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BACKGROUND: Depressive and anxiety symptoms are common in childhood-onset systemic lupus erythematosus (cSLE), yet their etiology and course remain unclear. We investigated the frequency of depressive and anxiety symptoms longitudinally in youth with cSLE, and associated socio-demographic and disease factors. METHODS: Participants 8-18 years with cSLE completed baseline measures [demographic questionnaire, Center for Epidemiologic Studies Depression Scale for Children (CES-DC), Screen for Childhood Anxiety Related Disorders (SCARED), and psychiatric interview] and follow-up measures (CES-DC and SCARED) > 6 months later. Prevalence of clinically significant depressive (score >15 on CES-DC) or anxiety symptoms (score ≥25 on SCARED) was calculated at baseline and follow-up. Baseline psychiatric interview diagnoses were tabulated. Relationships between socio-demographics (neighborhood-level material deprivation, ethnic concentration, adverse childhood event history, psychiatric condition in a first-degree relative), disease-related factors (disease duration, major organ disease, disease activity, glucocorticoid use, comorbid medical condition) and baseline depressive and anxiety scores, were examined in linear regression models. Factors with univariate associations with p < 0.2 were included in multivariable adjusted models. RESULTS: At baseline, of 51 participants with a mean disease duration of 4.3 years (SD 2.7), 35% (n = 18) and 35% (n = 18) had clinically significant depressive and anxiety symptoms, respectively. Anxiety disorder was diagnosed by psychiatric interview in 14% (n = 7), depressive disorders in 6% (n = 3), and post-traumatic stress disorder in 4% (n = 2). Adverse childhood events and first-degree relative with psychiatric condition were present in 40% (n = 20) and 37% (n = 18), respectively. In multivariable regression analysis, baseline depressive symptoms were positively correlated with neighbourhood-level material deprivation (ß = 4.2, 95% CI [1.0, 7.3], p = 0.01) and psychiatric condition in a first-degree relative (ß = 7.3, 95% CI [2.2, 12.4], p = 0.006). No associations were found between baseline anxiety scores and patient factors. At a median follow-up of 13.5 months (IQR 10.5, 18) for CES-DC (n = 34) and SCARED (n = 44), depressive and anxiety symptoms were persistent (18%, n = 6; 16%, n = 7), and newly present (24%, n = 8; 16% n = 7) at follow-up. CONCLUSION: In this sample, depressive and anxiety symptoms were prevalent and persistent. Depressive symptoms correlated with neighborhood-level material deprivation, and family psychiatric history. These findings support routine psychosocial assessment in cSLE, and provision of appropriate resources.
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Ansiedad , Depresión , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/psicología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Femenino , Masculino , Niño , Adolescente , Factores de Riesgo , Depresión/epidemiología , Depresión/etiología , Ansiedad/epidemiología , Ansiedad/etiología , Prevalencia , Escalas de Valoración Psiquiátrica , Estudios Longitudinales , Edad de Inicio , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/etiología , Encuestas y CuestionariosRESUMEN
Objectives: This study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA. Methods: We present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient's disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience. Results: Two patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2-7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT. Conclusion: We report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk-benefit ratio of this procedure.
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OBJECTIVE: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.
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BACKGROUND: There are no validated screening measures for depressive or anxiety disorders in childhood Systemic Lupus Erythematosus (cSLE). We investigated cross-sectionally (1) the prevalence of depressive and anxiety disorder in cSLE. (2) the validity of the Centre for Epidemiologic Studies Depression Scale for Children (CES-DC) and the Screen for Childhood Anxiety and Related Disorders (SCARED) measures in identifyingthese disorders. METHODS: Participants 8-18 years with cSLE/incipient cSLE completed CES-DC, SCARED, and Quality OfMy Life (QOML) measures. Parents completed the SCARED-Parent measure. Diagnosis was by gold-standard psychiatric interview and determined prevalence of psychiatric disorder. Receiver Operating Characteristics Area under the Curve (ROCAUC) evaluated screening measure diagnostic performance. RESULTS: Ofseventy-two parent-child dyads, 56 interviews were completed. Mean screen scores were: CES-DC = 15 (range 1-49, SD 12), SCARED-C = 22 (range 2-61, SD 14), SCARED-P = 13 (range 0-36, SD 8). Depressive disorder screen positivity (CES-DC ≥ 15) was 35% (vs. prevalence 5%). Anxiety disorder screen positivity (SCARED ≥ 25) was 39% (vs. prevalence 16%). CES-DC ROCAUC = 0.98 and SCARED-C ROCAUC = 0.7 (cut-points 38 and 32 respectively). CONCLUSIONS: Diagnostic thresholds for depressive and anxiety disorderscreening measures are high for both CES-DC and SCARED-C in cSLE. Brief focused interview should follow to determine whether psychiatric evaluation is warranted.
