Antonio C. Pedroso de Lima

Pericytes Extend Survival of ALS SOD1 Mice and Induce the Expression of Antioxidant Enzymes in the Murine Model and in IPSCs Derived Neuronal Cells from an ALS Patient

AbstractAmyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset motor neuron disease causing a progressive, rapid and irreversible degeneration of motor neurons in the cortex, brain stem and spinal cord. No effective treatment is available and cell therapy clinical trials are currently being tested in ALS affected patients. It is well known that in ALS patients, approximately 50% of pericytes from the spinal cord barrier are lost. In the central nervous system, pericytes act in the formation and maintenance of the blood-brain barrier, a natural defense that slows the progression of symptoms in neurodegenerative diseases. Here we evaluated, for the first time, the therapeutic effect of human pericytes in vivo in SOD1 mice and in vitro in motor neurons and other neuronal cells derived from one ALS patient. Pericytes and mesenchymal stromal cells (MSCs) were derived from the same adipose tissue sample and were administered to SOD1 mice intraperitoneally. The effect of the two treatments was compared. Treatment with pericytes extended significantly animals survival in SOD1 males, but not in females that usually have a milder phenotype with higher survival rates. No significant differences were observed in the survival of mice treated with MSCs. Gene expression analysis in brain and spinal cord of end-stage animals showed that treatment with pericytes can stimulate the host antioxidant system. Additionally, pericytes induced the expression of SOD1 and CAT in motor neurons and other neuronal cells derived from one ALS patient carrying a mutation in FUS. Overall, treatment with pericytes was more effective than treatment with MSCs. Our results encourage further investigations and suggest that pericytes may be a good option for ALS treatment in the future. Graphical Abstractᅟ

A SAS macro for estimating transition probabilities in semiparametric models for recurrent events

In many clinical studies involving event history analysis, the event of interest is non-fatal and may occur more than once for each subject. Models based on the theory of counting processes have been developed to deal with such data, the recurrences being considered as transitions in a Markovian process. Under this setting, the experimental units can move between states over time, and it is possible to estimate the corresponding transition probabilities employing regression models that incorporate the influence of covariates. Despite of this, most of the softwares are concerned only in the estimation of regression parameters and do not provide transition probabilities estimates. The aim of this paper is to present a SAS macro developed to estimate the transition probabilities, considering three approaches for the regression modeling. The macro is flexible enough to allow the user to select the model to be fit providing, for a given set of covariates, plots of the estimates for the predicted transition probabilities as a function of time.

Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure

Background -Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly and Thr164Ile were suggested to have an effect in heart failure. We evaluated these polymorphisms relative to clinical characteristics and prognosis of alarge cohort of patients with heart failure of different etiologies.Methods -We studied 501 patients with heart failure of different etiologies. Mean age was 58 years (standard deviation 14.4 years), 298 (60%) were men. Polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism.Results -During the mean follow-up of 12.6 months (standard deviation 10.3 months), 188 (38%) patients died. Distribution of genotypes of polymorphism Arg16Gly was different relative to body mass index (χ2 = 9.797;p = 0.04). Overall the probability of survival was not significantly predicted by genotypes of Gln27Glu, Arg16Gly, or Thr164Ile. Allele and haplotype analysis also did not disclose any significant difference regarding mortality. Exploratory analysis through classification trees pointed towards a potential association between the Gln27Glu polymorphism and mortality in older individuals.Conclusion -In this study sample, we were not able to demonstrate an overall influence of polymorphisms Gln27Glu and Arg16Gly of beta-2 receptor gene on prognosis. Nevertheless, Gln27Glu polymorphism may have a potential predictive value in older individuals.

