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Open access

J Chycki, A Zajac, M Michalczyk, A Maszczyk and J Langfort

Objectives

The present study verified the effect of moderate-to-high-intensity aerobic exercise on the endocrine response profile and adipose tissue in young healthy men with different phenotype characteristics.

Design

Eighteen men were divided into three experimental groups with defined body components and specific physical fitness: Endurance phenotype – EP (n = 6; low body mass; low fat content; aerobic endurance trained), Athletic phenotype – AP (n = 6; high body mass; low fat content, resistance trained), Obesity phenotype – OP (n = 6; high body mass; high fat content, untrained).

Methods

The participants performed an progressive exercise protocol on a treadmill (30% VO2max, 50% VO2max, 70% VO2max), separated by 45 s of passive rest for blood collection.

Results

Plasma glucose oxidation increased in relation to exercise intensity, but to a greater extent in the AP group. The free fatty acids’ plasma level decreased with a rise in exercise intensity, but with different kinetics in particular phenotypes. Plasma growth hormone increased after the cessation of exercise and was significantly higher in all groups 45 min into recovery compared to resting values. Plasma insulin decreased during exercise in all groups, but in the OP, the decrease was blunted.

Conclusions

The results indicate that the rate of lipolysis, hormonal and metabolic response to aerobic exercise depends on the individuals’ phenotype. Thus, exercise type, duration and intensity have to be strictly individualized in relation to phenotype in order to reach optimal metabolic benefits.

Open access

Amarjit Saini, Linda Björkhem-Bergman, Johan Boström, Mats Lilja, Michael Melin, Karl Olsson, Lena Ekström, Peter Bergman, Mikael Altun, Eric Rullman and Thomas Gustafsson

The CC genotype of the vitamin D receptor (VDR) polymorphism TaqI rs731236 has previously been associated with a higher risk of developing myopathy compared to TT carriers. However, the mechanistic role of this polymorphism in skeletal muscle is not well defined. The effects of vitamin D on patients genotyped for the VDR polymorphism TaqI rs731236, comparing CC and TT carriers were evaluated. Primary human myoblasts isolated from 4 CC carriers were compared with myoblasts isolated from four TT carriers and treated with vitamin D in vitro. A dose-dependent inhibitory effect on myoblast proliferation and differentiation was observed concurrent with modifications of key myogenic regulatory factors. RNA sequencing revealed a vitamin D dose–response gene signature enriched with a higher number of VDR-responsive elements (VDREs) per gene. Interestingly, the greater the expression of muscle differentiation markers in myoblasts, the more pronounced was the vitamin D-mediated response to suppress genes associated with myogenic fusion and myotube formation. This novel finding provides a mechanistic explanation to the inconsistency regarding previous reports of the role of vitamin D in myoblast differentiation. No effects in myoblast proliferation, differentiation or gene expression were related to CC vs TT carriers. Our findings suggest that the VDR polymorphism TaqI rs731236 comparing CC vs TT carriers did not influence the effects of vitamin D on primary human myoblasts and that vitamin D inhibits myoblast proliferation and differentiation through key regulators of cell cycle progression. Future studies need to employ strategies to identify the primary responses of vitamin D that drive the cellular response towards quiescence.

Open access

Helle Døssing, Finn Noe Bennedbæk and Laszlo Hegedüs

Objective

Laser therapy (LT) is considered a safe and effective procedure for inducing thyroid nodule necrosis, fibrosis and shrinkage. Little is known about long-term efficacy of LT in benign complex thyroid nodules, which we report here.

Design and methods

One hundred and ten euthyroid outpatients (28 men and 82 women; median age 48 years (range 17–82)) with a recurrent cytologically benign cystic (≥2 mL cyst volume) thyroid nodule causing local discomfort were assigned to LT. LT was performed after complete cyst aspiration and under continuous ultrasound (US) guidance. Nineteen patients (17 within 6 months) had surgery after LT. The median follow-up for the remaining 91 patients was 45 months (range: 12–134).

