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2nd Department of Internal Medicine, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University in Prague, Srobarova, Prague, Czech Republic
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Diabetes Centre, Institute for Clinical and Experimental Medicine (IKEM), Videnska, Prague, Czech Republic
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Objective
Patients with type 2 diabetes (T2DM) generally experience a higher incidence of cancer. However, the association between T2DM and thyroid cancer is inconclusive.
Methods
Case-control prospective study, where 722 patients were screened for T2DM and prediabetes (PDM) and underwent thyroid ultrasound and biochemical tests. The patients were assigned to groups of PDM (n = 55), T2DM (n = 79) or a non-diabetes group (NDM) (n = 588). Fine-needle aspiration biopsy was carried out in 263 patients. Histological examinations were done for 109 patients after surgery, with findings of 52 benign (BS) and 57 malignant tumors (MS).
Results
Thirty-three percent of patients with T2DM and especially PDM were newly diagnosed by our screening: 6.5% with T2DM and 72% with PDM, respectively. The percentage of thyroid cancers did not significantly differ between the groups (χ2 test = 0.461; P = 0.794). Relevant positive thyroid predictors for T2DM (t-statistic = 25.87; P < 0.01) and PDM (21.69; P < 0.01) contrary to NDM (−26.9; P < 0.01) were thyroid volume (4.79; P < 0.01), thyroid nodule volume (3.25; P < 0.01) and multinodular thyroid gland (4.83; P < 0.01), while negative relevant predictors included the occurrence of autoimmune thyroid disease (AITD) (−2.01; P < 0.05).
Conclusion
In general, we did not observe an increased risk for thyroid cancer in the diabetic and prediabetic groups in comparison to controls, in spite of well-established increased risk for other malignancies. Structural and benign changes such as larger and multinodular thyroid glands, in comparison to autoimmune thyroid disease, are present more often in diabetics.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Guangdong Geriatric Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Reproductive Medicine Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Graves’ disease (GD) is a common autoimmune disease that affects the thyroid gland. As a new class of modulators of gene expression, long noncoding RNAs (lncRNAs) have been reported to play a vital role in immune functions and in the development of autoimmunity and autoimmune disease. The aim of this study is to identify lncRNAs in CD4+ T cells as potential biomarkers of GD. lncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs and mRNAs in GD CD4+ T cells compared with healthy control CD4+ T cells. Quantitative PCR (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and clinical parameters. The microarray identified 164 lncRNAs and 93 mRNAs in GD CD4+ T cells differentially expressed compared to healthy control CD4+ T cells (fold change >2.0 and a P < 0.05). Further analysis consistently showed that the expression of HMlincRNA1474 (P < 0.01) and TCONS_00012608 (P < 0.01) was suppressed, while the expression of AK021954 (P < 0.01) and AB075506 (P < 0.01) was upregulated from initial GD patients. In addition, their expression levels were recovered in euthyroid GD patients and GD patients in remission. Moreover, these four aberrantly expressed lncRNAs were correlated with GD clinical parameters. Moreover, the areas under the ROC curve were 0.8046, 0.7579, 0.8115 for AK021954, AB075506, HMlincRNA1474, respectively. The present work revealed that differentially expressed lncRNAs were associated with GD, which might serve as novel biomarkers of GD and potential targets for GD treatment.
School of Nursing, Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Vitamin D has well-documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D system, notably the vitamin D receptor (VDR) and the vitamin D-activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as to attenuate inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported the correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function and increase the risk of inflammatory autoimmune disease.
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Background
Growth hormone-releasing hormone (GHRH) plays an important role in brain functions. The aim of this study was to examine cognitive functions and emotional behaviour in a mouse model of isolated GH deficiency due to bi-allelic ablation of the GHRH gene (GHRH knockout, GHRHKO).
Methods
Learning, memory and emotional behaviour were evaluated using a series of validated tests (Morris water maze, eight-arm radial maze, open field, elevated plus maze test, forced swim tests) in 2-, 5- and 12-month-old male mice either homozygous (−/−) or heterozygous (+/−) for the GHRHKO allele.
Results
Compared with age-matched +/− mice, −/− mice showed decreased cognitive performance in Morris water maze and eight-arm radial maze tests. By comparing the effects of aging in each genotype, we observed an age-related impairment in test results in +/− mice, while in −/− mice a significant decline in cognitive function was found only in 12 months compared with 2-month-old mice, but no difference was found between 5 months old vs 2 months old. −/− mice showed increased exploration activity compared to age-matched +/− controls, while both strains of mice had an age-related decrease in exploration activity. When evaluated through open field, elevated plus maze and forced swim tests, −/− mice demonstrated a decrease in anxiety and depression-related behaviour compared to age-matched +/− controls.
