Corneal Replication Is an Interferon Response-Independent Bottleneck for Virulence of Herpes Simplex Virus 1 in the Absence of Virion Host Shutoff

Herpes simplex viruses lacking the virion host shutoff function (Δvhs) are avirulent and hypersensitive to type I and type II interferon (IFN). In this study, we demonstrate that even in the absence of IFN responses in AG129 (IFN-αβγR−/−) mice, Δvhs remains highly attenuated via corneal infection but is fully virulent via intracranial infection. The data demonstrate that the interferon-independent inherent replication defect of Δvhs has a significant impact upon peripheral replication and neuroinvasion

Microfluidic Endothelium for Studying the Intravascular Adhesion of Metastatic Breast Cancer Cells

BACKGROUND:The ability to properly model intravascular steps in metastasis is essential in identifying key physical, cellular, and molecular determinants that can be targeted therapeutically to prevent metastatic disease. Research on the vascular microenvironment has been hindered by challenges in studying this compartment in metastasis under conditions that reproduce in vivo physiology while allowing facile experimental manipulation. METHODOLOGY/PRINCIPAL FINDINGS:We present a microfluidic vasculature system to model interactions between circulating breast cancer cells with microvascular endothelium at potential sites of metastasis. The microfluidic vasculature produces spatially-restricted stimulation from the basal side of the endothelium that models both organ-specific localization and polarization of chemokines and many other signaling molecules under variable flow conditions. We used this microfluidic system to produce site-specific stimulation of microvascular endothelium with CXCL12, a chemokine strongly implicated in metastasis. CONCLUSIONS/SIGNIFICANCE:When added from the basal side, CXCL12 acts through receptor CXCR4 on endothelium to promote adhesion of circulating breast cancer cells, independent of CXCL12 receptors CXCR4 or CXCR7 on tumor cells. These studies suggest that targeting CXCL12-CXCR4 signaling in endothelium may limit metastases in breast and other cancers and highlight the unique capabilities of our microfluidic device to advance studies of the intravascular microenvironment in metastasis

'On the Wet Side of the Womb’:The construction of mothers in anti-abortion activism in England and Wales

Across the UK, there has been an increase in anti-abortion activism outside abortion clinics. The activism deployed includes explicitly religious activities such as ‘prayerful witnessing’ and ‘pavement counselling’, which aim to discourage women from entering clinics. This article stems from a wider ethnographic study of public activism over abortion to determine what claims about motherhood are being made within these debates. Two arguments are presented. First, how women’s role as mothers is central and essentialised in anti-abortion discourses, with the body of the mother often disappearing as activists seek to erode the distinction between a foetus and a baby by constructing pregnancy as a foetal environment. Motherhood is constructed as ‘natural’ and sacred, therefore abortion must be damaging because it destroys women’s ‘natural’ position. Second, the article argues that although the activists’ arguments are always religiously framed, their activism takes place in a largely secular context, meaning that they have to find ways of appealing to secular audiences. This leads to a complex interrelationship between secular and religious discourses, where theological viewpoints sit alongside ‘scientific’ claims to buttress activists’ views. This article explores how the presence and absence of mothers within activists’ narratives is due to the tensions between religiously based understandings of motherhood, and the need to appeal to a secular audience

Life expectancy inequalities in Wales before COVID-19: an exploration of current contributions by age and cause of death and changes between 2002 and 2018

Objectives The COVID-19 pandemic in Wales and the UK has highlighted significant and historic inequalities in health between social groups. To better understand the composition of these inequalities and inform planning after the pandemic, we undertook a decomposition of life expectancy inequalities between the most and least deprived quintiles for men and women by age and cause of death and explored trends between 2002 and 2018. Study design Statistical decomposition of life expectancy inequalities by age and cause of death using routine population mortality datasets. Methods We used routine statistics from the Office for National Statistics for the period 2002–2018 on population and deaths in Wales stratified by age, gender, Welsh Index of Multiple Deprivation (WIMD) 2019 quintile and cause of death, categorised by International Classification of Disease, version 10, code into 15 categories of public health relevance. We aggregated data to 3-year rolling figures to account for low numbers of events in some groups annually. Next, we estimated life expectancy at birth by quintile, gender and period using life table methods. Lastly, we performed a decomposition analysis using the Arriaga method to identify the specific disease categories and ages at which excess deaths occur in more disadvantaged areas to highlight potential areas for action. Results Life expectancy inequalities between the most and least WIMD quintiles rose for both genders between 2002 and 2018: from 4.69 to 6.02 years for women (an increase of 1.33 years) and from 6.34 to 7.42 years for men (an increase of 1.08 years). Exploratory analysis of these trends suggested that the following were most influential for women: respiratory disease (1.50 years), cancers (1.36 years), circulatory disease (1.35 years) and digestive disease (0.51 years). For men, the gap was driven by circulatory disease (2.01 years), cancers (1.39 years), respiratory disease (1.25 years), digestive disease (0.79 years), drug- and alcohol-related conditions (0.54 years) and external causes (0.54 years). Contributions for women from respiratory disease, cancers, dementia and drug- and alcohol-related conditions appeared to be increasing, while among men, there were rising contributions from respiratory, digestive and circulatory disease. Conclusions Life expectancy inequalities in Wales remain wide and have been increasing, particularly among women, with indications of worsening trends since 2010 following the introduction of fiscal austerity. As agencies recover from the pandemic, these findings should be considered alongside any resumption of services in Wales or future health and public policy

