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Objectives: Increased rates of mental health disorders and substance use among youth and young adults have increased globally, furthering the strain on an already burdened mental health system. Digital solutions have been proposed as a potential option for the provision of timely mental health services for youth, with little research exploring mental health professional views about using such innovative tools. In Alberta, Canada, we are evaluating the implementation and integration of a digital mental health (dMH) platform into existing service pathways. Within this paper we seek to explore mental health professionals' perceptions of the barriers and facilitators that may influence their utilization of digital MH-enabled measurement-based care (MBC) with the youth who access their services. Methods: A qualitative, descriptive methodology was used to inductively generate themes from focus groups conducted with mental health professionals from specialized mental health services and primary care networks in Alberta. Results: As mental health professionals considered the barriers and facilitators of using dMH with youth, they referenced individual and family barriers and facilitators to consider. Providers highlighted perceived barriers, including: first, cultural stigma, family apprehension about mental health care, and parental access to dMH and MBC as deterrents to providers adopting digital platforms in routine care; second, perceptions of increased responsibility and liability for youth in crisis; third, perception that some psychiatric and neurodevelopmental disorders in youth are not amenable to dMH; fourth, professionals contemplated youth readiness to engage with dMH-enabled MBC. Participants also highlighted pertinent facilitators to dMH use, noting: first, the suitability of dMH for youth with mild mental health concerns; second, youth motivated to report their changes in mental health symptoms; and lastly, youth proficiency and preference for dMH options. Conclusions: By identifying professionals' perceptions of barriers and facilitators for youth users, we may better understand how to address misconceptions about who is eligible and appropriate for dMH through training and education.
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BACKGROUND: Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is associated with high levels of morbidity and mortality. The primary aim of this systematic review was to determine the duration of survival, from time of diagnosis of RA-ILD. METHODS: Medline (Ovid), Embase (OVID), CINAHL (EBSCO), PubMed, and the Cochrane Library were searched for studies that reported duration of survival from time of diagnosis of RA-ILD. Risk of bias of included studies was assessed based upon 4 domains of the Quality In Prognosis Studies tool. Results for median survival were presented by tabulation and discussed qualitatively. Meta-analysis of cumulative mortality at 1 year, >1y to ≤3 years, >3 years to ≤5 years, and >5 years to≤ 10 years was undertaken, for total RA-ILD population, and according to ILD pattern. RESULTS: 78 studies were included. Median survival for the total RA-ILD population ranged from 2 to 14 years. Pooled estimates for cumulative percentage mortality up to 1 year were 9.0% (95% CI 6.1, 12.5, I2 88.9%), >1 to ≤3 years 21.4% (17.3, 25.9, I2 85.7%), >3 to ≤ 5 years 30.2% (24.8, 35.9, I2 87.7%), and > 5 to ≤ 10 years 49.1% (40.6, 57.7 I2 85.0%). Heterogeneity was high. Only 15 studies were rated as low risk of bias in all 4 domains assessed. CONCLUSION: This review summarises the high mortality of RA-ILD, however the strength of conclusions that can be made is limited by the heterogeneity of the available studies, due to methodological and clinical factors. Further studies are needed to better understand the natural history of this condition.
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Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Humanos , Adulto , Artritis Reumatoide/epidemiología , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , PronósticoRESUMEN
OBJECTIVES: Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1ß. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. METHODS: Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. RESULTS: High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. CONCLUSION: Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.
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Gota , Ácido Úrico , Animales , Epigénesis Genética , Gota/genética , Humanos , Leucocitos Mononucleares , Proteínas de la Membrana , Ratones , Monocitos , Proteínas de Unión al ARNRESUMEN
As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.
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AIM AND BACKGROUND: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. METHODS: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. RESULTS: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R2=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005). CONCLUSIONS: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout.
