Determinants of circulating calcitriol in cardiovascular disease.

Circulating calcitriol may contribute to the risk of cardiovascular disease (CVD), but its regulation in patients with CVD is poorly characterized. We therefore aimed to assess determinants of circulating calcitriol in these patients. We analyzed 2183 independent samples from a large cohort of patients scheduled for coronary angiography and 1727 independent samples from different other cohorts from patients with a wide range of CVDs, including heart transplant candidates, to quantify the association of different parameters with circulating calcitriol. We performed univariable and multivariable linear regression analyses using the mathematical function that fitted best with circulating calcitriol. In the multivariable analysis of the large single cohort, nine parameters remained significant, explaining 30.0 % (32.4 % after exclusion of 22 potential outliers) of the variation in circulating calcitriol (r=0.548). Log-transformed 25-hydroxyvitamin D [25(OH)D] and log-transformed glomerular filtration rate were the strongest predictors, explaining 17.6 % and 6.6 %, respectively, of the variation in calcitriol. In the analysis of the combined other cohorts, including heart transplant candidates, the multivariable model explained a total of 42.6 % (46.1 % after exclusion of 21 potential outliers) of the variation in calcitriol (r=0.653) with log-transformed fibroblast growth factor-23 and log-transformed 25(OH)D explaining 29.0 % and 6.2 %, respectively. Circulating 25(OH)D was positively and FGF-23 inversely associated with circulating calcitriol. Although significant, PTH was only a weak predictor of calcitriol in both analyses (<2.5 %). In patients with CVD, FGF-23 and 25(OH)D are important independent determinants of circulating calcitriol. The relative importance of these two parameters may vary according to CVD severity. Future studies should focus on the clinical importance of regulating circulating calcitriol by different parameters.

Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria.

BACKGROUND: Lenvatinib has proven efficacy in progressive, radioiodine- (RAI-) refractory thyroid cancer (TC). Dose reductions are commonly performed due to decreased tolerability and adverse effects. This retrospective multicenter study analyzed overall survival (OS) and progression-free survival (PFS) and tolerability in the Austrian patient population treated with lenvatinib. METHODS: Clinical data of 43 patients (25 males and 18 females) with a median age of 70 years (range: 39-91 years) and RAI-refractory TC with metastases to the lymph nodes (74%), lungs (86%), bone (35%), liver (16%), and brain (12%) were analyzed. The mean duration of treatment with lenvatinib was 26.6 ± 15.4 months with dosage reductions required in 39 patients (91%). RESULTS: PFS after 24 months was 71% (95% CI: 56-87), and overall survival (OS) was 74% (95% CI: 60-88), respectively. OS was significantly shorter (p=0.048) in patients with a daily maintenance dosage ≤ 10 mg (63%) (95% CI: 39-86) as compared to patients on ≥ 14 mg lenvatinib (82%) (95% CI: 66-98) daily. Dose reduction was noted in 39 patients (91%). Grade ≥3 toxicities (hypertension, diarrhea, weight loss, and palmar-plantar erythrodysesthesia syndrome) were most common leading to discontinuation of lenvatinib in 7 patients (16%). CONCLUSION: Lenvatinib showed sustained clinical efficacy in patients with metastatic RAI-refractory TC even with reduced maintenance dosages over years. The effects were comparable to the registration trial, although patients had a higher median age and, more commonly, dose reductions.

Effects of Vitamin D3 on asymmetric- and symmetric dimethylarginine in arterial hypertension.

