Teresa Arrigo

Oxidative Stress in Obesity: A Critical Component in Human Diseases

Obesity, a social problem worldwide, is characterized by an increase in body weight that results in excessive fat accumulation. Obesity is a major cause of morbidity and mortality and leads to several diseases, including metabolic syndrome, diabetes mellitus, cardiovascular, fatty liver diseases, and cancer. Growing evidence allows us to understand the critical role of adipose tissue in controlling the physic-pathological mechanisms of obesity and related comorbidities. Recently, adipose tissue, especially in the visceral compartment, has been considered not only as a simple energy depository tissue, but also as an active endocrine organ releasing a variety of biologically active molecules known as adipocytokines or adipokines. Based on the complex interplay between adipokines, obesity is also characterized by chronic low grade inflammation with permanently increased oxidative stress (OS). Over-expression of oxidative stress damages cellular structures together with under-production of anti-oxidant mechanisms, leading to the development of obesity-related complications. The aim of this review is to summarize what is known in the relationship between OS in obesity and obesity-related diseases.

Bone demineralization in cystic fibrosis : Evidence of imbalance between bone formation and degradation

Bone turnover, collagen metabolism, and bone mineral status were investigated in 59 patients with cystic fibrosis and in 72 sex- and age-matched control subjects. In all patients and control subjects serum concentrations of osteocalcin (OC), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen(PIIINP), and cross-linked carboxy-terminal telopeptide of type I collagen(ICTP), and urinary values of cross-linked N-telopeptides of type I collagen (NTX), as well as total body bone mineral content (TBBM) were measured. Higher ICTP (μg/L) and NTX (bone collagen equivalent/urinary creatinine (nmol/mmol) values were found in prepubertal, pubertal, and young adult patients than in control subjects (ICTP: 15.4 ± 2.1 and 13.2± 1.8, p < 0.001; 23.3 ± 5.3 and 20.1 ± 4.1,p < 0.02; 4.8 ± 1.1 and 4.0 ± 1.0, p < 0.05, respectively; NTX: 1047.5 ± 528.6 and 227.8 ± 71.8,p < 0.01; 997.8 ± 391.7 and 376.3 ± 91.0,p < 0.01; 993.2 ± 398.0 and 73.9 ± 28.5,p < 0.01, respectively). Lower OC and PICP levels (μg/L) were showed in pubertal patients in comparison with control subjects (OC: 20.2± 12.3 and 39.0 ± 15.1, p < 0.01; PICP: 305.8± 130.4 and 436.2 ± 110.1, p < 0.02, respectively). Lower OC and higher PIIINP levels (μg/L) were found in young adult patients than in control subjects (OC: 4.4 ± 3.0 and 7.0 ± 3.1,p < 0.05; PIIINP: 4.8 ± 1.1 and 3.1 ± 1.0,p < 0.001, respectively). TBBM (z score) was reduced in prepubertal, pubertal, and young adult patients (-0.8 ± 0.4, -1.0± 0.4, -1.1 ± 0.5, respectively). Patients with cystic fibrosis have bone demineralization and imbalance between bone formation and degradation.

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study.

This study reports the results of genotype characterization and of a 10‐y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow‐up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: ΔF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) ΔF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.

High-mobility group protein B1: a new biomarker of metabolic syndrome in obese children.

