Mitochondrial Bioenergetic Alterations in Mouse Neuroblastoma Cells Infected with Sindbis Virus: Implications to Viral Replication and Neuronal Death

The metabolic resources crucial for viral replication are provided by the host. Details of the mechanisms by which viruses interact with host metabolism, altering and recruiting high free-energy molecules for their own replication, remain unknown. Sindbis virus, the prototype of and most widespread alphavirus, causes outbreaks of arthritis in humans and serves as a model for the study of the pathogenesis of neurological diseases induced by alphaviruses in mice. In this work, respirometric analysis was used to evaluate the effects of Sindbis virus infection on mitochondrial bioenergetics of a mouse neuroblastoma cell lineage, Neuro 2a. The modulation of mitochondrial functions affected cellular ATP content and this was synchronous with Sindbis virus replication cycle and cell death. At 15 h, irrespective of effects on cell viability, viral replication induced a decrease in oxygen consumption uncoupled to ATP synthesis and a 36% decrease in maximum uncoupled respiration, which led to an increase of 30% in the fraction of oxygen consumption used for ATP synthesis. Decreased proton leak associated to complex I respiration contributed to the apparent improvement of mitochondrial function. Cellular ATP content was not affected by infection. After 24 h, mitochondria dysfunction was clearly observed as maximum uncoupled respiration reduced 65%, along with a decrease in the fraction of oxygen consumption used for ATP synthesis. Suppressed respiration driven by complexes I- and II-related substrates seemed to play a role in mitochondrial dysfunction. Despite the increase in glucose uptake and glycolytic flux, these changes were followed by a 30% decrease in ATP content and neuronal death. Taken together, mitochondrial bioenergetics is modulated during Sindbis virus infection in such a way as to favor ATP synthesis required to support active viral replication. These early changes in metabolism of Neuro 2a cells may form the molecular basis of neuronal dysfunction and Sindbis virus-induced encephalitis

Trends in esophageal cancer and body mass index by race and gender in the state of Michigan

<p>Abstract</p> <p>Background</p> <p>Adenocarcinoma of the esophagus has been increasing in incidence in the U.S. over the past several decades, particularly among white males. The factors driving the racial disparity in adenocarcinomas rates are not well understood.</p> <p>Methods</p> <p>Here we examine trends in both esophageal cancer incidence and body mass index (BMI) in a geographically defined cohort by gender and race. Age-adjusted esophageal cancer incidence rates from 1985 to 2005 were calculated from data collected by the Michigan state cancer registry. Trends were analyzed along with trends in BMI data obtained from the Behavioral Risk Factor Survey administered by the Centers for Disease Control.</p> <p>Results</p> <p>Overall, age adjusted incidence rates in esophageal carcinoma increased from 4.49 to 4.72 cases/100,000 persons per year in Michigan from 1985 to 2005. Among white males, the rate of adenocarcinomas increased by 0.21 cases/100,000 per year to a maximum of 6.40 cases/100,000 in 1999, after which these rates remained constant. There was a slight but non-significant increase in the rate of adenocarcinomas among African American males, for whom the average incidence rate was 8 times lower than that for white males (0.58 vs 4.72 cases/100,000 person years). While average BMI is rising in Michigan (from 26.68 in 1988 to 30.33 in 2005), average BMI was slightly higher among African Americans on average, and the rates of increase in BMI were not different between African American males and white males.</p> <p>Conclusion</p> <p>The disparity between African American males and white males is not explained by ecological-level trends in BMI. Further research to identify the factors responsible for this disparity, possibly including anatomic fat distribution, are required.</p

Comparative radiological features of disseminated disease due to Mycobacterium tuberculosis vs non-tuberculosis mycobacteria among AIDS patients in Brazil

Background: Disseminated mycobacterial disease is an important cause of morbidity and mortality in patients with HIV-infection. Nonspecific clinical presentation makes the diagnosis difficult and sometimes neglected. Methods: We conducted a retrospective cohort study to compare the presentation of disseminated Mycobacterial tuberculosis (MTB) and non-tuberculous Mycobacterial (NTM) disease in HIV-positive patients from 1996 to 2006 in Brazil. Results: Tuberculosis (TB) was diagnosed in 65 patients (67.7%) and NTM in 31 (32.3%) patients. Patients with NTM had lower CD4 T cells counts (median 13.0 cells/mm3 versus 42.0 cells/mm3, P = 0.002). Patients with tuberculosis had significantly more positive acid-fast smears (48.0% vs 13.6%, P = 0.01). On chest X-ray, miliary infiltrate was only seen in patients with MTB (28.1% vs. 0.0%, P = 0.01). Pleural effusion was more common in patients with MTB (45.6% vs. 13.0%, P = 0.01). Abdominal adenopathy (73.1% vs. 33.3%, P = 0.003) and splenic hypoechoic nodules (38.5% vs. 0.0%, P = 0.002) were more common in patients with TB. Conclusion: Miliary pulmonary pattern on X-ray, pleural effusion, abdominal adenopathy, and splenic hypoechoic nodules were imaging findings associated with the diagnosis of tuberculosis in HIV-infected patients. Recognition of these imaging features will help to distinguish TB from NTM in AIDS patients with fever of unknown origin due to disseminated mycobacterial disease

