An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.

Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.

An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.

Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.

Aberrant dynein function promotes TDP-43 aggregation and upregulation of p62 in male mice harboring transgenic human TDP-43.

OBJECTIVE: Most TDP-43 mouse models of ALS do not display cytoplasmic mislocalisation or protein aggregation of TDP-43 in spinal motor neurons in vivo. Thus, we investigated whether a combination of defective dynein with a TDP-43 mutation could trigger TDP-43 pathology. METHODS: Using immunohistochemical methods we examined the intracellular motor neuron pathology of the offspring of TDP-43WT and TDP-43M337V transgenic mice bred to heterozygous Loa mice, which carry an autosomal dominant mutation in dynein cytoplasmic 1 heavy chain 1 (Dync1h1). RESULTS: These mice did not exhibit TDP-43 mislocalisation in spinal motor neurons, but the expression of mutant dynein in combination with wildtype human TDP-43 resulted in p62 upregulation and TDP-43 aggregation, thus partially recapitulating the human disease. CONCLUSIONS: These findings provide new insights into the possible relationship between dynein and TDP-43 and could prove useful in future studies looking to elucidate the mechanism behind the TDP-43 pathology observed in ALS.

Nationwide Survey in Greece about Knowledge, Risk Perceptions, and Preventive Behaviors for COVID-19 during the General Lockdown in April 2020.

BACKGROUND: The aim of this study was to investigate the knowledge, attitudes, and practices of the Greek general population toward coronavirus disease 2019 (COVID-19) during the lockdown period in April 2020, to examine factors associated with misperceptions and to determine behavioral patterns that may require interventions. METHODS: A cross-sectional study of the general Greek population (N = 1858) was conducted. A geographically stratified cluster sampling was implemented. A questionnaire was composed consisting of 35 questions. Data collection took place from 15 April to 2 May 2020. A random-digit dialing survey was conducted by 29 interviewers. RESULTS: The majority of respondents (62.7%) answered ≥12/17 questions correctly. Participants aged 18-44 years, male gender, specific occupations (freelancer, unemployed, housewife, retiree) and those who sought information about COVID-19 from less than two sources received lower aggregated scores on knowledge questions. Regarding attitudes toward future vaccination, 18.9% declared that were against it, while 81.1% that they may consider or will be vaccinated. About 40% were not using a face mask and only 42% washed their hands appropriately. CONCLUSION: Adjusting information campaigns targeting especially people below 45 years of age can help to sensitize them and realise their role to control the spread. Further targeted surveys are needed to adjust/design prevention campaigns.

Potential of activated microglia as a source of dysregulated extracellular microRNAs contributing to neurodegeneration in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron degeneration in adults, and several mechanisms underlying the disease pathology have been proposed. It has been shown that glia communicate with other cells by releasing extracellular vesicles containing proteins and nucleic acids, including microRNAs (miRNAs), which play a role in the post-transcriptional regulation of gene expression. Dysregulation of miRNAs is commonly observed in ALS patients, together with inflammation and an altered microglial phenotype. However, the role of miRNA-containing vesicles in microglia-to-neuron communication in the context of ALS has not been explored in depth. This review summarises the evidence for the presence of inflammation, pro-inflammatory microglia and dysregulated miRNAs in ALS, then explores how microglia may potentially be responsible for this miRNA dysregulation. The possibility of pro-inflammatory ALS microglia releasing miRNAs which may then enter neuronal cells to contribute to degeneration is also explored. Based on the literature reviewed here, microglia are a likely source of dysregulated miRNAs and potential mediators of neurodegenerative processes. Therefore, dysregulated miRNAs may be promising candidates for the development of therapeutic strategies.

Exit and Entry Screening Practices for Infectious Diseases among Travelers at Points of Entry: Looking for Evidence on Public Health Impact.

A scoping search and a systematic literature review were conducted to give an insight on entry and exit screening referring to travelers at points of entry, by analyzing published evidence on practices, guidelines, and experiences in the past 15 years worldwide. Grey literature, PubMed. and Scopus were searched using specific terms. Most of the available data identified through the systematic literature review concerned entry screening measures at airports. Little evidence is available about entry and exit screening measure implementation and effectiveness at ports and ground crossings. Exit screening was part of the World Health Organisation's (WHO) temporary recommendations for implementation in certain points of entry, for specific time periods. Exit screening measures for Ebola Virus Disease (EVD) in the three most affected West African countries did not identify any cases and showed zero sensitivity and very low specificity. The percentages of confirmed cases identified out of the total numbers of travelers that passed through entry screening measures in various countries worldwide for Influenza Pandemic (H1N1) and EVD in West Africa were zero or extremely low. Entry screening measures for Severe Acute Respiratory Syndrome (SARS) did not detect any confirmed SARS cases in Australia, Canada, and Singapore. Despite the ineffectiveness of entry and exit screening measures, authors reported several important concomitant positive effects that their impact is difficult to assess, including discouraging travel of ill persons, raising awareness, and educating the traveling public and maintaining operation of flights from/to the affected areas. Exit screening measures in affected areas are important and should be applied jointly with other measures including information strategies, epidemiological investigation, contact tracing, vaccination, and quarantine to achieve a comprehensive outbreak management response. Based on review results, an algorithm about decision-making for entry/exit screening was developed.

Using Online Screening in the General Population to Detect Participants at Clinical High-Risk for Psychosis.

