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Background: The safety and efficacy of mycophenolate mofetil (MMF) for lupus nephritis (LN) treatment is established in adults and in some children. MMF is rapidly converted to the biologically active metabolite mycophenolic acid (MPA) whose pharmacokinetics (PK) is characterized by large inter- and intra-individual variability. Methods/Design: This randomized, double-blind, active comparator, controlled clinical trial of pediatric subjects with proliferative LN compares pharmacokinetically-guided precision-dosing of MMF (MMFPK, i.e. the dose is adjusted to the target area under the concentration-time curve (AUC0-12h) of MPA ≥ 60-70 mg*h/L) and MMF dosed per body surface area (MMFBSA, i.e. MMF dosed 600 mg/m2 body surface area), with MMF dosage taken about 12 hours apart. At baseline, subjects are randomized 1:1 to receive blinded treatment with MMFPK or MMFBSA for up to 53 weeks. The primary outcome is partial clinical remission of LN (partial renal response, PRR) at week 26, and the major secondary outcome is complete renal response (CRR) at week 26. Subjects in the MMFBSA arm with PRR at week 26 will receive MMFPK from week 26 onwards, while subjects with CRR will continue MMFBSA or MMFPK treatment until week 53. Subjects who achieve PRR at week 26 are discontinued from study intervention. Discussion: The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) study will provide a thorough evaluation of the PK of MMF in pediatric LN patients, yielding a head-to-head comparison of MMFBSA and MMFPK for both safety and efficacy. This study has the potential to change current treatment recommendations for pediatric LN, thereby significantly impacting childhood-onset SLE (cSLE) disease prognosis and current clinical practice.
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BACKGROUND/PURPOSE: Adequate transition from pediatric to adult care is associated with better adherence to treatment and better outcomes in pediatric patients with chronic diseases. There are little data on transition programs, outcomes, use of transition guidelines, and available tools in pediatric rheumatology centers from Latin America (LATAM). In this study, we described the characteristics of transition programs from 3 pediatric rheumatology centers. We also introduced results of the first survey examining the transition experience in countries from LATAM. METHODS: The experience and implementation process of transition programs from 3 pediatric rheumatology centers were described. A survey based on a questionnaire created by Chira et al (J Rheumatol. 2014;41:768-779) from the Childhood Arthritis and Rheumatology Research Alliance was also administrated to pediatric rheumatology centers from LATAM. RESULTS: A total of 49 (68%) pediatric rheumatologists answered the survey. Most centers do not have an official and written transition program and reported a need for more tools and resources in their services to facilitate the transition experience. CONCLUSIONS: Transition guidelines culturally tailored to developing countries are needed in LATAM.
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BACKGROUND: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. METHODS: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. RESULTS: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. CONCLUSIONS: Lower complement levels are associated with proliferative lesions in pediatric LN-both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Niño , Estudios Retrospectivos , Estudios Prospectivos , Lupus Eritematoso Sistémico/complicaciones , Proteínas del Sistema Complemento , Biomarcadores , Riñón/patología , Biopsia/efectos adversos , ADNRESUMEN
OBJECTIVE: The long-term impact of childhood-onset systemic lupus erythematosus (SLE) on health-related quality of life (HRQoL) in adult SLE patients in comparison to those with adult-onset SLE is unknown. We aim to examine and compare HRQoL trajectories in adults with adolescent- and adult-onset SLE. METHODS: Patients enrolled in the LUpus in MInorities: NAture versus Nurture cohort were included. Adolescent-onset SLE were those diagnosed before 24 years of age, and adult-onset SLE were those diagnosed otherwise. Sociodemographic, clinical, medications, behavioral/psychological, and functioning data were obtained. Longitudinal trajectories of the physical component summary (PCS) and the mental component summary (MCS) Short Form 36 health survey scores were compared between the groups using a linear mixed model accounting for time-dependent and independent covariates. RESULTS: A total of 470 SLE patients were included (95 with adolescent-onset SLE and 375 with adult-onset SLE). The mean ± SD age at diagnosis was 19.7 ± 2.8 years in the adolescent group and 39.3 ± 11.0 years in the adult group. The baseline PCS scores were higher (better physical functioning) in adolescent-onset SLE than in adult-onset SLE (38.9 versus 34.3, respectively; P < 0.001); however, the baseline MCS scores were comparable between the groups (41.4 versus 40.5, respectively; P = 0.53). The HRQoL improved equally in both groups with no statistically significant difference within and between the groups (last mean PCS and MCS scores 43.9 and 45.3 in adolescent-onset SLE; 38.1 and 43 in adult-onset SLE). CONCLUSIONS: Adults with adolescent-onset SLE exhibited better physical functioning than those in the adult SLE group, despite more severe disease; noteworthy, HRQoL was below the general US population, despite clinically meaningful improvement in HRQoL over time in both groups.
