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.

Proinflammatory Polyphosphate Increases in Plasma of Obese Children with Insulin Resistance and Adults with Severe Type 2 Diabetes.

Obesity increases the risk of insulin resistance and type 2 diabetes through increased inflammation at cellular and tissue levels. Therefore, study of the molecular elements involved in obesity-related inflammation may contribute to preventing and controlling it. Inorganic polyphosphate is a natural phosphate polymer that has recently been attracting more attention for its role in inflammation and hemostasis processes. Polyphosphates are one of the main constituents of human platelets, which are secreted after platelet activation. Among other roles, they interact with multiple proteins of the coagulation cascade, trigger bradykinin release, and inhibit the complement system. Despite its importance, determinations of polyphosphate levels in blood plasma had been elusive until recently, when we developed a method to detect these levels precisely. Here, we perform cross sectional studies to evaluate plasma polyphosphate in: 25 children, most of them with obesity and overweight, and 20 adults, half of them with severe type 2 diabetes. Our results show that polyphosphate increases, in a significant manner, in children with insulin resistance and in type 2 diabetes patients. As we demonstrated before that polyphosphate decreases in healthy overweight individuals, these results suggest that this polymer could be an inflammation biomarker in the metabolic disease onset before diabetes.

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.

Lung ultrasound score and diuretics in preterm infants born before 32 weeks: A pilot study.

OBJECTIVE: To describe if weekly determined lung ultrasound (LU) scores in preterm infants born before 32 weeks (PTB32W) change with diuretic therapy. DESIGN: We included infants who received diuretics and compared LU scores according to their evolution on respiratory support (RS) before and after diuretics. RESULTS: We included 18 PTB32W divided into two groups. Both groups were similar in terms of median gestational age: 26 weeks (interquartile range [IQR]: 25-28) in the responders' group and 27 weeks (IQR: 24-28) in the other. They differed, however, in the median number of days on invasive mechanical ventilation: 27 (IQR: 11-43) versus 76 (IQR: 35-117), p = .03; in addition to the number of infants with moderate-severe bronchopulmonary dysplasia: 3 (33%) versus 8 (89%), p = .025. The responders' group showed lower LU scores 2 days after diuretics, with a median LU score of 6 (IQR: 3-12) versus 14 (IQR: 12-17) in the nonresponders group, p = .03; 1 week after (3 [IQR: 0-10] versus 12 [12-12], p = .04); and 3 weeks after (5 [IQR: 3-6] versus 12 [10-15], p = .01). RS also decreased at the same time: 7 out of 9 (78%) were extubated in the responders' group, and 1 out of 9 (11%) in the nonresponders group, p = .02, and these differences remained throughout the entire follow-up. CONCLUSIONS: There is a group of PTB32W patients whose LU score improves after diuretics. This change appears only in those patients that can be weaned off from RS, and at the same period of time as the administration of diuretics.

Iron Metabolism in Obesity and Metabolic Syndrome.

Obesity is an excessive adipose tissue accumulation that may have detrimental effects on health. Particularly, childhood obesity has become one of the main public health problems in the 21st century, since its prevalence has widely increased in recent years. Childhood obesity is intimately related to the development of several comorbidities such as nonalcoholic fatty liver disease, dyslipidemia, type 2 diabetes mellitus, non-congenital cardiovascular disease, chronic inflammation and anemia, among others. Within this tangled interplay between these comorbidities and associated pathological conditions, obesity has been closely linked to important perturbations in iron metabolism. Iron is the second most abundant metal on Earth, but its bioavailability is hampered by its ability to form highly insoluble oxides, with iron deficiency being the most common nutritional disorder. Although every living organism requires iron, it may also cause toxic oxygen damage by generating oxygen free radicals through the Fenton reaction. Thus, iron homeostasis and metabolism must be tightly regulated in humans at every level (i.e., absorption, storage, transport, recycling). Dysregulation of any step involved in iron metabolism may lead to iron deficiencies and, eventually, to the anemic state related to obesity. In this review article, we summarize the existent evidence on the role of the most recently described components of iron metabolism and their alterations in obesity.

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.

Broad spectrum antibiotics in newborns increase multi-drug resistant infections.

