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Background: We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy. Methods: We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls. Results: In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1+ plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6+ mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19. Conclusions: Matrix expansion, through syndecan-1+ cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1+ cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders, IL-6 is upregulated and represents a logical target for immunotherapy in patients with coeliac disease refractory to gluten-free diet. [ABSTRACT FROM AUTHOR]

The articles in Part IV of the feature share information from leading adapted sport groups to serve as resources for inservices or for the creation of infrastructures and events in local schools districts. [ABSTRACT FROM PUBLISHER]

The article discusses usefulness of good literature choices to ensure success of male choral singers with special reference to the success of the Young Men's Vocal Workshop (YMVW) at the University of Oklahoma. Carefully chosen literature is stated to have contributed to the success of the event that consisted of challenging and inspirational music. Members of the American Choral Directors Association (ACDA) helped to organize the event that contributed to the success.

In vitro organ culture (IVOC) represents a gold standard model to study enteropathogenic E. coli (EPEC) infection of human intestinal mucosa. However, the optimal examination of the bacterial–host cell interaction requires a directional epithelial exposure, without serosal or cut surface stimulation. A polarized IVOC system (pIVOC) was developed in order to overcome such limitations: apical EPEC infection produced negligible bacterial leakage via biopsy edges, resulted in enhanced colonization compared with standard IVOC, and showed evidence of bacterial detachment, as in natural rabbit EPEC infections. Examination of mucosal innate immune responses in pIVOC showed both interleukin (IL)-8 mRNA and protein levels were significantly increased after apical EPEC infection. Increased IL-8 levels mainly depended on flagellin expression as fliC-negative EPEC did not elicit a significant IL-8 response despite increased mucosal colonization compared with wild-type EPEC. In addition, apical application of purified flagella significantly increased IL-8 protein levels over non-infected controls. Immunofluorescence staining of EPEC-infected small intestinal biopsies revealed apical and basolateral distribution of Toll-like receptor (TLR) 5 on epithelium, suggesting that EPEC can trigger mucosal IL-8 responses by apical flagellin/TLR5 interaction ex vivo and does not require access to the basolateral membrane as postulated in cell culture models. [ABSTRACT FROM AUTHOR]

Introduction: Venoarterial extracorporeal membrane oxygenation (VA‐ECMO) is utilized as a life‐saving procedure and bridge to myocardial recovery for patients in refractory cardiogenic shock. Despite technical advancements, VA‐ECMO retains high mortality. This study aims to identify the clinical predictors of in‐hospital mortality after VA‐ECMO to improve risk stratification for this tenuous patient population. Methods: The REgistry for Cardiogenic Shock: Utility and Efficacy of Device Therapy database is a multicenter, observational registry of ECMO patients. From 2013 to 2018, 789 patients underwent VA‐ECMO. Bivariate analysis was performed on more than 300 variables regarding their association with in‐hospital mortality. Logistic regression analyses were performed with variables chosen based upon clinical and statistical significance in the bivariate analysis. Tests were considered significant at a two‐sided P <.05. Results: Although 63.5% patients were successfully weaned from VA‐ECMO, in‐hospital mortality was 57.9%. Nonsurvivors were older (P <.0001), had higher body mass index (P =.01), higher rates of hypertension (P =.02), coronary artery disease (P =.02), chronic obstructive pulmonary disease (P =.02), chronic liver disease (P =.008), percutaneous coronary intervention (P =.02), and surgical revascularization (P =.02). Multivariate predictors for in‐hospital mortality include older age (odds ratio [OR], 1.019; P =.007), cardiac arrest (OR, 2.76; P =.006), chronic liver disease (OR, 8.87; P =.04), elevated total bilirubin (OR, 1.093; P <.0001), and the presence of a left ventricular vent (OR, 2.018; P =.03). Pre‐ECMO sinus rhythm was protective (OR, 0.374; P =.006). Conclusions: In a large study of recent VA‐ECMO patients, in‐hospital mortality remains significant, but acceptable given the severe pathology manifested in this population. Identification of pre‐ECMO predictors of mortality helps stratify high‐risk patients when deciding on ECMO placement, prolonged support, and prognosis. [ABSTRACT FROM AUTHOR]

