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Monika Bilic Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
Department of Nutritional Sciences, University of Toronto, Toronto, Canada

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Huma Qamar Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
Department of Nutritional Sciences, University of Toronto, Toronto, Canada

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Akpevwe Onoyovwi Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada

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Jill Korsiak Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada

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Eszter Papp Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada

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Abdullah Al Mahmud Nutrition and Clinical Services Division, icddr,b, Dhaka, Bangladesh

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Rosanna Weksberg Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
Molecular and Medical Genetics, University of Toronto, Toronto, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada

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Alison D Gernand Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA

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Jennifer Harrington Division of Endocrinology, Hospital for Sick Children, Toronto, Canada

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Daniel E Roth Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
Department of Nutritional Sciences, University of Toronto, Toronto, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada

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Fetal growth restriction is linked to adverse health outcomes and is prevalent in low- and middle-income countries; however, determinants of fetal growth are still poorly understood. The objectives were to determine the effect of prenatal vitamin D supplementation on the insulin-like growth factor (IGF) axis at birth, to compare the concentrations of IGF-I in newborns in Bangladesh to a European reference population and to estimate the associations between IGF protein concentrations and birth size. In a randomized controlled trial in Dhaka, Bangladesh, pregnant women enrolled at 17–24 weeks of gestation were assigned to weekly oral vitamin D3 supplementation from enrolment to delivery at doses of 4200 IU/week, 16,800 IU/week, 28,000 IU/week or placebo. In this sub-study, 559 woman–infant pairs were included for analysis and cord blood IGF protein concentrations were quantified at birth. There were no significant effects of vitamin D supplementation on cord blood concentrations of IGF-I (P = 0.398), IGF-II (P = 0.525), binding proteins (BPs) IGFBP-1 (P = 0.170), IGFBP-3 (P = 0.203) or the molar ratio of IGF-I/IGFBP-3 (P = 0.941). In comparison to a European reference population, 6% of girls and 23% of boys had IGF-I concentrations below the 2.5th percentile of the reference population. IGF-I, IGF-II, IGFBP-3 and the IGF-I/IGFBP-3 ratio were positively associated with at least one anthropometric parameter, whereas IGFBP-1 was negatively associated with birth anthropometry. In conclusion, prenatal vitamin D supplementation does not alter or enhance fetal IGF pathways.

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Changwei Liu Children’s Hospital of Nanjing Medical University, Nanjing, China

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Jingwen Wang Children’s Hospital of Nanjing Medical University, Nanjing, China

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Yuanyuan Wan Children’s Hospital of Nanjing Medical University, Nanjing, China

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Xiaona Xia Children’s Hospital of Nanjing Medical University, Nanjing, China

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Jian Pan Children’s Hospital of Nanjing Medical University, Nanjing, China

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Wei Gu Children’s Hospital of Nanjing Medical University, Nanjing, China

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Mei Li Children’s Hospital of Nanjing Medical University, Nanjing, China

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Background

To investigate the relationship 25-hydroxy vitamin D (25OHD) level among children and in children with type 1 diabetes mellitus (T1DM).

Methods

A case–control study was conducted to compare the serum 25OHD levels between cases and controls. This study recruited 296 T1DM children (106 newly diagnosed T1DM patients and 190 established T1DM patients), and 295 age- and gender-matched healthy subjects as controls.

Results

The mean serum 25OHD in T1DM children was 48.69 ± 15.26 nmol/L and in the controls was 57.93 ± 19.03 nmol/L. The mean serum 25OHD in T1DM children was lower than that of controls (P < 0.01). The mean serum 25OHD level (50.42 ± 14.74 nmol/L) in the newly diagnosed T1DM children was higher than that (47.70 ± 15.50 nmol/L) in the established T1DM children but the difference was not statistically significant (P = 0.16). HbA1c values were associated with 25OHD levels in established T1DM children (r = 0.264, P < 0.01), and there was no association between 25OHD and HbA1c in newly diagnosed T1DM children (r = 0.164; P > 0.05).

