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Open access

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

Background

Anti-inflammatory treatment with interleukin-1 (IL-1) antagonism decreases both cortisol and adrenocorticotropin hormone (ACTH) levels in individuals with obesity 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 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 nmol/L (IQR 241–385) and C-reactive protein (CRP) levels were 3.4 mg/L (IQR 1.7–4.8). 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 28 nmol/L (95% CI, −7 to −43; P = 0.03). After 4 weeks, the cortisol-lowering effect of anakinra was attenuated and overall was statistically not significant (P = 0.72). Injection-site reactions occurred in 21 patients receiving anakinra and were associated with higher CRP and cortisol levels.

Conclusions

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

Open access

Mengxue Yang, Bowen Sun, Jianhui Li, Bo Yang, Jie Xu, Xue Zhou, Jie Yu, Xuan Zhang, Qun Zhang, Shan Zhou, and Xiaohua Sun

Objectives

The pathogenesis of Graves’ disease (GD) remains unclear. In terms of environmental factors, GD development may be associated with chronic inflammation caused by alteration of the intestinal flora. This study explored the association of intestinal flora alteration with the development of GD among the Han population in southwest China.

Design and methods

Fifteen GD patients at the Affiliated Hospital of Zunyi Medical College between March 2016 and March 2017 were randomly enrolled. Additionally, 15 sex- and age-matched healthy volunteers were selected as the control group during the same period. Fresh stool samples were collected, and bacterial 16S RNA was extracted and amplified for gene sequencing with the Illumina MiSeq platform. The sequencing results were subjected to operational taxonomic unit-based classification, classification verification, alpha diversity analysis, taxonomic composition analysis and partial least squares-discriminant analysis (PLS-DA).

Results

The diversity indices for the GD group were lower than those for the control group. The GD group showed significantly higher abundances of Firmicutes, Proteobacteria and Actinobacillus and a higher Firmicutes/Bacteroidetes ratio than the control group. PLS-DA suggested the satisfactory classification of the flora between the GD group and the control group. The abundances of the genera Oribacterium, Mogibacterium, Lactobacillus, Aggregatibacter and Mogibacterium were significantly higher in the GD group than in the control group (P < 0.05).

Conclusions

The intestinal flora of GD patients was significantly different from that of the healthy population. Thus, alteration of intestinal flora may be associated with the development of GD.

Open access

Angela Köninger, Philippos Edimiris, Laura Koch, Antje Enekwe, Claudia Lamina, Sabine Kasimir-Bauer, Rainer Kimmig, and Hans Dieplinger

Oxidative stress seems to be present in patients with polycystic ovary syndrome (PCOS). The aim of this study was to evaluate the correlation between characteristics of PCOS and serum concentrations of afamin, a novel binding protein for the antioxidant vitamin E. A total of 85 patients with PCOS and 76 control subjects were investigated in a pilot cross-sectional study design between 2009 and 2013 in the University Hospital of Essen, Germany. Patients with PCOS were diagnosed according to the Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Afamin and diagnostic parameters of PCOS were determined at early follicular phase. Afamin concentrations were significantly higher in patients with PCOS than in controls (odds ratio (OR) for a 10 mg/ml increase in afamin=1.3, 95% CI=1.08–1.58). This difference vanished in a model adjusting for age, BMI, free testosterone index (FTI), and sex hormone-binding globulin (SHBG) (OR=1.05, 95% CI=0.80–1.38). In patients with PCOS, afamin correlated significantly with homeostatic model assessment-insulin resistance (HOMA-IR), fasting glucose, BMI, FTI, and SHBG (P<0.001), but in a multivariate linear model, only HOMA-IR remained significantly associated with afamin (P=0.001). No correlation was observed between afamin and androgens, LH, FSH, LH/FSH ratio, antral follicle count, ovarian volume, or anti-Müllerian hormone. In conclusion, elevated afamin values may indicate a state of oxidative stress and inflammation, strongly associated with IR and offering an indicator of impaired glucose tolerance in patients with PCOS irrespective of obesity.

Open access

Ghazala Zaidi, Vijayalakshmi Bhatia, Saroj K Sahoo, Aditya Narayan Sarangi, Niharika Bharti, Li Zhang, Liping Yu, Daniel Eriksson, Sophie Bensing, Olle Kämpe, Nisha Bharani, Surendra Kumar Yachha, Anil Bhansali, Alok Sachan, Vandana Jain, Nalini Shah, Rakesh Aggarwal, Amita Aggarwal, Muthuswamy Srinivasan, Sarita Agarwal, and Eesh Bhatia

Objective

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients.

Design

Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years.

Methods

Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied.

Results

Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.

