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BACKGROUND AND OBJECTIVES: Recently, a comprehensive study presented evidence that a long-disputed REarranged during Transfection (RET) variant, RET Y791F, should be classified as nonpathogenic. In spite of this, several subsequently published papers, including the revised American Thyroid Association guidelines for medullary thyroid carcinoma, refer to the variant as pathogenic. This study presents data from a unique national Danish cohort of RET Y791F carriers who have been followed by watchful waiting instead of being subjected to early thyroidectomy, to determine if any carrier shows evidence of multiple endocrine neoplasia 2A (MEN2A) at long-term follow-up.METHODS: A national cohort of all patients tested for RET mutations in Denmark from September 1994 to October 2017 was searched for carriers of RET Y791F. Medical records and laboratory reports of carriers were reviewed for signs of MEN2A at latest follow-up (medullary thyroid carcinoma, primary hyperparathyroidism, pheochromocytoma, cutaneous lichen amyloidosis, or Hirschsprung's disease).RESULTS: In total, twenty RET Y791F-carriers were identified, none of whom showed any evidence of MEN2A, despite an age range from 7 to 87 years.CONCLUSIONS: Our national cohort study of all Danish RET Y791F carriers substantiates the claim that the RET Y791F variant is nonpathogenic.

BACKGROUND: Bone remodeling takes place in the bone marrow environment. We investigated if levels of bone turnover markers (BTMs) differ between bone marrow and peripheral blood, if the bone marrow is an independent compartment, and how well the measurements in bone marrow correlate with bone mineral density.METHODS: Sixty-six men participated in a placebo controlled study designed to evaluate the effect of 16 weeks supplementation with resveratrol on bone mineral density and BTM. Bone marrow aspirates and blood samples were drawn at baseline and at week 16. Procollagen I N-terminal propeptide (PINP), C-terminal telopeptide of type I collagen (CTx), osteocalcin, bone specific alkaline phosphatase (BAP), and osteoprogeterin (OPG) were analyzed. Bland-Altman analysis was used to compare measurements across compartment to detect possible systematic or proportional differences. Paired t-test was performed if no proportional difference was revealed at the difference vs concentration plot.RESULTS: Measurements of PINP, CTx, and BAP differed proportionally between compartments depending on concentration; at low concentrations absolute values were only slightly different, while at higher average concentrations the levels were much higher in bone marrow than blood. Osteocalcin measures in bone marrow were systematically and significantly lower than in blood (mean ± SD; 14.4 μg/L ± 5.3 μg/L versus 21.7 μg/L ± 6.0 μg/L respectively, p DISCUSSION: The levels of most BTMs differed significantly between bone marrow and peripheral blood, while OPG was comparable. Levels of PINP, CTx, and BAP differed between compartments depending on concentration, suggesting bone marrow to represent a compartment separate from the general circulation. Unexpectedly, osteocalcin was lower in the marrow, a gradient that was independent of concentration. BTMs measured in bone marrow did not show any association with bone mineral density. Although further studies are needed to investigate potential explanatory causes of the differences, BTMs in bone marrow do not seem to contribute further to fracture risk assessment.

Resveratrol (RSV) is a natural polyphenolic compound. A recent study suggests a positive effect on BMD in men; however, the underlying changes in microstructure and strength remain unknown. We aimed to investigate the effects of RSV on the skeleton in hindlimb-immobilized and non-immobilized rats. Seventy-two female Wistar rats were divided into six groups. Two baseline (BSL) groups underwent short-term diet intervention for 4 weeks before sacrifice [phytoestrogen-deficient diet (PD) (BSL + PD) or RSV diet (600 mg/kg body weight/day) (BSL + RSV)]. Four groups were injected in the right hindlimb with botulinum toxin (BTX) (immobilized) or saline (non-immobilized), and fed either PD diet or RSV diet 4 weeks pre-injection and 6 weeks post-injection before sacrifice (BTX + PD, BTX + RSV, PD, and RSV, respectively). DXA, µCT, dynamic histomorphometry, and mechanical tests were performed. Short-term RSV treatment did not affect bone parameters, whereas long-term RSV exposure had a consistent negative impact on non-immobilized rats (RSV vs. PD); whole femoral aBMD (p = 0.01) and distal femoral metaphyseal Tb.N (p = 0.01), Tb.Sp (p = 0.02), and BV/TV (p = 0.07). At the femoral mid-diaphysis, RSV increased periosteal resorption (p = 0.01) and increased endosteal formation (p = 0.02), while mineralization was unaffected. In addition, RSV reduced femoral mid-diaphyseal three-point bending strength (p = 0.03) and stiffness (p = 0.04). BTX-induced immobilization resulted in significant bone loss and reduced bone strength; however, RSV supplementation was unable to prevent this. In conclusion, long-term high-dose RSV reduced bone mass and fracture strength and did not prevent immobilization-induced bone loss in rats.

