Safety and Effectiveness of a Biosimilar Recombinant Human Growth Hormone in Children Requiring Growth Hormone Treatment: Analysis of Final Data from PATRO Children, an International, Post-Marketing Surveillance Study.

Purpose: Omnitrope® (somatropin) was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Here, we report final data from the PAtients TReated with Omnitrope® (PATRO) Children study, a post-marketing surveillance study designed to monitor the long-term safety and effectiveness of this treatment in pediatric patients. Methods: The study population included all pediatric patients treated with Omnitrope® (biosimilar rhGH), administered via daily injection, in routine clinical practice. The primary objective was to assess long-term safety, with effectiveness assessed as a secondary objective. Results: In total, 7359 patients were enrolled and treated in the PATRO Children study; 86.0% were treatment-naïve at baseline. Growth hormone deficiency was the most frequent indication (57.9%), followed by patients born small for gestational age (SGA; 26.6%). The mean (SD) duration of exposure to biosimilar rhGH was 3.66 years (2.39). A total of 16,628 adverse events (AEs) were reported in 3981 (54.1%) patients, most of which were mild/moderate. AEs suspected to be treatment related occurred in 8.3% of patients, most frequently headache (1.6%), injection-site pain (1.1%), or injection-site hematoma (1.1%). The incidence rate (IR) of type 2 diabetes mellitus was 0.11 per 1000 person-years (PY) across all patients, and 0.13 per 1000 PY in patients born SGA. The IR of newly diagnosed primary malignancies was 0.22 per 1000 PY across all patients. In the 6589 patients included in the effectiveness population, a sustained catch-up growth was observed across all indications. After 5 years of treatment, height SDS increased from baseline by a median (range) of +1.79 (-3.7 to 6.2) in treatment-naïve patients and +0.73 (-1.4 to 3.7) in pretreated patients. Conclusion: This final analysis of the PATRO Children study indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice. These data are consistent with the well-characterized safety profile of rhGH treatment in pediatric patients.

Altered insulin secretion dynamics relate to oxidative stress and inflammasome activation in children with obesity and insulin resistance.

BACKGROUND: Insulin resistance (IR) is considered the main driver of obesity related metabolic complications, and is related to oxidative stress and inflammation, which in turn promote each other. There is currently no specific definition of IR in children, rather, that for adult population is used by pediatric endocrinologists instead. Altered insulin secretion dynamics are associated with worse metabolic profiles and type 2 diabetes mellitus development, thus we aimed to test whether insulin response relates to oxidative stress and inflammation in children. METHODS: We conducted a case-control study, including 132 children classified as follows: 33 children without obesity (Lean); 42 with obesity but no IR according to the American Diabetes Association criteria for adults (OBIR-); 25 with obesity and IR and an early insulin response to an oral glucose tolerance test (OGTT) (EP-OBIR +); 32 with obesity, IR, and a late insulin peak (LP-OBIR +); and studied variables associated with lipid and carbohydrate metabolism, oxidative stress, inflammation and inflammasome activation. RESULTS: The measured parameters of children with obesity, IR, and an early insulin response were similar to those of children with obesity but without IR. It was late responders who presented an impaired antioxidant system and elevated oxidative damage in erythrocytes and plasma, and inflammasome activation at their white blood cells, despite lower classical inflammation markers. Increased uric acid levels seems to be one of the underlying mechanisms for inflammasome activation. CONCLUSIONS: It is insulin response to an OGTT that identifies children with obesity suffering oxidative stress and inflammasome activation more specifically. Uric acid could be mediating this pathological inflammatory response by activating NLRP3 in peripheral blood mononuclear cells.

Assessment of the perception of vertical subjectivity in children born preterm.