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Lupus Eritematoso Sistémico , Calidad de Vida , Adulto , Humanos , Adolescente , Estudios Longitudinales , Encuestas y Cuestionarios , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Examen FísicoRESUMEN
OBJECTIVES: This study assesses the association of race/ethnicity with the Patient-Reported Outcomes Measurement Information System (PROMIS®) in childhood-onset systemic lupus erythematosus (cSLE) patients from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. METHODS: cSLE patients enrolled in the CARRA Registry within two years of cSLE diagnosis who met ACR and/or SLICC classification criteria for lupus were included. Baseline demographics, laboratory, and disease features as well as patient-reported outcomes were obtained. Multivariable linear regression analysis was used to examine the association of race and ethnicity with PROMIS scores at registry enrolment. RESULTS: 425 cSLE patients met inclusion criteria: 83.8% were female, 30.6% non-Hispanic White, 29.7% Black, 22.1% Hispanic. The mean age at diagnosis was 13.9 years (SD 2.5). Household income and highest parental education varied by race/ethnic group, as did frequency of rash, leukopenia, and anti-Smith antibodies. The cohort had low-moderate baseline disease activity (SLEDAI mean: 6.0 [SD 6.7]). The overall PROMIS Global Health mean T-score was 38.6 (SD 6.5), more than one standard deviation below the general population mean of 50. There was no association between race/ethnicity and PROMIS scores in multivariable linear regression analysis. CONCLUSIONS: In this multiethnic paediatric lupus cohort, PROMIS global health was lower when compared with the general paediatric US population. Moreover, PROMIS global health, pain interference, and physical function mobility did not vary across races/ethnicities.
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Etnicidad , Lupus Eritematoso Sistémico , Humanos , Niño , Femenino , Adolescente , Masculino , Hispánicos o Latinos , Medición de Resultados Informados por el Paciente , Índice de Severidad de la EnfermedadRESUMEN
Systemic lupus erythematosus (SLE) is an autoimmune disorder with significant health disparities, as it disproportionately and more severely affects vulnerable and disadvantaged population groups in the United States and around the world, that is, women, ethnic minorities, individuals living in poverty, less educated, and lacking medical insurance. Both, genetic and non-genetic factors, contribute to these disparities. To overcome these health disparities and reduce poor outcomes among disadvantaged SLE populations, interventions on non-genetic amendable factors, especially on social health determinants, are necessary.
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Etnicidad , Lupus Eritematoso Sistémico , Humanos , Estados Unidos/epidemiología , FemeninoAsunto(s)
Investigación Biomédica , Investigación Participativa Basada en la Comunidad , Disparidades en el Estado de Salud , Lupus Eritematoso Sistémico/epidemiología , Proyectos de Investigación , Reumatología , Determinantes Sociales de la Salud , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/terapia , Pronóstico , Medición de Riesgo , Factores de RiesgoRESUMEN
OBJECTIVE: Macrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset systemic lupus erythematosus (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients. METHODS: We conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to The Hospital for Sick Children from January 2003 to December 2007 (cohort 1) and January 2008 to December 2013 (cohort 2). All patients met ≥ 4 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria, and were steroid-naïve and infection-free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria. RESULTS: Cohort 1 (n = 34) and cohort 2 (n = 41) each had 10 patients with MAS. Recursive partitioning in cohort 1 identified ferritin ≥ 699 µg/L as the sole best discriminator between MAS and non-MAS patients (R2 = 0.48), and in cohort 2, ferritin ≥ 1107 µg/L was the best discriminator for MAS, followed by lymphocytes < 0.72 × 103/mm3 (R2 = 0.52). Cross-validation of our decision rules maintained 90-100% sensitivity and 65-85% specificity. CONCLUSION: Our decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society and familial hemophagocytic lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.
