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Iulia Soare University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania

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Anca Sirbu University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Endocrinology, Diabetes and Metabolic diseases, Elias Hospital, Bucharest, Romania

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Mihai Mircea Diculescu University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Gastroenterology, Fundeni Clinical Institute, Bucharest, Romania

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Bogdan Radu Mateescu University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Gastroenterology, Colentina Hospital, Bucharest, Romania

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Cristian Tieranu University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Gastroenterology, Elias Hospital, Bucharest, Romania

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Sorina Martin University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Endocrinology, Diabetes and Metabolic diseases, Elias Hospital, Bucharest, Romania

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Carmen Gabriela Barbu University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Endocrinology, Diabetes and Metabolic diseases, Elias Hospital, Bucharest, Romania

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Mirela Ionescu University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Gastroenterology, Elias Hospital, Bucharest, Romania

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Simona Fica University of Medicine and Pharmacy ‘Carol Davila’ Bucharest, Bucharest, Romania
Department of Endocrinology, Diabetes and Metabolic diseases, Elias Hospital, Bucharest, Romania

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Background and aim

Low bone mineral density (BMD) is a common complication in patients with inflammatory bowel disease (IBD). However, debates are ongoing with regard to the other involved factors, especially in younger patients. This study aimed to evaluate the parameters that contribute to decreased BMD, focusing on premenopausal women and men aged <50 years.

Methods

This study included 81 patients with IBD and 81 age-, sex- and BMI-matched controls. Blood tests were conducted on IBD patients, and a dual-energy X-ray absorptiometry (DXA) scan was performed on both groups.

Results

Low BMD and fragility fracture were found to be more prevalent in IBD patients than in healthy subjects (49.3% vs 23.4%, P = 0.001 and 9.8% vs 1.2%, P = 0.01, respectively). Patients with low BMD were older, with a longer disease duration, higher faecal calprotectin (FC) levels and lower magnesium and lean mass (appreciated as appendicular skeletal muscle index (ASMI)). Multiple regression analysis revealed that ASMI, age and use of glucocorticoids were the independent parameters for decreased BMD. Although 91.3% of the patients had a 25-hydroxy vitamin D level of <30 ng/mL, it was not a statistically significant factor for decreased BMD.

Conclusion

In our study, the levels of vitamin D did not seem to have an important impact on BMD. Conversely, FC, magnesium and lean mass are important factors, suggesting that good control of disease, adequate magnesium intake and increased lean mass can have a good impact on bone metabolism in patients with IBD.

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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.

Open access
Fabienne A U Fox Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

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Lennart Koch Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
University for Health Sciences, Medical Informatics and Technology (UMIT TIROL), Tirol, Austria

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Monique M B Breteler Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany

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N Ahmad Aziz Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Department of Neurology, Faculty of Medicine, University of Bonn, Bonn, Germany

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Objective

Maintaining muscle function throughout life is critical for healthy ageing. Although in vitro studies consistently indicate beneficial effects of 25-hydroxyvitamin D (25-OHD) on muscle function, findings from population-based studies remain inconclusive. We therefore aimed to examine the association between 25-OHD concentration and handgrip strength across a wide age range and assess potential modifying effects of age, sex and season.

Methods

We analysed cross-sectional baseline data of 2576 eligible participants out of the first 3000 participants (recruited from March 2016 to March 2019) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Multivariate linear regression models were used to assess the relation between 25-OHD levels and grip strength while adjusting for age, sex, education, smoking, season, body mass index, physical activity levels, osteoporosis and vitamin D supplementation.

Results

Compared to participants with deficient 25-OHD levels (<30 nmol/L), grip strength was higher in those with inadequate (30 to <50 nmol/L) and adequate (≥50 to ≤125 nmol/L) levels (ßinadequate = 1.222, 95% CI: 0.377; 2.067, P = 0.005; ßadequate = 1.228, 95% CI: 0.437; 2.019, P = 0.002). Modelling on a continuous scale revealed grip strength to increase with higher 25-OHD levels up to ~100 nmol/L, after which the direction reversed (ßlinear = 0.505, 95% CI: 0.179; 0.830, P = 0.002; ßquadratic = –0.153, 95% CI: –0.269; -0.038, P = 0.009). Older adults showed weaker effects of 25-OHD levels on grip strength than younger adults (ß25OHDxAge = –0.309, 95% CI: –0.594; –0.024, P = 0.033).

