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1.
Ann Rheum Dis ; 79(3): 356-362, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31915121

RESUMO

OBJECTIVES: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states. RESULTS: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001). CONCLUSIONS: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.

2.
Rheumatology (Oxford) ; 58(7): 1259-1267, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753683

RESUMO

OBJECTIVES: To assess the prevalence of combined hormonal contraceptives (CHCs) in reproductive-age women with SLE with and without possible contraindications and to determine factors associated with their use in the presence of possible contraindications. METHODS: This observational cohort study included premenopausal women ages 18-45 years enrolled in the SLICC Registry ⩽15 months after SLE onset, with annual assessments spanning 2000-2017. World Health Organization Category 3 or 4 contraindications to CHCs (e.g. hypertension, aPL) were assessed at each study visit. High disease activity (SLEDAI score >12 or use of >0.5 mg/kg/day of prednisone) was considered a relative contraindication. RESULTS: A total of 927 SLE women contributed 6315 visits, of which 3811 (60%) occurred in the presence of one or more possible contraindication to CHCs. Women used CHCs during 512 (8%) visits, of which 281 (55%) took place in the setting of one or more possible contraindication. The most frequently observed contraindications were aPL (52%), hypertension (34%) and migraine with aura (22%). Women with one or more contraindication were slightly less likely to be taking CHCs [7% of visits (95% CI 7, 8)] than women with no contraindications [9% (95% CI 8, 10)]. CONCLUSION: CHC use was low compared with general population estimates (>35%) and more than half of CHC users had at least one possible contraindication. Many yet unmeasured factors, including patient preferences, may have contributed to these observations. Further work should also aim to clarify outcomes associated with this exposure.

3.
J Rheumatol ; 46(5): 492-500, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30647177

RESUMO

OBJECTIVE: In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes. METHODS: We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively. RESULTS: Compared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01). CONCLUSION: The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.

5.
Curr Med Res Opin ; 34(8): 1449-1455, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29638148

RESUMO

OBJECTIVE: To assess the efficacy and safety of esomeprazole in preventing upper gastrointestinal (GI) bleeding in critically ill Chinese patients, using cimetidine as an active comparator. METHODS: A pre-specified non-inferiority limit (5%) was used to compare rates of significant upper GI bleeding in this randomized, double-blind, parallel-group, phase 3 study across 27 intensive care units in China. Secondary endpoints included safety and tolerability measures. Patients required mechanical ventilation and had at least one additional risk factor for stress ulcer bleeding. Patients were randomized to receive either active esomeprazole 40 mg, as a 30-min intravenous (IV) infusion twice daily, and an IV placebo cimetidine infusion or active cimetidine 50 mg/h, as a continuous infusion following an initial bolus of 300 mg, and placebo esomeprazole injections, given up to 14 days. Patients were blinded using this double-dummy technique. RESULTS: Of 274 patients, 2.7% with esomeprazole and 4.6% with cimetidine had significant upper GI bleeding (bright red blood in the gastric tube not clearing after lavage or persistent Gastroccult-positive "coffee grounds" material). Non-inferiority of esomeprazole to cimetidine was demonstrated. The safety profiles of both drugs were similar and as expected in critically ill patients. CONCLUSIONS: Esomeprazole is effective in preventing upper GI bleeding in critically ill Chinese patients, as demonstrated by the non-inferiority analysis using cimetidine as an active control. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02157376.


Assuntos
Cimetidina/uso terapêutico , Estado Terminal , Esomeprazol/uso terapêutico , Hemorragia Gastrointestinal/prevenção & controle , Adulto , Idoso , Cimetidina/administração & dosagem , Método Duplo-Cego , Esomeprazol/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
J Gastroenterol Hepatol ; 33(5): 980-989, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29319191

