Insulin pump failures in Italian children with Type 1 diabetes: retrospective 1-year cohort study.

AIMS: Insulin pump failure and/or malfunction requiring replacement have not been thoroughly investigated. This study evaluated pump replacement in children and adolescents with Type 1 diabetes using insulin pump therapy. METHODS: Data were collected for all participants younger than 19 years, starting insulin pump therapy before 31 December 2013. For each child, age, disease duration, date of insulin pump therapy initiation, insulin pump model, failure/malfunction/replacement yes/no and reason were considered for the year 2013. RESULTS: Data were returned by 40 of 43 paediatric centres belonging to the Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. In total, 1574 of 11 311 (13.9%) children and adolescents with Type 1 diabetes were using an insulin pump: 29.2% Animas VIBE™ , 9.4% Medtronic MiniMed 715/515™ , 34.3% Medtronic MiniMed VEO™ , 24.3% Accu-Check Spirit Combo™ and 2.8% other models. In 2013, 0.165 insulin pump replacements per patient-year (11.8% due to pump failure/malfunction and 4.7% due to accidental damage) were recorded. Animas VIBE™ (22.1%) and Medtronic MiniMed VEO™ (17.7%) were the most replaced. CONCLUSIONS: In a large cohort of Italian children and adolescents with Type 1 diabetes, insulin pump failure/malfunction and consequent replacement are aligned with rates previously reported and higher in more sophisticated pump models.

Fluid intake and hydration status in obese vs normal weight children.

BACKGROUND/OBJECTIVES: Little is known on the relationship between obesity and hydration levels in children. This study assessed whether and by which mechanisms hydration status differs between obese and non-obese children. SUBJECTS/METHODS: Hydration levels of 86 obese and 89 normal weight children (age: 7-11 years) were compared. Hydration was measured as the average free water reserve (FWR=urine output/24 h minus the obligatory urine output [total 24 h excreted solutes/97th percentile of urine osmolality of children with adequate water intake, that is, 830 mOsm/kg]) over 2 days. Three days of weighed dietary and fluid intakes were recorded. Non-parametric tests were used to compare variables that were skewed and to assess which variables correlated with hydration. Variables mediating the different hydration levels of obese and normal weight children were assessed by co-variance analysis. RESULTS: Obese children were less hydrated than normal weight peers [FWR=median (IQR): 0.80 (-0.80-2.80) hg/day vs 2.10 (0.10-4.45) hg/day, P<0.02; 32% of obese children vs 20% of non-obese peers had negative FWR, P<0.001]. Body mass index (BMI) z-score (z-BMI) and water intake from fluids correlated with FWR (ρ=-0.18 and 0.45, respectively, both P<0.05). Water intake from fluids completely explained the different hydration between obese and normal weight children [FWR adjusted for water from fluids and z-BMI=2.44 (0.44) hg vs 2.10 (0.50) hg, P=NS; B coefficient of co-variation between FWR (hg/day) and water intake from fluids (hg/day)=0.47, P<0.001]. CONCLUSIONS: Obese children were less hydrated than normal weight ones because, taking into account their z-BMI, they drank less. Future prospective studies are needed to explore possible causal relationships between hydration and obesity.

Screening for impaired glucose tolerance in obese children and adolescents: a validation and implementation study.