Conclusions
Our results suggest that homozygous ablation of GHRH gene is associated with decreased performance in learning and memory tests, possibly linked to increased spontaneous locomotor activity. In addition, we observed an age-related decline in cognitive functions in both genotypes.
Department of Child and Adolescent Medicine, Section of Pediatric Cardiology, University Hospital Jena, Am Klinikum, Jena, Germany
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Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany
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Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany
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Background and objectives
As part of the LIFE Child study, we previously described the associations between N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP) and hs-troponin T (hs-TnT) levels and an individual’s sex, age and pubertal status, as well as with body mass index (BMI) and serum lipid levels. For NT-proBNP, we found inverse associations with advancing puberty, increasing BMI and serum lipid levels. These findings led us to further question the putative influences of the developing individual’s metabolic and growth status as represented by levels of insulin-like growth factor-1 (IGF-1) and IGF-1-binding protein-3 (IGF-BP3) as well as hemoglobin A1c (HbA1c) and Cystatin C (CysC).
Material and methods
Serum values, medical history and anthropometric data provided by 2522 children aged 0.25–18 years were collected and analyzed as per study protocol.
Results
A strong negative association between NT-proBNP values and IGF-1, IGF-BP3 and HbA1c levels was identified. For IGF-BP3, this interaction was modulated by sex and age, for HbA1c only by age. For hs-TnT, a positive association was found with IGF-BP3, IGF-1 and CysC. The association between hs-TnT and IGF-1 was sex dependent. The association between CysC and hs-TnT was stronger in girls, but the interaction with age was only seen in boys. Between hs-TnT and HbA1c, the association was significantly negative and modulated by age.
Conclusion
Based on our large pediatric cohort, we could identify age- and sex-dependent interactions between the metabolic status represented by IGF-1, IGF-BP3, CysC and HbA1c levels and the cardiac markers NT-proBNP and hs-TnT.
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Objective
Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children.
Design
Data from children (aged <18 years) with hypophosphatasia were analyzed from the observational Global Hypophosphatasia Registry.
Methods
Anthropometric parameters were evaluated by age group (<2 years and ≥2 years) at assessment. The frequency of hypophosphatasia manifestations was compared between children with short stature (< percentile) and those with normal stature.
Results
This analysis included 215 children (54.4% girls). Short stature presented in 16.1% of children aged <2 years and 20.4% of those aged ≥2 years at assessment. Among those with available data (n = 62), height was below the target height (mean: −0.66 standard deviations). Substantial worsening of growth (mean delta height z score: −1.45; delta weight z score: −0.68) occurred before 2 years of age, while in those aged ≥2 years, anthropometric trajectories were maintained (delta height z score: 0.08; delta weight z score: 0.13). Broad-ranging hypophosphatasia manifestations (beyond dental) were observed in most children.
Conclusions
Short stature was not a consistent characteristic of children with hypophosphatasia, but growth impairment was observed in those aged <2 years, indicating that hypophosphatasia might affect growth plate activity during infancy. In addition, a broad range of clinical manifestations occurred in those above and below the third percentile for height, suggesting that height alone may not accurately reflect hypophosphatasia disease burden and that weight is less affected than longitudinal growth.
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France
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Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France
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Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France
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Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France
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Department of Endocrinology and Reproductive Medicine, AP-HPIE3M, Hôpital Pitié-Salpêtrière, ICAN, Paris, France
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Department of Endocrinology and Reproductive Medicine, AP-HPIE3M, Hôpital Pitié-Salpêtrière, ICAN, Paris, France
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Centre for Rare Gynecological Disorders, Hospital Universitaire Necker-Enfants Malades, Paediatric Endocrinology, Gynaecology and Diabetology, AP-HP, Université de Paris, Paris, France
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Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France
Centre for Rare Gynecological Disorders, Hospital Universitaire Necker-Enfants Malades, Paediatric Endocrinology, Gynaecology and Diabetology, AP-HP, Université de Paris, Paris, France
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Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000–60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3–52 years)) and 47 males (median age, 19 years (3–45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.
