Publications by authors named "Bessie E Spiliotis"

33 Publications

Cardiorespiratory Fitness Predicted by Fibrinogen and Leptin Concentrations in Children with Obesity and Risk for Diabetes: A Cross-Sectional Study and a ROC Curve Analysis.

Nutrients 2021 Feb 19;13(2). Epub 2021 Feb 19.

Paediatric Endocrine Research Laboratory, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, School of Medicine, University of Patras, University Campus, GR-26504 Patras, Greece.

Obesity is defined as abnormal or excessive fat accumulation that presents a risk to health. The ability to exercise is affected by adiposity, and this mechanism involves low-grade chronic inflammation and homeostatic stress produced mainly in adipocytes, which can result in abnormal adipokine secretion. To date, the gold standard for cardiorespiratory fitness assessment is considered to be the maximum oxygen uptake (VO). The aim of the present study was to assess the prognostic value of hematological parameters of childhood obesity, as potential predictors of cardiorespiratory fitness (VO), using a sample of children and adolescents with obesity and risk for diabetes. A total of 84 clinically healthy children and adolescents were recruited, of which 21 were considered lean, 22 overweight and 41 obese, with a mean age of 12.0 ± 1.9, 11.4 ± 2.0, and 11.2 ± 2.1 years old, in each weight status category, respectively. Age and sex did not differ between groups. Hematologic testing was performed after 12 h of fasting including glucose, serum lipids, insulin, hc-CRP, adiponectin, leptin and fibrinogen levels. Cardiorespiratory capacity for exercise was assessed to determine VO, using a cycle ergometer. The VO was negatively correlated with progressive strength to the BMIz (-0.656, ≤ 0.001), hs-CRP (r = -0.341, ≤ 0.002), glucose (r = -0.404, ≤ 0.001) and insulin levels (r = -0.348, ≤ 0.001), the homeostasis model assessment of insulin resistance (HOMA-IR) (r = -0.345, ≤ 0.002), as well as to the leptin (r = -0.639, ≤ 0.001) and fibrinogen concentrations (r = -0.520, ≤ 0.001). The multivariate analysis revealed that only leptin and fibrinogen concentrations could predict the VO adjusted for the BMIz of participants. The receiver operating characteristic (ROC) curve for the diagnostic accuracy of leptin, hs-CRP and fibrinogen concentrations for the prediction of VO revealed a good diagnostic ability for all parameters, with leptin being the most promising one (area under the curve (AUC): 99%). The results verify that in children with obesity, VO may be predicted from hematological parameters (leptin and fibrinogen), possibly bypassing more invasive methods.
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http://dx.doi.org/10.3390/nu13020674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923274PMC
February 2021

Correlation between insulin-like peptide 3 and appendix testis length in congenital cryptorchidism.

J Paediatr Child Health 2020 Aug 15;56(8):1283-1289. Epub 2020 Jul 15.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, University of Patras, Patras, Greece.

Aim: The appendix testis (AT) is a vestigial remnant of Müller's paramesonephric duct. Insulin-like 3 hormone (INSL3) is produced in the Leydig cells of the testis. We investigated the possible correlation between AT length and plasma INSL3 concentrations in patients with congenital cryptorchidism (CCO) and patients with hydrocele, who served as controls.

Methods: A total of 40 patients with CCO and 34 patients with hydrocele and orthotopic testes were investigated. Sixteen patients presented high cryptorchidism and 24 low cryptorchidism. During surgery, AT was identified in 34 patients with CCO (high cryptorchidism:15, low cryptorchidism:19) and 28 controls. Plasma INSL3 levels were measured with a spectrophotometry enzyme immunoassay Elisa sandwich technique.

Results: AT was present in 85.0% of the boys with CCO and 82.4% of the controls. A significant positive correlation was found between the AT length and INSL3 concentrations in CCO patients.

Conclusions: A longer AT may reflect better testicular function in boys with CCO, since it is correlated with higher INSL3 concentrations.
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http://dx.doi.org/10.1111/jpc.14924DOI Listing
August 2020

Polycystic ovary Syndrome in Adolescents: Pitfalls in Diagnosis and Management.

Curr Obes Rep 2020 Sep;9(3):193-203

Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Purpose Of Review: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder during a woman's reproductive lifespan, with well-documented diagnostic criteria and therapeutic strategies in adults; the same is not necessarily true for adolescents. The purpose of this review was to identify frequent pitfalls in PCOS diagnosis and management during adolescence.

Recent Findings: Although there is no global consensus on the definition, most experts converge to the presence of both oligo/amenorrhea and (clinical and/or biochemical) hyperandrogenism, as a prerequisite for diagnosis in adolescents. The former criterion includes: (a) consecutive menstrual intervals > 90 days even in the first year after menarche; (b) menstrual intervals persistently < 21 or > 45 days for ≥ 2 years after menarche; or (c) lack of menses by the age of 15 or 2-3 years after pubarche. However, these menstrual irregularity patterns may overlap with other common entities in adolescents, such as frequent or infrequent uterine bleeding or anovulation due to immaturity of the hypothalamic-pituitary-ovarian axis. Clinical signs of hyperandrogenism are obscure, without well-validated criteria. Finally, the criterion of polycystic morphology cannot be safely used in adolescents, mostly due to technical limitations of the transabdominal ultrasound. Except for the efficacy of lifestyle intervention in overweight and obese adolescents with PCOS, limited and low-quality data exist regarding the available medications, such as oral contraceptives, metformin, and anti-androgens. Individualized management, guided by clinical experience and research data and close monitoring appear the most effective approach in this PCOS population for optimal control of its reproductive and metabolic outcomes. Research focusing on PCOS genetic and molecular mechanisms may elucidate what diagnostic and therapeutic strategies will be most appropriate in adolescents with PCOS in the future.
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http://dx.doi.org/10.1007/s13679-020-00388-9DOI Listing
September 2020

Seasonal variation and epidemiological parameters in children from Greece with type 1 diabetes mellitus (T1DM).

Pediatr Res 2021 Feb 23;89(3):574-578. Epub 2020 Apr 23.

Department of Paediatrics, University of Patras School of Medicine, 26500, Patras, Greece.

Background: A positive correlation between T1DM onset and winter has been suggested by several studies. We investigated the seasonal variation of T1DM diagnosis and epidemiological parameters in children from Western Greece with T1DM.

Methods: One hundred and five patients, 44 males, aged 1-16 years were studied. The month of the diagnosis, the order of birth, gestational age, birth weight, the mode of delivery, parental age and pubertal status were recorded from the patients' files.

