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Open access

Cornelia Then, Holger Then, Andreas Lechner, Cornelia Huth, Christa Meisinger, Margit Heier, Annette Peters, Wolfgang Koenig, Wolfgang Rathmann, Christian Herder, Michael Roden, Jürgen Scherberich and Jochen Seissler

Objective

Metabolic syndrome and obesity are risk factors for chronic kidney disease. However, early kidney alterations may escape diagnosis in these conditions due to glomerular hyperfiltration. Uromodulin, a glycoprotein exclusively synthesized in tubular cells of the thick ascending limb of Henle's loop, is a novel tissue-specific biomarker for kidney function. In contrast to the commonly used markers creatinine and cystatin C, serum uromodulin does not primarily depend on glomerular filtration. We hypothesized that serum uromodulin is a marker for metabolic syndrome and related components.

Design

The analyses included 1088 participants of the population-based KORA F4 study aged 62–81 years. Metabolic syndrome was present in 554 participants. After a mean follow-up time of 6.5 years, 621 participants were reevaluated, of which 92 had developed incident metabolic syndrome.

Methods

The association of serum uromodulin with metabolic syndrome and its components were assessed using multivariable logistic regression models.

Results

Serum uromodulin was inversely associated with metabolic syndrome after adjustment for sex, age, estimated glomerular filtration rate, physical activity, smoking, alcohol consumption and high-sensitivity C-reactive protein (OR 0.65; 95% CI 0.56–0.76 per standard deviation uromodulin; P < 0.001). Serum uromodulin was inversely associated with all single components of metabolic syndrome. However, serum uromodulin was not associated with new-onset metabolic syndrome after the follow-up period of 6.5 ± 0.3 years (OR 1.18; 95% CI 0.86–1.60).

Conclusions

Serum uromodulin is independently associated with prevalent, but not with incident metabolic syndrome. Low serum uromodulin may indicate a decreased renal reserve in the metabolic syndrome.

Open access

Stephen A Martin, Kenneth Philbrick, Carmen P Wong, Dawn A Olson, Adam J Branscum, Donald Jump, Charles Marik, Jonathan DenHerder, Jennifer Sargent, Russell T Turner and Urszula T Iwaniec

Mice are a commonly-used model to investigate aging-related bone loss but, in contrast to humans, mice exhibit cancellous bone loss prior to skeletal maturity. The mechanisms mediating premature bone loss are not well established. However, our previous work in female mice suggests housing temperature is a critical factor. Premature cancellous bone loss was prevented in female C57BL/6J mice by housing the animals at thermoneutral temperature (where basal rate of energy production is at equilibrium with heat loss). In the present study, we determined if the protective effects of thermoneutral housing extend to males. Male C57BL/6J mice were housed at standard room temperature (22°C) or thermoneutral (32°C) from 5 (rapidly growing) to 16 (slowly growing) weeks of age. Mice housed at room temperature exhibited reductions in cancellous bone volume fraction in distal femur metaphysis and 5th lumbar vertebra; these effects were abolished at thermoneutral conditions. Mice housed at thermoneutral temperature had higher levels of bone formation in distal femur (based on histomorphometry) and globally (serum osteocalcin), and lower global levels of bone resorption (serum C-terminal telopeptide of type I collagen) compared to mice housed at room temperature. Thermoneutral housing had no impact on bone marrow adiposity but resulted in higher abdominal white adipose tissue and serum leptin. The overall magnitude of room temperature housing-induced cancellous bone loss did not differ between male (current study) and female (published data) mice. These findings highlight housing temperature as a critical experimental variable in studies using mice of either sex to investigate aging-related changes in bone metabolism.

Open access

Marc Blondon, Emmanuel Biver, Olivia Braillard, Marc Righini, Pierre Fontana and Alessandro Casini

Objective: Vitamin D deficiency is associated with increased risks of arterial and venous cardiovascular events. Hypothetically, supplementation with vitamin D may lead to a less prothrombotic phenotype, as measured by global coagulation assays and fibrin clot structure.

