Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging

CONTEXT: Dehydroepiandrosterone (DHEA) mainly exerts indirect action via downstream conversion toward sex steroids within peripheral target cells including immune cells. In vitro DHEA has been shown to enhance IL-2 release from T lymphocytes, whereas it inhibits IL-6 secretion. Conversely, aging is associated with a decline in both DHEA and IL-2, whereas IL-6 increases. OBJECTIVE: The objective of the study was to investigate age-related differences in expression and functional activity of steroidogenic enzymes involved in downstream conversion of DHEA in peripheral blood mononuclear cells (PBMCs). DESIGN: This study was cross-sectional. PARTICIPANTS/SETTING: Healthy young men (n = 8; age range, 23-29 yr) and healthy middle-aged men (n = 8; age range, 52-66 yr) were studied in an academic setting. MEASURES: mRNA expression of steroidogenic enzymes in PBMCs was measured by qualitative and quantitative RT-PCR analysis and enzyme activity assays after incubation of PBMCs with radiolabeled DHEA, 4-androstene-3,17-dione (androstenedione), and testosterone. RESULTS: RT-PCR analysis showed expression of all enzymes required for DHEA conversion toward active androgens and to the immune-stimulatory metabolite androstenediol. Steroid conversion patterns indicated a particularly increased activity of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5) in the older men, demonstrated by significantly higher conversion rates of DHEA to androstenediol and of androstenedione to testosterone (all P < 0.05). By contrast, conversion of DHEA to androstenedione via 3beta-HSD occurred at a similar rate. Quantitative RT-PCR analysis revealed increased expression of 17beta-HSD 5 mRNA in PBMCs from the older men. CONCLUSIONS: Our results provide evidence for significant changes in sex steroid metabolism by human PBMCs with aging, which may represent an endocrine link to immune senescence.     

Recruiting Rural Healthcare Providers Today: a Systematic Review of Training Program Success and Determinants of Geographic Choices

Background

Rural areas have historically struggled with shortages of healthcare providers; however, advanced communication technologies have transformed rural healthcare, and practice in underserved areas has been recognized as a policy priority. This systematic review aims to assess reasons for current providers’ geographic choices and the success of training programs aimed at increasing rural provider recruitment.

Methods

This systematic review (PROSPERO: CRD42015025403) searched seven databases for published and gray literature on the current cohort of US rural healthcare practitioners (2005 to March 2017). Two reviewers independently screened citations for inclusion; one reviewer extracted data and assessed risk of bias, with a senior systematic reviewer checking the data; quality of evidence was assessed using the GRADE approach.

Results

Of 7276 screened citations, we identified 31 studies exploring reasons for geographic choices and 24 studies documenting the impact of training programs. Growing up in a rural community is a key determinant and is consistently associated with choosing rural practice. Most existing studies assess physicians, and only a few are based on multivariate analyses that take competing and potentially correlated predictors into account. The success rate of placing providers-in-training in rural practice after graduation, on average, is 44% (range 20–84%; N = 31 programs). We did not identify program characteristics that are consistently associated with program success. Data are primarily based on rural tracks for medical residents.

Discussion

The review provides insight into the relative importance of demographic characteristics and motivational factors in determining which providers should be targeted to maximize return on recruitment efforts. Existing programs exposing students to rural practice during their training are promising but require further refining. Public policy must include a specific focus on the trajectory of the healthcare workforce and must consider alternative models of healthcare delivery that promote a more diverse, interdisciplinary combination of providers.

     

The factor subdimensions of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) help to specify hip and knee osteoarthritis. a prospective evaluation and validation study

OBJECTIVE: To determine whether it is possible to specify different score patterns for hip and knee osteoarthritis (OA), and to identify the degree of responsiveness and the validity of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) factors, which are alternative health dimensions obtained by factor analysis of the WOMAC items. METHODS: WOMAC scales and WOMAC factors were compared in a prospective setting examining patients with hip and knee OA before and after rehabilitative inpatient intervention (n = 317). In a partial sample (n = 103), the validity of the WOMAC factors was determined by a global rating of their activities. RESULTS: The WOMAC factor "ascending/descending" was significantly different for hip and knee OA in the health state before therapy (score in hip 5.09, in knee 6.59; p < 0.001); this was also true of the effect size after therapy (hip 0.39, knee 0.65; p = 0.012). The WOMAC scales did not differ for the 2 conditions. The WOMAC factor "ascending/descending" was the most responsive dimension in knee OA (effect size 0.65), but in hip OA the WOMAC pain scale was most responsive (effect size 0.55). Most of the WOMAC factors correlated moderately (r = 0.52-0.69) with the patient's self-rating on the validation questionnaire. CONCLUSION: The WOMAC factors are valid measures. Analyzing the WOMAC by the WOMAC factors facilitates and improves the differential relevance and accuracy of the WOMAC for specific conditions such as hip and knee OA.     

Screening for impaired liver function as a risk factor for drug safety at hospital admission of surgical patients

International Journal of Clinical Pharmacy - Background Hepatic insufficiency can affect patient safety and should therefore be considered during drug therapy. Hospital admission offers an ideal...     

Transgenic expression of survivin compensates for OX40‐deficiency in driving Th2 development and allergic inflammation

Survivin, an inhibitor of apoptosis family molecule, has been proposed as a crucial intermediate in the signaling pathways leading to T‐cell development, proliferation, and expansion. However, the importance of survivin to T‐cell‐driven inflammatory responses has not been demonstrated. Here, we show that survivin transgenic mice exhibit an increased antigen‐driven Th2 lung inflammation and that constitutive expression of survivin reversed the defective lung inflammation even in the absence of OX40 costimulation. We found that OX40‐deficient mice were compromised in generating Th2 cells, airway eosinophilia, and IgE responses. In contrast, OX40‐deficient/survivin transgenic mice generated normal Th2 responses and exhibited strong lung inflammation. These results suggest that OX40 costimulation crucially engages survivin during antigen‐mediated Th2 responses. These findings also promote the notion that OX40 costimulation regulates allergic responses or lung inflammation by targeting survivin thereby enhancing T‐cell proliferation and resulting in more differentiated Th2 cells in the allergic inflammatory response.     

DC-LAMP+ Dendritic Cells Are Recruited to Gastric Lymphoid Follicles in Helicobacter pylori-Infected Individuals

Infection with Helicobacter pylori is associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs in H. pylori-infected gastric mucosa. Gastric antral biopsy specimens were collected from patients with H. pylori-associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in the H. pylori-infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP⁺) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP⁺ DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP⁺ DCs with low costimulatory capacity accumulate in the lymphoid follicles in human H. pylori-infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.     

Personality and physiological reactions to acute psychological stress

Stable personality traits have long been presumed to have biological substrates, although the evidence relating personality to biological stress reactivity is inconclusive. The present study examined, in a large middle aged cohort (N = 352), the relationship between key personality traits and both cortisol and cardiovascular reactions to acute psychological stress. Salivary cortisol and cardiovascular activity were measured at rest and in response to a psychological stress protocol comprising 5 min each of a Stroop task, mirror tracing, and a speech task. Participants subsequently completed the Big Five Inventory to assess neuroticism, agreeableness, openness to experience, extraversion, and conscientiousness. Those with higher neuroticism scores exhibited smaller cortisol and cardiovascular stress reactions, whereas participants who were less agreeable and less open had smaller cortisol and cardiac reactions to stress. These associations remained statistically significant following adjustment for a range of potential confounding variables. Thus, a negative personality disposition would appear to be linked to diminished stress reactivity. These findings further support a growing body of evidence which suggests that blunted stress reactivity may be maladaptive.