Interaction and influence of child and family characteristics upon success of weight management treatment.

PURPOSE: Interventions to address childhood obesity demonstrate moderate effects at best. Previous research has focused on factors of the intervention that influence success. Yet, effective overweight and obesity interventions require an interaction between family and individual factors. It is vital to characterize those who are successful vs. those who are not within treatment based on these factors. METHODS: This study utilized data from an existing multidisciplinary (i.e., nutrition, physical therapy, psychology, and medicine) group treatment for children with overweight and obesity. Children (N = 113) were given the Behavior Assessment System for Children, the Pediatric Quality of Life Inventory, and completed an interview at baseline, then height and weight were measured at 6 months and 12 months post-intervention. Latent class analysis was used to determine how family and individual characteristics and behavior interact and group together to characterize individuals who lose weight vs. do not lose weight during treatment. RESULTS: The four-cluster model was the best fit for the data. The four identified groups delineated one for whom treatment was successful, and three for whom treatment was not successful. Those three were differentiated by families who appeared to have inconsistent engagement with treatment, families who appeared to not be engaged with treatment, and families who had baseline risk factors that likely require a significantly higher level of treatment. CONCLUSION: Characterizing the differences between those who successfully respond to this treatment from those who were unsuccessful can help identify those most likely to benefit from treatment. Future research and treatment considerations should include treatment modifications for nonresponders. LEVEL OF EVIDENCE: Level III, longitudinal cohort study.

Overview of the epidemiology and management of childhood obesity.

Pediatric obesity is rapidly emerging as a serious chronic disease affecting an increasing number of children worldwide. In this report, we review current aspects of pediatric obesity and obesity related management as it relates to the primary care provider who is often the first line of prevention in pediatric obesity.

Critical analysis of bariatric procedures in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex genetic disorder localized to chromosome 15 and is considered the most common genetic cause of the development of life-threatening obesity. Although some morbidities associated with PWS, including respiratory disturbance/hypoventilation, diabetes, and stroke, are commonly seen in obesity, others such as osteoporosis, growth hormone deficiency, and hypogonadism, and also altered pain threshold and inability to vomit, pose unique issues. Various bariatric procedures have been used to cause gastric stasis, decrease gastric volume, and induce malabsorption, with poor results in PWS patients in comparison with normal obese individuals.

Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma.

Fatal peripheral cholangiocarcinoma developed in 2 girls with progressive familial intrahepatic cholestasis, ABCB11 mutations, and absent bile salt export pump (BSEP) expression. BSEP deficiency may cause cholangiocarcinoma through bile-composition shifts or bile-acid damage within cells capable of hepatocytic/cholangiocytic differentiation. This observation suggests the need for hepatobiliary-malignancy surveillance and early consideration for liver transplantation.

Lack of validity of a French adaptation of a scale measuring attitudes towards clinical practice guidelines.

BACKGROUND: Valid instruments to measure practitioners' attitudes towards clinical practice guidelines need to be developed. However, few of the available instruments have been thoroughly validated. OBJECTIVE: To adapt into French and to test the reliability and validity of a scale for measurement of attitudes towards guidelines developed by Elovainio et al. METHODS: A 27-item scale (divided into six dimensions) measuring attitudes towards guidelines was translated into French by two English native translators, reviewed and finalized by expert committee and administered to 314 practitioners who agreed to participate. Main practitioners' characteristics were collected. Item and dimension reproducibility were assessed for 62 practitioners by calculation of intraclass correlation coefficients. Internal construct validity was assessed by principal components analyses. Convergent and discriminant validity were analysed. RESULTS: Item response rates ranged from 82 to 100%. In the test-retest procedure, intraclass correlation coefficients for separate items ranged from 0.1 to 0.7 and those for dimensions were 0.7 [95% confidence interval (CI): 0.5-0.8] for usefulness, 0.5 (0.3-0.6) for reliability, 0.4 (0.2-0.5) for individual competence, 0.5 (0.3-0.6) for organizational competence, 0.7 (0.5-0.8) for impracticality and 0.4 (0.3-0.6) for availability. The factorial structure after Varimax rotation showed that none of the different solutions obtained had a strictly comparable structure to that of the original scale. External construct validity was satisfactory. CONCLUSION: This scale does not have satisfactory psychometric properties and therefore cannot confidently be used in future research assessing whether attitudes towards guidelines are a determining factor in physicians' compliance with guidelines. More research is needed to develop valid scales in a more rigorous procedure, involving qualitative and quantitative steps.

Role of three FKHR phosphorylation sites in insulin inhibition of FKHR action in hepatocytes.