Background: Roux-en-Y gastric bypass (RYGB) has been associated with negative effects on bone. Whether this association is affected by pre-surgical type 2 diabetes (T2D) and surgically induced diabetes remission is unknown. Methods: In this cross-sectional, matched cohort study 6 years after RYGB, we investigated bone health in 96 individuals with body mass index (BMI) > 35 kg/m 2 and T2D (stratified on current diabetes status) treated by RYGB 6 years earlier compared with 49 non-operated individuals with T2D matched with respect to sex, age, and current BMI. Main outcome measures were areal and volumetric bone mineral density (aBMD and vBMD), bone turnover, and odds ratio of osteoporosis/osteopenia. Results: The RYGB group had lower hip (0.916 vs 1.010 g/cm 2, p < 0.001), forearm (0.497 g/cm 2 vs 0.554 g/cm 2, p < 0.001) aBMD, (269.63 mg/cm 3 vs 306.07 mg/cm 3, p < 0.001) tibial, and radial (238.57 mg/cm 3 vs 278.14 mg/cm 3, p < 0.0001) vBMD than the control group. Relative to the control group, c-terminal cross-linked telopeptide, procollagen type I amino-terminal propeptide, and osteocalcin were 75%, 41%, and 72% higher in the RYGB group, respectively (all p < 0.001). Odds ratio for osteopenia/osteoporosis in operated individuals was 2.21 (95% CI 1.06; 4.79, p = 0.05). Overall, stratified analysis on current diabetes status did not alter these outcomes. Conclusions: Individuals with T2D treated by RYGB, compared to individuals with T2D of similar age and body composition not treated by RYGB, have lower BMD, lower bone strength, and increased levels of several bone turnover markers. Bone health was not associated with current diabetes status in the RYGB group.

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation.

available at http://www.ncbi.nlm.nih.gov/pubmed/25939591 Editorial Comment: Folks are always seeking the latest and greatest ways to maintain health and live longer, preferably without a prescription. One of the magic ingredients touted was resveratrol, a type of natural phenol and phytoalexin produced naturally by several plants in response to injury. Food sources of resveratrol include the skin of grapes, blueberries and raspberries. To date, despite all of the hoopla, there has been little evidence that this agent has any beneficial effects on heart disease, blood pressure, cancer or metabolism, although data exist that support a potential benefit in controlling some biomarkers in diabetes. There have been studies suggesting that resveratrol may have direct effects on the prostate, including androgen receptor expression at the gene and protein levels. The authors of this proof of concept study sought to determine the effects, if any, of resveratrol on prostate size, prostate specific antigen and sex hormone status. The results indicate that while resveratrol reduced the concentration of some androgen precursors, such as androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate, there were no effects on prostate size, prostate specific antigen, testosterone, free testosterone or dihydrotestosterone. Is it possible that a longer study (more than 4 months) would have produced a more robust response? That is doubtful, given what we would expect to see from other androgen type drugs in the prostate. Often a good story, eg red wine can prolong life, can lead to a cadre of studies and entrepreneurial endeavors, many of which result in either neutral or negative results. The bottom line is that to prolong health span, we should focus on eating a well-balanced diet, exercising and trying to find suitable ways to reduce stress. And, of course, enjoy a glass of delicious red wine!

