Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation

Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa (KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives

Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach

Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful “core hopping” and “glide docking” techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the “core hopping” technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses

A microleakage study of gutta-percha/AH Plus and Resilon/Real self-etch systems after different irrigation protocols

The development and maintenance of the sealing of the root canal system is the key to the success of root canal treatment. The resin-based adhesive material has the potential to reduce the microleakage of the root canal because of its adhesive properties and penetration into dentinal walls. Moreover, the irrigation protocols may have an influence on the adhesiveness of resin-based sealers to root dentin. Objective: The objective of the present study was to evaluate the effect of different irrigant protocols on coronal bacterial microleakage of gutta-percha/AH Plus and Resilon/Real Seal Self-etch systems. Material and Methods: One hundred ninety pre-molars were used. The teeth were divided into 18 experimental groups according to the irrigation protocols and filling materials used. The protocols used were: distilled water; sodium hypochlorite (NaOCl)+eDTA; NaOCl+H3PO4; NaOCl+eDTA+chlorhexidine (CHX); NaOCl+H3PO4+CHX; CHX+eDTA; CHX+ H3PO4; CHX+eDTA+CHX and CHX+H3PO4+CHX. Gutta-percha/AH Plus or Resilon/Real Seal Se were used as root-filling materials. The coronal microleakage was evaluated for 90 days against Enterococcus faecalis. Data were statistically analyzed using Kaplan-Meier survival test, Kruskal-Wallis and Mann-Whitney tests. Results: No significant difference was verified in the groups using chlorhexidine or sodium hypochlorite during the chemo-mechanical preparation followed by eDTA or phosphoric acid for smear layer removal. The same results were found for filling materials. However, the statistical analyses revealed that a final flush with 2% chlorhexidine reduced significantly the coronal microleakage. Conclusion: A final flush with 2% chlorhexidine after smear layer removal reduces coronal microleakage of teeth filled with gutta-percha/AH Plus or Resilon/Real Seal SE

Cuidado de enfermagem ao paciente com comorbidade clínico-psiquiátrica em um pronto atendimento hospitalar

Pesquisa qualitativa, descritiva, exploratória desenvolvida em 2009 no pronto atendimento de um hospital geral de Curitiba, Paraná. Teve como objetivo conhecer o cuidado de enfermagem desenvolvido ao paciente com comorbidade clínico-psiquiátrica. Participaram seis enfermeiros, sete técnicos de enfermagem e 14 auxiliares de enfermagem. Os dados foram obtidos mediante entrevista semiestruturada e submetidos à análise de conteúdo temático-categorial. As categorias que emergiram dos dados foram: O cuidado é técnico e sem especificidade; Segurança e proteção ao paciente; e Contenção física e química como medidas de proteção. Evidenciouse que os cuidados de enfermagem desenvolvidos aos pacientes com comorbidade clínico-psiquiátrica são sem especificidade, com ênfase em cuidados básicos, contenção química e física. Concluiu-se que há necessidade da implantação de programas locais de capacitação em saúde mental e sensibilização dos profissionais de enfermagem quanto aos cuidados a tal clientela

Teste de Morisky-Green e Brief Medication Questionnaire para avaliar adesão a medicamentos

OBJETIVO: Analisar a confiabilidade e o desempenho da versão em português de instrumentos de avaliação da adesão ao tratamento anti-hipertensivo. MÉTODOS: Pacientes hipertensos atendidos de janeiro a setembro de 2010 em uma unidade de atenção primária em Porto Alegre, RS, foram selecionados aleatoriamente (n = 206). Na avaliação da adesão foram utilizadas versões em português do Teste de Morisky-Green (TMG) e do Brief Medication Questionnaire (BMQ). Foram analisados consistência interna, estabilidade temporal e desempenho com relação a três padrões-ouro: controle inadequado da pressão arterial (&gt; 140/90 mmHg); taxa insuficiente de retirada de medicação na farmácia da Unidade Básica de Saúde (< 80%); e a combinação de ambos. RESULTADOS: Dos pacientes avaliados, 97 utilizavam medicamentos dispensados somente pela farmácia da Unidade Básica de Saúde. Os testes apresentaram boa consistência interna: BMQ &#945; de Cronbach de 0,66 (IC95% 0,60;0,73) e o TMG 0,73 (IC95% 0,67;0,79). O desempenho do BMQ no domínio regime apresentou sensibilidade de 77%, especificidade de 58% e área sob a curva ROC de 0,70 (IC95% 0,55;0,86), e o TMG sensibilidade de 61%, especificidade de 36% e área sob a curva ROC de 0,46 (IC95% 0,30;0,62). A correlação entre o BMQ e o TMG foi de r = 0,28, p &gt; 0,001. A baixa adesão ao BMQ está associada a maiores níveis tensionais quando comparada com pacientes aderentes (148,4 [dp 20,1] vs 128,8 [dp 17,8], p < 0,001), mas não para o TMG. CONCLUSÕES: O BMQ apresentou melhor desempenho que o TMG, com maiores sensibilidade e especificidade. A avaliação da adesão pode auxiliar o clinico na discriminação entre uso inadequado da medicação e esquema terapêutico insuficiente.OBJETIVO: Analizar la confiabilidad y el desempeño de la versión en portugués de instrumentos de evaluación de la adherencia al tratamiento antihipertensivo. MÉTODOS: Pacientes hipertensos atendidos de enero a septiembre de 2010 en una unidad de atención primaria en Porto Alegre, Sur de Brasil, fueron seleccionados aleatoriamente (n=206). En la evaluación de la adherencia fueron utilizadas versiones en portugués de la Prueba de Morisky-Green (TMG) y del Brief Medication Questionnarie (BMQ). Se analizaron consistencia interna, estabilidad temporal y desempeño con relación a tres patrones-oro: control inadecuado de la presión arterial (&gt; 140/90 mmHg); tasa insuficiente de retirada de medicación en la farmacia de la Unidad Básica de Salud (< 80%) y la combinación de ambos. RESULTADOS: De los pacientes evaluados, 97 utilizaban medicamentos dispensados solamente por la farmacia de la Unidad Básica de Salud. Las pruebas presentaron buena consistencia interna: BMQ &#945; de Cronbach de 0,66 (IC95% 0,60;0,73) y el TMG 0,73 (IC95% 0,67;0,79). El desempeño del BMQ en el dominio régimen presentó sensibilidad de 77%, especificidad de 58%, y área bajo la curva ROC de 0,70 (IC95% 0,55;0,86) y el TMG sensibilidad de 61%, especificidad de 36% y área bajo la curva ROC de 0,46 (IC95% 0,30;0,62). La correlación entre el BMQ y el TMG fue de r=0,28, p&gt;0,001. La baja adherencia al BMQ está asociada a mayores niveles tensionales al compararlo con pacientes adherentes 148,4 [de 0,1] vs 128,8 [de 17,8], pOBJECTIVE: To analyze the reliability and performance of the Portuguese version of questionnaires used to evaluate adherence to hypertensive treatment. METHODS: Hypertensive patients attending a primary healthcare unit in Porto Alegre, Southern Brazil, from January to September 2010, were randomly selected (n = 206). To evaluate adherence, Portuguese versions of the Morisky-Green test (MGT) and the Brief Medication Questionnaire (BMQ) were used. The analysis considered internal consistency, temporal stability and performance compared to three gold standards, which are: inadequate control of blood pressure (BP &gt; 140/90 mmHg); insufficient rate of medication acquisition at the institution's pharmacy