Conclusion

Vitamin D deficiency is common in T1DM children, and it should be worthy of attention on the lack of vitamin D in established T1DM children.

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Malachi J McKenna St Michael's Hospital, Metabolism Laboratory, School of Medicine and Medical Sciences, Dún Laoghaire, Dublin, Ireland
St Michael's Hospital, Metabolism Laboratory, School of Medicine and Medical Sciences, Dún Laoghaire, Dublin, Ireland
St Michael's Hospital, Metabolism Laboratory, School of Medicine and Medical Sciences, Dún Laoghaire, Dublin, Ireland

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Barbara F Murray St Michael's Hospital, Metabolism Laboratory, School of Medicine and Medical Sciences, Dún Laoghaire, Dublin, Ireland

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Objective

The recommended daily intakes of vitamin D according to the recent Clinical Practice Guideline (CPG) of the Endocrine Society are three- to fivefold higher than the Institute of Medicine (IOM) report. We speculated that these differences could be explained by different mathematical approaches to the vitamin D dose response.

Methods

Studies were selected if the daily dose was ≤2000 IU/day, the duration exceeded 3 months, and 25-hydroxyvitamin D (25OHD) concentrations were measured at baseline and post-therapy. The rate constant was estimated according to the CPG approach. The achieved 25OHD result was estimated according to the following: i) the regression equation approach of the IOM; ii) the regression approach of the Vitamin D Supplementation in Older Subjects (ViDOS) study; and iii) the CPG approach using a rate constant of 2.5 (CPG2.5) and a rate constant of 5.0 (CPG5.0). The difference between the expected and the observed 25OHD result was expressed as a percentage of observed and analyzed for significance against a value of 0% for the four groups.

Results

Forty-one studies were analyzed. The mean (95% CI) rate constant was 5.3 (4.4–6.2) nmol/l per 100 IU per day, on average twofold higher than the CPG rate constant. The mean (95% CI) for the difference between the expected and observed expressed as a percentage of observed was as follows: i) IOM, −7 (−16,+2)% (t=1.64, P=0.110); ii) ViDOS, +2 (−8,+12)% (t=0.40, P=0.69); iii) CPG2.5, −21 (−27,−15)% (t=7.2, P<0.0001); and iv) CPG5.0+3 (−4,+10)% (t=0.91, P=0.366).

Conclusion

The CPG ‘rule of thumb’ should be doubled to 5.0 nmol/l (2.0 ng/ml) per 100 IU per day, adopting a more risk-averse position.

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Anna Liori Division of Endocrinology, Department of Internal Medicine, University of Patras, School of Health Sciences, Patras, Greece

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Damaskini Polychroni Division of Endocrinology, Department of Internal Medicine, University of Patras, School of Health Sciences, Patras, Greece

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Georgios K Markantes Division of Endocrinology, Department of Internal Medicine, University of Patras, School of Health Sciences, Patras, Greece

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Maria Stamou Division of Endocrinology, Department of Internal Medicine, University of Patras, School of Health Sciences, Patras, Greece

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Sarantis Livadas Endocrine Unit, Athens Medical Centre, Athens, Greece

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George Mastorakos Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Neoklis Georgopoulos Division of Endocrinology, Department of Internal Medicine, University of Patras, School of Health Sciences, Patras, Greece

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Adequate vitamin D levels are particularly important in pregnant women for both maternal and neonatal health. Prior studies have shown a significantly high prevalence of vitamin D deficiency (VDD) among refugees. However, no study has addressed the prevalence of VDD in pregnant refugees and its effects on neonatal health. In this study, we examined the prevalence of VDD in refugee pregnant women living in Greece and compared our results with Greek pregnant inhabitants. VDD was frequent in both groups but was significantly more common in refugees (92.2 vs 67.3% of Greek women, P  = 0.003) with 70.6% of refugees having severe hypovitaminosis D (<10 ng/mL). As a result, most newborns had VDD, which affected refugee newborns to a greater extent. Our results suggest a need to screen newcomer children and pregnant women for VDD in all host countries around the world. Such a screen will appropriately guide early and effective interventions with the goal to prevent adverse neonatal and maternal outcomes.