Results: The mean age at diagnosis was 8.1 ± 4.0 years. The majority of the studied patients were diagnosed during the period of October-March. The majority were born at full term, 11.7% were preterm babies and 52.3% were first born. The mean birth weight was 3266 ± 596 g. 60% were born by vaginal delivery. The majority of the patients were prepubertal at diagnosis.

Conclusions: Our results are in agreement with the reported seasonal variation of T1DM onset in other regions of Greece and Europe. The positive correlation between T1DM presentation and colder temperatures may be explained by factors such as viral infections. This is the first report on epidemiological parameters that may be related to T1DM presentation in Western Greece. The study of such parameters extends the understanding on the disease as a whole.

Impact: A seasonality of the T1DM diagnosis is shown, with a predominance of the colder months of the year. This is in agreement with previous reports from other countries. Our findings confirm previously reported data and add to the existing knowledge on T1DM in general. Additionally, this is one of the few reports on the incidence and epidemiology of T1DM in Greece and the first in the region of Western Greece. Safer and more accurate conclusions can be drawn with regards to the possible causes and predisposing factors of T1DM by the assessment of statistical data from different populations throughout the world. This offers a better understanding of T1DM and may also contribute to the identification of factors that may reduce the incidence of the disease in the future.
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http://dx.doi.org/10.1038/s41390-020-0899-1DOI Listing
February 2021

The role of carbohydrate counting in glycemic control and oxidative stress in patients with type 1 diabetes mellitus (T1DM).

Hormones (Athens) 2020 Sep 27;19(3):433-438. Epub 2020 Mar 27.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, University of Patras, 26504, Patras, Greece.

Purpose: Oxidative stress is closely related to type 1 diabetes mellitus (T1DM), playing a key role in the pathogenesis of the disease and progression of complications. It is characterized by loss of equilibrium between oxidative factors and antioxidant protective mechanisms. Several markers have been used to assess both components of oxidative status; two of which are malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP).

Methods: We investigated glycated hemoglobin (HbA1c), lipid profile, MDA, and FRAP in 35 patients with T1DM, aged 2-23 years, at the end of two 4-month observational periods: period A: standard insulin dosing per meal, and period B: proper prandial insulin dosing based on the amount of carbohydrates contained in each meal.

Results: At the end of period B, (i) glucose control (HbA1c) was improved; (ii) oxidative stress, estimated by MDA, showed a tendency to decrease; and (iii) antioxidant capacity, estimated by FRAP, was significantly increased compared with that of period A. No significant differences were observed in the lipid profile of the patients between the two periods.

Conclusion: Proper insulin dosing based on carbohydrate counting (CC) may have an impact on the antioxidant defensive mechanisms of patients with T1DM through the attainment of a better glycemic profile. There are also indications that it may reduce MDA, an important biomarker of oxidative stress and a significant mediator of complications in T1DM. Therefore, prompt dietetic intervention using CC as early as possible after the diagnosis of T1DM is important for achieving optimal glycemic control and improved oxidative status.
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http://dx.doi.org/10.1007/s42000-020-00189-8DOI Listing
September 2020

The metabolic implications of aquaporin 7 (AQP7) promoter variants in lean children and children with obesity.

Hormones (Athens) 2020 Jun 7;19(2):187-195. Epub 2020 Mar 7.

Department of Paediatrics, Research Laboratory of the Division of Paediatric Endocrinology and Diabetes, University of Patras School of Medicine, 26504, Patras, Greece.

Purpose: AQP7, a water/glycerol transporting protein, regulates adipocyte glycerol efflux and influences lipid and glucose homeostasis. Altered AQP7 expression in adults leads to impaired glycerol dynamics, adipocyte hypertrophy, and a predisposition to obesity and diabetes. AQP7 gene promoter variants lead to impaired AQP7-mediated adipocyte glycerol efflux and adipocyte hypertrophy. To assess its possible involvement in childhood obesity and metabolic abnormalities, the AQP7 promoter was studied in order to identify possible mutations and/or polymorphisms in children.

Methods: Genomic DNA was extracted from the blood of 61 lean children (BMI < 85%) (46 prepubertal and 15 pubertal) and 41 children with obesity (BMI > 95%) (22 prepubertal and 19 pubertal). The samples were sequenced for AQP7 promoter region - 2580 (2421) to - 1161 (3840) using Automated Sanger sequence analysis.

Results: One novel mutation -2185 (T2816A) was found in an obese prepubertal child with low AQP7 mRNA expression, high levels of serum glycerol, and low serum insulin levels. The novel single nucleotide polymorphisms (SNPs) - 2291 (A2710G), - 2219 (C2782A), - 2091 (C2910A), and - 1932 (G3069A) were identified, together with the previously described SNP - 1884 (C3117T), rs3758268. The heterozygous state and the recessive allele of all four SNPs were related to a positive family history of diabetes mellitus type 2 (p = 0.001).

Conclusions: The novel mutation - 2185 (T2816A) might be associated with the lower gene expression of AQP7 and high levels of serum glycerol that possibly contribute to the obese phenotype. The heterozygous genotype of the four SNPs - 2291 (A2710G), - 2219 (C2782A), - 2091 (C2910A), and - 1884 (C3117T) in children may be related to a familial predisposition to diabetes mellitus type 2.
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http://dx.doi.org/10.1007/s42000-020-00184-zDOI Listing
June 2020

Investigation of the role of β-TrCP in growth hormone transduction defect (GHTD).

Horm Mol Biol Clin Investig 2020 Mar 2;41(2). Epub 2020 Mar 2.

Paediatric Endocrine Research Laboratory, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Patras School of Medicine, Patras 26500, Greece.

