Allosteric activation of Hsp70 reduces mutant huntingtin levels, the clustering of N-terminal fragments, and their nuclear accumulation

AIMS: Huntington's disease (HD) is caused by a mutant huntingtin protein that misfolds, yields toxic N-terminal fragments, aggregates, and disrupts proteostasis. The Hsp70 chaperone is a potential therapeutic target as it prevents proteotoxicity by favouring protein folding, disaggregation, or degradation. We tested the hypothesis that allosteric Hsp70 activation with a pharmacological mimetic of the Hsp70 co-chaperone Hip, YM-1, could modulate huntingtin proteostasis. MAIN METHODS: We used HD cell models expressing either N-terminal or full-length huntingtin. Using single-cell analysis we studied huntingtin aggregation in different cellular compartments by fluorescence microscopy. Protein interaction was evaluated by immunoprecipitation, while protein levels were quantified by immunofluorescence and western-blot. KEY FINDINGS: N-terminal huntingtin interacted with Hsp70 and increased its levels. Treatment with YM-1 reduced N-terminal huntingtin clustering and nuclear aggregation. Full-length mutant huntingtin also interacted with Hsp70, and treatment with YM-1 reduced huntingtin levels when combined with Hsp70 induction by heat shock. Mechanistically, YM-1 increases the Hsp70 affinity for substrates, promoting their proteasomal degradation. Consistently, YM-1 reduced the levels of ubiquitinated proteins. Interestingly, YM-1 accumulated in mitochondria, interfered with its Hsp70 isoform involved in protein import, and increased NRF1 levels, a regulator of proteasome genes. We thus suggest that YM-1 may trigger the coordination of mitochondrial and cytosolic proteostasis, enhancing protein degradation. SIGNIFICANCE: Our findings show that the strategy of allosteric Hsp70 activation holds potential for HD. While drug efficacy may be limited to tissues with elevated Hsp70, combined therapies with Hsp70 elevating strategies could harness the full potential of allosteric Hsp70 activators for HD

Ocular sequelae of congenital toxoplasmosis in Brazil compared with Europe

Toxoplasmic retinochoroiditis appears to be more severe in Brazil, where it is a leading cause of blindness, than in Europe, but direct comparisons are lacking. Evidence is accumulating that more virulent genotypes of Toxoplasma gondii predominate in South America

Biodegradability of diesel and biodiesel blends

The biodegradability of pure diesel and biodiesel and blends with different proportions of biodiesel (2%(commercial); 5% and 20%) was evaluated employing the respirometric method and the redox indicator2,6-dichlorophenol indophenol (DCPIP) test. In the former, experiments simulating the contamination of natural environments (soil from a petrol station or water from a river) were carried out in Bartha biometer flasks (250 ml), and used to measure the microbial CO2 production. With the DCPIP test, the capability of three inocula to biodegrade the blends was tested. Results show that although biodiesel is more easily and faster biodegraded than diesel oil, among the blends evaluated (2%, 5% and 20%), only the blend with higher concentration of biodiesel presented biodegradability significantly different from diesel and it was not verified an improvement on the biodegradation of the diesel by means of  cometabolism

Predicting Successful Tapering of Biologic Therapy for Patients with Rheumatoid Arthritis in Remission – Why are we still using clinical remission criteria to inform decisions?

Remission is the optimum treatment target for patients with rheumatoid arthritis. With the advent of biologic therapies, and the use of treat to target strategies, many more patients are achieving remission. Once a patient has achieved a period of sustained remission, there is little to guide subsequent management and patients usually continue treatment long-term. This may be inappropriate. Recent evidence suggests that some patients may be able to reduce or even stop therapy however, the ideal patient profile is yet to be determined. Potential predictors have been identified, however have not entered routine clinical practice. There is a need for robust biomarkers to facilitate the prediction of successful tapering