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Suma Uday Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK

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Ardita Kongjonaj MEAL Specialist at Save the Children International, Albania Country Office, Tirana, Albania

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Magda Aguiar Health Economics Unit, University of Birmingham, Birmingham, UK

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Ted Tulchinsky Braun School of Public Health and Community Medicine, and Ashkelon College, Ashkelon, Israel

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Wolfgang Högler Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

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Background

Nutritional rickets is a growing global public health concern despite existing prevention programmes and health policies. We aimed to compare infant and childhood vitamin D supplementation policies, implementation strategies and practices across Europe and explore factors influencing adherence.

Methods

European Society for Paediatric Endocrinology Bone and Growth Plate Working Group members and other specialists completed a questionnaire on country-specific vitamin D supplementation policy and child health care programmes, socioeconomic factors, policy implementation strategies and adherence. Factors influencing adherence were assessed using Kendall’s tau-b correlation coefficient.

Results

Responses were received from 29 of 30 European countries (97%). Ninety-six per cent had national policies for infant vitamin D supplementation. Supplements are commenced on day 1–5 in 48% (14/29) of countries, day 6–21 in 48% (14/29); only the UK (1/29) starts supplements at 6 months. Duration of supplementation varied widely (6 months to lifelong in at-risk populations). Good (≥80% of infants), moderate (50–79%) and low adherence (<50%) to supplements was reported by 59% (17/29), 31% (9/29) and 10% (3/29) of countries, respectively. UK reported lowest adherence (5–20%). Factors significantly associated with good adherence were universal supplementation independent of feeding mode (P = 0.007), providing information at neonatal unit (NNU) discharge (P = 0.02), financial family support (P = 0.005); monitoring adherence at surveillance visits (P = 0.001) and the total number of factors adopted (P < 0.001).

Conclusions

Good adherence to supplementation is a multi-task operation that works best when parents are informed at birth, all babies are supplemented, and adherence monitoring is incorporated into child health surveillance visits. Implementation strategies matter for delivering efficient prevention policies.

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Julia Herteux Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Simon Johannes Geiger Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Christina Starchl Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Johanna Windisch Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Theresa Lerchl Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Adelina Tmava-Berisha Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Gerit Wünsch Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Kathrin Eller Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Astrid Fahrleitner-Pammer Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Karin Amrein Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Objective

Chronic hypoparathyroidism (HP) is associated with acute and chronic complications, especially those related to hypocalcemia. We aimed to analyze details on hospital admissions and the reported deaths in affected patients.

Design and methods

In a retrospective analysis, we reviewed the medical history of 198 patients diagnosed with chronic HP over a continuous period of up to 17 years at the Medical University Graz.

Results

The mean age in our mostly female cohort (70.2%) was 62.6 ± 18.7 years. The etiology was predominantly postsurgical (84.8%). About 87.4% of patients received standard medication (oral calcium/vitamin D), 15 patients (7.6%) used rhPTH1–84/Natpar® and 10 patients (4.5%) had no/unknown medication. Two hundred and nineteen emergency room (ER) visits and 627 hospitalizations were documented among 149 patients, and 49 patients (24.7%) did not record any hospital admissions. According to symptoms and decreased serum calcium levels, 12% of ER (n = 26) visits and 7% of hospitalizations (n = 44) were likely attributable to HP. A subgroup of 13 patients (6.5%) received kidney transplants prior to the HP diagnosis. In eight of these patients, parathyroidectomy for tertiary renal hyperparathyroidism was the cause of permanent HP. The mortality was 7.8% (n = 12), and the causes of death appeared to be unrelated to HP. Although the awareness for HP was low, calcium levels were documented in 71% (n = 447) of hospitalizations.

Conclusions

Acute symptoms directly related to HP did not represent the primary cause of ER visits. However, comorbidities (e.g. renal/cardiovascular diseases) associated with HP played a key role in hospitalizations and deaths.

