Intermediate filament cytoskeleton of the liver in health and disease

Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising ~70 genes expressed in tissue specific manner. In addition to scaffolding function, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deficient animals exhibit a marked susceptibility to various toxic agents and Fas-induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with development of liver fibrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated K8/K18, chaperones and sequestosome1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non-alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transamidation of keratin 8 and p62 upregulation

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.C-E Chong, P Venugopal, PH Stokes, YK Lee, PJ Brautigan, DTO Yeung, M Babic, GA Engler, SW Lane, M Klingler-Hoffmann, JM Matthews, RJ D'Andrea, AL Brown, CN Hahn, and HS Scot

The potential interaction between time perception and gaming: a narrative review

Compromised time control is a variable of interest among disordered gamers because time spent on videogames can directly affect individuals’ lives. Although time perception appears to be closely associated with this phenomenon, previous studies have not systematically found a relationship between time perception and gaming. Therefore, the purpose of this narrative review is to explore how gaming disorder may be associated with time perception. It has been found that gamers exhibit a stronger attentional focus as well as an improved working memory compared with non-gamers. However, gamers (and especially disordered gamers) exhibit a stronger reaction to gaming cues which—coupled with an altered emotion regulation observed among disordered gamers—could directly affect their time perception. Finally, “'flow states”' direct most of the attentional resources to the ongoing activity, leading to a lack of resources allocated to the time perception. Therefore, entering a flow state will result in an altered time perception, most likely an underestimation of duration. The paper concludes that the time loss effect observed among disordered gamers can be explained via enhanced emotional reactivity (facilitated by impaired emotion regulation)

Princípios e padrões em metaavaliação: diretrizes para os programas de saúde Principles and standards in metaevaluation: guidelines for health programs

Este artigo apresenta questões imperativas para o uso de princípios e padrões em avaliação, permitindo destacar diretrizes para estudos de metaavaliação, tendo como exemplo os Estudos de Linha de Base (ELB) do Projeto de Expansão e Consolidação do Saúde da Família (Proesf). Essas questões são importantes em países em que a Política Nacional de Avaliação ainda é incipiente, como é o caso do Brasil, onde se observa a ausência de dispositivos legais, diretrizes, ou parâmetros que busquem claramente garantir a qualidade, credibilidade e reconhecimento da prática da avaliação. Apresenta-se uma breve revisão da literatura sobre princípios e normas que fundamentam as diretrizes gerais formuladas para uma metaavaliação formativa dos estudos de linha de base, orientada pela aplicação dos quatro padrões internacionais para avaliação das políticas sociais: utilidade, exeqüibilidade, propriedade e precisão, que têm igualmente servido de guia para o desenho dos estudos de avaliação de programas de promoção e proteção à saúde, aos quais se associam padrões de especificidade definidos por uma técnica de consenso mista baseada nas prescrições do Termo de Referência dos ELB. O principal interesse é incentivar o amplo uso dessas ferramentas na avaliação em saúde como um ponto crucial para aperfeiçoamento e desenvolvimento do SUS.<br>This article poses questions imperative for the use of principles and standards of evaluation allowing for pointing out directives for meta-evaluation on the example of the Baseline Studies (BLS) of PROESF. These questions are important in countries like Brazil, where a National Evaluation Policy is still in its beginning, and where one observes absence of legal devices, directives or parameters clearly seeking to ensure the quality, credibility and recognition of the practice of evaluation. We present a brief review of the literature about principles and norms constituting the bases for the general directives formulated for a formative metaevaluation of the baseline studies, oriented by the four international standards for evaluation of social policies &shy; utility, feasibility, propriety and accuracy. The same standards were used for guiding the design of studies for evaluating health promotion and protection programs, together with specificity standards defined by a mixed consensus technique based on the prescriptions of the Terms of Reference of the BLS. The main interest rests in encouraging a broad use of these evaluation tools in the field of health, as a crucial point for its improvement and the development of the Unified Health System