Children born preterm have increased rates of paediatric mortality and morbidity. Prematurity has been associated with impaired visual perception and visuo-motor integration. The alteration of the perception of verticality translates into alterations of the vestibular system at central and/or peripheral level, which may manifest itself in symptoms such as imbalance, dizziness or even vertigo. The aim of this study was to compare subjective visual vertical (SVV) test scores in children born preterm with those of children born at term at ages between 7 and 10. One hundred ten children with no neurodevelopmental disorder of 7 to 10 years of age were studied using a mobile application on a smartphone attached to a wall by means of a rotating plate. The SVV test was compared between two groups: a group of 55 preterm children (53 very preterm children born under 32 weeks of gestational age and 2 preterm with very low birth weight) and another group of 55 children born at term (after 37 weeks of gestational age). The SVV results were analysed for comparison with respect to prematurity, sex and age. We found no significant differences in the SVV study in the comparison between preterm and term children. In addition, no significant differences were observed regarding sex or age between 7 and 10 years.  Conclusion: We found no alterations in the perception of vertical subjectivity in children between 7 and 10 years of age, with antecedents of very preterm birth and/or very low birth weight. What is Known: • The different studies published so far suggest the existence of balance disorders in premature children, although in most of these studies the children are examined at an age when the vestibular system is not mature and with non-specific tests for the study of the vestibular system. What is New: • We compared the results of the subjective visual vertical (SVV) test in a group of 55 preterm children (53 very preterm children born under 32 weeks of gestational age and 2 preterm with very low weight at birth) and in a group of 55 children born at term (after 37 weeks of gestational age), at the ages of 7 to 10 years and observed no differences. • We conclude that, if there had been any vestibular alterations due to very premature birth, these must have been compensated by the age of 7.

Test-retest of the Subjective Visual Vertical Test performed using a mobile application with the smartphone anchored to a turntable.

PURPOSE: The alterations of the Subjective visual vertical test are related to vestibular pathology. Our previously validated method to distinguish between healthy and pathological individuals measures the deviation from the Subjective visual vertical using a mobile application installed on a smartphone fixed to a turntable anchored to the wall. The aim of this study was evaluating the intra-observer reliability of our method in individuals with or without vestibular pathology. METHODS: Participants were recruited consecutively. In each individual two measurements with an interval of 2 h were made. Both tests were performed by the same examiner. A total of 91 patients were included in this study, of which 25 were healthy and 66 diseased. Intra-observer reliability was evaluated using the intraclass correlation coefficient (ICC). To assess the clinical accuracy of the measurement, we calculated the standard error of the measurement (SEM) and the minimum detectable change (MDC) with a 95% confidence interval. RESULTS: Intra-observer reliability was excellent with an ICC 0.95 (0.92-0.97) in the whole sample, in healthy patients 0.91 (0.80-0.96) and in pathological patients 0.92 (0.87-0.95). The SEM was calculated to be 0.59 for the whole sample (0.26 in the "healthy" group, and 0.67 in the pathological group). Likewise, the sample's MDC was 1.16, being 0.52 and 1.36 for the healthy and the pathological group, respectively. CONCLUSIONS: Considering the results, our method presents an excellent intraobserver reliability. Furthermore, changes in deviation greater than 0.52 in healthy individuals and 1.36 in pathological individuals can be considered a real change in deviation.

Catalase post-translational modifications as key targets in the control of erythrocyte redox homeostasis in children with obesity and insulin resistance.

Insulin resistance (IR) is the most common metabolic disturbance in children with obesity. Children with obesity and insulin resistance (ObIR+) display a detriment in erythroid antioxidant defenses, caused by an impaired catalase activity and the increase in oxidative and pro-inflammatory markers. Therefore, erythrocytes from ObRI+ are more vulnerable to any oxidative stress elicitor. Since catalase is one of the erythrocytes' first antioxidant defenses, we intended to delve into the mechanisms underlying catalase's impaired activity. Given the lack of cellular organelles in erythrocytes, which prevents protein synthesis, we aimed study catalase post-translational modifications (PTMs) as targets of pro-inflammatory and pro-oxidant status of these cells in children with obesity and IR. Catalase levels of O-glycosylation, tyrosine nitration and S-glutathionylation were analyzed by Western blotting (WB) using immunoprecipitated catalase (IP-CAT) from erythrocyte lysates. Furthermore, Catalase was also identified by LC-MS/MS after isolation and enrichment of erythrocyte nitrosated proteins with a biotin switch approach. The results obtained suggest that catalase inhibition seen in children with obesity is partly due to the increase in the S-nitrosation of the enzyme. Indeed, exogenous administration of nitric oxide (NO) to cultured erythrocytes resulted in a decrease in catalase activity in all groups. Signals of other PTMs (O-glycosylation, Tyr-nitration and S-glutathionylation) were also detected in the erythrocyte catalase in every groups, although levels of catalase O-glycosylation and S-glutathionylation decreased in ObIR+. No evidence of differences in Tyr-nitration of catalase levels were found among groups. The study again highlights the role of erythrocytes as sensors of the inflammatory and pro-oxidant response to which these cells are subjected in children with obesity and insulin resistance.