Significance statement

Hypoparathyroidism (HP) is the most common complication after anterior neck surgery. Yet, it remains underdiagnosed as well as undertreated, and the burden of disease and long-term complications are usually underestimated. There are few detailed data on emergency room (ER) visits hospitalizations and death in patients with chronic HP, although acute symptoms due to hypo-/hypercalcemia are easily detectable. We show that HP is not the primary cause for presentation but that hypocalcemia is a typical laboratory finding (when ordered) and thus may contribute to subjective symptoms. Patients often present with renal/cardiovascular/oncologic illness for which HP is known to be a contributing factor. A small but very special group (n = 13, 6.5%) are patients after kidney transplantations who showed a high ER hospitalization rate. Surprisingly, HP was never the cause for their frequent hospitalizations but rather the result of chronic kidney disease. The most frequent cause for HP in these patients was parathyroidectomy due to tertiary hyperparathyroidism. The causes of death in 12 patients appeared to be unrelated to HP, but we found a high prevalence of chronic organ damages/comorbidities related to it in this group. Less than 25% documented HP correctly in the discharge letters, which indicates a high potential for improvement.

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Alexander V Amram Department of Physiology, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA

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Stephen Cutie Department of Physiology, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA

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Guo N Huang Department of Physiology, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA

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Research conducted across phylogeny on cardiac regenerative responses following heart injury implicates endocrine signaling as a pivotal regulator of both cardiomyocyte proliferation and heart regeneration. Three prominently studied endocrine factors are thyroid hormone, vitamin D, and glucocorticoids, which canonically regulate gene expression through their respective nuclear receptors thyroid hormone receptor, vitamin D receptor, and glucocorticoid receptor. The main animal model systems of interest include humans, mice, and zebrafish, which vary in cardiac regenerative responses possibly due to the differential onsets and intensities of endocrine signaling levels throughout their embryonic to postnatal organismal development. Zebrafish and lower vertebrates tend to retain robust cardiac regenerative capacity into adulthood while mice and other higher vertebrates experience greatly diminished cardiac regenerative potential in their initial postnatal period that is sustained throughout adulthood. Here, we review recent progress in understanding how these three endocrine signaling pathways regulate cardiomyocyte proliferation and heart regeneration with a particular focus on the controversial findings that may arise from different assays, cellular-context, age, and species. Further investigating the role of each endocrine nuclear receptor in cardiac regeneration from an evolutionary perspective enables comparative studies between species in hopes of extrapolating the findings to novel therapies for human cardiovascular disease.

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Søs Dragsbæk Larsen Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

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Christine Dalgård Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Department of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark

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Mathilde Egelund Christensen Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

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Sine Lykkedegn Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark

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Louise Bjørkholt Andersen Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Department of Obstetrics and Gynecology, Herlev Hospital, Copenhagen, Denmark

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Marianne Andersen Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Department of Medical Endocrinology, Odense University Hospital, Odense, Denmark

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Dorte Glintborg Department of Medical Endocrinology, Odense University Hospital, Odense, Denmark

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Henrik Thybo Christesen Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark

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Background

Low foetal vitamin D status may be associated with higher blood pressure (BP) in later life.

Objective

To examine whether serum 25-hydroxyvitamin D2+3 (s-25OHD) in cord and pregnancy associates with systolic and diastolic BP (SBP; DBP) in children up to 3 years of age.

Design

Prospective, population-based cohort study.

Methods

We included 1594 singletons from the Odense Child Cohort with available cord s-25OHD and BP data at median age 3.7 months (48% girls), 18.9 months (44% girls) or 3 years (48% girls). Maternal s-25OHD was also assessed at gestational ages 12 and 29 weeks. Multiple regression models were stratified by sex a priori and adjusted for maternal educational level, season of birth and child height, weight and age.

