RESUMEN
BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE. PROCEDURE: HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. RESULTS: Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors. CONCLUSIONS: Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Seudoobstrucción Intestinal/terapia , Distrofia Muscular Oculofaríngea/terapia , Oftalmoplejía/congénito , Adolescente , Adulto , Niño , Estudios de Cohortes , Femenino , Humanos , Masculino , Oftalmoplejía/terapia , Linaje , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. METHODS: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. RESULTS: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. CONCLUSIONS: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.
Asunto(s)
Colitis/diagnóstico , Colitis/etiología , Enteritis/diagnóstico , Enteritis/etiología , Eosinofilia/diagnóstico , Eosinofilia/etiología , Gastritis/diagnóstico , Gastritis/etiología , Homocigoto , Proteínas de Microfilamentos/genética , Mutación , Fenotipo , Edad de Inicio , Secuencia de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Proteínas de Microfilamentos/química , Modelos Moleculares , Relación Estructura-Actividad , Secuenciación del ExomaRESUMEN
OBJECTIVES: Loss of the complement inhibitor CD55 leads to a syndrome of early-onset protein-losing enteropathy (PLE), associated with intestinal lymphangiectasia and susceptibility to large-vein thrombosis. The in vitro and short-term treatment benefits of eculizumab (C5-inhibitor) therapy for CD55-deficiency have been previously demonstrated. Here we present the 18-months treatment outcomes for 3 CD55-deficiency patients with sustained therapeutic response. METHODS: Three CD55-deficiency patients received off-label eculizumab treatment. Clinical and laboratory treatment outcomes included frequency and consistency of bowl movements, weight, patient/parent reports of overall well-being, and serum albumin and total protein levels. Membrane attack complex deposition on leukocytes was tested by flow cytometry, before and during eculizumab treatment. RESULTS: Marked clinical improvement was noted in all 3 patients with resolution of PLE manifestations, that is, diarrhea, edema, malabsorption, overall well-being, growth, and quality of life. In correlation with the clinical observations, we observed progress in all laboratory outcome parameters, including increase in albumin and total protein levels, and up to 80% reduction in membrane attack complex deposition on leukocytes (P < 0.001). The progress persisted over 18 months of treatment without any severe adverse events. CONCLUSIONS: CD55-deficiency patients present with early-onset diarrhea, edema, severe hypoalbuminemia, abdominal pain, and malnutrition. Targeted therapy with the terminal complement inhibitor eculizumab has positive clinical and laboratory outcomes in PLE related to CD55 loss-of-function mutations, previously a life-threatening condition. Our results demonstrate the potential of genetic diagnosis to guide tailored treatment, and underscore the significant role of the complement system in the intestine.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígenos CD55/deficiencia , Inactivadores del Complemento/administración & dosificación , Enteropatías Perdedoras de Proteínas/tratamiento farmacológico , Adulto , Niño , Preescolar , Ensayos de Uso Compasivo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Linfangiectasia Intestinal/complicaciones , Linfangiectasia Intestinal/patología , Uso Fuera de lo Indicado , Estudios Prospectivos , Enteropatías Perdedoras de Proteínas/etiología , Calidad de Vida , Inducción de RemisiónRESUMEN
BACKGROUND: Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency. OBJECTIVE: To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years. METHODS: Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function. RESULTS: We identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein's transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected. CONCLUSIONS: Biallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP's importance in EC barrier function in the gut.
