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Open access

Wenqi Yang, Ling Liu, Yuan Wei, Chunlu Fang, Fu Zhou, Jinbao Chen, Qinghua Han, Meifang Huang, Xuan Tan, Qiuyue Liu, Qiang Pan, Lu Zhang, Xiaojuan Lei and Liangming Li

Objective

The protective effects of exercise against glucose dysmetabolism have been generally reported. However, the mechanism by which exercise improves glucose homeostasis remains poorly understood. The FGF21–adiponectin axis participates in the regulation of glucose metabolism. Elevated levels of FGF21 and decreased levels of adiponectin in obesity indicate FGF21–adiponectin axis dysfunction. Hence, we investigated whether exercise could improve the FGF21–adiponectin axis impairment and ameliorate disturbed glucose metabolism in diet-induced obese mice.

Methods

Eight-week-old C57BL/6J mice were randomly assigned to three groups: low-fat diet control group, high-fat diet group and high-fat diet plus exercise group. Glucose metabolic parameters, the ability of FGF21 to induce adiponectin, FGF21 receptors and co-receptor levels and adipose tissue inflammation were evaluated after 12 weeks of intervention.

Results

Exercise training led to reduced levels of fasting blood glucose and insulin, improved glucose tolerance and better insulin sensitivity in high-fat diet-induced obese mice. Although serum FGF21 levels were not significantly changed, both total and high-molecular-weight adiponectin concentrations were markedly enhanced by exercise. Importantly, exercise protected against high-fat diet-induced impaired ability of FGF21 to stimulate adiponectin secretion. FGF21 co-receptor, β-klotho, as well as receptors, FGFR1 and FGFR2, were upregulated by exercise. We also found that exercise inhibited adipose tissue inflammation, which may contribute to the improvement in the FGF21–adiponectin axis impairment.

Conclusions

Our data indicate exercise protects against high-fat diet-induced FGF21–adiponectin axis impairment, and may thereby exert beneficial effects on glucose metabolism.

Open access

Qianqian Pang, Yuping Xu, Xuan Qi, Yan Jiang, Ou Wang, Mei Li, Xiaoping Xing, Ling Qin and Weibo Xia

Background: Primary hypertrophic osteoarthropathy (PHO) is a rare genetic multi-organic disease characterized by digital clubbing, periostosis and pachydermia. Two genes, HPGD and SLCO2A1, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin transporter (PGT), respectively, have been reported to be related to PHO. Deficiency of the aforementioned 2 genes leads to failure of prostaglandin E2 (PGE2) degradation and thereby elevated levels of PGE2. PGE2 plays an important role in tumorigenesis. Studies revealed a tumor suppressor activity of 15-PGDH in tumors, such as lung, bladder and breast cancers. However, to date, no HPGD mutated PHO patients presenting concomitant tumor has been documented. In the present study, we reported the first case of HPGD mutated PHO patient with soft tissue giant tumors at lower legs and evaluated the efficacy of selective COX-2 inhibitor (Etorcoxib) treatment in the patient.

Methods: In this study, we summarized the clinical data, collected the serum and urine samples for biochemical test, and analyzed the HPGD gene in our patient.

Results: A common HPGD mutation c.310_311delCT was identified in the patient. In addition to typical clinical features (digital clubbing, periostosis and pachydermia), the patient demonstrated a new clinical manifestation, a giant soft tissue tumor on the left lower leg which has not been reported in HPGD-mutated PHO patient before. After six-month treatment with Etoricoxib, the patient showed decreased PGE2 levels and improved PHO related symptoms. Though the soft tissue tumor persisted, it seemed to be controlled under the Etoricoxib treatment.

Conclusion: This finding expanded the clinical spectrum of PHO and provided unique insights into the HPGD-mutated PHO.

Open access

Marilena Nakaguma, Fernanda A Correa, Lucas S Santana, Anna F F Benedetti, Ricardo V Perez, Martha K P Huayllas, Mirta B Miras, Mariana F A Funari, Antonio M Lerario, Berenice B Mendonca, Luciani R S Carvalho, Alexander A L Jorge and Ivo J P Arnhold

Aim

Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism.

Methods

Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel.

Results

We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A].