Results

In 3-year-old girls, SBP decreased with −0.7 mmHg (95% CI −1.1; −0.3, P = 0.001) and DBP with −0.4 mmHg (95% CI −0.7; −0.1, P = 0.016) for every 10 nmol/L increase in cord s-25OHD in adjusted analyses. Moreover, the adjusted odds of having SBP >90th percentile were reduced by 30% for every 10 nmol/L increase in cord s-25OHD (P = 0.004) and by 64% for cord s-25OHD above the median 45.1 nmol/L (P = 0.02). Similar findings were observed between pregnancy s-25OHD and 3-year SBP, cord s-25OHD and SBP at 18.9 months, and cord s-25OHD and DBP at 3 years. No consistent associations were observed between s-25OHD and BP in boys.

Conclusion

Cord s-25OHD was inversely associated with SBP and DBP in young girls, but not in boys. Higher vitamin D status in foetal life may modulate BP in young girls. The sex difference remains unexplained.

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Athanasios D Anastasilakis Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece

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Marina Tsoli 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Gregory Kaltsas 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Polyzois Makras Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece

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Langerhans cell histiocytosis (LCH) is a rare disease of not well-defined etiology that involves immune cell activation and frequently affects the skeleton. Bone involvement in LCH usually presents in the form of osteolytic lesions along with low bone mineral density. Various molecules involved in bone metabolism are implicated in the pathogenesis of LCH or may be affected during the course of the disease, including interleukins (ILs), tumor necrosis factor α, receptor activator of NF-κB (RANK) and its soluble ligand RANKL, osteoprotegerin (OPG), periostin and sclerostin. Among them IL-17A, periostin and RANKL have been proposed as potential serum biomarkers for LCH, particularly as the interaction between RANK, RANKL and OPG not only regulates bone homeostasis through its effects on the osteoclasts but also affects the activation and survival of immune cells. Significant changes in circulating and lesional RANKL levels have been observed in LCH patients irrespective of bone involvement. Standard LCH management includes local or systematic administration of corticosteroids and chemotherapy. Given the implication of RANK, RANKL and OPG in the pathogenesis of the disease and the osteolytic nature of bone lesions, agents aiming at inhibiting the RANKL pathway and/or osteoclastic activation, such as bisphosphonates and denosumab, may have a role in the therapeutic approach of LCH although further clinical investigation is warranted.

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Ozlem Atan Sahin Department of Pediatrics, Acıbadem University School of Medicine, Atasehir, Istanbul, Turkey

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Damla Goksen Department of Pediatric Endocrinology, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey

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Aysel Ozpinar Department of Biochemistry, Acıbadem University, School of Medicine, Atasehir, Istanbul, Turkey

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Muhittin Serdar Department of Biochemistry, Acıbadem University, School of Medicine, Atasehir, Istanbul, Turkey

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Huseyin Onay Department of Medical Genetics, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey

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Background

There have been studies focused on FokI, BsmI, ApaI and TaqI polymorphisms of the vitamin D receptor (VDR) gene and susceptibility to type 1 diabetes mellitus with controversial results.

Methods

This present study is a meta-analysis investigating the association between FokI, ApaI, TaqI and BsmI polymorphisms of VDR gene and type 1 DM in children. A literature search was performed using Medline, EMBASE, Cochrane and PubMed. Any study was considered eligible for inclusion if at least one of FokI, ApaI, TaqI and BsmI polymorphisms was determined, and outcome was type 1 DM at pediatric age.

Results

A total of 9 studies comprising 1053 patients and 1017 controls met the study inclusion criteria. The pooled odds ratios (ORs) of the FokI, ApaI, TaqI and BsmI polymorphisms were combined and calculated. Forest plots and funnel plots of the OR value distributions were drawn. Our meta-analysis has demonstrated statistically significant associations between DM1 and VDR genotypes, BsmIBB (P < 0.05), BsmIBb, (P < 0.05), BsmIbb (P < 0.05), TaqITT (P < 0.05) and TaqItt (P < 0.05) in children.

Conclusion

The results indicated that BsmIBB, BsmIBb and TaqItt polymorphisms were associated with an increased risk of type 1 DM, whereas BsmIbb and TaqITT had protective effect for type 1 DM in children.

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