UNLABELLED: What is already known about this subject Fasting triglycerides above 1.17 mmol/L have been shown to be useful to select obese children and adolescents who may present impaired glucose tolerance in a Canadian cohort. Fasting plasma glucose is associated with the risk to present impaired glucose tolerance in several cohorts of obese children and adolescents. What this study adds When applied to Italian cohorts of obese children and adolescents, the triglycerides cut-off of 1.17 mmol/L has similar validity as in the Canadian cohort to select patients who may present impaired glucose tolerance. Fasting plasma glucose and fasting triglycerides can be combined to obtain an accurate criterion to select obese children and adolescents who may present impaired glucose tolerance. OBJECTIVES: We aimed to validate fasting triglycerides > 1.17 mmol L(-1) , a criterion recently proposed for selecting obese children at risk of impaired glucose tolerance (IGT), and to assess whether the accuracy of triglycerides (TG) can be improved by the use of other variables. METHODS: We studied an Italian cohort of 817 obese children and adolescents (8-18.4 years) who underwent clinical examination, fasting blood analysis and the oral glucose tolerance test (OGTT). The discriminative properties of TG > 1.17 mmol L(-1) were assessed and compared with those observed in a Canadian cohort from which this criterion was derived: 71.4 [57.8-85.1]% sensitivity and 64.1 [57.7-70.4]% specificity. The possible contribution of other variables was evaluated by assessing the net reclassification improvement (NRI), i.e., the net increase in the percentage of subjects correctly classified. RESULTS: Thirty-nine children (4.7%) had IGT. The 1.17 mmol L(-1) TG threshold showed 66.6 [51.8-81.4]% sensitivity and 68.2 [64.9-71.5]% specificity, thus successfully validated. Fasting plasma glucose (FPG) was independently associated with IGT (odds ratio = 3.86 [2.09-7.14], P < 0.001), besides TG. The bivariate criterion of TG ≥ 1.13 mmol L(-1) plus FPG ≥ 4.44 mmol L(-1) had a 69.2 [54.7-83.7]% sensitivity and a 78.2 [76.8-79.6]% specificity, thus displaying a 12.6% NRI (P < 0.001) compared with TG>1.17 mmol L(-1) . CONCLUSIONS: TG > 1.17 mmol L(-1) is a useful criterion to detect roughly 66% of obese children with IGT through OGTT performed in about 33% of all obese children. However, the 'TG≥1.13 mmol L(-1) plus FPG≥4.44 mmol L(-1) ' criterion improved discrimination accuracy, leading to the possibility of detecting even more than 66% of obese children with IGT though limiting OGTT to just 25% of all obese children.

Metabolic and hormonal consequences of two different meals after a moderate intensity exercise bout in obese prepubertal children.

BACKGROUND/OBJECTIVES: To investigate the relationship between postprandial nutrient balance, satiety and hormone changes induced by two different meals taken after a moderate intensity exercise bout. SUBJECTS/METHODS: Ten prepubertal obese children participated in the study. The experiment was designed as a cross-over study for repeated measures. Each test period lasted five consecutive hours during which the children were under medical supervision. The effects of two isocaloric meals were compared after a moderate intensity exercise (4 multiples of resting metabolic rate, 30 min, cycling): a low-fat/high-carbohydrate meal (meal A) and a high-fat/low-carbohydrate meal (meal B). Pre and postprandial (3 h) substrate oxidation, biochemical parameters, gastrointestinal hormone concentrations and appetite were measured. RESULTS: The main results were: (i) higher fat balance (5.1±5.0 vs -5.0±6.6 g, P=0.001) and lower carbohydrate balance after meal B than A (-9.7±13.3 vs 11.3±18.3 g, P<0.01); (ii) higher energy balance after meal B than after meal A (5.9±21.5 vs -13.9±20.2 kcal, P<0.05); (iii) higher plasma triglyceride concentrations (area under the curve) after meal B than after meal A (2962.5±2095.8 mg*180 min/dl vs -169.5±1633.7 mg*180 min/dl, P<0.01); (iv) higher serum glucagon-like peptide-1 concentrations after meal B than after meal A (1101.5±873.0 pmol*180 min/l vs 478.8±638.3 pmol*180 min/l, P<0.05). CONCLUSIONS: After a bout of moderate intensity exercise, a meal with a high-fat/low-carbohydrate ratio had a less favorable metabolic impact than an isoenergetic, isoproteic low-fat/high-carbohydrate meal.

Adenovirus-mediated delivery of antiangiogenic genes as an antitumor approach.