BACKGROUND AND AIMS: Accumulating evidence has proposed a correlation between vitamin D (25(OH)D) insufficiency and cardiovascular (CV) disease. Vitamin D associated effects on endothelial function have been suggested to be a possible culprit. The present study investigated the association of vitamin D3 treatment on markers of endothelial dysfunction in patients with arterial hypertension. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a double-blind, placebo-controlled, single-centre study conducted at the Medical University of Graz, Austria. A total of 200 study participants with arterial hypertension and 25(OH)D levels below 30ng/mL were enrolled. The study participants were randomized to receive 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for a duration of eight weeks. The present study uses an analysis of covariance (ANCOVA) to investigate the effect of vitamin D3 treatment on symmetric (SDMA) and asymmetric dimethylarginine (ADMA). A total of 187 participants (mean [SD] age 60.0 [11.3] years; 47% women; 25(OH)D 21.2 [5.6]ng/mL; mean systolic blood pressure of 131.4 [8.9] mmHg on a median of 2 antihypertensive drugs) completed the trial. Mean treatment effect was -0.004 (95%CI [-0.03 to 0.04]; P=0.819) on ADMA and 0.001 (95%CI [-0.05 to 0.05]; P=0.850) on SDMA. In the subgroup analysis patients with a 25(OH)D concentration <20ng/mL had a significant increase in their log l-arginine/ADMA ratio (mean treatment effect 18.4 95%CI [1.84-34.9]µmol/L/µmol/L; P=0.030). ClinicalTrials.gov Identifier: NCT02136771 EudraCT number: 2009-018125-70 CONCLUSIONS: Vitamin D3 supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on ADMA and SDMA.

Effect of vitamin D3 on bone turnover markers in critical illness: post hoc analysis from the VITdAL-ICU study.

In this post hoc analysis of the VITdAL-ICU study, an RCT in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml, vitamin D3 did not have a significant effect on ß-Crosslaps and osteocalcin. INTRODUCTION: Observational studies have shown accelerated bone loss in ICU survivors. A reversible contributor is vitamin D deficiency. In a post hoc analysis of the VITdAL-ICU study, we evaluated the effect of high-dose vitamin D3 on the bone turnover markers (BTM) ß-Crosslaps (CTX) and osteocalcin (OC). METHODS: The VITdAL-ICU study was a randomized, double-blind, placebo-controlled trial in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml who received placebo or high-dose vitamin D3 (a loading dose of 540,000 IU and starting 1 month after the loading dose five monthly maintenance doses of 90,000 IU). In this analysis on 289 survivors (209 telephone, 80 personal follow-up visits), BTM were analyzed on days 0, 3, 7, 28, and 180; self-reported falls and fractures were assessed. Bone mineral density (BMD) was measured after 6 months. RESULTS: At baseline, CTX was elevated; OC was low in both groups-after 6 months, both had returned to normal. There were no differences between groups concerning BTM, BMD, falls, or fractures. In linear mixed effects models, CTX and OC showed a significant change over time (p < 0.001, respectively), but there was no difference between the vitamin D and placebo group (p = 0.688 and p = 0.972, respectively). CONCLUSIONS: Vitamin D supplementation did not have a significant effect on BTM. Further studies should assess the effectiveness of vitamin D on musculoskeletal outcomes in ICU survivors.

High salivary testosterone-to-androstenedione ratio and adverse metabolic phenotypes in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by a combination of hormonal and metabolic disturbances, such as insulin resistance, glucose intolerance, anovulation and hyperandrogenism. Clinical phenotypes of PCOS show different patterns of steroid hormones that have been investigated to some extent. This study aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of salivary testosterone and androstenedione and to describe the salivary testosterone-to-androstenedione (T/A4) ratio as a new tool for the assessment of hyperandrogenism and metabolic health. MATERIAL AND METHODS: Saliva and serum samples of 274 patients with PCOS and 51 healthy women were used for the quantification of steroid hormones. A comprehensive clinical and metabolic assessment was performed. Salivary testosterone and androstenedione were measured via LC-MS/MS. The salivary T/A4 ratio was calculated and correlated with hormones and metabolic parameters. RESULTS: Salivary testosterone (P < 0·001), androstenedione (P < 0·001) and the salivary T/A4 ratio (P < 0·001) were significantly higher in patients with patients compared to healthy women. In patients with PCOS, a high salivary T/A4 ratio was associated with an adverse metabolic phenotype, that is glucose intolerance (P = 0·019), insulin resistance (P < 0·001), metabolic syndrome (P < 0·001), obesity (P < 0·001) and oligo-/anovulation (P = 0·001). Significant correlations of the salivary T/A4 ratio with adverse metabolic parameters were found. CONCLUSION: Quantification of salivary androgens provides an attractive alternative to serum analysis and helps in characterizing metabolic health in women with PCOS. Our data show a strong link between a high salivary T/A4 ratio and an adverse metabolic phenotype in patients with PCOS.