Racial differences in central adiposity in a longitudinal cohort of black and white adolescent females

<p>Abstract</p> <p>Background</p> <p>Central adiposity is related to chronic disease risk in adolescents. Racial differences in waist circumference have been identified using cross-sectional data from this age group. We tested for racial differences in age-related growth in waist circumference in a longitudinal cohort of black and white adolescent girls.</p> <p>Methods</p> <p>We analyzed 9 years of publicly available data from the National Heart, Lung, and Blood Institute Growth and Health Study, for 2379 girls (1213 black and 1166 white) enrolled at age 9-10 years in 1987-1988 and followed annually. Individual growth trajectories of waist circumference were constructed for girls with >3 annual measures. Mixed models were used to compare changes in waist circumference during adolescence between black and white females. BMI and age at menarche were included in the models.</p> <p>Results</p> <p>At each age, black females had significantly higher waist circumference. Mean annual increase in waist circumference was significantly higher for black females compared to white females (1.46 cm/yr vs. 1.36 cm/yr, respectively). After adjusting for BMI, the mean annual increase in waist circumference for white females was significantly higher than for black females (0.08 cm/yr vs. -0.07 cm/yr, respectively). These relationships remained significant after adjusting for age at menarche.</p> <p>Conclusions</p> <p>Black females had significantly steeper increases in waist circumference over adolescence than white females. After adjusting for BMI and age at menarche, however, the annual increase in waist circumference for black females was significantly shallower than for their white peers. These data suggest racial differences in the deposition of fat over the adolescent period.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Prediction of the survival and functional ability of severe stroke patients after ICU therapeutic intervention

<p>Abstract</p> <p>Background</p> <p>This study evaluated the benefits and impact of ICU therapeutic interventions on the survival and functional ability of severe cerebrovascular accident (CVA) patients.</p> <p>Methods</p> <p>Sixty-two ICU patients suffering from severe ischemic/haemorrhagic stroke were evaluated for CVA severity using APACHE II and the Glasgow coma scale (GCS). Survival was determined using Kaplan-Meier survival tables and survival prediction factors were determined by Cox multivariate analysis. Functional ability was assessed using the stroke impact scale (SIS-16) and Karnofsky score. Risk factors, life support techniques and neurosurgical interventions were recorded. One year post-CVA dependency was investigated using multivariate analysis based on linear regression.</p> <p>Results</p> <p>The study cohort constituted 6% of all CVA (37.8% haemorrhagic/62.2% ischemic) admissions. Patient mean(SD) age was 65.8(12.3) years with a 1:1 male: female ratio. During the study period 16 patients had died within the ICU and seven in the year following hospital release.</p> <p>The mean(SD) APACHE II score at hospital admission was 14.9(6.0) and ICU mean duration of stay was 11.2(15.4) days. Mechanical ventilation was required in 37.1% of cases. Risk ratios were; GCS at admission 0.8(0.14), (p = 0.024), APACHE II 1.11(0.11), (p = 0.05) and duration of mechanical ventilation 1.07(0.07), (p = 0.046). Linear coefficients were: type of CVA – haemorrhagic versus ischemic: -18.95(4.58) (p = 0.007), GCS at hospital admission: -6.83(1.08), (p = 0.001), and duration of hospital stay -0.38(0.14), (p = 0.40).</p> <p>Conclusion</p> <p>To ensure a better prognosis CVA patients require ICU therapeutic interventions. However, as we have shown, where tests can determine the worst affected patients with a poor vital and functional outcome should treatment be withheld?</p

Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production

BACKGROUND: The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. METHODOLOGY AND PRINCIPAL FINDINGS: Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = -0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = -0.36, p = 0.01). CONCLUSIONS AND SIGNIFICANCE: We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis

Spatial and temporal dimensions of landscape fragmentation across the Brazilian Amazon

The Brazilian Amazon in the past decades has been suffering severe landscape alteration, mainly due to anthropogenic activities, such as road building and land clearing for agriculture. Using a high-resolution time series of land cover maps (classified as mature forest, non-forest, secondary forest) spanning from 1984 through 2011, and four uncorrelated fragmentation metrics (edge density, clumpiness index, area-weighted mean patch size and shape index), we examined the temporal and spatial dynamics of forest fragmentation in three study areas across the Brazilian Amazon (Manaus, Santarém and Machadinho d’Oeste), inside and outside conservation units. Moreover, we compared the impacts on the landscape of: (1) different land uses (e.g. cattle ranching, crop production), (2) occupation processes (spontaneous vs. planned settlements) and (3) implementation of conservation units. By 2010/2011, municipalities located along the Arc of Deforestation had more than 55% of the remaining mature forest strictly confined to conservation units. Further, the planned settlement showed a higher rate of forest loss, a more persistent increase in deforested areas and a higher relative incidence of deforestation inside conservation units. Distinct agricultural activities did not lead to significantly different landscape structures; the accessibility of the municipality showed greater influence in the degree of degradation of the landscapes. Even with a high proportion of the landscapes covered by conservation units, which showed a strong inhibitory effect on forest fragmentation, we show that dynamic agriculturally driven economic activities, in municipalities with extensive road development, led to more regularly shaped, heavily fragmented landscapes, with higher densities of forest edge