IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity

Genome sequence of the button mushroom Agaricus bisporus reveals mechanisms governing adaptation to a humic-rich ecological niche

Agaricus bisporus is the model fungus for the adaptation, persistence, and growth in the humic-rich leaf-litter environment. Aside from its ecological role, A. bisporus has been an important component of the human diet for over 200 y and worldwide cultivation of the "button mushroom" forms a multibillion dollar industry. We present two A. bisporus genomes, their gene repertoires and transcript profiles on compost andduringmushroomformation.The genomes encode a full repertoire of polysaccharide-degrading enzymes similar to that of wood-decayers. Comparative transcriptomics of mycelium grown on defined medium, casing-soil, and compost revealed genes encoding enzymes involved in xylan, cellulose, pectin, and protein degradation aremore highly expressed in compost. The striking expansion of heme-thiolate peroxidases and β-etherases is distinctive from Agaricomycotina wood-decayers and suggests a broad attack on decaying lignin and related metabolites found in humic acid-rich environment. Similarly, up-regulation of these genes together with a lignolytic manganese peroxidase, multiple copper radical oxidases, and cytochrome P450s is consistent with challenges posed by complex humic-rich substrates. The gene repertoire and expression of hydrolytic enzymes in A. bisporus is substantially different from the taxonomically related ectomycorrhizal symbiont Laccaria bicolor. A common promoter motif was also identified in genes very highly expressed in humic-rich substrates. These observations reveal genetic and enzymatic mechanisms governing adaptation to the humic-rich ecological niche formed during plant degradation, further defining the critical role such fungi contribute to soil structure and carbon sequestration in terrestrial ecosystems. Genome sequence will expedite mushroom breeding for improved agronomic characteristics

Effect of weighting for sampling and non-response on estimates of STI prevalence in the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3)

OBJECTIVES: In addition to researcher-designed sampling biases, population-representative surveys for biomarker measurement of STIs often have substantial missingness due to non-contact, non-consent and other study-implementation issues. STI prevalence estimates may be biased if this missingness is related to STI risk. We investigated how accounting for sampling, interview non-response and non-provision of biological samples affects prevalence estimates in the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). METHODS: Natsal-3 was a multistage, clustered and stratified probability sample of 16–74 year-olds conducted between 2010 and 2012. Individuals were sampled from all private residential addresses in Britain; respondents aged 16–44 were further sampled to provide a urine specimen based on characteristics including self-reported sexual behaviours. We generated prevalence estimates and confidence intervals for six STIs in five stages: first without accounting for sampling or non-response, then applying inverse-probability weights cumulatively accounting for interview sampling, interview non-response, urine sampling and urine non-response. RESULTS: Interview non-completion occurred for 42.3% of interview-sampled individuals; urine non-completion occurred for 43.5% of urine-sampled individuals. Interview-sampled individuals, interview respondents, those selected for urine samples and those providing urine samples were each in turn slightly more at-risk for most STIs, leading to lower prevalence estimates after incorporating each set of weights. Researcher-controlled sampling had more impact than respondent-controlled response. CONCLUSIONS: Accounting for both sampling structures and willingness to interview or provide urine specimens can affect national STI prevalence estimates. Using both types of weights, as was done in Natsal-3, is important in reporting on population-based biomarker surveys

Examining the potential public health benefit of offering STI testing to men in amateur football clubs: evidence from cross-sectional surveys

