RESUMEN
INTRODUCTION: Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor. OBJECTIVES: To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy. RESULTS: Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy ("ganglionopathy"). All patients harbored at least one c.1528G>C mutation. DISCUSSION: We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy.
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Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/diagnóstico , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/etiología , Rabdomiólisis/complicaciones , Rabdomiólisis/diagnóstico , Adulto , Factores de Edad , Cardiomiopatías/patología , Femenino , Humanos , Errores Innatos del Metabolismo Lipídico/patología , Masculino , Persona de Mediana Edad , Miopatías Mitocondriales/patología , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso Periférico/patología , Fenotipo , Rabdomiólisis/patología , Adulto JovenRESUMEN
BACKGROUND: Nociceptin in the peripheral circulation has been proposed to have an immunoregulatory role with regards to inflammation and pain. However, the mechanisms involved in its regulation are still not clear. The aim of this study was to investigate signalling pathways contributing to the regulation of the expression of nociceptin under inflammatory conditions. METHODS: Mono Mac 6 cells (MM6) were cultured with or without phorbol-12-myristate-13-acetate (PMA). Prepronociceptin (ppNOC) mRNA was detected by RT-qPCR and extracellular nociceptin by fluorescent-enzyme immunoassay. Intracellular nociceptin and phosphorylated kinases were measured using flow cytometry. To evaluate the contribution of various signalling pathways to the regulation of ppNOC mRNA and nociceptin protein, cells were pre-treated with specific kinase inhibitors before co-culturing with PMA. RESULTS: ppNOC mRNA was expressed in untreated MM6 at low concentrations. Exposure of cells to PMA upregulated ppNOC after nine h compared with controls without PMA (median normalized ratio with IQR: 0.18 (0.15-0.26) vs. 0 (0-0.02), P<0.01). Inhibition of mitogen-activated protein kinases specific for signal transduction reversed the PMA effects (all P<0.001). Induction of nociceptin protein concentrations in PMA stimulated MM6 was prevented predominantly by identity of ERK inhibitor (P<0.05). CONCLUSIONS: Upregulation of nociceptin expression by PMA in MM6 cells involves several pathways. Underlying mechanisms involved in nociceptin expression may lead to new insights in the treatment of pain and inflammatory diseases.
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Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Péptidos Opioides/biosíntesis , Inhibidores de Proteínas Quinasas/farmacología , Acetato de Tetradecanoilforbol/farmacología , Línea Celular Tumoral , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Humanos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos , NociceptinaRESUMEN
The present study investigated maternal emotion regulation as mediating the association between maternal posttraumatic stress symptoms and children's emotional dysregulation in a community sample of 431 Israeli mothers and children exposed to trauma. Little is known about the specific pathways through which maternal posttraumatic symptoms and deficits in emotion regulation contribute to emotional dysregulation. Inspired by the intergenerational process of relational posttraumatic stress disorder (PTSD), in which posttraumatic distress is transmitted from mothers to children, we suggest an analogous concept of relational emotion regulation, by which maternal emotion regulation problems may contribute to child emotion regulation deficits. Child emotion regulation problems were measured using the Child Behavior Checklist-Dysregulation Profile (CBCL-DP; T.M. Achenbach & I. Rescorla, 2000), which is comprised of three subscales of the CBCL: Attention, Aggression, and Anxiety/Depression. Maternal PTSD symptoms were assessed by the Posttraumatic Diagnostic Scale (E.B. Foa, L. Cashman, L. Jaycox, & K. Perry, 1997) and maternal emotion regulation by the Difficulties in Emotion Regulation Scale (K.L. Gratz & L. Roemer, 2004). Results showed that the child's emotion regulation problems were associated with both maternal posttraumatic symptoms and maternal emotion dysregulation. Further, maternal emotion regulation mediated the association between maternal posttraumatic symptoms and the child's regulation deficits. These findings highlight the central role of mothers' emotion regulation skills in the aftermath of trauma as it relates to children's emotion regulation skills. The degree of mothers' regulatory skills in the context of posttraumatic stress symptoms reflects a key process through which the intergenerational transmission of trauma may occur. Study results have critical implications for planning and developing clinical interventions geared toward the treatment of families in the aftermath of trauma and, in particular, the enhancement of mothers' emotion regulation skills after trauma.
