Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson's Disease Patients

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect

A combined analysis of the short-term effects of photochemical air pollutants on mortality within the EMECAM project.

In recent years, some epidemiologic studies have attributed adverse effects of air pollutants on health not only to particles and sulfur dioxide but also to photochemical air pollutants (nitrogen dioxide and ozone). The effects are usually small, leading to some inconsistencies in the results of the studies. Furthermore, the different methodologic approaches of the studies used has made it difficult to derive generic conclusions. We provide here a quantitative summary of the short-term effects of photochemical air pollutants on mortality in seven Spanish cities involved in the EMECAM project, using generalized additive models from analyses of single and multiple pollutants. Nitrogen dioxide and ozone data were provided by seven EMECAM cities (Barcelona, Gijón, Huelva, Madrid, Oviedo, Seville, and Valencia). Mortality indicators included daily total mortality from all causes excluding external causes, daily cardiovascular mortality, and daily respiratory mortality. Individual estimates, obtained from city-specific generalized additive Poisson autoregressive models, were combined by means of fixed effects models and, if significant heterogeneity among local estimates was found, also by random effects models. Significant positive associations were found between daily mortality (all causes and cardiovascular) and NO(2), once the rest of air pollutants were taken into account. A 10 microg/m(3) increase in the 24-hr average 1-day NO(2)level was associated with an increase in the daily number of deaths of 0.43% [95% confidence interval (CI), -0.003-0.86%] for all causes excluding external. In the case of significant relationships, relative risks for cause-specific mortality were nearly twice as much as that for total mortality for all the photochemical pollutants. Ozone was independently related only to cardiovascular daily mortality. No independent statistically significant relationship between photochemical air pollutants and respiratory mortality was found. The results in this study suggest that, given the present levels of photochemical pollutants, people living in Spanish cities are exposed to health risks derived from air pollution

A scalable analytical framework for spatio-temporal analysis of neighborhood change: A sequence analysis approach

© Springer Nature Switzerland AG 2020. Spatio-temporal changes reflect the complexity and evolution of demographic and socio-economic processes. Changes in the spatial distribution of population and consumer demand at urban and rural areas are expected to trigger changes in future housing and infrastructure needs. This paper presents a scalable analytical framework for understanding spatio-temporal population change, using a sequence analysis approach. This paper uses gridded cell Census data for Great Britain from 1971 to 2011 with 10-year intervals, creating neighborhood typologies for each Census year. These typologies are then used to analyze transitions of grid cells between different types of neighborhoods and define representative trajectories of neighborhood change. The results reveal seven prevalent trajectories of neighborhood change across Great Britain, identifying neighborhoods which have experienced stable, upward and downward pathways through the national socioeconomic hierarchy over the last four decades

The effectiveness of a health promotion with group intervention by clinical trial. Study protocol

<p>Abstract</p> <p>Background</p> <p>The promotion of health and the interventions in community health continue to be one of the pending subjects of our health system. The most prevalent health problems (cardiovascular diseases, cancer, diabetes...) are for the most part related to life habits. We propose a holistic and integral approach as the best option for tackling behavior and its determinants. The research team has elaborated the necessary educational material to realize group teaching, which we call "Health Workshops". The goal of the present study is to evaluate the effectiveness of these Health Workshops in the following terms: Health Related Quality of Life (HRQOL), incorporate and maintain a balanced diet, do physical activity regularly, maintain risk factors such as tension, weight, cholesterol within normal limits and diminish cardiovascular risk.</p> <p>Methods/Design</p> <p>Controlled and random clinical testing, comparing a group of persons who have participated in the Health Workshops with a control group of similar characteristics who have not participated in the Health Workshops.</p> <p>Field of study: the research is being done in Health Centers of the city of Barcelona, Spain.</p> <p>Population studied: The group is composed of 108 persons that are actually doing the Health Workshops, and 108 that are not and form the control group. They are assigned at random to one group or the other.</p> <p>Data Analysis: With Student's t-distribution test to compare the differences between numerical variables or their non parametric equivalent if the variable does not comply with the criteria of normality. (Kolmogorov-Smirnof test). Chi-square test to compare the differences between categorical variables and the Logistic Regression Model to analyze different meaningful variables by dichotomous analysis related to the intervention.</p> <p>Discussion</p> <p>The Health Workshop proposed in the present study constitutes an innovative approach in health promotion, placing the emphasis on the person's self responsibility for his/her own health.</p> <p>The rhythm of a weekly session during 8 weeks with recommended activities to put into practice, as well as the support of the group is an opportunity to incorporate healthy habits and make a commitment to self-care. The sheets handed out are a Health Manual that can always be consulted after the workshop ends.</p> <p>Trial registration</p> <p>Clinical Trials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01440738">NCT01440738</a></p

Imported Plasmodium falciparum malaria in HIV-infected patients: a report of two cases