Results

The overall median nodule volume in the 110 patients decreased from 9.0 mL (range: 2.0–158.0) to 1.2 mL (range: 0.0–85.0) (P < 0.001) at the final evaluation, corresponding to a median reduction of 85% (range: −49 to 100%). Remission of the cystic part (volume ≤1 mL) was obtained in 82 of 110 (75%) patients after LT. The median cyst volume decreased from 6.3 mL (range: 2.0–158.0) to 0.0 mL (range: 0.0–85.0) (P < 000.1), corresponding to a median reduction of 100% (range: −49 to 100%). These results correlated with a significant decrease in pressure as well as cosmetic complaints. Side effects were restricted to mild local pain.

Conclusion

US-guided aspiration and subsequent LT of benign recurrent cystic thyroid nodules results in a satisfactory long-term clinical response in the majority of patients. LT constitutes a clinically relevant alternative to surgery in such patients.

Open access

Jakob Høgild Langdahl, Anja Lisbeth Frederiksen, John Vissing, Morten Frost, Knud Bonnet Yderstræde and Per Heden Andersen

Aim

This case–control study aimed to examine impairments in glucose metabolism in non-diabetic carriers of the mitochondrial mutation m.3243A>G by evaluating insulin secretion capacity and sensitivity.

Methods

Glucose metabolism was investigated in 23 non-diabetic m.3243A>G carriers and age-, sex- and BMI-matched healthy controls with an extended 4-h oral glucose tolerance test (OGTT). Insulin sensitivity index and acute insulin response were estimated on the basis of the OGTT. This was accompanied by examination of body composition by dual-energy X-ray absorptiometry (DXA), maximum aerobic capacity and a Recent Physical Activity Questionnaire (RPAQ).

Results

Fasting p-glucose, s-insulin and s-c-peptide levels did not differ between m.3243A>G carriers and controls. Insulin sensitivity index (BIGTT-S1) was significantly lower in the m.3243A>G carriers, but there was no difference in the acute insulin response between groups. P-lactate levels were higher in carriers throughout the OGTT. VO2max, but not BMI, waist and hip circumferences, lean and fat body mass%, MET or grip strength, was lower in mutation carriers. BIGTT-S1 remained lower in mutation carriers after adjustment for multiple confounding factors including VO2max in regression analyses.

Conclusions

Glucose metabolism in m.3243A>G carriers was characterized by reduced insulin sensitivity, which could represent the earliest phase in the pathogenesis of m.3243A>G-associated diabetes.

Open access

K G Samsom, L M van Veenendaal, G D Valk, M R Vriens, M E T Tesselaar and J G van den Berg

Background

Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis.

Aim

We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs.

Method

A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019.

Results

The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44–100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs.

Conclusion

SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.

Open access

Gaëtan Prévost, Marie Picot, Marie-Anne Le Solliec, Arnaud Arabo, Hind Berrahmoune, Mouna El Mehdi, Saloua Cherifi, Alexandre Benani, Emmanuelle Nédélec, Françoise Gobet, Valéry Brunel, Jérôme Leprince, Hervé Lefebvre, Youssef Anouar and Nicolas Chartrel

Objective

Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients.

Design and methods

Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test.

Results

26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance.

Conclusion

The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.

Open access

Eva Jakobsson Ung, Ann-Charlotte Olofsson, Ida Björkman, Tobias Hallén, Daniel S Olsson, Oskar Ragnarsson, Thomas Skoglund, Sofie Jakobsson and Gudmundur Johannsson

Objective

Experiences and need of support during surgery and start of replacement therapy in patients with pituitary tumours are highly unknown. This study aimed at exploring patient experiences during pre- and postoperative care and recovery after pituitary surgery in patients with a pituitary tumour.

Methods

Within a qualitative study design, 16 consecutive patients who underwent surgery for pituitary tumours were repeatedly interviewed. In total, 42 interviews were performed before and after surgery. Analysis was performed using qualitative interpretation.

Results

Suffering a pituitary tumour was overwhelming for many patients and struggling with existential issues was common. Patients expressed loneliness and vulnerability before and after surgery. How professionals handled information in connection with diagnosis greatly affected the patients. Other patients with the same diagnosis were experienced as the greatest support. Normalisation of bodily symptoms and relationships with others were reported during postoperative recovery. However, a fear that the tumour would return was present.

