Cardiovascular risk biomarkers and metabolically unhealthy status in prepubertal children: Comparison of definitions.

BACKGROUND AND AIMS: The early onset of cardio-metabolic abnormalities, known as metabolically unhealthy (MU) status, is highly associated with obesity and cardiovascular disease (CVD), as well as with increased morbidity and mortality later in life. Given the lack of a consensus MU classification for prepubertal children, we aimed to compare available MU definitions in terms of their association with CVD risk biomarkers. METHODS AND RESULTS: A total of 930 prepubertal children (622 with overweight/obesity, 462 males) aged 5-10.9 years were recruited, anthropometric measures were taken and biomarkers were analyzed. Children were classified using eight MU definitions based on different cut-offs for blood pressure, triacylglycerides, high-density lipoprotein cholesterol, glucose and homeostasis model assessment for insulin resistance (HOMA-IR). MU prevalence in children with overweight/obesity ranged between 30% and 60% across definitions. Plasma concentrations of resistin, leptin, myeloperoxidase (MPO) and total plasminogen activator inhibitor 1 (tPAI-1) were higher, and those of adiponectin were lower, in MU compared to MH children with overweight/obesity. Linear regression analyses confirmed the contribution of MPO and tPAI-1 concentrations to MU status, with most significant results derived from definitions that use age and sex-specific criteria and that account for HOMA-IR. CONCLUSION: Plasma concentrations of MPO and tPAI-1 are increased in prepubertal MU children irrespective of having normal-weight or overweight/obesity. Inclusion of age and sex-specific cut-offs for cardio-metabolic components as well as insulin resistance criteria increases the quality of MU definitions as seen by their stronger association with CVD biomarkers concentrations.

Vesiculobullous variant of erythema elevatum diutinum.

The vesiculobullous variant of erythema elevatum diutinum (EED) is a very rare variant of EED. We describe a 16-year-old boy who presented with symmetrical nodular lesions accompanied by vesicles on the dorsa of his hands. Biopsy findings were consistent with EED. The histopathological presence of IgA and neutrophils in the vesicles indicates that the joint action of both is responsible for formation of these subepidermic vesicles. We hypothesize that absence of human leucocyte antigen related to dermatitis herpetiformis (DH) in our patient might have influenced the location and distribution of the lesions, so that they were not typical of DH. We report the second case of the vesiculobullous variant of EED with IgA deposits in the dermoepidermal membrane. To our knowledge, there are only 14 previously reported cases of the vesiculobullous variant of EED.

Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders.

INTRODUCTION: Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain cases genotype-phenotype correlations are important for predicting the clinical course of the disease and to allow tailor-made follow-up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next-generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost. AIM: The aim of this study was to design and to analyse the applicability of a 23-gene NGS panel in the molecular diagnosis of patients with IBCDs. METHODS: A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology. RESULTS: In all patients, our NGS approach detected causative mutations. Twenty-one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant. CONCLUSION: Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.

Differential Diagnosis of Genetic Disorders Associated with Moderate to Severe Refractory Eczema and Elevated Immunoglobulin E.

The association of moderate to severe eczema and elevated plasma levels of immunoglobulin E is a characteristic not only of atopic dermatitis but also of various genodermatoses: hyperimmunoglobulin E syndromes, Omenn syndrome, Netherton syndrome, peeling skin syndrome type B, severe dermatitis, multiple allergies, and metabolic wasting syndrome, Wiskott-Aldrich syndrome, prolidase deficiency, Loeys-Dietz syndrome, IPEX syndrome, STAT5B deficiency, and pentasomy X. The clinical presentation of these genodermatoses -typically in children- is consistent with severe atopic dermatitis. Immunoglobulin E is elevated from birth and response to conventional treatments is poor. Diagnosis is further complicated by the fact that these genodermatoses often share other clinical manifestations and laboratory findings. We present practical guidelines for differentiating among these various entities, with the aim of helping physicians decide what type of genetic test should be carried out -and when- in order to establish a definitive diagnosis.

Effect of two bakery products on short-term food intake and gut-hormones in young adults: a pilot study.

