Publications by authors named "Eirini Kostopoulou"

37 Publications

When is it best to discontinue diazoxide in children with persistent hyperinsulinaemic hypoglycaemia and negative genetics for K channel gene variants?

Clin Endocrinol (Oxf) 2021 Aug 9. Epub 2021 Aug 9.

Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Diazoxide is the first-line treatment in children with hyperinsulinaemic hypoglycaemia (HH); however, limited information is available on the duration of diazoxide treatment in children who require over 2 years of it. Hence, we retrospectively reviewed the clinical and biochemical aspects, as well as the duration of therapy and neurodevelopmental assessment, in genetically uncharacterised diazoxide-responsive HH patients admitted to a tertiary hospital over the last 16 years, who had successfully discontinued diazoxide and remained euglycaemic. To exclude transient HH forms, only patients that required diazoxide for over 2 years were studied. We identified a total of 17 patients (70% males), in whom HH was diagnosed between 1 day and 18 months of age, and 88% were born at term with a median birth weight of 3.79 kg. All children responded to diazoxide at a median dose of 11.5 mg/kg/day, and it was stopped at a median age of 8.5 years, with a median duration of therapy of 7.25 years. The cases that required diazoxide the longest manifested no specific biochemical or clinical characteristics. Fasting tests performed after diazoxide discontinuation showed no longer requirement of diazoxide in all the cases. A total of 64.7% of the children showed mild to moderate developmental delay. Therefore, it seems that long-term resolution of HH in children with negative genetics for K channel genes who required diazoxide for over 2 years will ensue, and thus regular evaluation is crucial. The possible molecular mechanisms involved are unclear.
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http://dx.doi.org/10.1111/cen.14581DOI Listing
August 2021

Association of the apoptotic marker APO1/Fas with children's predisposing factors for metabolic syndrome and with mean platelet volume.

J Pediatr Endocrinol Metab 2021 Aug 2. Epub 2021 Aug 2.

Laboratory of Biology and Biochemistry, Faculty of Health Sciences, Department of Nursing, University of Peloponnese, Tripoli, Greece.

Background: Apoptosis antigen 1/FAS receptor (APO1/Fas) signaling in endothelial cells plays a significant role in angiogenesis while increased mean platelet volume (MPV) is an important marker for platelet activation. We investigated the possible correlation between APO1/Fas and both metabolic parameters and platelet activity (indicated by the MPV) in a healthy pediatric population.

Methods: One hundred and eighty-five children, aged 5-17 years old, were enrolled in the study. The participants were divided into subgroups according to their age and body mass index percentile (BMI%). APO1/Fas was measured by enzyme-linked immunosorbent assay (ELISA) and MPV by the MEK-6410K.

Results: Eighty-one children (43.8%) had excess weight, which was more prevalent in children ≤9 years of age. Sixty-five children (35.1%) exhibited a predisposition for metabolic syndrome. A negative correlation was found between APO1/Fas and predisposing factors for metabolic syndrome: Glucose, cholesterol, uric acid, low-density lipoprotein (LDL), and triglycerides. In contrast, a positive correlation was found between APO1/Fas and C-reactive protein (CRP). Receiver operating characteristic (ROC) analysis showed a predisposition to metabolic syndrome when APO1/Fas was <78.46 pg/mL. A negative correlation was also observed between APO1/Fas and MPV. MPV was also positively correlated with predisposing factors for metabolic syndrome: BMI%, glucose, cholesterol, uric acid, LDL, and negatively with high-density lipoprotein.

Conclusions: APO1/Fas expression is associated with a lower predisposition to metabolic syndrome may be through endothelial homeostasis, the induction of apoptosis of cells involved in atherosclerosis, and platelet activity. It may also enhance CRP-mediated noninflammatory clearance of apoptotic cells. Early monitoring of all the components of metabolic syndrome in overweight children is important in order to prevent metabolic and cardiovascular complications.
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http://dx.doi.org/10.1515/jpem-2021-0352DOI Listing
August 2021

Association of antimullerian hormone with the size of the appendix testis, the androgen and estrogen receptors and their expression in the appendix testis, in congenital cryptorchidism.

J Pediatr Endocrinol Metab 2021 Jul 16. Epub 2021 Jul 16.