RESUMO

BACKGROUND AND AIM: Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions. METHODS: This Phase 3, double-blind trial randomized IBS-C patients to once-daily oral 290-µg linaclotide or placebo at centers in China, North America, and Oceania. Patients reported bowel and abdominal symptoms daily; adverse events were monitored. Co-primary and secondary endpoints were tested using a predefined three-step serial gatekeeping multiple comparisons procedure. RESULTS: The intent-to-treat population included 839 patients (mean age = 41 years; 82% female; 81% Asian). The trial met all co-primary and secondary endpoints. Co-primary responder criteria were met by 60.0% of linaclotide patients versus 48.8% of placebo patients for abdominal pain/discomfort (≥ 30% decrease for ≥ 6/12 weeks; P < 0.05), and 31.7% of linaclotide versus 15.4% of placebo patients for IBS degree of relief (score ≤ 2 for ≥ 6/12 weeks; P < 0.0001). Secondary 12-week change-from-baseline endpoints (spontaneous bowel movement/complete spontaneous bowel movement frequency, stool consistency, straining, abdominal pain, abdominal discomfort, and abdominal bloating) were significantly improved with linaclotide versus placebo (all P < 0.0001). Diarrhea was the most common adverse event (9.4% linaclotide, 1.2% placebo). Discontinuation rates due to diarrhea were low (0.7% linaclotide, 0.2% placebo). CONCLUSIONS: Once-daily 290-µg linaclotide improved bowel habits, abdominal symptoms, and global measures in a predominantly Chinese IBS-C population.


Assuntos
Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/etiologia , Agonistas da Guanilil Ciclase C/administração & dosagem , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Agonistas da Guanilil Ciclase C/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
7.
Arthritis Res Ther ; 19(1): 287, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29273092

RESUMO

BACKGROUND: In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. METHODS: We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. RESULTS: Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. CONCLUSIONS: Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.


Assuntos
Lúpus Eritematoso Sistêmico/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Nucleossomos/metabolismo , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
F1000Res ; 6: 199, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28344777

RESUMO

Physical inactivity is a well-established risk factor for colorectal cancer (CRC). Recent studies have characterized physical activity (PA), sedentary behavior, and cardiorespiratory fitness as distinct, interrelated constructs that influence the risk of CRC and related outcomes. PA levels required to confer protection against CRC may be higher than previously thought. Sedentary behavior, defined as time spent sitting, increases CRC risk independent of PA and may require novel interventions distinct from those targeting PA. Finally, cardiorespiratory fitness is inversely associated with CRC risk and mortality and may provide a potential tool for risk stratification and intervention.

9.
Lupus Sci Med ; 3(1): e000139, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27752335

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) disproportionately affects women and often develops during their reproductive years. Research suggests that some women who receive cyclophosphamide as treatment for SLE experience earlier decline in menstrual function, but reproductive health among women with SLE who have not taken this drug is less well understood. This study aims to better understand the relation between SLE and reproduction by assessing early secondary amenorrhoea and pregnancy in women treated with and without cyclophosphamide from a population-based cohort with large numbers of African-Americans. METHODS: Female patients with SLE, ages 20-40 at time of diagnosis, who were 40 years or older at the time of the survey were included in this analysis (N=147). Participants in the Georgians Organized Against Lupus (GOAL) study were asked about their reproductive histories including early secondary amenorrhoea, defined as loss of menstruation before age 40. RESULTS: Women who were cyclophosphamide naïve had an increased prevalence of early secondary amenorrhoea compared with population estimates, 13-17% compared with 1-5%. Factors associated with early secondary amenorrhoea in women not treated with cyclophosphamide were marital status and receipt of a kidney transplant. Treatment with cyclophosphamide doubled the prevalence after adjustment for patient characteristics. Over 88% of women reported being pregnant at least once, and about 83% of these had a child, but the majority of pregnancies occurred before diagnosis. CONCLUSIONS: SLE diagnosed in early adulthood may affect women's reproductive health even if they are not treated with cyclophosphamide. Better understanding of other factors related to reproductive health in this population will improve clinicians' and patients' abilities to make treatment and family planning decisions.

