Long-term follow-up of RET Y791F carriers in Denmark 1994-2017: A National Cohort Study.

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.

Long-Term High-Dose Resveratrol Supplementation Reduces Bone Mass and Fracture Strength in Rats.

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.

Comprehensive Metabolomic Analysis in Blood, Urine, Fat, and Muscle in Men with Metabolic Syndrome: A Randomized, Placebo-Controlled Clinical Trial on the Effects of Resveratrol after Four Months' Treatment.

Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either resveratrol or placebo treatment for four months. Changes in steroid hormones across all four matrices were the most pronounced changes observed. Resveratrol treatment reduced sulfated androgen precursors in blood, adipose tissue, and muscle tissue, and increased these metabolites in urine. Furthermore, markers of muscle turnover were increased and lipid metabolism was affected, with increased intracellular glycerol and accumulation of long-chain saturated, monounsaturated, and polyunsaturated (n3 and n6) free fatty acids in resveratrol-treated men. Finally, urinary derivatives of aromatic amino acids, which mainly reflect the composition of the gut microbiota, were altered upon resveratrol treatment. In conclusion, the non-targeted metabolomics approach applied to four different matrices provided evidence of subtle but robust effects on several metabolic pathways following resveratrol treatment for four months in men with metabolic syndrome-effects that, for the most part, would not have been detected by routine analyses. The affected pathways should be the focus of future clinical trials on resveratrol's effects, and perhaps particularly the areas of steroid metabolism and the gut microbiome.

Resveratrol and inflammation: Challenges in translating pre-clinical findings to improved patient outcomes.

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.

Resveratrol Increases Osteoblast Differentiation In Vitro Independently of Inflammation.

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.

Resveratrol reduces the levels of circulating androgen precursors but has no effect on, testosterone, dihydrotestosterone, PSA levels or prostate volume. A 4-month randomised trial in middle-aged men.

BACKGROUND: Resveratrol is a naturally occurring polyphenol with purported inhibitory effects on prostate growth and cancer development. A number of studies have demonstrated that resveratrol reduces prostate growth in animal models and reduces prostate cell growth in vitro. Based on these pre-clinical findings, interest in resveratrol is increasing in relation to the management of benign prostate hyperplasia (BPH) and prostate cancer. So far, no human trials have evaluated the effects of resveratrol on circulating androgens, prostate size, or biochemical markers of prostate size. METHODS: In a randomized placebo controlled clinical study using two doses of resveratrol (150 mg or 1,000 mg resveratrol daily) for 4 months, we evaluated the effects on prostate size, prostate specific antigen (PSA) and sex steroid hormones in 66 middle-aged men suffering from the metabolic syndrome(MetS). RESULTS: At baseline, prostate size and PSA were positively correlated (R = 0.34, P < 0.007) as was prostate size and age (R = 0.37, P < 0.003). Prostate size did not correlate with testosterone, free testosterone, dihydrotestosterone (DHT), or any other androgen precursor at baseline. The highest dose of resveratrol lowered the serum level of androstenedione 24% (P = 0.052), dehydroepiandrosterone (DHEA) 41% (P < 0.01), and dehydroepiandrosterone-sulphate (DHEAS) 50% (p<0.001), compared to the control group. However, prostate size and levels of PSA, testosterone, free testosterone and DHT remained unchanged. CONCLUSION: In this population of middle-aged men suffering from MetS, high dose resveratrol (1,000 mg daily) administration for 4 months significantly lowered serum levels of the androgen precursors androstenedione, DHEA and DHEAS, whereas prostate size and circulating levels of PSA, testosterone, free testosterone, and dihydrotestosterone were unaffected. The present study suggests that resveratrol does not affect prostate volume in healthy middle-aged men as measured by PSA levels and CT acquired prostate volumes. Consequently, we find no support for the use of resveratrol in the treatment of benign prostate hyperplasia.

Prolonged erythropoietin treatment does not impact gene expression in human skeletal muscle.

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.

Acute effects of testosterone on whole body protein metabolism in hypogonadal and eugonadal conditions: a randomized, placebo-controlled, crossover study.

