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Open access

Elisabet Einarsdottir, Minna Pekkinen, Kaarel Krjutškov, Shintaro Katayama, Juha Kere, Outi Mäkitie and Heli Viljakainen

Objective

The effect of vitamin D at the transcriptome level is poorly understood, and furthermore, it is unclear if it differs between obese and normal-weight subjects. The objective of the study was to explore the transcriptome effects of vitamin D supplementation.

Design and methods

We analysed peripheral blood gene expression using GlobinLock oligonucleotides followed by RNA sequencing in individuals participating in a 12-week randomised double-blinded placebo-controlled vitamin D intervention study. The study involved 18 obese and 18 normal-weight subjects (of which 20 males) with mean (±s.d.) age 20.4 (±2.5) years and BMIs 36 (±10) and 23 (±4) kg/m2, respectively. The supplemental daily vitamin D dose was 50 µg (2000 IU). Data were available at baseline, 6- and 12-week time points and comparisons were performed between the vitamin D and placebo groups separately in obese and normal-weight subjects.

Results

Significant transcriptomic changes were observed at 6 weeks, and only in the obese subjects: 1724 genes were significantly upregulated and 186 genes were downregulated in the vitamin D group compared with placebo. Further analyses showed several enriched gene categories connected to mitochondrial function and metabolism, and the most significantly enriched pathway was related to oxidative phosphorylation (adjusted P value 3.08 × 10−14). Taken together, our data suggest an effect of vitamin D supplementation on mitochondrial function in obese subjects.

Conclusions

Vitamin D supplementation affects gene expression in obese, but not in normal-weight subjects. The altered genes are enriched in pathways related to mitochondrial function. The present study increases the understanding of the effects of vitamin D at the transcriptome level.

Open access

Anna-Pauliina Iivonen, Johanna Känsäkoski, Kirsi Vaaralahti and Taneli Raivio

In approximately half of congenital hypogonadotropic hypogonadism (cHH) patients, the genetic cause remains unidentified. Since the lack of certain miRNAs in animal models has led to cHH, we sequenced human miRNAs predicted to regulate cHH-related genes (MIR7-3, MIR141, MIR429 and MIR200A-C) in 24 cHH patients with Sanger sequencing. A heterozygous variant in MIR200A (rs202051309; general population frequency of 0.02) was found in one patient. Our results suggest that mutations in the studied miRNAs are unlikely causes of cHH. However, the complex interplay between miRNAs and their target genes in these diseases requires further investigations.

Open access

Adrian F Daly, David A Cano, Eva Venegas-Moreno, Patrick Petrossians, Elena Dios, Emilie Castermans, Alvaro Flores-Martínez, Vincent Bours, Albert Beckers and Alfonso Soto-Moreno

Background

Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy.

Aims

We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center.

Methods

Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response.

Results

Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen.

Conclusions

Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients.

Open access

Adrian F Daly, Liliya Rostomyan, Daniela Betea, Jean-François Bonneville, Chiara Villa, Natalia S Pellegata, Beatrice Waser, Jean-Claude Reubi, Catherine Waeber Stephan, Emanuel Christ and Albert Beckers

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

Open access

Xiujuan Su, Yan Zhao, Zhijuan Cao, Yingying Yang, Tony Duan and Jing Hua

Background

The effect of isolated maternal hypothyroxinaemia (IMH) on pregnancy complications and neonatal outcomes in human beings is still controversial.

Methods

This was a retrospective cohort study based on the electronic medical register system. The records of women with a singleton pregnancy who sought antenatal examination between January 2014 and December 2015 at Shanghai First Maternity and Infant Hospital were extracted from the electronic medical records system. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and anti-thyroperoxidase autoantibody (TPO-Ab) was measured before 20 gestational weeks, and a multiple logistic regression model was used to estimate the odds ratios of pregnancy complications and neonatal outcomes between euthyroid women and those with isolated hypothyroxinaemia.

Results

A total of 8173 women were included in this study, of whom 342 (4.18%) were diagnosed with IMH. Regression analysis showed that IMH diagnosed in the second trimester (13–20 weeks) was associated with an increased risk of hypertensive disorders of pregnancy (OR = 2.66, 95% CI: 1.38–5.10) and placenta abruption (OR = 3.64, 95% CI: 1.07–12.41), but not with preterm delivery (OR = 1.09, 95% CI: 0.50–2.40), small or large gestational age of infant (OR = 0.91, 95% CI: 0.39–2.12; OR = 1.16, 95% CI: 0.72–1.86), macrosomia (OR = 1.71, 95% CI: 0.95–3.07), gestational diabetes mellitus (OR = 1.36, 95% CI: 0.86–2.15) and placenta previa (OR = 1.62, 95% CI: 0.39–7.37).

Conclusion

IMH could be a risk factor for hypertensive disorders of pregnancy.

Open access

Marko Stojanovic, Zida Wu, Craig E Stiles, Dragana Miljic, Ivan Soldatovic, Sandra Pekic, Mirjana Doknic, Milan Petakov, Vera Popovic, Christian Strasburger and Márta Korbonits

Background

Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients.

Subjects and methods

Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP.

Results

Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT.

Conclusions

Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

Open access

Marieke Stientje Velema, Aline de Nooijer, Ad R M M Hermus, Henri J L M Timmers, Jacques W M Lenders, Olga Husson and Jaap Deinum

Objective

To develop a primary aldosteronism (PA) disease-specific Health-Related Quality of Life (HRQoL) questionnaire.