Conclusions

Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

Open access

Meena Asmar, Ali Asmar, Lene Simonsen, Flemming Dela, Jens Juul Holst and Jens Bülow

Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increase blood flow and triglyceride clearance in subcutaneous abdominal adipose tissue in lean humans. The present experiments were performed to determine whether the increase involves capillary recruitment. Eight lean healthy volunteers were studied before and after 1-h infusion of GIP or saline during a hyperglycemic-hyperinsulinemic clamp, raising plasma glucose and insulin to postprandial levels. Subcutaneous abdominal adipose tissue blood flow (ATBF) was measured by the 133Xenon clearance technique, and microvascular blood volume was determined by contrast-enhanced ultrasound imaging. During infusion of saline and the clamp, both ATBF (2.7 ± 0.5 ml/min, 100 g/tissue) and microvascular blood volume remained unchanged throughout the experiments. During GIP infusion and the clamp, ATBF increased ~fourfold to 11.4 ± 1.9 ml/min 100 g/tissue, P<0.001. Likewise, the contrast-enhanced ultrasound signal intensity, a measure of the microvascular blood volume, increased significantly one hour after infusion of GIP and the clamp (P=0.003), but not in the control experiments. In conclusion, the increase in ATBF during GIP infusion involves recruitment of capillaries in healthy lean subjects, which probably increases the interaction of circulating lipoproteins with lipoprotein lipase, thus promoting adipose tissue lipid uptake.

Open access

Monica F Stecchini, Zilda Braid, Candy B More, Davi C Aragon, Margaret Castro, Ayrton C Moreira and Sonir R Antonini

Objective

To investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood.

Methods

Retrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared.

Results

The study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75).

Conclusions

Gonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.

Open access

T Szarvas, B Jardin-Watelet, N Bourgoin, M J Hoffmann, P Nyirády, C Oláh, T Széll, A Csizmarik, B Hadaschik and H Reis

Recently, a neuroendocrine-like molecular subtype has been discovered in muscle-invasive urothelial bladder cancer (BC). Chromogranin A (CGA) is a widely used tissue and serum marker in neuroendocrine tumors. Our aim was to evaluate serum CGA (sCGA) concentrations and their associations with clinical and follow-up data in BC and renal cell carcinoma (RCC). sCGA concentrations were analyzed in the following cohorts: (1) BC training set (n = 188), (2) BC validation set (n = 125), (3) RCC patients (n = 77), (4) healthy controls (n = 97). CGA immunohistochemistry and RT-qPCR analyses were performed in 20 selected FFPE and 29 frozen BC tissue samples. Acquired data were correlated with clinicopathological parameters including comorbidities with known effect on sCGA as well as with patients’ follow-up data. sCGA levels were significantly higher in BC but not in RCC patients compared to healthy controls. High sCGA levels were independently associated with poor overall and disease-specific survival both in the BC training (P < 0.001, P = 0.002) and validation set (P = 0.009, P = 0.017). sCGA levels were inversely correlated with glomerulus filtrating rate (GFR) and linearly correlated with creatinine clearance and urea concentrations. These correlations were not related to the prognostic value of sCGA. Tissue CGA levels were low to absent independently of sCGA concentrations. Our results demonstrate elevated levels and an independent prognostic value for sCGA in BC but not in RCC. Despite the significant correlation between sCGA and GFR, the prognostic relevance of sCGA seems not related to impaired renal function or other comorbidities.

Open access

Madalena von Hafe, João Sergio Neves, Catarina Vale, Marta Borges-Canha and Adelino Leite-Moreira

Thyroid hormones have a central role in cardiovascular homeostasis. In myocardium, these hormones stimulate both diastolic myocardial relaxation and systolic myocardial contraction, have a pro-angiogenic effect and an important role in extracellular matrix maintenance. Thyroid hormones modulate cardiac mitochondrial function. Dysfunction of thyroid axis impairs myocardial bioenergetic status. Both overt and subclinical hypothyroidism are associated with a higher incidence of coronary events and an increased risk of heart failure progression. Endothelial function is also impaired in hypothyroid state, with decreased nitric oxide-mediated vascular relaxation. In heart disease, particularly in ischemic heart disease, abnormalities in thyroid hormone levels are common and are an important factor to be considered. In fact, low thyroid hormone levels should be interpreted as a cardiovascular risk factor. Regarding ischemic heart disease, during the late post-myocardial infarction period, thyroid hormones modulate left ventricular structure, function and geometry. Dysfunction of thyroid axis might even be more prevalent in the referred condition since there is an upregulation of type 3 deiodinase in myocardium, producing a state of local cardiac hypothyroidism. In this focused review, we summarize the central pathophysiological and clinical links between altered thyroid function and ischemic heart disease. Finally, we highlight the potential benefits of thyroid hormone supplementation as a therapeutic target in ischemic heart disease.

Open access

Eugenie S Lim, Shanty G Shah, Mona Waterhouse, Scott Akker, William Drake, Nick Plowman, Daniel M Berney, Polly Richards, Ashok Adams, Ewa Nowosinska, Carmel Brennan and Maralyn Druce

Context

Differentiated thyroid cancer (DTC) is usually treated by thyroidectomy followed by radioiodine ablation and generally has a good prognosis. It may now be possible to limit the amount of treatment without impacting on efficacy. It is not known whether coexistent thyroiditis impacts on radioiodine uptake or on its potential efficacy, but this could provide a rationale for modification to current therapeutic protocols.