Background Growth hormone(GH) and epidermal growth factor (EGF) stimulate cell growth and differentiation, and crosstalking between their signaling pathways is important for normal cellular development. Growth hormone transduction defect (GHTD) is characterized by excessive GH receptor (GHR) degradation, due to over-expression of the E3 ubiquitin ligase, cytokine inducible SH2-containing protein (CIS). GH induction of GHTD fibroblasts after silencing of messenger RNA (mRNA) CIS (siCIS) or with higher doses of GH restores normal GH signaling. β-Transducing-repeat-containing protein (β-TrCP), another E3 ubiquitin ligase, also plays a role in GHR endocytosis. We studied the role of β-TrCP in the regulation of the GH/GHR and EGF/EGF receptor (EGFR) pathways in normal and GHTD fibroblasts. Materials and methods Fibroblast cultures were developed from gingival biopsies of a GHTD (P) and a control child (C). Protein expression and cellular localization of β-TrCP were studied by Western immunoblotting and immunofluorescence, respectively, after: (1) GH 200 μg/L human GH (hGH) induction, either with or without silence CIS (siCIS), and (2) inductions with 200 μg/L GH or 1000 μg/L GH or 50 ng/mL EGF. Results After induction with: (1) GH200/siCIS, the protein expression and cytoplasmic-membrane localization of β-TrCP were increased in the patient, (2) GH200 in the control and GH1000 in the patient, the protein and cytoplasmic-membrane localization of β-TrCP were increased and (3) EGF, the protein expression and cytoplasmic-membrane localization of β-TrCP were increased in both the control and the patient. Conclusions (1) β-TrCP appears to be part of the negative regulatory mechanism of the GH/GHR and EGF/EGFR pathways. (2) There appears to be a negative correlation between β-TrCP and CIS. (3) In the control and GHTD patient, β-TrCP increases when CIS is suppressed, possibly as a compensatory inhibitor of the GH/GHR pathway.
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http://dx.doi.org/10.1515/hmbci-2019-0029DOI Listing
March 2020

New insights into the expression of androgen and estrogen receptors of the appendix testis in congenital cryptorchidism.

J Pediatr Endocrinol Metab 2020 Apr;33(4):503-508

Research Laboratory of the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras School of Medicine, Patras, Greece.

Background The appendix testis (AT) is the most common vestigial remnant of the human testis. Variations in the presence and expression of AT androgen receptor (AR) and estrogen receptor (ER) have been reported in cryptorchidism. We studied the possible association of AR and ER expression of the AT with cryptorchidism. Methods ATs were resected from 40 boys who underwent inguinoscrotal surgery, (20 patients with congenital unilateral cryptorchidism [UC] and 20 controls with orthotopic testes and hydrocele). AR and ER expression was evaluated with immunohistochemistry, and the percentage and intensity of AR and ER expression were evaluated by the Allred scoring method. AT length was compared between the two groups. Correlation of AR and ER expression was evaluated independently in patients and controls. Results The Allred score for AR trended toward lower values in UC compared to controls (p = 0.193), while ER scores presented statistically significant lower values in UC compared to controls (p = 0.017). No significant difference or trend was found in the expression of both receptors between high and low cryptorchidism (p = 0.981 for AR, p = 0.824 for ER) and for the appendiceal length between UC and controls (p = 0.369). Conclusions The findings of a trend for lower AR expression and a statistically significant lower expression of ER in UC may suggest an association of AR and ER with cryptorchidism and may provide an insight into the process of testicular descent.
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http://dx.doi.org/10.1515/jpem-2019-0392DOI Listing
April 2020

Decreased adipocyte glucose transporter 4 (GLUT4) and aquaglyceroporin-7 (AQP7) in adults with morbid obesity: possible early markers of metabolic dysfunction.

Hormones (Athens) 2019 Sep 7;18(3):297-306. Epub 2019 Oct 7.

Department of Pediatrics, Research Laboratory of the Division of Pediatric Endocrinology and Diabetes, University of Patras School of Medicine, Patras, Greece.

Purpose: Morbid obesity (BMI > 40) is often accompanied by metabolic disorders. In adipose tissue, serine/threonine kinase PKBβ/AktΙΙ plays a role in glucose uptake, mediated by glucose transporter 4 (GLUT4). The insulin pathway also affects aquaglyceroporin-7 (AQP7), which mediates lipolysis-derived glycerol efflux into the bloodstream. The aim of our study was to investigate the molecular mechanisms in adipocytes of adults with morbid obesity that may lead to insulin resistance (IR) and diabetes mellitus type 2 (DM2) in morbid obesity.

Methods: Primary in vitro adipocyte cultures were developed from surgical biopsies from visceral (Visc), abdominal (Sub), and gluteal subcutaneous (Glut) fat depots, from 20 lean adults and 36 adults with morbid obesity (OB), divided into two groups: 20 without (MOW) and 16 with DM2 (MODM). mRNA and protein expression (PE) of AktΙΙ, AQP7, and GLUT4 were studied with RT-PCR and Western immunoblotting (WI), respectively.

Results: The PE of (1) AktII and basal phosphorylated AktII (pAktII) showed no difference within the groups, (2) the 37 kDa and 34 kDa isoforms of AQP7 were decreased in Visc/Sub from OB/MOW/MODM, (3) GLUT4 was decreased in Visc/Sub from OB/MOW/MODM, and (4) the 34 kDa isoform of AQP7 was decreased in Sub of MODM compared with MOW.

Conclusions: Decreased 37 kDa (presented in this study as a novel isoform) and 34 kDa isoforms of AQP7 in MOW and MODM may cause reduced lipolysis, enhancement of adipocyte hypertrophy, and impairment of insulin, signaling possibly reflected by low GLUT4 expression. This may potentially cause systemic IR, since decreased adipose GLUT4 expression may affect whole-body insulin sensitivity, increasing the risk for DM2. Furthermore, decreased subcutaneous AQP7 34 kDa could represent an early marker of IR.
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http://dx.doi.org/10.1007/s42000-019-00130-8DOI Listing
September 2019

Novel combined insulin-like 3 variations of a single nucleotide in cryptorchidism.

J Pediatr Endocrinol Metab 2019 Sep;32(9):987-994

Department of Pediatrics, Research Laboratory of the Division of Pediatric Endocrinology and Diabetes, School of Medicine, University of Patras, Patras, Greece.

Background Insulin-like 3 hormone (INSL3) is involved in the process of testicular descent, and has been thoroughly studied in cryptorchidism. However, INSL3 allelic variations found in the human genome were heterozygous and only a few of them were found exclusively in patients with cryptorchidism. Under this perspective, we aimed to study the presence of INSL3 allelic variations in a cohort of patients with cryptorchidism and to estimate their potential consequences. Methods Blood samples were collected from 46 male patients with non-syndromic cryptorchidism and from 43 age-matched controls. DNA extraction and polymerase chain reaction (PCR) were performed for exons 1 and 2 of the INSL3 gene in all subjects. Sequencing analysis was carried out on the PCR products. All data were grouped according to testicular location. Results Seven variations of a single nucleotide (SNVs) were identified both in patients with cryptorchidism and in controls: rs2286663 (c.27G > A), rs1047233 (c.126A > G) and rs6523 (c.178A > G) at exon 1, rs74531687 (c.191-30C > T) at the intron, rs121912556 (c.305G > A) at exon 2 and rs17750642 (c.*101C > A) and rs1003887 (c.*263G > A) at the untranslated region (UTR). The allelic variants rs74531687 and rs121912556 were found for the first time in the Greek population. The novel homozygotic combination of the three allelic variants rs1047233-rs6523-rs1003887 seemed to present a stronger correlation with more severe forms of cryptorchidism. Conclusions The combination of specific INSL3 SNVs rather than the existence of each one of them alone may offer a new insight into the involvement of allelic variants in phenotypic variability and severity.
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http://dx.doi.org/10.1515/jpem-2018-0547DOI Listing
September 2019

Metabolic Association between Leptin and the Corticotropin Releasing Hormone.

