Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 aggregation and neuronal degeneration. There is no treatment available to block or delay disease progression. In this work we investigated whether trehalose, a natural occurring disaccharide widely used in food and cosmetic industry, would rescue biochemical, behavioral and neuropathological features of an in vitro and of a severe MJD transgenic mouse model.This work was funded by BioBlast Pharma, the ERDF through the Regional Operational Program Center 2020, Competitiveness Factors Operational Program (COMPETE 2020) and National Funds through FCT (Foundation for Science and Technology) - SFRH/BD/87404/2012, BrainHealth2020 projects (CENTRO-01-0145-FEDER-000008), ViraVector (CENTRO-01-0145FEDER-022095), CortaCAGs (POCI-01-0145-FEDER-016719), SpreadSilenc‑ing POCI-01-0145-FEDER-029716 and POCI-01-0145-FEDER-007440, as well as the SynSpread, ESMI and ModelPolyQ under the EU Joint ProgramNeurodegenerative Disease Research (JPND), the last two co-funded bythe European Union H2020 program, GA No. 643417; by National Ataxia Foundation (USA), the American Portuguese Biomedical Research Fund (APBRF) and the Richard Chin and Lily Lock Machado–Joseph Disease Research Fund.info:eu-repo/semantics/publishedVersio

A ruthenium(II)-trithiacyclononane curcuminate complex: synthesis, characterization, DNA-interaction, and cytotoxic activity

The coordination of ruthenium(II) complexes to anionic oxygen-based donors are very rare. This study describes a simple, one-pot method for obtaining [ruthenium(II)(trithiacyclononane)(curcumin)(S-DMSO)]Cl (1) in 37% yield. The structural characterization of complex 1 by elemental analysis, FT-IR, 1-D and 2-D NMR, ESI+-MS as well as UV–vis and fluorescence spectroscopies are presented. The DNA-melting temperature (Tm) assay shows that salmon sperm DNA (smDNA) in the presence of complex 1 has a higher melting temperature, with ΔTm = 7.4 °C, while in the presence of curcumin the melting temperature remains unaltered. The in vitro cytotoxic activities of curcumin and complex 1 were investigated using the tumor human prostate cell line, PC-3, and the healthy cell line, PNT-2. Complex 1 is innocuous toward normal prostate epithelial cells and, whereas curcumin is toxic, with inhibition rates of ca. 35 and 65% at 50 and 80 μM, respectively. On the tumor cell line PC-3, complex 1 did not cause viability changes, whereas curcumin exhibited dose-dependent inhibition, with ca. 73% inhibition at the highest concentration tested, i.e. 80 μM. This study suggests that coordination with the trithiacyclononane ruthenium(II) scaffold stabilizes the photochemical properties of curcumin and strongly changes its biologic activity.publishe

Cost analysis of centralized viral load testing for antiretroviral therapy monitoring in Nicaragua, a low-HIV prevalence, low-resource setting

<p>Abstract</p> <p>Background</p> <p>HIV viral load testing as a component of antiretroviral therapy monitoring is costly. Understanding the full costs and the major sources of inefficiency associated with viral load testing is critical for optimizing the systems and technologies that support the testing process. The objective of our study was to estimate the costs associated with viral load testing performed for antiretroviral therapy monitoring to both patients and the public healthcare system in a low-HIV prevalence, low-resource country.</p> <p>Methods</p> <p>A detailed cost analysis was performed to understand the costs involved in each step of performing a viral load test in Nicaragua, from initial specimen collection to communication of the test results to each patient's healthcare provider. Data were compiled and cross referenced from multiple information sources: laboratory records, regional surveillance centre records, and scheduled interviews with the key healthcare providers responsible for HIV patient care in five regions of the country.</p> <p>Results</p> <p>The total average cost of performing a viral load test in Nicaragua varied by region, ranging from US$99.01 to US$124.58, the majority of which was at the laboratory level: $88.73 to$97.15 per specimen, depending on batch size. The average cost to clinics at which specimens were collected ranged from $3.31 to$20.92, depending on the region. The average cost per patient for transportation, food, lodging and lost income ranged from $3.70 to$14.93.</p> <p>Conclusions</p> <p>The quantitative viral load test remains the single most expensive component of the process. For the patient, the distance of his or her residence from the specimen collection site is a large determinant of cost. Importantly, the efficiency of results reporting has a large impact on the cost per result delivered to the clinician and utility of the result for patient monitoring. Detailed cost analysis can identify opportunities for removing barriers to effective antiretroviral therapy monitoring programmes in limited-resource countries with low HIV prevalence.</p