Conclusions

Our findings highlight the importance of sufficient 25-OHD levels for optimal muscle function across the adult life span. However, vitamin D supplementation should be closely monitored to avoid detrimental effects.

Open access
Elena Valassi Endocrinology/Medicine Department, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

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Natalia García-Giralt URFOA, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autònoma de Barcelona, Barcelona, Spain

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Jorge Malouf Mineral Metabolism Unit, Medicine Department, Hospital Sant Pau, Barcelona, Spain

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Iris Crespo Endocrinology/Medicine Department, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

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Jaume Llauger Radiology Department, Hospital Sant Pau, Barcelona, Spain

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Adolfo Díez-Pérez URFOA, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autònoma de Barcelona, Barcelona, Spain

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Susan M Webb Endocrinology/Medicine Department, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

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Background

Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis.

Aims

Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters.

Patients and methods

Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR.

Results

In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001).

Conclusions

Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.

Open access
Mieke Van Hemelrijck
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Thurkaa Shanmugalingam
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Cecilia Bosco
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Wahyu Wulaningsih
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Sabine Rohrmann Cancer Epidemiology Group, Division of Chronic Disease Epidemiology, Division of Cancer Studies, King's College London, London, UK

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Background

Despite mounting evidence linking both calcium and IGF1, there is a lack of studies investigating any association between circulating levels of IGF1 and serum calcium.

Methods

Serum calcium, IGF1, and IGF-binding protein 3 (IGFBP3) were measured for 5368 participants in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of IGF1, IGFBP3, and IGF1/IGFBP3 by categories of calcium (lowest 5% (<1.16 mmol/l), mid 90%, and top 5% (≥1.31 mmol/l)). We also performed stratified analyses by sex, age, ethnicity, BMI, serum levels of vitamin D, and bone mineral density (BMD).

Results

Overall, we found that circulating calcium was positively associated with circulating levels of IGF1 and IGFBP3, but not their molar ratio (i.e., geometric mean of IGF1 by increasing calcium categories: 237.63, 246.51, and 264.22 ng/nl; P trend: 0.43; P first vs third category: 0.01). In particular, these associations were observed in women, people aged <60, non-Hispanic whites, those with vitamin D levels above the mean, and those with low BMD. In contrast, there was an inverse association with the molar ratio for those with BMI ≥30 kg/m2.

Conclusion

We found an overall positive association between circulating levels of IGF1 and IGFBP3 and serum calcium. However, stratification by potential effect-modifiers did not support all suggested hypotheses. Our findings provide more insight into the interplay between calcium and IGF1, which in the future can be investigated in larger observational studies allowing for additional stratifications based on a combination of the different effect-modifiers investigated here.

Open access
A Gizard Department of Pediatric Orthopedic Surgery, Besançon University Hospital, Paris, France

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A Rothenbuhler APHP, Department of Pediatric Endocrinology, Bicêtre Paris Sud, Le Kremlin Bicêtre, France
Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Le Kremlin Bicêtre, France
Plateforme d’Expertise Paris Sud Maladies Rares and Filière OSCAR, Bicêtre Paris Sud, Le Kremlin Bicêtre, France

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Z Pejin APHP, Department of Pediatric Orthopedic Surgery, Necker Hospital, Paris, France

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G Finidori APHP, Department of Pediatric Orthopedic Surgery, Necker Hospital, Paris, France

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C Glorion APHP, Department of Pediatric Orthopedic Surgery, Necker Hospital, Paris, France

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B de Billy Department of Pediatric Orthopedic Surgery, Besançon University Hospital, Paris, France

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A Linglart APHP, Department of Pediatric Endocrinology, Bicêtre Paris Sud, Le Kremlin Bicêtre, France
Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Le Kremlin Bicêtre, France
Plateforme d’Expertise Paris Sud Maladies Rares and Filière OSCAR, Bicêtre Paris Sud, Le Kremlin Bicêtre, France
INSERM U1169, Hôpital Bicêtre, Le Kremlin Bicêtre, et Université Paris-Saclay, Le Kremlin Bicêtre, France

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P Wicart Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Le Kremlin Bicêtre, France
APHP, Department of Pediatric Orthopedic Surgery, Necker Hospital, Paris, France

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Background

X-linked hypophosphatemic rickets (XLHR) is due to mutations in PHEX leading to unregulated production of FGF23 and hypophosphatemia. XLHR is characterized by leg bowing of variable severity. Phosphate supplements and oral vitamin analogs, partially or, in some cases, fully restore the limb straightness. Surgery is the alternative for severe or residual limb deformities.