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

Objectives: Antimullerian hormone (AMH) causes regression of the mullerian ducts in the male fetus. The appendix testis (AT) is a vestigial remnant of mullerian duct origin, containing both androgen (AR) and estrogen (ER) receptors. The role of both AMH and AT in testicular descent is yet to be studied. We investigated the possible association of AMH with AT size, the AR and ER, and their expression in the AT, in congenital cryptorchidism.

Methods: A total of 26 patients with congenital unilateral cryptorchidism and 26 controls with orthotopic testes were investigated, and 21 ATs were identified in each group. AMH and insulin-like three hormone (INSL3) concentrations were measured with spectrophotometry. AR and ER receptor expression was assessed with immunohistochemistry using monoclonal antibodies R441 for AR and MAB463 for ER. For the estimation of receptor expression, the Allred Score method was used.

Results: AMH concentrations did not present significant differences between patients with congenital cryptorchidism and the controls. Also, no correlation was found between AMH, INSL3, and AT length. Allred scores did not present significant differences. However, expression percentiles and intensity for both receptors presented significant differences. Three children with cryptorchidism and the highest AMH levels also had the highest estrogen receptor scores in the AT.

Conclusions: No association was found between AMH and the studied major parameters. However, higher AMH concentrations, in combination with higher estrogen receptor scores in the AT, may play a role in cryptorchidism in some children. Larger population samples are needed to verify this observation.
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http://dx.doi.org/10.1515/jpem-2021-0240DOI Listing
July 2021

Association of lifestyle factors with a high prevalence of overweight and obesity in Greek children aged 10-16 years.

Acta Paediatr 2021 May 29. Epub 2021 May 29.

Department of Pediatrics, University General Hospital of Patras, Patras, Greece.

Aim: To investigate the prevalence of overweight, obesity and central obesity in students of primary and secondary education, and the association with lifestyle parameters.

Methods: A total of 3504 students, aged 10-16 years old, from Western Greece participated in this cross-sectional epidemiological study (participation rate: 90%). Demographic, socioeconomic, dietary, physical activity and screen time data were obtained using a questionnaire. Anthropometric measurements were also obtained. Overweight and obesity were estimated using the Centers for Disease Control and Prevention (CDC) and International Obesity Task Force (IOTF) criteria and central obesity using the WHtR ≥0.5 and IDF criteria.

Results: The prevalence of overweight and obesity was 19.2% and 12.1% with CDC criteria, respectively, and 20.9% and 7.2%, with IOTF criteria respectively. Central obesity was 31.1 and 32.8% using the Waist-to-Height ratio (WHtR) ≥0.5 and International Diabetes Federation (IDF) criteria respectively. Male gender, small number of meals, breakfast skipping, frequent consumption of school food and sweets and the presence of a computer in children's rooms, were identified as the strongest lifestyle factors affecting weight.

Conclusion: Overweight, obesity and central obesity rates remain high among children and adolescents in Greece. The identification of risk factors associated with the manifestation of obesity and central obesity, may contribute to the implementation of targeted prevention and treatment interventions.
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http://dx.doi.org/10.1111/apa.15960DOI Listing
May 2021

Repetitiveness of the oral glucose tolerance test in children and adolescents.

World J Clin Pediatr 2021 May 9;10(3):29-39. Epub 2021 May 9.

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

Background: Data regarding the most suitable diagnostic method for the diagnosis of glucose impairment in asymptomatic children and adolescents are inconclusive. Furthermore, limited data are available on the reproducibility of the oral glucose tolerance test (OGTT) in children and adolescents who are obese (OB).

Aim: To investigate the usefulness of the OGTT as a screening method for glucose dysregulation in children and adolescents.

Methods: Eighty-one children and adolescents, 41 females, either overweight (OW), OB or normal weight (NW) but with a strong positive family history of type 2 diabetes mellitus (T2DM), were enrolled in the present observational study from the Outpatient Clinic of Paediatric Endocrinology of the University Hospital of Patras in Greece. One or two 3-h OGTTs were performed and glucose, insulin and C-peptide concentrations were measured at several time points ( = 0 min, = 15 min, = 30 min, = 60 min, = 90 min, = 120 min, = 180 min).