10.
Asia Pac Fam Med ; 14(1): 4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25937817

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a clinical syndrome encompassing a group of chronic, progressive, and debilitating respiratory conditions, that are characterized by incompletely reversible airflow limitation. Within the Asia-Pacific region, prevalence estimates have been derived using various protocols and study methods, and there is little data on the impact of COPD exacerbations. This study aimed to provide a comprehensive picture of the current prevalence and burden of COPD in this region. METHODS: A population-based survey was conducted in nine Asia-Pacific territories between 01 February 2012 and 16 May 2012. Overall, 112,330 households were screened to identify eligible subjects (aged ≥40 years, with a physician diagnosis of COPD, chronic bronchitis or emphysema, or with identifiable symptoms of chronic bronchitis). Out of a sample of 69,279 individuals aged ≥40 years, 4,289 subjects with COPD were identified. Data were collected via face-to-face interviews or by fixed-line telephone, using a structured questionnaire. A total of 1,841 completed questionnaires were analyzed. RESULTS: The overall estimated COPD prevalence was 6.2%, with 19.1% of subjects having severe COPD. In the 12 months prior to the survey, nearly half of all subjects (46%) had experienced exacerbations, and 19% had been hospitalized as a result of their condition. When subjects were asked about the impact of their condition on employment, 23% said their condition kept them from working, and 42% felt that their condition limited their ability to work or their activities. Of those who reported taking prescription drugs, 20% did not know the name of the drugs they were taking. Prescription of oral corticosteroids was common, with 44% of subjects having used these during the previous year to manage their respiratory symptoms; in contrast, inhaler use was low (25%). Only 37% of subjects had taken a lung function test, and the majority (89%) of those tested did not know their test results. CONCLUSIONS: Across the Asia-Pacific territories surveyed, the prevalence of COPD is high, indicating a substantial socioeconomic burden. Our findings suggest that there is considerable room for improvement in the management of COPD, and highlight a need to enhance patient and physician education in the region.

11.
Ann Rheum Dis ; 74(9): 1706-13, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24834926

RESUMO

BACKGROUND AND AIMS: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. RESULTS: We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). CONCLUSIONS: Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.


Assuntos
Grupos Étnicos , Nível de Saúde , Lúpus Eritematoso Sistêmico/fisiopatologia , Qualidade de Vida , Adulto , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Adulto Jovem
12.
Vaccine ; 32(39): 5041-8, 2014 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-25045806

RESUMO

METHODS: A novel, fully bacterially produced recombinant virus-like particle (VLP) based influenza vaccine (gH1-Qbeta) against A/California/07/2009(H1N1) was tested in a double-blind, randomized phase I clinical trial at two clinical sites in Singapore. The trial evaluated the immunogenicity and safety of gH1-Qbeta in the presence or absence of alhydrogel adjuvant. Healthy adult volunteers with no or low pre-existing immunity against A/California/07/2009 (H1N1) were randomized to receive two intramuscular injections 21 days apart, with 100µg vaccine, containing 42µg hemagglutinin antigen. Antibody responses were measured before and 21 days after each immunization by hemagglutination inhibition (HAI) assays. The primary endpoint was seroconversion on Day 42, defined as percentage of subjects which reach a HAI titer ≥40 or achieve an at least 4-fold rise in HAI titer (with pre-existing immunity). The co-secondary endpoints were safety and seroconversion on Day 21. RESULTS: A total of 84 Asian volunteers were enrolled in this study and randomized to receive the adjuvanted (n=43) or the non-adjuvanted (n=41) vaccine. Of those, 43 and 37 respectively (95%) completed the study. There were no deaths or serious adverse events reported during this trial. A total of 535 adverse events occurred during treatment with 49.5% local solicited symptoms, of mostly (76.4%) mild severity. The most common treatment-related systemic symptom was fatigue. The non-adjuvanted vaccine met all primary and secondary endpoints and showed seroconversion in 62.2% and 70.3% of participants respectively on Day 21 and Day 42. While the adjuvanted vaccine showed an increased seroconversion from 25.5% (Day 21) to 51.2% (Day 42), it did not meet the immunogenicity endpoint. CONCLUSION: In summary, non-adjuvanted gH1-Qbeta showed similar antibody mediated immunogenicity and a comparable safety profile in healthy humans to commercially available vaccines. These results warrant the consideration of this VLP vaccine platform for the vaccination against influenza infection (HSA CTC1300092).