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Lupus Eritematoso Sistémico , Adolescente , Ansiedad , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Tamizaje Masivo , AutoinformeRESUMEN
OBJECTIVE: Several autoimmune diseases have familial aggregation and, possibly, common genetic predispositions. In a large population-based study, we evaluated whether children born to mothers with systemic lupus erythematosus (SLE) have an increased risk of rheumatic and nonrheumatic autoimmune diseases versus children born to mothers without SLE. METHODS: Using the Offspring of SLE Mothers Registry, we identified children born live to SLE mothers and their matched controls, and ascertained autoimmune diseases based on ≥1 hospitalization or ≥2 physician visits with a relevant diagnostic code. We adjusted for maternal age, education, race/ethnicity, obstetric complications, calendar birth year, and sex of child. RESULTS: A total of 509 women with SLE had 719 children, while 5,824 matched controls had 8,493 children. The mean ± SD follow-up period was 9.1 ± 5.8 years. Children born to mothers with SLE had a similar frequency of rheumatic autoimmune diagnoses (0.14%; 95% confidence interval [95% CI] 0.01-0.90) versus controls (0.19% [95% CI 0.11-0.32]). There was a trend toward more nonrheumatic autoimmune diseases in SLE offspring (1.11% [95% CI 0.52-2.27]) versus controls (0.48% [95% CI 0.35-0.66]). In multivariate analyses, we did not see a clear increase in rheumatic autoimmune disease (odds ratio [OR] 0.71 [95% CI 0.11-4.82]), but children born to mothers with SLE had a substantially increased risk of nonrheumatic autoimmune disease versus controls (OR 2.30 [95% CI 1.06-5.03]). CONCLUSION: Although the vast majority of offspring have no autoimmune disease, children born to women with SLE may have an increased risk of nonrheumatic autoimmune diseases versus controls. Additional studies assessing offspring through to adulthood would be additionally enlightening.
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Enfermedades Autoinmunes/epidemiología , Hijo de Padres Discapacitados/estadística & datos numéricos , Lupus Eritematoso Sistémico , Complicaciones del Embarazo , Adolescente , Adulto , Artritis Juvenil/epidemiología , Artritis Psoriásica/epidemiología , Enfermedad Celíaca/epidemiología , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/epidemiología , Esclerosis Múltiple/epidemiología , Análisis Multivariante , Miastenia Gravis/epidemiología , Embarazo , Psoriasis/epidemiología , Quebec/epidemiología , Enfermedades Reumáticas/epidemiología , Espondilitis Anquilosante/epidemiología , Vasculitis Sistémica/epidemiología , Tiroiditis Autoinmune/epidemiologíaRESUMEN
OBJECTIVE: Limited evidence suggests a potentially increased risk of allergic conditions in offspring born to women with systemic lupus erythematosus (SLE). In a large population-based study, we aimed to determine if children born to mothers with SLE have an increased risk of allergic conditions compared to children born to mothers without SLE. METHODS: Using the Offspring of SLE Mothers Registry, we identified children born live to mothers with SLE and their matched controls, and ascertained the number of allergic conditions (asthma, allergic rhinitis, eczema, urticaria, angioedema, and anaphylaxis) based on ≥1 hospitalization or ≥1 or 2 physician(s) visit(s) with a relevant diagnostic code. We adjusted for maternal age, education, race/ethnicity, obstetrics complications, calendar year of birth, sex of the child, and maternal medication. RESULTS: There were 509 women with SLE who had 719 children, while 5,824 matched controls had 8,493 children. The mean ± SD followup period was 9.1 ± 5.8 years. Compared to controls, more children born to mothers with SLE had evidence of allergic conditions (43.9% [95% confidence interval (95% CI) 40.4-47.6] versus 38.1% [95% CI 37.0-39.1]). In multivariate analysis (n = 9,212), children born to mothers with SLE had an increased risk of allergic conditions versus control children (odds ratio 1.35 [95% CI 1.13-1.61]). CONCLUSION: Compared to children from the general population, children born to women with SLE may have an increased risk of allergic conditions. Genetics, shared environmental exposures, as well as in utero exposure to maternal autoantibodies and cytokines may mediate this increased risk.
