Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases.

Gestational diabetes mellitus (GDM) is defined as the presence of high blood glucose levels with the onset, or detected for the first time during pregnancy, as a result of increased insulin resistance. GDM may be induced by dysregulation of pancreatic ß-cell function and/or by alteration of secreted gestational hormones and peptides related with glucose homeostasis. It may affect one out of five pregnancies, leading to perinatal morbidity and adverse neonatal outcomes, and high risk of chronic metabolic and cardiovascular injuries in both mother and offspring. Currently, GDM diagnosis is based on evaluation of glucose homeostasis at late stages of pregnancy, but increased age and body-weight, and familiar or previous occurrence of GDM, may conditionate this criteria. In addition, an earlier and more specific detection of GDM with associated metabolic and cardiovascular risk could improve GDM development and outcomes. In this sense, 1st-2nd trimester-released biomarkers found in maternal plasma including adipose tissue-derived factors such as adiponectin, visfatin, omentin-1, fatty acid-binding protein-4 and retinol binding-protein-4 have shown correlations with GDM development. Moreover, placenta-related factors such as sex hormone-binding globulin, afamin, fetuin-A, fibroblast growth factors-21/23, ficolin-3 and follistatin, or specific micro-RNAs may participate in GDM progression and be useful for its recognition. Finally, urine-excreted metabolites such as those related with serotonin system, non-polar amino-acids and ketone bodies, may complete a predictive or early-diagnostic panel of biomarkers for GDM.

Relationship of high leptin levels with an adverse lipid and insulin profile in 6-8 year-old children in Spain.

BACKGROUND AND AIMS: Leptin, an adipokine elevated in obesity, may be related to an adverse cardiovascular risk profile in childhood. However, evidence for this relationship in pre-pubertal children is scarce. We aimed to analyze the relationship between leptin levels and lipid and insulin profiles in Spanish children. METHODS AND RESULTS: Our population-based sample included 389 males and 369 females aged 6-8 years. Lipid levels were determined by standard methods, insulin by radioimmunoassay and leptin by sandwich ELISA. Leptin levels were higher in girls (8.6 ng/ml) than boys (4.7 ng/ml) (p < 0.001). Leptin increased from ages 6 to 8 in girls, but remained steady in boys. In both sexes, leptin increased significantly (p < 0.001) across weight category from normal weight to obese. Children in the highest tertile of leptin concentration showed significantly (p < 0.01) lower levels of HDL-cholesterol (HDL-C) and apolipoprotein-AI (apo-AI) and significantly higher triglyceride (TG) levels than children in lower tertiles. However, in linear regression analysis, after adjustment for body mass index (BMI), leptin only accounted for 1.5% of the variance of HDL-C in boys, and 2.6% of the variance of apo-AI in girls. Leptin was strongly and positively correlated with insulin and HOMA. Upon regression analysis, leptin contributed to over 20% of the variability in insulin and HOMA, independent of BMI. CONCLUSION: Leptin levels show sex differences in pre-pubertal children. In this age group, leptin levels are strongly related to insulin, and affect lipid profile -namely HDL-C, apo-AI and TG- particularly when leptin levels are high.

[Triptorelin therapy in girls with central precocious puberty increases body mass index]. / El tratamiento con triptorelina en las niñas con pubertad precoz central provoca incremento del índice de masa corporal.

INTRODUCTION: The most important complications of central precocious puberty (CPP) in girls are loss of height and multiple psychosocial problems. OBJECTIVES: To study the effect of triptorelin therapy in a cohort of girls with CPP. PATIENTS AND METHODS: Thirty-four girls diagnosed with organic or idiopathic CPP and treated with monthly triptorelin were studied. Age, height in standard deviation (SD), bone age (Greulich and Pyle), height prediction (Bayle-Pinneau), body mass index (BMI) in SD, uterine size (pelvic ultrasound), target height, cranial magnetic resonance imaging, triptorelin dose, and treatment duration were studied. RESULTS: Triptorelin produced a statistically significant reduction in growth velocity and an increase in BMI after 1 year of therapy and these changes were maintained after discontinuation of therapy. Adult height in these patients was in accordance with their target genetic height, as well as with their predicted height according to the method of Bayley-Pinneau. No significant differences were found between age of menarche in our patients and in controls. Adult height in patients with organic CPP was significantly lower than that in patients with idiopathic CPP. CONCLUSIONS: 1. Triptorelin can increase BMI in girls with CPP. 2. The presence of an organic cause in patients with CPP worsens the prognosis for adult height. 3. The Bayley-Pinneau prediction method for "average" bone age is useful for establishing a prognosis of adult height in girls with CPP treated with triptorelin.

