Increased CCL2, CCL3, CCL5, and IL-1β cytokine concentration in piriform cortex, hippocampus, and neocortex after pilocarpine-induced seizures

BACKGROUND: Cytokines and chemokines play an important role in the neuroinflammatory response to an initial precipitating injury such as status epilepticus (SE). These signaling molecules participate in recruitment of immune cells, including brain macrophages (microglia), as well as neuroplastic changes, deterioration of damaged tissue, and epileptogenesis. This study describes the temporal and brain region pattern expression of numerous cytokines, including chemokines, after pilocarpine-induced seizures and discusses them in the larger context of their potential involvement in the changes that precede the development of epilepsy. FINDINGS: Adult rats received pilocarpine to induce SE and 90 min after seizure onset were treated with diazepam to mitigate seizures. Rats were subsequently deeply anesthetized and brain regions (hippocampus, piriform cortex, neocortex, and cerebellum) were freshly dissected at 2, 6, and 24 h or 5 days after seizures. Using methodology identical to our previous studies, simultaneous assay of multiple cytokines (CCL2, CCL3, CCL5, interleukin IL-1β, tumor necrosis factor (TNF-α)), and vascular endothelial growth factor (VEGF) was performed and compared to control rats. These proteins were selected based on existing evidence implicating them in the epileptogenic progression. A robust increase in CCL2 and CCL3 concentrations in the hippocampus, piriform cortex, and neocortex was observed at all time-points. The concentrations peaked with a ~200-fold increase 24 h after seizures and were two orders of magnitude greater than the significant increases observed for CCL5 and IL-1β in the same brain structures. TNF-α levels were altered in the piriform cortex and neocortex (24 h) and in the hippocampus (5 days) after SE. CONCLUSIONS: Pilocarpine-induced status epilepticus causes a rapid increase of multiple cytokines in limbic and neocortical regions. Understanding the precise spatial and temporal pattern of cytokines and chemokine changes could provide more viable therapeutic targets to reduce, reverse, or prevent the development of epilepsy following a precipitating injury

Population ageing and deaths attributable to ambient PM2·5 pollution: a global analysis of economic cost

BACKGROUND: The health impacts of ambient air pollution impose large costs on society. Although all people are exposed to air pollution, the older population (ie, those aged ≥60 years) tends to be disproportionally affected. As a result, there is growing concern about the health impacts of air pollution as many countries undergo rapid population ageing. We investigated the spatial and temporal variation in the economic cost of deaths attributable to ambient air pollution and its interaction with population ageing from 2000 to 2016 at global and regional levels. METHODS: In this global analysis, we developed an age-adjusted measure of the value of a statistical life-year (VSLY) to estimate the economic cost of deaths attributable to ambient PM2·5 pollution using Global Burden of Diseases, Injuries, and Risk Factors Study 2017 data and country-level socioeconomic information. First, we estimated the global age-specific and cause-specific mortality and years of life lost (YLLs) attributable to PM2·5 pollution using the global exposure mortality model and global estimates of exposure at 0·1° × 0·1° (about 11 km × 11 km at the equator) resolution. Second, for each year between 2000 and 2016, we translated the YLLs within each age group into a health-related cost using a country-specific, age-adjusted measure of VSLY. Third, we decomposed the major driving factors that contributed to the temporal change in health costs related to PM2·5. Finally, we did a sensitivity test to analyse the variability of the estimated health costs to four alternative valuation measures. We identified the uncertainty intervals (UIs) from 1000 draws of the parameters and concentration–response functions by age, cause, country, and year. All economic values are reported in 2011 purchasing power parity-adjusted US dollars. All simulations were done with R, version 3.6.0. FINDINGS: Globally, in 2016, PM2·5 was estimated to have caused 8·42 million (95% UI 6·50–10·52) attributable deaths, which was associated with 163·68 million (116·03–219·44) YLLs. In 2016, the global economic cost of deaths attributable to ambient PM_{2·5} pollution for the older population was US$2·40 trillion (1·89–2·93) accounting for 59$4·09 trillion [3·19–5·05]). The economic cost per capita for the older population was $2739 (2160–3345) in 2016, which was 10 times that of the younger population (ie, those aged <60 years). By assessing the factors that contributed to economic costs, we found that increases in these factors changed the total economic cost by 77% for gross domestic product (GDP) per capita, 21% for population ageing, 16% for population growth, −41% for age-specific mortality, and −0·4% for PM_{2·5} exposure. INTERPRETATION: The economic cost of ambient PM_{2·5} borne by the older population almost doubled between 2000 and 2016, driven primarily by GDP growth, population ageing, and population growth. Compared with younger people, air pollution leads to disproportionately higher health costs among older people, even after accounting for their relatively shorter life expectancy and increased disability. As the world's population is ageing, the disproportionate health cost attributable to ambient PM2·5 pollution potentially widens the health inequities for older people. Countries with severe air pollution and rapid ageing rates need to take immediate actions to improve air quality. In addition, strategies aimed at enhancing health-care services, especially targeting the older population, could be beneficial for reducing the health costs of ambient air pollution. FUNDING: National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Qiushi Foundation

Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

Inter-hemispheric EEG coherence analysis in Parkinson's disease : Assessing brain activity during emotion processing

Parkinson’s disease (PD) is not only characterized by its prominent motor symptoms but also associated with disturbances in cognitive and emotional functioning. The objective of the present study was to investigate the influence of emotion processing on inter-hemispheric electroencephalography (EEG) coherence in PD. Multimodal emotional stimuli (happiness, sadness, fear, anger, surprise, and disgust) were presented to 20 PD patients and 30 age-, education level-, and gender-matched healthy controls (HC) while EEG was recorded. Inter-hemispheric coherence was computed from seven homologous EEG electrode pairs (AF3–AF4, F7–F8, F3–F4, FC5–FC6, T7–T8, P7–P8, and O1–O2) for delta, theta, alpha, beta, and gamma frequency bands. In addition, subjective ratings were obtained for a representative of emotional stimuli. Interhemispherically, PD patients showed significantly lower coherence in theta, alpha, beta, and gamma frequency bands than HC during emotion processing. No significant changes were found in the delta frequency band coherence. We also found that PD patients were more impaired in recognizing negative emotions (sadness, fear, anger, and disgust) than relatively positive emotions (happiness and surprise). Behaviorally, PD patients did not show impairment in emotion recognition as measured by subjective ratings. These findings suggest that PD patients may have an impairment of inter-hemispheric functional connectivity (i.e., a decline in cortical connectivity) during emotion processing. This study may increase the awareness of EEG emotional response studies in clinical practice to uncover potential neurophysiologic abnormalities

Transverse electric field–induced deformation of armchair single-walled carbon nanotube

The deformation of armchair single-walled carbon nanotube under transverse electric field has been investigated using density functional theory. The results show that the circular cross-sections of the nanotubes are deformed to elliptic ones, in which the tube diameter along the field direction is increased, whereas the diameter perpendicular to the field direction is reduced. The electronic structures of the deformed nanotubes were also studied. The ratio of the major diameter to the minor diameter of the elliptic cross-section was used to estimate the degree of the deformation. It is found that this ratio depends on the field strength and the tube diameter. However, the field direction has little role in the deformation

Factors associated with good self-rated health of non-disabled elderly living alone in Japan: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Self-rated health (SRH) is reported as a reliable predictor of disability and mortality in the aged population and has been studied worldwide to enhance the quality of life of the elderly. Nowadays, the elderly living alone, a particular population at great risk of suffering physical and mental health problems, is increasing rapidly in Japan and could potentially make up the majority of the aged population. However, few data are available pertaining to SRH of this population. Given the fact that sufficient healthcare is provided to the disabled elderly whereas there is little support for non-disabled elderly, we designed this population-based survey to investigate SRH of non-disabled elderly living alone and to identify the factors associated with good SRH with the purpose of aiding health promotion for the elderly.</p> <p>Methods</p> <p>A cross-sectional study was conducted in a metropolitan suburb in Japan. Questionnaires pertaining to SRH and physical conditions, lifestyle factors, psychological status, and social activities, were distributed in October 2005 to individuals aged ≥ 65 years and living alone. Response rate was 75.1%. Among these respondents, a total of 600 male and 2587 female respondents were identified as non-disabled elderly living alone and became our subjects. Multivariate logistic regression was used to identify the factors associated with good SRH and sex-specific effect was tested by stepwise logistic regression.</p> <p>Results</p> <p>Good SRH was reported by 69.8% of men and 73.8% of women. Multivariate logistic regression analysis showed that good SRH correlated with, in odds ratio sequence, "can go out alone to distant places", no depression, no weight loss, absence of self-rated chronic disease, good chewing ability, and good visual ability in men; whereas with "can go out alone to distant places", absence of self-rated chronic disease, no weight loss, no depression, no risk of falling, independent IADL, good chewing ability, good visual ability, and social integration (attend) in women.</p> <p>Conclusion</p> <p>For the non-disabled elderly living alone, sex-appropriate support should be considered by health promotion systems from the view point of SRH. Overall, the ability to go out alone to distant places is crucial to SRH of both men and women.</p

Human Papillomavirus (HPV) in breast tumors: prevalence in a group of Mexican patients