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Hipersensibilidad/etiología , Lupus Eritematoso Sistémico/complicaciones , Efectos Tardíos de la Exposición Prenatal , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/inmunología , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Masculino , Embarazo , Quebec , Sistema de Registros , Medición de Riesgo , Factores de RiesgoRESUMEN
PURPOSE OF REVIEW: This article will provide an update of studies published in the last year regarding epidemiology, pathogenesis, major disease manifestations and outcomes, and therapies in childhood-onset systemic lupus erythematosus (cSLE). RECENT FINDINGS: Recent studies on cSLE epidemiology supported previous findings that cSLE patients have more severe disease and tend to accumulate damage rapidly. Lupus nephritis remains frequent and is still a significant cause of morbidity and mortality. In the past year unfortunately there were no new reproducible, biomarker studies to help direct therapy of renal disease. However, some progress was made in neuropsychiatric disease assessment, with a new and promising automated test to screen for cognitive dysfunction reported. There were no prospective interventional treatment trials designed for patients with cSLE published in the last year, but some studies involving children are currently active and might improve the therapeutic options for patients with cSLE. SUMMARY: There is a need to get a better understanding of pathogenesis and identify new biomarkers in cSLE to more accurately predict outcomes. New insights into characterization of different clinical manifestations may enable to optimize individual interventions and influence the prognosis.
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Enfermedades Cardiovasculares/epidemiología , Lupus Eritematoso Sistémico/epidemiología , Nefritis Lúpica/epidemiología , Adolescente , Edad de Inicio , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Niño , Ciclofosfamida/uso terapéutico , Humanos , Inmunidad Innata , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Interleucina-1beta/genética , Lupus Eritematoso Cutáneo/epidemiología , Lupus Eritematoso Cutáneo/etiología , Lupus Eritematoso Cutáneo/inmunología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/etiología , Nefritis Lúpica/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/tratamiento farmacológico , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Vasculitis por Lupus del Sistema Nervioso Central/etiología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Osteonecrosis/etiología , Osteonecrosis/inmunología , Polimorfismo de Nucleótido Simple , Pronóstico , Receptor de Muerte Celular Programada 1/genética , Estudios Prospectivos , Calidad de Vida , Rituximab/uso terapéutico , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/genética , Virosis/inmunologíaRESUMEN
This mixed-methods study uses Maslow's hierarchy as a theoretical lens to investigate the experiences of 63 newly enrolled clients of housing first and traditional programs for adults with serious mental illness who have experienced homelessness. Quantitative findings suggests that identifying self-actualization goals is associated with not having one's basic needs met rather than from the fulfillment of basic needs. Qualitative findings suggest a more complex relationship between basic needs, goal setting, and the meaning of self-actualization. Transforming mental health care into a recovery-oriented system will require further consideration of person-centered care planning as well as the impact of limited resources especially for those living in poverty.
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Objetivos , Vivienda , Personas con Mala Vivienda , Trastornos Mentales/rehabilitación , Adulto , Trastorno Bipolar/rehabilitación , Trastorno Depresivo Mayor/rehabilitación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Motivación , Planificación de Atención al Paciente , Pobreza , Trastornos Psicóticos/rehabilitación , Esquizofrenia/rehabilitaciónRESUMEN
Juvenile granulosa cell tumour (JGCT) of the testis is a benign neoplasm rarely seen in children. It usually presents as a unilateral scrotal mass and can be associated with genital ambiguity and chromosomal anomalies. Radical orchiectomy is the treatment of choice. We present an infant with a JGCT of the testis and we review the typical findings of the disease.
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Cardiovascular diseases (CVDs) represent a huge health burden for older patients with diabetes. Acetylsalicylic acid (ASA) has long been used as a cardioprotective agent in primary and secondary prevention of CVD. However, there are important issues regarding the benefits and risks of ASA therapy in primary prevention of CVDs, for the older group in general and for individuals of all ages with diabetes. In this review, we summarize the benefits and risks related to ASA therapy by outlining the evidence for older patients and for patients with diabetes. There appear to be significant gaps in knowledge. The balance of benefits and risks is not well defined but ASA treatment seems to be unfavorable in many older patients.