Direct comparison of regulators of calcification between bone and vessels in humans.

Calcification is not only physiologically present in bone but is a main pathophysiological process in vasculature, favouring cardiovascular diseases. Our aim was to investigate changes in the expression of calcification regulators during vascular calcification in bone and vasculature. Levels of gene expression of osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), osteopontin (OPN), matrix gla protein (MGP), bone sialoprotein (BSP), SMAD6, and runt-related transcription factor 2 (RUNX2) were determined in bone, aorta, and external iliac artery tissue samples of transplant donors. Histological stages of atherosclerosis (AS) in vessels are defined as "no changes", "intima thickening", or "intima calcification". Patients' bone samples were subgrouped accordingly. We demonstrate that in vessels BSP and OPN expression significantly increased during intima thickening and decreased during intima calcification, whereas the expression of regulators of calcification did not significantly change in bone during intima thickening and intima calcification. At the stage of intima thickening, MGP, OPG, and SMAD6 expression and at stage of intima calcification only MGP expression was lower in bone than in vessel. The expression of BSP and RANKL was regulated in opposite ways in bone and vessels, whereas the expression of MGP, OC, RUNX2, and OPN was regulated in a tissue-specific manner. Our study is the first direct comparison of gene expression changes during AS progression in bone and vessels. Our results indicate that changes in the expression of regulators of calcification in the vessel wall as well as in bone occur early in the calcification process, even prior to deposition of calcium/phosphate precipitation.

Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous disease with many different aspects, including hyperandrogenism and metabolic disturbances. Clinical phenotypes show different patterns of steroid hormones that have been investigated to some extent. OBJECTIVE: This study intended to determine the role of the testosterone (TT) to dihydrotestosterone (DHT) ratio (TT/DHT ratio) in PCOS patients and to further assess the correlation of this ratio with hormonal, anthropometric, and metabolic parameters. DESIGN AND SETTING: Serum samples of 275 premenopausal PCOS patients fulfilling Rotterdam criteria and 35 BMI-matched, premenopausal, healthy controls were analyzed for testosterone, DHT, dehydroepiandrosterone (DHEA), and androstenedione using liquid chromatography/mass spectrometry. MAIN OUTCOME MEASURES: We measured total levels of testosterone and DHT and calculated unbound hormone levels as well as the ratio of testosterone to DHT. Further, impaired glucose tolerance, basal and stimulated serum insulin levels, metabolic syndrome and insulin resistance according to the homeostatic model assessment (HOMA-IR) were assessed. RESULTS: PCOS patients showed significantly higher levels of TT (P < .001), free testosterone (P < .001), and free DHT (P < .001) compared to healthy controls. The TT/DHT ratio was significantly higher in PCOS patients (P < .001). No difference was found for total DHT levels (P = .072). In PCOS patients alone, the TT/DHT ratio was significantly higher in obese patients (P < .001) and patients with metabolic syndrome (P < .001), impaired glucose tolerance (IGT) (P < .001) or insulin resistance (P < .001). Significant correlations of the TT/DHT ratio with various adverse anthropometric, hormonal, lipid and liver parameters and parameters of glucose metabolism were found. CONCLUSION: Our data provide evidence for a strong link between a high TT/DHT ratio and an adverse metabolic phenotype in PCOS patients. This correlation was only found in PCOS patients, suggesting the TT/DHT ratio to be a new biomarker for an adverse metabolic phenotype in PCOS patients.

Serum vitamin D levels and hypogonadism in men.