Adherence to Mediterranean Diet Is Associated With Better Glycemic Control in Children With Type 1 Diabetes: A Cross-Sectional Study.

Type 1 diabetes (T1D) is a chronic condition, with increased morbidity and mortality, due to a higher rate of cardiovascular disease among other factors. Cardiovascular risk increases with the worse glycemic profile. Nutrition has a deep impact on diabetes control. Adherence to the Mediterranean diet (MD) has been shown to decrease cardiovascular risk in children and adults with obesity and adults with type 2 diabetes, but its impact on T1D children has been scarcely analyzed. We hypothesized that the degree of adherence to MD could relate to the increased time in range in children with T1D. Patients and Methods: Cross-sectional analysis involving two university hospitals. We measured the adherence to MD with the Mediterranean Diet Quality Index for children and teenagers (KIDMED) questionnaire, which is a validated tool for this purpose. A score of <5 indicates poor adherence to MD, while a good adherence is indicated by a score of >7. Demographic and clinical data were registered on the same day that the questionnaire was taken, with informed consent. Additionally, the patients' ambulatory glucose profiles (AGPs), were registered from the participants' glucose monitors (continuous or flash devices), and daily insulin needs were recorded from patients' insulin pumps (n=28). Other cardiovascular risk factors such as lipid profile, vitamin D levels, and other biochemical parameters were registered from a blood test, performed 2 weeks before recruitment, as part of the patients' annual screening. Results: Ninety-seven patients (44 girls), with an average age of 11.4 years (± 3.01), were included. Seventy-one of them were on multiple daily injection regimens, and all had either continuous or flash glucose monitoring. Fifty-three had HbA1c levels of <7.5%, while only 21 had a time in range (TIR) of >70%. Contingency analysis showed that the odds of having HbA1c <7.5% increase in children with KIDMED score of >7 (O.R. 2.38; ICR 1.05-5.41; p = 0.036). Moreover, the KIDMED score and the HbA1c levels were negatively correlated (R: -0.245; p-value: 0.001), while the KIDMED score and TIR showed a positive correlation (R: 0.200; p-value: 0.009). Conclusions: Our data suggest that adherence to MD may contribute to better glycemic control in children. This should be taken into account at the time of nutritional education on T1D patients and their families.

Growth hormone treatment does not to lead to insulin resistance nor excessive rise in IGF-1 levels, while improving height in patients small for gestational age A long-term observational study.

OBJECTIVE: In children born small for gestational age (SGA), the relationship between growth hormone (GH) treatment and insulin resistance (IR) has only been investigated for a short period, necessitating a longer observation period. This study aimed to evaluate the long-term (10 years) effect of GH to SGA-children on IR and safety during treatment. DESIGN: This was a multicenter observational study. PATIENTS: SGA-children who received GH treatment in Spain (stratified by Tanner-stage and age at GH onset [two groups: ≤6 years old or >6 years old]). MEASUREMENTS: The analysed variables (yearly measures) included auxologic, metabolic (insulin-like growth factor-1 (IGF-1), height velocity [HV], weight and homeostatic model assessment-IR [HOMA-IR]) and safety data. Data were collected prospectively (since the study approval: 2007) and retrospectively (since the initiation of GH treatment: 2005-2007). RESULTS: A total of 389 SGA children (369 Tanner-I) were recruited from 27 centres. The mean age (standard deviation) of the children at GH treatment onset was 7.2 (2.8) years old. IGF-1 (standard deviation score [SDS]) and HOMA-IR values tended to increase until the sixth year of GH-treatment, with significant differences being observed only during the first year, while these remained stable in the later years (within normal ranges). Height (SDS) increased significantly (basal: -3.0; tenth year: -1.13), and the maximum HV (SDS) occurred during the first year (2.75 ± 2.39). CONCLUSIONS: HOMA-IR values increased significantly in SGA-children during the first year of GH-treatment, remained stable and were within normal ranges in all cases. Our 10-year data suggests that long-term GH treatment does not promote IR and is well-tolerated, safe and effective.