Our objective was to determine if broad spectrum antibiotics (BSA) are associated with multi-resistant bacterial (MRB) infections in neonatal patients. We conducted a case-control study with two groups of patients: those with and without a MRB infection. We included 43 cases and 43 controls. MRB strains were: 21 S. maltophila (49%), 11 ESBL-producing Enterobacteriae (25%), 8 P. aeruginosa (19%) and 3 MRSA (7%). Odds ratio (OR) for MRB after seven days of carbapenems was 4.25 (95% confidence interval (CI) 1.4-17.4) and OR for MRB after seven days of third generation cephalosporin was 8 (95% CI 1.1-34.9). BSA longer than seven days, increases MRB infections 22.5 times in patients with bronchopulmonary dysplasia (BPD). Our data show a clear association between the use of BSA and the development of MRB infections, especially in BPD. Although we cannot state this is a causal relationship, we can recommend avoiding prolonged treatment with these antibiotics in preterm babies at risk of BPD.

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.

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

OBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.

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.

Severe pneumonia by Mycoplasma as an adverse event of everolimus therapy in patients with tuberous sclerosis complex.

BACKGROUND: Epilepsy is one of the most common symptoms in Tuberous Sclerosis Complex (TSC), appearing mainly in the first year of life and often resistant to therapy. Several studies have demonstrated the effectiveness of everolimus but its safety in children has not yet been well reported. We present two cases of severe pneumonia caused by Mycoplasma in two children receiving everolimus for epilepsy secondary to TSC. STUDY CASES: Both patients were admitted to the PICU for severe pneumonia with pleural effusion. One of them needed support with high concentration of oxygen and broad spectrum antibiotics and the other developed a septic shock with acute respiratory distress needing mechanical ventilation, vasoactive drugs, pleural drainage and broad-spectrum antibiotics. Everolimus was discontinued and in both patients Mycoplasma pneumoniae was identified by PCR. Both patients were discharged without sequelae. CONCLUSION: Everolimus therapy for epilepsy in the context of TCS could be associated, as in these two cases, with severe bacterial infection by Mycoplasma.

Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus.

Alzheimer's disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and borderlines are blurred in many cases. Aging remains the main risk factor to suffer dementia; however, epidemiological studies reveal that diabetes may also predispose to suffer AD. In order to further study this relationship, we have induced hypoinsulinemic diabetes to APPswe/PS1dE9 (APP/PS1) mice, a classical model of AD. APP/PS1 mice received streptozotocin (STZ) ip at 18 weeks of age, when AD pathology is not yet established in this animal model. Cognition was evaluated at 26 weeks of age in the Morris water maze and the new object discrimination tests. We observed that STZ-induced episodic and working memory impairment was significantly worsened in APP/PS1 mice. Postmortem assessment included brain atrophy, amyloid-beta and tau pathology, spontaneous bleeding, and increased central inflammation. Interestingly, in APP/PS1-STZ diabetic mice, we detected a shift in Aß soluble/insoluble levels, towards more toxic soluble species. Phospho-tau levels were also increased in APP/PS1-STZ mice, accompanied by an exacerbated inflammatory process, both in the close proximity to senile plaque (SP) and in SP-free areas. The presence of hemorrhages was significantly higher in APP/PS1-STZ mice, and although pericytes and endothelium were only partially affected, it remains possible that blood-brain barrier alterations underlie observed pathological features. Our data support the implication of the diabetic process in AD and VaD, and it is feasible that improving metabolic control could delay observed central pathology.

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.

Nitric oxide is a mediator of antiproliferative effects induced by proinflammatory cytokines on pancreatic beta cells.