Background: In Britain, young people continue to bear the burden of sexually transmitted infections (STIs) so efforts are required, especially among men, to encourage STI testing. The SPORTSMART study trialled an intervention that sought to achieve this by offering chlamydia and gonorrhoea test-kits to men attending amateur football clubs between October and December 2012. With football the highest participation team sport among men in England, this paper examines the potential public health benefit of offering STI testing to men in this setting by assessing their sociodemographic characteristics, sexual behaviours, and healthcare behaviour and comparing them to men in the general population. Methods: Data were collected from 192 (male) members of 6 football clubs in London, United Kingdom, aged 18–44 years via a 20-item pen-and-paper self-completion questionnaire administered 2 weeks after the intervention. These were compared to data collected from 409 men of a similar age who were resident in London when interviewed during 2010–2012 for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a national probability survey that used computer-assisted-personal-interviewing with computer-assisted-self-interview. Age standardisation and multivariable regression were used to account for sociodemographic differences between the surveys. Results: Relative to men in the general population, SPORTSMART men were younger (32.8 % vs. 21.7 % aged under 25 y), and more likely to report (all past year) at least 2 sexual partners (adjusted odds ratio, AOR: 3.25, 95 % CI: 2.15–4.92), concurrent partners (AOR: 2.05, 95 % CI: 1.39–3.02), and non-use of condoms (AOR: 2.17, 95 % CI: 1.39–3.41). No difference was observed in STI/HIV risk perception (AOR for reporting “not at all at risk” of STIs: 1.25, 95 % CI: 0.76–2.04; of HIV: AOR: 1.54, 95 % CI: 0.93–2.55), nor in reporting STI testing in the past year (AOR: 0.83, 95 % CI: 0.44–1.54), which was reported by only one in six men. Conclusions: Relative to young men in the general population, football club members who completed the SPORTSMART survey reported greater sexual risk behaviour but similar STI/HIV risk perception and STI testing history. Offering STI testing in amateur football clubs may therefore widen access to STI testing and health promotion messages for men at higher STI risk, which, given the minority currently testing and the popularity of football in England, should yield both individual and public health benefit

Cost-effectiveness of the implantable cardioverter-defibrillator: Effect of improved battery life and comparison with amiodarone therapy

AbstractThe implantable cardioverter-defibrillator (ICD) greatly reduces the incidence of sudden cardiac death among patients with recurrent sustained ventricular tachycardia and fibrillation who do not respond to conventional antiarrhythmic therapy. A cost-effectiveness analysis was performed, comparing the ICD, amiodarone and conventional agents. Actual variable costs of hospitalization and follow-up care were used for 21 ICD- and 43 amiodarone-treated patients. Life expectancy and total variable costs were predicted with use of a Markov decision analytic model. Clinical event rates and probabilities were based on published reports or expert opinion.Life expectancy with an ICD (6.1 years) was 50% greater than that associated with treatment with amiodarone (3.9 years) and 2.5 times that associated with conventional treatment (2.5 years). Assuming replacement every 24 months, ICD lifetime treatment costs (in 1989 dollars) for a 55-year old patient are expected to be $89,600 compared with$24,800 for amiodarone and $16,100 for conventional therapy, yielding a marginal cost/effectiveness ratio for ICD versus amiodarone therapy of$29,200/year of life saved, which is comparable to that of other accepted medical treatments. If technologic improvements extend average battery life to 36 months, the marginal cost/effectiveness ratio would be $21,880/ year of life saved, and at 96 months it would be$13,800/year of life saved. Patient age at implantation did not significantly affect these results.If quality of life on amiodarone therapy is 30% lower than that with the ICD, the marginal cost/effectiveness ratio decreases by 35%. If the quality of life for patients receiving drugs is 40% lower than that of patients treated with an ICD, use of the defibrillator becomes the dominant strategy

Binding of soluble fibronectin to integrin α5ß1 - link to focal adhesion redistribution and contractile shape