Endocr Metab Immune Disord Drug Targets 2019 ;19(4):458-466

Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece.

Objective: In healthy individuals, leptin is produced from adipose tissue and is secreted into the circulation to communicate energy balance status to the brain and control fat metabolism. Corticotropin- Releasing Hormone (CRH) is synthesized in the hypothalamus and regulates stress responses. Among the many adipokines and hormones that control fat metabolism, leptin and CRH both curb appetite and inhibit food intake. Despite numerous reports on leptin and CRH properties and function, little has been actually shown about their association in the adipose tissue environment.

Methods: In this article, we summarized the salient information on leptin and CRH in relation to metabolism. We also investigated the direct effect of recombinant CRH on leptin secretion by primary cultures of human adipocytes isolated from subcutaneous abdominal adipose tissue of 7 healthy children and adolescents, and measured CRH and leptin levels in plasma collected from peripheral blood of 24 healthy children and adolescents to assess whether a correlation exists between CRH and leptin levels in the periphery.

Results And Conclusion: The available data indicate that CRH exerts a role in the regulation of leptin in human adipocytes. We show that CRH downregulates leptin production by mature adipocytes and that a strong negative correlation exists between CRH and leptin levels in the periphery, and suggest the possible mechanisms of CRH control of leptin. Delineation of CRH control of leptin production by adipocytes may explain unknown pathogenic mechanisms linking stress and metabolism.
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http://dx.doi.org/10.2174/1871530319666190206165626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360915PMC
January 2020

The role of p21/CIP1/WAF1 (p21) in the negative regulation of the growth hormone/growth hormone receptor and epidermal growth factor/epidermal growth factor receptor pathways, in growth hormone transduction defect.

Ann Pediatr Endocrinol Metab 2018 Dec 31;23(4):204-209. Epub 2018 Dec 31.

Paediatric Endocrine Research Laboratory, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Patras School of Medicine, Patras, Greece.

Purpose: Growth hormone transduction defect (GHTD) is characterized by severe short stature, impaired STAT3 (signal transducer and activator of transcription-3) phosphorylation and overexpression of the cytokine inducible SH2 containing protein (CIS) and p21/CIP1/WAF1. To investigate the role of p21/CIP1/WAF1 in the negative regulation of the growth hormone (GH)/GH receptor and Epidermal Growth Factor (EGF)/EGF Receptor pathways in GHTD.

Methods: Fibroblast cultures were developed from gingival biopsies of 1 GHTD patient and 1 control. The protein expression and the cellular localization of p21/CIP1/WAF1 was studied by Western immunoblotting and immunofluorescence, respectively: at the basal state and after induction with 200-μg/L human GH (hGH) (GH200), either with or without siRNA CIS (siCIS); at the basal state and after inductions with 200-μg/L hGH (GH200), 1,000-μg/L hGH (GH1000) or 50-ng/mL EGF.

Results: After GH200/siCIS, the protein expression and nuclear localization of p21 were reduced in the patient. After successful induction of GH signaling (control, GH200; patient, GH1000), the protein expression and nuclear localization of p21 were reduced. After induction with EGF, p21 translocated to the cytoplasm in the control, whereas in the GHTD patient it remained located in the nucleus.

Conclusion: In the GHTD fibroblasts, when CIS is reduced, either after siCIS or after a higher dose of hGH (GH1000), p21's antiproliferative effect (nuclear localization) is also reduced and GH signaling is activated. There also appears to be a positive relationship between the 2 inhibitors of GH signaling, CIS and p21. Finally, in GHTD, p21 seems to participate in the regulation of both the GH and EGF/EGFR pathways, depending upon its cellular location.
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http://dx.doi.org/10.6065/apem.2018.23.4.204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312915PMC
December 2018

Adipocyte aquaporin 7 (AQP7) expression in lean children and children with obesity. Possible involvement in molecular mechanisms of childhood obesity.

J Pediatr Endocrinol Metab 2018 Oct;31(10):1081-1089

Research Laboratory of the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras School of Medicine, Patras, Greece.

Background Aquaporin 7 (AQP7), a water/glycerol transporting protein, regulates adipocyte glycerol efflux and influences lipid and glucose homeostasis. Altered AQP7 expression in adults leads to impaired glycerol dynamics, adipocyte hypertrophy and it predisposes them to obesity and diabetes. To assess its possible involvement in childhood obesity, this study investigated the expression of adipocyte AQP7 in cultured adipocytes of children. Methods Primary in vitro differentiated adipocyte cultures were developed from surgical biopsies of subcutaneous abdominal adipose tissue from 61 (46 prepubertal, 15 pubertal) lean children (body mass index [BMI] <85%) and 41 (22 prepubertal, 19 pubertal) children with obesity (BMI >95%). AQP7 expression was studied by reverse transcription polymerase chain reaction and Western immunoblotting and insulin by enzyme-linked immunosorbent assay. Results AQP7 messenger RNA (mRNA) was increased in the younger obese prepubertal (YOP) children but decreased in the obese adolescents (OA) (p=0.014) who also had increased insulin and homeostatic model assessment - insulin resistance (HOMA-IR). Lean pubertal (LP) children and YOP had increased 41 kDa AQP7 protein expression (p=0.001 and p=0.005, respectively). The OA who expressed 34 kDa AQP7 had lower triglyceride (TG) levels than those who did not express it (p=0.013). In the lean children, TG were negatively correlated with 34 kDa AQP7 (p=0.033). Conclusions The lower AQP7 mRNA expression in the OA may reflect a predisposition to adipocyte hypertrophy and metabolic dysfunction, as in the adults, whereas the YOP may be protected from this. The increased 41 kDa AQP7 protein expression in the LP may reflect the increased energy requirements of puberty for glycerol while in the YOP it may also be protective against the development of adipocyte hypertrophy.
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http://dx.doi.org/10.1515/jpem-2018-0281DOI Listing
October 2018

Epidermal growth factor receptor (EGFR) involvement in successful growth hormone (GH) signaling in GH transduction defect.

