Adoption of an “Open” Envelope Conformation Facilitating CD4 Binding and Structural Remodeling Precedes Coreceptor Switch in R5 SHIV-Infected Macaques

A change in coreceptor preference from CCR5 to CXCR4 towards the end stage disease in some HIV-1 infected individuals has been well documented, but the reasons and mechanisms for this tropism switch remain elusive. It has been suggested that envelope structural constraints in accommodating amino acid changes required for CXCR4 usage is an obstacle to tropism switch, limiting the rate and pathways available for HIV-1 coreceptor switching. The present study was initiated in two R5 SHIVSF162P3N-infected rapid progressor macaques with coreceptor switch to test the hypothesis that an early step in the evolution of tropism switch is the adoption of a less constrained and more “open” envelope conformation for better CD4 usage, allowing greater structural flexibility to accommodate further mutational changes that confer CXCR4 utilization. We show that, prior to the time of coreceptor switch, R5 viruses in both macaques evolved to become increasingly sCD4-sensitive, suggestive of enhanced exposure of the CD4 binding site and an “open” envelope conformation, and this correlated with better gp120 binding to CD4 and with more efficient infection of CD4low cells such as primary macrophages. Moreover, significant changes in neutralization sensitivity to agents and antibodies directed against functional domains of gp120 and gp41 were seen for R5 viruses close to the time of X4 emergence, consistent with global changes in envelope configuration and structural plasticity. These observations in a simian model of R5-to-X4 evolution provide a mechanistic basis for the HIV-1 coreceptor switch

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8 % in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat

Causal Network Accounts Of Ill-being: Depression & Digital Well-being

Depression is a common and devastating instance of ill-being which deserves an account. Moreover, the ill-being of depression is impacted by digital technology: some uses of digital technology increase such ill-being while other uses of digital technology increase well-being. So a good account of ill-being would explicate the antecedents of depressive symptoms and their relief, digitally and otherwise. This paper borrows a causal network account of well-being and applies it to ill-being, particularly depression. Causal networks are found to provide a principled, coherent, intuitively plausible, and empirically adequate account of cases of depression in every-day and digital contexts. Causal network accounts of ill-being also offer philosophical, scientific, and practical utility. Insofar as other accounts of ill-being cannot offer these advantages, we should prefer causal network accounts of ill-being

Cytoskeletal protein kinases: titin and its relations in mechanosensing

Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca2+–calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other “MLCKs”, is not Ca2+–calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation

Desigualdade no acesso a medicamentos para doenças crônicas em mulheres brasileiras

O objetivo deste trabalho foi analisar a prevalência de acesso a medicamentos para tratamento de doenças crônicas e a existência de desigualdades socioeconômicas no acesso. Os dados são da Pesquisa Nacional de Demografia e Saúde e da Mulher e da Criança de 2006, com uma amostra de 15.575 mulheres (15 a 49 anos). Dessas, 7.717 tiveram diagnóstico de doença crônica com necessidade de obtenção de medicamento e foram consideradas elegíveis para o estudo. O desfecho foi construído com base no diagnóstico de doença crônica e na necessidade de obtenção de medicamento para o tratamento. A análise ajustada foi conduzida usando-se a regressão de Poisson. Os grupos que apresentaram maior prevalência de acesso foram os domiciliados na zona rural, com uma ou duas doenças crônicas e com nível socioeconômico mais elevado. A prevalência de acesso encontrada foi alta, no entanto, as análises demonstram que existe desigualdade socioeconômica no acesso a medicamentos a favor dos mais ricos, identificando como grupo mais vulnerável aquele dos indivíduos mais pobres e com maior número de doenças crônicas

Risk factors in patients with type 2 diabetes mellitus Factores de riesgo en pacientes con diabetes mellitus tipo 2 Fatores de risco em pacientes com diabetes mellitus tipo 2

