An increasing number of patients worldwide suffer from bone fractures that occur after low intensity trauma. Such fragility fractures are usually associated with advanced age and osteoporosis but also with long-term immobilization, corticosteroid therapy, diabetes mellitus, and other endocrine disorders. It is important to understand the skeletal origins of increased bone fragility in these conditions for preventive and therapeutic strategies to combat one of the most common health problems of the aged population. This review summarizes current knowledge pertaining to the phenomenon of micropetrosis (osteocyte lacunar mineralization). As an indicator of former osteocyte death, micropetrosis is more common in aged bone and osteoporotic bone. Considering that the number of mineralized osteocyte lacunae per bone area can distinguish healthy, untreated osteoporotic and bisphosphonate-treated osteoporotic patients, it could be regarded as a novel structural marker of impaired bone quality. Further research is needed to clarify the mechanism of lacunar mineralization and to explore whether it could be an additional target for preventing or treating bone fragility related to aging and various endocrine diseases.
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Petar Milovanovic and Björn Busse
Wentao Zhou, Tiantao Kuang, Xu Han, Wenqi Chen, Xuefeng Xu, Wenhui Lou and Dansong Wang
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).
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.
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.
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.
Filippo Ceccato, Diego Cecchin, Michele Gregianin, Giacomo Ricci, Cristina Campi, Filippo Crimì, Marta Bergamo, Annibale Versari, Carmelo Lacognata, Federico Rea, Mattia Barbot and Carla Scaroni
Introduction and aim
Ectopic ACTH secretion (EAS) is mostly secondary to thoracic/abdominal neuroendocrine tumours (NETs) or small cell-lung carcinoma (SCLC). We studied the diagnostic accuracy of CT with 68Ga-Dota derivatives (68Ga-SSTR) PET in localizing ACTH-secreting tumor in patients with EAS.
Materials and methods
68Ga-SSTR-PET/CT was performed and compared with the nearest enhanced CT in 18 cases (16 primary and 2 recurrent neoplasms). Unspecific, indeterminate and false-positive uptakes were assessed using conventional imaging, follow-up or histology.
We diagnosed 13 thoracic (9 primary and 2 recurrent bronchial carcinoids, 2 SCLCs) and 1 abdominal (pancreatic NET) tumors. Eight ACTH-secreting tumors were promptly identified at EAS diagnosis (’overt’, four pulmonary carcinoids with two recurrences and two SCLC); six EAS have been discovered during the subsequent follow-up (’covert’, five bronchial carcinoids and one pancreatic NET). At the time of EAS diagnosis, imaging was able to correctly detect the ACTH-secreting tumour in 8/18 cases (6 new diagnosis and 2 recurrences). During the follow-up, six out of initially ten ‘occult’ cases became ‘covert’. At last available follow-up, CT and 68Ga-SSTR-PET/CT were able to diagnose 11/18 and 12/18 ACTH-secreting tumours, respectively (11/14 and 12/14 considering only overt and covert cases, respectively). Four cases have never been localized by conventional or nuclear imaging (’occult EAS’), despite an average follow-up of 5 years.
The 68Ga-SSTR-PET/CT is useful in localizing EAS, especially to enhance positive prediction of the suggestive CT lesions and to detect occult neoplasms.
Kim K B Clemmensen, Jonas S Quist, Dorte Vistisen, Daniel R Witte, Anna Jonsson, Oluf Pedersen, Torben Hansen, Jens J Holst, Torsten Lauritzen, Marit E Jørgensen, Signe Torekov and Kristine Færch
Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of ‘weekend behavior’ on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.
Florian Schederecker, Alexander Cecil, Cornelia Prehn, Jana Nano, Wolfgang Koenig, Jerzy Adamski, Tanja Zeller, Annette Peters and Barbara Thorand
Sex hormone-binding globulin (SHBG) and androgens have been associated with mortality in women and men, but controversy still exists. Our objective was to investigate associations of SHBG and androgens with all-cause and cause-specific mortality in men and women.
1006 men and 709 peri- and postmenopausal women (age range: 45–82 years) from the German population-based KORA F4 cohort study were followed-up for a median of 8.7 years.
SHBG was measured with an immunoassay, total testosterone (TT) and dihydrotestosterone (DHT) with mass-spectrometry in serum samples and we calculated free testosterone (cFT). To assess associations between SHBG and androgen levels and mortality, we calculated hazard ratios (HRs) with 95% CIs using Cox proportional-hazards models.
In the cohort, 128 men (12.7%) and 70 women (9.9%) died. In women, we observed positive associations of SHBG with all-cause (HR: 1.54, 95% CI: 1.16–2.04) and with other disease-related mortality (HR: 1.86, 95% CI: 1.08–3.20) and for DHT with all-cause mortality (HR: 1.32, 95% CI: 1.00–1.73). In men, we found a positive association of SHBG (HR: 1.24 95% CI: 1.00–1.54) and inverse associations of TT (HR: 0.87, 95% CI: 0.77–0.97) and cFT (HR: 0.84, 95% CI: 0.73–0.97) with all-cause mortality. No other associations were found for cause-specific mortality.
Higher SHBG levels were associated with increased risk of all-cause mortality in men and women. Lower TT and cFT levels in men and higher DHT levels in women were associated with increased risk of all-cause mortality. Future, well-powered population-based studies should further investigate cause-specific mortality risk.
Anna Olsson-Brown, Rosemary Lord, Joseph Sacco, Jonathan Wagg, Mark Coles and Munir Pirmohamed
Immune checkpoint inhibitors can lead to thyroid dysfunction. However, the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort.
