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OBJECTIVES: Tumor necrosis factor-α plays a central role in chronic intestinal inflammation of Crohn’s disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohn’s disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohn’s disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohn’s disease. METHODS: Fifteen consecutive children (mean age 12.8 ± 3.2 yr) with medically refractory Crohn’s disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohn’s Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response. RESULTS: In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients. CONCLUSIONS: Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohn’s disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohn’s disease.

Kashin–Beck disease is an osteoarthropathy of uncertain cause that is endemic in Tibet and other areas of China, Siberia, and North Korea — areas where selenium deficiency is also endemic. 1 Affected subjects have varying degrees of joint deformation and limited joint mobility. In the most severe cases, there is necrosis of growth plates and joint cartilage, resulting in decreased limb length and short stature. Osteoarthropathy usually becomes evident between the ages of 5 and 15 years. The disorder is probably of environmental origin. It has been reported in white migrants to the areas of endemic disease, 1 and clinical and radiologic . . .

Epidemiological studies of pediatric inflammatory bowel diseases (IBD) are needed to generate etiological hypotheses and inform public policy; yet, rigorous population-based studies of the incidence and natural history of Crohn's disease (CD) and ulcerative colitis (UC) in the United States are limited. We developed a field-tested prospective system for identifying all new cases of IBD among Wisconsin children over an 8-year period (2000-2007). Subsequently, at the end of the study period, we retrospectively reconfirmed each case and characterized the clinical course of this incident cohort. The annual incidence of IBD among Wisconsin children was 9.5 per 100,000 (6.6 per 100,000 for CD and 2.4 per 100,000 for UC). Approximately 19% of incident cases occurred in the first decade of life. Over the 8-year study period, the incidence of both CD and UC remained relatively stable. Additionally, (1) childhood IBD affected all racial groups equally, (2) over a follow-up of 4 years, 17% of patients with CD and 13% of patients with patients with UC required surgery, and (3) 85% and 40% of children with CD were treated with immunosuppressives and biologics, respectively, compared with 62% and 30% of patients with UC. As in other North American populations, these data confirm a high incidence of pediatric-onset IBD. Importantly, in this Midwestern U.S. population, the incidence of CD and UC seems to be relatively stable over the last decade. The proportions of children requiring surgery and undergoing treatment with immunosuppressive and biological medications underscore the burden of these conditions.

Tumor necrosis factor-α plays a central role in chronic intestinal inflammation of Crohn's disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohn's disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohn's disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohn's disease. Fifteen consecutive children (mean age 12.8 ± 3.2 yr) with medically refractory Crohn's disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response. In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients. Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohn's disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohn's disease.