<p>Abstract</p> <p>Background</p> <p>Breast cancer is one of the main health problems in developed countries, occupying first place in mortality in women. It is well-known that there are risk factors associated with breast cancer development. Nonetheless, in 50–80% of cases known risk factors have not been identified, this has generated the attempt to identify new factors related with this neoplasia as viral infections. The aim of this work is investigate the prevalence of HPV DNA in patients with breast lesions at the Instituto Nacional de Cancerologia de Mexico.</p> <p>Methods</p> <p>Fifty-one cases of breast cancer were selected from the files of the institute and compared by age and tumor size with 43 cases of non malignant breast lesions (fibroadenoma, fibrocystic disease and phyllodes tumor). Paraffin embedded specimens were selected, HPV DNA was analyzed by polymerase chain reaction (PCR) and sequenced for different types of HPV in case of positivity for HPV-DNA. Descriptive analysis of clinical and pathological variables was performed and comparisons between positive and negative cases was done.</p> <p>Results</p> <p>All patients were mexican, mean age was 53.3, median age of menarche was 13 and median tumor size 9 cms. Cervicovaginal cytology was performed to all patients, 1 patient (1.9%) of cancer group had HPV and none in the other group, no cases were diagnosed with cervical dysplasia. In the group of carcinomas 36 (70.5%) were negative and 15 (29.4%) were positive to HPV-DNA, 10(66.6%) were positive for HPV 16, 3(20%) for HPV 18, two cases (13.4%) were positive for both. In the group of benign conditions all were negative to HPV-DNA.</p> <p>Conclusion</p> <p>Presence of HPV in breast cancer in our group of cases is high in comparison to other authors; larger numbers of cases need to be analyzed in order to establish the exact role of this virus in the pathogenesis of breast cancer.</p

Interactive effects of ambient fine particulate matter and ozone on daily mortality in 372 cities: two stage time series analysis

Objective To investigate potential interactive effects of fine particulate matter (PM2.5) and ozone (O3) on daily mortality at global level. Design Two stage time series analysis. Setting 372 cities across 19 countries and regions. Population Daily counts of deaths from all causes, cardiovascular disease, and respiratory disease. Main outcome measure Daily mortality data during 1994-2020. Stratified analyses by co-pollutant exposures and synergy index (>1 denotes the combined effect of pollutants is greater than individual effects) were applied to explore the interaction between PM2.5 and O3 in association with mortality. Results During the study period across the 372 cities, 19.3 million deaths were attributable to all causes, 5.3 million to cardiovascular disease, and 1.9 million to respiratory disease. The risk of total mortality for a 10 μg/m3 increment in PM2.5 (lag 0-1 days) ranged from 0.47% (95% confidence interval 0.26% to 0.67%) to 1.25% (1.02% to 1.48%) from the lowest to highest fourths of O3 concentration; and for a 10 μg/m3 increase in O3 ranged from 0.04% (−0.09% to 0.16%) to 0.29% (0.18% to 0.39%) from the lowest to highest fourths of PM2.5 concentration, with significant differences between strata (P for interaction <0.001). A significant synergistic interaction was also identified between PM2.5 and O3 for total mortality, with a synergy index of 1.93 (95% confidence interval 1.47 to 3.34). Subgroup analyses showed that interactions between PM2.5 and O3 on all three mortality endpoints were more prominent in high latitude regions and during cold seasons. Conclusion The findings of this study suggest a synergistic effect of PM2.5 and O3 on total, cardiovascular, and respiratory mortality, indicating the benefit of coordinated control strategies for both pollutants

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

Transplacental Passage of Interleukins 4 and 13?

The mechanisms by which prenatal events affect development of adult disease are incompletely characterized. Based on findings in a murine model of maternal transmission of asthma risk, we sought to test the role of the pro-asthmatic cytokines interleukin IL-4 and -13. To assess transplacental passage of functional cytokines, we assayed phosphorylation of STAT-6, a marker of IL-4 and -13 signaling via heterodimeric receptor complexes which require an IL-4 receptor alpha subunit. IL-4 receptor alpha−/− females were mated to wild-type males, and pregnant females were injected with supraphysiologic doses of IL-4 or 13. One hour after injection, the receptor heterozygotic embryos were harvested and tissue nuclear proteins extracts assayed for phosphorylation of STAT-6 by Western blot. While direct injection of embryos produced a robust positive control, no phosphorylation was seen after maternal injection with either IL-4 or -13, indicating that neither crossed the placenta in detectable amounts. The data demonstrate a useful approach to assay for transplacental passage of functional maternal molecules, and indicate that molecules other than IL-4 and IL-13 may mediate transplacental effects in maternal transmission of asthma risk