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Enfermedades Cardiovasculares/metabolismo , Gota/metabolismo , Telomerasa/genética , Telómero/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Células Dendríticas/metabolismo , Progresión de la Enfermedad , Femenino , Gota/epidemiología , Humanos , Células Asesinas Naturales/metabolismo , Modelos Lineales , Masculino , Persona de Mediana Edad , Monocitos/metabolismoRESUMEN
Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Alopurinol/uso terapéutico , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Proteínas de Neoplasias/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Alopurinol/sangre , Biomarcadores/sangre , Femenino , Frecuencia de los Genes , Genotipo , Gota/sangre , Gota/genética , Supresores de la Gota/sangre , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Oxipurinol/sangre , Farmacogenética , Fenotipo , Factores de Riesgo , Resultado del Tratamiento , Ácido Úrico/sangre , Adulto JovenRESUMEN
BACKGROUND: It has been suggested that environmental pollution from an earthquake might be associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). AIM: To determine the incidence of AAV during the 3-year period before (period 1), and the 3 years following (period 2), the earthquake that occurred on 22 February 2011 in Christchurch, New Zealand. METHODS: All ANCA tests performed in the Canterbury region for 3 years before the earthquake (period 1, 2007-2010), and for 3 years after the earthquake (period 2, 2011-2014) were examined. AAV was defined according to The European Medicines Agency classification algorithm. Medical records were reviewed and cases were included if they were newly diagnosed within the study period. Incidence was calculated using population data from the 2013 New Zealand census. RESULTS: A total of 52 new cases of AAV was identified. The incidence in period 1 was 1.87/100 000/annum (95% C.I. 1.23-2.72), and for period 2 was 1.73/100 000/annum (95% C.I. 1.12-2.55). There was no statistically significant difference in incidence between the two study periods. There was no difference when analysing by myeloperoxidase (MPO) or proteinase-3 status, or restricting the analyses to those residing in an urban environment. The mean age at diagnosis for MPO AAV was significantly younger in period 2 than period 1 (61 years vs 71 years, P = 0.05). There were no other clinically important differences between the two groups. CONCLUSION: This study does not support the hypothesis that an environmental agent, caused by dust pollution related to earthquake damage, has a causative role in the pathogenesis of AAV.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/epidemiología , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Desastres , Terremotos , Adulto , Anciano , Anciano de 80 o más Años , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Femenino , Humanos , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiologíaRESUMEN
As current options for treating most enteric neuropathies are either non-effective or associated with significant ongoing problems, cell therapy is a potential attractive possibility to treat congenital and acquired neuropathies. Studies using animal models have shown that following transplantation of enteric neural progenitors into the bowel of recipients, the transplanted cells migrate, proliferate, and generate neurons that are electrically active and receive synaptic inputs. Recent studies have transplanted human enteric neural progenitors into the mouse colon and shown engraftment. In this article, we summarize the significance of these recent advances and discuss priorities for future research that might lead to the use of regenerative medicine to treat enteric neuropathies in the clinic.
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Seudoobstrucción Intestinal/terapia , Células-Madre Neurales/trasplante , Medicina Regenerativa/tendencias , Trasplante de Células Madre/tendencias , Animales , Sistema Nervioso Entérico/fisiología , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/fisiopatología , Enfermedad de Hirschsprung/terapia , Humanos , Seudoobstrucción Intestinal/diagnóstico , Seudoobstrucción Intestinal/fisiopatología , Medicina Regenerativa/métodos , Trasplante de Células Madre/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Benzbromarone is a potent uricosuric but is not widely available due to concerns about hepatotoxicity. In Aotearoa New Zealand, benzbromarone has been available since April 2013, subject to funding restrictions, for patients with inadequate urate-lowering response or intolerance to allopurinol and probenecid. AIM: To assess the safety and efficacy of benzbromarone in a real-life setting. METHODS: All patients who received funding for benzbromarone from 1 April 2013 to 30 September 2014 were identified. Prescribers were sent a questionnaire for each individual. Information on demographics, efficacy of previous urate-lowering drugs and reasons for discontinuation were collected. Specific information about the dose, effect on serum urate, adverse effects and liver function tests after commencing benzbromarone was recorded. RESULTS: Completed questionnaires were returned for 123 of 164 (75%) patients. Mean (SD) serum urate prior to benzbromarone was 0.57 (0.12) mmol/L, and estimated glomerular filtration rate was 50.3 (22.8) mL/min/1.73 m(2) . The median dose of benzbromarone was 100 mg/day (25-200 mg/day). Six months after commencing benzbromarone, mean (SD) serum urate was 0.35 (0.12) mmol/L. Benzbromarone-related adverse events included rash (n = 4), diarrhoea (n = 9), nausea (n = 6) and urate stones (n = 3). Liver function test abnormalities were uncommon and tended to be mild. There were 14 patient deaths; none was considered related to benzbromarone. Allopurinol had been prescribed prior to benzbromarone in 117 of 123 patients; median maximum allopurinol dose was 200 mg/day (range 25-600 mg/day), and 19% patients received allopurinol >300 mg/day. CONCLUSION: Benzbromarone provides useful urate-lowering efficacy and does not appear unsafe in patients with gout. Urate-lowering therapy prescribing requires further optimisation.