INTRODUCTION:VEO - Inflammatory bowel disease (IBD), in children younger than 6 years of age, is frequently associated with a more severe course and distinct genetic profile compared with later onset IBD. We report the case of a child with VEO - UC complicated with PSC and HLH/MAS.CASE DESCRIPTION/METHODS:A 10-year-old male, presented with bloody diarrhea, hepatomegaly and elevated transaminases when he was 30 months old. He had moderate pancolitis associated with C difficile (Cdiff) infection. He improved after metronidazole and sulfasalazine (SFZ) treatment. Two months later, he had hematochezia and endoscopic worsening of his colitis, which improved after discontinuing SFZ and receiving steroids and 6-MP. MRCP was consistent with PSC (Figure 1) and he was started on ursodiol. At ∼ 7 years of age, while receiving treatment with 6MP and Infliximab, he was hospitalized due to fever, hepatomegaly, diarrhea and pancytopenia. Blood and stool cultures, and tests for Cdiff, EBV, CMV, rota and parvovirus were negative. Triglyceride and ferritin levels were normal. He improved clinically and his pancytopenia resolved after 5 days of empirical antibiotic treatment (AbTx). Bone marrow biopsy (BMBx) was deferred. Metabolites of 6MP were normal but 6MP was held temporarily. Six months later, he had fever and diarrhea associated with pancytopenia and high levels of ESR, CRP, ferritin, triglyceride and interleukin 2 receptor. Number and function of NK cells were decreased. Stools and blood cultures, and tests for EBV, HSV and CMV were negative. Cdiff stool antigen was positive but PCR was negative. BMBx showed histiocytosis and erythophagocytosis (Figure 2). Lymphocyte flow cytometry was negative for lymphoproliferative disorder. After AbTx he improved and pancytopenia and ferritin level corrected within one week. Routine immunodeficiency tests were normal. Gene mutations associated with familial HLH: PRF1, Rab27A, SH2D1A, STX11, STXBP2, UNC 13D and XIAP were negative. 6MP was held. Infliximab initially, and subsequently Adalimubab, were discontinued because of high antibodies and allergic reactions. Five months later 6MP was restarted. He has been in remission of UC for 16 months.DISCUSSION:HLH/MAS is a very rare, potentially fatal complication in IBD patients. Our patient has a history of VEO - UC, PSC and two episodes of pancytopenia not associated with EBV or CMV - one of which fulfilled criteria for HLH/MAS. Remarkably, he recovered within one week after empirical AbTx without steroids or other treatment for HLH/MAS.

The aim of this research is to analyze Attention Deficit Hyperactivity Disorder Rating Scales IV (ADHD RS-IV) criteria validity and its clinical usefulness for the assessment of Attention Deficit Hyperactivity Disorder (ADHD) as a function of assessment method and age. A sample was obtained from an epidemiological study (n = 1095, 6-16 years). Clinical cases of ADHD (ADHD-CL) were selected by dimensional ADHD RS-IV and later by clinical interview (DSM-IV). ADHD-CL cases were compared with four categorical results of ADHD RS-IV provided by parents (CATPA), teachers (CATPR), either parents or teachers (CATPAOPR) and both parents and teachers (CATPA&PR). Criterion validity and clinical usefulness of the answer modalities to ADHD RS-IV were studied. ADHD-CL rate was 6.9% in childhood, 6.2% in preadolescence and 6.9% in adolescence. Alternative methods to the clinical interview led to increased numbers of ADHD cases in all age groups analyzed, in the following sequence: CATPAOPR> CATPRO> CATPA> CATPA&PR> ADHD-CL. CATPA&PR was the procedure with the greatest validity, specificity and clinical usefulness in all three age groups, particularly in the childhood. Isolated use of ADHD RS-IV leads to an increase in ADHD cases compared to clinical interview, and varies depending on the procedure used.

Epidemiological studies of pediatric inflammatory bowel diseases (IBD) are needed to generate etiological hypotheses and inform public policy; yet, rigorous population-based studies of the incidence and natural history of Crohn's disease (CD) and ulcerative colitis (UC) in the United States are limited.MethodsWe developed a field-tested prospective system for identifying all new cases of IBD among Wisconsin children over an 8-year period (2000–2007). Subsequently, at the end of the study period, we retrospectively reconfirmed each case and characterized the clinical course of this incident cohort.ResultsThe annual incidence of IBD among Wisconsin children was 9.5 per 100,000 (6.6 per 100,000 for CD and 2.4 per 100,000 for UC). Approximately 19% of incident cases occurred in the first decade of life. Over the 8-year study period, the incidence of both CD and UC remained relatively stable. Additionally, (1) childhood IBD affected all racial groups equally, (2) over a follow-up of 4 years, 17% of patients with CD and 13% of patients with patients with UC required surgery, and (3) 85% and 40% of children with CD were treated with immunosuppressives and biologics, respectively, compared with 62% and 30% of patients with UC.ConclusionsAs in other North American populations, these data confirm a high incidence of pediatric-onset IBD. Importantly, in this Midwestern U.S. population, the incidence of CD and UC seems to be relatively stable over the last decade. The proportions of children requiring surgery and undergoing treatment with immunosuppressive and biological medications underscore the burden of these conditions.