Insulin inhibits insulin-like growth factor binding protein-1 (IGFBP-1) transcription by preventing FKHR protein family members from binding a specific insulin response element in the IGFBP-1 promoter. In most cells, three serine/threonine moieties in FKHR family members are phosphorylated after insulin treatment or protein kinase B/Akt (PKB) transfection, and each of the three phosphorylated PKB sites contributes to insulin- or PKB-mediated inhibition of both the action and the nuclear localization of FKHR family members. In hepatocytes, however, the middle PKB site (PKB2) of FKHR was required for insulin to phosphorylate FKHR and was the only PKB site that participated in insulin inhibition of FKHR action, indicating that insulin utilizes a unique pathway to regulate FKHR action in hepatocytes. In studies presented here, plasmids expressing native or mutant FKHR forms, either with or without N-terminal fusion to green fluorescent protein (GFP), were transiently transfected into HEP G2 cells. All FKHR forms stimulated IGFBP-1 promoter activity, and mutating any of the three FKHR PKB sites impaired the ability of insulin both to inhibit FKHR-stimulated IGFBP-1 promoter activity and to induce FKHR accumulation in cytoplasm. Thus, in hepatocytes as in other cell lines, all three FKHR PKB sites participate in insulin-mediated inhibition of FKHR action and in insulin-mediated accumulation of FKHR in cytoplasm.

The role of upper gastrointestinal endoscopy in the diagnosis and treatment of caustic ingestion, esophageal strictures, and achalasia in children.

The practice of upper gastrointestinal endoscopy in children continues to evolve. Therapeutic endoscopic procedures are now routinely performed in children. Patient preparation, sedation, and instrumentation have improved, allowing therapeutic endoscopy to be performed for a wide variety of conditions. This article focuses on the role of endoscopy in the diagnosis and care of caustic ingestion, balloon dilation of esophageal strictures, and new developments in the treatment of achalasia in children.

Percutaneous liver biopsy in children: impact of ultrasonography and spring-loaded biopsy needles.

BACKGROUND: Percutaneous liver biopsy is a valued tool of pediatric hepatology. Recent advances in technology have incorporated spring-loaded biopsy needles and ultrasonography in percutaneous liver biopsy. METHODS: To determine the frequency of complications after liver biopsy and whether variables such as needle selections (Jamshidi, Monopty, or ASAP) and ultrasound guidance could predict complications, medical records were retrospectively reviewed of all patients who underwent percutaneous liver biopsy during a 7-year period. Available data were collected from 123 patients who had undergone a total of 249 percutaneous liver biopsies. All patients with evidence of mild clotting abnormalities (8.83%) received platelets, cryoprecipitate, or fresh-frozen plasma. RESULTS: There was a 6.83% incidence of overall complications, and a 2.4% incidence of major complications. The mortality rate was 0.4%. Ultrasound localization did not diminish the risk of bleeding during biopsy. There was no significant difference in the change of hematocrit between the aspiration (Jamshidi) and spring-loaded (Monopty) needles. However, in patients less than 5 years of age, the change of hematocrit was significantly higher (P < 0.05) with the 15- or 18-gauge ASAP needle (Microvasive, Quincy, MA, U.S.A.) than with either the Jamshidi (Allegience Healthcare, Columbia, MD, U.S.A.) or Monopty (Bard Technologies, Covington, GA, U.S.A.) needles. CONCLUSION: Percutaneous liver biopsy is safe, using either aspiration or spring-loaded needles. Ultrasound guidance may not be helpful except in patients who underwent segmental liver transplantation.

FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter.

The insulin response element (IRE) in the IGFBP-1 promoter, and in other gene promoters, contains a T(A/G)TTT motif essential for insulin inhibition of transcription. Studies presented here test whether FKHR may be the transcription factor that confers insulin inhibition through this IRE motif. Immunoblots using antiserum to the synthetic peptide FKHR413-430, RNase protection, and Northerns blots show that FKHR is expressed in HEP G2 human hepatoma cells. Southwestern blots, electromobility shift assays, and DNase I protection assays show that Escherichia coli-expressed GST-FKHR binds specifically to IREs from the IGFBP-1, PEPCK and TAT genes; however, unlike HNF3beta, another protein proposed to be the insulin regulated factor, GST-FKHR does not bind the insulin unresponsive G/C-A/C mutation of the IGFBP-1 IRE. When HEP G2 cells were cotransfected with FKHR expression vectors and with IGFBP-1 promoter plasmids containing either native or mutant IREs, FKHR expression induced a 5-fold increase in activity of the native IGFBP-1 promoter but no increase in activity of promoter constructs containing insulin unresponsive IRE mutants. These data suggest that FKHR, and/or a related family member, is the important T(G/A)TTT binding protein that confers the inhibitory effect of insulin on gene transcription.

Immunosuppressive therapy with microemulsion cyclosporine A shortens the hospitalization of pediatric liver transplant recipients.