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Benzbromarona/administración & dosificación , Gota/tratamiento farmacológico , Uricosúricos/administración & dosificación , Anciano , Alopurinol/uso terapéutico , Benzbromarona/efectos adversos , Comorbilidad , Exantema/etiología , Femenino , Supresores de la Gota/uso terapéutico , Humanos , Pruebas de Función Renal , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Nueva Zelanda , Estudios Retrospectivos , Ácido Úrico/sangre , Uricosúricos/efectos adversosRESUMEN
OBJECTIVES: Twenty-eight genetic loci are associated with serum urate levels in Europeans. Evidence for association with gout at most loci is absent, equivocal or not replicated. Our aim was to test the loci for association with gout meeting the American College of Rheumatology gout classification criteria in New Zealand European and Polynesian case-control sample sets. METHODS: 648 European cases and 1550 controls, and 888 Polynesian (Ma¯ori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex. Power was adequate (>0.7) to detect effects of OR>1.3. RESULTS: We focused on 24 loci without previous consistent evidence for association with gout. In Europeans, we detected association at seven loci, one of which was the first report of association with gout (IGF1R). In Polynesian, association was detected at three loci. Meta-analysis revealed association at eight loci-two had not previously been associated with gout (PDZK1 and MAF). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF (HLF is the first report of association with gout). There was obvious inconsistency of gout association at four loci (GCKR, INHBC, SLC22A11, SLC16A9) that display very similar effects on urate levels. CONCLUSIONS: We provide the first evidence for association with gout at four loci (IGF1R, PDZK1, MAF, HLF). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.
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Gota/sangre , Gota/genética , Nativos de Hawái y Otras Islas del Pacífico/genética , Ácido Úrico/sangre , Población Blanca/genética , Proteínas Quinasas Activadas por AMP/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proteínas Portadoras/genética , Estudios de Casos y Controles , Genotipo , Humanos , Subunidades beta de Inhibinas/genética , Proteínas de la Membrana , Transportadores de Ácidos Monocarboxílicos/genética , Nueva Zelanda , Transportadores de Anión Orgánico Sodio-Independiente/genética , Proteínas Proto-Oncogénicas c-maf/genética , Receptor IGF Tipo 1 , Receptores de Somatomedina/genéticaRESUMEN
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).
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Alopurinol/administración & dosificación , Biomarcadores Farmacológicos , Guías como Asunto/normas , Antígenos HLA-B/genética , Esquema de Medicación , Genotipo , HumanosRESUMEN
BACKGROUND: During development of the enteric nervous system, a subpopulation of enteric neuron precursors transiently expresses catecholaminergic properties. The progeny of these transiently catecholaminergic (TC) cells have not been fully characterized. METHODS: We combined in vivo Cre-lox-based genetic fate-mapping with phenotypic analysis to fate-map enteric neuron subtypes arising from tyrosine hydroxylase (TH)-expressing cells. KEY RESULTS: Less than 3% of the total (Hu(+) ) neurons in the myenteric plexus of the small intestine of adult mice are generated from transiently TH-expressing cells. Around 50% of the neurons generated from transiently TH-expressing cells are calbindin neurons, but their progeny also include calretinin, neurofilament-M, and serotonin neurons. However, only 30% of the serotonin neurons and small subpopulations (<10%) of the calbindin, calretinin, and neurofilament-M neurons are generated from TH-expressing cells; only 0.2% of nitric oxide synthase neurons arise from TH-expressing cells. CONCLUSIONS & INFERENCES: Transiently, catecholaminergic cells give rise to subpopulations of multiple enteric neuron subtypes, but the majority of each of the neuron subtypes arises from non-TC cells.
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Catecolaminas/biosíntesis , Mapeo Cromosómico/métodos , Sistema Nervioso Entérico/citología , Sistema Nervioso Entérico/enzimología , Tirosina 3-Monooxigenasa/biosíntesis , Animales , Catecolaminas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Tirosina 3-Monooxigenasa/genéticaRESUMEN
BACKGROUND: There are few current data on the prevalence of hyperuricaemia and gout in New Zealand, particularly among the indigenous Maori population. AIMS: To determine the prevalence of gout and hyperuricaemia in rural and urban Maori and non-Maori community samples and describe the treatment and comorbidities of participants with gout. METHODS: Participants aged 20-64 years were recruited by random selection from the electoral roll. Maori samples were selected from among those identified as being of Maori descent on the roll and who self-identified as being of Maori ethnicity at interview. Personal medical history, blood pressure, anthropometrics, fasting lipids, glucose, HbA1c and urate were recorded. RESULTS: There were 751 participants. Mean serum urate (SU) was 0.30 mmol/L (0.06-0.69 mmol/L). Maori had a significantly higher prevalence of hyperuricaemia (SU > 0.40 mmol/L) compared with non-Maori (17.0% vs 7.5%, P = 0.0003). A total of 57 participants had a history of gout, with a higher prevalence in Maori compared with non-Maori (10.3% vs 2.3%, P < 0.0001). Of the participants, 18/57 (31.6%) with gout were receiving urate-lowering therapy, but in 38.9%, SU was >0.36 mmol/L. Participants with gout were more likely to have metabolic syndrome, diabetes, cardiac disease or hypertension. CONCLUSIONS: Gout and hyperuricaemia were more prevalent in Maori, and participants with gout were more likely to have comorbidities. There was not a higher overall adjusted cardiovascular disease risk in Maori participants with gout. Despite the high prevalence of gout, management remains suboptimal.