Chronic testosterone (T) substitution and short-term T administration positively affect protein metabolism, however, data on acute effects in humans are sparse. This study aimed to investigate T's acute effects on whole body protein metabolism in hypogonadal and eugonadal conditions. We designed a randomized, double-blind, placebo-controlled, crossover study, including 12 healthy young males. Whole body protein metabolism was evaluated during 1) eugonadism, and after medically induced hypogonadism, with application of a gel on each trial day containing either 2) placebo, 3) T 50 mg, or 4) T 150 mg; under basal (5-h basal period) and insulin-stimulated conditions (3-h clamp). The main outcome measure was a change in net protein balance. The net protein loss was 62% larger in the placebo-treated hypogonadal state compared with the eugonadal state during the basal period (-5.5 ± 3.5 µmol/kg/h vs. -3.4 ± 1.2 µmol/kg/h, P = 0.038), but not during the clamp (P = 0.06). Also, hypogonadism resulted in a 25% increase in whole body urea flux (P = 0.006). However, T did not result in any significant changes in protein breakdown, synthesis, or net balance during either the basal period or clamp (all P > 0.05). Protein breakdown was reduced during clamp compared with the basal period regardless of gonadal status or T exposure (all P ≤ 0.001). In conclusion, the application of transdermal T did not counteract the negative effects of hypogonadism with no effects on protein metabolism within 5 h of administration. Insulin (during clamp) mitigated the effects of hypogonadism. This study is the first to investigate acute protein metabolic effects of T in hypogonadal men.NEW & NOTEWORTHY In a model of medically induced hypogonadism in male volunteers, we found increased whole body urea flux and net protein loss as an expected consequence of hypogonadism. Our study demonstrates the novel finding that the application of transdermal testosterone had no acute effects on whole body protein metabolism under eugonadal conditions, nor could it mitigate the hypogonadism-induced changes in protein metabolism. In contrast, insulin (during clamp) mitigated the effects of hypogonadism on protein metabolism.

Late diagnosis of partial 3ß-hydroxysteroid dehydrogenase type 2 deficiency - characterization of a new genetic variant.

Summary: Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs*17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs*17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future. Learning points: Non-classic 3ßHSD2 is likely underdiagnosed. Late diagnosis of mild non-classic 3ßHSD2 does occur and one should be aware of this diagnosis. Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections. Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.

Patients with Hypocortisolism Treated with Continuous Subcutaneous Hydrocortisone Infusion (CSHI): An Option for Poorly Controlled Patients.

Objective: Despite appropriate oral glucocorticoid replacement therapy, patients with hypocortisolism often suffer from impaired health and frequent hospitalizations. Continuous subcutaneous hydrocortisone infusion (CSHI) has been developed as an attempt to improve the health status of these patients. The objective of this study was to compare the effects of CSHI to conventional oral treatment on hospitalizations, glucocorticoid doses, and subjective health status. Patients. Nine Danish patients (males: 4 and females: 5) with adrenal insufficiency (AI) were included, with a median age of 48 years, due to Addison (n = 4), congenital adrenal hyperplasia (n = 1), steroid induced secondary adrenal insufficiency (n = 2), morphine induced secondary adrenal insufficiency (n = 1), and Sheehan's syndrome (n = 1). Only patients with severe symptoms of cortisol deficit on oral treatment were selected for CSHI. Their usual oral hydrocortisone doses varied from 25-80 mg per day. The duration of follow-up depended on when the treatment was changed. The first patient started CSHI in 2009 and the last in 2021. Design: A retrospective case series comparing hospitalizations and glucocorticoid doses before and after treatment with CSHI. In addition, patients were retrospectively interviewed about their health-related quality of life (HRQoL) after the change of treatment modality. Results: Patients significantly reduced their daily dose of glucocorticoids by 16.1 mg (p = 0.02) after changing to CSHI. The number of hospital admission due to adrenal crisis decreased by 1.3 per year on CSHI, which was a 50% reduction (p = 0.04). All patients found it easier to handle an adrenal crisis with CSHI, and almost all patients found it easier to overcome everyday activities and had fewer symptoms of cortisol deficit such as abdominal pain and nausea (7-8 out of 9 patients). Conclusions: The change of treatment from conventional oral hydrocortisone to CSHI resulted in a reduced daily dose of glucocorticoids and a reduced number of hospitalizations. Patients reported regain of energy, achievement of better disease control, and better handling of adrenal crisis.

Ectopic Cushing's syndrome from a corticotropin-releasing hormone-secreting medullary thyroid carcinoma: a rare pitfall of inferior petrosal sinus sampling.

Summary: This case report describes a rare presentation of ectopic Cushing's syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous. Learning points: Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases.

Bone Density and Structure in Overweight Men With and Without Diabetes.

Objective: Metabolic syndrome (MetS), type 1 diabetes (T1D), and type 2 diabetes, are associated with an increased risk of fractures; however, the impact of obesity on bone deficits in diabetes is unknown. We aimed to compare markers of bone structure, bone density, and bone turnover in non-diabetic overweight men with MetS and overweight men with T1D or T2D. Methods and Research Design: In this cross-sectional study we included participants from two previously described study cohorts consisting of participants with diabetes and participants with MetS. Participants underwent dual-energy X-ray absorptiometry measuring areal bone mineral density (aBMD) at the hip and lumbar spine, High Resolution peripheral Quantitative (HRpQCT) scan of the tibia and radius and measurement of circulating bone turnover markers. We compared groups with unpaired t test and performed multiple linear regression with adjustment for age, body mass index, and smoking. Results: We included 33 participants with T1D, 25 participants with T2D, and 34 participants with MetS. Bone turnover markers levels were comparable between T1D and MetS. aBMD at the hip was lower in T1D compared to MetS, also after adjustment. P1NP and Osteocalcin levels were lower among individuals with T2D compared to MetS, whereas aBMD were similar between the groups after multiple adjustments. We observed no difference in volumetric BMD at the tibia or radius between MetS and T1D and T2D, respectively. Participants with T2D had a higher trabecular number and lower trabecular separation compared to individuals with MetS at the tibia, which remained signficant after multiple adjustments. Conclusion: In conclusion, we observed no clinically important differences in bone density or structure between men with T2D, T1D, or MetS. However, men with T2D displayed lower bone turnover compared to MetS highlighting that T2D per se and not obesity, is associated with low bone turnover.