J Pediatr Endocrinol Metab 2017 Feb;30(2):221-230

Background: Growth hormone (GH) transduction defect (GHTD) is a growth disorder with impaired signal transducer and activator of transcription 3 (STAT3) phosphorylation mediated by overexpression of cytokine-inducible SH2-containing protein (CIS), which causes increased growth hormone receptor (GHR) degradation. This study investigated the role of epidermal growth factor (EGF) in the restoration of normal GH signaling in GHTD.

Methods: Protein expression, cellular localization and physical contact of proteins of the GH and EGF signaling pathways were studied by Western immunoblotting, immunofluorescence and co-immunoprecipitation, respectively. These were performed in fibroblasts of one GHTD patient (P) and one control child (C) at the basal state and after induction with human GH (hGH) 200 μg/L (GH200), either with or without silencing of CIS mRNA, and after induction with hGH 1000 μg/L (GH1000) or 50 ng/mL EGF.

Results: The membrane availability of the EGF receptor (EGFR) and the activated EGFR (pEGFR) was increased in P only after simultaneous GH200 and silencing of CIS mRNA or with GH1000, whereas this occurred in C after GH200 alone. After EGF induction, the membrane localization of GHR, STAT3 and that of EGFR were increased in P more than in C.

Conclusions: In conclusion, in GHTD, the EGFR seems to participate in successful GH signaling, but induction of GHTD fibroblasts with a higher dose of hGH is needed. The EGF/EGFR pathway, in contrast to the GH/GHR pathway, seems to function normally in P and is more primed compared to C. The involvement of the EGFR in successful GH signaling may explain the catch-up growth seen in the Ps when exogenous hGH is administered.
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http://dx.doi.org/10.1515/jpem-2016-0189DOI Listing
February 2017

Osteoprotegerin, RANKL, ADMA, and Fetuin-A serum levels in children with type I diabetes mellitus.

Pediatr Diabetes 2017 06 29;18(4):277-282. Epub 2016 Mar 29.

Division of Endocrinology, Department of Pediatrics, Medical School, University of Patras, Patra, Greece.

Introduction: Patients with type I diabetes mellitus (T1DM) have increased incidence of atherosclerosis and cardiovascular disease. Although these complications are unusual in children with T1DM, prevention, and early intervention could decrease morbidity and mortality. Osteoprotegerin (OPG), asymmetric dimethylarginine (ADMA), and Fetuin-A have been associated with increased cardiovascular risk (CVR). Increased OPG and ADMA, and decreased or increased Fetuin-A serum levels have been associated with increased CVR.

Aim: Because patients with T1DM have higher CVR we investigated OPG, ADMA, and Fetuin-A, in children with T1DM.

Methods: We determined the serum levels of OPG, receptor activator of nuclear factor-κB ligand (RANKL), ADMA, and Fetuin-A by enzyme-linked immunosorbent assay (ELISA) in 56 children with T1DM aged 12.1 ± 3.4 yr and in 46 normal control children, (C) aged 11.3 ± 3.0 yr.

Results: Serum OPG levels were significantly increased in patients with T1DM (3.352 ± 0.73 pmol/L) compared with C (2.75 ± 0.67 pmol/L, p < 0.0001) but RANKL did not change. ADMA was significantly decreased in T1DM compared with C (0.68 ± 0.13 µmol/L versus 0.82 ± 0.18 µmol/L, p < 0.0001). Fetuin-A was similar in T1DM (0.551 ± 0.13 g/L) and C (0.540 ± 0.11 g/L) subjects. OPG was positively associated with glycosylated hemoglobin A1c (p < 0.001) and negatively associated with BMI (p < 0.01). ADMA and Fetuin-A were not associated with A1c and ADMA was only negatively associated with age (p < 0.05).

Conclusion: OPG is increased, ADMA is decreased, but RANKL and Fetuin-A are unchanged in T1DM children. Whereas increased OPG has been firmly related to increased CVR, more studies, especially longitudinal studies, are needed to delineate the role and clinical significance of decreased ADMA and if Fetuin-A has any role in T1DM.
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http://dx.doi.org/10.1111/pedi.12384DOI Listing
June 2017

Ten-year obesity and overweight prevalence in Greek children: a systematic review and meta-analysis of 2001-2010 data.

Hormones (Athens) 2013 Oct-Dec;12(4):537-49

4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Greece.

Objective: While the US today has the highest rates worldwide of obesity, Europe, and particularly Southern Europe, is catching up fast. The aim of this study was to report the prevalence of obesity in Greek children, aged 1-12 years.

Design: A systematic review--including all studies published in English and Greek from January 2001 until December 2010 regarding childhood obesity, using the IOTF criteria--was performed. Twenty-five out of 134 published studies were finally selected, including 219,996 boys and 210,772 girls.

Results: Meta-analysis revealed that 10.2% (CI 95%: 9.8-10.7%) of Greek children (1-12 years) are obese, 23.7% (CI 95%: 22.7-24.8%) are overweight and the combined prevalence of overweight and obesity is 34% (CI 95%: 32.7-35.3%). Subgroup analysis by gender showed that 11% of the boys and 9.7% of the girls were obese, while 24.1% of the boys and 23.2% of the girls were overweight. The combined prevalence of excess in body weight predominated in boys (35%), while in girls the above prevalence was 32.7%. Cumulative analysis revealed an upward trend of the phenomenon (2001-2003), followed by a stabilization (2003-2010).

Conclusions: During the decade 2001-2010, 1/10 Greek children was obese and 3/10 were overweight. The implementation of policies to reverse childhood obesity is of the utmost urgency.
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http://dx.doi.org/10.14310/horm.2002.1442DOI Listing
September 2014

Protective mechanisms against oxidative stress and angiopathy in young patients with diabetes type 1 (DM1).

J Pediatr Endocrinol Metab 2013 ;26(3-4):309-17

Department of Pediatrics, University of Patras School of Medicine, Patras, Achaia, Greece.

Objective: Advanced glycation end-products (AGEs) via their receptor, RAGE, are involved in diabetic angiopathy. Soluble RAGE, an inhibitor of this axis, is formed by enzymatic catalysis (sRAGE) or alternative splicing (esRAGE). Malondialdehyde (MDA) is an oxidative stress marker, and ferric reducing ability of plasma (FRAP) is an anti-oxidant capacity marker.

Methods: In isolated mononuclear blood cells from 110 DM1-patients (P) and 124 controls (C) (4-29 years) RAGE mRNA (g) and protein expression (pe) were measured by RT-PCR and Western immunoblotting, respectively. Plasma levels of CML (AGEs) and sRAGE were measured by ELISA, MDA by flurometry and FRAP according to 'Benzie and Strain'.