Assuntos
Formação de Anticorpos , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adulto , Hidróxido de Alumínio/administração & dosagem , Anticorpos Antivirais/sangue , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Masculino , Pessoa de Meia-Idade , Singapura , Vacinas de Partículas Semelhantes a Vírus/uso terapêutico , Adulto Jovem
13.
J Biomed Opt ; 18(3): 037003, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23455965

RESUMO

We present a Monte Carlo lookup table (MCLUT)-based inverse model for extracting optical properties from tissue-simulating phantoms. This model is valid for close source-detector separation and highly absorbing tissues. The MCLUT is based entirely on Monte Carlo simulation, which was implemented using a graphics processing unit. We used tissue-simulating phantoms to determine the accuracy of the MCLUT inverse model. Our results show strong agreement between extracted and expected optical properties, with errors rate of 1.74% for extracted reduced scattering values, 0.74% for extracted absorption values, and 2.42% for extracted hemoglobin concentration values.


Assuntos
Modelos Biológicos , Método de Monte Carlo , Imagens de Fantasmas , Análise Espectral/métodos , Absorção , Simulação por Computador , Hemoglobinas/química , Humanos , Processamento de Imagem Assistida por Computador , Reprodutibilidade dos Testes , Análise Espectral/instrumentação
14.
Ann Rheum Dis ; 72(8): 1308-14, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22945501

RESUMO

BACKGROUND: The metabolic syndrome (MetS) may contribute to increased cardiovascular risk in systemic lupus erythematosus (SLE). We aimed to examine the association of demographic factors, lupus phenotype and therapy exposure with the presence of MetS. METHODS: The Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis inception cohort enrolled recently diagnosed (<15 months) SLE patients from 30 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected according to a standardised protocol. MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Univariate and backward stepwise multivariate logistic regression were used to assess the relationship of individual variables with MetS. RESULTS: We studied 1686 patients, of whom 1494 (86.6%) had sufficient data to determine their MetS status. The mean (SD) age at enrolment and disease duration was 35.2 years (13.4) and 24.1 weeks (18.0), respectively. MetS was present at the enrolment visit in 239 (16%). In backward stepwise multivariable regression analysis, higher daily average prednisolone dose (mg) (OR 1.02, 95% CI 1.00 to 1.03), older age (years) (OR 1.04, 95% CI 1.03 to 1.06), Korean (OR 6.33, 95% CI 3.68 to 10.86) and Hispanic (OR 6.2, 95% CI 3.78 to 10.12) ethnicity, current renal disease (OR 1.79, 95% CI 1.14 to 2.80) and immunosuppressant use (OR 1.81, 95% CI 1.18 to 2.78) were associated with MetS. CONCLUSIONS: Renal lupus, higher corticosteroid doses, Korean and Hispanic ethnicity are associated with MetS in SLE patients. Balancing disease control and minimising corticosteroid exposure should therefore be at the forefront of personalised treatment decisions in SLE patients.


Assuntos
Lúpus Eritematoso Sistêmico/epidemiologia , Síndrome Metabólica/epidemiologia , Adulto , Ásia/epidemiologia , Estudos de Coortes , Comorbidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Cooperação Internacional , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Síndrome Metabólica/diagnóstico , América do Norte/epidemiologia , Prevalência , Sistema de Registros
15.
Ann Rheum Dis ; 71(9): 1502-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22492779

RESUMO

OBJECTIVE: The aim of this study was to describe the frequency, attribution, outcome and predictors of seizures in systemic lupus erythematosus (SLE). METHODS: The Systemic Lupus International Collaborating Clinics, or SLICC, performed a prospective inception cohort study. Demographic variables, global SLE disease activity (SLE Disease Activity Index 2000), cumulative organ damage (SLICC/American College of Rheumatology Damage Index (SDI)) and neuropsychiatric events were recorded at enrolment and annually. Lupus anticoagulant, anticardiolipin, anti-ß(2) glycoprotein-I, antiribosomal P and anti-NR2 glutamate receptor antibodies were measured at enrolment. Physician outcomes of seizures were recorded. Patient outcomes were derived from the SF-36 (36-Item Short Form Health Survey) mental component summary and physical component summary scores. Statistical analyses included Cox and linear regressions. RESULTS: The cohort was 89.4% female with a mean follow-up of 3.5±2.9 years. Of 1631 patients, 75 (4.6%) had ≥1 seizure, the majority around the time of SLE diagnosis. Multivariate analysis indicated a higher risk of seizures with African race/ethnicity (HR (CI): 1.97 (1.07 to 3.63); p=0.03) and lower education status (1.97 (1.21 to 3.19); p<0.01). Higher damage scores (without neuropsychiatric variables) were associated with an increased risk of subsequent seizures (SDI=1:3.93 (1.46 to 10.55); SDI=2 or 3:1.57 (0.32 to 7.65); SDI≥4:7.86 (0.89 to 69.06); p=0.03). There was an association with disease activity but not with autoantibodies. Seizures attributed to SLE frequently resolved (59/78 (76%)) in the absence of antiseizure drugs. There was no significant impact on the mental component summary or physical component summary scores. Antimalarial drugs in the absence of immunosuppressive agents were associated with reduced seizure risk (0.07 (0.01 to 0.66); p=0.03). CONCLUSION: Seizures occurred close to SLE diagnosis, in patients with African race/ethnicity, lower educational status and cumulative organ damage. Most seizures resolved without a negative impact on health-related quality of life. Antimalarial drugs were associated with a protective effect.