Asunto(s)
Proteínas Portadoras/genética , Estudios de Asociación Genética , Homocigoto , Proteínas de la Membrana/genética , Mutación Missense , Fenotipo , Enteropatías Perdedoras de Proteínas/diagnóstico , Enteropatías Perdedoras de Proteínas/genética , Adulto , Sustitución de Aminoácidos , Biomarcadores , Biopsia , Proteínas Portadoras/química , Biología Computacional/métodos , Consanguinidad , Femenino , Humanos , Recién Nacido , Masculino , Proteínas de la Membrana/química , Modelos Moleculares , Linaje , Conformación Proteica , Enteropatías Perdedoras de Proteínas/metabolismo , Relación Estructura-Actividad , Adulto JovenAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD55/genética , Mutación del Sistema de Lectura , Enteropatías Perdedoras de Proteínas/tratamiento farmacológico , Enteropatías Perdedoras de Proteínas/genética , Niño , Preescolar , Ensayos de Uso Compasivo , Activación de Complemento , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Diarrea/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Análisis de Secuencia de ADN , Albúmina Sérica/metabolismo , Adulto JovenRESUMEN
AIM: Our aim was to determine bronchial hyper-responsiveness (BHR) and fractional exhaled NO (FeNO) in a cohort followed and treated for Crohn's disease (CD) in a Pediatric Gastroenterology Unit. METHODS: Consecutive children with CD were referred to the Pediatric Pulmonary Unit. Each patient completed a questionnaire, followed by spirometry, methacholine challenge test (MCT) and determination of FeNO. The control group included patients evaluated for functional cough who had negative MCT. RESULTS: Twenty-three children and young adults (mean age, 17.39 ± 2.96 years) with CD were compared to 24 healthy controls. 20/23 patients received immunomodulating treatment. Forced expiratory volume in 1 sec (FEV1) was significantly lower prior to (93.74 ± 10.81%, p = 0.009) and at the end of (78.91 ± 18.39%, p = 0.001) the MCT in the CD group compared with the control group (102.2 ± 10.477% and 95.33 ± 11.075%, respectively). Bronchial hyper-responsiveness was observed in 30.4% of patients with CD. FeNO levels were 15.37 ± 24.17 in CD and 11.38 ± 5.42 in the control group (p = 0.21). Neither the response to MCT nor FeNO levels were affected by the disease duration or activity index. CONCLUSION: In our series, BHR is less frequent than previously described in children with CD. We hypothesize that our finding could result from immunomodulating treatments or lower disease activity.
Asunto(s)
Hiperreactividad Bronquial/metabolismo , Enfermedad de Crohn/fisiopatología , Óxido Nítrico/metabolismo , Adolescente , Pruebas Respiratorias , Pruebas de Provocación Bronquial , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Femenino , Humanos , Inmunomodulación , Masculino , Espirometría , Adulto JovenRESUMEN
BACKGROUND: Cystic fibrosis (CF) is frequently associated with gastrointestinal complaints that can be due to gastrointestinal dysmotility. Electrogastrography (EGG) is an attractive, non-invasive procedure to assess gastric electric activity. The aims of our study were to investigate EGG abnormalities in pancreatic sufficient and pancreatic insufficient CF patients, and to examine whether EGG correlates with gastric emptying as assessed by scintigraphy. METHODS: EGG was performed in 23 CF patients (12 pancreatic sufficient patients, 11 pancreatic insuffficient) by using cutaneous recording pre- and postprandialy. Pre- and postpostprandial EGG indexes were compared to 19 healthy control patients. Gastric emptying was assessed simultaneously by gastric scintigraphy in 11 of the 23 CF patients. Six patients underwent a repeated scintigraphy recording following a month of treatment with cisapride. RESULTS: Abnormal patterns of EGG were found in 78.3% of CF patients compared to 31.3% of controls during fasting (pAsunto(s)
Fibrosis Quística/complicaciones
, Conductividad Eléctrica
, Vaciamiento Gástrico/fisiología
, Enfermedades Gastrointestinales/diagnóstico
, Motilidad Gastrointestinal/fisiología
, Adolescente
, Adulto
, Niño
, Fibrosis Quística/fisiopatología
, Femenino
, Enfermedades Gastrointestinales/etiología
, Humanos
, Masculino
, Complejo Mioeléctrico Migratorio/fisiología
, Pruebas de Función Pancreática/métodos
, Periodo Posprandial
, Cintigrafía
RESUMEN
