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1.
J Allergy Clin Immunol ; 145(5): 1438-1451, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31945409

RESUMO

BACKGROUND: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era. OBJECTIVES: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies. METHODS: Whole-genome methylation and transcriptional data from isolated CD4+ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources. RESULTS: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4+ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4+ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally. CONCLUSIONS: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.

2.
Health Promot J Austr ; 31(1): 133-139, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31087792

RESUMO

ISSUE ADDRESSED: The aim of this study was to assess potential barriers to the implementation of clinical guideline recommendations regarding maternal alcohol consumption by antenatal clinicians and managers. METHODS: Cross-sectional surveys of antenatal clinicians and managers employed in a New South Wales Local Health District were undertaken. Survey items were developed based on 11 domains of the Theoretical Domains Framework. Consistent with previous studies, a cut point of less than 4 was applied to mean values of survey items (range: 1-5) to identify domains representing barriers to the implementation. RESULTS: Thirty-three antenatal clinicians and eight managers completed the surveys. For clinicians, the domains with the lowest mean values included "environmental context and resources" (ie, complexity of appointments and availability of supporting systems) (mean: 3.13, SD: 0.93); "social influences" (ie, expectations of others that alcohol will be addressed) (mean: 3.33, SD: 0.68); "beliefs about capabilities" (ie, confidence in providing guideline recommendations) (mean: 3.51, SD: 0.67); and "behavioural regulation" (ie, planning and responding to feedback) (mean: 3.53, SD: 0.64). For managers, "emotion regulation" (ie, stress in managing change) (mean: 2.13, SD: 0.64) and "environmental context and resources" (ie, complexities of managing change) (mean: 3.13, SD: 0.83) were the lowest scoring domains. CONCLUSIONS: The antenatal service environment and availability of resources appear to be primary barriers to both clinicians and managers implementing guidelines for maternal alcohol consumption. SO WHAT?: In the development of interventions to support the delivery of clinical guideline recommendations addressing alcohol consumption during pregnancy, a broad range of potential barriers at both the clinician and manager levels need to be considered and targeted by effective implementation strategies.

3.
J Transl Med ; 17(1): 375, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727095

RESUMO

BACKGROUND: Autologous tolerogenic dendritic cells (tolDC) are a promising therapeutic strategy for inflammatory arthritis (IA) as they can regulate autoantigen-specific T cell responses. Here, we investigated two outstanding priorities for clinical development: (i) the suitability of using heat-shock proteins (HSP), abundant in inflamed synovia, as surrogate autoantigens to be presented by tolDC and (ii) identification of functional biomarkers that confirm tolDC regulatory activity. METHODS: Cell proliferation dye-labelled human peripheral blood mononuclear cells of IA (rheumatoid arthritis (RA) and psoriatic arthritis (PsA)) patients or healthy donors were cultured with HSP40-, HSP60- and HSP70-derived peptides or recall antigens (e.g. tuberculin purified protein derivative (PPD)) in the presence or absence of tolDC or control DC for 9 days. Functional characteristics of proliferated antigen-specific T-cells were measured using flow cytometry, gene expression profiling and cytokine secretion immunoassays. Repeated measures analysis of variance (ANOVA) with Bonferroni correction for comparisons between multiple groups and paired Student t test for comparisons between two groups were used to determine significance. RESULTS: All groups showed robust CD4+ T-cell responses towards one or more HSP-derived peptide(s) as assessed by a stimulation index > 2 (healthy donors: 78%, RA: 73%, PsA: 90%) and production of the cytokines IFNγ, IL-17A and GM-CSF. Addition of tolDC but not control DC induced a type 1 regulatory (Tr1) phenotype in the antigen-specific CD4+ T-cell population, as identified by high expression of LAG3, CD49b and secretion of IL-10. Furthermore, tolDC inhibited bystander natural killer (NK) cell activation in a TGFß dependent manner. CONCLUSIONS: HSP-specific CD4+ T-cells are detectable in the majority of RA and PsA patients and can be converted into Tr1 cells by tolDC. HSP-loaded tolDC may therefore be suitable for directing T regulatory responses to antigens in inflamed synovia of IA patients. Tr1 markers LAG3, CD49b and IL-10 are suitable biomarkers for future tolDC clinical trials.

