Neutrophils are involved in the increased vascular permeability produced by activated complement in man

To investigate the role of neutrophils in complement-induced changes in vascular permeability, skin wheal and flare responses to intradermal injection of autologous activated serum complement were measured in normal and neutropenic subjects. In normal subjects, responses were dose-dependent and were abolished by removal of C5 from serum. Biopsy of a wheal revealed neutrophils adherent to vascular endothelium. In neutropenic subjects (neutrophil count less than 0.5 X 10(9)/l), responses to complement-activated serum or a low molecular weight fraction from it were significantly reduced. This could not be accounted for by a reduction in concentration of C5 conversion products. In one subject with chronic granulomatous disease a normal response was produced. Local injection of the anti-histamine (H1) drug clemastine produced only partial inhibition of responses, while almost totally abolishing histamine-induced wheals. Systemic anti-inflammatory drugs had no effect. The data suggest that the microvascular response to activated complement in man is at least partly due to an interaction between C5 fragments and neutrophils.     

Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120‐catenin with the cytoplasmic tail of MUC1

Adherens junctions (AJs) containing epithelial cadherin (E‐cad) bound to p120‐catenin (p120ctn) and β‐catenin (β‐ctn) play a crucial role in regulating cell–cell adhesion. Cigarette smoke abrogates cell–cell adhesion between epithelial cells by disrupting E‐cad, a hallmark of epithelial–mesenchymal transition (EMT), yet the underlying mechanism remains unknown. We used an organotypic culture of primary human bronchial epithelial (HBE) cells treated with smoke‐concentrated medium (Smk) to establish an essential role for the interaction between p120ctn and the cytoplasmic tail of MUC1 (MUC1‐CT) in regulating E‐cad disruption. Within the first 4 h of smoke exposure, apical MUC1‐CT repositioned to the basolateral membrane of pseudo‐stratified HBE cells, where it interacted with p120ctn. A time‐dependent increase in MUC1‐CT/p120ctn complexes occurred in conjunction with a time‐dependent dissociation of p120ctn/E‐cad/β‐ctn complexes, as well as the coordinated degradation of p120ctn and E‐cad. Interestingly, Smk induced a similar interaction between MUC1‐CT and β‐ctn, but this occurred 44 h after MUC1‐CT's initial interaction with p120ctn, and well after the AJs were destroyed. Blocking MUC1‐CT's interaction with p120ctn using a MUC1‐CT dominant‐negative peptide, PMIP, successfully abolished Smk's disruptive effects on AJs and recovered apical‐basolateral polarity of HBE cells. The MUC1‐CT/p120ctn interaction was highly dependent on EGFR/Src/Jnk‐mediated tyrosine phosphorylation (TyrP) of MUC1‐CT. Accordingly, EGFR, Src or Jnk inhibitors (AG1478, PP2, SP600125, respectively) abrogated Smk‐induced MUC1‐CT‐TyrP, MUC1‐CT/p120ctn interaction, AJ disruption, and loss of cellular polarity. Our work identified MUC1‐CT and p120ctn as important regulators of epithelial polarity and cell‐cell adhesion during a smoke‐induced EMT‐like process. Novel therapeutics designed to inhibit MUC1‐CT/p120ctn complex formation may prevent EMT in the smoker's airway. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Impact of a Rapid-Access Ambulatory Psychiatry Encounter on Subsequent Emergency Department Utilization

The authors sought to determine whether providing a rapid-access ambulatory psychiatry encounter correlated with emergency department utilization during a 6-month follow-up period. Electronic medical records of patients who accessed ambulatory psychiatric care through an urgent care psychiatry clinic that offers treatment exclusively on a walk-in basis over a 1-year period (N?=?157) were reviewed retrospectively to track emergency department encounters with and without a psychiatric chief complaint in the 6 months before and after the initial psychiatry evaluation. Among patients who had not previously received ambulatory psychiatric care (N?=?88), emergency department utilization decreased from 0.68 visits per patient to 0.36, and this difference was statistically significant (p?= 0.0147). No statistically significant differences were found between the average number of emergency department encounters in the 6 months before and after the rapid-access ambulatory psychiatry encounter, regardless of chief complaint, when all patients were included in the analysis. Providing a rapid-access ambulatory psychiatry encounter may reduce subsequent emergency department utilization among patients who have not previously received ambulatory psychiatric care.

     

ADRB2, brain white matter integrity and cognitive ageing in the Lothian Birth Cohort 1936

The non-synonymous mutations arg16gly (rs1042713) and gln27glu (rs1042714) in the adrenergic β-2 receptor gene (ADRB2) have been associated with cognitive function and brain white matter integrity. The current study aimed to replicate these findings and expand them to a broader range of cognitive and brain phenotypes. The sample used is a community-dwelling group of older people, the Lothian Birth Cohort 1936. They had been assessed cognitively at age 11 years, and undertook further cognitive assessments and brain diffusion MRI tractography in older age. The sample size range for cognitive function variables was N = 686–765, and for neuroimaging variables was N = 488–587. Previously-reported findings with these genetic variants did not replicate in this cohort. Novel, nominally significant associations were observed; notably, the integrity of the left arcuate fasciculus mediated the association between rs1042714 and the Digit Symbol Coding test of information processing speed. No significant associations of cognitive and brain phenotypes with ADRB2 variants survived correction for false discovery rate. Previous findings may therefore have been subject to type 1 error. Further study into links between ADRB2, cognitive function and brain white matter integrity is required.     

Disentangling levels of mother–infant neuroendocrine attunement and longitudinal relations with maternal risk and protective factors

Scientific understanding of mother–infant HPA axis attunement has been limited by discrepant methods for assessing attunement that often conflate different levels of association. We sought to refine the conceptualization of attunement by investigating whether mother–infant cortisol attunement exists as coupling of response trajectories within an acute stress episode, separate from shared developmental patterns and/or overall dyadic similarity in cortisol levels, and whether the degree of attunement depends on within‐ or between‐dyad differences in maternal risk and protective factors. We examined these questions using a longitudinal study with mother/infant salivary cortisol during dyadic stressors at 6, 12, and 18 months postnatal. A three‐level hierarchical linear model showed that sample‐wide associations between mother and infant cortisol were not significant at any level, suggesting normative lack of attunement; however, there was significant variability in degree of attunement across dyads. Concurrent levels of family resources and social support satisfaction predicted lower mother–infant cortisol attunement within the session, and overall (mean) parenting stress predicted the opposite. Follow‐up analyses showed this was typically due to an increase in infants’ (but not their mothers’) within‐session cortisol response slopes with increasing support and decreasing stress. Implications for the role of mother–infant cortisol attunement in intergenerational stress transmission are discussed.     

Three cases of autoimmune hepatitis in HIV-infected patients

Autoimmune hepatitis (AIH) is an uncommon liver disease that has previously been reported only 4 times in HIV-infected patients. Our report describes 3 new cases of AIH, 2 probable, and 1 definite. Two of these cases developed while the patient was virologically suppressed on antiretroviral therapy. Liver biopsy findings were critical in establishing the diagnosis of AIH. Because abnormal liver function tests in HIV-positive patients are often ascribed to antiretroviral medications and/or comorbid conditions, AIH may be underdiagnosed in this population. These cases underscore the value of liver biopsy in evaluating hepatitis of unclear etiology in HIV-positive patients. The clinical course of these cases also suggests that standard immunosuppressive therapy for AIH remains the optimal treatment regimen, even in HIV-positive patients.