Ubiquitination of CXCR7 Controls Receptor Trafficking

The chemokine receptor CXCR7 binds CXCL11 and CXCL12 with high affinity, chemokines that were previously thought to bind exclusively to CXCR4 and CXCR3, respectively. Expression of CXCR7 has been associated with cardiac development as well as with tumor growth and progression. Despite having all the canonical features of G protein-coupled receptors (GPCRs), the signalling pathways following CXCR7 activation remain controversial, since unlike typical chemokine receptors, CXCR7 fails to activate Gαi-proteins. CXCR7 has recently been shown to interact with β-arrestins and such interaction has been suggested to be responsible for G protein-independent signals through ERK-1/2 phosphorylation. Signal transduction by CXCR7 is controlled at the membrane by the process of GPCR trafficking. In the present study we investigated the regulatory processes triggered by CXCR7 activation as well as the molecular interactions that participate in such processes. We show that, CXCR7 internalizes and recycles back to the cell surface after agonist exposure, and that internalization is not only β-arrestin-mediated but also dependent on the Serine/Threonine residues at the C-terminus of the receptor. Furthermore we describe, for the first time, the constitutive ubiquitination of CXCR7. Such ubiquitination is a key modification responsible for the correct trafficking of CXCR7 from and to the plasma membrane. Moreover, we found that CXCR7 is reversibly de-ubiquitinated upon treatment with CXCL12. Finally, we have also identified the Lysine residues at the C-terminus of CXCR7 to be essential for receptor cell surface delivery. Together these data demonstrate the differential regulation of CXCR7 compared to the related CXCR3 and CXCR4 receptors, and highlight the importance of understanding the molecular determinants responsible for this process

Is chronic pelvic pain a comfortable diagnosis for primary care practitioners: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Chronic pelvic pain (CPP) has a prevalence similar to asthma and chronic back pain, but little is known about how general practitioners (GPs) and practice nurses manage women with this problem. A clearer understanding of current management is necessary to develop appropriate strategies, in keeping with current health care policy, for the supported self-management of patients with long term conditions. The aim of this study was to explore GPs' and practice nurses' understanding and perspectives on the management of chronic pelvic pain.</p> <p>Methods</p> <p>Data were collected using semi-structured interviews with a purposive sample of 21 GPs and 20 practice nurses, in three primary care trusts in the North West of England. Data were analysed using the principles of Framework analysis.</p> <p>Results</p> <p>Analysis suggests that women who present with CPP pose a challenge to GPs and practice nurses. CPP is not necessarily recognized as a diagnostic label and making the diagnosis was achieved only by exclusion. This contrasts with the relative acceptability of labels such as irritable bowel syndrome (IBS). GPs expressed elements of therapeutic nihilism about the condition. Despite practice nurses taking on increasing responsibilities for the management of patients with long term conditions, respondents did not feel that CPP was an area that they were comfortable in managing.</p> <p>Conclusions</p> <p>The study demonstrates an educational/training need for both GPs and practice nurses. GPs described a number of skills and clinical competencies which could be harnessed to develop a more targeted management strategy. There is potential to develop facilitated self- management for use in this patient group, given that this approach has been successful in patients with similar conditions such as IBS.</p

Effects and feasibility of a multi-disciplinary orientation program for newly registered cancer patients: design of a randomised controlled trial

Background Diagnosis and treatment of cancer can contribute to psychological distress and anxiety amongst patients. Evidence indicates that information giving can be beneficial in reducing patient anxiety, so oncology specific information may have a major impact on this patient group. This study investigates the effects of an orientation program on levels of anxiety and self-efficacy amongst newly registered cancer patients who are about to undergo chemotherapy and/or radiation therapy in the cancer care centre of a large tertiary Australian hospital. Methods The concept of interventions for orienting new cancer patients needs revisiting due to the dynamic health care system. Historically, most orientation programs at this cancer centre were conducted by one nurse. A randomised controlled trial has been designed to test the effectiveness of an orientation program with bundled interventions; a face-to-face program which includes introduction to the hospital facilities, introduction to the multi-disciplinary team and an overview of treatment side effects and self care strategies. The aim is to orientate patients to the cancer centre and to meet the health care team. We hypothesize that patients who receive this orientation will experience lower levels of anxiety and distress, and a higher level of self-efficacy. Discussion An orientation program is a common health care service provided by cancer care centres for new cancer patients. Such programs aim to give information to patients at the beginning of their encounter at a cancer care centre. It is clear in the literature that interventions that aim to improve self-efficacy in patients may demonstrate potential improvement in health outcomes. Yet, evidence on the effects of orientation programs for cancer patients on self-efficacy remains scarce, particularly with respect to the use of multidisciplinary team members. This paper presents the design of a randomised controlled trial that will evaluate the effects and feasibility of a multidisciplinary orientation program for new cancer patients