4.
BMC Pregnancy Childbirth ; 19(1): 299, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419964

RESUMO

BACKGROUND: Antenatal clinical guidelines recommend that during initial and subsequent antenatal visits all pregnant women: have their alcohol consumption assessed; be advised that it is safest not to consume alcohol during pregnancy and of the potential risks of consumption; and be offered referrals for further support if required. However, the extent to which pregnant women attending public antenatal services receive guideline recommended care at these visits, and the characteristics associated with its receipt, is unknown. The purpose of this study was to examine: 1) pregnant women's reported receipt of guideline recommended care addressing alcohol consumption during pregnancy; 2) characteristics associated with the receipt of care; and 3) pregnant women's acceptability of care. METHODS: From July 2017 - February 2018 a survey (telephone or online) was undertaken with 1363 pregnant women who had recently visited a public antenatal service in one health district in Australia. Receipt and acceptability of recommended care were assessed via descriptive statistics and associations via logistic regression analyses. RESULTS: At the initial antenatal visit, less than two thirds (64.3%) of pregnant women reported that they received an assessment of their alcohol consumption and just over one third (34.9%) received advice and referral appropriate to their self-reported level of alcohol consumption since pregnancy recognition. Less than 10% of women received such care at subsequent antenatal visits. Characteristics that significantly increased the odds of receiving all guideline elements at the initial antenatal visit included: less than university attainment (OR = 1.93; 95% CI:1.12, 3.34), not residing in an advantaged area (OR = 2.11; 95% CI:1.17, 3.79), first pregnancy (OR = 1.91; 95% CI:1.22, 2.99) and regional/rural service location (OR = 2.38; 95% CI:1.26, 4.48); and at subsequent visits: younger age (OR = 0.91; 95% CI:0.84, 0.99) and Aboriginal origin (OR = 3.17; 95% CI:1.22, 8.24). Each of the recommended care elements were highly acceptable to pregnant women (88.3-99.4%). CONCLUSIONS: Although care for alcohol consumption is both recommended by clinical guidelines and highly acceptable to pregnant women, its receipt in public antenatal services is suboptimal. There is a need and an opportunity for interventions to support antenatal care providers to routinely and consistently provide such care to all pregnant women.


Assuntos
Alcoolismo/diagnóstico , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Complicações na Gravidez/diagnóstico , Gestantes/psicologia , Cuidado Pré-Natal/psicologia , Diagnóstico Pré-Natal/psicologia , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Austrália , Feminino , Fidelidade a Diretrizes , Humanos , Guias de Prática Clínica como Assunto , Gravidez , Complicações na Gravidez/psicologia , Cuidado Pré-Natal/normas , Diagnóstico Pré-Natal/normas , População Rural , Inquéritos e Questionários , Adulto Jovem
5.
Front Immunol ; 10: 1535, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333666

RESUMO

Objective: We have previously shown that increased circulating interleukin-6 (IL-6) results in enhanced CD4+ T cell signaling via signal transduction and activator of transcription-3 (STAT3) in early rheumatoid arthritis (RA). We tested the hypothesis that transcriptional "imprinting" of T-cells by this mechanism skews downstream effector responses, reinforcing immune dysregulation at a critical, but targetable, disease phase. Methods: We modeled naïve CD4+ T cell exposure to pathophysiological concentrations of IL-6 in vitro, assessing the dynamic transcriptional and functional consequences for downstream effector cells utilizing microarray and flow cytometry. Fresh blood from treatment-naïve early arthritis patients was phenotyped in parallel for comparison. Results: T cell sensitivity to IL-6 was most marked in the naïve subset, and related to gp130 rather than IL-6R expression. Exposure of healthy naïve CD4+ T cells to IL-6 induced the same STAT3 target genes as previously seen to discriminate RA patients from disease controls. After TCR stimulation IL-6 pre-exposed cells exhibited enhanced proliferative capacity, activation, and a propensity toward Th1 differentiation, compared to non-exposed cells. An entirely analogous phenotype was observed in early RA compared to control CD4+ T cells. Conclusions: Sustained IL-6 exposure at a critical point in the natural history of RA "primes" the adaptive immune system to respond aberrantly to TCR stimulation, potentiating disease induction with implications for the optimal timing of targeted therapy.

