Calcium Influx Rescues Adenylate Cyclase-Hemolysin from Rapid Cell Membrane Removal and Enables Phagocyte Permeabilization by Toxin Pores

Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium-conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium-conducting CyaA-AC− toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca2+ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca2+ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-ΔAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca2+ influx promoted by molecules locked in a Ca2+-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux

Health care for irregular migrants: pragmatism across Europe. A qualitative study

<p>Abstract</p> <p>Background</p> <p>Health services in Europe face the challenge of delivering care to a heterogeneous group of irregular migrants (IM). There is little empirical evidence on how health professionals cope with this challenge. This study explores the experiences of health professionals providing care to IM in three types of health care service across 16 European countries.</p> <p>Results</p> <p>Semi-structured interviews were conducted with health professionals in 144 primary care services, 48 mental health services, and 48 Accident & Emergency departments (total n = 240). Although legal health care entitlement for IM varies across countries, health professionals reported facing similar issues when caring for IM. These issues include access problems, limited communication, and associated legal complications. Differences in the experiences with IM across the three types of services were also explored. Respondents from Accident & Emergency departments reported less of a difference between the care for IM patients and patients in a regular situation than did respondents from primary care and mental health services. Primary care services and mental health services were more concerned with language barriers than Accident & Emergency departments. Notifying the authorities was an uncommon practice, even in countries where health professionals are required to do this.</p> <p>Conclusions</p> <p>The needs of IM patients and the values of the staff appear to be as important as the national legal framework, with staff in different European countries adopting a similar pragmatic approach to delivering health care to IM. While legislation might help to improve health care for IM, more appropriate organisation and local flexibility are equally important, especially for improving access and care pathways.</p

Association of sleep, screen time and physical activity with overweight and obesity in Mexico

PURPOSE: Approximately 70% of adults in Mexico are overweight or obese. Unhealthy lifestyle behaviors are also prevalent. We examined the association of three lifestyle behaviors with body mass index (BMI) categories in adults from Mexico. METHODS: We used publicly available data from the ENSANUT 2016 survey (n = 6419). BMI was used to categorize participants. Differences in sleep duration, suffering from symptoms of insomnia, TV watching time, time in front of any screen, vigorous physical activity (yes vs no), moderate physical activity (> 30 min/day-yes vs. no) and walking (> 60 min/day-yes vs. no) were compared across BMI groups using adjusted linear and logistic regression analyses. RESULTS: Thirty-nine percent of participants were overweight and 37% obese. Time in front of TV, in front of any screen, sleep duration and physical activity were significantly associated with overweight and obesity. Compared to normal weight participants, participants in the obese II category spend on average 0.60 h/day (95% CI 0.36-0.84, p = 0.001) and participants in the obese III category 0.54 h/day (95% CI 0.19-0.89, p < 0.001) more in front of any screen; participants in the obese II category reported 0.55 h/day less sleep (95% CI - 0.67 to - 0.43, p < 0.001); participants in the obese III category were less likely to engage in vigorous activity (OR = 0.60, 95% CI 0.43-0.84, p ≤ 0.003), or walking (OR = 0.65, 95% CI 0.49-0.88, p = 0.005). CONCLUSION: Screen time, sleeping hours, and physical activity were associated with overweight and obesity. However, these associations were not consistent across all BMI categories. Assuming established causal connections, overweight individuals and individuals with obesity would benefit from reduced screen time and engaging in moderate/vigorous physical activity. LEVEL OF EVIDENCE: Level III: observational case-control analytic study

ANALYSIS OF GROUND FAULT CURRENT DISTRIBUTION ALONG UNDERGROUND CABLES

It is important to determine the segment-by-segment distribution of the fault current in a multigrounded power network for better power system operation and grounding structure design. In this paper, a new method for the analysis of ground fault current distribution along underground cables (and/or overhead lines) is presented. The method is sufficiently accurate and comprehensive to simultaneously consider all the significant variables. The equivalent circuit developed utilizes both lumped and distributed parameters. The method is based on the successive computation of driving point impedance matrices at each grounding structure location. Simulations have been done on a computer. Verification studies and various parametric studies have been performed

Refugee and migrant women's engagement with sexual and reproductive health care in Australia: A socio-ecological analysis of health care professional perspectives

BACKGROUND:In Australia only 2.2% of published health research has focused on multi-cultural health despite the increase of culturally and linguistically diverse populations. Research on the perceptions and experiences of health care professionals (HCPs) in engaging with refugee and migrant women is also lacking. Given the integral role of HCPs in providing sexual and reproductive health (SRH) care for these populations, an understanding of the challenges they experience is required. Therefore, this study sought to examine the perspectives and practices of Australian HCPs with regard to the provision of SRH care for refugee and migrant women. METHODS:Employing qualitative methods, twenty-one semi-structured interviews were conducted with HCPs representing various professions, work experiences, cultural backgrounds, age and healthcare sectors. The interviews were analysed using thematic analysis and the socio-ecological model was utilised to interpret the data. RESULTS:The complexities of HCP's engagement with refugee and migrant women were identified in three major themes: Being a Migrant; Gender Roles and SRH Decision-making; and Women in the Healthcare System. HCPs discussed the impact of accessing SRH care in women's country of origin and the influence of re-settlement contexts on their SRH knowledge, engagement with care and care provision. Perception of gender roles was integral to SRH decision-making with the need to involve male partners having an impact on the provision of women-centred care. Barriers within the healthcare system included the lack of services to address sexual functioning and relationship issues, as well as lack of resources, time constraints, cost of services, and funding. CONCLUSION:Australian HCPs interviewed reported that migrant and refugee women do not have appropriate access to SRH care due to multifaceted challenges. These challenges are present across the entire socio-ecological arena, from individual to systemic levels. Multiple and multidimensional interventions are required to increase SRH utilisation and improve outcomes for refugee and migrant women