Publications

Linear growth restriction is a unique feature of paediatric inflammatory bowel diseases (IBD), and reduced insulin-like growth factor (IGF-1) is a major determinant of short stature. We aimed to assess factors influencing somatic height in children suffering from IBD.This was a retrospective, cross-sectional study conducted after approval by Institutional authorities. Anthropometric data, disease-related factors, biochemical and clinical indices of inflammation and endocrine parameters were recorded and considered as explanatory covariates. A structural equation model analysis was utilized. Somatic height was the outcome of interest, and possible associations of explanatory covariates directly or through the mediation effect of IGF-1 were assessed.Systemic inflammation, as expressed by high-sensitivity intereukin-6 (IL-6), and nutritional status described by body mass index (BMI) were the pathways that significantly affected stature through the mediation effect of IGF-1. Cortisol showed a direct, positive and independent of IGF-1 association with height.Insulin-like growth factor-1 is a key player in the process that results in impaired linear growth. Malnutrition and systemic inflammation have a restrictive action on growth by reducing circulating IGF-1. The positive relation of serum cortisol to height could correspond to suppressed pituitary-adrenal axis due to long-term use of glucocorticoids.

Background Insulin-like growth factor-1 (IGF-1) has been implicated in the growth and/or metastasis of osteosarcoma (OS) and chondrosarcoma based on in vitro and experimental animal studies. Study Purpose To determine the degree of growth hormone (GH), IGF-1 axis blockade, toxicities, and antitumor effect of OncoLar (ONC) (Novartis, East Hanover, NJ, U.S.A.) in OS. Design/Methods A phase 1 study with ONC enrolled 21 OS patients (median age 19 y) in four cohorts: ONC 60 mg or 90 mg intramuscularly every 4 weeks with/without tamoxifen (TAM) 20 mg oral daily. Results There were no dose-limiting toxicities. Nineteen percent of patients had grade III drug-related toxicities including: 62% of patients showed progressive disease after two courses (8 wk). Nineteen percent received four courses. No clinical responses were observed. At weeks two and eight of therapy, IGF-1 serum levels dropped 46% (P < 0.0001, n = 21) and 53% (P = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (ΔAUC) for arginine-stimulated GH serum levels at week two was lower than baseline (P < 0.01). At weeks two and eight, GH peak values were lower than baseline (P < 0.0001 and P = 0.002, respectively). Conclusions A long-acting somatostatin analog was able to lower IGF-1 levels of OS patients. IGF-BP-3 and GH were only transiently reduced. Although ONC was well tolerated, no sustained clinical responses were observed. The pathophysiology of serum versus tissue concentrations of IGF-1 as well as the interplay of IGFs, IGF-binding proteins, and other growth factors and cytokines in osteosarcoma warrants further investigation. A better understanding of these processes should lead to a more effective exploitation of these pathways for the targeted therapy of OS.

Existing studies of children with vasculitis are limited. The aim of this study was to assess the epidemiology, clinical manifestations, laboratory findings, course, and outcome of Greek children presenting with vasculitic rash.The relevant data included in the study were collected retrospectively using a standardized form from children who were admitted into our department between 2003 and 2013, with the provisional diagnosis of vasculitis of the skin.The study sample consisted of 95 children (58 boys, 37 girls) with a mean age of 5.9 years. In total, 76 out of 95 (80%) of the children were diagnosed with Henoch-Schönlein purpura, 10/95 (10.5%) with hypersensitivity vasculitis, 6/95 (6.3%) with urticarial vasculitis, and 3/95 (3.1%) with acute hemorrhagic edema of infancy. The mean age of the children was 5.7 years for Henoch-Schönlein purpura, 9 years for hypersensitivity vasculitis, 5.1 years for urticarial vasculitis, and 0.5 years for acute hemorrhagic edema of infancy.(i) The most common vasculitis presenting with skin rash in children is Henoch-Schönlein purpura; (ii) hypersensitivity vasculitis occurs in older children more often when compared to other types of vasculitis; (iii) urticarial vasculitis lesions may be a sign of severe underlying disease; therefore a thorough examination of these patients is warranted; (iv) Despite relapses, the overall prognosis of patients with pediatric skin vasculitides is good, with the exception of those with the urticarial vasculitis type.