Introduction We tested for the presence of erythropoietin receptor (Epo-R) in human skeletal muscle and alterations in gene expression after prolonged use of an erythropoiesis-stimulating agent (ESA). Methods Nine healthy men were treated with ESA for 10 weeks (darbepoietin alfa). Muscle biopsies were collected before and after treatment. Alterations in gene expression were evaluated by gene array. Western blot and PCR analysis were used to test for Epo-R presence in human skeletal muscle. Results Very low Epo-R mRNA levels were found, but a new and sensitive antibody did not identify Epo-R protein in human skeletal muscle. The between-subject variation in skeletal muscle gene expression was greater than that observed in response to prolonged ESA treatment. Conclusions Erythropoietin is unlikely to exert direct effects in human skeletal muscle due to a lack of Epo-R protein. Furthermore, prolonged ESA treatment does not seem to exert either direct or indirect effects on skeletal muscle gene expression. Muscle Nerve 51: 554–561, 2015

Context: Metabolic syndrome (MetS) is associated with low-grade inflammation, which may harmfully affect bone. Resveratrol (RSV) possesses anti-inflammatory properties, and rodent studies suggest bone protective effects. Objective: This study sought to evaluate effects of RSV treatment on bone in men with MetS. Setting and Design: The study was conducted at Aarhus University Hospital as a randomized, double-blinded, placebo-controlled trial assessing changes in bone turnover markers, bone mineral density (BMD), and geometry. Participants: The study population comprised 74 middle-aged obese men with MetS recruited from the general community, of which 66 completed all visits. Mean age of participants was 49.3 ± 6.3 years and mean body mass index was 33.7 ± 3.6 kg/m(2). Intervention: Oral treatment with 1.000 mg RSV (RSVhigh), 150mg RSV (RSVlow), or placebo daily for 16 weeks. Main Outcome Measure: Prespecified primary endpoint was change in bone alkaline phosphatase (BAP). Results: BAP increased dose dependently with RSV (R = 0.471, P < .001), resulting in a significantly greater increase in BAP in the RSVhigh group compared with placebo at all time-points (week 4, 16.4 ± 4.2%, P < .001; week 8, 16.5 ± 4.1%, P < .001; week 16, 15.2 ± 3.7%, P < .001). Lumbar spine trabecular volumetric bone mineral density (LS vBMDtrab) also increased dose dependently with RSV (R = 0.268, P = .036), with a significant increase of 2.6 ± 1.3% in the RSVhigh group compared with placebo (P = .043). In addition, changes in BAP and LS vBMDtrab were positively correlated (R = 0.281, P = .027). No consistent changes were detected in bone density at the hip. Conclusions: Our data suggest that high-dose RSV supplementation positively affects bone, primarily by stimulating formation or mineralization. Future studies of longer duration comprising populations at risk of osteoporosis are needed to confirm these results.

BACKGROUND AND OBJECTIVE: CD36 is implicated in fatty acid uptake in multiple tissues, including hepatocytes and adipocytes. Circulating CD36 (sCD36) is increased in non-alcoholic fatty liver disease (NAFLD).We explored this association further by investigating correlations between sCD36 levels, intrahepatic lipid content and markers of obesity in NAFLD patients and controls.METHODS: 111 NAFLD patients and 33 normal/overweight controls were included. Intrahepatic lipid content was measured by MR spectroscopy; and subgroups of participants had a dual-energy X-ray absorptiometry (n=99), magnetic resonance imaging (n=94, subcutaneous and visceral adipose tissue) and liver biopsy (n=28 NAFLD patients) performed. Plasma sCD36 was assessed by ELISA.RESULTS: NAFLD patients had elevated sCD36 levels compared to controls (0.68 (0.12-2.27) versus 0.43 (0.10-1.18), PCONCLUSIONS: sCD36 levels increased with the level of intrahepatic lipid, insulin resistance and dyslipidemia. The weak association with markers of obesity and the association with hepatic CD36 mRNA expression suggest that excess sCD36 in NAFLD patients is derived from the hepatocytes, which may support that CD36 is involved in NAFLD development. An unhealthy and unbalanced CD36 expression in adipose and hepatic tissue may shift the fatty acid load to the liver.Clinical Trials.gov (NCT01464801, NCT01412645, NCT01446276).International Journal of Obesity accepted article preview online, 05 December 2016. doi:10.1038/ijo.2016.223.