Based on the observation that the growth of solid tumors is dependent on the formation of new blood vessels, therapeutic strategies aimed at inhibiting angiogenesis have been proposed. A number of proteins with angiostatic activity have been described, but their development as therapeutic agents has been hampered by difficulties in their production and their poor pharmacokinetics. These limitations may be resolved using a gene therapy approach whereby the genes are delivered and expressed in vivo. Here we compared adenoviral delivery of endostatin, proliferin-related protein (PRP), and interferon-inducible protein 10 (IP10) genes. Recombinant adenoviruses carrying the three angiostatic genes express biologically active gene products as determined in vitro in endothelial cell proliferation and migration assays, and in vivo by inhibition of neoangiogenesis in rat chambers. Eradication of established tumors in vivo, in the murine B16F10 melanoma model in immunocompetent mice, was not achieved by intratumoral injection of the different vectors. However, the combination of intravenous plus intratumoral injections allowed rejection of tumors. Ad-PRP or Ad-IP10 were significantly more efficient than Ad-endostatin, leading to complete tumor rejection and prolonged survival in a high proportion of treated animals. These data support the use of in vivo gene delivery approaches to produce high-circulating and local levels of antiangiogenic agents for the therapy of local and metastatic human tumors.

[In vitro and in vivo inhibition of HIV1 replication by retroviral transfer of interferon alpha, beta, or gamma genes: application to gene therapy of AIDS]. / Inhibition in vitro et in vivo de la réplication du VIH1 par transfert rétroviral des gènes d'interféron alpha, beta ou gamma: application à la thérapie génique du sida.

Somatic gene therapy is defined as the transfer of a heterologous gene into an organism for the purpose of correcting a genetic defect or providing a new therapeutic function to the target cell and thus inducing a cure or improving associated symptoms. While encouraging results have been generated by recent clinical evaluation of combination of anti-viral drugs, Aids still constitute an obvious candidate among the infectious diseases which might be treated by gene therapy. We have therefore chosen to develop and evaluate a gene therapy strategy based on the transfer into human target cells of HIV1-inducible interferon (IFN) alpha, beta or gamma genes. In a preliminary study, myeloïd U937 cell lines transfected with expression vectors containing the IFN alpha, beta or gamma genes under the control of the long terminal repeat (LTR) sequences of HIV1 were shown to be strongly resistant against an in vitro and in vivo (in HIV1 challenged SCID mice model) HIV1 infection. This cellular resistance was correlated with a strong induction of transgenic IFN synthesis and for IFN gamma, with a defect of HIV particles maturation. Secondly, construction and production of high titer retroviral vectors containing Tat-inducible IFN genes allowed efficient transduction of lymphoïd cell lines and human primary lymphocytes. These transduced cells were shown to be highly resistant against laboratory and primary HIV isolates. Taken together, our in vitro and in vivo results suggest that HIV1 inducible IFN gene therapy can be beneficial to HIV-infected individuals provided the fact that methods are developed that allow the efficient transduction of human hematopoïetic stem cells.

Experimental gene therapy: the transfer of Tat-inducible interferon genes protects human cells against HIV-1 challenge in vitro and in vivo in severe combined immunodeficient mice.

OBJECTIVES: To evaluate in vitro and in vivo a strategy for gene therapy for AIDS based on the transfer on interferon (IFN)-alpha, -beta and -gamma genes to human cells. DESIGN: Human U937 promonocytic cells were stably transfected with Tat-inducible IFN expression vectors conferring an antiviral state against infection with HIV. METHODS: Transfected cells were either infected by HIV-1 in vitro or transplanted into severe combined immunodeficient (SCID) mice for an HIV challenge in vivo. RESULTS: U937 cell lines stably carrying IFN transgenes under the positive control of the HIV-1 Tat protein were highly resistant to HIV-1 replication in vitro. This antiviral resistance was associated with a strong induction of IFN synthesis immediately following the viral infection. HIV-1 proteins were found to be specifically trapped within the genetically modified cells. In contrast, all IFN-U937 cells permitted full HIV-2 replication. Transfected cells injected into SCID mice and challenged against HIV-1 were strongly resistant to infection when cells were transduced with IFN-alpha of IFN-beta genes. However, IFN-gamma-transfected cells permitted HIV-1 infection in vivo despite the induction of a high level of IFN-gamma secretion. The quantity of proviral DNA was 10(5)-fold lower in IFN-alpha- or IFN-beta-transfected U937 cells collected from these SCID mice than that in non-transfected cells. CONCLUSIONS: Our results substantiated the validity of a strategy, bases on the transfer of HIV-1-inducible IFN-alpha or IFN-beta genes, to confer antiviral resistance to human cells.