Efficacy of the subjective visual vertical test performed using a mobile application to detect vestibular pathology.

BACKGROUND: The subjective visual vertical (SVV) test is a sensitive test of vestibular dysfunction that allows the evaluation of otolithic organs; however, with the current method, there are technical and logistical limitations that make the application of this test difficult in the conventional clinic. OBJECTIVE: The objective of this study is to assess the effectiveness of detecting vestibular pathology using the SVV via a new screening method. METHODS: A consecutive sample of 62 patients with suspected vestibular pathology was included in the study. The patients were clinically diagnosed according to the Barany Society criteria. An exploratory system was designed using a mobile application in Android that detects accelerometer oscillations and involves placing the smartphone on a rotating disk anchored to the wall. All patients underwent a SVV examination using the bucket method and the study test. A cut-off point of the ROC curve was calculated for each test, and its sensitivity, specificity, diagnostic accuracy and probability ratios for detecting vestibular pathology were analysed. The SVV results were compared using the bucket test and the study test. RESULTS: We observed significant differences in sensitivity between the two tests: 86.95% for the study test versus 67.4% for the bucket test (p < 0.01). In the ROC curve, an area under the curve of 0.90 was observed for the study test, with a cut-off of 2.43 for a sensitivity of 86.95% and a specificity of 93.75%. CONCLUSIONS: SVV testing using a smartphone placed on a rotating disk anchored to the wall offers greater diagnostic accuracy than SVV using the bucket test. Both methods are inexpensive, harmless and easily accepted by patients.

Hybrid Closed-Loop System Achieves Optimal Perioperative Glycemia in a Boy With Type 1 Diabetes: A Case Report.

The goal in type 1 diabetes (T1D) therapy is to maintain optimal glycemic control under any circumstance. Diabetes technology is in continuous development to achieve this goal. The most advanced Food and Drug Administration- and European Medicines Agency-approved devices are hybrid closed-loop (HCL) systems, which deliver insulin subcutaneously in response to glucose levels according to an automated algorithm. T1D is frequently encountered in the perioperative period. The latest international guidelines for the management of children with diabetes undergoing surgery include specific adjustments to the patient's insulin therapy, hourly blood glucose monitoring, and intravenous (IV) insulin infusion. However, these guidelines were published while the HCL systems were still marginal. We present a case of a 9-year-old boy with long-standing T1D, under HCL system therapy for the last 9 months, and needing surgery for an appendectomy. We agreed with the family, the surgical team, and the anesthesiologists to continue HCL insulin infusion, without further adjustments, hourly blood glucose checks or IV insulin, while monitoring closely. The HCL system was able to keep glycemia within range for the total duration of the overnight fast, the surgery, and the initial recovery, without any external intervention or correction bolus. This is, to the best of our knowledge, the first reported pediatric case to undergo major surgery using a HCL system, and the results were absolutely satisfactory for the patient, his family, and the medical team. We believe that technology is ripe enough to advocate for a "take your pump to surgery" message, minimizing the impact and our interventions. The medical team may discuss this possibility with the family and patients.

Toxicity Induced by Cytokines, Glucose, and Lipids Increase Apoptosis and Hamper Insulin Secretion in the 1.1E7 Beta Cell-Line.

Basic research on types 1 and 2 diabetes mellitus require early stage studies using beta cells or cell lines, ideally of human origin and with preserved insulin secretion in response to glucose. The 1.1E7 cells are a hybrid cell line resulting from the electrofusion of dispersed human islets and PANC-1 cells, capable of secreting insulin in response to glucose, but their survival and function under toxic conditions remains untested. This characterization is the purpose of the present study. We treated these cells with a cytokine mix, high glucose, palmitate, and the latter two combined. Under these conditions, we measured cell viability and apoptosis (MTT, Caspase Glo and TUNEL assays, as well as caspase-8 and -9 levels by Western blotting), endoplasmic reticulum stress markers (EIF2AK3, HSPA4, EIF2a, and HSPA5) by real-time PCR, and insulin secretion with a glucose challenge. All of these stimuli (i) induce apoptosis and ER stress markers expression, (ii) reduce mRNA amounts of 2-5 components of genes involved in the insulin secretory pathway, and (iii) abrogate the insulin release capability of 1.1E7 cells in response to glucose. The most pronounced effects were observed with cytokines and with palmitate and high glucose combined. This characterization may well serve as the starting point for those choosing this cell line for future basic research on certain aspects of diabetes.