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Lupus Eritematoso Sistémico , Síndrome de Activación Macrofágica , Reumatología , Niño , Fiebre , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Estudios Retrospectivos , Estados UnidosRESUMEN
OBJECTIVE: To describe the features and treatment of macrophage activation syndrome (MAS) in a single-center cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare childhood-onset SLE manifestations and outcomes between those with and those without MAS. METHODS: We included all patients with childhood-onset SLE followed up at The Hospital for Sick Children from 2002 to 2012, and identified those also diagnosed as having MAS. Demographic, clinical, and laboratory features of MAS and SLE, medication use, hospital and pediatric intensive care unit (PICU) admissions, as well as damage indices and mortality data were extracted from the Lupus database. Student's t-tests and Fisher's exact tests were used to compare continuous and categorical variables, respectively. We calculated incidence rate ratios of hospital and PICU admissions comparing patients with and those without MAS, using Poisson models. Kaplan-Meier survival analysis was used to examine the time to disease damage accrual. RESULTS: Of the 403 patients with childhood-onset SLE, 38 (9%) had MAS. The majority (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of steroids, and time to disease damage were similar between those with and those without MAS. We observed a higher mortality rate among those with MAS (5%) than those without MAS (0.2%) (P = 0.02). CONCLUSION: MAS was most likely to develop concomitantly with childhood-onset SLE diagnosis. The majority of the MAS patients were successfully treated with corticosteroids with no MAS relapses. Although the numbers were small, there was a higher risk of death associated with MAS compared to SLE without MAS.
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Lupus Eritematoso Sistémico/inmunología , Síndrome de Activación Macrofágica/mortalidad , Adolescente , Corticoesteroides/uso terapéutico , Edad de Inicio , Niño , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Estimación de Kaplan-Meier , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/inmunología , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND AND AIM: This cluster randomized trial evaluated the efficacy of a disease and care management (D&CM) model in cardiovascular (CVD) prevention in primary care. METHODS AND RESULTS: Eligible subjects had ≥ 1 among: blood pressure ≥ 140/90 mmHg; glycated hemoglobin ≥ 7%; LDL-cholesterol ≥ 160 or ≥ 100 mg/dL (primary or secondary prevention, respectively); BMI ≥ 30; current smoking. The D&CM intervention included a teamwork including nurses as care managers for the implementation of tailored care plans. Control group was allocated to usual-care. The main outcome was the proportion of subjects achieving recommended clinical targets for ≥ 1 of uncontrolled CVD risk factors at 12-month. During 2008-2009 we enrolled 920 subjects in the Abruzzo/Marche regions, Italy. Following the exclusion of L'Aquila due to 2009 earthquake, final analyses included 762 subjects. The primary outcome was achieved by 39.1% (95%CI: 34.2-44.2) and 25.2% (95%CI: 20.9-29.9) of subjects in the intervention and usual-care group, respectively (p < 0.001). The D&CM intervention significantly increased the proportion of subjects who achieved clinical targets for both diabetes and hypertension, with no differences in hypercholesterolemia, smoking status and obesity. CONCLUSIONS: The D&CM intervention was effective in controlling cardiovascular risk factors, in particular hypertension and diabetes. Numbers needed to treat were small. Such intervention may deserve further consideration in clinical practice. REGISTRATION NUMBER: ACTRN12611000813987.
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Enfermedades Cardiovasculares/prevención & control , Atención Primaria de Salud , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea , Índice de Masa Corporal , LDL-Colesterol/sangre , Análisis por Conglomerados , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/metabolismo , Humanos , Hipercolesterolemia/sangre , Hipertensión/sangre , Italia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Resultado del TratamientoRESUMEN
We measured the response of HepG2 cells to the classic cytochrome (cyt.) P-450 inducers 3-methylcholanthrene (3-MC) and phenobarbital (PB), by evaluating oxidative and/or reductive metabolism of the nitroarenes, 1-NP and 1,6-dinitropyrene (1,6-DNP), in control and induced cells. In HepG2 cells, 3-MC induces ring-hydroxylation of 1-NP, whereas PB stimulates its nitroreduction. PB induces NADPH-cyt. c reductase, but does not affect other cytosolic and microsomal enzymes which contribute to 1-NP nitroreduction in these cells. However, PB-inducible nitroreductase activity seems to be associated primarily with cyt. P-450 isoenzymatic form(s), as indicated by the requirement for NADPH and the response to specific inhibitors such as alpha-naphthoflavone and CO.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metilcolantreno/farmacología , Fenobarbital/farmacología , Pirenos/metabolismo , Carcinoma Hepatocelular/enzimología , Inducción Enzimática , Humanos , Neoplasias Hepáticas/enzimología , Mutágenos/metabolismo , Fracciones Subcelulares/enzimología , Células Tumorales CultivadasRESUMEN
The inducing effects of 1-nitropyrene (1-NP) on the microsomal cytochrome P-450 system were studied in rats. Intraperitoneal administration of 1-NP led to increases in cytochrome P-450 content and aryl hydrocarbon hydroxylase, ethoxycoumarin, and ethoxyresorufin-O-deethylase activities. These increases were dose dependent. Cytochrome b5 content and aminopyrine and p-nitroanisole demethylase activities were not affected by treatment of rats with 1-NP. Substrate specificity, sensitivity to mixed-function oxidase inhibitors, and electrophoretic pattern of 1-NP-induced cytochrome(s) P-450 were compared to the major forms of cytochrome P-450 induced by phenobarbital and methylcholanthrene. Furthermore microsomes from 1-NP-induced rats showed greater ability to metabolize the chemical as compared with those from control animals; this result indicates that 1-NP induces a form(s) of cytochrome P-450 especially effective in the metabolism of the substance itself.