Throughout the Western world obesity prevalence is steadily increasing, and associated metabolic co-morbidities are projected to rise during the years to come. As weight loss and weight maintenance remains a major problem, new strategies to protect against obesity-related morbidity are needed. There is a clear association between obesity, low-grade inflammation and obesity-associated diseases, thus, the development of new anti-inflammatory substances is urgently needed as these may ultimately pave the way for novel treatments of obesity and lifestyle-related diseases. A candidate molecule is the polyphenolic compound resveratrol, and in the present review, we provide an overview of the field, and discuss the future scientific perspectives. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

ObjectiveVisceral adipose tissue (VAT) is associated with an increased risk of metabolic syndrome (MetS). Recent studies have suggested that VAT negatively affects bone. However, MetS has also been associated with higher estradiol (E2) levels, which is bone protective. We therefore investigated the impact of VAT and E2levels on bone density, structural parameters, and strength estimates.DesignA cross-sectional study was conducted in 72 obese men with MetS to investigate the impact of VAT and E2levels on bone.MethodsBone parameters were assessed by dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HRpQCT) at lumbar spine, proximal femur, radius, and tibia. VAT volume was measured by magnetic resonance imaging (MRI) and sexual hormones were measured in blood samples.ResultsMen with high VAT had a lower bone density at the hip (PP=0.008 andP=0.02), compared with men with low VAT, despite a similar body weight and BMI. Generally, E2levels were low (median 43 pmol/l), and men with E2levels below median had reduced bone density at lumbar spine (P=0.04), and impaired structural parameters at radius and tibia, compared with men with E2levels above median. At the hip, VAT volume and E2levels affected bone density independently and additively, and 50% of men with high VAT and low E2levels had osteopenia with significantly lowerT-score at FN (P=0.004).ConclusionsHigh VAT and low E2negatively affect bone in obese men with MetS. VAT and E2affect bone density at the hip independently and additively, revealing an unexpected high prevalence of osteopenia in middle-aged men with MetS.

We tested for the presence of erythropoietin receptor (Epo-R) in human skeletal muscle and alterations in gene expression after prolonged use of an erythropoiesis-stimulating agent (ESA).Nine healthy men were treated with ESA for 10 weeks (darbepoietin alfa). Muscle biopsies were collected before and after treatment. Alterations in gene expression were evaluated by gene array. Western blot and PCR analysis were used to test for Epo-R presence in human skeletal muscle.Very low Epo-R mRNA levels were found, but a new and sensitive antibody did not identify Epo-R protein in human skeletal muscle. The between-subject variation in skeletal muscle gene expression was greater than that observed in response to prolonged ESA treatment.Erythropoietin is unlikely to exert direct effects in human skeletal muscle due to a lack of Epo-R protein. Furthermore, prolonged ESA treatment does not seem to exert either direct or indirect effects on skeletal muscle gene expression.

A previously healthy 71 year-old woman presented at our medical department with fever, back pain and weight loss. Laboratory analysis demonstrated elevated erythrocyte sedimentation, elevated C-reactive protein and normal white blood cell count. Clinical examination revealed a systolic murmur. On the third day she was found dead in her bed. Autopsy revealed massive aspiration of blood. We report the rare pathologic finding of massive aspiration of blood originating from a ruptured atherosclerotic aneurysm of the thoracic aorta into the left lung, because of infectious aortitis.

Despite the substantial preclinical evidence for a positive effect of the polyphenolic compound resveratrol, human data are very scarce, and currently no clinical data addressing the potential impact on bone metabolism have been published. In the present study we addressed this issue in order to identify potential bone metabolic effects of resveratrol in human subjects. In a randomised, placebo-controlled, double-blinded and parallel-group design, 24 obese [BMI (kg/m2): 34.2 ± 0.7] non-diabetic men were randomly assigned to 500 mg resveratrol or placebo treatment three times daily for four weeks. Biomarkers of bone metabolism, inflammatory parameters and circulating hormones were measured before and after the intervention period. Plasma levels of bone-specific alkaline phosphatase increased significantly in the resveratrol group as compared to placebo [delta changes (U/l); resveratrol: 4.9 ± 0.6 vs. placebo: −1.7 ± 0.7; P