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.

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.

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.

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.

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.

Bariatric surgery influences ß-cell turnover in non obese rats.

BACKGROUND: The aim of this study was to investigate the relation between the different bariatric surgeries and pancreatic ß-cell turnover. MATERIAL AND METHODS: We used healthy adult male Wistar rats to undergo the different techniques. Three surgical techniques were developed (malabsorptive, Sleeve gastrectomy and Roux-Y Gastric Bypass-), together with two control groups (Sham and fasting control). Pancreatic ß-cell mass was measured, as well as apoptosis, proliferation and neogenesis related to cellular turnover. Otherwise, we measured the functional issues to elucidate the physiological role that these surgical techniques trigger in the carbohydrate metabolism (e.g. food intake, weight gain, intraperitoneal glucose tolerance test, and basal glycaemia). Results included the differences in phenotypes of the rat after the surgery. The rats did not show important differences in glycaemic parameters between the surgical groups. The ß-cell mass presented modifications related with proliferation processes. A significant increase of ß-cell mass in the malabsorptive technique was reported. On the other hand, the peripheral resistance to insulin tended to be reduced in rats which underwent malabsorptive and mixed techniques. CONCLUSION: This work showed an increase in ß-cell mass after the resection of an important portion of small bowel. The Roux-Y Gastric Bypass produced a non-significant increase in ß-cell mass. We considered that these implications of surgery over the endocrine pancreas must be one of the mechanisms related to the improvement of type 2 Diabetes mellitus following bariatric surgery.

A surgical model of short bowel syndrome induces a long-lasting increase in pancreatic beta-cell mass.

Several surgical techniques are used nowadays as a severe treatment for obesity and diabetes mellitus type 2. These techniques are aggressive due to drastic changes in the nutrient flow and non-reversible modifications on the digestive tube. In this paper we present the effects of a massive intestinal resection on the pancreas. Results have shown that short bowel technique is less aggressive to normal anatomy and physiology of the intestinal tract than Gastric bypass or biliopancreatic diversion (e.g.). In this paper we reproduce a model of short bowel syndrome (SIC), with similar surgical conditions and clinical complications as seen in human cases. This work was conducted on normal Wistar rats, with no other concurrent factors, in order to determine the effects on normal pancreas islets. We measured pancreatic implications by histomorphometric studies, which included beta-cell mass by immunocytochemistry, and apoptosis/proliferation test with TUNEL technique and Ki-67. Briefly, we reported on an increased relative area of the islets of the pancreas, as well as an increase in the average size of islets in the SIC versus the control group. Furthermore we stated that this increase in size of the pancreatic islets is due to the mechanisms of proliferation of beta cells in animals undergoing SIC. These goals could reveal a direct influence of surgical modification of the digestive tract over the pancreatic beta cell homeostasis. In this sense, there are many potential stimulators of intestinal adaptation, including peptide hormones and growth components which are associated or involved as effectors of the endocrine pancreas.

[Obesity associated metabolic impairment is evident at early ages: Spanish collaborative study]. / Las alteraciones metabólicas asociadas a la obesidad están ya presentes en los primeros años de vida: estudio colaborativo español.

UNLABELLED: The objectives of this study are to provide a description of the demographic, anthropometric characteristics and metabolic abnormalities in children with early-onset (< 10 years) and of very-early-onset obesity (< 5 years). We also evaluate the diagnostic ability using the definition of metabolic syndrome (MS) according to different criteria. METHODS: It is a retrospective, case-control, cross-sectional, multicenter study. A total of 10 Pediatric Endocrinology Units in different Spanish hospitals were involved. A group of 469 children with early-onset obesity and another group of 30 children with very early-onset obesity were studied. The control group consisted of 224 healthy children younger than 10 years. Anthropometric and analytical determination of carbohydrates metabolism parameters and the lipid profile were performed. RESULTS: The presence of metabolic alterations associated with obesity in children and adolescents in Spain is remarkable, either on their own, or encompassed within the definition of MS. This prevalence increases substantially when considering the peripheral resistance to insulin action as a diagnostic criterion. It also shows how children who could not be diagnosed with MS according to the definition provided by the International Diabetes Federation (IDF) due to age below 10 years, these alterations are already present in a remarkable percentage. In fact, metabolic abnormalities are already present in the very-early-onset obese children ( <5 years). CONCLUSION: In Spanish children there are metabolic alterations associated with obesity in the infant-juvenile stages alone or encompassed within the definition of MS,and are already present at earlier ages.

Los objetivos de este estudio son, realizar una descripción de las características demográficas, antropométricas y de las alteraciones metabólicas de niños atendidos por obesidad resaltando las características aquellos casos de obesidad de inicio temprano (< 10 años) y los de inicio precoz (< 5 años), y evaluar la capacidad diagnóstica de la definición de síndrome metabólico (SM) según diferentes criterios. Métodos: Es un estudio retrospectivo, caso-control, transversal, multicéntrico. Han participado un total de 10 Unidades de Endocrinología Pediátrica de diferentes hospitales españoles con un grupo de 469 niños con obesidad de inicio temprano y otro grupo de 30 niños con obesidad de inicio precoz. El grupo control estuvo constituido por 224 niños sanos menores de 10 años. Se realizó una valoración antropométrica y determinación analítica de parámetros del metabolismo de los hidratos de carbono y lipidograma. Resultados: La presencia de alteraciones metabólicas asociadas a la obesidad en la etapa infanto-juvenil en España es notable, de forma aislada, o englobada bajo la definición de SM. La prevalencia de éste aumenta sustancialmente cuando se considera la resistencia periférica a la acción de la insulina como criterio diagnóstico. Se demuestra cómo en niños menores de 10 años, dichas alteraciones están presentes en un porcentaje reseñable, y se encuentran las primeras alteraciones metabólicas ya en niños obesos < 5 años. Conclusión: En los niños españoles existen alteraciones metabólicas asociadas a la obesidad en la etapa infanto- juvenil de forma aislada o englobada bajo la definición de SM, y ya están presentes a edades precoces.