6.
Rheumatology (Oxford) ; 58(7): 1250-1258, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753680

RESUMO

OBJECTIVES: Dysregulated signal transduction and activator of transcription-3 (STAT3) signalling in CD4+ T cells has been proposed as an early pathophysiological event in RA. We sought further evidence for this observation, and to determine its clinical relevance. METHODS: Microarray technology was used to measure gene expression in purified peripheral blood CD4+ T cells from treatment-naïve RA patients and disease controls newly recruited from an early arthritis clinic. Analysis focused on 12 previously proposed transcripts, and concurrent STAT3 pathway activation was determined in the same cells by flow cytometry. A pooled analysis of previous and current gene expression findings incorporated detailed clinical parameters and employed multivariate analysis. RESULTS: In an independent cohort of 161 patients, expression of 11 of 12 proposed signature genes differed significantly between RA patients and controls, robustly validating the earlier findings. Differential regulation was most pronounced for the STAT3 target genes PIM1, BCL3 and SOCS3 (>1.3-fold difference; P < 0.005), each of whose expression correlated strongly with paired intracellular phospho-STAT3. In a meta-analysis of 279 patients the same three genes accounted for the majority of the signature's ability to discriminate RA patients, which was found to be independent of age, joint involvement or acute phase response. CONCLUSION: The STAT3-mediated dysregulation of BCL3, SOCS3 and PIM1 in circulating CD4+ T cells is a discriminatory feature of early RA that occurs independently of acute phase response. The mechanistic and functional implications of this observation at a cellular level warrant clarification.


Assuntos
Artrite Reumatoide/diagnóstico , Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica/imunologia , Fator de Transcrição STAT3/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite/diagnóstico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Análise por Conglomerados , Diagnóstico Diferencial , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transcriptoma , Adulto Jovem
7.
Implement Sci ; 13(1): 112, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30126437

RESUMO

BACKGROUND: Despite clinical guideline recommendations, implementation of antenatal care addressing alcohol consumption by pregnant women is limited. Implementation strategies addressing barriers to such care may be effective in increasing care provision. The aim of this study is to examine the effectiveness, cost and cost-effectiveness of a multi-strategy practice change intervention in increasing antenatal care addressing the consumption of alcohol by pregnant women. METHODS: The study will be a randomised, stepped-wedge controlled trial conducted in three sectors in a health district in New South Wales, Australia. Stepped implementation of a practice change intervention will be delivered to sectors in a random order to support the introduction of a model of care for addressing alcohol consumption by pregnant women. A staged process was undertaken to develop the implementation strategies, which comprise of: leadership support, local clinical practice guidelines, electronic prompts and reminders, opinion leaders, academic detailing (audit and feedback), educational meetings and educational materials, and performance monitoring. Repeated cross-sectional outcome data will be gathered weekly across all sectors for the study duration. The primary outcome measures are the proportion of antenatal appointments at 'booking in', 27-28 weeks gestation and 35-36 weeks gestation for which women report (1) being assessed for alcohol consumption, (2) being provided with brief advice related to alcohol consumption during pregnancy, (3) receiving relevant care for addressing alcohol consumption during pregnancy, and (4) being assessed for alcohol consumption and receiving relevant care. Data on resources expended during intervention development and implementation will be collected. The proportion of women who report consuming alcohol since knowing they were pregnant will be measured as a secondary outcome. DISCUSSION: This will be the first randomised controlled trial to evaluate the effectiveness, cost and cost-effectiveness of implementation strategies in improving antenatal care that addresses alcohol consumption by pregnant women. If positive changes in clinical practice are found, this evidence will support health service adoption of implementation strategies to support improved antenatal care for this recognised risk to the health and wellbeing of the mother and child. TRIAL REGISTRATIONS: Australian and New Zealand Clinical Trials Registry, No. ACTRN12617000882325 (date registered: 16/06/2017).


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/prevenção & controle , Comportamento Materno/psicologia , Complicações na Gravidez/prevenção & controle , Gestantes/psicologia , Cuidado Pré-Natal/métodos , Consumo de Bebidas Alcoólicas/psicologia , Austrália , Criança , Estudos Transversais , Feminino , Humanos , New South Wales , Nova Zelândia , Planejamento de Assistência ao Paciente , Gravidez , Complicações na Gravidez/etiologia , Gestantes/educação , Comportamento de Redução do Risco
8.
Front Immunol ; 9: 755, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867920

