Co-Regulation and Interdependence of the Mammalian Epidermal Permeability and Antimicrobial Barriers

Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), β-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1–8hours after acute permeability barrier disruption and normalize by 24hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP−/− mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis

Screening and diagnosing depression in women visiting GPs' drop in clinic in Primary Health Care

<p>Abstract</p> <p>Background</p> <p>Only half of all depressions are diagnosed in Primary Health Care (PHC). Depression can remain undetected for a long time and entail high costs for care and low quality of life for the individuals. Drop in clinic is a common form of organizing health care; however the visits are short and focus on solving the most urgent problems. The aim of this study was to investigate the prevalence and severity of depression among women visiting the GPs' drop in clinic and to identify possible clues for depression among women.</p> <p>Methods</p> <p>The two-stage screening method with "high risk feedback" was used. Beck's Depression Inventory (BDI) was used to screen 155 women visiting two GPs' drop in clinic. Women who screened positive (BDI score ≥10) were invited by the GP to a repeat visit. Major depression (MDD) was diagnosed according to DSM-IV criteria and the severity was assessed with Montgomery-Asberg Depression Rating Scale (MADRS). Women with BDI score <10 constituted a control group. Demographic characteristics were obtained by questionnaire. Chart notations were examined with regard to symptoms mentioned at the index visit and were categorized as somatic or mental.</p> <p>Results</p> <p>The two-stage method worked well with a low rate of withdrawals in the second step, when the GP invited the women to a repeat visit. The prevalence of depression was 22.4% (95% CI 15.6–29.2). The severity was mild in 43%, moderate in 53% and severe in 3%. The depressed women mentioned mental symptoms significantly more often (69%) than the controls (15%) and were to a higher extent sick-listed for a longer period than 14 days. Nearly one third of the depressed women did not mention mental symptoms. The majority of the women who screened as false positive for depression had crisis reactions and needed further care from health professionals in PHC. Referrals to a psychiatrist were few and revealed often psychiatric co-morbidity.</p> <p>Conclusion</p> <p>The prevalence of previously undiagnosed depression among women visiting GPs' drop in clinic was high. Clues for depression were identified in the depressed women's symptom presentation; they often mention mental symptoms when they visit the GP for somatic reasons e.g. respiratory infections. We suggest that GPs do selective screening for depression when women mention mental symptoms and offer to schedule a repeat visit for follow-up rather than just recommending that the patient return if the mental symptoms do not disappear.</p

Involucrin expression is decreased in Hailey-Hailey keratinocytes owing to increased involucrin mRNA degradation

Hailey–Hailey disease (HHD) (MIM 16960) is an autosomal-dominant blistering skin disease caused by a mutation in the Ca2+-ATPase ATP2C1 (protein SPCA1), responsible for controlling Ca2+ concentrations in the cytoplasm and Golgi in human keratinocytes. Cytosolic Ca2+ concentrations, in turn, play a major role in the regulation of keratinocyte differentiation. To study how ATP2C1 function impacts keratinocyte differentiation, we assessed involucrin expression in HHD keratinocytes. Involucrin is a protein that makes up the cornified envelope of keratinocytes and is expressed in response to increased intracellular Ca2+ concentrations. Even though HHD keratinocytes suffer from abnormally high cytosolic Ca2+, we found that these cells expressed lower involucrin protein levels at both low and high extracellular Ca2+ concentrations when compared with normal control keratinocytes. Decreased involucrin protein levels were caused by lower involucrin mRNA levels in HHD keratinocytes. Decreased involucrin mRNA, in turn, was caused by increased rates of involucrin mRNA degradation. Ca2+-sensitive involucrin AP-1 promotor activity was increased, both in HHD keratinocytes and in an small interfering RNA (siRNA) experimental model, suggesting compensatory promoter upregulation in the face of increased mRNA degradation. This report provides new insights into differentiation defects in HHD and its relationship to Ca2+ signaling

Assessing costs and benefits of improved soil quality management in remediation projects: A study of an urban site contaminated with PAH and metals

Contaminants in the soil may threaten soil functions (SFs) and, in turn, hinder the delivery of ecosystem services (ES). A framework for ecological risk assessments (ERAs) within the APPLICERA - APPLICable site-specific Environmental Risk Assessment research project promotes assessments that consider other soil quality parameters than only contaminant concentrations. The developed framework is: (i) able to differentiate the effects of contamination on SFs from the effects of other soil qualities essential for soil biota; and (ii) provides a robust basis for improved soil quality management in remediation projects. This study evaluates the socio-economic consequences of remediation alternatives stemming from a Tier 1 ERA that focusses on total contaminant concentrations and soil quality standards and a detailed, site-specific Tier 3 Triad approach that is based on the APPLICERA framework. The present study demonstrates how Tier 1 and Tier 3 ERAs differ in terms of the socioeconomic consequences of their remediation actions, as well as presents a novel method for the semi-quantitative assessment of on-site ES. Although the presented Tier 3 ERA is more expensive and time-consuming than the more traditional Tier 1 ERA approach, it has the potential to lower the costs of remediation actions, decrease greenhouse gas emissions, reduce other environmental impacts, and minimise socio-economic losses. Furthermore, the remediation actions stemming from the Tier 3 ERA were predicted to exert far less negative ES effects than the actions proposed based on the results of the Tier 1 ERA. (C) 2019 Elsevier B.V. All rights reserved