Novel mutation in the epithelial sodium channel causing type I pseudohypoaldosteronism in a patient misdiagnosed with cystic fibrosis.

UNLABELLED: Cystic fibrosis (CF) is an inherited disorder with a devastating prognosis. Determination of chloride concentration in sweat has been the gold standard test for diagnosing CF for over 50 years and still remains the primary screening test. However, now that the genetic cause is known and can be studied, genetic confirmation is mandatory in every suspected patient. We present a patient who had been clinically diagnosed and whose genetic testing could not confirm CF, leading us to search for other options that may also give a positive sweat test. The patient turned out to suffer type 1 pseudohypoaldosteronism, a condition that may cause severe dehydration, hyponatremia and hyperkalemia episodes if not diagnosed and treated early with sodium supplementation. We found a genetic variation in the epithelial sodium channel gene which has not been reported previously, and we discuss the possibility of it being the cause of our patient's phenotype. CONCLUSION: this patient clearly illustrates the usefulness of genetic confirmation for CF for the diagnosis and genetic counselling, even when it is clinically oriented, and describes a novel mutation of the amiloride-sensitive epithelial sodium channel possibly causing type 1 pseudohypoaldosteronism.

Cell-specific expression of X-linked inhibitor of apoptosis in the anterior pituitary of streptozotocin-induced diabetic rats.

Cell death is increased in the anterior pituitary of poorly controlled diabetic rats, but anti-apoptotic mechanisms are also activated. We hypothesized that specific cell types are selectively protected against diabetes-induced cell death. To determine when anti-apoptotic mechanisms are activated, streptozotocin-induced diabetic rats were killed after 1, 4, 6 and 8 weeks of evolution. Anterior pituitaries were processed for western blot analysis to determine changes in the intrinsic cell death pathway and upstream kinases involved in cell protection mechanisms. An increase in cell death was detected by ELISA at 4 weeks of diabetes. TUNEL labelling demonstrated that this corresponded to death of primarily lactotrophs, a few somatotrophs, and no thyrotrophs, corticotrophs or gonadotrophs. Levels of phosphorylated (p) Akt were increased at 1 week of diabetes, while pERK1/2 levels increased at 4 weeks and pJNK at 6 weeks. Activation of caspase 3 decreased and anti-apoptotic members of the Bcl-2 protein family increased as early as 1 week after diabetes onset. These changes were coincident with increased IGF-I receptor levels. Levels of X-linked inhibitor of apoptosis protein (XIAP) increased significantly after 6 weeks of diabetes, as did activation of nuclear factor (NF)kappaB. Double immunohistochemistry indicated that XIAP was expressed in less than 1% of lactotrophs and gonadotrophs, approximately 50% of somatotrophs and more than 90% of corticotrophs and thyrotrophs. These results suggest that some cell survival mechanisms are rapidly activated in the anterior pituitary, even before increased cell death can be detected, while others are more delayed. Furthermore, both pituitary cell death and expression of protective mechanisms such as XIAP are cell-type specific.

Increased apoptosis of lactotrophs in streptozotocin-induced diabetic rats is followed by increased proliferation.

Poorly controlled diabetes mellitus can result in decreased prolactin production and thus problems with lactation, reproduction, and other physiological processes. This may be due to a loss of lactotrophs, as we have previously shown that long-term (8 weeks) poorly controlled streptozotocin-induced diabetes results in increased death of lactotrophs and that this most likely occurs through the activation of caspase-8 and the extrinsic cell death cascade. However, cell proliferation is also increased in the anterior pituitary at this time, although the cell type undergoing this proliferation and whether it is a response to the increased cell death remains unknown. In order to determine the time-course of increased cell death and proliferation in the anterior pituitary and if this is related to changes in tumor necrosis factor (TNF)-alpha, a cytokine involved in the activation of the extrinsic cell death pathway, rats were killed at 1, 4, 6, and 8 weeks after the induction of diabetes. Cell death was significantly increased after 4 weeks, as was caspase-8 activation, although circulating levels of TNF-alpha were increased as early as 1 week. Pituitary levels of TNF-alpha did not change significantly until 8 weeks after diabetes onset. Similarly, Western-blot analysis of proliferating cell nuclear antigen showed that anterior pituitary cell proliferation increased significantly 8 weeks after diabetes onset, with the majority of proliferating cells, as detected by BrdU incorporation, corresponding to lactotrophs. These results suggest that the increased death of lactotrophs in poorly controlled diabetic rats is followed by increased proliferation of this cell type, even when no treatment is given.