Conclusions

Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

Open access

Justyna Modrzynska, Christine F Klein, Kasper Iversen, Henning Bundgaard, Bolette Hartmann, Maike Mose, Nikolaj Rittig, Niels Møller, Jens J Holst, and Nicolai J Wewer Albrechtsen

Objective

Glucagon and glucagon-like peptide-1 (GLP-1) originate from the common precursor, proglucagon, and their plasma concentrations have been reported to be increased during inflammatory conditions. Increased blood glucose levels are frequently observed in septic patients, and therefore we hypothesized that glucagon, but not GLP-1, is increased in individuals with inflammation.

Design

Prospective longitudinal cohort study.

Materials and methods

We measured glucagon and GLP-1 in plasma sampled consecutively in three cohorts consisting of patients with infective endocarditis (n = 16), urosepsis (n = 28) and post-operative inflammation following percutaneous aortic valve implantation or thoracic endovascular aortic repair (n = 5). Correlations between C-reactive protein (CRP), a marker of systemic inflammation, and glucagon and GLP-1 concentrations were investigated. Additionally, glucagon and GLP-1 concentrations were measured after a bolus infusion of lipopolysaccharide (LPS, 1 ng/kg) in nine healthy young males.

Results

Glucagon and CRP were positively and significantly correlated (r = 0.27; P = 0.0003), whereas no significant association between GLP-1 and CRP was found (r = 0.08, P = 0.30). LPS infusion resulted in acute systemic inflammation reflected by increased temperature, pulse, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and concomitantly increased concentrations of glucagon (P < 0.05) but not GLP-1.

Conclusions

Systemic inflammation caused by bacterial infections or developed as a non-infected condition is associated with increased plasma concentration of glucagon, but not GLP-1. Hyperglucagonemia may contribute to the impaired glucose control in patients with systemic inflammatory diseases.

Open access

Ermina Bach, Niels Møller, Jens Otto L Jørgensen, Mads Buhl, and Holger Jon Møller

Aims/hypothesis

The macrophage-specific glycoprotein sCD163 has emerged as a biomarker of low-grade inflammation in the metabolic syndrome and related disorders. High sCD163 levels are seen in acute sepsis as a result of direct lipopolysaccharide-mediated shedding of the protein from macrophage surfaces including Kupffer cells. The aim of this study was to investigate if low-grade endotoxinemia in human subjects results in increasing levels of sCD163 in a cortisol-dependent manner.

Methods

We studied eight male hypopituitary patients and eight age- and gender-matched healthy controls during intravenous low-dose LPS or placebo infusion administered continuously over 360 min. Furthermore, we studied eight healthy volunteers with bilateral femoral vein and artery catheters during a 360-min infusion with saline and low-dose LPS in each leg respectively.

Results:

Systemic low-grade endotoxinemia resulted in a gradual increase in sCD163 from 1.65 ± 0.51 mg/L (placebo) to 1.92 ± 0.46 mg/L (LPS) at 220 min, P = 0.005 and from 1.66 ± 0.42 mg/L (placebo) to 2.19 ± 0.56 mg/L (LPS) at 340 min, P = 0.006. A very similar response was observed in hypopituitary patients: from 1.59 ± 0.53 mg/L (placebo) to 1.83 ± 0.45 mg/L (LPS) at 220 min, P = 0.021 and from 1.52 ± 0.53 mg/L (placebo) to 2.03 ± 0.44 mg/L (LPS) at 340 min, P < 0.001. As opposed to systemic treatment, continuous femoral artery infusion did not result in increased sCD163.

Conclusion:

Systemic low-grade endotoxinemia resulted in increased sCD163 to levels seen in the metabolic syndrome in both controls and hypopituitary patients. This suggests a direct and cortisol-independent effect of LPS on the shedding of sCD163. We observed no effect of local endotoxinemia on levels of serum sCD163.

Open access

Lia Ferreira, João Silva, Susana Garrido, Carlos Bello, Diana Oliveira, Hélder Simões, Isabel Paiva, Joana Guimarães, Marta Ferreira, Teresa Pereira, Rita Bettencourt-Silva, Ana Filipa Martins, Tiago Silva, Vera Fernandes, Maria Lopes Pereira, and Adrenal Tumors Study Group of the Portuguese Society of Endocrinology

Introduction

Primary adrenal insufficiency (PAI) is a rare but severe and potentially life-threatening condition. No previous studies have characterized Portuguese patients with PAI.

Aims

To characterize the clinical presentation, diagnostic workup, treatment and follow‐up of Portuguese patients with confirmed PAI.

Methods

This multicentre retrospective study examined PAI patients in 12 Portuguese hospitals.