Assuntos
Epilepsia/complicações , Epilepsia/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco
16.
J Inflamm (Lond) ; 9: 5, 2012 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-22401596

RESUMO

BACKGROUND: Asthma is characterised by increased numbers of Th2-like cells in the airways and IgE secretion. Generation of Th2 cells requires interleukin (IL)-4 and IL-13 acting through their specific receptors and activating the transcription factor, signal transducer and activator of transcription 6 (STAT6). STAT6 knockout mice fail to produce IgE, airway hyperresponsiveness and bronchoalveolar lavage eosinophilia after allergen sensitisation, suggesting a critical role for STAT6 in allergic responses. METHODS: We have investigated the expression of STAT6 in peripheral blood T-lymphocytes, alveolar macrophages and bronchial biopsies from 17 normal subjects and 18 mild-moderate steroid-naïve stable asthmatic patients. RESULTS: STAT6 expression was variable and was detected in T-lymphocytes, macrophages and bronchial epithelial cells from all subjects with no difference between normal and stable asthmatic subjects. CONCLUSIONS: STAT6 expression in different cells suggests that it may be important in regulating the expression of not only Th2-like cytokines in T cells of man, but may also regulate STAT-inducible genes in alveolar macrophages and airway epithelial cells.

17.
Respir Res ; 13: 11, 2012 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-22300506

RESUMO

BACKGROUND: While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling. METHODS: 22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks. RESULTS: FP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP. CONCLUSIONS: 200 µg/day of FP was as effective as 1000 µg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Androstadienos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Inflamação/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Remodelação das Vias Aéreas/fisiologia , Asma/fisiopatologia , Membrana Basal/fisiopatologia , Testes Respiratórios , Citocinas/biossíntese , Feminino , Fluticasona , Humanos , Inflamação/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Manitol , Óxido Nítrico/análise , Testes de Função Respiratória , Adulto Jovem
18.
Am J Physiol Lung Cell Mol Physiol ; 300(6): L951-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21460120

RESUMO

Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration. RV infection of nonasthmatic airway smooth muscle (ASM) cells significantly increased the deposition of fibronectin (40% increase, n = 12) and perlecan (80% increase, n = 14), while infection of asthmatic ASM cells significantly increased fibronectin (75% increase, n = 9) and collagen IV (15% increase, n = 9). We then treated the ASM cells with the Toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid, imiquimod, and pure RV RNA and were able to show that the mechanism through which RV induced ECM deposition was via the activation of TLR3 and TLR7/8. Finally, we assessed whether the virus-induced ECM was bioactive by measuring the amount of migration and proliferation of virus-naive cells that seeded onto the ECM. Basically, ECM from asthmatic ASM cells induced twofold greater migration of virus-naive ASM cells than ECM from nonasthmatic ASM cells, and these rates of migration were further increased on RV-modulated ECM. Increased migration on the RV-modulated ECM was not due to increased cell proliferation, as RV-modulated ECM decreased the proliferation of virus-naive cells. Our results suggest that viruses may contribute to airway remodeling through increased ECM deposition, which in turn may contribute to increased ASM mass via increased cell migration.