Methods: In this prospective cohort study, we enrolled adult outpatients attending the Primary Care division of the Geneva University Hospitals with a severe vitamin D deficiency (25-hydroxyvitamin-D3 (25-OHD) <25nmol/L), excluding obese patients or with a recent acute medical event. We evaluated changes in coagulation times, thrombin generation assay, clot formation and clot lysis time, 25-OHD and parathormone before and 1-3 months after cholecalciferol oral supplementation with one-time 300,000UI then 800UI daily. Paired t-tests with a two-sided alpha of 0.05 compared absolute mean differences.

Results: The 48 participants had a mean age of 43.8±13.8 years. After supplementation, 25-OHD levels increased from 17.9±4.6 nmol/L to 62.5±20.7 nmol/L 6.4±3.0 weeks after inclusion. Endogenous thrombin potential and thrombin generation peak values both decreased significantly (-95.4nM*min (95%CI -127.9 to -62.8), P<0.001; -15.1nM (-23.3 to -6.8), P<0.001). The maximum absorbance by turbidimetry decreased significantly (P=0.001) after supplementation. There was no change in clot lysis time, coagulation times or plasminogen activator inhibitor-1 and homocysteine levels.

Conclusions: In severe vitamin D deficiency, a high-dose cholecalciferol supplementation was associated with a reduction in thrombin generation and an average decreased number of fibrin protofibrils per fibers and fibrin fiber size measured by turbidimetry. This suggests that severe vitamin D deficiency may be associated with a potentially reversible prothrombotic profile.

Open access

Ravikumar Shah, Anurag R Lila, Ramteke-Swati Jadhav, Virendra Patil, Abhishek Mahajan, Sushil Sonawane, Puja Thadani, Anil Dcruz, Prathamesh Pai, Munita Bal, Subhada Kane, Nalini Shah and Tushar Bandgar

Tumor-induced osteomalacia in the head and neck region remains a challenging diagnosis to manage. Literature pertaining to management and outcome details remains sparse. We describe two cohorts: cohort 1 included seven patients from a single center in Western India with tumors located in paranasal sinuses (n = 3), intracranial (n = 2) and maxilla (n = 2). The unique features from our series is the management of persistent disease with radiation therapy (n = 2) and peptide receptor radionuclide therapy (PRRT) (n = 1). Cohort two has 163 patients identified from 109 publications for systematic review. Paranasal sinuses, mandible, intracranial disease, maxilla and oral cavity, in descending order, are reportedly common tumor sites. Within this cohort, mean age was 46 ± 14 years at presentation with 44.1% having local symptoms. Duration of symptoms varied from 1 to 240 months. Pre-surgery mean serum phosphorus was 1.4 ± 0.4 mg/dL and median FGF-23 levels were 3.6 (IQR:1.8–6.8) times of normal upper limit of normal. Majority (97.5%) were managed primarily with surgical excision; however, primary radiotherapy (n = 2) and surgery combined with radiotherapy (n = 2) were also reported. Twenty patients had persistent disease while nine patients had recurrence, more commonly noted with intracranial and oral cavity tumors. Surgery was the most common second mode of treatment employed succeeded by radiotherapy. Four patients had metastatic disease. The most common histopathological diagnosis reported is PMT mixed connective tissue, while the newer terminology ‘PMT mixed epithelial and connective tissue type’ has been described in 15 patients.

Open access

Mauricio Alvarez, Oswaldo Rincón Sierra, Ginna Saavedra and Sergio Moreno

Objective

Vitamin B12 deficiency resulting from metformin use has been demonstrated in multiple studies. In this study, we aimed to evaluate the prevalence of vitamin B12 deficiency in patients with chronic metformin use and the relationship between vitamin B12 deficiency and diabetic neuropathy.

Methods

A cross-sectional study was conducted with 162 patients. Vitamin B12 levels were measured by chemiluminescence immunoassay. Diabetic neuropathy was evaluated by patient record, nerve conduction and Michigan test for the diagnosis of diabetic neuropathy. Additional data, including demographic characteristics were collected. A linear regression model was used to evaluate variables that correlated with vitamin B12 levels and diabetic neuropathy.