RESUMO

Objective: Dendritic cells (DCs) are key orchestrators of immune function. To date, rheumatoid arthritis (RA) researchers have predominantly focused on a potential pathogenic role for CD1c+ DCs. In contrast, CD141+ DCs and plasmacytoid DCs (pDCs) have not been systematically examined, at least in early RA. In established RA, the role of pDCs is ambiguous and, since disease duration and treatment both impact RA pathophysiology, we examined pDCs, and CD1c+ and CD141+ conventional DCs (cDCs), in early, drug-naïve RA (eRA) patients. Methods: We analyzed the frequency and phenotype of pDCs, CD1c+, and CD141+ DCs from eRA patients and compared findings with healthy controls. In parallel, we performed transcriptional analysis of >600 immunology-related genes (Nanostring) from peripheral blood pDCs, CD1c+ DCs, B cells, T cells, and monocytes. Results: All DC subsets were reduced in eRA (n = 44) compared with healthy controls (n = 30) and, for pDCs, this was most marked in seropositive patients. CD141+ and CD1c+ DCs, but not pDCs, had a comparatively activated phenotype at baseline (increased CD86) and CD1c+ DC frequency inversely associated with disease activity. All DC frequencies remained static 12 months after initiation of immunomodulatory therapy despite a fall in activation markers (e.g., HLA-DR, CD40). There was no association between the whole blood interferon gene signature (IGS) and pDC or CD1c+ DC parameters but an inverse association between CD141+ DC frequency and IGS was noted. Furthermore, IFN-I and IFN-III mRNA transcripts were comparable between eRA pDC and other leukocyte subsets (B cells, CD4+, and CD8+ T cells and monocytes) with no obvious circulating cellular source of IFN-I or IFN-III. Transcriptomic analysis suggested increased pDC and CD1c+ DC proliferation in eRA; pDC differentially expressed genes also suggested enhanced tolerogenic function, whereas for CD1c+ DCs, pro-inflammatory transcripts were upregulated. Discussion: This is the first detailed examination of DC subsets in eRA peripheral blood. Compared with CD1c+ DCs, pDCs are less activated and may be skewed toward tolerogenic functions. CD141+ DCs may be implicated in RA pathophysiology. Our findings justify further investigation of early RA DC biology.


Assuntos
Artrite Reumatoide/imunologia , Células Dendríticas/imunologia , Artrite Reumatoide/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Transcriptoma
9.
Curr Opin Rheumatol ; 30(2): 207-214, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29206659

RESUMO

PURPOSE OF REVIEW: Rheumatoid arthritis is a systemic disease of evolving immune dysregulation that culminates in joint destruction and disability. The principle by which pro-inflammatory cytokines may be therapeutically targeted to abrogate disease is well established, but has yet to translate into reliable cures for patients. Emerging insights into cytokine-mediated pathobiology during rheumatoid arthritis development are reviewed, and their implications for future treatment strategies considered. RECENT FINDINGS: Accumulating data highlight cytokine perturbations before the clinical onset of rheumatoid arthritis. Some of these have now been linked to the arthritogenic activation of autoantibodies and associated pain and bone destruction in affected joints. These observations suggest cytokines may trigger the transition from systemic immunity to arthritis. Cytokine exposure could furthermore 'prime' synovial stromal cells to perpetuate a dominant pro-inflammatory environment. By facilitating cross-talk between infiltrating immune cells and even sustaining ectopic lymphoid structure development in some cases, cytokine interplay ultimately underpins the failure of arthritis to resolve. SUMMARY: Successful therapeutic stratification will depend upon an increasingly sophisticated appreciation of how dominant players amongst cytokine networks vary across time and anatomical space during incipient rheumatoid arthritis. The prize of sustained remission for all patients justifies the considerable effort required to achieve this understanding.


Assuntos
Artrite Reumatoide/imunologia , Citocinas/imunologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/imunologia , Doença Crônica , Progressão da Doença , Humanos
10.
Arthritis Rheumatol ; 70(3): 361-370, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29193869

RESUMO

OBJECTIVE: Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms of RA by conducting an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped patients with early arthritis who were naive to therapeutic immunomodulation. METHODS: RNA and DNA were isolated from purified B and/or CD4+ T cells obtained from the peripheral blood of 344 patients with early arthritis. Genotyping and global gene expression measurements were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non-HLA RA single-nucleotide polymorphisms (defined as r2 ≥ 0.8) were analyzed, seeking evidence of cis- or trans-eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks. RESULTS: Genes subject to cis-eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were FADS1, FADS2, BLK, FCRL3, ORMDL3, PPIL3, and GSDMB. In contrast, those acting on METTL21B, JAZF1, IKZF3, and PADI4 were unique to CD4+ lymphocytes, with the latter candidate risk gene being identified for the first time in this cell subset. B lymphocyte-specific eQTLs for SYNGR1 and CD83 were also found. At the 8p23 BLK-FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the FAM167A effect displayed striking B lymphocyte specificity. No trans-eQTLs approached experiment-wide significance, and linear modeling did not identify a significant influence of biologic covariates on cis-eQTL effect sizes. CONCLUSION: These findings further refine the understanding of candidate causal genes in RA pathogenesis, thus providing an important platform from which downstream functional studies, directed toward particular cell types, may be prioritized.