Materials and methods
To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre, a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres.
Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy and in combination with ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism (12/16) or de novo hypothyroidism (4/16). Most patients were female (n = 11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies.
There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage the hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement, reducing the symptomatic burden of hypothyroidism.
Kaiyu Pan, Chengyue Zhang, Xiaocong Yao and Zhongxin Zhu
Ensuring adequate calcium (Ca) intake during childhood and adolescence is critical to acquire good peak bone mass to prevent osteoporosis during older age. As one of the primary strategies to build and maintain healthy bones, we aimed to determine whether dietary Ca intake has an influence on bone mineral density (BMD) in children and adolescents.
We conducted a cross-sectional study composed of 10,092 individuals from the National Health and Nutrition Examination Survey (NHANES). Dietary Ca intake and total BMD were taken as independent and dependent variables, respectively. To evaluate the association between them, we conducted weighted multivariate linear regression models and smooth curve fittings.
There was a significantly positive association between dietary Ca intake and total BMD. The strongest association was observed in 12–15 year old whites, 8–11 year old and 16–19 year old Mexican Americans, and 16–19 year old individuals from other race/ethnicity, in whom each quintile of Ca intake was increased. We also found that there were significant inflection points in females, blacks, and 12–15 year old adolescents group, which means that their total BMD would decrease when the dietary Ca intake was more than 2.6–2.8 g/d.
This cross-sectional study indicated that a considerable proportion of children and adolescents aged 8–19 years would attain greater total BMD if they increased their dietary Ca intake. However, higher dietary Ca intake (more than 2.6–2.8 g/d) is associated with lower total BMD in females, blacks, and 12–15 year old adolescents group.
Aleksandra Krygier, Ewelina Szczepanek-Parulska, Dorota Filipowicz and Marek Ruchała
Hepcidin is an acute-phase protein and a key regulator of iron homeostasis. Anaemia frequently occurs in patients with thyroid dysfunction, and hepcidin may be a potential link.
Prospective assessment of hepcidin serum concentration and other parameters related to Fe homeostasis in hyperthyroid patients in the course of GD at diagnosis and during remission.
Patients and Methods
Out of the 70 patients recruited, 42 (32 women, 10 men), aged 42.5 ± 15.1 years, met the inclusion criteria. Clinical and biochemical assessment, including hepcidin measurement by ELISA, was performed at baseline (T0) and after restoration of euthyroidism (T1).
Hepcidin concentration at T0 in the 24 patients who completed the study was significantly higher than the value during euthyroidism (28.7 (8.1–39.4) ng/mL vs 7.9 (4.3–12.9) ng/mL, P < 0.001). Hepcidin level was most significantly correlated with ferritin (rho = 0.723) in women at T0. In both men (377 (171–411) vs 165 (84–237) ng/mL, P = 0.001) and women (84 (23–104) vs 35 (16–64) ng/mL, P = 0.001), a significant decrease in ferritin level was demonstrated following therapy. A significant (P < 0.001) increase in mean corpuscular volume (MCV) (83.5 (82.5–87.1) vs 89.5 (88.8–90.0) fL) and mean concentration of haemoglobin (MCH) (29.0 (28.0–29.4) vs 30.4 (29.5–31.1) pg) was observed.
Hepcidin and ferritin decrease significantly during the transition from a hyperthyroid state to euthyroidism in patients with GD. The observed changes occur in parallel to iron homeostasis fluctuations. During the transition from the hyperthyroid state to euthyroidism, the improvement of haematological status is reflected mainly by the increase in MCV and MCH.
Trevor Lewis, Eva Zeisig and Jamie E Gaida
While metabolic health is acknowledged to affect connective tissue structure and function, the mechanisms are unclear. Glucocorticoids are present in almost every cell type throughout the body and control key physiological processes such as energy homeostasis, stress response, inflammatory and immune processes, and cardiovascular function. Glucocorticoid excess manifests as visceral adiposity, dyslipidemia, insulin resistance, and type 2 diabetes. As these metabolic states are also associated with tendinopathy and tendon rupture, it may be that glucocorticoids excess is the link between metabolic health and tendinopathy.
To synthesise current knowledge linking glucocorticoid exposure to tendon structure and function.
Narrative literature review.
We provide an overview of endogenous glucocorticoid production, regulation, and signalling. Next we review the impact that oral glucocorticoid has on risk of tendon rupture and the effect that injected glucocorticoid has on resolution of symptoms. Then we highlight the clinical and mechanistic overlap between tendinopathy and glucocorticoid excess in the areas of visceral adiposity, dyslipidemia, insulin resistance and type 2 diabetes. In these areas, we highlight the role of glucocorticoids and how these hormones might underpin the connection between metabolic health and tendon dysfunction.
There are several plausible pathways through which glucocorticoids might mediate the connection between metabolic health and tendinopathy.
Sumana Chatterjee, Emily Cottrell, Stephen J Rose, Talat Mushtaq, Avinaash V Maharaj, Jack Williams, Martin O Savage, Louise A Metherell and Helen L Storr
The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this.
6Ψ-GHR and WT-GHR mRNA transcripts of four 6Ψ patients (height SDS −4.2 to −3.1) and one control fibroblast were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing.
RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not in the control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29–71:1 for patients 1–4 and correlated negatively with height SDS (R = −0.85; P < 0.001). Eight deleterious variants in six genes were detected, but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients.
Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT-GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.