Results: P showed: (i) higher g of RAGE, especially in p>13 years of age and >5 years DM1, (ii) increased pe of esRAGE in DM1>5 years and (iii) increased FRAP and MDA.

Conclusions: The increased esRAGE and FRAP with increased levels of CML and MDA possibly reflects a protective response against the formation of diabetic complications in these young diabetic patients.
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http://dx.doi.org/10.1515/jpem-2012-0183DOI Listing
August 2013

Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents.

J Pediatr Endocrinol Metab 2012 ;25(7-8):697-704

Research Laboratory of the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras School of Medicine, Patras, Achaea, Greece.

Background: The effects of carbohydrate-restricted (ketogenic) diets on metabolic parameters in children have been incompletely assessed.

Objective: To compare the efficacy and metabolic impact of ketogenic and hypocaloric diets in obese children and adolescents.

Subjects: Fifty-eight obese subjects were placed on one of the two diets for 6 months.

Methods: Anthropometric measurements, body composition, oral glucose/insulin tolerance test, lipidemic profile, high molecular weight (HMW) adiponectin, whole-body insulin sensitivity index (WBISI), and homeostatic model assessment-insulin resistance (HOMA-IR) were determined before and after each diet.

Results: Both groups significantly reduced their weight, fat mass, waist circumference, fasting insulin, and HOMA-IR (p = 0.009 for ketogenic and p = 0.014 for hypocaloric), but the differences were greater in the ketogenic group. Both groups increased WBISI significantly, but only the ketogenic group increased HMW adiponectin significantly (p = 0.025).

Conclusions: The ketogenic diet revealed more pronounced improvements in weight loss and metabolic parameters than the hypocaloric diet and may be a feasible and safe alternative for children's weight loss.
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http://dx.doi.org/10.1515/jpem-2012-0131DOI Listing
January 2013

Endocannabinoid (EC) receptor, CB1, and EC enzymes' expression in primary adipocyte cultures of lean and obese pre-pubertal children in relation to adiponectin and insulin.

J Pediatr Endocrinol Metab 2010 Oct;23(10):1011-24

Research Laboratory of the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras School of Medicine, Patras, Greece.

Aim: The over-expression of CB1 in adult obesity is associated with insulin resistance (IR),but it is not elucidated in childhood obesity. We studied CB1 and endocannabinoid enzymes (EE), Adiponectin (Ad), and Insulin (SI) in lean and obese pre-pubertal (PP) children.

Methods: CB1 mRNA and protein (Pr) expression were studied by RT-PCR, western immunoblotting and immunohistochemistry in primary cultures of adipose tissue. The EE(NAPE-PLD, DAGL-alpha, FAAH, MAGL) expression was assessed by Real-Time PCR. Ad and SI were measured by ELISA and IR by HOMA-IR index.

Results: In the older obese vs older lean children: (1) CB1 Pr was decreased, (2) FAAHmRNA and DAGL-alpha mRNA were increased. Ad was decreased and SI and HOMA-IR increased in the older PP children.

Conclusions: Increased CB1 and decreased adiponectin in older lean PP children may facilitate fat deposition and "physiologic" IR necessary for the increased body growth of puberty. The reduced expression of CB1 in the older obese may be an attempt to reduce lipogenesis to avoid greater insulin resistance.
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http://dx.doi.org/10.1515/jpem.2010.162DOI Listing
October 2010

Decreased contrast sensitivity in children and adolescents with type 1 diabetes mellitus.

J Pediatr Ophthalmol Strabismus 2011 Mar-Apr;48(2):92-7. Epub 2010 Apr 22.

Department of Ophthalmology, University of Patras School of Medicine, Patras, Greece.

Purpose: To evaluate contrast sensitivity in children and adolescents with diabetes mellitus without evidence of diabetic retinopathy.

Methods: Sixty patients with insulin-dependent diabetes mellitus (age range: 8 to 18 years) were studied. Their contrast sensitivity scores were obtained using the CSV-1000 device (Vector Vision, Dayton, OH) for four spatial frequencies and were compared with v scores of 45 age-matched and gender-matched "healthy" patients. Contrast sensitivity values were also correlated to patient's age, duration of disease, and metabolic control of diabetes mellitus.

Results: The patients with insulin-dependent diabetes mellitus had a significant contrast sensitivity score reduction at all spatial frequencies tested. Glycosylated hemoglobin levels were inversely related to the contrast sensitivity thresholds. No significant correlation was found between the contrast sensitivity scores and the patient's age or duration of disease.

Conclusion: Contrast sensitivity defects are detected in patients with insulin-dependent diabetes mellitus. These defects may represent an early dysfunction of the retina, visual pathway, or both in patients with insulin-dependent diabetes mellitus who do not show any signs of diabetic retinopathy.
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http://dx.doi.org/10.3928/01913913-20100420-02DOI Listing
August 2013

Association between serum levels of the soluble receptor (sRAGE) for advanced glycation endproducts (AGEs) and their receptor (RAGE) in peripheral blood mononuclear cells of children with type 1 diabetes mellitus.

J Pediatr Endocrinol Metab 2009 Oct;22(10):895-904

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras, School of Medicine, Patras, Greece.

Aim: The binding of AGEs to RAGE is involved in diabetic vascular complications. We studied sRAGE levels and RAGE protein expression (P) together with N-carboxymethyl lysine (CML), a major AGE, in 74 patients with type 1 diabetes mellitus (DM1) and 43 healthy (C) children.

Methods: sRAGE and CML levels were determined by ELISA and RAGE P was evaluated in mononuclear cells by Western immunoblotting.

Results: Serum sRAGE was higher in DM1 than in C (1430 +/- 759 vs 1158 +/- 595 pg/ml, p = 0.047), inversely correlated to diabetes duration (r = -0.265, p = 0.037) and directly correlated to LDL-cholesterol levels (r = 0.224, p = 0.039). Diabetes duration correlated independently with sRAGE (p = 0.034). Circulating CML levels were not significantly different between DM1 and C groups (3.51 +/- 1.49 vs 3.59 +/- 1.83 ng/ml, p > 0.05) and RAGE P was lower in DM1 than in C (61 +/- 46 vs 102 +/- 63%, p = 0.0001).

Conclusions: Increased serum sRAGE in children with DM1 may provide temporary protection against cell damage and may be sufficient to eliminate excessive circulating CML.
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http://dx.doi.org/10.1515/jpem.2009.22.10.895DOI Listing
October 2009

The insulin-like growth factor-I (IGF-I) generation test as an indicator of growth hormone status.

Hormones (Athens) 2009 Apr-Jun;8(2):117-28

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras, School of Medicine, Rion, Patras, Greece.