[Central precocious puberty is associated with a high prevalence of organic disease]. / La pubertad precoz central en niños está asociada a una elevada prevalencia de patología orgánica.

INTRODUCTION: The incidence of central precocious puberty (CPP) is lower in boys than in girls; however, the presence of organic disease is more common in boys. OBJECTIVES: To investigate the percentage of CPP secondary to organic disease in boys and to analyze their clinical and biological characteristics at diagnosis, during follow-up, and at the end of therapy. PATIENTS AND METHODS: Eight boys with a diagnosis of CPP treated with triptorelin every 28 days were included. Age, height in standard deviation (SD), body mass index (BMI) in SD, growth velocity in SD, bone age (Greulich and Pyle), predicted height (Bayle-Pinneau), and target height were analyzed. Testicular volume was measured (according to Prader standards) and peak lutein hormone (LH) values and testosterone levels were determined after gonadotropin-releasing hormone (GnRH) stimulus. RESULTS: Seventy-five percent of the patients with CPP had organic disease. After treatment with triptorelin, growth reduction significantly decreased. In contrast, no changes were seen in the difference between bone age and chronological age, due to the slight difference found at diagnosis. Likewise, during treatment, there was no LH peak and testosterone levels were lower than 0.5 ng/ml in response to GnRH stimulus. No changes were observed in weight or BMI. Three patients reached an adult height similar to their genetic height and their predicted height, as estimated by the Bayle-Pinneau method. CONCLUSIONS: 1. Among boys with CPP we found a substantial number of patients with organic disease. 2. Adult height after treatment with triptorelin can reach the normal range. 3. Determination of testosterone levels can be useful in the follow-up of these children during treatment.

Earlier menarcheal age in Spanish girls is related with an increase in body mass index between pre-pubertal school age and adolescence.

BACKGROUND: Higher body mass index (BMI) has been associated with earlier pubertal development. OBJECTIVE: The aim of this longitudinal study was to determine menarcheal age in a Spanish cohort and to assess its association with anthropometric variables at birth, childhood and adolescence. We also analyse whether the tracking of weight between different ages could affect the timing of menarche. METHODS: The sample population included 195 randomly selected 6-8-year-old girls who participated in the baseline of the Four Provinces Study and in the follow-up of this study at 13-16 years old. Anthropometrical variables were measured and BMI and BMI z-score were calculated. Information regarding birth weight and menarche was obtained by means of self-report questionnaire. RESULTS: Correlation analysis showed a significant negative association of age at menarche with weight, BMI and BMI z-score in the baseline and follow-up groups but not with weight at birth. Fat mass at adolescence is related to a significantly earlier menarcheal age. When comparing weight categories, earliest menarcheal age is associated with an increase of BMI between 6-8-year-old and 13-16-year-old girls. CONCLUSION: In our study, high weight in girls is associated with the earliest age at menarche. This becomes a major influence when weight gain occurs between pre-pubertal school age and adolescence.

[Gynecomastia secondary to Leydig cell tumor]. / Ginecomastia secundaria a tumor de células de Leydig.

We describe a 16-year-old boy with Leydig cell tumor who initially presented bilateral gynecomastia with increased estradiol concentrations, decreased testosterone concentrations and normal gonadotropin levels. Testicular ultrasonography showed a tumor in the left testicle, and orchidectomy was performed. Histopathological analysis revealed a Leydig cell tumor. Two months after surgery, the gynecomastia diminished gradually and estrogen levels returned to normal. No recurrences have occurred during a 2-year follow-up.

[Graves' disease in patients with Down syndrome]. / Enfermedad de Graves en pacientes con síndrome de Down.