Methods

We included newly diagnosed patients with PA (n = 26), and patients with PA after adrenalectomy (n = 25) or treated with mineralocorticoid receptor antagonists (n = 25). According to the guidelines for developing HRQoL questionnaires from the European Organization for Research and Treatment of Cancer (EORTC): Phase I: systematic literature review followed by focus group meetings with patients (n = 13) resulting in a list of 94 HRQoL issues. Relevance of issues was rated by 18 other patients and by health care professionals (n = 15), resulting in 30 remaining issues. Phase II: selected issues were converted into questions. Phase III: the provisional questionnaire was pre-tested by a third group of patients (n = 45) who also completed the EORTC core Quality of Life questionnaire (QLQ-C30). Psychometric testing resulted in a final selection of questions with their scale structure.

Results

After the collection and selection of HRQoL issues a provisional questionnaire consisting of 30 items was formed. Of these items, 26 could be assigned to one of the four scales ‘physical and mental fatigue’, ‘anxiety and stress’, ‘fluid balance’ and ‘other complaints’ cumulatively accounting for 68% of variation in all items. All scales had good reliability and validity. There was a significant correlation of all four scales with the QLQ-C30 in most cases.

Conclusions

We developed the first PA-specific HRQoL questionnaire (PA-QoL) using standard, methodologically proven guidelines. After completion of the final validation (phase IV, international field testing), the questionnaire can be implemented into clinical practice.

Open access

Lukas Engler, Christian Adolf, Daniel A Heinrich, Anna-Katharine Brem, Anna Riester, Anna Franke, Felix Beuschlein, Martin Reincke, Axel Steiger and Heike Künzel

Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.

Open access

Xiao-jun Zhou, Lin Ding, Jia-xin Liu, Le-qun Su, Jian-jun Dong and Lin Liao

Aims

To investigate the difference in the efficacy among dipeptidyl peptidase-4 (DPP-4) inhibitors in Chinese adults with newly diagnosed diabetes.

Materials and methods

In a multicenter, randomized study, we enrolled adults who were either treatment naive or off prior anti-hyperglycemic therapy for at least 3 months. Eligible patients had hemoglobin A1c (HbA1c) concentrations of 6.5–9.5%. Three hundred patients had been randomly allocated to sitagliptin 100 mg, once daily; vildagliptin 50 mg, twice daily and saxagliptin 5 mg, once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 12. This study was completed and registered with ClinicalTrials.gov, number NCT 01703637.

Results

Totally 277 patients were enrolled in the final analysis, and 93 patients received sitagliptin, 94 received vildagliptin and 90 received saxagliptin. Compared with baseline, adjusted mean differences in change from baseline HbA1c at week 12 were −0.50% (95% CI: −0.20 to −0.90), −0.65% (95% CI: −0.40 to −1.40), −0.70 (95% CI: −0.50 to −1.00) for sitagliptin, vildagliptin and saxagliptin group, respectively. The overall HbA1c-lowering effect was similar for all three selected DPP-4 inhibitors after adjustment for age and baseline HbA1c. Notably, in secondary outcome analysis, patients in vildagliptin group showed a significant decrease in total cholesterol levels, compared with participants in sitagliptin and saxagliptin groups. No significant between-group difference was shown in adverse events (AE).

Conclusions

The overall HbA1c-lowering effect and incidence of AE were similar for sitagliptin, vildagliptin and saxagliptin in Chinese adults with newly diagnosed diabetes.

Open access

Yun Hu, Na Li, Peng Jiang, Liang Cheng, Bo Ding, Xiao-Mei Liu, Ke He, Yun-Qing Zhu, Bing-li Liu, Xin Cao, Hong Zhou and Xiao-Ming Mao

Objective

Thyroid nodules are usually accompanied by elevated thyroglobulin (Tg) level and autoimmune thyroid diseases (AITDs). However, the relationship between Tg and AITDs is not fully understood. Dysfunction of regulatory T cells (Tregs) plays an important role in the development of AITDs. We aimed to evaluate the effects of Tg on the function of Tregs in patients with thyroid nodules.

Methods

Tg levels and the functions of Tregs in peripheral blood and thyroid tissues of patients with thyroid nodules from Nanjing First Hospital were evaluated. The effects of Tg on the function of Tregs from healthy donors were also assessed in vitro. The function of Tregs was defined as an inhibitory effect of Tregs on the effector T cell (CD4+ CD25 T cell) proliferation rate.

Results

The level of Tg in peripheral blood correlated negatively with the inhibitory function of Tregs (R = 0.398, P = 0.03), and Tregs function declined significantly in the high Tg group (Tg >77 μg/L) compared with the normal Tg group (11.4 ± 3.9% vs 27.5 ± 3.5%, P < 0.05). Compared with peripheral blood, the function of Tregs in thyroid declined significantly (P < 0.01), but the proportion of FOXP3+ Tregs in thyroid increased (P < 0.01). High concentration of Tg (100 μg/mL) inhibited the function of Tregs and downregulated FOXP3, TGF-β and IL-10 mRNA expression in Tregs in vitro.

Conclusions

Elevated Tg level could impair the function of Tregs, which might increase the risk of AITDs in patient with thyroid nodules.