Successful recruitment of a multi-site international randomized placebo-controlled trial in people with HIV with attention to diversity of race and ethnicity: critical role of central coordination

Background: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is a multicenter, randomized, placebo-controlled trial, designed to test whether a statin medication can prevent cardiovascular disease in people with HIV. REPRIEVE recently completed enrollment of 7557 participants at over 100 clinical sites globally. Participant groups of focus were women, and racial and ethnic minorities. Objective: To describe recruitment methods and strategies developed by the REPRIEVE Clinical Coordinating Center (CCC) and share best practices learned from the recruitment process. Methods: Enrollment targets were agreed upon with the primary funder, the National Heart, Lung, and Blood Institute (NHLBI) and were milestone driven. Milestones included number of sites activated, number of participants enrolled within specific time frames, and proportion of women and minorities enrolled. Strategies to achieve these milestones included structured interviews with site-designated REPRIEVE Recruitment Champions to develop best practices, development of a multimedia campaign, and site level recruitment support. Results: Recruitment initiated March, 2015 and completed March, 2019. The final accrual target was 7500 participants over 48 months. The trial met this target within the time specified. Overall, 10,613 screens were completed, 48% of participants enrolled from sites outside of North America, 32% were female, 44% were Black or African American, and 25% were Hispanic or Latino. Conclusions: REPRIEVE met its overall projected recruitment goal by using multiple, simultaneous strategies to specifically target a diverse population including minority subgroups. REPRIEVE benefited from the development of recruitment strategies with clear targets and communication of accrual targets to study teams

Rhinitis, Asthma and Respiratory Infections among Adults in Relation to the Home Environment in Multi-Family Buildings in Sweden

Risk factors for rhinitis, asthma and respiratory infections in the home environment were studied by a questionnaire survey. Totally 5775 occupants (&gt;= 18 years old) from a stratified random sample of multi-family buildings in Sweden participated (46%). 51.0% had rhinitis in the last 3 months (current rhinitis); 11.5% doctor diagnosed asthma; 46.4% respiratory infections in the last 3 months and 11.9% antibiotic medication for respiratory infections in the last 12 months. Associations between home environment and health were analyzed by multiple logistic regression, controlling for gender, age and smoking and mutual adjustment. Buildings constructed during 1960-1975 were risk factors for day time breathlessness (OR = 1.53, 95%CI 1.03-2.29). And those constructed during 1976-1985 had more current rhinitis (OR = 1.43, 95%CI 1.12-1.84) and respiratory infections (OR = 1.46, 95%CI 1.21-1.78). Cities with higher population density had more current rhinitis (p = 0.008) and respiratory infections (p&lt;0.001). Rented apartments had more current rhinitis (OR = 1.23, 95%CI 1.07-1.40), wheeze (OR = 1.20, 95%CI 1.02-1.41), day time breathlessness (OR = 1.31, 95%CI 1.04-1.66) and respiratory infections (OR = 1.13, 95%CI 1.01-1.26). Living in colder parts of the country was a risk factor for wheeze (p = 0.03) and night time breathlessness (p = 0.002). Building dampness was a risk factor for wheeze (OR = 1.42, 95%CI 1.08-1.86) and day time breathlessness (OR = 1.57, 95%CI 1.09-2.27). Building dampness was a risk factor for health among those below 66 years old. Odor at home was a risk factor for doctor diagnosed asthma (OR = 1.49, 95%CI 1.08-2.06) and current asthma (OR = 1.52, 95%CI 1.03-2.24). Environmental tobacco smoke (ETS) was a risk factor for current asthma (OR = 1.53, 95%CI 1.09-2.16). Window pane condensation was a risk factor for antibiotic medication for respiratory infections (OR = 1.41, 95%CI 1.10-1.82). In conclusion, rhinitis, asthma and respiratory infections were related to a number of factors in the home environment. Certain building years (1961-1985), building dampness, window pane condensation and odor in the dwelling may be risk factors

Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice

The skin is the first line of defense against microbial infection, and psychological stress (PS) has been shown to have adverse effects on cutaneous barrier function. Here we show that PS increased the severity of group A Streptococcus pyogenes (GAS) cutaneous skin infection in mice; this was accompanied by increased production of endogenous glucocorticoids (GCs), which inhibited epidermal lipid synthesis and decreased lamellar body (LB) secretion. LBs encapsulate antimicrobial peptides (AMPs), and PS or systemic or topical GC administration downregulated epidermal expression of murine AMPs cathelin-related AMP and β-defensin 3. Pharmacological blockade of the stress hormone corticotrophin-releasing factor or of peripheral GC action, as well as topical administration of physiologic lipids, normalized epidermal AMP levels and delivery to LBs and decreased the severity of GAS infection during PS. Our results show that PS decreases the levels of 2 key AMPs in the epidermis and their delivery into LBs and that this is attributable to increased endogenous GC production. These data suggest that GC blockade and/or topical lipid administration could normalize cutaneous antimicrobial defense during PS or GC increase. We believe this to be the first mechanistic link between PS and increased susceptibility to infection by microbial pathogens