided the surgical approach and assessed coronary patency after revascularisation surgery.     

Nouns and verbs in the brain: A review of behavioural, electrophysiological, neuropsychological and imaging studies

In the past 30 years there has been a growing body of research using different methods (behavioural, electrophysiological, neuropsychological, TMS and imaging studies) asking whether processing words from different grammatical classes (especially nouns and verbs) engage different neural systems. To date, however, each line of investigation has provided conflicting results. Here we present a review of this literature, showing that once we take into account the confounding in most studies between semantic distinctions (objects vs. actions) and grammatical distinction (nouns vs. verbs), and the conflation between studies concerned with mechanisms of single word processing and those studies concerned with sentence integration, the emerging picture is relatively clear-cut: clear neural separability is observed between the processing of object words (nouns) and action words (typically verbs), grammatical class effects emerge or become stronger for tasks and languages imposing greater processing demands. These findings indicate that grammatical class per se is not an organisational principle of knowledge in the brain; rather, all the findings we review are compatible with two general principles described by typological linguistics as underlying grammatical class membership across languages: semantic/pragmatic, and distributional cues in language that distinguish nouns from verbs. These two general principles are incorporated within an emergentist view which takes these constraints into account.     

Association of intronic variants of the KCNAB1 gene with lateral temporal epilepsy

The KCNAB1 gene is a candidate susceptibility factor for lateral temporal epilepsy (LTE) because of its functional interaction with LGI1, the gene responsible for the autosomal dominant form of LTE. We investigated association between polymorphic variants across the KCNAB1 gene and LTE. The allele and genotype frequencies of 14 KCNAB1 intronic SNPs were determined in 142 Italian LTE patients and 104 healthy controls and statistically evaluated. Single SNP analysis revealed one SNP (rs992353) located near the 3'end of KCNAB1 slightly associated with LTE after multiple testing correction (odds ratio=2.25; 95% confidence interval 1.26-4.04; P=0.0058). Haplotype analysis revealed two haplotypes with frequencies higher in cases than in controls, and these differences were statistically significant after permutation tests (Psim=0.047 and 0.034). One of these haplotypes was shown to confer a high risk for the syndrome (odds ratio=12.24; 95% confidence interval 1.32-113.05) by logistic regression analysis. These results support KCNAB1 as a susceptibility gene for LTE, in agreement with previous studies showing that this gene may alter susceptibility to focal epilepsy.