Blunted Reducing Power Generation in Erythrocytes Contributes to Oxidative Stress in Prepubertal Obese Children with Insulin Resistance.

Childhood obesity, and specifically its metabolic complications, are related to deficient antioxidant capacity and oxidative stress. Erythrocytes are constantly exposed to multiple sources of oxidative stress; hence, they are equipped with powerful antioxidant mechanisms requiring permanent reducing power generation and turnover. Glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) are two key enzymes on the pentose phosphate pathway. Both enzymes supply reducing power by generating NADPH, which is essential for maintaining the redox balance within the cell and the activity of other antioxidant enzymes. We hypothesized that obese children with insulin resistance would exhibit blunted G6PDH and 6PGDH activities, contributing to their erythrocytes' redox status imbalances. We studied 15 control and 24 obese prepubertal children, 12 of whom were insulin-resistant according to an oral glucose tolerance test (OGTT). We analyzed erythroid malondialdehyde (MDA) and carbonyl group levels as oxidative stress markers. NADP+/NADPH and GSH/GSSG were measured to determine redox status, and NADPH production by both G6PDH and 6PGDH was assayed spectrophotometrically to characterize pentose phosphate pathway activity. Finally, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) activities were also assessed. As expected, MDA and carbonyl groups levels were higher at baseline and along the OGTT in insulin-resistant children. Both redox indicators showed an imbalance in favor of the oxidized forms along the OGTT in the insulin-resistant obese group. Additionally, the NADPH synthesis, as well as GR activity, were decreased. H2O2 removing enzyme activities were depleted at baseline in both obese groups, although after sugar intake only metabolically healthy obese participants were able to maintain their catalase activity. No change was detected in SOD activity between groups. Our results show that obese children with insulin resistance present higher levels of oxidative damage, blunted capacity to generate reducing power, and hampered function of key NADPH-dependent antioxidant enzymes.

Respiratory adverse events during upper digestive endoscopies in children under ketamine sedation.

BACKGROUND: There is no evidence of the need for oxygen supplementation during upper digestive endoscopies under ketamine sedation in children, and the latest recommendations specifically state that it is not mandatory for the procedure. The aim of our study is to assess the incidence of respiratory adverse events during upper digestive endoscopies in children under Ketamine sedation when performed without oxygen supplementation, in accordance with the latest recommendations. METHODS: Eighty-eight children undergoing ketamine sedation for programmed upper digestive endoscopy at our Pediatric Intensive Care Unit were included. Patients needing other sedative agents different from ketamine were excluded. No patients received previous oxygen therapy. Suction equipment, oxygen, a bag-valve-mask, and age-appropriate equipment for advanced airway management were immediately available. The primary outcome measure was the incidence of desaturation episodes (i.e. FiO2 below 90% requiring an intervention). RESULTS: Fifty-five patients (62.5%) presented a desaturation episode during the procedure. Most desaturation episodes occurred during the endoscope introduction (78.2%), and 5 episodes were previous to the endoscope introduction (minute 0). Around sixty percent of patients (58.9%) required oxygen therapy and four patients required bag-mask ventilation. Once oxygen therapy was initiated, 34 patients (70.5%) required it during the complete procedure or part of it. CONCLUSIONS: Desaturation episodes occur frequently early on in the procedure. Our data suggest that the role of oxygen supplementation prior to, and during upper digestive endoscopies under ketamine sedation in children should be thoroughly assessed for future recommendations.

Placental Adaptive Changes to Protect Function and Decrease Oxidative Damage in Metabolically Healthy Maternal Obesity.

