Fusion of Sendai virus with the target cell membrane is required for T cell cytotoxicity

INFECTION of mice with viruses can generate cytotoxic T lymphocytes (CTL) which show restricted specificity for target cell lysis. Specific lysis requires that the virus used to prime the target cells must be of the same type as that used to sensitise the CTL, and that both target and CTL cells must express the same major histocompatability complex (MHC) gene product(s). The nature of the viral gene product(s) and their interaction with the MHC gene product(s) have been the subject of recent stud1−5. Previously we used Sendai virus to show that lysable target cells can be obtained using membrane vesicles which contain only the viral glycoproteins, indicating that these may be the specific viral gene products involved in target formation5. Sendai virus contains two glycoproteins—the haemagglutinin-neuraminidase (HANA) which promotes attachment of virus to cells and the fusion protein (F) which is involved in subsequent virus cell fusion7−9. Both activities are necessary for insertion of these viral glycoproteins into the plasma membrane of the cell10. In this letter we suggest that the insertion of the viral glycoproteins into the cell membrane is an essential step in target cell formation since we can show that virus containing an inactive fusion protein precursor (F0) cannot elicit T cell cytotoxicity unless the fusion activity is generated by proteolytic cleavage of the precursor. Sugamura et al. 6 have suggested that it is primarily the F glycoprotein of the Sendai virus envelope which is essential for the formation of the target antigen, as virus lacking the functional activities of F following trypsin digestion was inactive in priming target cells for T cell killing. However, we show that proteolytic inactivation of either of the two glycoproteins (F or HANA) of virus used to prime target cells will abolish the cytotoxic response

Novel IL10 gene family associations with systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic childhood disability and encompasses a number of disease subgroups. In this study we have focused on systemic JIA (sJIA), which accounts for approximately 11% of UK JIA cases. This study reports the investigation of three members of the IL10 gene family as candidate susceptibility loci in children with sJIA. DNA from 473 unaffected controls and 172 patients with sJIA was genotyped for a single nucleotide polymorphism (SNP) in IL19 and IL20 and two SNPs in IL10. We examined evidence for association of the four SNPs by single marker and haplotype analysis. Significant differences in allele frequency were observed between cases and controls, for both IL10-1082 (p = 0.031) and IL20-468 (p = 0.028). Furthermore, examination of the haplotypes of IL10-1082 and IL20-468 revealed greater evidence for association (global p = 0.0006). This study demonstrates a significant increased prevalence of the low expressing IL10-1082 genotype in patients with sJIA. In addition, we show a separate association with an IL20 polymorphism, and the IL10-1082A/IL20-468T haplotype. The two marker 'A-T' haplotype confers an odds ratio of 2.24 for sJIA. This positive association suggests an important role for these cytokines in sJIA pathogenesis

Translation of evidence-based Assistive Technologies into stroke rehabilitation: Users' perceptions of the barriers and opportunities

Background: Assistive Technologies (ATs), defined as "electrical or mechanical devices designed to help people recover movement", demonstrate clinical benefits in upper limb stroke rehabilitation; however translation into clinical practice is poor. Uptake is dependent on a complex relationship between all stakeholders. Our aim was to understand patients', carers' (P&Cs) and healthcare professionals' (HCPs) experience and views of upper limb rehabilitation and ATs, to identify barriers and opportunities critical to the effective translation of ATs into clinical practice. This work was conducted in the UK, which has a state funded healthcare system, but the findings have relevance to all healthcare systems. Methods. Two structurally comparable questionnaires, one for P&Cs and one for HCPs, were designed, piloted and completed anonymously. Wide distribution of the questionnaires provided data from HCPs with experience of stroke rehabilitation and P&Cs who had experience of stroke. Questionnaires were designed based on themes identified from four focus groups held with HCPs and P&Cs and piloted with a sample of HCPs (N = 24) and P&Cs (N = 8). Eight of whom (four HCPs and four P&Cs) had been involved in the development. Results: 292 HCPs and 123 P&Cs questionnaires were analysed. 120 (41%) of HCP and 79 (64%) of P&C respondents had never used ATs. Most views were common to both groups, citing lack of information and access to ATs as the main reasons for not using them. Both HCPs (N = 53 [34%]) and P&C (N = 21 [47%]) cited Functional Electrical Stimulation (FES) as the most frequently used AT. Research evidence was rated by HCPs as the most important factor in the design of an ideal technology, yet ATs they used or prescribed were not supported by research evidence. P&Cs rated ease of set-up and comfort more highly. Conclusion: Key barriers to translation of ATs into clinical practice are lack of knowledge, education, awareness and access. Perceptions about arm rehabilitation post-stroke are similar between HCPs and P&Cs. Based on our findings, improvements in AT design, pragmatic clinical evaluation, better knowledge and awareness and improvement in provision of services will contribute to better and cost-effective upper limb stroke rehabilitation. © 2014 Hughes et al.; licensee BioMed Central Ltd

Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity

TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5α but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations

Resident macrophages influence stem cell activity in the mammary gland

Introduction Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis. Although it is well established that macrophages influence normal mammopoiesis, the mammary cell types that these accessory cells influence have not been determined. Here we have explored a role for macrophages in regulating mammary stem cell (MaSC) activity, by assessing the ability of MaSCs to reconstitute a mammary gland in a macrophage-depleted fat pad. Methods Two different in vivo models were used to deplete macrophages from the mouse mammary fat pad, allowing us to examine the effect of macrophage deficiency on the mammary repopulating activity of MaSCs. Both the Csf1(op/op) mice and clodronate liposome-mediated ablation models entailed transplantation studies using the MaSC-enriched population. Results We show that mammary repopulating ability is severely compromised when the wild-type MaSC-enriched subpopulation is transplanted into Csf1(op/op) fat pads. In reciprocal experiments, the MaSC-enriched subpopulation from Csf1(op/op) glands had reduced regenerative capacity in a wildtype environment. Utilizing an alternative strategy for selective depletion of macrophages from the mammary gland, we demonstrate that co-implantation of the MaSC-enriched subpopulation with clodronate-liposomes leads to a marked decrease in repopulating frequency and outgrowth potential. Conclusions Our data reveal a key role for mammary gland macrophages in supporting stem/progenitor cell function and suggest that MaSCs require macrophage-derived factors to be fully functional. Macrophages may therefore constitute part of the mammary stem cell nich

The Role of Appearance in Adolescents’ Experiences of Neurofibromatosis Type 1: A Survey of Young People and Parents

© 2016, National Society of Genetic Counselors, Inc. Neurofibromatosis type 1 (NF1) is a genetic condition which can result in varying degrees of visible difference (disfigurement). Adolescence is a time when appearance concerns become more salient for many young people and is acknowledged as a particularly challenging time for individuals with NF1. There is currently little research into the psychosocial impact of the appearance changes associated with NF1 during this stage of life. In order to address this, surveys of young people with NF1 aged 14–24years (n=73), and parents of young people with NF1 (n=55) were developed following interview studies with these groups. The surveys included the Perceived Stigma Questionnaire, Social Comfort Questionnaire, Body Esteem Scale (appearance subscale) and the Subjective Happiness Scale. Young people and parents identified appearance as central to young peoples’ experience of NF1, however no significant difference was found on measures of body esteem, happiness, stigma or social comfort between those young people who reported their NF1 was noticeable to others and those who reported it was not. Findings from the parent survey indicated that their reports of greater perceived noticeability did relate to greater perceived stigma and lower levels of social comfort. Findings highlight the importance of attending to young people’s concerns around appearance in general and managing the possibility of future appearance changes, rather than the current noticeability of NF1

A Framework for Examining Social Stress and Susceptibility to Air Pollution in Respiratory Health

Objective: There is growing interest in disentangling the health effects of spatially clustered social and physical environmental exposures and in exploring potential synergies among them, with particular attention directed to the combined effects of psychosocial stress and air pollution. Both exposures may be elevated in lower-income urban communities, and it has been hypothesized that stress, which can influence immune function and susceptibility, may potentiate the effects of air pollution in respiratory disease onset and exacerbation. In this paper, we attempt to synthesize the relevant research from social and environmental epidemiology, toxicology, immunology, and exposure assessment to provide a useful framework for environmental health researchers aiming to investigate the health effects of environmental pollution in combination with social or psychological factors. Data synthesis: We review the existing epidemiologic and toxicologic evidence on synergistic effects of stress and pollution, and then describe the physiologic effects of stress and key issues related to measuring and evaluating stress as it relates to physical environmental exposures and susceptibility. Finally, we identify some of the major methodologic challenges ahead as we work toward disentangling the health effects of clustered social and physical exposures and accurately describing the interplay among these exposures. Conclusions: There is still tremendous work to be done toward understanding the combined and potentially synergistic health effects of stress and pollution. As this research proceeds, we recommend careful attention to the relative temporalities of stress and pollution exposures, to nonlinearities in their independent and combined effects, to physiologic pathways not elucidated by epidemiologic methods, and to the relative spatial distributions of social and physical exposures at multiple geographic scales

The Diagnostic Accuracy of Syndromic Management for Genital Ulcer Disease: A Systematic Review and Meta-Analysis.