Massa Ventricular Esquerda em Portadores de Insuficiência Cardíaca

OBJETIVO: Avaliar a massa ventricular esquerda em pacientes com insuficiencia cardiaca, as correlacoes com outras variaveis clinicas e com o prognostico. METODOS: Foram estudados 587 pacientes com idades entre 13,8 anos e 68,9 anos, 461 (78,5%) homens e 126 (21,5%) mulheres. A massa ventricular esquerda foi estimada com o uso do ecocardiograma no modo M e indexada pela altura. RESULTADOS: O indice da massa ventricular esquerda variou de 35,3 g/m a 333,5 g/m e aumentou conforme a idade. O indice da massa ventricular esquerda foi maior nos homens (media 175,7 g/m) do que nas mulheres (media 165,7 g/m). O indice da massa ventricular esquerda foi maior nos portadores de cardiomiopatia hipertensiva (media 188,1 g/m), de cardiomiopatia dilatada idiopatica (media 177,7 g/m) e de cardiomiopatias de outras etiologias (media 175,1 g/m) do que nos portadores de cardiomiopatia chagasica (media 164,3 g/m) e isquemica (media 162 g/m). O indice da massa ventricular esquerda de portadores de insuficiencia cardiaca demonstrou associacao com a idade, o sexo, a etiologia e o diâmetro do atrio esquerdo. A correlacao com a fracao de ejecao do ventriculo esquerdo foi negativa - o aumento do indice da massa ventricular esquerda associou-se a reducao da fracao de ejecao. O risco relativo de obito foi 1,22 para cada acrescimo de 50 g/m no indice da massa ventricular esquerda. CONCLUSOES: A estimacao da massa ventricular esquerda pode contribuir para a avaliacao prognostica de portadores de insuficiencia cardiaca.

Time-dependent coefficients in a multi-event model for survival analysis

In an earlier work, a matrix-valued counting process model was proposed to deal with the occurrence of multiple events for each experimental unit, appealing to a Cox-type model to accommodate plausible concomitant variates. This model is generalized here to a more flexible one that incorporates time-dependent concomitant variates that might have time-dependent coefficients.

Plasmodium falciparum infection during pregnancy impairs fetal head growth: prospective and populational-based retrospective studies

Background Malaria in pregnancy is associated with adverse effects on the fetus and newborns. However, the outcome on a newborn’s head circumference (HC) is still unclear. Here, we show the relation of malaria during pregnancy with fetal head growth. Methods Clinical and anthropometric data were collected from babies in two cohort studies of malaria-infected and non-infected pregnant women, in the Brazilian Amazon. One enrolled prospectively (PCS, Jan. 2013 to April 2015) through volunteer sampling, and followed until delivery, 600 malaria-infected and non-infected pregnant women. The other assembled retrospectively (RCS, Jan. 2012 to Dec. 2013) clinical and malaria data from 4697 pregnant women selected through population-based sampling. The effects of malaria during pregnancy in the newborns were assessed using a multivariate logistic regression. According with World Health Organization guidelines babies were classified in small head (HC < 1 SD below the median) and microcephaly (HC < 2 SD below the median) using international HC standards. Results Analysis of 251 (PCS) and 232 (RCS) malaria-infected, and 158 (PCS) and 3650 (RCS) non-infected women with clinical data and anthropometric measures of their babies was performed. Among the newborns, 70 (17.1%) in the PCS and 934 (24.1%) in the RCS presented with a small head (SH). Of these, 15 (3.7%) and 161 (4.2%), respectively, showed microcephaly (MC). The prevalence of newborns with a SH (30.7% in PCS and 36.6% in RCS) and MC (8.1% in PCS and 7.3% in RCS) was higher among babies born from women infected with Plasmodium falciparum during pregnancy. Multivariate logistic regression analyses revealed that P. falciparum infection during pregnancy represents a significant increased odds for the occurrence of a SH in newborns (PCS: OR 3.15, 95% CI 1.52-6.53, p=0.002; RCS: OR 1.91, 95% CI 1.21-3.04, p=0.006). Similarly, there is an increased odds of MC in babies born from mothers that were P. falciparum-infected (PCS: OR 5.09, 95% CI 1.12-23.17, p=0.035). Moreover, characterization of placental pathology corroborates the association analysis, particularly through the occurrence of more syncytial nuclear aggregates and inflammatory infiltrates in placentas from babies with the reduced head circumference. Conclusions This work indicates that falciparum-malaria during pregnancy presents an increased likelihood of occurring reduction of head circumference in newborns, which is associated with placental malaria. Trial Registration registered as RBR-3yrqfq in the Brazilian Clinical Trials Registry

From Finite Sample to Asymptotic Methods in Statistics: Stochastic Processes: An Overview

1. Motivation and basic tools 2. Estimation theory 3. Hypothesis testing 4. Elements of statistical decision theory 5. Stochastic processes: an overview 6. Stochastic convergence and probability inequalities 7. Asymptotic distributions 8. Asymptotic behavior of estimators and tests 9. Categorical data models 10. Regression models 11. Weak convergence and Gaussian processes.