Intravenous administration of cyclosporine (Sandimmune) to rapidly and effectively achieve therapeutic serum levels in transplant recipients has been the treatment standard in many transplantation centers. With the development of microemulsion cyclosporine (Neoral), that standard is changing. Neoral has greater bioavailability than the oral form of Sandimmune and, consequently, can be more efficacious and cost-effective. To test this hypothesis, we undertook a retrospective study of Sandimmune and Neoral in the treatment of 66 children who underwent uncomplicated orthotopic liver transplantation in the Texas Medical Center between April 1991 and December 1997. Both forms of cyclosporine were evaluated in terms of in-patient treatment cost, recuperative time in the intensive care unit and duration of hospitalization. Twenty-two patients were treated orally with Neoral, and 44 patients were treated intravenously with Sandimmune for a mean time of 14 d. Once the blood concentration of Sandimmune reached a steady state, as confirmed by daily measurements of the trough level, the patients in the Sandimmune group were converted to oral cyclosporine. None of the 22 patients treated with Neoral required intravenous treatment. The mean time spent in the intensive care unit was 4 d for the Neoral group and 5.5 d for the Sandimmune group. The mean duration of hospitalization from the date of transplantation to discharge was 12 d for the Neoral group and 20 d for the Sandimmune group (p < 0.001). Based on these results, we determined that the overall cost per patient in the Neoral group was $3598 less than that per patient in the Sandimmune group.

Hepatic nuclear factor 3 and high mobility group I/Y proteins bind the insulin response element of the insulin-like growth factor-binding protein-1 promoter.

The insulin response element (IRE) of the human insulin-like growth factor-binding protein-1 (IGFBP-1) promoter contains a palindrome of the T(A/G)TTT sequence crucial to hormonal regulation of many genes. In initial studies of how this IRE participates in hormonal regulation, the electromobility shift assay was used under a variety of conditions to identify IRE-binding proteins. An exhaustive search identified five proteins that specifically bind this IRE; purified proteins were used to show that all five are related to either the high mobility group I/Y (HMGI/Y) or hepatic nuclear factor 3 (HNF3) protein families. Further studies used purified HNF3 and HMGI proteins to show: 1) eah protects the IGFBP-1 IRE from deoxyribonuclease I (DNaseI) digestion; and 2) HNF3 but not HMGI/Y binds to the related phosphoenolpyruvate carboxykinase and Apo CIII IREs. A series of IRE mutants with variable responsiveness to insulin were used to show that the presence of a TGTTT sequence in the mutants did parallel, but HMGI/Y and HNF3 binding to the mutants did not parallel, the ability of the mutants to confer the inhibitory effect of insulin. In contrast, HNF3 binding to these IRE mutants roughly correlates with response of the mutants to glucocorticoids. The way by which HNF3 and/or other as yet unidentified IRE-binding proteins confer insulin inhibition to IGFBP-1 transcription and the role of HMGI/Y in IRE function have yet to be established.

Multiple proteins bind the insulin response element in the human IGFBP-1 promoter.

An insulin response element (IRE) has been identified approximately 100 base pairs (bp) 5' to the transcription start site of the human insulin-like growth factor binding protein-1 (hIGFBP-1) gene. This cis element appears crucial to the multihormonal regulation of hIGFBP-1 expression in liver, since (i) an intact IRE is required for maximal stimulation of hIGFBP-1 promoter activity by dexamethasone, and (ii) the IRE confers insulin inhibition of both basal and dexamethasone-stimulated hIGFBP-1 promoter activity. Further progress in understanding how the IRE confers insulin and glucocorticoid effects requires identification of transcription factors confering effects of these hormones. D-site binding protein (DBP), and members of the hepatic nuclear factor 3 (HNF 3) and high mobility group I/Y (HMG I/Y) protein families, each known to bind DNA elements similar in sequence to the IRE, were tested for IRE binding. DBP, HMGI and HNF 3 beta each protected the hIGFBP-1 IRE from DNAseI digestion. Additional studies are required to establish whether binding of any of these proteins to the IRE is important to the regulation of hIGFBP-1 expression by insulin and/or glucocorticoids.

High dose nicotinamide fails to prevent diabetes in BB rats.

Nicotinamide which is an inhibitor of poly (ADPR) synthetase and precursor of NAD has been observed to prevent diabetes in some experimental models possibly by protecting beta cells. To determine whether nicotinamide could cure or prevent type 1 diabetes, we administered large doses (0.5 g/Kg/d) to BB rats. When used in the 45 days following diagnosis nicotinamide failed to bring remission. As a preventive treatment, nicotinamide administered between the 40th and 90th day of age, alone or in association with desferrioxamine did not significantly lower the incidence of diabetes (23% and 30.8% respectively vs. 56.6%). When used earlier, immediately after weaning, nicotinamide did not affect the incidence of diabetes in this model (62.5%). The degree of protection was not comparable with that obtained with cyclosporin A (15% of diabetic animals). Histology study of the pancreas from the animals killed either immediately or 1 year after treatment revealed no endocrine tumor. These findings suggest that in BB rats nicotinamide has little or no effect on the course of autoimmune diabetes mellitus thus dampening the high hopes for this drug in the treatment of human diabetes.