The aim of this study is to compare the effect of conventional bread and a whole grain bread on appetite and energy intake, satiety and satiety gut-hormones. A randomized controlled crossover pilot study was carried out in 11 university students (age: 18.7 ± 0.9 years; body mass index: 22.7 ± 2.7 kg/m(2)). Participants consumed two different mid-morning cereal-based snacks, including a conventional or whole grain bread. Two testing days were completed, including satiety questionnaires, blood sampling and consumption of standardized breakfast, mid-morning test-snacks and ad libitum lunch. Several gut-hormones were analysed and satiation was assessed using Visual Analogue Scale scores. The consumption of whole grain bread increased satiety perception, decreased the remained energy intake during the testing day, and decreased the postprandial response of peptide YY, compared with conventional bread (p < 0.005). These data suggest that the consumption of whole grain bread might be a useful strategy to improve satiety.

Paraoxonase 1 activities and genetic variation in childhood obesity.

Changes in paraoxonase 1 (PON1) activities have been observed in a variety of diseases involving oxidative stress, such as CVD. However, its role in obesity has not been fully established. In the present study, we aimed (1) to genotype sixteen PON1 SNP, (2) to measure serum PON1 activities and (3) to correlate these findings with the incidence of childhood obesity and related traits. We conducted a case-control study of 189 normal-weight and 179 obese prepubertal children, and we measured four different PON1 activities: lactonase; paraoxonase; arylesterase; diazoxonase. Although none of these activities was significantly different between the obese and normal-weight children, lactonase activity was found to be positively correlated with HDL-cholesterol and ApoA1 levels and negatively correlated with myeloperoxidase and fatty acid-binding protein 4 levels. Among the sixteen genotyped PON1 SNP, only the intronic SNP rs854566 exhibited a significant association with obesity (OR 0·61, 95 % CI 0·41, 0·91; P= 0·016). This genetic variant was also associated with increased diazoxonase, lactonase and arylesterase activities and decreased paraoxonase activity. Other genetic variants exhibited different association patterns with serum activities based on their location within the PON1 gene, and SNP that were located within the promoter were strongly associated with lactonase, arylesterase and diazoxonase activities. The functional variant Q192R exhibited the greatest effect on paraoxonase activity (P= 5·88 × 10(-42)). In conclusion, SNP rs854566 was negatively associated with childhood obesity and with increased serum PON1 activities in prepubertal children. We determined that lactonase is a reliable indicator of PON1 activities and should be included in future studies of PON1 function.

A gene variant of 11ß-hydroxysteroid dehydrogenase type 1 is associated with obesity in children.

BACKGROUND: The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme catalyses the regeneration of active cortisol from inert cortisone and plays a critical role in tissue-specific corticosteroid reactions; therefore, 11ß-HSD1 is a key molecule associated with the development of obesity. Despite evidence for its role in obesity, no genetic polymorphisms have been significantly associated with the disease per se. OBJECTIVE: The aim of this study was to evaluate whether HSD11B1 gene variants, which have never been studied before, are associated with obesity and its related traits, as well as its relation to biomarkers of inflammation, liver damage and cardiovascular disease in a cohort of Spanish children. DESIGN: We performed a prospective case-control study. SUBJECTS: A total of 534 children were examined and classified as being obese (n=292) or normal weight (n=242). Anthropometric and biochemical measurements related to obesity, including inflammation, liver damage and cardiovascular disease, were determined. Genomic DNA was extracted and 10 HSD11B1 gene single-nucleotide polymorphisms (SNPs) were genotyped. RESULTS: A novel SNP, rs3753519, was strongly associated with obesity and this SNP was the only statistically significant HSD11B1 gene SNP remaining after a Bonferroni correction (odds ratio=1.97 for allelic effect, 95% confidence interval 1.23-3.16; P=0.004 and Bonferroni corrected P=0.046). In addition, this SNP was significantly and positively associated with increased body mass index (BMI), BMI z-score, weight, waist circumference, plasma γ-glutamyl transpeptidase and plasma active plasminogen activator inhibitor 1. The SNP was negatively associated with plasma adiponectin and cortisol after adjusting for sex and age. None of the inflammation biomarkers tested were associated with the risk allele. CONCLUSION: These data, which link an HSD11B1 genotype with both disease prevalence and its related phenotypes, strongly support a role for the rs3753519 polymorphism in the pathogenesis of pediatric-onset obesity.

Cloning and expression pattern of facilitative glucose transporter 1 (GLUT1) in gilthead sea bream Sparus aurata in response to salinity acclimation.