Results: Good repetitiveness was observed in the OGTT response with regard to T2DM, while low repetitiveness was noted in the OGTT response with regard to impaired glucose tolerance (IGT) and no repetitiveness with regard to impaired fasting glucose (IFG). In addition, no concordance was observed between IFG and IGT. During the 1 and 2 OGTTs, no significant difference was found in the glucose concentrations between NW, OW and OB patients, whereas insulin and C-peptide concentrations were higher in OW and OB compared to NW patients at several time points during the OGTTs. Also, OW and OB patients showed a worsening insulin and C-peptide response during the 2 OGTT as compared to the 1 OGTT.

Conclusion: In mild or moderate disorders of glucose metabolism, such as IFG and IGT, a diagnosis may not be reached using only one OGTT, and a second test or additional investigations may be needed. When glucose metabolism is profoundly impaired, as in T2DM, one OGTT is probably more reliable and adequate for establishing the diagnosis. Excessive weight and/or a positive family history of T2DM possibly affect the insulin and C-peptide response in the OGTT from a young age.
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http://dx.doi.org/10.5409/wjcp.v10.i3.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085718PMC
May 2021

Attitudes and beliefs of parents about routine childhood vaccination in Greece.

Hum Vaccin Immunother 2021 Sep 10;17(9):3066-3072. Epub 2021 May 10.

Department of Paediatrics, Medical School, University of Patras, Patras, Greece.

Vaccine hesitancy remains one of the 10 major global threats as per the WHO report in 2019. The aim of the present study is to assess attitudes and perceptions of vaccine hesitant parents in Greece with a view to implementing strategies to increase vaccine uptake. A cross-sectional questionnaire-based prospective survey was conducted between September 2019 and June 2020 on parents of children attending primary education in the city of Patras in Western Greece. Data on parental attitudes and beliefs about vaccinations were collected and analyzed. Multivariable logistic regression was used to investigate factors associated with vaccine uptake. Out of 2154 distributed questionnaires, 1227 were completed and returned (response rate 56.9%). The main vaccine information source for Greek parents was their primary care pediatrician (90.8%). Doubts still exist amongst approximately one-third of them (33.5%) regarding a possible relationship between vaccines and autism. Of note, 44% of the study participants believe that unvaccinated children could attend school. 84.6% of the parents in our cohort admitted that they had fully vaccinated their children. In the multivariable analysis, marital status ( < .002) and Greek nationality ( < .001) were found to be the most significant determinants of vaccine uptake. Overall, we found that the percentage of parents in Greece that are vaccine hesitant is small yet not negligible. Based on our results, targeted public health interventions should particularly focus on single parents and those with non-Greek nationality. Training healthcare professionals to provide adequate information is crucial to clarify misperceptions.
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http://dx.doi.org/10.1080/21645515.2021.1914805DOI Listing
September 2021

Thyroid angiosarcoma (TAS) - A rare diagnosis not to be missed.

Clin Case Rep 2021 Jan 11;9(1):173-176. Epub 2020 Nov 11.

Department of General Surgery University Hospital of Patras Rio Greece.

Raising awareness about primary TAS, a rare and aggressive mesenchymal tumor, is important so that early diagnosis and undelayed radical surgery along with complementary radiation are possible. Extending the existing knowledge on the course and final outcome of the disease may help identify the best treatment approach to improve survival.
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http://dx.doi.org/10.1002/ccr3.3492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813081PMC
January 2021

Genetics of primary congenital hypothyroidism-a review.

Hormones (Athens) 2021 Jun 5;20(2):225-236. Epub 2021 Jan 5.

Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics|, University of Patras School of Medicine, Patras, Greece.

Purpose: Congenital primary hypothyroidism (CH) is a state of inadequate thyroid hormone production detected at birth, caused either by absent, underdeveloped or ectopic thyroid gland (dysgenesis), or by defected thyroid hormone biosynthesis (dyshormonogenesis). A genetic component has been identified in many cases of CH. This review summarizes the clinical and biochemical features of the genetic causes of primary CH.

Methods: A literature review was conducted of gene defects causing congenital hypothyroidism.