Conclusions

Patients with pituitary tumours need structured support, including peer support, which acknowledges physical, cognitive as well as emotional and existential concerns. Information related to diagnosis and surgery should be adapted in relation to the loneliness and the existential seriousness of the situation. Care and support for patients with pituitary tumours should preferably be organised based on continuity and an unbroken care pathway from the first pre-operative evaluation through to postoperative care and the start of a life-long endocrine treatment and tumour surveillance.

Open access

Marloes Emous, Merel van den Broek, Ragnhild B Wijma, Loek J M de Heide, Gertjan van Dijk, Anke Laskewitz, Erik Totté, Bruce H R Wolffenbuttel and André P van Beek

Objective

Roux-en-Y gastric bypass (RYGB) is an effective way to induce sustainable weight loss and can be complicated by postprandial hyperinsulinaemic hypoglycaemia (PHH). To study the prevalence and the mechanisms behind the occurrence of hypoglycaemia after a mixed meal tolerance test (MMTT) in patients with primary RYGB.

Design

This is a cross-sectional study of patients 4 years after primary RYGB.

Methods

From a total population of 550 patients, a random sample of 44 patients completed the total test procedures. A standardized mixed meal was used as stimulus. Venous blood samples were collected at baseline, every 10 min during the first half hour and every 30 min until 210 min after the start. Symptoms were assessed by questionnaires. Hypoglycaemia is defined as a blood glucose level below 3.3 mmol/L.

Results

The prevalence of postprandial hypoglycaemia was 48% and was asymptomatic in all patients. Development of hypoglycaemia was more frequent in patients with lower weight at surgery (P = 0.045), with higher weight loss after surgery (P = 0.011), and with higher insulin sensitivity calculated by the homeostasis model assessment indexes (HOMA2-IR, P = 0.014) and enhanced beta cell function (insulinogenic index at 20 min, P = 0.001).

Conclusion

In a randomly selected population 4 years after primary RYGB surgery, 48% of patients developed a hypoglycaemic event during an MMTT without symptoms, suggesting the presence of hypoglycaemia unawareness in these patients. The findings in this study suggest that the pathophysiology of PHH is multifactorial.

Open access

Boju Pan, Anqi Wang, Junyi Pang, Yuhan Zhang, Ming Cui, Jian Sun and Zhiyong Liang

Introduction

PD-L1 is associated with prognosis and immunotherapeutic response in patients with malignancies. In previous studies, PD-L1 expression was detected in many endocrine tumors. However, the PD-L1 expression status in parathyroid tumors is unknown.

Methods

We included 26 parathyroid carcinoma and 37 adenoma samples, as well as the corresponding patient information. PD-L1 was stained using the FDA-approved PD-L1 IHC 22C3 pharmDx and Ventana PD-L1 (SP263) assays, and staining was assessed by the estimated percentages of positive tumor cells and immune cells, respectively.

Results

We classified the PD-L1 expression in the parathyroid tumors into four groups: (0) <1%, (1) 1–4%, (2) 5–9% and (3) ≥10% positive. With the SP263 clone, 37 (carcinoma:adenoma = 18:19) samples scored 0, 13 (carcinoma:adenoma = 4:9) scored 1, 7 (carcinoma:adenoma = 1:6) scored 2 and 6 (carcinoma:adenoma = 3:3) scored 3. However, in the series of cases using the 22C3 clone, 45 (carcinoma:adenoma = 20:25) samples scored 0, 10 (carcinoma: adenoma = 3:7) scored 1, 5 (carcinoma:adenoma = 1:4) scored 2, and 3 (carcinoma:adenoma = 2:1) scored 3. Concerning tumor-infiltrating immune cells, 57 samples were negative and six were positive with SP263, and 59 were negative and four were positive with 22C3. Moreover, PD-L1 expression was negatively correlated with the Ki-67 index and mitotic rate in parathyroid tumors depending on the different clones. However, the results indicated only moderate consistency between the SP263 and 22C3 clones in parathyroid tumors.

Conclusion

We found deficient PD-L1 expression in the majority of parathyroid tumors. However, the PD-L1 expression score in parathyroid tumors depended greatly on the antibody clone used.

Open access

Chan Sub Park, Jihye Choi, Min-Ki Seong, Sung-Eun Hong, Jae-Sung Kim, In-Chul Park, Hyesil Seol, Woo Chul Noh and Hyun-Ah Kim

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.