Facilitative glucose transporters (GLUT) are transmembrane transporter proteins involved in glucose transport across the plasma membrane. In fish, several GLUT mRNAs have been cloned, but to date there is no information about these transporters in the marine euryhaline teleost Sparus aurata. In the present study we obtained the complete coding sequence from S. aurata GLUT1 (saGLUT1), composed by 4483 bases, presenting a 79 to 95% identity with respect to other fish GLUT1 mRNAs. The analysis of the 5' and 3' UTRs showed the presence of several post-transcriptional regulatory elements. In addition, the effect on saGLUT1 mRNA expression of the osmotic acclimation to four different environmental salinities (5, 12, 40 and 55 ppt), in gills, kidney, liver and brain, was studied. Changes in mRNA expression levels were detected in gills and brain, indicating that GLUT1 has an important role in these organs for osmotic acclimation in S. aurata.

[E-consultation as a tool for the relationship between Primary Care and Endocrinology. Impact of COVID-19 epidemic in its use]. / La e-consulta como herramienta para la relación entre Atención Primaria y Endocrinología. Impacto de la epidemia por COVID-19 en su uso.

INTRODUCTION: Electronic consultation (eConsultation) can precede, complete, or replace visits to the specialist. OBJECTIVE: To describe the profile of eConsultations issued from Primary Care (PC) to the Endocrinology Unit since their implementation in our hospital, to assess the response time and to evaluate changes in trends in relation to the COVID19 pandemic. A secondary objective is to evaluate the degree of satisfaction of PC specialists with this tool. MATERIAL AND METHODS: An observational retrospective study of Endocrinology eConsultations conducted from June 2019 to October 2020 analysing 2periods: pre-COVID and post-COVID. The degree of satisfaction of the Family and Community Medicine specialists was assessed by means of a questionnaire. RESULTS: 391 eConsultations were answered (69 pre-COVID and 322 post-COVID). The response time was less than 24h in 85% of them. A total of 35.3% were resolved without the need for visits or additional tests. Thyroid pathology was the most consulted. The incidence was significantly higher in the post-COVID period. The proportion of high resolution was significantly higher in the pre-COVID period. There were no differences in the rest of the parameters analysed in both periods. Thirty-nine point 2percent of PC specialists answered the survey. The degree of satisfaction of PC specialists was high. A total of 92.7% considered that the tool met their expectations and 90.5% were satisfied or very satisfied with its use. CONCLUSION: The COVID epidemic has driven the use of eConsultation in Endocrinology, which makes it possible to precede, complete or replace visits to the specialist, with a high degree of user satisfaction.

Fasting and postprandial adiponectin alterations anticipate NEFA and TNF-α changes in prepubertal obese children.

BACKGROUND AND AIMS: It has been suggested that adipokine changes might precede changes in plasma non-esterified fatty acids and other obesity metabolic biomarkers. The aim of the present study was to evaluate changes in fasting and postprandial plasma levels of adiponectin, non-esterified fatty acids, and tumor necrosis factor-alpha in prepubertal obese children and age-matched normal-weight children. METHODS AND RESULTS: Fifty-four children of prepubertal age (34 obese, comprising 23 males and 11 females, and 20 normal-weight comprising 11 males and 9 females) were studied. A standard 438 kcal breakfast was given to both groups. Baseline measurements included anthropometry and plasma lipids. The following parameters were determined in plasma before and after breakfast: glucose, insulin, and C-peptide at baseline and 2h and non-esterified fatty acids, adiponectin, and tumor necrosis factor-alpha at baseline and 1, 2, and 3h. Fasting plasma non-esterified fatty acid levels were lower in the obese versus normal-weight children (P=0.021). Both at baseline and postprandially, plasma adiponectin levels were lower in the obese versus normal-weight children (P<0.001). A trend was observed (P=0.06) that levels of tumor necrosis factor-alpha were lower in the obese versus normal-weight children. Adiponectin was inversely associated with insulin in the obese children after adjustment for BMI and sex (r=-0.401, P=0.025). CONCLUSION: At prepubertal age, obese children show lower fasting and postprandial plasma adiponectin levels in comparison to normal-weight children, whereas non-esterified fatty acids and tumor necrosis factor-alpha were not yet increased. Therefore, adiponectin appears to be a good marker of early metabolic alterations associated with childhood obesity.