Pregnancy-related disorders, including preeclampsia and gestational diabetes, are characterized by the presence of an adverse intrauterine milieu that may ultimately result in oxidative and nitrosative stress. This scenario may trigger uncontrolled production of reactive oxygen species (ROS) such as superoxide anion (O●-) and reactive nitrogen species (RNS) such as nitric oxide (NO), along with an inactivation of antioxidant systems, which are associated with the occurrence of relevant changes in placental function through recognized redox post-translational modifications in key proteins. The general objective of this study was to assess the impact of a maternal obesogenic enviroment on the regulation of the placental nitroso-redox balance at the end of pregnancy. We measured oxidative damage markers-thiobarbituric acid-reacting substances (TBARS) and carbonyl groups (C=O) levels; nitrosative stress markers-inducible nitric oxide synthase, nitrosothiol groups, and nitrotyrosine residues levels; and the antioxidant biomarkers-catalase and superoxide dismutase (SOD) activity and expression, and total antioxidant capacity (TAC), in full-term placental villous from both pre-pregnancy normal weight and obese women, and with absence of metabolic complications throughout gestation. The results showed a decrease in C=O and TBARS levels in obese pregnancies. Although total SOD and catalase concentrations were shown to be increased, both activities were significantly downregulated in obese pregnancies, along with total antioxidant capacity. Inducible nitric oxide sintase levels were increased in the obese group compared to the lean group, accompanied by an increase in nitrotyrosine residues levels and lower levels of nitrosothiol groups in proteins such as ERK1/2. These findings reveal a reduction in oxidative damage, accompanied by a decline in antioxidant response, and an increase via NO-mediated nitrative stress in placental tissue from metabolically healthy pregnancies with obesity. All this plausibly points to a placental adaptation of the affected antioxidant response towards a NO-induced alternative pathway, through changes in the ROS/RNS balance, in order to reduce oxidative damage and preserve placental function in pregnancy.

Plant catalases as NO and H2S targets.

Catalase is a powerful antioxidant metalloenzyme located in peroxisomes which also plays a central role in signaling processes under physiological and adverse situations. Whereas animals contain a single catalase gene, in plants this enzyme is encoded by a multigene family providing multiple isoenzymes whose number varies depending on the species, and their expression is regulated according to their tissue/organ distribution and the environmental conditions. This enzyme can be modulated by reactive oxygen and nitrogen species (ROS/RNS) as well as by hydrogen sulfide (H2S). Catalase is the major protein undergoing Tyr-nitration [post-translational modification (PTM) promoted by RNS] during fruit ripening, but the enzyme from diverse sources is also susceptible to undergo other activity-modifying PTMs. Data on S-nitrosation and persulfidation of catalase from different plant origins are given and compared here with results from obese children where S-nitrosation of catalase occurs. The cysteine residues prone to be S-nitrosated in catalase from plants and from bovine liver have been identified. These evidences assign to peroxisomes a crucial statement in the signaling crossroads among relevant molecules (NO and H2S), since catalase is allocated in these organelles. This review depicts a scenario where the regulation of catalase through PTMs, especially S-nitrosation and persulfidation, is highlighted.

GLP-1 mediated improvement of the glucose tolerance in the T2DM GK rat model after massive jejunal resection.

OBJECTIVE: The aim of this study was to clarify the role of the middle gut in the entero-pancreatic axis modification that leads to glucose improvement in the Goto-Kakizaki (GK) rat as a non-obese T2DM model. BACKGROUND: Bariatric surgery is considered an assured solution for type 2 Diabetes (T2DM). Enterohormones such as ghrelin, gastric inhibitory polypeptide and mainly glucagon-like peptide-1 (GLP-1) were recognized as key players in the physiophathological mechanisms associated with entero-pancreatic axis regulation and glucose tolerance improvement. However, the influence of anatomical arrangements post-bariatric surgery on this axis is still debatable. METHOD: To this purpose, 50% of small intestine resections were performed on GK rats (n = 6), preserving the proximal half of the jejunum and the ileum (IR50). Phenotypic and functional changes, such as performance in oral glucose tolerance tests, ileal release of GLP-1, beta-cell sensitivity to GLP-1, beta-cell mass, and turnover were characterized in IR50 and the surgical control group (Sham). RESULTS: The glucose tolerance was improved and ileal release of GLP-1 was enhanced four weeks after IR50 versus the control group rats. Beta-cell mass, beta-cell proliferation, and beta-cell sensitivity to GLP-1 were also increased in the pancreas of IR50 versus the control group rats. CONCLUSION: the jejunal exclusion increases beta-cell-mass and improves glucose tolerance by increasing in GLP-1 expression and number of receptors via the entero-pancreatic axis.