This study was carried out to evaluate the risk factors of type 2 diabetic patients through sociodemographic data, habits of health, anthropometric and biochemist profiles, assisted at a basic public health care unit in Maringá, Paraná. Sixty-six patients, 56 women aged over than 50 years-old were interviewed. High prevalence factors for cardiovascular risk were observed, such as: overweight and obesity, hypertension, dyslipidemia, sedentariness and inadequate diet. Data suggested the need for multidisciplinary intervention programs in health care units associated to educative programs, adjusted diet intake and regular physical activity for these diabetic patients.<br>El objetivo de este estudio fue verificar los factores de riesgo de las complicaciones de la diabetes mellitus tipo 2, por medio del levantamiento de datos sociodemográficos, hábitos de salud, perfil antropométrico y bioquímico, de pacientes diabéticos tipo 2 atendidos en una Unidad Básica de Salud en la ciudad de Maringá, Paraná. Fueron entrevistados y evaluados 66 pacientes con más de 50 años; 56 eran del sexo femenino. Se verificó una elevada presencia de factores de riesgo cardiovascular en los pacientes investigados: sobrepeso y obesidad, hipertensión, dislipidemia, sedentarismo y dieta no saludable. Los resultados indican la necesidad de la implantación de programas de intervención multidisciplinares en unidades básicas de la salud asociada a prácticas educativas, estimulando la adopción de una dieta saludable y la práctica de actividad física regular para estos pacientes.<br>O objetivo deste estudo foi verificar os fatores de risco das complicações do diabetes mellitus tipo 2, por meio de levantamento de dados sociodemográficos, hábitos de saúde, perfil antropométrico e bioquímico de pacientes diabéticos tipo 2, atendidos em Unidade Básica de Saúde, na cidade de Maringá, Paraná. Foram entrevistados e avaliados 66 pacientes acima de 50 anos, sendo 56 do sexo feminino. Verificou-se elevada prevalência de fatores de risco cardiovascular nos pacientes investigados: sobrepeso e obesidade, hipertensão, dislipidemia, sedentarismo e dieta não saudável. Os resultados indicam a necessidade da implantação de programas de intervenção multidisciplinares em unidades básicas de saúde, associados a práticas educativas, estimulando a adoção de dieta saudável e a prática de atividade física regular para esses pacientes

Assistência Farmacêutica no Sistema Único de Saúde: da Política Nacional de Medicamentos à Atenção Básica à Saúde Pharmaceutical Assistance in the Basic Units of Health: from the National Drug Policy to the Basic Attention to Health

Este artigo é um estudo de revisão teórica que discute a Assistência Farmacêutica no Sistema Único de Saúde, resgatando-se brevemente a história da Política Nacional de Medicamentos, os mecanismos de financiamento no processo de descentralização da saúde e a Assistência Farmacêutica na Atenção Básica à Saúde. A ampliação do acesso da população ao sistema de saúde exigiu mudanças na distribuição de medicamentos, de maneira a aumentar a cobertura e ao mesmo tempo minimizar custos. Identificam-se avanços no arcabouço jurídico e institucional: descentralização da gestão das ações da assistência farmacêutica; ampliação do acesso da população aos medicamentos essenciais; e estruturação da assistência farmacêutica nos municípios. No entanto, persistem ações prioritárias em relação ao financiamento e cobertura populacional, em detrimento da qualidade dos processos. Conclui-se que em muitos municípios brasileiros ocorrem baixa disponibilidade e descontinuidade da oferta de medicamentos essenciais; dispensação por trabalhadores sem qualificação; condições inadequadas de armazenamento que comprometem a qualidade dos medicamentos; prescrição de medicamentos que não pertencem à Relação Nacional de Medicamentos Essenciais; e problemas relacionados ao acesso dos usuários à farmacoterapia.<br>This study of theoretical revision discuss the Pharmaceutical Assistance in the Basic Units of Health, rescuing briefly the history of the National Drug Policy, the mechanisms of financing in the process of health decentralization and Pharmaceutical Assistance on the Basic Attention to Health. The expansion of the population access to the health system has demanded changes on drug distribution in order to increase the coverage and at the same time to reduce costs. It was identified advances in legal and institutional structures: the management decentralization of actions on pharmaceutical assistance; the expansion of the population access to essential medicines; and the establishment of the pharmaceutical assistance in some cities. However, it still persists priority actions in relation to the financing and population coverage, in detriment of quality processes. The conclusion is that, many Brazilian cities has low availability and discontinuity of essential medicine offer; dispensation by workers without qualification; inadequate conditions of storage that compromise the quality of medicines; medicine prescription that does not belong to the National Reference of Essential Medicines; and problems related to the access of users to the pharmacotherapy