PURPOSE: To detail the process for importing a defined data set into a centralized global registry via a secure file transfer platform and to understand the barriers to the establishment of a centralized global registry. RESULTS: A bespoke solution was developed to allow transmission of data from international local data centers to a centralized repository. Data elements included in the import template were drawn from existing International Consortium for Health Outcome Measurement variables and refined to ensure accurate benchmarking as well as feasibility in data completeness. The data set was organized in accordance with the prostate cancer care trajectory. Key considerations in developing the data transfer platform included import file format, process of input validation, and technical provisions. Given the diversity in the legislation and ethical requirements with respect to consent, data handling, and cross-border data transfer across geographic locations, we encouraged each local data center to consult with its legal advisors and research ethics committee early on in the process. DISCUSSION: A global collaboration, although highly valuable, posed many challenges because of inconsistent methods of data collection. User acceptance of a system is paramount to the success of establishing a metaregistry. Local information technology support and regular regression testing ensures quality and maintenance of the database. CONCLUSION: We developed a Web-based system to facilitate the collection and secure storage of common data, which is scalable and secure. It is anticipated that through systematic recording of data, global standards of clinical practice and outcomes of care will see vast improvements. [ABSTRACT FROM AUTHOR]

Rationale: Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers of the severity of stimulant drug dependence. Methodology: We employed a double-blind, placebo-controlled cross-over design, administering a single dose of the selective dopamine D receptor agonist pramipexole (0.5 mg) to increase dopamine transmission in one session and a placebo treatment in another session in 36 volunteers. Half the volunteers had a formal diagnosis of stimulant dependence, while half had no psychiatric history. Participants performed neurocognitive tests from the CANTAB battery on both occasions, and stimulant-dependent individuals rated drug craving using visual analog scales. Whole-blood mRNA levels were measured for three dopamine-related genes: DRD3 and DRD4 (dopamine receptors), and catechol- O-methyltransferase (COMT; a dopamine catabolic enzyme). Results: Stimulant users performed worse than healthy volunteers on the cognitive tests. The variation in peripheral dopamine D receptor mRNA expression explained over one quarter of the variation in response to pramipexole on the spatial working memory test across all participants. The severity of stimulant dependence was also significantly associated with peripheral COMT mRNA expression in stimulant users. Conclusions: Peripheral expression of dopamine-related genes may be useful as a biomarker of cognitive response to dopamine agonist drugs and of severity of addiction to dopamine-releasing stimulant drugs. [ABSTRACT FROM AUTHOR]

Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a significant burden to the healthcare system and are potentially preventable. In this study, we sought to determine the incidence of, and risk factors for, unplanned hospital readmissions within 30 days following PCI. We prospectively collected data on 28,488 patients undergoing PCI between 2013 and 2019, who were enrolled in the state-wide multi-centre Victorian Cardiac Outcomes Registry. Patients' data were then linked to data from the Victorian Department of Health administrative database that records statewide hospital admissions. Disease diagnosis codes were used to identify cause of readmission. Patients who had an unplanned readmission were further divided into those who had a cardiac vs. non-cardiac cause for readmission. Overall, 3059 patients (10.7%) had an unplanned hospital readmission within 30 days of PCI, of which 1848 patients (60.4%) were readmitted for primarily cardiac diagnoses. Independent predictors of both 30-day unplanned cardiac and non-cardiac readmissions post-PCI were female sex, having ≥1 admission in the 12 months prior to PCI, acute coronary syndrome presentation, having any in-hospital complication and being discharged on an oral anticoagulant (all p < 0.05). A stepwise increase in readmission risk was observed with increasing number of admissions from 1 to ≥4 admissions in the 12 months prior to PCI. In conclusion, a substantial proportion of patients undergoing PCI have unexpected readmissions to hospital in the 30 days following PCI. Targeted strategies for patients with risk factors for readmission may be useful to reduce this significant burden to the healthcare system. [ABSTRACT FROM AUTHOR]

Genomic cancer medicine promises revolutionary change in oncology. The impacts of ‘personalized medicine’, based upon a molecular classification of cancer and linked to targeted therapies, will extend from individual patient outcomes to the health economy at large. To address the ‘whole-of-system’ impact of genomic cancer medicine, we have established a prospective cohort of patients with newly diagnosed cancer in the state of Victoria, Australia, about whom we have collected a broad range of clinical, demographic, molecular, and patient-reported data, as well as data on health resource utilization. Our goal is to create a model for investigating public investment in genomic medicine that maximizes the cost:benefit ratio for the Australian community at large. [ABSTRACT FROM AUTHOR]