OBJECTIVES: Prolonged lamivudine treatment in adults has been shown to improve hepatitis B e (HBe) seroconversion rates in patients with chronic hepatitis B. This prospective open study reports the results of prolonged lamivudine treatment in a group of children with chronic hepatitis B. PATIENTS AND METHODS: Twenty-two children and adolescents age 13.2 years (range, 9.5-18 years), who have been treated with lamivudine for 1 year, continued treatment with lamivudine (3 mg/kg/day, up to 100 mg/d) as long as there was evidence of continued biochemical and virological benefit compared with baseline. We evaluated virological and biochemical responses, the occurrence of YMDD mutants and adverse effects during 4 years of follow-up. RESULTS: After 4 years on lamivudine, only 4 patients (18%) underwent HBe seroconversion. In addition, in 3 patients (13%), the treatment was stopped when lamivudine's lack of efficacy became evident. During the 4-year study period, we recorded a continuing decline in the participants' number, mostly because of lack of compliance with treatment (9/22, 41%). Only 5 children were still receiving lamivudine and showing benefit after 4 years. In 2 children, treatment termination and YMDD mutant emergence were associated with hepatitis flare. Besides subclinical elevation of creatine phosphokinase, no other adverse events were recorded during the study period. CONCLUSIONS: Four years after starting lamivudine treatment, most children from this study were off lamivudine, mainly because of lack of compliance and poor HBe seroconversion. These findings suggest that continuing treatment with lamivudine for undefined periods is hard to implement and does not improve HBe seroconversion.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/uso terapéutico , Adolescente , Alanina Transaminasa/sangre , Niño , Estudios de Seguimiento , Antígenos e de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Hepatitis B Crónica/inmunología , Humanos , Interferones/uso terapéutico , Estudios Prospectivos , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del Tratamiento , Negativa del Paciente al Tratamiento , Carga ViralRESUMEN
OBJECTIVE: The role of insulin in atherosclerosis progression in diabetes is uncertain. We examined the effects of oral insulin supplementation on atherogenesis in apolipoprotein E-deficient (E(0)) mice. METHODS AND RESULTS: One-month-old male E(0) mice were orally supplemented with human insulin (0.1, 0.5, and 1 U/mL) or placebo for 3 months. At the end of the study, serum and macrophage oxidative stress and atherosclerosis progression were studied. Insulin reduced lesion size by 22% to 37% (P<0.05) in all study groups. Lipid peroxides serum levels were 18% lower (P<0.01), and serum paraoxonase activity was 30% higher (P<0.01) in mice supplemented with 1.0 U/mL insulin compared with controls. Insulin reduced mouse peritoneal macrophage (MPM) lipid peroxides content and superoxide anion release by up to 44% and 62%, respectively (P<0.01). In addition, oral insulin reduced MPM cholesterol content and cholesterol biosynthesis by up to 36% and 53%, respectively (P<0.01). In vitro incubation of E(0) mice MPM with increasing insulin concentrations (0 to 100 micro U/mL) resulted in a dose-dependent reduction of cholesterol synthesis by up to 66% (P<0.05). CONCLUSIONS: In E(0) mice, oral insulin supplementation attenuates the atherosclerotic process. This may be attributable to insulin-mediated reduction of oxidative stress in serum and macrophages as well as reduction in macrophage cholesterol content.
Asunto(s)
Apolipoproteínas E/deficiencia , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/genética , Insulina/uso terapéutico , Administración Oral , Animales , Aorta/efectos de los fármacos , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/tratamiento farmacológico , Apolipoproteínas E/genética , Arteriosclerosis/sangre , Arildialquilfosfatasa , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol/biosíntesis , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Esterasas/sangre , Humanos , Insulina/administración & dosificación , Insulina/sangre , Peroxidación de Lípido/efectos de los fármacos , Lípidos/sangre , Macrófagos Peritoneales/química , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. This prospective open study reports the results of lamivudine treatment in children with chronic hepatitis B infection who did not respond to previous interferon treatment. PATIENTS AND METHODS: Lamivudine, 3 mg/kg/day (maximum, 100 mg/day), was given for 52 weeks to 20 children and adolescents, ages 8.5 to 19 years, with chronic hepatitis B infection who had been treated with interferon 2 to 5 years earlier. We evaluated virologic and biochemical responses, the occurrence of YMDD mutants and adverse effects. RESULTS: All children were HBV DNA+, hepatitis B e antigen (HBeAg) /anti-hepatitis B e antibody- at start of treatment. At the end of 1 year, HBV DNA declined by 95% in all patients, and 8 of 18 (44%) had sustained undetectable HBV DNA by hybridization assay. Median pretreatment alanine aminotransferase (ALT) x1.5 upper limit of normal decreased to ALT x0.9 upper limit of normal after 1 year. One child became HBeAg-negative. YMDD mutants were detected in 11 of 17 (65%) children after 1 year of lamivudine treatment. Among children with YMDD mutant variants, 54% maintained normal ALT values and 45% had undetectable HBV DNA by hybridization assay. No adverse effects were observed. CONCLUSIONS: Children with chronic hepatitis B infection treated with lamivudine after failure of interferon therapy had decreased HBV replication and improved ALT values. However, lamivudine treatment resulted in an exceptionally high rate of lamivudine-resistant mutants and low HBeAg seroconversion rate.