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Emociones , Madres/psicología , Psicología Infantil , Trastornos por Estrés Postraumático , Niño , Trastornos de la Conducta Infantil , Preescolar , Femenino , Humanos , Entrevistas como Asunto , Israel , Relaciones Madre-Hijo , ViolenciaRESUMEN
Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.
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Transcobalaminas/deficiencia , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Hidroxocobalamina/uso terapéutico , Lactante , Recién Nacido , Masculino , Mutación , Resultado del Tratamiento , Vitamina B 12/uso terapéuticoRESUMEN
Patients with glutaric aciduria type 1, without early diagnosis and initiation of preventive treatment, often develop movement disorders and various degrees of motor disability due to striatal area-specific damage induced by an acute episode of metabolic decompensation. The neuroimaging phenotype of patients with glutaric aciduria type 1 includes characteristic cyst-like bilateral enlargement of the Sylvian fissures and anterior subarachnoid spaces and signal abnormalities including supratentorial white matter and deep gray matter structure T2 hyperintensities, frequently associated with restricted diffusion. In this retrospective study, we add to the neuroimaging spectrum of glutaric aciduria type 1, a novel imaging finding present regardless of a previous metabolic crisis: the enlargement of the optic chiasm associated with signal abnormalities in the anterior intracranial visual structures observed in 6 of 10 patients. These optic pathway abnormalities are suggested as useful diagnostic clues for glutaric aciduria type 1, and possible pathophysiologic mechanisms are discussed.
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Errores Innatos del Metabolismo de los Aminoácidos , Personas con Discapacidad , Trastornos Motores , Encefalopatías Metabólicas , Glutaril-CoA Deshidrogenasa/deficiencia , Humanos , Imagen por Resonancia Magnética , Quiasma Óptico/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
OBJECTIVES: To assess the ability of efficacy measures that incorporate onset or sustainability to detect treatment effect or reflect patient satisfaction, using exploratory analyses of data from the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate Responders) trial. METHODS: 218 abatacept- and 99 placebo-treated patients were evaluated. Reporting methods included time to onset (first American College of Rheumatology [ACR] 50 response/Low Disease Activity State [LDAS; DAS28 < or =3.2]) and sustainability of ACR50/LDAS, both assessed according to discriminatory capacity (number of patients needed to study [NNS]) and patient satisfaction with treatment. RESULTS: Efficacy measures incorporating elements of sustainability or onset decreased discriminatory capacity, while sustainability, but not onset of action, was important in reflecting patient satisfaction. CONCLUSIONS: Optimal assessment methods depend on whether the outcome of interest is ability to detect treatment effects or to reflect patient satisfaction. Sustainability of response (and possibly, at a lower magnitude, fast onset of action) may be important when evaluating patient satisfaction with RA therapies in patients who have previously failed anti-TNF therapy.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Inmunoconjugados/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Abatacept , Bases de Datos Factuales , Humanos , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Índice de Severidad de la Enfermedad , Insuficiencia del TratamientoRESUMEN
OBJECTIVE: To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo controlled, 24-week trial. METHODS: Patients received adalimumab 40 mg every other week (eow) or placebo for 24 weeks in ATLAS. At week 24, patients were switched to open-label adalimumab 40 mg eow. Efficacy measures included 20% improvement in the Assessment in SpondyloArthritis International Society (ASAS) criteria (ASAS20), ASAS40 and ASAS partial remission responses and changes in individual components of the ASAS20 response evaluations, for example, Bath AS Functional Index (BASFI) and Bath AS Disease Activity Index (BASDAI). Two-year interim data were analysed based on the total duration of adalimumab exposure, irrespective of the treatment randomisation group. RESULTS: At 2 years, 255 (82.0%) of the original 311 ATLAS patients continued receiving adalimumab treatment. Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment; 64.5% (200/310) were ASAS20 responders, 50.6% (157/310) were ASAS40 responders and 33.5% (104/310) had maintained ASAS-defined partial remission. Changes in individual ASAS response components were sustained or improved during long-term adalimumab treatment. From ATLAS baseline to 2 years of adalimumab exposure, respectively, BASDAI improved from 6.3 (SD 1.7) to 2.4 (SD 2.3) and BASFI improved from 5.2 (SD 2.4) to 2.9 (SD 2.5). Adalimumab was well tolerated. No cases of tuberculosis, congestive heart failure, lupus-like symptoms, or demyelinating disease were reported. CONCLUSIONS: Adalimumab reduced the signs and symptoms of AS and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile. Trial registration information: NCT00085644.