Nitric oxide (NO) is involved in several biological processes. In type 1 diabetes mellitus (T1DM), proinflammatory cytokines activate an inducible isoform of NOS (iNOS) in ß cells, thus increasing NO levels and inducing apoptosis. The aim of the current study is to determine the role of NO (1) in the antiproliferative effect of proinflammatory cytokines IL-1 ß , IFN- γ , and TNF- α on cultured islet ß cells and (2) during the insulitis stage prior to diabetes onset using the Biobreeding (BB) rat strain as T1DM model. Our results indicate that NO donors exert an antiproliferative effect on ß cell obtained from cultured pancreatic islets, similar to that induced by proinflammatory cytokines. This cytokine-induced antiproliferative effect can be reversed by L-NMMA, a general NOS inhibitor, and is independent of guanylate cyclase pathway. Assays using NOS isoform specific inhibitors suggest that the NO implicated in the antiproliferative effect of proinflammatory cytokines is produced by inducible NOS, although not in an exclusive way. In BB rats, early treatment with L-NMMA improves the initial stage of insulitis. We conclude that NO is an important mediator of antiproliferative effect induced by proinflammatory cytokines on cultured ß cell and is implicated in ß -cell proliferation impairment observed early from initial stage of insulitis.

Implications of family socioeconomic level on risk behaviors in child-youth obesity.

INTRODUCTION: Socioeconomical status may indirectly affect the obesity prevalence. This study gathers together dietary behaviour, physical activity and sedentary lifestyle in relation to the family socioeconomic status in a sample of Spanish children. DESIGN: Population-based cross-sectional study of 3-16 years children. METHODS: Questionnaires about dietary behaviors, physical activity and sedentary lifestyles, and direct anthropometric measures. Criteria of physical activity recommended was >5METs (metabolic equivalence) during 60 min/day, and sedentary lifestyle as 120 min/day of sedentary activities, using obesity criteria from the ENKID study. We derived a single "family socioeconomic level" indicator (FSEL) from the level of studies, professional category and work situation of both parents. RESULTS: 1620 children were studied. 59.5% met the physical activity recommendations. Boys with the higher FSEL quartile tend to do more physical activity. In girls, physical activity increases with the age and degree of overweight. 57.7% of boys and 48.1% of girls were found to be sedentary, with a lower rate in families with higher FSEL. Higher FSEL quartile was related to healthy dietary habits such as having breakfast, 5 meals per day and less snacking. The FSEL was related also to the consumption of whole grains, dairy products and fruits, but not to vegetables, meat or fish. The greatest risk of excess weight was found in girls >6 years old, with a low FSEL, sedentary habits, that snack frequently and eat few proteins. DISCUSSION: Family socioeconomic status seems to determine the level of physical activity, sedentary lifestyle and dietary behavior. The elaboration of a simple socioeconomic indicator may be useful to study factors involved in child obesity.

INTRODUCCIÓN. La situación socioeconómica puede afectar indirectamente las cifras de obesidad. Este trabajo recoge hábitos alimenticios, actividad física y sedentarismo y su relación con el nivel socioeconómico familiar en población infantojuvenil española. DISEÑO. Estudio transversal de base poblacional en escolares de 3-16 años. MÉTODOS. Encuesta de hábitos alimentarios, actividad física y sedentarismo con mediciones antropométricas directas. Se consideró actividad física adecuada si alcanzaba >5METs (equivalentes metabólicos) durante 60 min/día, y sedentarismo 120 min/día de actividades sedentarias. Utilizamos los criterios de obesidad del estudio ENKid. Se confeccionó un indicador del "nivel socioeconómico de la familia" (FSEL) con el nivel de estudios, categoría profesional y situación laboral de ambos padres. RESULTADOS. Se estudiaron 1.620 niños. El 59.5% cumplían las recomendaciones de actividad física. En los niños es mayor la actividad física en el cuartil superior de FSEL, aumentando en las niñas con la edad y el sobrepeso. El 57,7% de varones y el 48,1% de niñas eran sedentarios, disminuyendo en familias con mayores FSEL. El cuartil superior de FSEL se asoció con hábitos alimenticios saludables: desayunos, 5 comidas y menor picoteo. El FSEL se asoció al consumo de cereales, lácteos y frutas, pero no al de verduras, carne o pescado. Obtuvimos mayor riesgo de sobrepeso en niñas >6 años, FSEL bajos, sedentarismo, picoteos y menores ingestas proteicas. DISCUSIÓN. El nivel socioeconómico familiar parece condicionar actividad física, sedentarismo y alimentación infantil. La elaboración de un indicador simple del FSEL familiar puede ser útil para el estudio de factores que intervienen en la obesidad infantil.

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.