INTRODUCTION Obesity is associated with a chronic low-grade inflammation. High-mobility group box 1 protein (HMGB1) plays a key role in inflammation and immunostimulatory and chemotactic processes. The aim of the study was to assess the role of HMGB1 in obese children and to evaluate its diagnostic profile in identifying childhood obesity-related complications, such as the metabolic syndrome (MS). PATIENTS AND METHODS Sixty obese children were enrolled and compared with 40 healthy children (control). Homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile, thyroid hormones, and pro- and anti-inflammatory peptides such as C-reactive protein (CRP), adiponectin, interleukin 6 (IL6), IL18, IL23, TNFα, resistin, and HMGB1 were evaluated. Receiver operating characteristics (ROC) analysis was employed to calculate the area under the curve (AUC) for HMGB1, IL6, and adiponectin to find the best cutoff values capable of identifying MS in obese children. RESULTS HMGB1 levels were statistically higher in obese patients than in the control group (19.4±6.8 vs 3.7±1.2 ng/ml; P<0.0001). In obese patients, IL18, IL6, and resistin levels were significantly high, while adiponectin levels were low. At multivariate analysis, HMGB1 was found to be independently correlated with BMI, IL23, IL6, free triiodothyronine, HDL, and HOMA-IR. At ROC analysis, HMGB1 showed higher sensitivity and specificity (AUC, 0. 992; sensitivity, 94.7%; specificity, 97.5%) than IL6 and adiponectin in identifying MS in obese children. CONCLUSION HMGB1 plays an important role in the inflammatory process associated with childhood obesity. This peptide may be an important diagnostic marker for obesity-related complications, such as MS.

Late hormonal function after testicular torsion

INTRODUCTION Testicular torsion may be an important cause of male infertility. We aimed to investigate the late hormonal function in patients with testicular ischemia/reperfusion injury of the testis after orchidectomy or detorsion. METHODS Twenty patients (mean age, 13.6 years) were prospectively evaluated at a mean of 5 years after testicular torsion. The serum follicle-stimulating hormone, luteinizing hormone (before and after gonadotropin-releasing hormone stimulation), testosterone, and inhibin B were measured. Fifteen age-matched adolescents without evidence of endocrine disease were used as controls for inhibin B values. Data are quoted as mean +/- SEM. RESULTS Twelve patients were treated with detorsion and orchidopexy, and 8 underwent orchidectomy. Serum follicle-stimulating hormone, luteinizing hormone, and testosterone were all within the reference range. Inhibin B levels were significantly reduced in the 2 groups compared with the controls (34.5 +/- 5.2 vs 63.9 +/- 12.8 pg/mL, P = .02), but were not significantly different between the orchidectomy group and the group that underwent detorsion (41.3 +/- 9.7 vs 30.4 +/- 5.9 pg/mL, P = .41). CONCLUSION Hormonal testicular function can be compromised after testicular torsion, although the type of surgery (orchidectomy or orchidopexy) does not seem to change the effect of this ischemia/reperfusion injury.

Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant

Abstract:  Endotracheal intubation is a common painful procedure in newborn care. Neonates are more sensitive to pain than older infants, children, and adults, and this hypersensitivity is further exacerbated in preterm neonates. The aim of this study was to evaluate the analgesic activity of melatonin during endotracheal intubation of the newborn by using the Neonatal Infant Pain Scale (NIPS) and Premature Infant Pain Profile (PIPP) score. Secondary outcome was an evaluation of melatonin as inflammatory responses. This was performed by measuring the levels of pro‐ and anti‐inflammatory cytokines implicated in the pain. Sixty preterm infants were enrolled in the study and were randomly divided into two groups: 30 infants treated with melatonin plus common sedation and analgesia recommended by Italian Society of Neonatology (group 1) and 30 infants treated with only common sedation and analgesia. The sedative and analgesic drugs included atropine, fentanyl, and vecuronium. The reduction in pain score (NIPS) was similar in both groups at an early phase, while it (PIPP score) was lower in melatonin‐treated group infants than the other newborns at a late phase, during intubation and mechanical ventilation. The differences were statistically significant at 12, 24, 48, and 72 hr (P < 0.001). Pro‐inflammatory and anti‐inflammatory cytokines (IL‐6, IL‐8, IL‐10 and IL‐12) were higher in the common sedation and analgesia group than in melatonin‐treated infants at 24, 48, 72 hr and 7 days (P < 0.001). This study suggests the use of melatonin as an adjunct analgesic therapy during procedural pain, especially when an inflammatory component is involved.