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Sistema Enzimático del Citocromo P-450/biosíntesis , Microsomas Hepáticos/enzimología , Pirenos/farmacología , Animales , Cromatografía Líquida de Alta Presión , Inducción Enzimática/efectos de los fármacos , Inyecciones Intraperitoneales , Masculino , Metilcolantreno/farmacología , Microsomas Hepáticos/efectos de los fármacos , Oxigenasas de Función Mixta/antagonistas & inhibidores , Fenobarbital/farmacología , Ratas , Ratas EndogámicasAsunto(s)
Catárticos/uso terapéutico , Estreñimiento/tratamiento farmacológico , Plantas Medicinales , Psyllium/uso terapéutico , Adulto , Anciano , Catárticos/administración & dosificación , Enfermedad Crónica , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plantas Tóxicas , Psyllium/administración & dosificación , RhamnusRESUMEN
Seventy-five patients affected by chronic constipation were treated for 4 weeks with an Ispaghula Husk preparation (Fibrolax), a bulk-forming laxative. Frequency, stool consistency, abdominal pain and signs of venous stasis improved after treatment. No important side-effect was recorded. Cholesterol, HDL-cholesterol and triglycerides did not show significant changes.
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Catárticos/uso terapéutico , Estreñimiento/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Adulto , Anciano , Colesterol/sangre , Enfermedad Crónica , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Triglicéridos/sangreAsunto(s)
Retracción del Coagulo , Fibroblastos/fisiología , Neoplasias/fisiopatología , Adolescente , Adulto , Línea Celular , Supervivencia Celular , Niño , Embrión de Mamíferos , Femenino , Fibrina/fisiología , Humanos , Recién Nacido , Masculino , Embarazo , Piel/fisiopatología , Fenómenos Fisiológicos de la PielRESUMEN
Stable spontaneous mutants resistant to diphtheria toxin are present in the human cell line (EUE) at a frequency of 0-8 x 10(-6). Mutation increases by a number of polycyclic hydrocarbons have been used as an estimate of their carcinogenic potency. Eight polycyclic hydrocarbons of decreasing carcinogenic potency were assayed: 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, benzo[a]pyrene, benz[a]anthracene, dibenz[a,c]anthracene, dibenz[a,h]anthracene, chrysene, anthracene, and a well known mutagenic substance, ethyl methanesulfonate. In our system, which does not require an exogenous source for metabolic activation, the most potent hydrocarbons, 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene and benzo[a]pyrene revealed a strong mutagenic effect, whereas three non-carcinogenic hydrocarbons, anthracene, benz[a]anthracene and chrysene were not mutagenic. Our results indicate that there is a relationship between mutagenesis and carcinogenic potency for the tested polycyclic hydrocarbons. The maximum recovery of diphtheria toxin mutants was observed after an expression time of three weeks, corresponding to 10 cell generations.
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Carcinógenos/toxicidad , Toxina Diftérica/farmacología , Mutagénesis/efectos de los fármacos , Mutágenos/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , Biotransformación , Carcinógenos/farmacocinética , Resistencia a Medicamentos/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Metanosulfonato de Etilo/toxicidad , Humanos , Mutágenos/farmacocinética , Hidrocarburos Policíclicos Aromáticos/farmacocinéticaRESUMEN
This study aimed at evaluating by a quantitative assay the fibrin clot retractile activity (FCR) of C3H embryo fibroblasts during their growth and aging in culture. Cell from primary and subsequent subcultures were tested at defined times from seeding, in a specially devised micromethod. Results indicate that cell-induced FCR has a kinetic similar to platelet-induced FCR; it depends on the number of cells and time of incubation in the system. It is absent or low in cells harvested from primary culture, then increases and remains high in the following doublings decreasing sharply at the end of the replicative life span in culture.
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División Celular , Supervivencia Celular , Retracción del Coagulo , Fibroblastos/fisiología , Animales , Plaquetas/fisiología , Recuento de Células , Células Cultivadas , Femenino , Fibrina , Cinética , RatonesRESUMEN
Plasma and serum of humans or experimental animals contain a factor which destabilizes F-actin. The factor has no DNAse or thrombin activity and after incubation with F-actin does not modify the position of the actin band on a SDS polyacrylamide gel. Hence it probably depolymerizes F-actin.