Bone Health in Patients with Type 2 Diabetes Treated by Roux-En-Y Gastric Bypass and the Role of Diabetes Remission.

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/m2 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/cm2, p < 0.001), forearm (0.497 g/cm2 vs 0.554 g/cm2, p < 0.001) aBMD, (269.63 mg/cm3 vs 306.07 mg/cm3, p < 0.001) tibial, and radial (238.57 mg/cm3 vs 278.14 mg/cm3, 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.

No Beneficial Effects of Resveratrol on the Metabolic Syndrome: A Randomized Placebo-Controlled Clinical Trial.

Context: Low-grade inflammation is associated with obesity and the metabolic syndrome (MetS). Preclinical evidence suggests that resveratrol (RSV) has beneficial metabolic and anti-inflammatory effects that could have therapeutic implications. Objective: To investigate effects of long-term RSV treatment on inflammation and MetS. Setting and Design: A randomized, placebo-controlled, double-blind, parallel group clinical trial conducted at Aarhus University Hospital. Participants: Middle-aged community-dwelling men (N = 74) with MetS, 66 of whom completed all visits (mean ± standard error of the mean): age, 49.5 ± 0.796 years; body mass index, 33.8 ± 0.44 kg/m2; waist circumference, 115 ± 1.14 cm. Intervention: Daily oral supplementation with 1000 mg RSV (RSVhigh), 150 mg RSV, or placebo for 16 weeks. Main outcome measures: Plasma levels of high-sensitivity C-reactive protein (hs-CRP), circulating lipids, and inflammatory markers in circulation and adipose/muscle tissue biopsy specimens; glucose metabolism; and body composition including visceral fat and ectopic fat deposition. Results: RSV treatment did not lower circulating levels of hs-CRP, interleukin 6, or soluble urokinase plasminogen activator receptor in plasma, and inflammatory gene expression in adipose and muscle tissues also remained unchanged. RSV treatment had no effect on blood pressure, body composition, and lipid deposition in the liver or striated muscle. RSV treatment had no beneficial effect on glucose or lipid metabolism. RSVhigh treatment significantly increased total cholesterol (P < 0.002), low-density lipoprotein (LDL) cholesterol (P < 0.006), and fructosamine (P < 0.013) levels compared with placebo. Conclusion: RSV treatment did not improve inflammatory status, glucose homeostasis, blood pressure, or hepatic lipid content in middle-aged men with MetS. On the contrary, RSVhigh significantly increased total cholesterol, LDL cholesterol, and fructosamine levels compared with placebo.

Adipose tissue, estradiol levels, and bone health in obese men with metabolic syndrome.

OBJECTIVE: Visceral 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 E2 levels on bone density, structural parameters, and strength estimates. DESIGN: A cross-sectional study was conducted in 72 obese men with MetS to investigate the impact of VAT and E2 levels on bone. METHODS: Bone 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. RESULTS: Men with high VAT had a lower bone density at the hip (P<0.05), lower cortical thickness, and higher buckling ratio at femoral neck (FN) (P=0.008 and P=0.02), compared with men with low VAT, despite a similar body weight and BMI. Generally, E2 levels were low (median 43 pmol/l), and men with E2 levels below median had reduced bone density at lumbar spine (P=0.04), and impaired structural parameters at radius and tibia, compared with men with E2 levels above median. At the hip, VAT volume and E2 levels affected bone density independently and additively, and 50% of men with high VAT and low E2 levels had osteopenia with significantly lower T-score at FN (P=0.004). CONCLUSIONS: High VAT and low E2 negatively affect bone in obese men with MetS. VAT and E2 affect bone density at the hip independently and additively, revealing an unexpected high prevalence of osteopenia in middle-aged men with MetS.

Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: a randomized placebo-controlled trial.

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 (RSV(high)), 150 mg RSV (RSV(low)), 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 RSV(high) 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 vBMD(trab)) also increased dose dependently with RSV (R = 0.268, P = .036), with a significant increase of 2.6 ± 1.3% in the RSV(high) group compared with placebo (P = .043). In addition, changes in BAP and LS vBMD(trab) 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.

[Fatal aspiration of blood caused by infectious aortitis]. / Fatal aspiration af blod på baggrund af infektiøs aortitis.

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.