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Paget's disease of bone (PDB) is a common metabolic bone disorder with a significant genetic component. To date, only one gene associated with PDB has been identified, the p62-Sequestosome1 gene (SQSTM1), and more than 20 mutations of this gene have been reported in PDB, the most common being the P392L substitution. In order to search for differentially expressed genes in PDB, we investigated the relative gene expression profile of candidate genes in osteoclast (OCL) cultures from 12 PDB patients and six unmatched healthy controls with known genetic status regarding p62, including healthy carriers of the P392L mutation. We selected 48 OCL-expressed candidate genes that may be involved in relevant pathways of PDB pathogenesis, such as OCL signaling, survival, bone resorption activity, or adhesion. In OCL cultures derived from peripheral blood mononuclear cells, total RNA extraction was performed, followed by real-time PCR experiments. Relative quantification analysis utilized the qBase method where relative expression levels were normalized with respect to a set of reference primer pairs for three housekeeping genes. When compared to non-mutated healthy controls, OCL cultures from PDB patients displayed a significant down-regulation in genes involved in apoptosis (CASP3 and TNFRSF10A), in cell signaling (TNFRSF11A), in the OCL bone resorbing function (ACP5 and CTSK) and in the gene coding for Tau protein (MAPT) (all comparisons, p<0.0001). Comparison of relative gene expression in PDB patients with P392L mutation versus PDB patients without SQSTM1 mutation did not provide significant differential gene expression. However, we observed a non-significant decrease in the expression of several genes such as IL6ST, HIF1A, OSTM1, TNFRSF-10B and -10D, PDK1, MAPT and CASP3 in healthy carriers of the P392L mutation. These results provide important information about the mis-regulated activities of pagetic OCL, and highlight the role of altered apoptosis pathways in these cells. They also suggest that the SQSTM1 P392L mutation plays a role in PDB pathogenesis, even at early preclinical stages in healthy carriers of the P392L mutation.
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Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Osteítis Deformante/genética , Osteítis Deformante/patología , Osteoclastos/patología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Osteítis Deformante/metabolismo , Osteoclastos/fisiología , Proteína Sequestosoma-1Asunto(s)
Cardiotónicos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Administración Oral , Factores de Edad , Anciano , Anciano de 80 o más Años , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Diabetes Mellitus/fisiopatología , Prescripciones de Medicamentos , Femenino , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Oportunidad Relativa , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéuticoRESUMEN
Mutations of the gene encoding p62/SQSTM1 have been described in Paget's disease of bone (PDB), identifying p62 as an important player in osteoclast signaling. We investigated the phenotype of osteoclasts differentiated from peripheral blood monocytes obtained from healthy donors or PDB patients, all genotyped for the presence of a mutation in the p62 ubiquitin-associated domain. The cohort included PDB patients carrying or not the p62 P392L mutation and healthy donors carrying or not this mutation. Osteoclasts from PDB patients were more numerous, contained more nuclei, were more resistant to apoptosis, and had a greater ability to resorb bone than their normal counterparts, regardless of whether the p62 mutation was present or not. A strong increase in p62 expression was observed in PDB osteoclasts. The presence of the p62(P392L) gene in cells from healthy carriers conferred a unique, intermediate osteoclast phenotype. In addition, we report that two survival-promoting kinases, protein kinase Czeta and phosphoinositide-dependent protein kinase 1, were associated with p62 in response to receptor activator of NF-kappaB ligand (RANKL) stimulation in controls and before RANKL was added in PDB osteoclasts. In transfected osteoclasts derived from cord blood monocytes, the p62 P392L mutation contributed to increased activation of kinases protein kinase Czeta/lambda and phosphoinositide-dependent protein kinase 1, along with basal activation of NF-kappaB, independently of RANKL stimulation. These findings clearly indicate that the overexpression of p62 in PDB patients induces important shifts in the pathways activated by RANKL and up-regulates osteoclast functions. Moreover, the most-commonly reported p62 mutation, P392L, certainly contributes to the overactive state of osteoclasts in PDB.