Topical Pharyngeal Lidocaine Reduces Respiratory Adverse Events During Upper Gastrointestinal Endoscopies Under Ketamine Sedation in Children.

BACKGROUND: Upper gastrointestinal endoscopies (UGEs) performed under ketamine sedation may increase the risk of respiratory adverse events (RAEs) due to pharyngeal stimulation. Topical lidocaine prevents general anesthesia-induced laryngospasm. OBJECTIVE: Our objective was to determine whether topical lidocaine may reduce the incidence of RAEs induced by pharyngeal stimulation in UGEs performed on children sedated with ketamine. METHODS: We conducted a single-center prospective study. We included every patient admitted for an elective diagnostic UGE under ketamine sedation who received lidocaine prior to the technique. Patients requiring any other medication were excluded. Our main outcome measure was the number of desaturation episodes. We then compared these results with those obtained in an historic group who did not receive topical lidocaine, in which we registered a total of 54 desaturation episodes. RESULTS: In total, 88 children (52.3% boys) were included. The median age was 7 years [interquartile range (IQR) 3-11]. The mean duration of the procedure was 6.5 ± 2.4 min, and the median initial ketamine dose was 1.76 mg/kg (IQR 1.56-2.03). The total number of desaturation episodes was 3 (3.4%), and two of these occurred prior to the introduction of the endoscope. This result represents a lower incidence than in previously reported series, and a significant decrease (p < 0.0001) with respect to the 54 RAEs registered in the historic group of 87 children. CONCLUSIONS: Topical lidocaine premedication significantly reduced the incidence of RAEs in children during UGEs under ketamine sedation. Our findings should be confirmed by a double-blind randomized controlled trial.

Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism.

Low birth weight increases neonatal morbidity and mortality, and surviving infants have increased risk of metabolic and cardiovascular disturbances later in life, as well as other neurological, psychiatric, and immune complications. A gestational excess of glucocorticoids (GCs) is a well-known cause for fetal growth retardation, but the biological basis for this association remains elusive. Placental growth is closely related to fetal growth. The placenta is the main regulator of nutrient transport to the fetus, resulting from the difference between placental nutrient uptake and the placenta's own metabolism. The aim of this study was to analyze how excess hydrocortisone affects placental glucose and lipid metabolism. Human placenta explants from term physiological pregnancies were cultured for 18 hours under different hydrocortisone concentrations (2.75, 5.5, and 55 mM; 1, 2, and 20 mg/ml). Placental glucose and lipid uptake and the metabolic partitioning of fatty acids were quantified by isotopic techniques, and expression of specific glucose transporter GLUT1 was quantified by western blot. Cell viability was assessed by MTT, immunohistochemistry and caspase activity. We found that excess hydrocortisone impairs glucose uptake and lipoprotein lipase (LPL) activity, coincident with a GC-dose dependent inhibition of fatty acid oxidation and esterification. None of the experimental conditions showed an increased cell death. In conclusion, our results show that GC overexposure exerts a dysfunctional effect on lipid transport and metabolism and glucose uptake in human placental explants. These findings could well be directly related to a reduced placental growth and possibly to a reduced supply of nutrients to the fetus and the consequent fetal growth retardation and metabolic programming.

Normal Cerebellar Growth by Using Three-dimensional US in the Preterm Infant from Birth to Term-corrected Age.