Focal adhesions are randomly distributed across the ventral surface or along the edge of epithelial cells. In fibroblasts they orient centripetally and concentrate at a few peripheral sites connecting long F-actin stress fibers, causing a typical elongated, contractile morphology. Extensive remodeling of adhesions in fibroblasts also takes part in fibronectin fibrillogenesis, a process that depends on Rho-mediated contractility and results in the formation of a fibronectin matrix. Our current study shows that all these fibroblast characteristics are controlled by the ability of integrin alpha 5 beta 1 to bind soluble fibronectin molecules in their compact inactive conformation. The hypervariable region of the ligand-binding I-like domain of integrin alpha 5 beta 1 supports binding of soluble fibronectin. This supports the distribution of centripetally orientated focal adhesions in distinct peripheral sites, Rho activation and fibronectin fibrillogenesis through a mechanism that does not depend on Syndecan-4. Integrin alpha v beta 3, even when locked in high affinity conformations for the RGD recognition motif shows no appreciable binding of soluble fibronectin and, consequently, fails to support the typical fibroblast focal adhesion distribution, Rho activity and fibronectin fibrillogenesis in the absence of integrin alpha 5 beta 1. The ability of alpha 5 beta 1 integrin to interact with soluble fibronectin may thus drive the cell-matrix adhesion and cytoskeletal organization required for a contractile, fibroblast-like morphology, perhaps explaining why alpha 5 beta 1 integrin, similarly to fibronectin, is essential for development.Toxicolog

Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type

IntroductionClinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic currents, and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. However, emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are among others that the translation from this binary characterization to neuronal firing is currently not well-understood—especially when considering different neuronal cell types. In this study, we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations.MethodsTo this end, we simulated a diverse collection of single-compartment, conductance-based neuron models that differed in their composition of ionic currents. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of known mutations in KCNA1 gene encoding the KV1.1 potassium channel subtype associated with episodic ataxia type 1 (EA1).ResultsThese simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability depends on neuron type, i.e., the properties and expression levels of the unaffected ionic currents.DiscussionConsequently, neuron-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and are an important step toward improving the efficacy and precision of personalized medicine approaches

How can we objectively categorise partnership type? A novel classification of population survey data to inform epidemiological research and clinical practice

Abstract: Background Partnership type is a determinant of STI risk; yet, it is poorly and inconsistently recorded in clinical practice and research. We identify a novel, empirical-based categorisation of partnership type, and examine whether reporting STI diagnoses varies by the resulting typologies. Methods: Analyses of probability survey data collected from 15 162 people aged 16–74 who participated in Britain's third National Survey of Sexual Attitudes and Lifestyles were undertaken during 2010–2012. Computer-assisted self-interviews asked about participants' ≤3 most recent partners (N=14 322 partners/past year). Analysis of variance and regression tested for differences in partnership duration and perceived likelihood of sex again across 21 ‘partnership progression types’ (PPTs) derived from relationship status at first and most recent sex. Multivariable regression examined the association between reporting STI diagnoses and partnership type(s) net of age and reported partner numbers (all past year). Results: The 21 PPTs were grouped into four summary types: ‘cohabiting’, ‘now steady’, ‘casual’ and ‘ex-steady’ according to the average duration and likelihood of sex again. 11 combinations of these summary types accounted for 94.5% of all men; 13 combinations accounted for 96.9% of all women. Reporting STI diagnoses varied by partnership-type combination, including after adjusting for age and partner numbers, for example, adjusted OR: 6.03 (95% CI 2.01 to 18.1) for men with two ‘casual’ and one ‘now steady’ partners versus men with one ‘cohabiting’ partner. Conclusions: This typology provides an objective method for measuring partnership type and demonstrates its importance in understanding STI risk, net of partner numbers. Epidemiological research and clinical practice should use these methods and results to maximise individual and public health benefit

Use of the internet for sexual health among sexually experienced persons aged 16 to 44 years: evidence from a nationally representative survey of the British population

