Ambroxol as a novel disease-modifying treatment for Parkinson\u27s disease dementia: Protocol for a single-centre, randomized, double-blind, placebo-controlled trial

© 2019 The Author(s). Background: Currently there are no disease-modifying treatments for Parkinson\u27s disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson\u27s disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. Methods: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer\u27s disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician\u27s Global Impression of Change (CGIC). Secondary measures will include the Parkinson\u27s disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson\u27s disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. Discussion: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. Trial registration: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered

Viabilidade de uso do híbrido Hawaii 7996 como porta-enxerto de cultuvares comerciais de tomate.

A técnica de enxertia é utilizada em algumas hortaliças, principalmente em áreas infestadas, para atribuir resistência a patógenos do solo, minimizando as perdas de produção de cultivares suscetíveis. Este trabalho teve como objetivo avaliar o desenvolvimento e a produtividade de plantas de tomateiro enxertadas em híbrido, tido como resistente a Ralstonia solanacearum, em comparação a pés-francos. O experimento foi desenvolvido em viveiro (produção de mudas e enxertia) e em céu aberto, no município de Cruz das Almas, Bahia, no período de outubro de 2003 a fevereiro de 2004. Utilizou-se o método de enxertia de fenda cheia, com o híbrido ‘Hawaii 7996’ como porta-enxerto e as cultivares Santa Clara, Santa Cruz Kada e Débora Plus, suscetíveis a R. solanacearum, como enxerto. O delineamento experimental foi em blocos ao acaso, com seis tratamentos (3 enxertados e 3 pés-francos), 5 repetições e 6 plantas por parcela útil. Avaliaram-se os caracteres: diâmetro do caule, altura da planta e da primeira inflorescência, distância entre inflorescências e produtividade comercial de frutos. O desenvolvimento das plantas, a produção total e a massa média dos frutos foram semelhantes para os tratamentos enxertados em relação a seus respectivos pés-francos e não houve incompatibilidade entre porta-enxerto e enxerto. A cultivar Santa Cruz Kada foi mais sensível às condições agroecológicas do município de Cruz das Almas, refletindo negativamente na produção e no peso médio dos frutos. Observou-se na enxertia com o híbrido ‘Hawaii 7996’ potencial para viabilizar a produção de tomateiros comerciais suscetíveis à murcha bacteriana, em áreas infestadas com R. solanacearum

Equation of state for Universe from similarity symmetries

In this paper we proposed to use the group of analysis of symmetries of the dynamical system to describe the evolution of the Universe. This methods is used in searching for the unknown equation of state. It is shown that group of symmetries enforce the form of the equation of state for noninteracting scaling multifluids. We showed that symmetries give rise the equation of state in the form $p=-\Lambda+w_{1}\rho(a)+w_{2}a^{\beta}+0$ and energy density $\rho=\Lambda+\rho_{01}a^{-3(1+w)}+\rho_{02}a^{\beta}+\rho_{03}a^{-3}$, which is commonly used in cosmology. The FRW model filled with scaling fluid (called homological) is confronted with the observations of distant type Ia supernovae. We found the class of model parameters admissible by the statistical analysis of SNIa data. We showed that the model with scaling fluid fits well to supernovae data. We found that $\Omega_{\text{m},0} \simeq 0.4$ and $n \simeq -1$ ($\beta = -3n$), which can correspond to (hyper) phantom fluid, and to a high density universe. However if we assume prior that $\Omega_{\text{m},0}=0.3$ then the favoured model is close to concordance $\Lambda$CDM model. Our results predict that in the considered model with scaling fluids distant type Ia supernovae should be brighter than in $\Lambda$CDM model, while intermediate distant SNIa should be fainter than in $\Lambda$CDM model. We also investigate whether the model with scaling fluid is actually preferred by data over $\Lambda$CDM model. As a result we find from the Akaike model selection criterion prefers the model with noninteracting scaling fluid.Comment: accepted for publication versio

Efeitos da nutrição parenteral total associada à infecção bacteriana na função hepatobiliar de ratos da cepa Wistar

OBJECTIVE: To evaluate the hepatic alterations associated to parenteral nutrition inrats.MATERIAL AND METHODS: Four groups with 10 rats each: Group I (control group) -rats were orally fed with a regular diet; Group II - rats received a regular diet, and wereinfected with Escherichia coli through intraperitoneal inoculation; Group III - rats receivedparenteral nutrition; and group IV, rats received parenteral nutrition, and were infectedwith Escherichia coli. Serum concentrations of AST, ALT, GGT, and 5’ N were measuredon the first day of the experiment, and on the eighth day of parenteral nutrition (the dayanimals were sacrificed). Histological study of the liver of the rats included: evaluationof hydropic degeneration, dilation of the central lobular vein, cholestasis, sinusoidaldilation, proliferation of Kupffer cells, cellular necrosis, and steatosis. All alterationswere graded from 0 to 4+.RESULTS: The lab exams did not present consistent alterations at the end of theexperiment. Group IV presented a reduction in GGT concentration; in addition, thisgroup presented the largest variations in AST and ALT concentration, possibly as aresult of being submitted to more intense aggression to the hepatic parenchyma. Froma histological point-of-view, all animals (with the exception of one) presented dilation ofthe central lobular vein and of the sinusoids. Such findings were more frequent amonginfected animals. The animals did not present steatosis or cholestasis.CONCLUSIONS: 1) The proposed model of intraperitoneal inoculation of Escherichiacoli was appropriate for the study of bacterial infection in young rats of the Wistarstrain; 2) our results indicate that the association of parenteral nutrition and infectiondetermined histologic alterations which were unspecific, but more intense than thealterations determined by each of these situations in isolation.OBJETIVO: Avaliar as alterações hepáticas associadas à nutrição parenteral em ratos.MATERIAIS E MÉTODOS: Foram avaliados quatro grupos com 10 ratos cada: grupoI - controles alimentados, via oral, com dieta habitual; grupo II - em dieta habitual einfectados com Escherichia Coli inoculada por via intra peritoneal; grupo III - emnutrição parenteral; e grupo IV - em nutrição parenteral e infectados. Foram analisadasas concentrações séricas de AST, ALT, GGT e 5’N no primeiro dia do experimento eno oitavo dia da nutrição parenteral, por ocasião do sacrifício dos animais. O estudohistológico do fígado dos 40 ratos consistiu na avaliação de degeneração hidrópica,dilatação da veia centro-lobular, colestase, dilatação sinusoidal, proliferação de célulasde Kupffer, necrose celular e esteatose. As alterações foram graduadas de 0 a 4+.RESULTADOS: Os exames laboratoriais não foram consistentemente alterados aofinal do experimento. No grupo IV houve redução na concentração de GGT; alémdisso, este foi o grupo que apresentou as maiores variações de AST e ALT,possivelmente devido à maior agressão do parênquima hepático. Do ponto de vistahistológico, todos os animais submetidos à nutrição parenteral (com apenas umaexceção) apresentaram dilatação da veia centro-lobular e dos sinusóides. Estesachados foram mais comuns nos animais infectados. Não foram observadas esteatosee/ou colestase.CONCLUSÕES: 1) O modelo proposto de inoculação intra-peritoneal com EscherichiaColi foi adequado para estudar infecção em ratos jovens da cepa Wistar; 2) osresultados obtidos indicaram que a associação entre nutrição parenteral e infecçãodeterminou alterações histológicas inespecíficas, porém mais intensas do que asalterações determinadas em cada uma dessas situações isoladamente

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types