Atopic Eczema/Dermatitis Syndrome in Portugal – Sensitization Pattern

A dermatite atópica é uma doença inflamatória crónica da pele, tendo por base diversos mecanismos etiopatogénicos. Considerando a sua heterogeneidade, foi, recentemente, introduzida outra designação para esta patologia - Síndroma Eczema / Dermatite Atópica (SEDA). A associação com alergia alimentar ou respiratória parece ser variável entre as diferentes populações. Objectivo: Analisar um grupo de doentes referenciados à Consulta de Imunoalergologia com o diagnóstico de SEDA, com o intuito de avaliar a associação desta síndrome com a alergia alimentar e doença respiratória nesta população. Métodos: Do número total de primeiras consultas do nosso Serviço durante os anos 2000-01 (n = 3436) foram seleccionados todos os doentes com história de SEDA. A população foi analisada quanto a idade, sexo, existência de alergia alimentar, doença respiratória e resultados de testes cutâneos (TC) por picada. Resultados: Foram encontrados 193 doentes com uma idade média de 7,5 anos de idade (1 -54 anos) e relação F/M = 1 / 1,5. Eram 68 (35,8%) os doentes com SEDA isolada. SEDA associada a doença respiratória foi identificada em 113 (58,5%) e a alergia alimentar em 19 (9,8%) - na maioria dos casos manifestando-se por urticária / angioedema. Os TC revelaram-se positivos para aeroalergénios em 74% e para alergénios alimentares em 18% da amostra. Os TC foram positivos em 58,9% dos doentes com SEDA isolada, 84,2% dos doentes com alergia alimentar e 92% com doença respiratória. Conclusão: Em contraste com outras séries, foi encontrada uma baixa prevalência de alergia alimentar, na maioria dos casos manifestada por reacções imediatas. Mais de metade dos doentes estudados apresentava doença respiratória alérgica associada a uma elevada prevalência de sensibilização a aeroalergénios. Estes resultados reflectem a heterogeneidade das populações com SEDA e a importância dos aeroalergénios na nossa população

Utilidade do Strain Bidimensional por Speckle Tracking da Aurícula e Ventrículo Direito para Predizer Arritmias Tardias em Doentes Adultos com Tetralogia de Fallot Corrigida

OBJECTIVE: To determine whether right ventricular and/or atrial speckle tracking strain is associated with previous arrhythmic events in patients with repaired tetralogy of Fallot. METHODS AND RESULTS: We studied right ventricular and atrial strain in 100 consecutive patients with repaired tetralogy of Fallot referred for routine echocardiographic evaluation. Patients were divided into two groups, one with previous documentation of arrhythmias (n=26) and one without arrhythmias, in a median follow-up of 22 years. Patients with arrhythmias were older (p<0.001) and had surgical repair at an older age (p=0.001). They also had significantly reduced right ventricular strain (-14.7±5.5 vs. -16.9±4.0%, p=0.029) and right atrial strain (19.1±7.7% vs. 25.8±11.4%, p=0.001). Neither right ventricular nor right atrial strain were independent predictors of the presence of a history of documented arrhythmias, which was associated with age at correction and with the presence of residual defects. In a subanalysis after excluding 23 patients who had had more than one corrective surgery, right ventricular strain was an independent predictor of the presence of previous arrhythmic events (OR 1.19, 95% CI 1.02-1.38, p=0.025). Right atrial strain was also an independent predictor after adjustment (OR 0.93, 95% CI 0.87-0.99, p=0.029). The ideal cut-off for right ventricular strain was -15.3% and for right atrial strain 23.0%. CONCLUSIONS: Compared with conventional echocardiographic parameters, strain measures of the right heart are associated with the presence of arrhythmic events, and may be useful for risk stratification of patients with repaired tetralogy of Fallot, although a prospective study is required.info:eu-repo/semantics/publishedVersio