BACKGROUND: Those who go online regarding their sexual health are potential users of new Internet-based sexual health interventions. Understanding the size and characteristics of this population is important in informing intervention design and delivery. OBJECTIVE: We aimed to estimate the prevalence in Britain of recent use of the Internet for key sexual health reasons (for chlamydia testing, human immunodeficiency virus [HIV] testing, sexually transmitted infection [STI] treatment, condoms/contraceptives, and help/advice with one's sex life) and to identify associated sociodemographic and behavioral factors. METHODS: Complex survey analysis of data from 8926 sexually experienced persons aged 16-44 years in a 2010-2012 probability survey of Britain's resident population. Prevalence of recent (past year) use of Internet sources for key sexual health reasons was estimated. Factors associated with use of information/support websites were identified using logistic regression to calculate age-adjusted odds ratios (AORs). RESULTS: Recent Internet use for chlamydia/HIV testing or STI treatment (combined) was very low (men: 0.31%; women: 0.16%), whereas 2.35% of men and 0.51% of women reported obtaining condoms/contraceptives online. Additionally, 4.49% of men and 4.57% of women reported recent use of information/support websites for advice/help with their sex lives. Prevalence declined with age (men 16-24 years: 7.7%; 35-44 years: 1.84%, P<.001; women 16-24 years: 7.8%; 35-44 years: 1.84%, P<.001). Use of information/support websites was strongly associated with men's higher socioeconomic status (managerial/professional vs semiroutine/routine: AOR 1.93, 95% CI 1.27-2.93, P<.001). Despite no overall association with area-level deprivation, those in densely populated urban areas were more likely to report use of information/support websites than those living in rural areas (men: AOR 3.38, 95% CI 1.68-6.77, P<.001; women: AOR 2.51, 95% CI 1.34-4.70, P<.001). No statistically significant association was observed with number of sex partners reported after age adjustment, but use was more common among men reporting same-sex partners (last 5 years: AOR 2.44, 95% CI 1.27-4.70), women reporting sex with multiple partners without condoms (last year: AOR 1.90, 95% CI 1.11-3.26), and, among both sexes, reporting seeking sex online (last year, men: AOR 1.80, 95% CI 1.16-2.79; women: AOR 3.00, 95% CI 1.76-5.13). No association was observed with reporting STI diagnosis/es (last 5 years) or (after age adjustment) recent use of any STI service or non-Internet sexual health seeking. CONCLUSIONS: A minority in Britain used the Internet for the sexual health reasons examined. Use of information/support websites was reported by those at greater STI risk, including younger people, indicating that demand for online STI services, and Internet-based sexual health interventions in general, may increase over time in this and subsequent cohorts. However, the impact on health inequalities needs addressing during design and evaluation of online sexual health interventions so that they maximize public health benefit

Men who have sex with men in Great Britain: comparing methods and estimates from probability and convenience sample surveys

OBJECTIVE: To examine sociodemographic and behavioural differences between men who have sex with men (MSM) participating in recent UK convenience surveys and a national probability sample survey. METHODS: We compared 148 MSM aged 18-64 years interviewed for Britain's third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) undertaken in 2010-2012, with men in the same age range participating in contemporaneous convenience surveys of MSM: 15 500 British resident men in the European MSM Internet Survey (EMIS); 797 in the London Gay Men's Sexual Health Survey; and 1234 in Scotland's Gay Men's Sexual Health Survey. Analyses compared men reporting at least one male sexual partner (past year) on similarly worded questions and multivariable analyses accounted for sociodemographic differences between the surveys. RESULTS: MSM in convenience surveys were younger and better educated than MSM in Natsal-3, and a larger proportion identified as gay (85%-95% vs 62%). Partner numbers were higher and same-sex anal sex more common in convenience surveys. Unprotected anal intercourse was more commonly reported in EMIS. Compared with Natsal-3, MSM in convenience surveys were more likely to report gonorrhoea diagnoses and HIV testing (both past year). Differences between the samples were reduced when restricting analysis to gay-identifying MSM. CONCLUSIONS: National probability surveys better reflect the population of MSM but are limited by their smaller samples of MSM. Convenience surveys recruit larger samples of MSM but tend to over-represent MSM identifying as gay and reporting more sexual risk behaviours. Because both sampling strategies have strengths and weaknesses, methods are needed to triangulate data from probability and convenience surveys