Análise psicométrica preliminar da versão portuguesa da Kansas marital satisfaction scale

info:eu-repo/semantics/publishedVersio

HISTOPATOLOGÍA DEL HÍGADO CAUSADA POR LA INFECCIÓN POR ECHINOCOCCUS GRANULOSUS EN SUS SCROFA PROCEDENTE DE BRASIL

Museum specimens represent a valuable resource for helminthological research. We examined formalin-fixed livers preserved for periods in excess of 50 years from naturally infected pigs in archival material from the Helminthological Collection of the Oswaldo Cruz Institute (CHIOC), Oswaldo Cruz Foundation (FIOCRUZ). Microscopic examination revealed evidence of parasites in unilocular cystic structures containing a bladder worm vesicle lined with a thin laminated membrane. The inner germinal layer contained parasite debris and a proteinaceous hydatid-like fluid. The hepatic parenchyma showed a dense inflammatory infiltrate near the cyst, thick-walled arterial vessels, and occasionally necrosis. The adjacent hepatic parenchyma showed inter- and intra-lobular thin fibrosis, inflammatory cell infiltration and occasionally necrosis. Other histo-pathological sections showed a thick laminated wall cystic structure with brood capsules in the germinal layer containing small round projections with central internal vesicles on the inner surface, suggesting the presence of protoscolices. Given that Echinococcus multilocularis does not occur in Brazil, our histological findings were identified as Echinococcus granulosus in origin. In conclusion, the protocol presented in this study highlights the possibility of achieving remarkably high quality histological results in archival formalin-fixed and paraffin-embedded tissues retrieved from museum specimens that have been preserved for many years.Los especímenes de museo representan un recurso valioso para la investigación helmintológica. Hemos examinado los hígados fijados en formalina conservados por períodos de más de 50 años a partir de cerdos infectados naturalmente en el material de archivo de la Colección Helmintológica del Instituto Oswaldo Cruz (CHIOC), Fundación Oswaldo Cruz (FIOCRUZ). El examen microscópico reveló evidencia de parásitos en estructuras quísticas uniloculares que contienen una vesícula de la membrana del parásito recubierto con una lámina delgada. La capa interna germinal contiene los restos del parásito y un líquido proteíco como hidatídico. El parénquima hepático mostró un denso infiltrado inflamatorio cerca del quiste, los vasos arteriales de paredes gruesas y necrosis de vez en cuando. El parénquima hepático adyacente mostró fibrosis delgada inter e intralobular, la infiltración de células inflamatorias y necrosis de vez en cuando. Otros cortes histológicos mostraron una estructura de pared gruesa laminada quística con cápsulas de cría en la capa germinal que contienen proyecciones pequeñas y redondas con el centro de las vesículas internas en la superficie interna, lo que sugiere la presencia de protoescólices. Teniendo en cuenta que Echinococcus multilocularis no ocurre en Brasil, nuestros hallazgos histológicos fueron identificados como Echinococcus granulosus de origen. En conclusión, el protocolo que se presenta en este estudio pone de relieve la posibilidad de lograr resultados histológicos de muy alta calidad en archivos fijados en formalina y parafina de tejidos embebidos recuperados de especímenes de museo que se han conservado durante muchos años

Novel Strains of Mice Deficient for the Vesicular Acetylcholine Transporter: Insights on Transcriptional Regulation and Control of Locomotor Behavior

Defining the contribution of acetylcholine to specific behaviors has been challenging, mainly because of the difficulty in generating suitable animal models of cholinergic dysfunction. We have recently shown that, by targeting the vesicular acetylcholine transporter (VAChT) gene, it is possible to generate genetically modified mice with cholinergic deficiency. Here we describe novel VAChT mutant lines. VAChT gene is embedded within the first intron of the choline acetyltransferase (ChAT) gene, which provides a unique arrangement and regulation for these two genes. We generated a VAChT allele that is flanked by loxP sequences and carries the resistance cassette placed in a ChAT intronic region (FloxNeo allele). We show that mice with the FloxNeo allele exhibit differential VAChT expression in distinct neuronal populations. These mice show relatively intact VAChT expression in somatomotor cholinergic neurons, but pronounced decrease in other cholinergic neurons in the brain. VAChT mutant mice present preserved neuromuscular function, but altered brain cholinergic function and are hyperactive. Genetic removal of the resistance cassette rescues VAChT expression and the hyperactivity phenotype. These results suggest that release of ACh in the brain is normally required to “turn down” neuronal circuits controlling locomotion