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Espondilitis Anquilosante/tratamiento farmacológico , Adalimumab , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Estudios de Seguimiento , Indicadores de Salud , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Inducción de Remisión , Columna Vertebral/fisiopatología , Espondilitis Anquilosante/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: To validate and compare the definition of the Disease Activity Score 28 based on C-reactive protein (DAS28 (CRP)) to the definition based on erythrocyte sedimentation rate (ESR). METHODS: Data were analysed from two randomised, double-blind, placebo-controlled trials of abatacept of 6-month and 12-month duration in patients with rheumatoid arthritis. European League Against Rheumatism (EULAR) response criteria and the proportion of patients in remission (DAS28 <2.6) based on the two DAS28 definitions were examined. Trends in radiographic progression (erosion score, joint space narrowing score and total score) and physical function (Health Assessment Questionnaire Disability Index (HAQ-DI)) across the EULAR responder states (none, moderate and good) were analysed. RESULTS: There was general agreement in determining the EULAR responder state using both DAS28 definitions (kappa = 0.80, 95% CI 0.76 to 0.83). Overall, there was 82.4% agreement on the EULAR response criteria; when disagreements occurred, the DAS28 (CRP) yielded a better EULAR response more often then DAS28 (ESR) (12.6% vs 4.9%, respectively). There was also agreement in determining remission: kappa = 0.69 (95% CI 0.60 to 0.78). Radiographic progression decreased in patients treated with abatacept across EULAR states (from none to moderate to good) based on both definitions. For patients treated with placebo, the trend was not as pronounced, with radiographic scores higher for moderate vs non-responders. For physical function, similar trends were observed across the EULAR states for both DAS28 definitions. CONCLUSIONS: The DAS28 (CRP) has been validated against radiographic progression and physical function. While the DAS28 (CRP) yielded a better EULAR response more often than the DAS28 (ESR), the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Abatacept , Enfermedad Aguda , Adulto , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico por imagen , Artrografía , Biomarcadores/sangre , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , Ensayos Clínicos Fase III como Asunto , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. TRIAL REGISTRATION NUMBER: NCT00175877.
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Artritis Reumatoide/tratamiento farmacológico , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Metotrexato/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/inmunología , Artrografía , Coagulación Sanguínea/efectos de los fármacos , Certolizumab Pegol , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Fragmentos Fab de Inmunoglobulinas/efectos adversos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
OBJECTIVES: To evaluate different methods of reporting response to treatment or disease status for their ability to discriminate between active therapy and placebo, or to reflect structural progression or patient satisfaction with treatment using an exploratory analysis of the Abatacept in Inadequate Responders to Methotrexate (AIM) trial. METHODS: 424 active (abatacept approximately 10 mg/kg) and 214 placebo-treated patients with rheumatoid arthritis (RA) were evaluated. METHOD: of reporting included: (1) response (American College of Rheumatology (ACR) criteria) versus state (disease activity score in 28 joints (DAS28) criteria); (2) stringency (ACR20 vs 50 vs 70; moderate disease activity state (MDAS; DAS28 <5.1) vs low disease activity state (LDAS; DAS28
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Inmunoconjugados/uso terapéutico , Abatacept , Enfermedad Crónica , Análisis Discriminante , Progresión de la Enfermedad , Método Doble Ciego , Humanos , Metotrexato/uso terapéutico , Satisfacción del Paciente , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. METHODS: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose. RESULTS: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). CONCLUSION: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. TRIAL REGISTRATION NUMBER: NCT00124982.
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Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Abatacept , Adulto , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/sangre , Enfermedades Autoinmunes/inducido químicamente , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/inducido químicamente , Infecciones Oportunistas/inducido químicamente , Calidad de Vida , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
The click-evoked electrical responses of the human cochlear nerve were recorded from the external ear canal concurrently with the cortical evoked potentials from the scalp. Paying attention to the clicks during a discrimination task resulted in a highly significant enhancement of the cortical response but no change in the cochlear nerve response. Hence no evidence was obtained for the operation of a peripheral gating mechanism during attention in man.