INTRODUCTION: Identification of participants at clinical high-risk (CHR) for the development of psychosis is an important objective of current preventive efforts in mental health research. However, the utility of using web-based screening approaches to detect CHR participants at the population level has not been investigated. METHODS: We tested a web-based screening approach to identify CHR individuals. Potential participants were invited to a website via e-mail invitations, flyers, and invitation letters involving both the general population and mental health services. Two thousand two hundred seventy-nine participants completed the 16-item version of the prodromal questionnaire (PQ-16) and a 9-item questionnaire of perceptual and cognitive aberrations (PCA) for the assessment of basic symptoms (BS) online. 52.3% of participants met a priori cut-off criteria for the PQ and 73.6% for PCA items online. One thousand seven hundred eighty-seven participants were invited for a clinical interview and n = 356 interviews were conducted (response rate: 19.9%) using the Comprehensive Assessment of At-Risk Mental State (CAARMS) and the Schizophrenia Proneness Interview, Adult Version (SPI-A). n = 101 CHR participants and n = 8 first-episode psychosis (FEP) were detected. ROC curve analysis revealed good to moderate sensitivity and specificity for predicting CHR status based on online results for both UHR and BS criteria (sensitivity/specificity: PQ-16 = 82%/46%; PCA = 94%/12%). Selection of a subset of 10 items from both PQ-16 and PCA lead to an improved of specificity of 57% while only marginally affecting sensitivity (81%). CHR participants were characterized by similar levels of functioning and neurocognitive deficits as clinically identified CHR groups. CONCLUSION: These data provide evidence for the possibility to identify CHR participants through population-based web screening. This could be an important strategy for early intervention and diagnosis of psychotic disorders.

Respiratory disease related mortality and morbidity on an island of Greece exposed to perlite and bentonite mining dust.

A morbidity and mortality study took place, focused on Milos Island, where perlite and bentonite mining sites are located. Official data concerning number and cause of deaths, regarding specific respiratory diseases and the total of respiratory diseases, for both Milos Island and the Cyclades Prefecture were used. Standardized Mortality Ratios (SMRs) were computed, adjusted specifically for age, gender and calendar year. Tests of linear trend were performed. By means of a predefined questionnaire, the morbidity rates of specific respiratory diseases in Milos, were compared to those of the municipality of Oinofita, an industrial region. Chi-square analysis was used and the confounding factors of age, gender and smoking were taken into account, by estimating binary logistic regression models. The SMRs for Pneumonia and Chronic Obstructive Pulmonary Disease (COPD) were found elevated for both genders, although they did not reach statistical significance. For the total of respiratory diseases, a statistically significant SMR was identified regarding the decade 1989-1998. The morbidity study revealed elevated and statistically significant Odds Ratios (ORs), associated with allergic rhinitis, pneumonia, COPD and bronchiectasis. An elevated OR was also identified for asthma. After controlling for age, gender and smoking, the ORs were statistically significant and towards the same direction.

Bladder cancer and arsenic through drinking water: a systematic review of epidemiologic evidence.

Exposure to inorganic arsenic (As) through drinking water is a major international public health issue. We carried out a systematic review of the existing literature examining the association between the risk of bladder cancer in humans and exposure to arsenic through drinking water. We searched electronic databases for studies published from January 2000 up to April 2013. Eight ecological studies, six case-control studies, four cohort studies and two meta-analyses were identified. The vast majority of the studies were carried out in areas with high arsenic concentrations in drinking water such as southwestern and northeastern Taiwan, Pakistan, Bangladesh, Argentina (Cordoba Province), USA (southeastern Michigan, Florida, Idaho) and Chile. Most of the studies reported higher risks of bladder cancer incidence or mortality in areas with high arsenic concentrations in drinking water compared to the general population or a low arsenic exposed control group. The quality assessment showed that among the studies identified, arsenic exposure was assessed at the individual level only in half of them and only three assessed exposure using a biomarker. Further, five out of eight ecological studies presented results with adjustment for potential confounders except for age; all cohort and case-control studies presented results with adjustment for cigarette smoking status in the analysis. The majority of the studies with varying study designs carried out in different areas provided evidence of statistically siginificant increases in bladder cancer risk at high concentrations of arsenic (>50 µg L(-1)). Assessing bladder cancer risk at lower exposure concentrations requires further investigation.

Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece--an ecological study.

BACKGROUND: Hexavalent chromium is a known carcinogen when inhaled, but its carcinogenic potential when orally ingested remains controversial. Water contaminated with hexavalent chromium is a worldwide problem, making this a question of significant public health importance. METHODS: We conducted an ecological mortality study within the Oinofita region of Greece, where water has been contaminated with hexavalent chromium. We calculated gender, age, and period standardized mortality ratios (SMRs) for all deaths, cancer deaths, and specific cancer types of Oinofita residents over an 11-year period (1999 - 2009), using the greater prefecture of Voiotia as the standard population. RESULTS: A total of 474 deaths were observed. The SMR for all cause mortality was 98 (95% CI 89-107) and for all cancer mortality 114 (95% CI 94-136). The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value < 0.001). Furthermore, statistically significantly higher SMRs were identified for lung cancer (SMR = 145, 95% CI 100-203, p-value = 0.047) and cancer of the kidney and other genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value = 0.025). Elevated SMRs for several other cancers were also noted (lip, oral cavity and pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias 168), but these did not reach statistical significance. CONCLUSIONS: Elevated cancer mortality in the Oinofita area of Greece supports the hypothesis of hexavalent chromium carcinogenicity via the oral ingestion pathway of exposure. Further studies are needed to determine whether this association is causal, and to establish preventive guidelines and public health recommendations.