Objective: The aim of the study was to evaluate the IGF-I generation test (IGF-I gen) as a possible indirect test of Growth Hormone (GH) secretory status.

Methods: Sixty-five GH deficient (GHD 1 and 2) and 86 control children were studied. Children in the GHD-1 subgroup (n=33) had low GH values (<10 microg/L) after clonidine and levo-dopa while those in the GHD-2 subgroup (n=32) had normal GH values after pharmacologic provocation but low 24-hour GH secretory rates compared to 187 Normal Statured (NS) children. Of the 86 controls, who underwent IGF-I gen,50 were NS and 36 Short-Statured (SS). Serum IGF-I was measured prior to and daily during hGH administration (hGH 0.033 mg/kg/dayx4 days).

Results: The prepubertal and pubertal GHD-1 and GHD-2 children had low baseline IGF-I values but their peak IGF-I values during the IGF-I gen reached those of the controls. The percent increase of IGF-I during the test was greater in the GHD groups than in the controls; in the prepubertal groups: 516+/-58% in the GHD-1, 433+/-50% in the GHD-2, 106+/-12% in the NS, and 102+/-18% in the SS (p=0.001); in the pubertal groups: 191+/-28% in the GHD-1, 141+/-20% in the GHD-2, 48+/-8% in the NS, and 61+/-17% in the SS (p=0.003).

Conclusions: The IGF-I response during the IGF-I gen seems to reflect the GH status in children.
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http://dx.doi.org/10.14310/horm.2002.1228DOI Listing
August 2009

Recombinant human growth hormone in the treatment of Turner syndrome.

Ther Clin Risk Manag 2008 Dec;4(6):1177-83

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras, School of Medicine, Patras, Greece.

Turner syndrome (TS) is a common chromosomal disorder in women that is associated with the absence of one of the X chromosomes. Severe short stature and a lack of pubertal development characterize TS girls, causing psychosocial problems and reduced bone mass. The growth impairment in TS seems to be due to multiple factors including an abnormal growth hormone (GH) - insulin-like growth factor (IGF) - IGF binding protein axis and haploinsufficiency of the short stature homeobox-containing gene. Growth hormone and sex steroid replacement therapy has enhanced growth, pubertal development, bone mass, and the quality of life of TS girls. Recombinant human GH (hGH) has improved the height potential of TS girls with varied results though, depending upon the dose of hGH and the age of induction of puberty. The best final adult height and peak bone mass achievement results seem to be achieved when hGH therapy is started early and puberty is induced at the normal age of puberty in a regimen mimicking physiologic puberty. The initiation of estradiol therapy at an age-appropriate time may also help the TS patients avoid osteoporosis during adulthood. Recombinant hGH therapy in TS seems to be safe. Studies so far show no adverse effects on cardiac function, glucose metabolism or any association with neoplasms but research is still in progress to provide conclusive data on long-term safety.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2643099PMC
http://dx.doi.org/10.2147/tcrm.s1440DOI Listing
December 2008

Combined growth hormone-releasing hormone and growth hormone-releasing peptide-6 test for the evaluation of growth hormone secretion in children with growth hormone deficiency and growth hormone neurosecretory dysfunction.

Horm Res 2008 5;70(4):215-23. Epub 2008 Sep 5.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras, School of Medicine, Patras, Greece.

Background: The combined growth hormone-releasing hormone and growth hormone-releasing peptide-6 (GHRH + GHRP-6) test is most potent in evaluating GH secretion.

Aims: To assess its capability in children with GH deficiency and low spontaneous GH secretion (GH neurosecretory dysfunction).

Methods: 35 children with GH <10 microg/l after levo-dopa/clonidine (GHD), 15 with normal provocative tests but abnormal 24-hour spontaneous GH secretion (GHND), and 20 controls (C) were given 1 microg/kg of GHRH and GHRP-6 i.v. and GH (microg/l) was measured at -15, 0, 5, 10, 15, 30, 45 and 60 min.

Results: Six were nonresponders to the combined test, with significantly lower peak GH 20.7 (7.8-31.8) than C and the rest of the patients (responders). Peak GH was similar between prepubertal (PP) controls 167 +/- 88, GHD 202 +/- 110 and GHND 155 +/- 83. Pubertal (P) controls had higher peak GH 328 +/- 149 than P-GHD 203 +/- 105 and P-GHND 186 +/- 105. While P-C had higher peak GH than PP-C, PP and P children had similar responses within the GHD and GHND groups.

Conclusions: The GHRH + GHRP-6 test detects children with severe GH insufficiency. Patients with GHD respond similarly to those with GHND, indicating a possible hypothalamic GH neuroregulatory dysfunction in GHD. Responders to the combined test may be eligible for treatment with a synthetic GH secretagogue.
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http://dx.doi.org/10.1159/000151593DOI Listing
December 2008

Pediatric topic: expanding the spectrum of Noonan syndrome.

Horm Res 2007 10;68 Suppl 5:22-3. Epub 2007 Dec 10.

University of Patras School of MedicinePaediatric Endocrinology DivisionPatras , Greece.

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http://dx.doi.org/10.1159/000110467DOI Listing
March 2008

Renal dysgenesis and KAL1 gene defects in patients with sporadic Kallmann syndrome.

Fertil Steril 2007 Nov 2;88(5):1311-7. Epub 2007 Jul 2.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Patras Medical School, Patras, Greece.

Objective: To correlate the presence of renal agenesis/dysgenesis to the prevalence of KAL1 gene defects in patients with sporadic Kallmann syndrome (KS).

Design: Prospective assessment of renal structure and DNA sequence analysis of the KAL1 gene.

Setting: Outpatient clinics of the divisions of endocrinology of university hospitals.

Patient(s): Sixteen male patients with sporadic KS.

Intervention(s): Assessment of renal structure by abdominal ultrasounds scans and DNA extraction, polymerase chain reaction amplification, and DNA sequence analysis of all 14 exons of the KAL1 gene.

Main Outcome Measure(s): KAL 1 gene structure and presence of renal dysgenesis.

Result(s): Renal dysgenesis was identified in only two of 16 KS patients. Genetic defects were found in only two patients with KS, that is, in those with the identified renal dysgenesis. The first gene defect was identified in a patient with associated right renal agenesis who had two point mutations in the KAL1 gene: the first was a G to A transition in exon 11, turning codon 514 encoding glutamic acid into lysine; and the second was a G to A transition in exon 13, turning codon 660 encoding alanine into threonine. The second gene defect was identified in a patient with ichthyosis, right renal agenesis, and mirror movements of the upper limbs (synkinesia) and comprised a deletion of exons 5-10 of the KAL1 gene and a complete deletion of the steroid sulphatase gene.