Results

Low vitamin B12 levels were found in 7.3% (95% CI: 4.0–12%) of patients. In those with diabetic neuropathy, altered (low and borderline) vitamin B12 level was 64% (95% CI: 47–78%) compared to 17% (95% CI: 10–26%) in patients without diabetic neuropathy (coefficient: −110.8; CI 95%: −165.8, −59.7). Those taking a higher metformin dose had lower levels of vitamin B12 (coefficient: −0.061; CI 95%: −0.09, −0.024). In addition, female patients had higher levels of vitamin B12 compared to men (coefficient: 49.1; CI 95%: 2.3–95).

Conclusions

Vitamin B12 deficiency is highly prevalent, especially in patients with diabetic neuropathy. In this study an inverse correlation was found between diabetic neuropathy and the plasma level of vitamin B12. Higher doses of metformin and male sex were factors related to lower levels of vitamin B12.

Open access

María Dolores Rodríguez Arnao, Amparo Rodríguez Sánchez, Ignacio Díez López, Joaquín Ramírez Fernández, Jose Antonio Bermúdez de la Vega, Diego Yeste Fernández, María Chueca Guindulain, Raquel Corripio Collado, Jacobo Pérez Sánchez, Ana Fernández González and ECOS Spain Study Collaborative Investigator Group

Background

Non-adherence to r-hGH treatments occurs in a variable percentage of subjects. One problem found when evaluating adherence is the great variability in methods of detection and definitions utilized in studies. This study assessed the level of adherence in subjects receiving r-hGH with the easypod™ electronic device.

Methods

National, multicenter, prospective and observational study involving 238 subjects (144 with GH deficiency (GHD), and 86 with small for gestational age (SGA), 8 with Turner Syndrome), who received r-hGH with easypod™ for at least 3 months before inclusion. The follow-up period was 4 years.

Results

Overall adherence was 94.5%; 97.5% after 6 months, 95.3% after 1 year, 93.7% after 2, 94.4% after 3 and 95.5% after 4 years of treatment. No differences in adherence were observed between prepubertal and pubertal groups and GHD and SGA groups. Change in height after 1 and 2 years, change in height SDS after 1 and 2 years, HV after 1 year, HV SDS after at 1 and 4 years, change in BMI after 1 year and change in BMI SDS at 1 and 2 years showed significant correlation with adherence. No significant differences in adherence according to IGF-I levels were found in follow-up visits or between groups.

Conclusions

The easypod™ electronic device, apart from being a precise and objective measure of adherence to r-hGH treatment, allows high compliance rates to be achieved over long periods of time. Adherence significantly impacts growth outcomes associated with r-hGH treatment.

Open access

Ana P Estrada-Flórez, Mabel E Bohórquez, Alejandro Vélez, Carlos S Duque, Jorge H Donado, Gilbert Mateus, Cesar Panqueba-Tarazona, Guadalupe Polanco-Echeverry, Ruta Sahasrabudhe, Magdalena Echeverry and Luis G Carvajal-Carmona

Papillary thyroid cancer (PTC) is the second most commonly diagnosed malignancy in U.S. Latinas and in Colombian women. Studies in non-Latinos indicate that BRAF and TERT mutations are PTC prognostic markers. This study aimed to determine the prevalence and clinical associations of BRAF and TERT mutations in PTC Latino patients from Colombia. We analyzed mutations of BRAF (V600E) and TERT promoter (C228T, C250T) in tumor DNA from 141 patients (75 with classical variant PTC, CVPTC; 66 with follicular variant PTC, FVPTC) recruited through a multi-center study. Associations between mutations and clinical variables were evaluated with Fisher exact tests. Survival was evaluated with Kaplan–Meier plots. Double-mutant tumors (BRAF+/TERT+, n = 14 patients) were more common in CVPTC (P = 0.02). Relative to patients without mutations (n = 48), double mutations were more common in patients with large tumors (P = 0.03), lymph node metastasis (P = 0.01), extra-thyroid extension (P = 0.03), and advanced stage (P = 6.0 × 10−5). In older patients, TERT mutations were more frequent (mean age 51 years vs 45 years for wild type TERT, P = 0.04) and survival was lower (HR = 1.20; P = 0.017); however, given the small sample size, the decrease in survival was not statically significant between genotypes. Comparisons with published data in US whites revealed that Colombian patients had a higher prevalence of severe pathological features and of double-mutant tumors (10 vs 6%, P = 0.001). Mutations in both oncogenes show prognostic associations in Latinos from Colombia. Our study is important to advance Latino PTC precision medicine and replicates previous prognostic associations between BRAF and TERT in this population.