Assuntos
Asma/metabolismo , Asma/virologia , Proteínas da Matriz Extracelular/metabolismo , Músculo Liso/metabolismo , Infecções por Picornaviridae/metabolismo , Sistema Respiratório/metabolismo , Rhinovirus/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Remodelação das Vias Aéreas , Asma/patologia , Western Blotting , Adesão Celular , Movimento Celular , Proliferação de Células , DNA Viral/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Fibronectinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/patologia , Músculo Liso/virologia , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia , RNA Mensageiro/genética , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
19.
Respirology ; 16(2): 367-77, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21199160

RESUMO

BACKGROUND AND OBJECTIVE: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations. We evaluated whether rhinovirus (RV) infection induces airway remodelling, as assessed by ECM deposition. METHODS: Primary human bronchial epithelial cells and lung parenchymal fibroblasts were infected with RV-2 or RV-16, or treated with RV-16 RNA, imiquimod (Toll-like receptor (TLR) 7/8 agonist) or polyinosinic : polycytidylic acid (poly I : C) (activator of TLR 3, retinoic-acid-inducible protein I and melanoma-differentiated-associated gene 5). Changes in ECM proteins and their transcription were measured by ELISA and quantitative real-time PCR. In addition, gene expression for ECM proteins was assessed in a mouse model of RV infection. RESULTS: RV infection increased deposition of the ECM protein, perlecan, by human bronchial epithelial cells, and collagen V and matrix-bound vascular endothelial growth factor were increased in both human bronchial epithelial cell and fibroblast cultures. Purified RV-16 RNA, poly I : C and imiquimod induced similar increases in ECM deposition to those observed with RV-infected fibroblasts. However, only poly I : C induced ECM deposition by bronchial epithelial cells, suggesting that RV-induced ECM deposition is mediated through TLR. Furthermore, gene expression for fibronectin and collagen I was increased in lung homogenates of mice infected with RV-1b. CONCLUSIONS: RV infection and TLR ligands promote ECM deposition in isolated cell systems and RV induces ECM gene expression in vivo, thus demonstrating that RV has the potential to contribute to remodelling of the airways through induction of ECM deposition.


Assuntos
Remodelação das Vias Aéreas , Asma/virologia , Brônquios/virologia , Infecções por Picornaviridae/virologia , Aminoquinolinas/farmacologia , Animais , Asma/metabolismo , Brônquios/metabolismo , Células Cultivadas , Colágeno Tipo V/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/virologia , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Imiquimode , Camundongos , Infecções por Picornaviridae/metabolismo , Poli I-C/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas
20.
Respir Res ; 7: 71, 2006 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-16670028

RESUMO

BACKGROUND: Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV) are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential interaction of RV and human airway smooth muscle cells (HASM). We hypothesised that rhinovirus induction of inflammatory cytokine release from airway smooth muscle is augmented and differentially regulated in asthmatic compared to normal HASM cells. METHODS: HASM cells, isolated from either asthmatic or non-asthmatic subjects, were infected with rhinovirus. Cytokine production was assayed by ELISA, ICAM-1 cell surface expression was assessed by FACS, and the transcription regulation of IL-6 was measured by luciferase activity. RESULTS: RV-induced IL-6 release was significantly greater in HASM cells derived from asthmatic subjects compared to non-asthmatic subjects. This response was RV specific, as 5% serum- induced IL-6 release was not different in the two cell types. Whilst serum stimulated IL-8 production in cells from both subject groups, RV induced IL-8 production in only asthmatic derived HASM cells. The transcriptional induction of IL-6 was differentially regulated via C/EBP in the asthmatic and NF-kappaB + AP-1 in the non-asthmatic HASM cells. CONCLUSION: This study demonstrates augmentation and differential transcriptional regulation of RV specific innate immune response in HASM cells derived from asthmatic and non-asthmatics, and may give valuable insight into the mechanisms of RV-induced asthma exacerbations.


Assuntos
Asma/virologia , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Miócitos de Músculo Liso/virologia , Rhinovirus/patogenicidade , Adolescente , Adulto , Asma/imunologia , Proteína alfa Estimuladora de Ligação a CCAAT/imunologia , Morte Celular , Células Cultivadas , Feminino , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Miócitos de Músculo Liso/imunologia , Sistema Respiratório/virologia , Rhinovirus/imunologia , Transcrição Genética/imunologia , Transfecção
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