As HIV becomes a chronic infection, an increasing number of HIV-infected patients are travelling to malaria-endemic areas. Association of malaria with HIV/AIDS can be clinically severe. Severe falciparum malaria is a medical emergency that is associated with a high mortality, even when treated in an Intensive Care Unit. This article describes two cases of HIV-positive patients, who returned from malaria-endemic areas and presented a parasitaemia > 5% of erythrocytes and clinical signs of severe falciparum malaria, both with > 350 CD4 cell count/μl, absence of chemoprophylaxis and successful response. Factors like drug interactions and the possible implication of anti-malarial therapy bioavailability are all especially interesting in HIV-malaria co-infections

Antiretroviral Therapy Outcomes in HIV-Infected Children after Adjusting Protease Inhibitor Dosing during Tuberculosis Treatment

Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6-24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB. Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons. Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation

PAR1 is selectively over expressed in high grade breast cancer patients: a cohort study

<p>Abstract</p> <p>Background</p> <p>The protease-activated receptor (PAR1) expression is correlated with the degree of invasiveness in cell lines. Nevertheless it has never been directed involved in breast cancer patients progression. The aim of this study was to determine whether PAR1 expression could be used as predictor of metastases and mortality.</p> <p>Methods</p> <p>In a cohort of patients with infiltrating ductal carcinoma studied longitudinally since 1996 and until 2007, PAR1 over-expression was assessed by immunoblotting, immunohistochemistry, and flow citometry. Chi-square and log rank tests were used to determine whether there was a statistical association between PAR1 overexpression and metastases, mortality, and survival. Multivariate analysis was performed including HER1, stage, ER and nodes status to evaluate PAR1 as an independent prognostic factor.</p> <p>Results</p> <p>Follow up was 95 months (range: 2–130 months). We assayed PAR1 in a cohort of patients composed of 136 patients; we found PAR1 expression assayed by immunoblotting was selectively associated with high grade patients (50 cases of the study cohort; P = 0.001). Twenty-nine of 50 (58%) patients overexpressed PAR1, and 23 of these (46%) developed metastases. HER1, stage, ER and PAR1 overexpression were robustly correlated (Cox regression, P = 0.002, P = 0.024 and P = 0.002 respectively). Twenty-one of the 50 patients (42%) expressed both receptors (PAR1 and HER1 P = 0.0004). We also found a statistically significant correlation between PAR1 overexpression and increased mortality (P = 0.0001) and development of metastases (P = 0.0009).</p> <p>Conclusion</p> <p>Our data suggest PAR1 overexpression may be involved in the development of metastases in breast cancer patient and is associated with undifferentiated cellular progression of the tumor. Further studies are needed to understand PAR1 mechanism of action and in a near future assay its potential use as risk factor for metastasis development in high grade breast cancer patients.</p

Physical activity as a preventive measure against overweight, obesity, infections, allergies and cardiovascular disease risk factors in adolescents: AFINOS Study protocol

<p>Abstract</p> <p>Background</p> <p>Prior studies addressing the impacts of regular physical activity or sedentary habits on the immune system have been conducted in adults and laboratory settings. Thus, it is practically unknown how a healthy active lifestyle could affect low-grade inflammation processes, infections or allergies in young persons. The AFINOS Study was designed to determine the relationship between the regular physical activity levels of adolescents and overweight, infection, and allergies along with the presence of metabolic and immunological biomarkers of a deteriorated health status. A further objective of the AFINOS Study is to assess the health status and lifestyle habits of an adolescent population in an effort to identify any protective factors that could be used as preventive measures, since many chronic diseases and their associated co-morbidities often persist from adolescence into adulthood.</p> <p>Methods/Design</p> <p>This study was conducted as three separate sub-studies in three different populations as follows: (a) Study 1 was performed on a population sample of adolescents; (b) Study 2 on the adolescents' parents; and (c) Study 3 on a subset of the adolescents from Study 1. Study 1 assessed health and lifestyle indicators through a questionnaire administered to a representative sample of adolescents from the Madrid Region (n = 2400) aged 13 to 16 years. In Study 2, the parents of the teenagers participating in Study 1 were required to fill out a questionnaire. Finally in Study 3, body composition, physical activity, health-related physical fitness, and blood measurements were determined in a subset (n = 200) of the individuals included in Study 1.</p> <p>Discussion</p> <p>This paper describes the rationale, design, and methodologies used in the AFINOS Study. This multidisciplinary, multicenter study seeks to evaluate several aspects of existing relationships between routine physical activity/sedentary behaviour and several health status markers, specifically those related to the immune system. The results of this cross-sectional study will serve for comparisons with the available data obtained in laboratory settings and in adults. In addition, knowledge regarding the health status and lifestyle habits of Spanish adolescents and their parents will be useful for designing preventive measures.</p