"Cancer 2015" is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty-two percent are aged between 61-70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially "actionable" variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice. [ABSTRACT FROM AUTHOR]

Sphingosine-l-phosphate (SIP) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of SIP transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate SIP transport in cell culture. Spns2 was also shown to control SIP activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different SIP-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2tmlalKOMP)Wtsi allele (Spns2tmla). The Spns2tmla/tmla animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2tmla/tmla mice closely mimicked the phenotypes of partial SIP deficiency and impaired SIP-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2tmla/tmla resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the SIP signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard. [ABSTRACT FROM AUTHOR]

Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A(H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2Adeubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm11tm1a/tm1a and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation, and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes resulted from a cell-intrinsic requirement for Mysm1 in the BM. Importantly, Mysm1tm1a/tm1a HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors. Overall, these data establish a role for Mysmi in the maintenance of BM stem cell function, in the control of oxidative stress and genetic stability in hematopoietic progenitors, and in the development of lymphoid and erythroid lineages. [ABSTRACT FROM AUTHOR]

Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the type III effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ from Shigella, blocked translocation of the p65 subunit of the transcription factor, NF-κB, to the host cell nucleus. NF-κB inhibition by NleE was associated with decreased IL-8 expression in EPEC-infected intestinal epithelial cells. Ectopically expressed NleE also blocked nuclear translocation of p65 and c-Rel, but not p50 or STAT1/2. NleE homologues from other attaching and effacing pathogens as well OspZ from Shigella flexneri 6 and Shigella boydii, also inhibited NF-κB activation and p65 nuclear import; however, a truncated form of OspZ from S. flexneri 2a that carries a 36 amino acid deletion at the C-terminus had no inhibitory activity. We determined that the C-termini of NleE and full length OspZ were functionally interchangeable and identified a six amino acid motif, IDSY(M/I)K, that was important for both NleE- and OspZ-mediated inhibition of NF-κB activity. We also established that NleB, encoded directly upstream from NleE, suppressed NF-κB activation. Whereas NleE inhibited both TNFa and IL-1β stimulated p65 nuclear translocation and IkB degradation, NleB inhibited the TNFa pathway only. Neither NleE nor NleB inhibited AP-1 activation, suggesting that the modulatory activity of the effectors was specific for NF-κB signaling. Overall our data show that EPEC and Shigella have evolved similar T3SS-dependent means to manipulate host inflammatory pathways by interfering with the activation of selected host transcriptional regulators. [ABSTRACT FROM AUTHOR]

Although the bundle-forming pilus (BFP) of enteropathogenic Escherichia coli (EPEC) mediates microcolony formation on epithelial cells, the adherence of BFP-deficient mutants is significantly abrogated, but the mutants are still adherent due to the presence of intimin and possibly other adhesins. In this study we investigated the contribution of the recently described E. coli common pilus (ECP) to the overall adherence properties of EPEC. We found that ECP and BFP structures can be simultaneously observed in the course (between zero time and 7 h during infection) of formation of localized adherence on cultured epithelial cells. These two pilus types colocalized at different levels of the microcolony topology, tethering the adhering bacteria. No evidence of BFP disappearance was found after prolonged infection. When expressed from a plasmid present in nonadherent E. coli HB101, ECP rendered this organism highly adherent at levels comparable to those of HB101 expressing the BFP. Purified ECP bound in a dose-dependent manner to epithelial cells, and the binding was blocked with anti-ECP antibodies, confirming that the pili possess adhesin properties. An ECP mutant showed only a modest reduction in adherence to cultured cells due to background expression levels of BFP and intimin. However, isogenic mutants not expressing EspA or BFP were significantly less adherent when the ecpA gene was also deleted. Furthermore, a ΔespA ΔecpA double mutant (unable to translocate Tir and to establish intimate adhesion) was at least 10-fold less adherent than the ΔespA and ΔecpA single mutants, even in the presence of BFP. A Δbfp ΔespA ΔecpA triple mutant showed the least adherence compared to the wild type and all the isogenic mutant strains tested, suggesting that ECP plays a synergistic role in adherence. Our data indicate that ECP is an accessory factor that, in association with BFP and other adhesins, contributes to the multifactorial complex interaction of EPEC with host epithelial cells. [ABSTRACT FROM AUTHOR]