Objectives: Genital Ulcer Disease (GUD) carries a significant disease burden globally. With limited access to diagnostics, the 2001 World Health Organization (WHO) sexually transmitted illnesses (STI) guidelines proposed a syndromic management algorithm that required a clinical decision to determine the management of GUD. We assessed the diagnostic accuracy of this algorithm. Methods: We conducted a systematic review (Prospero: CRD42020153294) using eight databases for publications between 1995 and January 2021 that reported primary data on the diagnostic accuracy of clinical diagnosis to identify aetiological agents of GUD. Titles and abstracts were independently assessed for eligibility, and data were extracted from full texts for sensitivity/specificity. A hierarchical logistic regression model was used to derive pooled sensitivity and specificity. We used GRADE to evaluate the certainty of evidence. Results: Of 24,857 articles, 151 full texts were examined and 29 included in the analysis. The majority were from middle-income countries [(14/29 (48%) lower middle, 10/29 (34%) upper middle)]. We pooled studies where molecular testing was using to confirm the aetiology of GUD: 9 studies (12 estimates) for herpes, 4 studies (7 estimates) for syphilis, and 7 studies (10 estimates) for chancroid. The pooled sensitivity and specificity of GUD for the detection of herpes was 43.5% [95% confidence interval (CI): 26.2-62.4], and 88.0% (95% CI: 67.0-96.3), respectively (high certainty evidence); and for syphilis were 52.8% (95% CI: 23.0-80.7), and 72.1% (95% CI: 28.0-94.5) (moderate certainty evidence); and for chancroid were 71.9% (95% CI: 45.9-88.5) and 53.1% (95% CI: 36.6-68.9) (moderate certainty evidence), respectively. Conclusion: Algorithms requiring a clinical diagnosis to determine and treat the aetiology of GUD have poor sensitivities for syphilis and herpes simplex virus, resulting in significant numbers of missed cases. There is an urgent need to improve access to affordable and efficient diagnostics (e.g., point-of-care tests) to be incorporated into GUD algorithms to better guide appropriate management. Systematic Review Registration: PROSPERO, identifier: CRD42020153294

Use of complementary and alternative medicine by those with a chronic disease and the general population - results of a national population based survey

<p>Abstract</p> <p>Background</p> <p>The use of complementary and alternative medicine (CAM) is becoming more common, but population-based descriptions of its patterns of use are lacking. This study aimed to determine the prevalence of CAM use in the general population and for those with asthma, diabetes, epilepsy and migraine.</p> <p>Methods</p> <p>Data from cycles 1.1, 2.1 and 3.1 of the Canadian Community Health Survey (CCHS) were used for the study. The CCHS is a national cross-sectional survey administered to 400,055 Canadians aged ≥12 between 2001-2005. Self-reported information about professionally diagnosed health conditions was elicited. CCHS surveys use a multistage stratified cluster design to randomly select a representative sample of Canadian household residents. Descriptive data on the utilization of CAM services was calculated and logistic regression was used to determine what sociodemographic factors predict CAM use.</p> <p>Results</p> <p>Weighted estimates show that 12.4% (95% Confidence Interval (CI): 12.2-12.5) of Canadians visited a CAM practitioner in the year they were surveyed; this rate was significantly higher for those with asthma 15.1% (95% CI: 14.5-15.7) and migraine 19.0% (95% CI: 18.4-19.6), and significantly lower for those with diabetes 8.0% (95% CI: 7.4-8.6) while the rate in those with epilepsy (10.3%, 95% CI: 8.4-12.2) was not significantly different from the general population.</p> <p>Conclusion</p> <p>A large proportion of Canadians use CAM services. Physicians should be aware that their patients may be accessing other services and should be prepared to ask and answer questions about the risks and benefits of CAM services in conjunction with standard medical care.</p