Oxidative Stress-Mediated Aging during the Fetal and Perinatal Periods

Oxidative stress is worldwide recognized as a fundamental component of the aging, a process that begins before birth. There is a critical balance between free radical generation and antioxidant defenses. Oxidative stress is caused by an imbalance between the production of free radicals and the ability of antioxidant system to detoxify them. Oxidative stress can occur early in pregnancy and continue in the postnatal period; this damage is implicated in the pathophysiology of pregnancy-related disorders, including recurrent pregnancy loss, preeclampsia and preterm premature rupture of membranes. Moreover, diseases of the neonatal period such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and periventricular leukomalacia are related to free radical damage. The specific contribution of oxidative stress to the pathogenesis and progression of these neonatal diseases is only partially understood. This review summarizes what is known about the role of oxidative stress in pregnancy and in the pathogenesis of common disorders of the newborn, as a component of the early aging process.

Frequency of Hashimoto's thyroiditis antecedents in the history of children and adolescents with graves' disease.

Background: The development of Graves’ disease (GD) from Hashimoto’s thyroiditis (HT) has sporadically been reported, but no data are available concerning the prevalence of this sequence of events in GD patients. Our aim was to ascertain HT antecedents in the history of GD children in order to assess for the first time the relative frequency of the event sequence leading from HT to GD in a pediatric population. Study Population and Results: In 105/109 patients, no HT antecedents were documented at GD presentation. The remaining 4 patients had previously exhibited a picture of HT with either hypothyroidism or euthyroidism. The interval between HT diagnosis and GD presentation ranged from 1.5 to 2.8 years. Serum thyrotropin receptor antibodies were higher in the patients with no HT antecedents. Conclusions: In at least 3.7% of the children with GD, hyperthyroidism may be preceded by HT presentation with either hypothyroidism or euthyroidism. The clinical course of GD in these patients is not different from the one observed in those with no HT antecedents. Our report confirms the existence of a continuum between HT and GD within the spectrum of autoimmune thyroid diseases.

Prolactin in obese children: a bridge between inflammation and metabolic-endocrine dysfunction

Adipocytes, regulated by insulin, represent the major peripheral source of prolactin (PRL), which play a pivotal role in energy balance, acting on adipogenesis and lipolysis. The aim of this study was to investigate whether PRL was associated with obesity‐related inflammatory status and metabolic parameters. The diagnostic and prognostic role of PRL for metabolic syndrome (MS) was assessed. The effects of short‐term lifestyle therapy on PRL levels were evaluated.

Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: A pilot study

Abstract Aim: To unravel the potential idiopathic intracranial hypertension (IIH) endocrine-metabolic comorbidities by studying the natural (and targeted drug-modified) history of disease in children. IIH is a disorder of unclear pathophysiology, characterized by raised intracranial pressure without hydrocephalus or space-occupying lesion coupled with normal cerebrospinal fluid (CSF) composition. Methods: Retrospective study (years 2001–2010) of clinical records and images and prospective follow-up (years 2010–2013) in 15 children (11 girls, 4 boys; aged 5–16 years) diagnosed previously as “IIH”, according to the criteria for pediatric IIH proposed by Rangwala, at four university pediatric centers in northern, central, and southern Italy. Results: We identified six potential endocrine-metabolic comorbidities including, weight gain and obesity (n=5), recombinant growth hormone therapy (n=3), obesity and metabolic syndrome (n=1), secondary hyperaldosteronism (n=1), hypervitaminosis A (n=1), and corticosteroid therapy (n=1). Response to etiologically targeted treatments (e.g., spironolactone, octreotide) was documented. Conclusions: IIH is a protean syndrome caused by various potential (risk and) associative factors. Several conditions could influence the pressure regulation of CSF. An endocrine-metabolic altered homeostasis could be suggested in some IIH patients, and in this context, etiologically targeted therapies (spironolactone) should be considered