Assuntos
Artrite Reumatoide/genética , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Adulto , Idoso , Artrite Reumatoide/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Risco
12.
Health Promot J Austr ; 28(3): 266, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29248049

RESUMO

Issue addressed: Smoking, risky drinking, overweight and obesity, and physical inactivity are health-risk factors (HRFs) that contribute significantly to morbidity worldwide. Several initiatives have been introduced over the past two decades to reduce these HRFs. This paper examines changes in the prevalence of HRFs in young women (aged 18-23 years) between 1996 and 2013, overall and within demographic groups.Methods: Data from two cohorts of the Australian Longitudinal Study on Women's Health, born in 1973-78 (n=14247) and 1989-95 (n=17012) were weighted to provide national estimates. Prevalence ratios were used to compare HRFs in 2013 relative to 1996.Results: In 1996, 32% were current smokers, 38% were risky drinkers, 22% were overweight or obese and 7% were physically inactive. In 2013, corresponding estimates were 19%, 35%, 33% and 6%. Between 1996 and 2013, overall smoking prevalence decreased, but remained over 43% among least educated women. Overweight and obesity increased in all demographic groups.Conclusions: The findings suggest that only smoking, which has been the subject of changes in taxation, legislation and regulation, declined significantly, in all except the least educated women. In contrast, the prevalence of overweight and obesity, which has largely been addressed through awareness campaigns and voluntary actions by the food industry, increased markedly in all demographic sub-groups.So what?: The findings show that comprehensive health promotion interventions, such as those for tobacco control, are successful (but may still be ineffective among less educated women). In contrast the measures to control population weight gain among young women have been futile so far.

13.
PLoS One ; 12(6): e0178138, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28582406

RESUMO

OBJECTIVES: To determine the impact of intimate partner violence on women's mental and physical health over a 16 year period and across three generations. PARTICIPANTS: Participants were from the Australian Longitudinal study on Women's Health, a broadly representative national sample of women comprised of three birth cohorts 1973-78, 1946-51 and 1921-26 who were randomly selected from the Australian Medicare (i.e. national health insurer) database in 1996 to participate in the longitudinal health and wellbeing survey. Since baseline, six waves of survey data have been collected. Women from each cohort who had returned all six surveys and had a baseline measure (Survey 1) for intimate partner violence were eligible for the current study. MAIN OUTCOME MEASURES: The main outcome of interest was women's physical and mental health, measured using the Medical Outcome Study Short-Form (SF-36). The experience of intimate partner violence was measured using the survey item 'Have you ever been in a violent relationship with a partner/spouse?' Sociodemographic information was also collected. RESULTS: For all cohorts, women who had lived with intimate partner violence were more likely to report poorer mental health, physical function and general health, and higher levels of bodily pain. Some generational differences existed. Younger women showed a reduction in health associated with the onset of intimate partner violence, which was not apparent for women in the older two groups. In addition, the physical health differences between women born 1921-26 who had and had not experienced intimate partner violence tapered off overtime, whereas these differences remained constant for women born 1973-78 and 1946-51. CONCLUSIONS: Despite generational differences, intimate partner violence adversely impacted on mental and physical health over the 16 year study period and across generations.


Assuntos
Violência por Parceiro Íntimo/psicologia , Saúde Mental/estatística & dados numéricos , Qualidade de Vida/psicologia , Parceiros Sexuais/psicologia , Saúde da Mulher/estatística & dados numéricos , Adulto , Idoso , Austrália , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Inquéritos e Questionários
14.
Gastroenterology ; 153(1): 263-276.e8, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28363639

RESUMO

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients.