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Proteínas Adaptadoras Transductoras de Señales/genética , Sustitución de Aminoácidos/genética , Mutación/genética , Osteítis Deformante/genética , Osteítis Deformante/patología , Osteoclastos/patología , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/enzimología , Osteoclastos/metabolismo , Fenotipo , Unión Proteica/efectos de los fármacos , Proteína Quinasa C/metabolismo , Ligando RANK/farmacología , Proteína Sequestosoma-1 , Transducción de Señal/efectos de los fármacos , TransfecciónRESUMEN
The mechanisms by which beta1 integrins modulate T cell functions are still poorly defined. We have previously reported that signaling via the collagen type I (Coll I) receptor, alpha2beta1 integrin, inhibited FasL expression and protected Jurkat T cells from activation-induced cell death (AICD). In this study, we examined whether Coll I signaling in T cells also modulates the expression of the human receptor activator of nuclear factor-kappaB ligand (RANKL), a recently identified TNF family member which has important functions in osteoclastogenesis, cell survival and apoptosis. Our results show that in both Jurkat T cells and human primary T cells, Coll I signaling significantly reduces activation-induced RANKL expression by 50-60%. We also found that RANKL is not involved in AICD but participates in doxorubicin-induced apoptosis of leukemia T cell lines including Jurkat, CEM and HSB-2. In this respect, Coll I protected leukemia T cell lines from doxorubicin-induced apoptosis by inhibiting doxorubicin-induced RANKL expression. Together, our results suggest that by limiting the production of RANKL, Coll I signaling may contribute to the resistance of leukemia T cells to chemotherapy. Our study also emphasizes the importance Coll I signaling may have in the control of RANKL-associated T cell functions.
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Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/biosíntesis , Colágeno Tipo I/fisiología , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/biosíntesis , FN-kappa B/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Apoptosis/inmunología , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Línea Celular Tumoral , Células Cultivadas , Humanos , Células Jurkat , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Ligando RANK , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Receptor Activador del Factor Nuclear kappa-B , Transducción de Señal/inmunología , Linfocitos T/citologíaRESUMEN
The mechanisms by which T lymphocytes escape apoptosis during their activation are still poorly defined. In this study, we elucidated the intracellular signaling pathways through which beta1 integrins modulate Fas-mediated apoptosis in T lymphocytes. In experiments done in Jurkat T cells and activated peripheral blood T lymphocytes, engagement of alpha2beta1 integrin with collagen type I (Coll I) was found to significantly reduce Fas-induced apoptosis and caspase-8 activation; Annexin V binding and DNA fragmentation were reduced by approximately 42 and 38%, respectively. We demonstrated that the protective action of Coll I does not require new protein synthesis but was dependent on the activation of the MAPK/Erk pathway. Furthermore, we found that activation of protein phosphatase 2A (PP2A) by Coll I was required for both Coll I-mediated activation of Erk, and inhibition of Fas-induced caspase-8 activation and apoptosis. Other ligands of beta1 integrins, fibronectin (Fbn), and laminin (Lam), did not sustain significant Erk activation and had no effect on Fas-induced apoptosis. Taken together, these results provide the first evidence of a PP2A-dependent activation of the MAPK/Erk pathway downstream of alpha2beta1 integrin, which has a functional role in regulating Fas-mediated apoptosis in T lymphocytes. As such, this study emphasizes the potential importance that Coll I interactions may have on the control of T lymphocyte homeostasis and their persistence in chronic inflammatory diseases.
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Apoptosis/fisiología , Integrina alfa2beta1/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfoproteínas Fosfatasas/fisiología , Linfocitos T/citología , Receptor fas/fisiología , Colágeno Tipo I/fisiología , Activación Enzimática , Humanos , Células Jurkat , Proteína Fosfatasa 2 , Linfocitos T/enzimologíaRESUMEN
BACKGROUND: A cost-sharing drug insurance plan has been implemented among people receiving social assistance who had previously free access to medications. OBJECTIVE: To assess the impact of this drug plan on the use of three classes of medications: inhaled corticosteroids, neuroleptics and anticonvulsants. METHODS: From the computerized drug databases of the Régie de l'assurance maladie du Québec (RAMQ), we selected three random samples of Quebec residents receiving social assistance between August 1992 and June 1997 and aged 64 years or less: 55890 users of inhaled corticosteroids, 29461 users of neuroleptics and 44916 users of anticonvulsants. We also obtained data for individuals privately insured by the Commission de la construction du Québec (control group). Comparison of the monthly consumption of medications before and after the new drug plan was done using time series models. RESULTS: For individuals receiving social assistance and using inhaled corticosteroids, we observed a statistically significant decrease of 37% of the monthly consumption for the 11 months following the new drug plan. For neuroleptics and anticonvulsants, we observed a non significant decrease of 9 and 10%, respectively. No decrease in drug consumption was observed in the control group. CONCLUSION: Inhaled corticosteroids was the only class of medications that was found to decrease significantly after the implementation of the drug insurance plan.