El recien nacido con dolor: el papel del equipo de enfermeria

It's a quantitative, descriptive and cross study conducted with the nurse team working in the field of neonatology at the three hospitals, Alfenas-MG. Aimed to describe the forms of pain assessment of the newborn used by nurse team and analyze the practice of nursing as pain management of neonates. Data were collected through a semi-structured formulary, from August to September 2008, of 42 nurses working. The analyze was performed using SPSS software using descriptive statistics and correlation test. It was observed that the respondents recognize that the newborn is capable of feeling pain and evaluated by physiological and behavioral changes and that there isn't pain assessment scales standardized in the institutions. For the management, carry out pharmacological and nonpharmacological interventions. There is need to train professionals contributing to the assessment and management of pain, promoting of holistic care of the neonate.Estudio cuantitativo, descriptivo y transversal realizado con profesionales de Enfermería que actúan en el área de Neonatología en los tres hospitales de Alfenas, Minas Gerais. Se objetivó describir las formas de evaluación del dolor del recién nacido utilizados por el personal de enfermería y analizar la práctica de la enfermería como el manejo del dolor del neonato. La recolección de datos fue hecha por medio de un formulario semiestructurado, entre agosto y septiembre de 2008, con 42 profesionales. El análisis fue hecho con el software SPSS, utilizando la estadística descriptiva y la prueba de correlación. Los entrevistados reconocen que el neonato es capaz de sentir dolor y esto se evalúa a través de alteraciones fisiológicas y de comportamiento, no hay utilización de escalas de evaluación del dolor estandarizadas en las instituciones. Para el manejo, realizan intervenciones farmacológicas y no farmacológicas. Hay necesidad de capacitar profesionales contribuyendo para la evaluación y manejo del dolor, para la promoción del cuidado integral al neonato.Estudo quantitativo, descritivo e transversal realizado com profissionais de enfermagem que atuam em neonatologia nos três hospitais de Alfenas-MG. Objetivou descrever as formas de avaliação de dor do recém-nascido utilizadas pela equipe de enfermagem e analisar a prática da enfermagem quanto ao manejo da dor do neonato. A coleta de dados foi feita por meio de formulário semiestruturado, de agosto a setembro de 2008, com 42 profissionais. A análise foi feita pelo software SPSS utilizando estatística descritiva e teste de correlação. Os entrevistados acreditam que o recém-nascido é capaz de sentir dor e a avaliam por meio de alterações fisiológicas e comportamentais, e que não há utilização de escalas de avaliação álgica padronizadas nas instituições. Para o manejo, realizam intervenções farmacológicas e não farmacológicas. Há necessidade de capacitar os profissionais, contribuindo para a avaliação e o manejo da dor, e promovendo o cuidado integral ao neonato.Universidade de São Paulo Escola de Enfermagem de Ribeirao Preto Departamento de Enfermagem Materno-infantil e Saude PublicaUniversidade Federal de São Paulo (UNIFESP) Departamento de Enfermagem Pediatrica Escola Paulista de EnfermagemUniversidade Federal de Alfenas Escola de Enfermagem Programa de Pos-graduacao em EnfermagemUniversidade de São Paulo Escola de Enfermagem de Ribeirao Preto Departamento de Enfermagem Geral e EspecializadaUniversidade Federal de Alfenas Escola de EnfermagemPrograma de Pos-graduacao em Enfermagem Programa de Pos-graduacao em EnfermagemEscola de Enfermagem Escola de EnfermagemUniversidade de São PauloUNIFESP, Depto. de Enfermagem Pediatrica Escola Paulista de Enfermagem (EPE)SciEL

Phylogenetic inferences of Atelinae (Platyrrhini) based on multi-directional chromosome painting in Brachyteles arachnoides, Ateles paniscus paniscus and Ateles b. marginatus

We performed multi-directional chromosome painting in a comparative cytogenetic study of the three Atelinae species Brachyteles arachnoides, Ateles paniscus paniscus and Ateles belzebuth marginatus, in order to reconstruct phylogenetic relationships within this Platyrrhini subfamily. Comparative chromosome maps between these species were established by multi-color fluorescence in situ hybridization ( FISH) employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. The three species included in this study and four previously analyzed species from all four Atelinae genera were subjected to a phylogenetic analysis on the basis of a data matrix comprised of 82 discrete chromosome characters. The results confirmed that Atelinae represent a monophyletic clade with a putative ancestral karyotype of 2n = 62 chromosomes. Phylogenetic analysis revealed an evolutionary branching sequence \{Alouatta \{Brachyteles \{Lagothrix and Ateles\}\}\} in Atelinae and \{Ateles belzebuth marginatus \{Ateles paniscus paniscus \{Ateles belzebuth hybridus and Ateles geoffroyi\}\}\} in genus Ateles. The chromosomal data support a re-evaluation of the taxonomic status of Ateles b. hybridus. Copyright (C) 2005 S. Karger AG, Basel