Cardiometabolic and Cardiovascular Complications of Obesity in Children

The rise in obesity in both children and adults has made obesity one of the biggest public health problems of this century. Obesity along with other factors such as hypertension, insulin resistance, dyslipidemia and diabetes mellitus are risk factors for the development of cardiovascular diseases. Overweight and/or obesity during childhood and its maintenance until adult life has been associated with early stages of cardiovascular disease. For this reason, the aim of this study is to revise the state of the art of cardiometabolic and cardiovascular complications related with overweight and/or obesity in children and adolescents. The first consequence of weight gain is an increase in adipose tissue, with different distribution depending on the sex. The excess of fat mass entails dysfunction of adipose tissue with an altered secretion of adipokines and instauration of a proinflammatory environment, which may derive in metabolic syndrome condition. The increase of adipose tissue along with an increase in sympathetic nervous system, triggers an increased left ventricular mass and with a reduced diastolic function. Therefore, obesity should be prevented from the early stages of life, in order to avoid obesity itself and the metabolic disturbances that could undermine quality of life further on

Metabolic syndrome before puberty: Myth or reality?

Metabolic syndrome (MetS) is defined as a cluster of alterations related with insulin resistance (obesity, dyslipidemia, hypertension, and impaired glucose metabolism), which are associated with a higher risk of cardiovascular disease in adults. Several definitions have been proposed for older children and adolescents. However, no definitions have been made in accordance with pubertal status, and those in prepubertal state have not received attention enough, despite there are data suggesting the early presence of risk factors. The new insights concerning healthy and unhealthy metabolic status or the addition of novel metabolic risk biomarkers, may contribute to the knowledge about the development of MetS in children. This manuscript reviews the available evidence on MetS during childhood, focusing on the prepubertal period

Modificaciones en variables antropométricas, analíticas de riesgo metabólico y composición corporal en pequeños para la edad gestacional en tratamiento con hormona de crecimiento

Introducción Los niños pequeños para la edad gestacional (PEG) sin crecimiento recuperador pueden beneficiarse del tratamiento con hormona de crecimiento (rhGH). Sin embargo, deben ser monitorizados de forma muy estrecha ya que son población de riesgo metabólico. Material y métodos Se han incluido 28 niños PEG, con una media de edad de 8, 79 años, sin crecimiento recuperador, tratados con rhGH. Hemos evaluado las modificaciones producidas en la antropometría, variables de riesgo metabólico y composición corporal durante 4 años de tratamiento. Resultados El tratamiento con rhGH se acompañó de un aumento de talla (–2, 76 ± 0, 11 DE hasta –1, 53 ± 0, 17 DE; p = 0, 000), peso (–1, 50 ± 0, 09 DE hasta –1, 21 ± 0, 13 DE; p = 0, 016) y velocidad de crecimiento (–1, 43 ± 0, 35 DE hasta 0, 41 ± 0, 41 DE; p = 0, 009), sin producir modificaciones en el índice de masa corporal (IMC). Se han visto aumentos significativos de la insulinemia (9, 33 ± 1, 93 mU/ml hasta 16, 55 ± 1, 72 mU/ml; p = 0, 044) y del índice HOMA (3, 63 ± 0, 76 hasta 6, 43 ± 0, 67; p = 0, 042), sin producirse modificaciones en el perfil lipídico. En el estudio de composición corporal se ha comprobado un aumento significativo de la masa magra (73, 19 ± 1, 26 hasta 78, 74 ± 1, 31; p = 0, 037) con una disminución de la masa grasa (26, 81 ± 1, 26 hasta 21, 26 ± 1, 31; p = 0, 021). Conclusión El tratamiento con rhGH se ha acompañado de una ganancia en la talla sin producir alteraciones en el IMC. Asimismo, se han observado cambios en la composición corporal, con un aumento de la proporción de masa magra a expensas de una disminución de la de masa grasa, que podrían conducir a un descenso del riesgo metabólico de estos pacientes. Sin embargo, se ha detectado cierta resistencia insulínica. Es importante continuar el seguimiento de estos niños para determinar las posibles repercusiones en la edad adulta. Introduction and objectives Small for gestational age (SGA) children without catch-up growth can benefit from treatment with growth hormone (rhGH). However, they should be monitored very closely because they are at increased risk of metabolic syndrome. Material and method A group of 28 SGA children with a mean age of 8.79 years and undergoing treatment with rhGH were selected for evaluation. Over the course of 4 years, an annual evaluation was performed on the anthropometric variables (weight, height, body mass index [BMI], growth rate, blood pressure and waist perimeter), metabolic risk variables (glycaemia, glycosylated haemoglobin, cholesterol ratio, insulinaemia, insulin-like growth factor 1[IGF1], IGF binding protein-3 [IGFBP-3], IGF1/IGFBP3 ratio, and HOMA index), and body composition variables. Results Treatment with rhGH was associated with a significant increase in height (–2.76 ± .11 SD to –1.53 ± .17 SD, P = .000), weight (–1.50 ± .09 SD to –1.21 ± .13 SD; P = .016), and growth rate (–1.43 ± .35 SD to .41 ± .41 SD; P = .009), without a corresponding change in the BMI. Insulinaemia (9.33 ± 1.93 mU/ml to 16.55 ± 1.72 mU/ml; P = .044) and the HOMA index (3.63 ± .76 to 6.43 ± .67; P = .042) increased, approaching insulin resistance levels. No changes were observed in the lipid profile. Body composition changes were observed, with a significant increase in lean mass (73.19 ± 1.26 to 78.74 ± 1.31; P = .037), and a reduction of fat mass (26.81 ± 1.26 to 21.26 ± 1.31; P = .021). Conclusion Treatment with rhGH is effective for improving anthropometric variables in SGA patients who have not experienced a catch-up growth. It also produces changes in body composition, which may lead to a reduction in risk of metabolic syndrome. However, some insulin resistance was observed. It is important to follow up this patient group in order to find out whether these changes persist into adulthood