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Gota/etnología , Hiperuricemia/etnología , Nativos de Hawái y Otras Islas del Pacífico/etnología , Población Rural , Población Urbana , Adulto , Estudios de Cohortes , Femenino , Gota/diagnóstico , Humanos , Hiperuricemia/diagnóstico , Masculino , Persona de Mediana Edad , Nueva Zelanda/etnología , Adulto JovenRESUMEN
Our aim was to describe the treatment and survival characteristics of Wegener's granulomatosis (WG) in Canterbury, New Zealand. The medical records of 48 patients diagnosed between 1 July 1997 and 31 December 2008 and fulfilling validated classification criteria for WG were reviewed to characterise survivorship in the province of Canterbury, New Zealand. The age at diagnosis was 61 years (range 20 to 83 years) with an equal number of males and females. Using Kaplan-Meier product-limit analysis, the probability of survival at 1 and 10 years was 91% and 62% respectively. Of the 12 deaths in the cohort, four occurred within 12 months of diagnosis: two from pulmonary haemorrhage and two from renal failure. Beyond 12 months, two patients died of renal failure, two of myocardial infarction and one from cardiac arrhythmia, one from cerebrovascular disease and two from colorectal carcinoma. The median time to relapse was 6.75 years, and the probability of relapse within 10 years was 67%. Survivorship, treatment response rate and the rate of relapse from WG in a cohort of patients from this high-prevalence southern hemisphere region were similar to that reported for northern hemisphere cohorts with a similar prevalence.
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Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Granulomatosis con Poliangitis/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Prevalencia , Pronóstico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4(+) T-helper 17 (Th(17)) cells, whereas IL-12 negates IL-17A production by promoting Th(1)-cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml(-1) vs 176.11 ± 277.32 pg ml(-1); P = 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.
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Artritis Reumatoide/genética , Interleucina-17/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina/genética , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Femenino , Genotipo , Humanos , Interleucina-12/sangre , Interleucina-12/genética , Interleucina-17/sangre , Interleucinas/sangre , Interleucinas/genética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.
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Alopurinol/uso terapéutico , Artritis Gotosa/tratamiento farmacológico , Inhibidores Enzimáticos/sangre , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Oxipurinol/sangre , Ácido Úrico/sangre , Adulto , Anciano , Anciano de 80 o más Años , Alopurinol/efectos adversos , Alopurinol/metabolismo , Enfermedad Crónica , Creatinina/sangre , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/metabolismo , Femenino , Gota/sangre , Supresores de la Gota/efectos adversos , Supresores de la Gota/sangre , Supresores de la Gota/metabolismo , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Oxipurinol/efectos adversos , Oxipurinol/metabolismo , Nivel de AtenciónRESUMEN
AIMS: It has been suggested that elevated mean red cell volume (MCV) may be a predictor of haematological toxicity in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). We wished to identify whether there was an association between MCV, red cell folate and haematological toxicity in patients on MTX monotherapy for the long-term management of RA. METHODS: Evidence of haematological toxicity was sought by note review of patients recruited in a cross-sectional study of MTX monotherapy in RA. Retrospective data included MCVs from before MTX initiation and after 3 and 6 months of treatment. Data were collected prospectively every 6 months for up to 2 years after enrolment. Any record of cytopenia or the development of haematological malignancy was recorded from commencement of MTX until the present day. Red cell folate concentrations were tested on enrolment to the study. RESULTS: A total of 165 patients was included, 74.5% female, median disease duration 7 years (range 3 months-57 years). The median duration of MTX treatment was 74.9 months (range 10-241 months) giving 1030.2 patient-years of MTX exposure. Twenty-four patients (14.5%) had a MCV > 98 fL on study entry. Evidence of haematological abnormality was found in six patients (3.6%); chronic lymphocytic leukaemia (1), persistent lymphocytosis (1), persistent monocytosis (1) and neutropenia (3). There was no association between red cell folate or MCV and haematological toxicity. CONCLUSION: Neutropenia and pancytopenia are rare side-effects of MTX therapy in this cohort. Elevated MCV or low mean red cell folate does not appear to be associated with haematological malignancy or toxicity in this cohort of patients on long-term MTX therapy.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Volumen de Eritrocitos/efectos de los fármacos , Enfermedades Hematológicas/sangre , Metotrexato/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antirreumáticos/efectos adversos , Artritis Reumatoide/sangre , Estudios de Cohortes , Estudios Transversales , Volumen de Eritrocitos/fisiología , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/inducido químicamente , Pancitopenia/sangre , Pancitopenia/inducido químicamente , Estudios Prospectivos , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.