Asunto(s)
ADN Viral/análisis , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adolescente , Distribución de Chi-Cuadrado , Niño , ADN Viral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Medicamentos , Femenino , Estudios de Seguimiento , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/diagnóstico , Humanos , Interferones/administración & dosificación , Lamivudine/efectos adversos , Pruebas de Función Hepática , Masculino , Pronóstico , Estudios Prospectivos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Foods, which, in addition to their nutritional attributes, contain also elements that are considered to be health-promoting, have been termed "functional foods". In this regard, human milk has gained recognition as being the ultimate functional food for infants - by its biological compatibility, nutritional value and the undisputed added value of its health promoting qualities. Intensive research activity has recently evolved in a quest to identify and define the components of human milk that might confer disease-preventing and health-enhancing properties and to determine the instances and clinical conditions in which these factors become particularly important. The outcome of such research would also provide a rationale for advocating the supplementation of commercial infant formulas with such substances. In effect, the body of data accumulated from scientific and clinical studies on nucleotides, probiotics, prebiotics and long-chain polyunsaturated fatty acids in human milk and as additives to infant formula, has become regarded as convincing enough by the infant formula industry so as to launch into the market formulas supplemented with one or more of these factors - in an effort to emulate human milk and its beneficial effects. The following review is intended for the reader to obtain a general idea of the new supplements that have been introduced to infant formulas. We summarize the pertinent experimental and clinical observations concerning each of the supplements, pointing out their potential specific benefits, their possible disadvantages and the issues that still remain unresolved.
Asunto(s)
Suplementos Dietéticos , Fórmulas Infantiles/química , Ácidos Grasos Insaturados , Humanos , Lactante , Nucleótidos , ProbióticosRESUMEN
AIM: To study current treatment options for pediatric hepatitis C infection and their associated success rates. METHODS: We retrospectively reviewed charts of thirty children who had been treated with combination therapy of pegylated interferon alfa plus ribavirin for chronic hepatitis C infection. Patients had been treated with ribavirin (15 mg/kg per day) and either pegylated interferon alfa 2a (180 mg/m(2) once weekly) or pegylated interferon alfa 2b (1.5 mg/kg once weekly). Patients' follow-up included subjective assessment of complaints, physical examination including weight and height, as well as laboratory evaluations for viral load [before treatment, at 12 wk, and 6 mo following treatment completion, as determined by sustained viral response (SVR)], complete blood count, liver enzymes, alkaline phosphatase, bilirubin, renal function tests, and thyroid function tests. For patients not achieving a two log decrease in viral load at treatment week 12, treatment was discontinued and the patient was considered a treatment non-responder. RESULTS: Thirty children aged 3-18 years were included in the study. Twenty patients (11 males, 9 females) received pegylated interferon alfa 2b and ten patients (6 males, 4 females) received pegylated interferon alfa 2a. Twenty-three patients were infected with genotype 1, six patients were infected with genotype 3, and one patient was infected with genotype 2. Twenty patients (67%) achieved SVR. Treatment success rates were 90% with pegylated interferon alfa 2a vs 55% with pegylated interferon alfa 2b. Although a trend was noted for improved outcomes in the group receiving pegylated interferon alfa 2a, there were no statistically significant outcome differences between the two treatment groups (P = 0.1). Treatment success was 56.5% for patients infected with genotype 1 virus, compared to 100% for patients infected with other genotypes (P = 0.064). There was no difference in treatment response between males and females. A cut-off age of twelve years was used to dichotomize younger vs older participants; however, no difference in treatment response was observed between these groups. Using multivariate regression analysis, we could not determine predictors for achieving SVR from among the variables we examined (age, sex, and viral genotype). Although we noted a trend toward SVR with peginterferon alfa-2a, there was no statistical difference between the two peginterferons. A high incidence of adverse reactions to treatment was noted. Twenty-five patients (83%) suffered from at least one adverse reaction, but most experienced more than one adverse reaction. All patients except one became leukopenic (white blood cell count less than 5500 leukocytes/µL), six (20%) became anemic (hemoglobin less than 110 g/L), and one (3.3%) became thrombocytopenic (platelets less than 100â 000/µL). CONCLUSION: Combination therapy to treat hepatitis C in children is as effective as in adults. There may be a benefit for treatment with pegylated interferon alfa 2a.