Conclusion(s): The phenotype of renal agenesis/dysgenesis strongly indicates the existence of KAL1 gene defects in the genotype of patients with sporadic KS, providing evidence for the X-linked mode of inheritance and offering the opportunity for genetic counseling.
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http://dx.doi.org/10.1016/j.fertnstert.2006.12.044DOI Listing
November 2007

Combined effect of mutations of the GH1 gene and its proximal promoter region in a child with growth hormone neurosecretory dysfunction (GHND).

J Mol Med (Berl) 2007 Sep 4;85(9):1005-13. Epub 2007 May 4.

Laboratory of Molecular Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, University of Patras School of Medicine, 26504, Rio-Patras, Greece.

Mutational analysis of the growth hormone 1 (GH1) gene and its promoter in a patient with GH neurosecretory dysfunction (GHND) revealed a heterozygous new deletion of one base 7-bp downstream from the 3'-splice site of exon 4 (IVS4'del+7) of the GH1 gene and two new heterozygous mutations at sites -135 and -138 of the GH1 promoter. In addition, two polymorphisms at sites -301 and -308 of the GH1 promoter were observed. All other family members had either the -301/-308 polymorphisms or the IVS4'del+7 mutation, but none had both. The IVS4'del+7 mutation located close to the splice donor site possibly interferes with the success of the splicing process, or the mutant transcripts are highly unstable because of nonsense-mediated mRNA decay. The -135/-138 mutations, albeit in close proximity to a putative Pit-1 recognition site, do not seem to affect binding of this transcription factor. The combination of the two polymorphisms, -301/-308, results in significantly reduced DNA-binding activity as monitored by electrophoretic mobility-shift assay. Transcription factor recognition site analysis of the GH1 promoter (MatInspector) revealed that HES1, one of the effectors of the Notch signalling system, is the only transcription factor whose binding is expected to be disrupted by each haplotype or by their combination. We provide evidence that the combination of -301/-308 polymorphisms with the IVS4'del+7 mutation in a GHND patient probably accounts for the reduced amount of growth hormone spontaneously secreted from his pituitary gland and for the severe growth delay.
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http://dx.doi.org/10.1007/s00109-007-0200-7DOI Listing
September 2007

Glucose dysregulation in obese children: predictive, risk, and potential protective factors.

Obesity (Silver Spring) 2007 Apr;15(4):860-9

Endocrine Unit, Department of Pediatrics, Athens University School of Medicine, Aghia Sophia Children's Hospital, Thivon and Levadias, 115 27, Athens, Greece.

Objective: The aim of our study was to determine the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (DM2) in obese children and adolescents of Greek origin and compare our data with pertinent literature findings in an attempt to uncover predictive, risk, and preventive factors.

Research Methods And Procedures: A total of 117 obese children and adolescents 12.1+/-2.7 years old underwent a 2-hour oral glucose tolerance test (OGTT). Insulin resistance (IR) and beta-cell function were estimated using the homeostasis model assessment (HOMA)-IR and the insulinogenic index, respectively.

Results: A total of 17 patients (14.5%) had IGT, and none had DM2. The overall prevalence rates of both IGT and DM2 in our subjects were lower than those reported in a recent multiethnic U.S. study. Nevertheless, the difference between our IGT data and those of the U.S. study was due mostly to the prepubertal subjects (9% vs. 25.4%), whereas no difference was observed in the pubertal population (18% vs. 21%). Fasting glucose, insulin, and HOMA-IR values were not predictive of IGT. The absolute value of insulin at 2 hours of the OGTT combined with the time-integrated glycemia (AUCG) can strongly predict IGT, whereas higher area under the curve for insulin (AUCI) values were found to be protective.

Discussion: In ethnic groups less prone to diabetes development, IGT or DM2 in obese subjects is more likely to develop at puberty than at the prepubertal stage. It is advisable that physicians caring for obese adolescents perform an OGTT for early detection of IGT because HOMA-IR values, although higher in IGT subjects and indicative of IR, cannot predict IGT.
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http://dx.doi.org/10.1038/oby.2007.600DOI Listing
April 2007

Growth hormone/JAK-STAT axis signal-transduction defect. A novel treatable cause of growth failure.

FEBS J 2006 Aug;273(15):3454-66

Division of Pediatric Endocrinology, Department of Pediatrics, University of Patras School of Medicine, Greece.

Primary cultured fibroblasts of four patients with idiopathic short stature and severe growth delay, which displayed normal growth hormone receptor expression presented a reduced ability for activation of signal transducer and activator of transcription-3 (STAT3). Impaired STAT3 activation was accompanied by cell-cycle arrest at the Go /G1 phase. Increased levels of the cyclin-dependent kinase inhibitor, p21(WAF/CIPI), and reduced levels of cyclins were also detected in these patients. High concentrations of human growth hormone (1000 ng x mL(-1)) added to the culture medium induced activation of STAT3 and reduced the levels of p21(WAF/CIPI) in the fibroblasts of the four idiopathic short stature children. Treatment of these children with exogenous human growth hormone significantly augmented their growth velocity. Overall, our study provides the first evidence linking the idiopathic short stature phenotype with a functional aberration in the growth hormone signal transduction cascade which can be successfully overcome by exposure to high doses of growth hormone.
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http://dx.doi.org/10.1111/j.1742-4658.2006.05347.xDOI Listing
August 2006

Growth and long-term hormonal therapy.

Pediatr Endocrinol Rev 2006 Jan;3 Suppl 1:192-4

Pediatric Endocrinology, Pediatric Endocrine Division, Department of Pediatrics, University of Patras School of Medicine, Patras, Greece.

Sex hormone replacement therapy (HRT) in the female adolescent has the following goals: 1. to mimic physiologic puberty; 2. to enhance normal growth; 3. to induce and maintain normal menstruation, 4. to support normal bone maturation and calcification; 5. to initiate and maintain normal brain cell growth and brain plasticity; and 6. to preserve the woman's psycho-sexual well-being. A physiologic peak bone mass during puberty and young adulthood is achieved when HRT is started by the age of 12. Estrogen has a biphasic effect on longitudinal growth, stimulatory at low doses and inhibitory at high doses. Therefore HRT in the adolescent girl is initiated with low doses of estrogen which progressively increase during a two-year period. This facilitates normal longitudinal growth and normal growth of the uterus for normal menstruation and future pregnancy with a donor oocyte. Whether HRT will continue past the normal age of menopause is still controversial.
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January 2006