Objective

To retrospectively assess the results of surgical limb correction in XLHR (osteotomies and bone alignment except for 3 transient hemiepiphysiodesis).

Methods

We analyzed the incidence of recurrence and post-surgical complications in 49 XLHR patients (29F, 20M) (mean age at diagnosis 6.0 years (± 7.1)).

Results

At first surgery, the mean age was 13.4 years (± 5.0). Recurrence was observed in 14/49 (29%) patients. The number of additional operations significantly decreased with age (2.0 (± 0.9), 1.7 (± 1.0) and 1.2 (± 0.4) in children <11 years, between 11 and 15, and >15 years; P < 0.001). Incidence of recurrence seemed to be lower in patients with good metabolic control of the rickets (25% vs 33%). Complications were observed in 57% of patients.

Conclusion

We report a large series of surgical procedures in XLHR. Our results confirm that phosphate supplements and vitamin D analog therapy is the first line of treatment to correct leg bowing. Surgery before puberty is associated with a high risk of recurrence of the limb deformity. Such procedures should only be recommended, following multidisciplinary discussions, in patients with severe distortion leading to mechanical joint and ligament complications, or for residual deformities once growth plates have fused.

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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.

Open access
June Young Choi Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Korea

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Jin Wook Yi Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea

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Jun Hyup Lee Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea

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Ra-Yeong Song Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea

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Hyeongwon Yu Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Korea

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Hyungju Kwon Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea

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Young Jun Chai Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea

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Su-jin Kim Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea

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Kyu Eun Lee Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea

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The purpose of this study was to assess the relationship between vitamin D receptor gene (VDR) expression and prognostic factors in papillary thyroid cancer (PTC). mRNA sequencing and somatic mutation data from The Cancer Genome Atlas (TCGA) were analyzed. VDR mRNA expression was compared to clinicopathologic variables by linear regression. Tree-based classification was applied to find cutoff and patients were split into low and high VDR group. Logistic regression, Kaplan–Meier analysis, differentially expressed gene (DEG) test and pathway analysis were performed to assess the differences between two VDR groups. VDR mRNA expression was elevated in PTC than that in normal thyroid tissue. VDR expressions were high in classic and tall-cell variant PTC and lateral neck node metastasis was present. High VDR group was also associated with classic and tall cell subtype, AJCC stage IV and lower recurrence-free survival. DEG test reveals that 545 genes were upregulated in high VDR group. Thyroid cancer-related pathways were enriched in high VDR group in pathway analyses. VDR mRNA overexpression was correlated with worse prognostic factors such as subtypes of papillary thyroid carcinoma that are known to be worse prognosis, lateral neck node metastasis, advanced stage and recurrence-free survival.

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Silvia Ciancia Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium

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Vanessa Dubois Basic and Translational Endocrinology (BaTE), Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

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Martine Cools Department of Internal Medicine and Pediatrics, Ghent University, Pediatric Endocrinology Service, Ghent University Hospital, Ghent, Belgium

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Both in the United States and Europe, the number of minors who present at transgender healthcare services before the onset of puberty is rapidly expanding. Many of those who will have persistent gender dysphoria at the onset of puberty will pursue long-term puberty suppression before reaching the appropriate age to start using gender-affirming hormones. Exposure to pubertal sex steroids is thus significantly deferred in these individuals. Puberty is a critical period for bone development: increasing concentrations of estrogens and androgens (directly or after aromatization to estrogens) promote progressive bone growth and mineralization and induce sexually dimorphic skeletal changes. As a consequence, safety concerns regarding bone development and increased future fracture risk in transgender youth have been raised. We here review published data on bone development in transgender adolescents, focusing in particular on differences in age and pubertal stage at the start of puberty suppression, chosen strategy to block puberty progression, duration of puberty suppression, and the timing of re-evaluation after estradiol or testosterone administration. Results consistently indicate a negative impact of long-term puberty suppression on bone mineral density, especially at the lumbar spine, which is only partially restored after sex steroid administration. Trans girls are more vulnerable than trans boys for compromised bone health. Behavioral health measures that can promote bone mineralization, such as weight-bearing exercise and calcium and vitamin D supplementation, are strongly recommended in transgender youth, during the phase of puberty suppression and thereafter.

Open access