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adolescente , Factores de Edad , Antivirales/efectos adversos , Biomarcadores/sangre , Niño , Preescolar , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/diagnóstico , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Modelos Logísticos , Masculino , Polietilenglicoles/efectos adversos , ARN Viral/sangre , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Ribavirina/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVE: To evaluate the validity of quantitative ultrasound bone sonometry (QUBS) as a screening tool for the diagnosis of osteoporosis in children with chronic rheumatic diseases (CRD), compared to the conventional dual energy x-ray absorptiometry (DEXA). METHODS: Forty children with CRD [32 with juvenile idiopathic arthritis (JIA), 6 with systemic lupus erythematosus, and 2 with dermatomyositis] aged 9.9 +/- 4.3 years, were evaluated by QUBS of radius and tibia and DEXA of the lumbar spine. Twenty-five (62.5%) patients were treated with corticosteroids. Measurements of the velocity of the ultrasound wave, expressed as speed of sound (SOS) in m/s, and the results of the bone mineral density (BMD) assessed by DEXA were compared to reference data from healthy age and sex matched Israeli children. RESULTS: Compared to controls, patients with CRD had significantly lower values by QUBS and DEXA alike. BMD and SOS z scores < -1 SD were found in 45% and 38% of the patients, respectively. Reduced BMD and SOS values correlated with age at disease onset and corticosteroid treatment. BMD alone correlated negatively with disease duration and methotrexate therapy. BMD was significantly lower in patients with polyarticular JIA compared to patients with oligoarticular disease (p < 0.03). SOS values did not differ between subtypes of JIA. A significant positive correlation was found between the lumbar DEXA and radius SOS. CONCLUSION: QUBS evaluation of radius and tibia yielded results comparable to DEXA and may therefore be used for screening patients with CRD for osteoporosis. QUBS might represent a promising means of evaluating bone quality in at-risk children.
Asunto(s)
Absorciometría de Fotón/métodos , Densidad Ósea/fisiología , Osteoporosis/diagnóstico , Enfermedades Reumáticas/diagnóstico , Ultrasonografía/métodos , Adolescente , Huesos/diagnóstico por imagen , Niño , Preescolar , Enfermedad Crónica , Femenino , Humanos , Masculino , Osteoporosis/complicaciones , Osteoporosis/metabolismo , Reproducibilidad de los Resultados , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/metabolismoRESUMEN
OBJECTIVES: Only a few reports of nonsyndromic paucity of interlobular bile ducts (NS-PILBD) have been published. The authors' aim was to outline the clinical and laboratory profile of patients with NS-PILBD diagnosed at a tertiary referral center. METHODS: The authors reviewed all the reports of pediatric liver biopsies performed between 1991 and 2000 at their institution. Upon diagnosis of NS-PILBD, patients' records were examined for clinical, laboratory, and histologic data, and liver biopsy specimens were re-evaluated. RESULTS: Three hundred biopsies were performed in children during the study period, of which 64 were in infants younger than 1 year. NS-PILBD was diagnosed in 10 of 64 (16%) biopsy specimens. Mean age at presentation was 10 days (range, 1 day-6 weeks), and mean follow-up was 4.5 years (range, 1-9 years). An underlying condition was identified in 70% of children with NS-PILBD: namely congenital cytomegalovirus (n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), mitochondrial DNA depletion (n = 1), Niemann-Pick type C (n = 1), and arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC syndrome; n = 1). All children presented with jaundice. Four children had initially acholic stools. At their last follow-up visit, failure to thrive was present in five children, and cholestasis in six children. Mortality was noted only in children with metabolic diseases (n = 2). CONCLUSIONS: In the study, NS-PILBD was common in young children undergoing liver biopsy. Although NS-PILBD is nonspecific, a wide survey for inborn errors of metabolism should be included in the diagnostic work-up of NS-PILBD. In the authors' center, the association of certain metabolic diseases with NS-PILBD carries a grave prognosis.