Height-based equations as screening tools for high blood pressure in pediatric practice, the GENOBOX study

Due to the absence of easily applicable cut-off points to determine high blood pressure or hypertension in children, as in the adult population, blood pressure is rarely measured in the pediatrician''s clinical routine. This has led to an underdiagnosis of high blood pressure or hypertension in children. For this reason, the present study evaluate the utility of five equations for the screening of high blood pressure in children: blood pressure to height ratio, modified blood pressure to height ratio, new modified blood pressure to height ratio, new simple formula and height-based equations. The authors evaluated 1599 children between 5 and 18 years. The performance of the five equations was analyzed using the receiver-operating characteristics curves for identifying blood pressure above P90th according to the American Academy of Pediatrics Clinical Practice Guideline 2017. All equations showed an area under the curve above 0.882. The new modified blood pressure to height ratio revealed a high sensitivity whereas the height-based equations showed the best performance, with a positive predictive value above 88.2%. Finally, all equations showed higher positive predictive values in children with overweight or obesity. The height-based equation obtained the highest PPV values above 71.1% in children with normal weight and above 90.2% in children with overweight or obesity. In conclusions, the authors recommend the use of the height-based equations equation because it showed the best positive predictive values to identify children with elevated blood pressure, independently of their sex, pubertal and weight status. © 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor

Background: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. Methods: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. Results: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. Conclusion: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

BACKGROUND: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. METHODS: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. RESULTS: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. CONCLUSION: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies

High rate of autonomic neuropathy in Cornelia de Lange Syndrome

Background: Cornelia de Lange Syndrome (CdLS) is a rare congenital disorder characterized by typical facial features, growth failure, limb abnormalities, and gastroesophageal dysfunction that may be caused by mutations in several genes that disrupt gene regulation early in development. Symptoms in individuals with CdLS suggest that the peripheral nervous system (PNS) is involved, yet there is little direct evidence. Method: Somatic nervous system was evaluated by conventional motor and sensory nerve conduction studies and autonomic nervous system by heart rate variability, sympathetic skin response and sudomotor testing. CdLS Clinical Score and genetic studies were also obtained. Results: Sympathetic skin response and sudomotor test were pathological in 35% and 34% of the individuals with CdLS, respectively. Nevertheless, normal values in large fiber nerve function studies. Conclusions: Autonomic nervous system (ANS) dysfunction is found in many individuals with Cornelia de Lange Syndrome, and could be related to premature aging

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas: clinico-pathologic results