Results: Mutations in five genes have predominantly been implicated in thyroid dysgenesis (TSHR, FOXE1, NKX2-1, PAX8, and NKX2-5), the primary cause of CH (85%), and mutations in seven genes in thyroid dyshormonogenesis (SLC5A5, TPO, DUOX2, DUOXA2, SLC6A4, Tg, and DEHAL1). These genes encode for proteins that regulate genes expressed during the differentiation of the thyroid, such as TPO and Tg genes, or genes that regulate iodide organification, thyroglobulin synthesis, iodide transport, and iodotyrosine deiodination. Besides thyroid dysgenesis and dyshormonogenesis, additional causes of congenital hypothyroidism, such as iodothyronine transporter defects and resistance to thyroid hormones, have also been associated with genetic mutations.

Conclusion: The identification of the underlying genetic defects of CH is important for genetic counseling of families with an affected member, for identifying additional clinical characteristics or the risk for thyroid neoplasia and for diagnostic and management purposes.
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http://dx.doi.org/10.1007/s42000-020-00267-xDOI Listing
June 2021

Syndromic Forms of Hyperinsulinaemic Hypoglycaemia-A 15-year follow-up Study.

Clin Endocrinol (Oxf) 2021 03 31;94(3):399-412. Epub 2021 Jan 31.

Department of Pediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK.

Objective: Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith-Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH. This systematic review of children with HH referred to a tertiary centre aims at estimating the frequency of a syndromic/multisystem condition to help address stratification of genetic analysis in infants with HH.

Methods: We performed a retrospective study of 69 patients with syndromic features and hypoglycaemia in a specialist centre from 2004 to 2018.

Results: Biochemical investigations confirmed HH in all the cases and several genetic diagnoses were established. Responsiveness to medications and the final outcome following medical treatment or surgery were studied.

Conclusions: This study highlights the association of HH with a wide spectrum of syndromic diagnoses and that children with features suggestive of HH-associated syndromes should be monitored for hypoglycaemia. If hypoglycaemia is documented, they should also be screened for possible HH. Our data indicate that most syndromic forms of HH are diazoxide-responsive and that HH resolves over time; however, a significant percentage continues to require medications years after the onset of the disease. Early diagnosis of hyperinsulinism and initiation of treatment is important for preventing hypoglycaemic brain injury and intellectual disability.
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http://dx.doi.org/10.1111/cen.14393DOI Listing
March 2021

Adiponectin Signaling and Impaired GTPase Rab5 Expression in Adipocytes of Adolescents with Obesity.

Horm Res Paediatr 2020 19;93(5):287-296. Epub 2020 Oct 19.

Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Patras School of Medicine, Patras, Greece,

Introduction: Abnormalities in adipose tissue AdipoR1; adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 (APPL1); GTPase Rab5; adiponectin; leptin; and visfatin in adults with obesity have been associated with metabolic disturbances.

Objective: The objective of this study was to examine whether pediatric obesity disrupts elements of the adiponectin signaling pathway and GTPase Rab5 in adipose tissue.

Methods: Primary adipocyte cultures of subcutaneous abdominal tissue were obtained from 96 lean and 66 children and adolescents with obesity (AO). AdipoR1, APPL1, and GTPase Rab5 mRNA levels were measured by RT-PCR and their protein content by Western immunoblotting. Serum total and high-molecular-weight adiponectin, leptin, leptin soluble receptor (sOB-R), and visfatin were measured by ELISA.

Results: The mRNA expression and protein content of AdipoR1 and APPL1 did not differ significantly with obesity, age, or puberty. However, GTPase Rab5 protein was increased in the adipocytes of younger prepubertal children with obesity but decreased in AO. Leptin was increased in AO compared to lean adolescents (AL) and in older prepubertal lean (OPL) children and AL compared to younger prepubertal lean and obese children. sOB-R was higher in OPL children and in the AL and AO. Serum visfatin was increased in the younger prepubertal children and AO.

Conclusions: In contrast to adults, obesity did not change the expression of AdipoR1 and APPL1 in cultured adipocytes from biopsies of subcutaneous abdominal adipose tissue of children and adolescents. Similar to adipose tissue studies in adults with obesity and metabolic dysfunction, the AO in our study showed reduced adipocyte GTPase Rab5 expression.
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http://dx.doi.org/10.1159/000510851DOI Listing
October 2020

COVID-19 in Children and Adolescents with Endocrine Conditions.