✓ The potential efficacy of early repeat transsphenoidal surgery for persistent Cushing's disease has not previously been examined. On 222 patients with no prior pituitary treatment and a preoperative diagnosis of Cushing's disease, 29 (13%) remained hypercortisolemic after an initial transsphenoidal pituitary exploration. Seventeen of these 29 patients underwent further surgery 7 to 46 days after the initial transsphenoidal approach in order to completely excise suspected residual tumor. Patients were followed for 4 to 84 months (mean ± standard deviation, 34 ± 25 months) to document sustained remission or recurrence of Cushing's disease (a urine free cortisol level &gt; 90 µg/day was considered evidence of recurrence). Of the 17 patients with repeat surgery, 12 (71%) had resolution of hypercortisolism (morning plasma cortisol level &lt; 5 µg/dl); however, in three of these 12, hypercortisolism recurred 5, 12, and 24 months later. In 14 patients a lesion that appeared to be a tumor was identified during the initial procedure or on histological examination. Of these, 12 had immediate resolution of hypercortisolism and nine are still in remission. Three patients, in whom no adenoma could be identified during the initial surgery or an examination of the partial hypophysectomy specimen from the initial surgery, had persistent Cushing's syndrome after the second operation. Seven (41%) of the 17 patients developed hypopituitarism requiring treatment with thyroid hormone, gonadal steroid, or vasopressin replacement. The low incidence of identification of an adenoma on computerized tomography or magnetic resonance images (three of 17 patients), the failure to find a corticotrophic adenoma during the initial surgery (10 of 17 patients), and the failure of these 17 patients to respond to the initial transsphenoidal surgery suggest that they may comprise a subset of patients who are more difficult to treat successfully with surgery than most patients with Cushing's disease. Despite that, early reoperation induced immediate remission of hypercortisolism in 71% of cases, but did so at the expense of a high risk of hypopituitarism. However, since the alternative treatments (such as radiation therapy, long-term drug therapy, or bilateral adrenalectomy) also have potential adverse effects, early reoperation deserves consideration for the management of persistent Cushing's disease, especially when an adrenocorticotrophic hormone-secreting adenoma was partially excised during the first surgery.

The dramatic fluctuations in energy demands by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for biological temporal organization across phylogeny. The intrinsic circadian timing system (CS), represents a highly conserved and sophisticated internal "clock", adjusted to the 24-hour rotation period of the earth, enabling a nyctohemeral coordination of numerous physiologic processes, from gene expression to behavior. The human CS is tightly and bidirectionally interconnected to the stress system (SS). Both systems are fundamental for survival and regulate each other's activity in order to prepare the organism for the anticipated cyclic challenges. Thereby, the understanding of the temporal relationship between stressors and stress responses is critical for the comprehension of the molecular-basis of physiology and pathogenesis of disease. A critical loss of the harmonious timed order at different organizational levels may affect the fundamental properties of neuroendocrine, immune and autonomic systems, leading to a breakdown of biobehavioral adaptative mechanisms with increased stress sensitivity and vulnerability. In this review, following an overview of the functional components of the SS and CS, we present their multilevel interactions and discuss how traumatic stress can alter the interplay between the two systems. Circadian dysregulation after traumatic stress exposure may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of trauma through maladaptive stress regulation. Understanding the mechanisms susceptible to circadian dysregulation and their role in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and preventive strategies in stress-exposed populations.

Computed tomographic (CT) scans of the adrenal glands were obtained in nine patients with Cushing disease as a result of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and macronodular hyperplasia of the adrenal glands. The findings were compared retrospectively with those in six patients with Cushing syndrome as a result of an autonomous adrenal adenoma and 16 with Cushing syndrome as a result of ectopic ACTH production. Seven of nine patients with macronodular adrenal hyperplasia had hyperplastic adrenal glands in addition to single or multiple focal adrenal nodules. The six patients with hypercortisolism caused by an autonomous adrenal adenoma showed atrophic (four patients) or normal (two patients) ipsilateral and contralateral adrenal glands. Fourteen of 16 patients with the ectopic ACTH syndrome had hyperplasia of the adrenal glands without nodularity, and only two had focal nodules.

The aim of the present study was to investigate the associations of iron depletion (ID) with menstrual blood losses, lifestyle, and dietary habits, in pubertal girls. The study sample comprised 1222 girls aged 9–13 years old. Biochemical, anthropometrical, dietary, clinical, and physical activity data were collected. Out of 274 adolescent girls with menses, 33.5% were found to be iron depleted (defined as serum ferritin &lt; 12 μ g/L) compared to 15.9% out of 948 girls without menses. Iron-depleted girls without menses were found to have lower consumption of poultry (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.017</mml:mn></mml:math>) and higher consumption of fruits (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.044</mml:mn></mml:math>) and fast food (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.041</mml:mn></mml:math>) compared to their peers having normal iron status. Multivariate logistic regression analysis showed that girls with menses were 2.57 (95% CI: 1.37, 4.81) times more likely of being iron depleted compared to girls with no menses. Iron depletion was found to be associated with high calcium intake, high consumption of fast foods, and low consumption of poultry and fruits. Menses was the only factor that was found to significantly increase the likelihood of ID in these girls. More future research is probably needed in order to better understand the role of diet and menses in iron depletion.