Assuntos
Imunidade Adaptativa , Antígeno B7-1/sangue , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/metabolismo , Falência Hepática Aguda/imunologia , Acetaminofen/toxicidade , Insuficiência Hepática Crônica Agudizada/imunologia , Adulto , Animais , Anticorpos/farmacologia , Antígeno B7-1/metabolismo , Complexo CD3/farmacologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Proliferação de Células , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/sangue , Técnicas de Cocultura , Células Dendríticas , Hepatócitos/metabolismo , Humanos , Cirrose Hepática/imunologia , Ativação Linfocitária , Camundongos , Pessoa de Meia-Idade , Choque Séptico/imunologia
15.
Health Promot J Austr ; 28(3): 255-259, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28219013

RESUMO

Issue addressed Smoking, risky drinking, overweight and obesity, and physical inactivity are health-risk factors (HRFs) that contribute significantly to morbidity worldwide. Several initiatives have been introduced over the past two decades to reduce these HRFs. This paper examines changes in the prevalence of HRFs in young women (aged 18-23 years) between 1996 and 2013, overall and within demographic groups. Methods Data from two cohorts of the Australian Longitudinal Study on Women's Health, born in 1973-78 (n=14247) and 1989-95 (n=17012) were weighted to provide national estimates. Prevalence ratios were used to compare HRFs in 2013 relative to 1996. Results In 1996, 32% were current smokers, 38% were risky drinkers, 22% were overweight or obese and 7% were physically inactive. In 2013, corresponding estimates were 19%, 35%, 33% and 6%. Between 1996 and 2013, overall smoking prevalence decreased, but remained over 43% among least educated women. Overweight and obesity increased in all demographic groups. Conclusions The findings suggest that only smoking, which has been the subject of changes in taxation, legislation and regulation, declined significantly, in all except the least educated women. In contrast, the prevalence of overweight and obesity, which has largely been addressed through awareness campaigns and voluntary actions by the food industry, increased markedly in all demographic sub-groups. So what? The findings show that comprehensive health promotion interventions, such as those for tobacco control, are successful (but may still be ineffective among less educated women). In contrast the measures to control population weight gain among young women have been futile so far.


Assuntos
Consumo de Bebidas Alcoólicas , Exercício Físico , Sobrepeso , Fumar , Adolescente , Consumo de Bebidas Alcoólicas/epidemiologia , Austrália/epidemiologia , Índice de Massa Corporal , Feminino , Humanos , Estudos Longitudinais , Obesidade , Sobrepeso/epidemiologia , Prevalência , Fatores de Risco , Fumar/epidemiologia , Adulto Jovem
16.
Tissue Eng Part A ; 23(7-8): 253-262, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28073315

RESUMO

Brown adipose tissue (BAT) has a unique capacity to expend calories by decoupling energy expenditure from ATP production, therefore BAT could realize therapeutic potential to treat metabolic diseases such as obesity and type 2 diabetes. Recent studies have investigated markers and function of native BAT, however, successful therapies will rely on methods that supplement the small existing pool of brown adipocytes in adult humans. In this study, we engineered BAT from both human and rat adipose precursors and determined whether these ex vivo constructs could mimic in vivo tissue form and metabolic function. Adipose-derived stem cells (ASCs) were isolated from several sources, human white adipose tissue (WAT), rat WAT, and rat BAT, then differentiated toward both white and brown adipogenic lineages in two-dimensional and three-dimensional (3D) culture conditions. ASCs derived from WAT were successfully differentiated in 3D poly(ethylene glycol) hydrogels into mature adipocytes with BAT phenotype and function, including high uncoupling protein 1 (UCP1) mRNA and protein expression and increased metabolic activity (basal oxygen consumption, proton leak, and maximum respiration). By utilizing this "browning" process, the abundant and accessible WAT stem cell population can be engineered into 3D tissue constructs with the metabolic capacity of native BAT, ultimately for therapeutic intervention in vivo and as a tool for studying BAT and its metabolic properties.