Horm Metab Res 2020 Nov 8;52(11):769-774. Epub 2020 Sep 8.

Paediatric Endocrinology and Diabetes, The Royal London Children's Hospital, London, United Kingdom.

The rapid spread of coronavirus disease (COVID-19) worldwide justifies global effort to combat the disease but also the need to review effective preventive strategies and medical management for potentially high-risk populations during the pandemic. Data regarding the COVID-19 manifestations in adults with underlying endocrine conditions, especially diabetes mellitus, are increasingly emerging. Albeit children and adolescents are considered to be affected in a milder manner, paucity of information regarding COVID-19 in children who suffer from endocrinopathies is available. The present review comprehensively collects recommendations issued by various health organizations and endocrine associations for the management of pediatric endocrine conditions during the pandemic. Adhering to the specific "sick day management rules" and undelayed seeking for medical advice are only needed in most of the cases, as the vast majority of children with endocrine disorders do not represent a high-risk population for contamination or severe presentation of COVID-19. Psychological implications in these children and adolescents are also considered.
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http://dx.doi.org/10.1055/a-1227-6635DOI Listing
November 2020

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

Cardiovascular Complications in Patients with Turner's Syndrome.

Curr Pharm Des 2020 ;26(43):5650-5659

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

Turner's or Turner syndrome (TS) is the most prevalent chromosomal abnormality in live female births. Patients with TS are predisposed to an increased risk of cardiovascular diseases (CVD), mainly due to the frequently observed congenital structural cardiovascular defects, such as valvular and aortic abnormalities (coarctation, dilatation, and dissection). The increased prevalence of cardiometabolic risk factors, such as arterial hypertension, insulin resistance, diabetes mellitus, dyslipidaemia, central obesity, and increased carotid intima-media thickness, also contribute to increased morbidity and mortality in TS patients. Menopausal hormone therapy (MHT) is the treatment of choice, combined with growth hormone (GH). Although MHT may, in general, ameliorate CVD risk factors, its effect on CVD mortality in TS has not yet been established. The exact effect of GH on these parameters has not been clarified. Specific considerations should be provided in TS cases during pregnancy, due to the higher risk of CVD complications, such as aortic dissection. Optimal cardiovascular monitoring, including physical examination, electrocardiogram, CVD risk factor assessment, and transthoracic echocardiography, is recommended. Moreover, the cardiac magnetic resonance from the age of 12 years is recommended due to the high risk of aortic aneurysm and other anatomical vascular complications.
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http://dx.doi.org/10.2174/1381612826666200531152459DOI Listing
April 2021

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

Pediatr Res 2021 02 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

Dieulafoy's lesion: A challenging diagnosis.

J Paediatr Child Health 2020 11 12;56(11):1819-1820. Epub 2020 Mar 12.

Paediatric Department, University Hospital of Patras, Patras, Greece.

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http://dx.doi.org/10.1111/jpc.14862DOI Listing
November 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

Upgrade of Chilaiditi Sign to Syndrome: Are There Any Predisposing Factors?

J Emerg Med 2019 10;57(4):573-574

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

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http://dx.doi.org/10.1016/j.jemermed.2019.04.035DOI Listing
October 2019

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

Hyperinsulinaemic hypoglycaemia-an overview of a complex clinical condition.

Eur J Pediatr 2019 Aug 26;178(8):1151-1160. Epub 2019 Jun 26.

Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

Hyperinsulinaemic hypoglycaemia (HH) is a major cause of hypoglycaemia in the neonatal period, infancy and childhood. It is caused by unsuppressed insulin secretion in the setting of hypoglycaemia and carries a high risk of significant neurological sequelae, such as cognitive impairment. Genetic mutations have been implicated in the pathogenesis of the condition. Other causes include intra-uterine growth retardation, perinatal asphyxia, maternal diabetes mellitus and syndromes, such as Beckwith-Wiedemann. Based on the aetiology, the clinical presentation can range from absence of symptoms to the typical adrenergic symptoms and coma and even death. The diagnosis is based on biochemical findings and the gold-standard imaging technique is 18F-DOPA PET/CT scanning. Treatment options involve medications, such as diazoxide, nifedipine, glucagon and octreotide, as well as surgery. Novel treatment, such as long-acting octreotide, lanreotide and sirolimus, may be used as an alternative to pancreatectomy. Potential future medical treatments include exendin, a GLP-1 receptor antagonist, and glucagon infusion via a pump.Conclusion: Advances in the fields of genetic testing, imaging techniques and medical treatment are beginning to provide novel insights into earlier detection, less invasive treatment approaches and fewer complications associated with the complex entity of hyperinsulinaemic hypoglycaemia. What is Known: • HH is caused by dysregulated insulin release from the β cell due to genetic mutations and carries a risk for complications, such as neurocognitive impairment. 18F-DOPA PET/CT scanning is presented as the gold-standard imaging technique currently in children with hyperinsulinaemic hypoglycaemia. • Clinical presentation is heterogeneous and treatment options include medical therapy and pancreatectomy. What is New: • 18F-DOPA PET/CT is indicated in suspected focal CHI due to paternal transmitted mutations in ABCC8 or KCNJ11. • Novel treatment options have been introduced, such as long-acting octreotide, lanreotide, sirolimus and selective nonpeptide somatostatin receptor subtype 5 (SSTR5) agonists. Future medical treatments include exendin, a GLP-1 antagonist, and glucagon infusion via a pump. However, all these options are off-label at present.
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http://dx.doi.org/10.1007/s00431-019-03414-8DOI Listing
August 2019

Cardiac Murmurs in Children: A Challenge For The Primary Care Physician.

Curr Pediatr Rev 2019 ;15(3):131-138

Department of Paediatrics, University of Patras Medical School, Patras, Greece.

Congenital heart disease is present in almost 1% of live births and despite current progress in prenatal screening a significant percentage has delayed diagnosis or remain undiagnosed. A cardiac murmur may be the first or unique clinical sign of congenital heart disease in childhood, however, less than 1% of auscultated murmurs are of an organic cause. Distinguishing between an innocent and a pathologic murmur can be challenging and the experience of the examiner is crucial for identifying the distinctive properties of an innocent murmur. Timely diagnosis of underlying cardiovascular pathology is of great significance so that prompt management is provided and morbidity or mortality are restricted. Of similar importance is the avoidance of unnecessary anxiety for the parents and unreasonable referrals to Paediatric Cardiologists. Indications for referral include a medical history suggestive of a cardiac abnormality, such as the presence of relevant symptoms, the identification of abnormal findings on clinical examination, auscultatory findings suggestive of an organic murmur, and very young patient age. ECG and a chest X-ray are not usually part of the diagnostic approach of a child with a cardiac murmur, as they do not increase the success rate of diagnosing heart disease, as compared to a detailed medical history accompanied by a thorough physical examination. In conclusion, the recognition of suspicious distinctive features of cardiac murmurs is crucial and requires skills based on sufficient training and experience.
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http://dx.doi.org/10.2174/1573396315666190321105536DOI Listing
April 2020

Hyperinsulinaemic hypoglycaemia: A new presentation of 16p11.2 deletion syndrome.

Clin Endocrinol (Oxf) 2019 05 7;90(5):766-769. Epub 2019 Mar 7.

Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/cen.13951DOI Listing
May 2019

Native aortic coarctation presenting as prolonged pyrexia in a teenager with 22q11.2 deletion.

J Paediatr Child Health 2019 Jun 12;55(6):711-714. Epub 2019 Jan 12.

Department of Paediatric Cardiology and Adult with Congenital Heart Disease, Onassis Cardiac Surgery Center, Athens, Greece.

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http://dx.doi.org/10.1111/jpc.14341DOI Listing
June 2019

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

Acute Rheumatic Fever, Kawasaki Disease or Alternative Diagnoses? A Call for the General Paediatrician.

J Paediatr Child Health 2018 06;54(6):707-708

Department of Paediatrics, University of Patras Medical School, Patras, Greece.

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http://dx.doi.org/10.1111/jpc.14054DOI Listing
June 2018
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