The reversibility of thyroid dysfunction in children with endemic cretinism treated with supplemental iodine is unknown. To study this question we conducted a five-month follow-up of 51 patients with cretinism (age 14 and below), who were randomly assigned to treatment (0.5 ml of intramuscular iodized oil) and control groups. The geometric mean initial serum level of thyrotropin (223 μU per milliliter; SD, 97 to 513) and the mean (±SD) initial serum level of thyroxine (1.0±1.2 μg per deciliter) indicated that all patients had severe hypothyroidism. Within one month after receiving the iodized oil, 13 of 14 of the younger patients (<4 years) and 1 of 9 of the older patients (4 to 14 years; P<0.001) had thyrotropin values below 20 μU per milliliter. Five months after treatment, the levels of thyrotropin had decreased and those of thyroxine had increased in all children, but greater changes occurred in the 13 younger patients than in the 14 older patients. The mean levels of thyrotropin were 2 μU per milliliter (SD, 0.6 to 6) vs. 38 μU per milliliter (SD, 11 to 132; P<0.001), and the mean (±SD) levels of thyroxine were 13.1±2.8 vs. 8.1±4.6 μg per deciliter (P<0.001). In the untreated group, 3 of the 9 younger patients and none of the 15 older patients recovered normal thyroid function within five months. We conclude that iodine supplementation restored a biochemically euthyroid state in all younger children with cretinism but only some of the older children. In addition, some younger patients became euthyroid without iodine supplementation. (N Engl J Med 1986; 315: 791–5.) Endemic cretinism constitutes the principal public health problem associated with iodine deficiency. 1 , 2 This syndrome has two clinical presentations. 3 Neurologic cretinism is characterized by mental deficiency, spastic diplegia, an ataxic gait, abnormal hearing, and strabismus; it is not necessarily associated with either stunted growth or hypothyroidism. Myxedematous cretinism is characterized by various levels of mental deficiency, stunted growth, and overt hypothyroidism; neurologic signs are discrete or absent. The distribution of the two forms varies substantially according to the endemic area, and mixed forms are also encountered. 1 In Zaire, the myxedematous form accounts for most cases of cretinism. 4 The pathogenesis is poorly . . .

The neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning suggesting that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar further supporting the notion that differences in reward response in each paradigm are due to differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons such as dopamine cell number and size were similar in the VTA and SN but there were age differences in baseline firing rate, stimulated release and correlated spike activity suggesting that differences in reward responsiveness by adolescent dopamine neurons are not due to differences in intrinsic properties of these neurons but engagement of different networks.

Main Objective: To look for a reduced model of symptoms of the attention deficit hyperactivity disorder combined type (ADHD-C), that shows suitable levels of criterion validity for the diagnostic of the disease. Methods: Epidemiological study. Sample of 1095 children between 6 and 16 years. First stage: psicometric study using ADHD RS-IV answered by parents (P) and teachers (T). ADHD is suspected when both questionnaires are over 90th percentile. Second stage: Clinical interview DISC-IV (DSM-IV) only in those selected cases to confirm ADHD-C. Logistic regression is implemented to find the most parsimonious model to predict ADHD-C. Results: The model that predicts clinical ADHD-C consists of 8 of the 36 items of the ADHD RS-IV answered by P and T. If we consider the Odds Ratio obtained by regression, the items present a ranking of: 15 T> 1 P> 16 T> 12 P> 17 P> 10 P> 14 P> 4 T. The model has criterion validity for symptomatic ADHD-C (sensitivity: 97.9%. Specificity: 93.8%. Likelihood ratio: 16.02). Conclusions: It is possible to reduce the list of symptoms of ADHD-C with good criterion validity, removing redundant items and keeping those that provide greater discrimination between ADHD-C and the general population.