Open access

Dong Cen, Hui Liu, Zhe Wan, Zhongjie Lin, Yanting Wang, Junjie Xu and Yuelong Liang

Purpose

Gallbladder neuroendocrine neoplasm (GB-NEN) is a relatively rare neoplasm, accounting for 0.5% of all neuroendocrine neoplasm cases and 2.1% of gallbladder cancers. Because of the limited understanding of GB-NEN, the aim of this study was to explore the clinicopathology and survival of GB-NEN patients selected from the Surveillance, Epidemiology, and End Results (SEER) database.

Methods

A total of 248 GB-NEN patients from the SEER database diagnosed between 2004 and 2015 were included. Kaplan–Meier curves were used to examine the survival time. Multivariate Cox proportional hazard models were used to estimate hazard ratios with 95% confidence intervals to analyze the impact of factors on overall survival and cancer-specific survival.

Results

The majority of the GB-NEN patients were women (67.3%), white (77%), and married (61.7%). Most tumors were <2 cm in size (31.0%), G3 stage (25.8%), and distant SEER stage (41.1%). 62.9% and 64.5% of cases showed an absence of lymph node metastasis and tumor metastasis, respectively. Patients who received gallbladder surgery had significantly better survival outcomes (P < 0.001). However, patients who received both gallbladder surgery and lymph node resection did not have better survival outcome compared with patients who received only gallbladder surgery. Multivariate Cox proportional hazard models indicated that older age, unmarried status, large tumor size (>5 cm), and distant SEER stage were significant independent predictors for decreased overall survival time and cancer-specific survival time (P < 0.05).

Conclusion

Age, marital status, tumor size, and SEER stage were predictors for the survival of GB-NEN patients. Gallbladder surgery was associated with better survival, but the combination of gallbladder surgery and lymphadenectomy had no effect on survival outcomes.

Open access

Maryam Iravani, Marie K Lagerquist, Elham Karimian, Andrei S Chagin, Claes Ohlsson and Lars Sävendahl

Estrogens may affect bone growth locally or systemically via the known estrogen receptors ESR1, ESR2 and G protein-coupled estrogen receptor 1 (GPER1). Mouse and human growth plate chondrocytes have been demonstrated to express GPER1 and ablation of this receptor increased bone length in mice. Therefore, GPER1 is an attractive target for therapeutic modulation of bone growth, which has never been explored. To investigate the effects of activated GPER1 on the growth plate, we locally exposed mouse metatarsal bones to different concentrations of the selective GPER1 agonist G1 for 14 days ex vivo. The results showed that none of the concentrations of G1 had any direct effect on metatarsal bone growth when compared to control. To evaluate if GPER1 stimulation may systemically modulate bone growth, ovariectomized C57BL/6 mice were treated with G1 or β-estradiol (E2). Similarly, G1 did not influence tibia and femur growth in treated mice. As expected, E2 treatment suppressed bone growth in vivo. We conclude that ligand stimulation of GPER1 does not influence bone growth in mice.

Open access

Leanne Hodson and Fredrik Karpe

In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex series of steps, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism but also in the regulation of systemic glucose and lipid concentrations. Thus, when intra-hepatic insulin signalling becomes aberrant then this may lead to perturbations in intra-hepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intra-hepatic fat accumulation (known as non-alcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extra-hepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or IHTAG accumulation in humans.