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Objectives
Controversies regarding factors associated with distant metastasis in pediatric thyroid cancer remain among the scientific community. The aim of this study was to investigate factors influencing distant metastasis in pediatric thyroid cancer.
Methods
We reviewed 1376 patients (aged 2 to 18 years) with thyroid cancer treated between 2003 and 2014. Data collected and analyzed included sex, race, age at diagnosis, year of diagnosis, pathological type, number of tumor foci, tumor extension, T-stage, N-stage, surgical procedure and radiation. Univariate and multivariate analyses were conducted to evaluate factors influencing distant metastasis of pediatric thyroid cancer.
Results
In the univariate analysis, factors influencing distant metastasis of thyroid cancer were age at diagnosis (P < 0.001), N-stage (P < 0.001), number of tumor foci (P = 0.003), tumor extension (P < 0.001) and T-stage (T1 vs T2 (P = 0.803), T3 (P < 0.001) and T4 (P < 0.001)). In multivariate analysis, factors influencing distant metastasis of thyroid cancer were age at diagnosis (P = 0.001), N-stage (P < 0.001) and T-stage (T1 vs T3 (P = 0.036) and T4 (P < 0.001)). Sex, race, year of diagnosis, pathological type, number of tumor foci, tumor extension, surgical procedure and radiation had no significant influence on distant metastasis (all P > 0.05). Furthermore, according to chi-squared test, younger pediatric thyroid cancer patients with higher T- and N-stages are more likely to have distant metastasis.
Conclusion
Age at diagnosis, T-stage and N-stage influence distant metastasis of thyroid cancer patients aged 2 to 18 years; accordingly, more radical treatments may need to be used for patients with those risk elements.
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Introduction
Cancer registry data in the USA indicated that women diagnosed with breast cancer before the age of 40 were at increased risk of a new primary tumour within the brain and women aged 50 years or above were at lower risk than expected. Our aim was to investigate if similar results could be found in Danish population-based data, considering an explanatory role of hormonal status.
Methods
Our study cohort included all women diagnosed with breast cancer below the age of 60 between 1978 and 2013 in Denmark. A total of 47,920 women were followed up in the Danish Cancer Registry for primary brain cancer. Standardized incidence ratios (observed/expected cases (O/E)) were used to estimate the risk of getting a primary brain tumour in the breast cancer cohort.
Results
Data indicated an increased tendency of brain cancer following breast cancer at ages below 60 years (O/E = 1.24). For premenopausal women (age <49 at the diagnosis of breast cancer) the O/E was 1.25. Stratifying by time of breast cancer diagnosis, we observed an increased risk of being diagnosed with a brain tumour among women aged 49 years or younger at breast cancer diagnosis between 2004 and 2013.
Conclusion
The results indicate an increased tendency of developing a primary brain tumour in women with previous breast cancer history. Whereas the finding in premenopausal women is in line with the SEER data, the finding among postmenopausal is not. Primary brain tumours in breast cancer patients call for research in genetics and hormones to establish common risk factors.
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Background
The precision of adult height prediction by bone age determination in children with idiopathic growth hormone deficiency (IGHD) is unknown.
Methods
The near adult height (NAH) of patients with IGHD in the KIGS database was compared retrospectively to adult height prediction calculated by the Bayley–Pinneau (BP) prediction based on bone age by Greulich–Pyle (GP) in 315 children and based on the Tanner-Whitehouse 2 (TW2) method in 121 children. Multiple linear regression analyses adjusted for age at GH start, age at puberty, mean dose and years of of GH treatment, and maximum GH peak in stimulation test were calculated.
Results
The mean underestimation of adult height based on the BP method was at baseline 4.1 ± 0.7 cm in girls and 6.1 ± 0.6 cm in boys, at 1 year of GH treatment 2.5 ± 0.5 cm in girls and 0.9 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 0.4 ± 0.6 cm in girls and 3.8 ± 0.5 cm in boys. The mean underestimation of adult height based on the TW2 method was at baseline 5.3 ± 2.0 cm in girls and 7.9 ± 0.8 cm in boys, at 1 year of GH treatment adult height was overestimated in girls 0.1 ± 0.6 cm in girls and underestimated 4.1 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 3.1 ± 1.5 cm in girls and 3.6 ± 0.8 cm in boys.
Conclusions
Height prediction by BP and TW2 at onset of GH treatment underestimates adult height in prepubertal IGHD children, while in mean 6 years after onset of GH treatment these prediction methods overestimated adult height.