Background: intraductal papillary mucinous neoplasm (IPMN) shows a series of lesions which evolve from benign lesions –adenoma– to invasive carcinoma. Aim: to analyze the clinical and pathological results of 15 patients diagnosed of IPMN, and surgically treated according to the guidelines of International Consensus Conference. Material and methods: a retrospective analysis of 15 patients surgically treated between March 1993 and September 2009, according to the International Consensus recommendation. Demographic, diagnostic tools, surgical report, pathologic database and actuarial survival were analyzed with a follow-up from one and a half month through nine years. Results: 6 patients underwent pancreaticoduodenectomies, 4 total pancreatectomies, 2 body or central pancreatectomies, 2 partial pancreatectomies (enucleation) and 1 distal pancreatectomy. A morbidity of 46 and 0% hospital mortality were assessed, with a median length hospital stay of 10 days. In five cases, the IPMN was combined type (both main and branch pancreatic ducts involved) in four main duct-type and branch duct-type in the another six as well. Several atypia (IPMN carcinoma in situ) was observed in 2 patients and invasive carcinoma with negative lymph nodes was identified in 3 patients. A patient without invasive carcinoma died at 66 months of follow-up for pancreas adenocarcinoma. The actuarial survival up to recurrence or death was 105,133 months with a range of follow-up from 1 month and a half until 9 years. Conclusions: IPMN main duct or mixed type warrants complete resection due to its incidence of invasive carcinoma or precursor lesions of malignancy as well. Due to its multifocal pattern, patients should be followed in long-term surveillance. The management of asymptomatic IPMN type branch less than 3 cm is controversial

Prepubertal Children With Metabolically Healthy Obesity or Overweight Are More Active Than Their Metabolically Unhealthy Peers Irrespective of Weight Status: GENOBOX Study

Background and Aim: The association of a metabolically healthy status with the practice of physical activity (PA) remains unclear. Sedentarism and low PA have been linked to increased cardiometabolic risk. The aim of this study was to evaluate the PA levels in metabolically healthy (MH) or unhealthy (MU) prepubertal children with or without overweight/obesity. Methods: A total 275 children (144 boys) with 9 ± 2 years old were selected for the GENOBOX study. PA times and intensities were evaluated by accelerometry, and anthropometry, blood pressure, and blood biochemical markers were analyzed. Children were considered to have normal weight or obesity, and further classified as MH or MU upon fulfillment of the considered metabolic criteria. Results: Classification resulted in 119 MH children (21% with overweight/obesity, referred to as MHO) and 156 MU children (47% with overweight/obesity, referred to as MUO). Regarding metabolic profile, MHO showed lower blood pressure levels, both systolic and diastolic and biochemical markers levels, such as glucose, Homeostatic Model Assessment of Insulin Resistance, triglycerides and higher HDL-c levels than MUO (P < 0.001). In addition, MHO children spent more time in PA of moderate intensity compared with MUO children. In relation to vigorous PA, MH normal weight (MHN) children showed higher levels than MUO children. Considering sex, boys spent more time engaged in moderate, vigorous, and moderate–vigorous (MV) PA than girls, and the number of boys in the MH group was also higher. Conclusion: Prepubertal MHO children are less sedentary, more active, and have better metabolic profiles than their MUO peers. However, all children, especially girls, should increase their PA engagement, both in terms of time and intensity because PA appears to be beneficial for metabolic health status itself. Copyright © 2022 Llorente-Cantarero, Leis, Rupérez, Anguita-Ruiz, Vázquez-Cobela, Flores-Rojas, González-Gil, Aguilera, Moreno, Gil-Campos and Bueno

Are peripheral biomarkers determinants of eating styles in childhood and adolescence obesity? A cross-sectional study

Disturbances in eating behaviors have been widely related to obesity. However, little is known about the role of obesity-related biomarkers in shaping habitual patterns of eating behaviors (i.e., eating styles) in childhood. The objective of the present study was to explore the relationships between several biomarkers crucially involved in obesity (ghrelin, insulin resistance, and leptin/adiponectin ratio) and eating styles in children and adolescents with obesity. Seventy participants aged between 8 and 16 (56.2% men) fulfilled the Spanish version of the Dutch Eating Behavior Questionnaire for Children to measure external, emotional, and restrained eating styles. In addition, concentrations of ghrelin, leptin, adiponectin, insulin, and glucose were obtained through a blood test. Hierarchical multiple regression analyses controlling for age and sex were computed for each eating style. Results indicated that individuals with higher ghrelin concentration levels showed lower scores in restrained eating (beta = -0.61, p < 0.001). The total model explained 32% of the variance of the restrained pattern. No other relationships between obesity-related biomarkers and eating behaviors were found. This study highlights that one of the obesity-risk factors, namely lower plasma ghrelin levels, is substantially involved in a well-known maladaptive eating style, restraint eating, in childhood obesity