Dermatitis and Aging-Related Barrier Dysfunction in Transgenic Mice Overexpressing an Epidermal-Targeted Claudin 6 Tail Deletion Mutant

The barrier function of the skin protects the mammalian body against infection, dehydration, UV irradiation and temperature fluctuation. Barrier function is reduced with the skin's intrinsic aging process, however the molecular mechanisms involved are unknown. We previously demonstrated that Claudin (Cldn)-containing tight junctions (TJs) are essential in the development of the epidermis and that transgenic mice overexpressing Cldn6 in the suprabasal layers of the epidermis undergo a perturbed terminal differentiation program characterized in part by reduced barrier function. To dissect further the mechanisms by which Cldn6 acts during epithelial differentiation, we overexpressed a Cldn6 cytoplasmic tail deletion mutant in the suprabasal compartment of the transgenic mouse epidermis. Although there were no gross phenotypic abnormalities at birth, subtle epidermal anomalies were present that disappeared by one month of age, indicative of a robust injury response. However, with aging, epidermal changes with eventual chronic dermatitis appeared with a concomitant barrier dysfunction manifested in increased trans-epidermal water loss. Immunohistochemical analysis revealed aberrant suprabasal Cldn localization with marked down-regulation of Cldn1. Both the proliferative and terminal differentiation compartments were perturbed as evidenced by mislocalization of multiple epidermal markers. These results suggest that the normally robust injury response mechanism of the epidermis is lost in the aging Involucrin-Cldn6-CΔ196 transgenic epidermis, and provide a model for evaluation of aging-related skin changes

Interventions for behaviour change and self-management in stroke secondary prevention: protocol for an overview of reviews

Abstract Background Stroke secondary prevention guidelines recommend medication prescription and adherence, active education and behavioural counselling regarding lifestyle risk factors. To impact on recurrent vascular events, positive behaviour/s must be adopted and sustained as a lifestyle choice, requiring theoretically informed behaviour change and self-management interventions. A growing number of systematic reviews have addressed complex interventions in stroke secondary prevention. Differing terminology, inclusion criteria and overlap of studies between reviews makes the mechanism/s that affect positive change difficult to identify or replicate clinically. Adopting a two-phase approach, this overview will firstly comprehensively summarise systematic reviews in this area and secondly identify and synthesise primary studies in these reviews which provide person-centred, theoretically informed interventions for stroke secondary prevention. Methods An overview of reviews will be conducted using a systematic search strategy across the Cochrane Database of Systematic Reviews, PubMed and Epistomonikas. Inclusion criteria: systematic reviews where the population comprises individuals post-stroke or TIA and where data relating to person-centred risk reduction are synthesised for evidence of efficacy when compared to standard care or no intervention. Primary outcomes of interest include mortality, recurrent stroke and other cardiovascular events. In phase 1, two reviewers will independently (1) assess the eligibility of identified reviews for inclusion; (2) rate the quality of included reviews using the ROBIS tool; (3) identify unique primary studies and overlap between reviews; (4) summarise the published evidence supporting person-centred behavioural change and self-management interventions in stroke secondary prevention and (5) identify evidence gaps in this field. In phase 2, two independent reviewers will (1) examine person-centred, primary studies in each review using the Template for Intervention Description and Replication (TIDieR checklist), itemising, where present, theoretical frameworks underpinning interventions; (2) group studies employing theoretically informed interventions by the intervention delivered and by the outcomes reported (3) apply GRADE quality of evidence for each intervention by outcome/s identified from theoretically informed primary studies. Disagreement between reviewers at each process stage will be discussed and a third reviewer consulted. Discussion This overview will comprehensively bring together the best available evidence supporting person-centred, stroke secondary prevention strategies in an accessible format, identifying current knowledge gaps

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3>2.1×10-12¿¿s/eV at 90% C.L

First observations of separated atmospheric nu_mu and bar{nu-mu} events in the MINOS detector

The complete 5.4 kton MINOS far detector has been taking data since the beginning of August 2003 at a depth of 2070 meters water-equivalent in the Soudan mine, Minnesota. This paper presents the first MINOS observations of nuµ and [overline nu ]µ charged-current atmospheric neutrino interactions based on an exposure of 418 days. The ratio of upward- to downward-going events in the data is compared to the Monte Carlo expectation in the absence of neutrino oscillations, giving Rup/downdata/Rup/downMC=0.62-0.14+0.19(stat.)±0.02(sys.). An extended maximum likelihood analysis of the observed L/E distributions excludes the null hypothesis of no neutrino oscillations at the 98% confidence level. Using the curvature of the observed muons in the 1.3 T MINOS magnetic field nuµ and [overline nu ]µ interactions are separated. The ratio of [overline nu ]µ to nuµ events in the data is compared to the Monte Carlo expectation assuming neutrinos and antineutrinos oscillate in the same manner, giving R[overline nu ][sub mu]/nu[sub mu]data/R[overline nu ][sub mu]/nu[sub mu]MC=0.96-0.27+0.38(stat.)±0.15(sys.), where the errors are the statistical and systematic uncertainties. Although the statistics are limited, this is the first direct observation of atmospheric neutrino interactions separately for nuµ and [overline nu ]µ

Dopamine D4 Receptor Gene Associated with Fairness Preference in Ultimatum Game

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making

A novel emergency department based prevention intervention program for people living with HIV: evaluation of early experiences

<p>Abstract</p> <p>Background</p> <p>HIV prevention is increasingly focused on people living with HIV (PLWH) and the role of healthcare settings in prevention. Emergency Departments (EDs) frequently care for PLWH, but do not typically endorse a prevention mission. We conducted a pilot exploratory evaluation of the first reported ED program to address the prevention needs of PLWH.</p> <p>Methods</p> <p>This retrospective observational cohort evaluation reviewed program records to describe the first six months of participants and programmatic operation. Trained counselors provided a risk assessment and counseling intervention combined with three linkage interventions: i) linkage to health care, ii) linkage to case management, and iii) linkage to partner counseling and referral.</p> <p>Results</p> <p>Of 81 self-identified PLWH who were approached, 55 initially agreed to participate. Of those completing risk assessment, 17/53 (32%, 95 CI 20% to 46%) reported unprotected anal/vaginal intercourse or needle sharing in the past six months with a partner presumed to be HIV negative. Counseling was provided to 52/53 (98%). For those requesting services, 11/15 (73%) were linked to healthcare, 4/23 (17%) were coordinated with case management, and 1/4 (25%) completed partner counseling and referral.</p> <p>Conclusion</p> <p>Given base resources of trained counselors, it was feasible to implement a program to address the prevention needs for persons living with HIV in an urban ED. ED patients with HIV often have unmet needs which might be addressed by improved linkage with existing community resources. Healthcare and prevention barriers for PLWH may be attenuated if EDs were to incorporate CDC recommended prevention measures for healthcare providers.</p