Three patients showing the rare association of Down syndrome and Graves' disease are reported. While two of the patients were asymptomatic, the third showed goiter, nervousness, weight loss, and tachycardia. In addition to the typical features of hyperthyroidism, this patient showed right heart failure and hypertransaminasemia, which disappeared with antithyroid treatment. Because Graves' disease is rare in children, and the clinical presentation was unusual in one of our patients, we report three patients with Graves' disease and Down syndrome, and emphasize the importance of periodic evaluation of thyroid function in children with Down syndrome not only to detect hypothyroidism.

[Confusion as a presentation symptom of pseudomigraine with pleocytosis in a paediatric patient]. / Confusión como síntoma de presentación de una pseudomigraña con pleocitosis en un paciente pediátrico.

Transient headache and neurological deficits with cerebrospinal fluid lymphocytic pleocytosis (Handl) syndrome is a rare condition of unknown origin that is characterized by episodes of severe headache, transient neurological deficits that recur over less than 3 months, and lymphocytic pleocytosis in CSF. We report the case of a 14 year-old girl who presented with headache and vomiting that lasted 4 days, later combined with a clinical presentation of confusion, with a decrease in the level of consciousness, aphasia, peripheral facial paralysis, ataxia and fever for 24 hours. CSF analysis showed pleocytosis (110 cells/ml) and proteinorrachia (87 mg/dl). Electroencephalogram in the acute time showed generalized slowing, and later a focal slowing in the left hemisphere. She suffered 7 episodes of migraine (severe headache and vomiting) in the following two months, remaining asymptomatic thereafter. This is the first pediatric case published in the literature that presents with an agitated and/or confused state. This condition must be considered in the differential diagnosis of patients with headache and acute altered level of consciousness, in order to avoid prolonged treatments or unnecessary invasive testing.

[High prevalence of vitamin D deficiency among spanish obese children and adolescents]. / Elevada prevalencia de déficit de vitamina D entre los niños y adolescentes obesos españoles'

INTRODUCTION: Vitamin D deficiency has been associated with extra-skeletal outcomes such as, insulin resistance, type 2 diabetes, and cardiovascular disease. The aim of this study is to determine the prevalence of vitamin D deficiency among obese children and adolescents in Spain and to analyze the relationship between 25-OH-vitamin D (25-OH-D) levels and markers of abnormal glucose metabolism. PATIENTS AND METHODS: A cross-sectional study was conducted in which the clinical and biochemical data were recorded for 120 obese and 50 non-overweight children in Pediatric Clinics from January 2011 to January 2013. RESULTS: The mean 25-OH-D levels among obese children was 19.5 ng/ml and among non-overweight children was 31.6 ng/ml. 58,3% of obese subjects, and 10% of non-overweight subjects had vitamin D deficiency. Serum 25-OH-D levels were lower in winter. Higher HOMA-SDS (3.8 versus 2.4), and triglycerides (97 versus 81 mg/dl) were found in vitamin D deficient obese children compared to obese children without vitamin D deficiency. A negative correlation was found between 25-OH-D levels and HOMA in absolute values (r=-0.2; P=.04) that was not maintained when HOMA-SDS was analyzed. CONCLUSIONS: There is a high prevalence of vitamin D deficiency among obese children with a multifactorial etiology. A lower 25-OH-D level could be a risk factor for developing insulin resistance and type 2 diabetes in obese population.

[Left ventricular mass, forced baseline spirometry and adipocytokine profiles in obese children with and without metabolic syndrome]. / Masa ventricular izquierda, espirometría basal forzada y perfil de adipocitocinas en niños obesos con y sin síndrome metabólico.

INTRODUCTION: Recent reports have shown an increase in changes in cardiac and pulmonary function among obese patients. Furthermore, it has also been demonstrated that obesity is a state of chronic inflammation. We hypothesized that obese children with metabolic syndrome exhibit a higher percentage of left ventricular hypertrophy and altered spirometry values due to higher levels of inflammation. PATIENTS AND METHODS: Left ventricular mass was studied using echocardiography, baseline forced spirometry by spirometer (FlowScreen) and adipocytokine profiles (adiponectin, IL-6, leptin, MCP-1, PCR-Hs, RBP-4, TNF-( and visfatin) were evaluated in peripubertal obese children with and without metabolic syndrome. RESULTS: Forty-one patients (20 girls and 21 boys) were included in the study, 20 of whom (10 boys and 10 girls) were subjects with metabolic syndrome. Of the adipocytokines studied, only leptin, hs-CRP, MCP-1, and the leptin/adiponectin ratio yielded values that were substantially greater in the group with metabolic syndrome (P<.01). An analysis of left ventricular mass index and baseline spirometry showed no differences between the groups studied. However, of the entire cohort, 9.5% had left ventricular hypertrophy. No significant relationship was found between anthropometric data and adipocytokines and the parameters used to study left ventricular mass and spirometry values on the other. CONCLUSION: At the time the study was performed, left ventricular mass and baseline forced spirometry did not appear to be influenced by inflammatory mechanisms.