Design

This was a retrospective cohort study of radioiodine uptake on imaging after radioiodine ablation for DTC in patients with and without concurrent thyroiditis. All patients with histologically confirmed DTC treated with radioiodine ablation after thyroidectomy in a single centre from 2012 to 2015 were included. The primary outcome assessed was the presence of low or no iodine uptake on post-ablation scan, as reported by a nuclear medicine physician blinded to the presence or absence of thyroiditis.

Results

One hundred thirty patients with available histopathology results were included. Thyroiditis was identified in 42 post-operative specimens and 15 of these patients had low or no iodine uptake on post-ablation scan, compared to only 2 of 88 patients without thyroiditis (P < 0.0001) with further data analysis dividing the groups by ablation activity received (1100 MBq or 3000 MBq).

Conclusions

Concurrent thyroiditis may impair the uptake of radioactive iodine in management of DTC. Given that patients with DTC and thyroiditis already have a good prognosis, adopting a more selective approach to this step in therapy may be indicated. Large, longitudinal studies would be required to determine if omitting radioactive iodine therapy from those patients with concurrent thyroiditis has a measurable impact on mortality from thyroid cancer.

Open access

Ling Shan, Yingying Zhou, Shiqiao Peng, Xinyi Wang, Zhongyan Shan and Weiping Teng

Background: Pregnant women with subclinical hypothyroidism are associated with an increased risk of spontaneous abortion. This study aim to investigate the mechanisms underlying the effects of maternal subclinical hypothyroidism during early pregnancy on abortion in the uterus, focusing upon the LIF/STAT3 signaling pathway.

Methods: 105 Wistar rats were randomly divided into three groups (35 rats in each group): control (CON) group, subclinical hypothyroidism (SCH) group, and overt hypothyroidism (OH) group. We examined the weight of rat uteri, rat placenta and embryos. We also determined the number of implantation sites and the embryo absorption rates. The protein and mRNA expressions of TSHR, TR-α, TR-β, LIFR, gp130, JAK1, p-STAT3, and STAT3 were measured by immunohistochemical staining, real-time polymerase chain reaction (PCR), and western blotting.

Results: The weights of rat uteri, rat placenta and embryos were significantly reduced in the SCH and OH groups. The number of implantation sites were significantly decreased in the SCH and OH groups, while embryo absorption rates were significantly increased. The mRNA and protein expressions of TSHR were upregulated in the SCH and OH groups, while TR-α and TR-β showed no difference when compared between the three groups. The expressions of LIFR, gp130, JAK1, and p-STAT3 were significantly higher in the SCH and OH groups.

Conclusions: Clinical and subclinical hypothyroidism during early pregnancy might cause adverse pregnancy outcomes. Implantation failure in rats with subclinical hypothyroidism was associated with abnormal LIF/STAT3 signaling.

Open access

Fahim Ebrahimi, Sandrine Andrea Urwyler, Philipp Schuetz, Beat Mueller, Luca Bernasconi, Peter Neyer, Marc Yves Donath and Mirjam Christ-Crain

BACKGROUND: Anti-inflammatory treatment with Interleukin-1 (IL-1) antagonism decreases both cortisol and adrenocorticotropin hormone (ACTH) levels in obese individuals in short-term. However, it remains unknown whether these effects persist upon prolonged treatment.

METHODS: In this double-blind, parallel-group trial involving patients with features of the metabolic syndrome, 33 patients were randomly assigned to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice daily and 34 patients to receive placebo for a duration of 4 weeks. For this analysis change in cortisol and ACTH levels from baseline to 4 weeks were predefined end-points of the trial.

RESULTS: The mean age was 54 years, baseline cortisol levels were 314.0 nmol/L (IQR 240.8 to 384.8) and c-reactive protein (CRP) levels were 3.4 mg/L (IQR 1.7 to 4.8). Treatment with anakinra led to a significant decrease in cortisol levels at day 1 when compared to placebo with an adjusted between-group difference of 27.6 nmol/L (95% CI, (-7.3) to (-43.3); P= 0.03). After 4 weeks the cortisol-lowering effect of anakinra was attenuated in individuals experiencing injection-site reactions and overall was statistically not significant (P=0.72).

CONCLUSIONS: IL-1 antagonism decreases cortisol levels in obese male patients with chronic low-grade inflammation on the short-term. After prolonged treatment, this effect is attenuated, probably due to injection-site reactions. (ClinicalTrials.gov, NCT02672592).