Assuntos
Tecido Adiposo Marrom/citologia , Tecido Adiposo/citologia , Células-Tronco/citologia , Engenharia Tecidual/métodos , Adipogenia/fisiologia , Animais , Células Cultivadas , Feminino , Ratos , Ratos Sprague-Dawley
17.
Arthritis Res Ther ; 18(1): 302, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27993172

RESUMO

BACKGROUND: Alemtuzumab, an anti-CD52 monoclonal antibody, was administered to patients with RA between 1991 and 1994. We have followed a cohort of recipients since that time and previously reported significant delays in immune reconstitution. Here we report >20 years of follow-up data from this unique cohort. METHOD: Surviving alemtuzumab recipients were age, sex and disease duration matched with RA controls. Updated mortality and morbidity data were collected for alemtuzumab recipients. For both groups antigenic responses were assessed following influenza, Pneumovax II and combined diphtheria/tetanus/poliovirus vaccines. Circulating cytokines and lymphocyte subsets were also quantified. RESULTS: Of 16 surviving alemtuzumab recipients, 13 were recruited: 9 recipients underwent a full clinical assessment and 4 had case notes review only. Since our last review 10 patients had died from causes of death consistent with long-standing RA, and no suggestion of compromised immune function. Compared with controls the alemtuzumab cohort had significantly reduced CD4+ and CD8+ central memory T-cells, CD5+ B cells, naïve B cells and CD19+CD24hiCD38hi transitional (putative regulatory) B cells. Nonetheless vaccine responses were comparable between groups. There were significantly higher serum IL-15 and IFN-γ levels in the alemtuzumab cohort. IL-15 levels were inversely associated with CD4+ total memory and central memory T cells. CONCLUSION: After 20 years the immune system of alemtuzumab recipients continues to show differences from disease controls. Nonetheless mortality and morbidity data, alongside vaccination responses, do not suggest clinical immune compromise. As lymphodepleting therapies, including alemtuzumab, continue to be administered this work is important with regard to long-term immune monitoring and stages of immune recovery.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Linfócitos/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunofenotipagem , Depleção Linfocítica/métodos , Masculino , Pessoa de Meia-Idade
18.
Genome Biol ; 17(1): 212, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27799070

RESUMO

BACKGROUND: The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk. RESULTS: Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells. CONCLUSIONS: Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.


Assuntos
Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Psoríase/genética , Receptores de Interleucina/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Cromatina/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único , Psoríase/imunologia , Psoríase/patologia , Linfócitos T/imunologia
19.
PeerJ ; 4: e2300, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27635311

RESUMO

Cellular therapies with tolerogenic antigen-presenting cells (tolAPC) show great promise for the treatment of autoimmune diseases and for the prevention of destructive immune responses after transplantation. The methodologies for generating tolAPC vary greatly between different laboratories, making it difficult to compare data from different studies; thus constituting a major hurdle for the development of standardised tolAPC therapeutic products. Here we describe an initiative by members of the tolAPC field to generate a minimum information model for tolAPC (MITAP), providing a reporting framework that will make differences and similarities between tolAPC products transparent. In this way, MITAP constitutes a first but important step towards the production of standardised and reproducible tolAPC for clinical application.

20.
Ann Rheum Dis ; 75(2): 466-73, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25649145

RESUMO

OBJECTIVES: A previously identified signal transduction and activator of transcription-3 (STAT3) target-enriched gene signature in circulating CD4+ T cells of patients with early rheumatoid arthritis (RA) was prominent in autoantibody-negative individuals. Here, interleukin (IL)-6-mediated STAT signalling was investigated in circulating lymphocytes of an independent early arthritis patient cohort, seeking further insight into RA pathogenesis and biomarkers of potential clinical utility. METHODS: Constitutive and IL-6-induced expression of phosphorylated STAT1 (pSTAT1) and pSTAT3 was determined in T and B cells using Phosflow cytometric analysis in patients with RA and controls. Contemporaneous levels of serum cytokines were measured by immunoassay. Induced gene expression was measured in cultured CD4+T cells by quantitative real-time PCR. RESULTS: Among circulating lymphocytes of 187 patients with early arthritis, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T cells of patients with early anticitrullinated peptide autoantibody (ACPA)-negative RA compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R-targeted treatment. Among patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells contributed substantially to an algorithm for predicting progression to classifiable RA during a median of 20 months follow-up (area under receiver operator characteristic curve=0.84; p<0.001). CONCLUSIONS: Our findings support a particular role for IL-6-driven CD4+ T cell activation via STAT3 during the induction of RA, particularly as a feature of ACPA-negative disease. CD4+ T cell pSTAT measurements show promise as biomarkers of UA-RA progression and now require independent validation.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Linfócitos T CD4-Positivos/metabolismo , Interleucina-6/metabolismo , Peptídeos Cíclicos/imunologia , Fator de Transcrição STAT3/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Linfócitos B/metabolismo , Biomarcadores/metabolismo , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT1/metabolismo , Adulto Jovem
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