The insulin sensitizing effects of PPAR-γ agonist are associated to changes in adiponectin index and adiponectin receptors in Zucker fatty rats.

The adiponectin high molecular weight isoform (HMW-adp) and its relation with the other adiponectin isoforms (adiponectin index, S(A)), have been identified as essential for the adiponectin insulin sensitizing effects. The objective of this study is to gain further insight on the effect of the insulin sensitizing agents, PPAR-γ agonists, on the distribution of the adiponectin isoforms and the adiponectin receptors, adipoR1 and adipoR2 in an animal model of obesity and insulin resistance. To achieve the objective, Zucker fatty rats were treated with pioglitazone, rosiglitazone or placebo for six weeks. At the end of the treatment, total adiponectin, adiponectin isoforms and adiponectin receptors expression were measured. In order to see the possible relation with insulin sensitivity parameters, HOMA-IR, muscle insulin-stimulated glucose transport, muscle GLUT4 and plasma free fatty acids were also measured. The two glitazones improved insulin sensitivity and both muscle insulin-stimulated glucose transport and GLUT4 total content. Total plasma adiponectin and visceral fat HMW-adp were increased only by pioglitazone. On the other hand, both glitazones changed the distribution of adiponectin isoforms in plasma, leading to an increase in the S(A) of 21% by pioglitazone and 31% by rosiglitazone. Muscle adipoR1 expression was increased by both glitazones whereas liver adipoR2 expression was increased by rosiglitazone and tended to increase in the pioglitazone group. The insulin sensitizing action of glitazones is mediated, at least in part, by their effect on muscle insulin-stimulated glucose transport and by their direct influence on the adiponectin index and the adiponectin receptors expression.

[Peripheral precocious puberty: clinical, diagnostic and therapeutical principles]. / Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos.

Peripheral precocious puberty (PPP) is the result of the presence of precocious puberty due to the increase of sex steroids with no evidence of activation of the hypothalamic-pituitary-gonadal axis. It is much less common than central precocious puberty (CPP) and it is secondary to either genetic disorders or very heterogeneous acquired diseases. In recent years, molecular advances have made remarkable progress in understanding the pathophysiology of some of these disorders, most notably in McCune-Albright syndrome and testotoxicosis. In addition, new imaging techniques and better hormone assays have improved the early diagnosis of acquired disorders, particularly tumour disease causing PPP. Unfortunately, medical advances in the diagnosis of these disorders have not been reflected in the medical treatment of McCune-Albright syndrome and testotoxicosis. Despite having tried various treatment options in both disorders, the results are very disappointing, especially in patients with McCune-Albright syndrome. To our knowledge, this failure is based on the absence of well-designed clinical trials that include an adequate number of patients followed up until the end of their growth.

Manifestaciones neuropsiquiátricas de la enfermedad de Graves en la edad pediátrica / Neuropsychiatric manifestations of Graves’ disease in paediatric patients

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[Central precocious puberty: epidemiology, etiology, diagnosis and treatment]. / Pubertad precoz central: aspectos epidemiológicos, etiológicos y diagnóstico-terapéuticos.

Central precocious puberty (CPP) is a rare disease with female predominance and a higher incidence among adopted children. Of idiopathic aetiology in most cases, in the past few years the first mutations in patients with CPP have been described. The prevalence of organic disease is notably lower among girls with CPP. However, no predictors have been described to select which kind of girls should undergo an imaging tests. Although the sensitivity of the determination of basal LH as a marker of CPP has improved with the new techniques, to date, the LH peak after LHRH stimulation test remains the gold standard for the diagnosis of CPP. Finally, the use of GnRH analogues has shown to be particularly effective in the treatment of CPP patients less than 6 years-old.