Asunto(s)
Conductos Biliares/anomalías , Artrogriposis/complicaciones , Biopsia , Colestasis Intrahepática/complicaciones , Colestasis Intrahepática/genética , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/congénito , ADN Mitocondrial/análisis , Enfermedades en Gemelos , Femenino , Estudios de Seguimiento , Hematopoyesis Extramedular , Humanos , Lactante , Recién Nacido , Ictericia , Enfermedades Renales/complicaciones , Hígado/patología , Masculino , Enfermedades de Niemann-Pick/complicaciones , SíndromeRESUMEN
OBJECTIVES: Osteoporosis is the most common manifestation of untreated celiac disease (CD). Bone quantitative ultrasound (QUS) has recently emerged as a new modality for bone status assessment. We evaluated bone status in children with CD using dual-energy x-ray absorptiometry and quantitative ultrasound. METHODS: This cross-sectional study included 41 children (13 girls, 28 boys) aged 11.2 +/- 3.6 years with CD. All children had been diagnosed with CD for at least 1 year (mean, 5.7 +/- 4.3 years). The results of lumbar spine bone mineral density assessed by dual-energy x-ray absorptiometry and the measurements of the velocity of ultrasound wave (at distal radius and midshaft tibia sites), expressed as speed of sound in m/s, were compared between children adherent to gluten-free diet (GFD) and non-compliant children. RESULTS: Speed of sound z-scores at tibia were below -2 SD in 20 of 41 children (49%), whereas lumbar spine bone mineral density z-scores were below -2 SD in 4 of 41 (10%) children with CD (P = 0.0002). Only 19 of 41 children were strictly compliant to GFD. The prevalence of tibia speed of sound z-scores <-2 SD was significantly higher in non-compliant children (15 of 22, 68%) compared with children on GFD (5 of 19, 26%), (P = 0.01). Children non-compliant with GFD had significantly worse tibia speed of sound z-scores (-2.3 +/- 1.8, mean +/- SD) compared with children on GFD (-1.2 +/- 1.5, mean +/- SD) (P = 0.04). CONCLUSIONS: Children with CD on a gluten-containing diet had higher prevalence of abnormal tibia bone SOS and lower z-scores compared with children on a GFD. These differences were not detected by spinal dual-energy x-ray absorptiometry or radius speed of sound. The value of quantitative ultrasound for screening and follow-up of children with CD should be further evaluated.
Asunto(s)
Enfermedad Celíaca/complicaciones , Glútenes/administración & dosificación , Osteoporosis/diagnóstico por imagen , Tibia/diagnóstico por imagen , Absorciometría de Fotón/métodos , Adolescente , Densidad Ósea/efectos de los fármacos , Densidad Ósea/fisiología , Estudios de Casos y Controles , Enfermedad Celíaca/fisiopatología , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , Osteoporosis/etiología , Cooperación del Paciente , Radio (Anatomía)/diagnóstico por imagen , Sensibilidad y Especificidad , UltrasonografíaRESUMEN
BACKGROUND: During total parenteral nutrition (TPN), hepatic concentration of the important intracellular antioxidant glutathione (GSH) is decreased. This study sought to determine whether enteral trophic (small quantity) feeding of GSH precursors would increase hepatic GSH levels during TPN and result in decreased peroxidative injury after endotoxin exposure. METHODS: Sprague-Dawley rats received full TPN for 7 days with postpyloric infusions of either (1) amino acid GSH precursors (cysteine, 60 mg/d; glycine, 86 mg/d; glutamate, 31 mg/d; F1); (2) iso-nitrogenous alanine (132 mg/d; F2); or (3) normal saline (SA). Hepatic GSH concentration was measured by gas chromatography/mass spectrometry. In a parallel study, animals were given TPN and either F1 or SA for 7 days, and endotoxin was administered intravenously before death. Hepatic lipid peroxidation and histology were assessed. RESULTS: Hepatic GSH concentration measured 11.7 +/- 0.6 micromol/g in F1. This was significantly higher (P <.001) than in F2 (7.0 +/- 0.8 micromol/g) or SA (5.0 +/- 0.4 micromol/g). F2 and SA were not significantly different. Hepatic malondialdehyde concentration after exposure to endotoxin was significantly higher in SA (10.36 micromol/g +/- 0.65) than in F1 (7.38 micromol/g +/- 0.77; P <.01). All SA animals had histologic evidence of hepatic necrosis, whereas none of the F1 group showed these changes. CONCLUSIONS: Targeted trophic feeding of GSH amino acid precursors during parenteral nutrition markedly increased hepatic GSH concentration. This was associated with decreased lipid peroxidation and enhanced hepatocellular protection after endotoxin challenge. Thus, targeted trophic feedings may aid in the prevention of TPN-related liver disease.