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Percepción Auditiva , Umbral Auditivo , Audición , Potenciales de Acción , Atención , Corteza Auditiva/fisiología , Corteza Cerebral/fisiología , Nervio Coclear/fisiología , Electrodos , Potenciales Evocados , Humanos , Núcleo Olivar/fisiología , Lectura , SonidoRESUMEN
Failure rates observed (13 +/- 6 percent for school failures, 17 +/- 5 percent for scores below 95 on a collective IQ test) were far below those expected from the social class of birth (55 percent, 51 percent) or observed in a control group (56 +/- 8 percent, 49 +/- 9 percent) but close to those expected from the social class of adoption (15 percent, 15 percent).
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Adopción , Inteligencia , Humanos , Pruebas de Inteligencia , Factores Socioeconómicos , Escalas de WechslerRESUMEN
Diabetes mellitus is occasionally observed in patients with skeletal muscle respiratory chain deficiency, suggesting that skeletal muscle mitochondrial dysfunction might play a pathogenic role in type 2 diabetes (T2D). In support of this hypothesis, decreased muscle mitochondrial activity has been reported in T2D patients and in mouse models of diabetes. However, recent work by several groups suggests that decreased muscle mitochondrial function may be a consequence rather than a cause of diabetes, since decreased mitochondrial function in mice affords protection from diabetes and obesity. We review the data on this controversial but important issue of potential links between mitochondrial dysfunction and diabetes.
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Diabetes Mellitus Tipo 2/etiología , Mitocondrias Musculares/fisiología , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Células Secretoras de Insulina/fisiología , Ratones , Mitocondrias Musculares/metabolismo , Enfermedades Mitocondriales/complicaciones , Modelos Biológicos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Transducción de Señal/fisiologíaRESUMEN
UNLABELLED: Hyperargininaemia is a rare inborn error of metabolism due to a defect in the final step of the urea cycle. Infantile onset is the most common presentation with recurrent vomiting and psychomotor delay associated with spastic paraparesis; chronic hyperammonaemia is often overlooked. Neonatal and early-onset presentations are very uncommon and their clinical course not well-described. We report on a 3-week-old hyperargininaemic girl who presented with neurological deterioration associated with liver failure and 47-day ammonia intoxication before diagnosis could be made and treatment started. Despite appropriate but delayed treatment, our patient exhibited severe psychomotor delay at age 1 year. CONCLUSION: Early identification and management of this rare but potentially treatable affection is crucial as delayed management may result in poor neurological outcome.
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Hiperargininemia/diagnóstico , Edad de Inicio , Diagnóstico Tardío , Dieta con Restricción de Proteínas , Diagnóstico Precoz , Femenino , Humanos , Hiperargininemia/complicaciones , Hiperargininemia/patología , Lactante , Recién Nacido , Trastornos Psicomotores/etiologíaRESUMEN
OBJECTIVES: This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo. The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score (based on erythrocyte sedimentation rates; DAS28 (ESR)) for the abatacept vs placebo groups at day 197. METHODS: Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) were randomised 3:3:2 to abatacept ( approximately 10 mg/kg every 4 weeks, n = 156), infliximab (3 mg/kg every 8 weeks, n = 165), or placebo (every 4 weeks, n = 110) and background MTX. Safety and efficacy were assessed throughout the study. RESULTS: Similar patient demographics and clinical characteristics were present at baseline between groups, with mean scores of approximately 1.7 for HAQ-DI and 6.8 for DAS28 (ESR). At 6 months, mean changes in DAS28 (ESR) were significantly greater for abatacept vs placebo (-2.53 vs -1.48, p<0.001) and infliximab vs placebo (-2.25 vs -1.48, p<0.001). For abatacept vs infliximab treatment at day 365, reductions in the DAS28 (ESR) were -2.88 vs -2.25. At day 365, the following response rates were observed for abatacept and infliximab, respectively: American College of Rheumatology (ACR) 20, 72.4 and 55.8%; ACR 50, 45.5 and 36.4%; ACR 70, 26.3 and 20.6%; low disease activity score (LDAS), 35.3 and 22.4%; DAS28-defined remission, 18.7 and 12.2%; good European League Against Rheumatism (EULAR) responses, 32.0 and 18.5%; and Health Assessment Questionnaire Disability Index (HAQ-DI), 57.7 and 52.7%. Mean changes in physical component summary (PCS) were 9.5 and 7.6, and mental component summary (MCS) were 6.0 and 4.0, for abatacept and infliximab, respectively. Over 1 year, adverse events (AEs) (89.1 vs 93.3%), serious AEs (SAEs) (9.6 vs 18.2%), serious infections (1.9 vs 8.5%) and discontinuations due to AEs (3.2 vs 7.3%) and SAEs (2.6 vs 3.6%) were lower with abatacept than infliximab. CONCLUSIONS: In this study, abatacept and infliximab (3 mg/kg every 8 weeks) demonstrated similar efficacy. Overall, abatacept had a relatively more acceptable safety and tolerability profile, with fewer SAEs, serious infections, acute infusional events and discontinuations due to AEs than the infliximab group. TRIAL REGISTRATION NUMBER: NCT00095147.