Results

We investigated 278 patients with PAI (55.8% were females), with a mean age of 33.6 ± 19.3 years at diagnosis. The most frequent presenting clinical features were asthenia (60.1%), mucocutaneous hyperpigmentation (55.0%) and weight loss (43.2%); 29.1% of the patients presented with adrenal crisis. Diagnosis was established by high plasma ACTH and low serum cortisol in most patients (43.9%). The most common aetiology of PAI was autoimmune adrenalitis (61.0%). There were 38 idiopathic cases. Autoimmune comorbidities were found in 70% of the patients, the most frequent being autoimmune thyroiditis (60.7%) and type 1 diabetes mellitus (17.3%). Seventy-nine percent were treated with hydrocortisone (mean dose 26.3 ± 8.3 mg/day) mostly in three (57.5%) or two (37.4%) daily doses. The remaining patients were treated with prednisolone (10.1%), dexamethasone (6.2%) and methylprednisolone (0.7%); 66.2% were also on fludrocortisone (median dose of 100 µg/day). Since diagnosis, 33.5% of patients were hospitalized for disease decompensation. In the last appointment, 17.2% of patients had complaints (7.6% asthenia and 6.5% depression) and 9.7% had electrolyte disturbances.

Conclusion

This is the first multicentre Portuguese study regarding PAI. The results emphasize the need for standardization in diagnostic tests and etiological investigation and provide a framework for improving treatment.

Open access

Hauke Thomsen, Xinjun Li, Kristina Sundquist, Jan Sundquist, Asta Försti, and Kari Hemminki

Design

Addison’s disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, present as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce, and we aimed to carry out an unbiased study on AD and related AIDs.

Methods

We collected data on patients diagnosed with AIDs in Swedish hospitals and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks.

Results

The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was associated with 11 other AIDs, including thyroid AIDs and type 1 diabetes and some rarer AIDs such as Guillain–Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren’s syndrome.

Conclusions

The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.

Open access

Wentao Zhou, Tiantao Kuang, Xu Han, Wenqi Chen, Xuefeng Xu, Wenhui Lou, and Dansong Wang

Objectives

Systemic inflammation markers have been demonstrated to be associated with prognosis in various tumors. In this study, we aimed to assess the value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index and the counts of lymphocyte, monocyte and neutrophil in predicting prognosis among patients with resected pancreatic neuroendocrine neoplasms (pNENs).

Methods

A total of 174 patients were included in the study. Univariate and multivariate analyses were performed to evaluate the predictive roles of inflammation markers for relapse-free survival (RFS) and overall survival (OS) in pNEN patients.

Results

The optimal cut-off values of NLR, LMR and lymphocyte count were 1.9, 5.0 and 1.4 × 109/L, respectively, determined by the X-tile software. RFS was found to be significantly longer in patients with NLR ≤1.9 (P = 0.041), LMR >5.0 (P < 0.001) and lymphocyte count >1.4 × 109/L (P = 0.002) in comparison to those with NLR >1.9, LMR ≤5.0 and lymphocyte count ≤1.4 × 109/L, respectively. Multivariate analysis revealed that LMR (hazard ratio 0.30, 95% CI 0.11–0.85, P = 0.023) was an independent predictor for RFS, but not NLR or lymphocyte count. For long-term survival analysis, patients with NLR ≤1.9 (P = 0.016) were found to be associated with favorable OS, but NLR was not an independent factor validated by multivariate analysis.

Conclusions

Preoperative LMR is an independent systemic inflammation marker to predict relapses in pNEN patients who underwent curative resections, whose clinical value needs to be verified in further large sample-based prospective studies.

Open access

Zhiwei Zhang, Hui Zhao, and Aixia Wang

Background

Gestational diabetes mellitus (GDM) has a high incidence rate among pregnant women. The objective of the study was to assess the effect of plant-derived oleuropein in attenuating inflammatory and oxidative stress of GDM.

Methods

Oleuropein was administered to GDM mice at the doses of 5 or 10 mg/kg/day. Body weight, blood glucose, insulin and hepatic glycogen levels were recorded. To evaluate the effect of oleuropein in reducing oxidative stress, ELISA was used to measure the hepatic oxidative stress markers. The inflammation levels of GDM mice were evaluated by measuring serum levels of IL-6 and TNF-α by ELISA and mRNA levels of IL-1β, TNF-α and IL-6 by real-time PCR (RT-PCR). The AMP-activated protein kinase (AMPK) signaling pathway was assessed by Western blot. Gestational outcome was analyzed through comparing litter size and birth weight.

Results

Oleuropein attenuated the elevated body weight of GDM mice and efficiently reduced blood glucose, insulin and hepatic glycogen levels. Oxidative stress and inflammation were alleviated by oleuropein treatment. The AMPK signaling was activated by oleuropein in GDM mice. Gestational outcome was markedly improved by oleuropein treatment.

Conclusions

Our study suggests that oleuropein is effective in alleviating symptoms of GDM and improving gestational outcome in the mouse model. This effect is achieved by attenuating oxidative stress and inflammation, which is mediated by the activation of the AMPK signaling pathway.