Purpose To establish cross-sectional and longitudinal reference values for cerebellar size in preterm infants with normal neuroimaging findings and normal 2-year neurodevelopmental outcome by using cranial ultrasonography (US). Materials and Methods This prospective study consecutively enrolled preterm infants admitted to a neonatal intensive care unit from June 2011 to June 2014 with a birth weight of less than or equal to 1500 g and/or gestational age (GA) of less than or equal to 32 weeks. They underwent weekly cranial US from birth to term-equivalent age and magnetic resonance (MR) imaging at term-equivalent age. The infants underwent neurodevelopmental assessments at age 2 years with Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). Patients with adverse outcomes (death or abnormal neuroimaging findings and/or BSID-III score of <85) were excluded. The following measurements were performed: vermis height, craniocaudal diameter, superior width, inferior width, vermis area, and transcerebellar diameter. Statistical analyses were conducted by using multilevel analyses. Results A total of 137 infants with a mean GA at birth of 29.4 weeks (range, 25-32 weeks) were included. Transcerebellar diameter increased by 1.04 mm per week on average; vermis height and craniocaudal diameter increased by 0.55 mm and 0.59 mm, respectively. Superior vermian width increased by an average of 0.45 mm, whereas inferior vermian width increased by an average of 0.51 mm per week. Vermis area was found to increase by 0.22 cm2 per week on average. The sex effect was significant (female lower than male) for vermis height (P < .05), craniocaudal diameter (P < .05), inferior vermian width (P <. 05), and vermis area (P <. 05). Conclusion Cross-sectional and longitudinal reference values were established for cerebellar growth in preterm infants, which may be included in routine cranial US.

Obesity induced alterations in redox homeostasis and oxidative stress are present from an early age.

OBJECTIVES: Oxidative stress and inflammation have been postulated as underlying mechanisms for the development of obesity-related insulin resistance. This association however, remains elusive especially in childhood. We sought to investigate this relation by measuring oxidative stress and antioxidant response biomarkers, before and during an oral glucose tolerance test (OGTT), in different biological samples from obese children. SUBJECTS: 24 children were recruited for the study, (18 obese and 6 controls). After OGTT, the obese group was subdivided in two, according to whether or not carbohydrate metabolic impairment (Ob.IR+, Ob.IR-; respectively) was found. Different biomarkers were analyzed after fasting (T = 0) and during an OGTT (T = 60 and 120 min). Lipoperoxides were measured in plasma, erythrocytes, and urine; while advanced glycation end products were determined in plasma, and redox status (GSH/GSSG ratio) in erythrocytes. RESULTS: We found marked differences in the characterization of the oxidative status in urine and erythrocytes, and in the dynamics of the antioxidant response during OGTT. Specifically, Ob.IR+ children show increased oxidative stress, deficient antioxidant response and a significant imbalance in redox status, in comparison to controls and Ob.IR- children. CONCLUSION: Obese children with insulin resistance show increased levels of oxidative stress biomarkers, and a stunted antioxidant response to an OGTT leading to increased oxidative stress after a single glucose load, as detected in erythrocytes, but not in plasma. We propose erythrocytes as sensors of early and acute changes in oxidative stress associated with insulin resistance in childhood obesity. This is a pilot study, performed with a limited sample size, so data should be interpreted with caution until reproduced.

Amplitude-Integrated EEG and Brain Sparing in Preterm Small-for-Gestational-Age Infants.

PURPOSE: Preterm small-for-gestational-age (SGA) infants are at risk for a high mortality rate and impaired cognitive development. Only a few studies have focused on amplitude-integrated EEG (aEEG) in preterm SGA infants. They have been shown to have a slower rate of brain maturation, but these findings have not consistently been related to neurodevelopmental outcomes. The aim of our study was to evaluate early aEEG monitoring in SGA compared with adequate-for-gestational-age preterms. METHODS: This prospective cohort study enrolled infants with very low birth weight who were admitted to the neonatal intensive care unit at Hospital Puerta del Mar, Cádiz, Spain, from June 2009 to September 2012. This study was a subanalysis of SGA from the global cohort previously described by our group. Adverse outcome included severe intraventricular hemorrhage and/or death. Cerebral function was monitored using aEEG recordings during the first 72 hours of life. RESULTS: Preterm SGA infants (18 SGA in the global cohort of 92 patients) had lower 1- and 5-minute Apgar scores, higher score for neonatal acute physiology perinatal extension II scores, and higher proportion of adverse outcomes. When comparing preterm adequate-for-gestational-age infants with SGA infants with good prognosis, those with SGA had more mature and continuous aEEG patterns. Low margin amplitude depression was not as severe in these patients, and a higher proportion of these patients developed sleep-wake cycles. CONCLUSIONS: The results of our study suggest that SGA infants with a good prognosis have a more mature aEEG pattern than preterm adequate-for-gestational-age patients with the same outcome. These findings support the brain sparing theory in SGA infants.