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Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Abatacept , Adulto , Análisis de Varianza , Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/uso terapéutico , Artritis Reumatoide/inmunología , Artritis Reumatoide/psicología , Sedimentación Sanguínea , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunosupresores/efectos adversos , Infliximab , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Placebos , Calidad de Vida , Seguridad , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). DESIGN: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). RESULTS: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. CONCLUSION: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. TRIAL REGISTRATION NUMBER: NCT00085644.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Espondilitis Anquilosante/tratamiento farmacológico , Adalimumab , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antirreumáticos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis. METHODS: Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept approximately 10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years. RESULTS: 317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (< or = 3.2) and DAS28 (C-reactive protein)-defined remission (< 2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment. CONCLUSION: No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease. TRIAL REGISTRATION NUMBER: NCT00124982.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Abatacept , Adulto , Anciano , Antirreumáticos/efectos adversos , Artritis Reumatoide/complicaciones , Enfermedades Autoinmunes/inducido químicamente , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Neoplasias/inducido químicamente , Infecciones Oportunistas/complicaciones , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Neurological crises do not occur in patients with tyrosinaemia type I treated with NTBC. We report an 8 month-old boy with severe neurological crisis after interruption of NTBC treatment including progressive ascending polyneuropathy and diaphragmatic paralysis, arterial hypertension, respiratory distress requiring mechanical ventilation who later also developed impaired liver function and tubulopathy. After re-introduction of NTBC the patient slowly regained normal neurological functions and recovered completely.
Asunto(s)
Ciclohexanonas/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Nitrobenzoatos/administración & dosificación , Polineuropatías/etiología , Parálisis Respiratoria/etiología , Tirosinemias/tratamiento farmacológico , Esquema de Medicación , Humanos , Hipertensión/etiología , Lactante , Masculino , Cumplimiento de la Medicación , Polineuropatías/fisiopatología , Polineuropatías/terapia , Respiración Artificial , Insuficiencia Respiratoria/etiología , Parálisis Respiratoria/fisiopatología , Parálisis Respiratoria/terapia , Tirosinemias/complicaciones , Tirosinemias/diagnósticoRESUMEN
OBJECTIVE: To evaluate the risk of adverse maternal and perinatal outcomes among pregnant women hospitalised following falls. DESIGN: A population-based retrospective cohort study. SETTING: Washington State, USA. POPULATION: Pregnant women with a fetal death or live birth certificate linked to the hospitalisation discharge data from 1987 to 2004. METHODS: Pregnant women who experienced a fall (n = 693) were identified by the presence of an International Classification of Disease-9th Edition external causation code of E880 through E888 and were compared with a randomly chosen group of pregnant women (n = 2079) not experiencing a fall hospitalisation during pregnancy. Poisson regression analysis was used to estimate adjusted relative risks (RR) and 95% CI for associations between falls and pregnancy outcomes. MAIN OUTCOME MEASURES: Preterm labour and delivery, placental abruption, fetal distress, and fetal hypoxia. RESULTS: This study found an incidence rate of 48.9 pregnant fall hospitalisations per 100 000 deliveries. The majority of the fall hospitalisations occurred in the third trimester (79.3%), with 11.3% in the second trimester and 9.4% in the first trimester. The majority of injuries due to falls were fractures (47.4%), especially of the lower extremity, followed by contusions (18.0%) and sprains (17.3%). Falls were associated with an increased risk of preterm labour (RR 4.4, 95% CI 3.4-5.7), placental abruption (RR 8.0, 95% CI 4.3-15.0), fetal distress (RR 2.1, 95% CI 1.6-2.8), and fetal hypoxia (RR 2.9, 95% CI 1.3-6.5). CONCLUSION: In light of the increased risk of adverse maternal and perinatal outcomes associated with major falls resulting in hospitalisation, careful maternal and fetal monitoring following a major fall is warranted.