There is inconsistent evidence on a possible association of vitamin D and androgen levels in men. We therefore aim to investigate the association of 25-hydroxyvitamin D (25(OH)D) with androgen levels in a cohort of middle-aged men. This cross-sectional study included 225 men with a median (interquartile range) age of 35 (30-41) years. We measured 25(OH)D, total testosterone (TT) and SHBG concentrations. Hypogonadism was defined as TT <10.4 nmol/L. We found no significant correlation of 25(OH)D and androgen levels. Furthermore, androgen levels were not significantly different across 25(OH)D quintiles. The overall prevalence of hypogonadism was 21.5% and lowest in men within 25(OH)D quintile 4 (82-102 nmol/L). We found a significantly increased risk of hypogonadism in men within the highest 25(OH)D quintile (>102 nmol/L) compared to men in quintile 4 (reference) in crude (OR 5.10, 1.51-17.24, p = 0.009) as well as in multivariate adjusted analysis (OR 9.21, 2.27-37.35, p = 0.002). We found a trend towards increased risk of hypogonadism in men within the lowest 25(OH)D quintile (≤43.9 nmol/L). In conclusion, our data suggest that men with very high 25(OH)D levels (>102 nmol/L) might be at an increased risk of hypogonadism. Furthermore, we observed a trend towards increased risk of hypogonadism in men with very low vitamin D levels indicating a U-shaped association of vitamin D levels and hypogonadism. With respect to risk of male hypogonadism, our results suggest optimal serum 25(OH)D concentrations of 82-102 nmol/L.

[CT-guided electrode placement for sacral nerve stimulation in the treatment of faecal incontinence (cSNS)]. / CT-gesteuerte Elektrodenplatzierung zur Sakralnervenstimulation bei Stuhlinkontinenz (cSNS).

BACKGROUND: The sacral nerve stimulation (SNS) can be performed in the screening phase under local anaesthesia. Implantation of the tined-lead electrodes is usually performed in an inpatient setting under general anaesthesia. An outpatient procedure for both PNE and implantation of the electrodes offers decisive advantages with respect to the accuracy of electrode placement. MATERIALS AND METHODS: From 2006 to 2011 a total of 51 patients was treated with SNS in an outpatient setting. RESULTS: Of 51 patients having the PNE, in four patients the procedure could not successfully be completed. In 39 of the 47 patients screened, the testing was positive. Eight times the screening was negative. The functional results show a significant decline in the Cleveland scores from 14.9 to 6.4. The manometric resting pressure improved from 23.4 mmHg to 43.81 mmHg, the squeezing pressure improved from 42.2 mmHg to 76.12 mmHg. Due to patients' perception and according to the response on the stimulus, the electrodes were placed on the left in S4 11 times, 23 times in the left S3, 3 times in the right S3, once in the left S2 and once in the right S2. CONCLUSION: CT-guided electrode placement is safe for temporary (subchronic) and permanent (chronic) sacral nerve stimulation and provides a valuable means for placement of the stimulating material.

[Lesions around the rectum. Diagnosing and treatment abscesses and fistulas]. / Läsionen rund ums Rektum. Wie Sie Abszesse und Fisteln diagnostizieren und behandeln.

Anorectal abscesses and fistulas are among the most common anorectal lesions. They represent different phases of one and the same condition, the abscess being the acute manifestation, the fistula the chronic form. In the event of a strong suspicion, rapid referral to hospital, preferably one specializing in proctology, is indicated. The treatment of choice of both abscesses and fistulas is surgery. Abscesses are widely incised and decompressed. Fistulas showing signs of fresh secretion may be treated initially by the insertion of a thread, and subsequently undergo definitive surgical treatment. The surgical procedure is determined by the site of the fistula. Attendant risks include recurrence and incontinence. When fistulas occur in Crohn's disease, the indication for surgical treatment must be stringently applied. In the absence of complications, postoperative healing of the wound should be checked regularly.

[Percutaneous placement of feeding tubes for long-term nutrition and decompression. Indications, techniques and complications]. / Perkutane Sondeneinlage zur Langzeiternährung und Dekompression. Indikation, Techniken und Komplikationen.

In the recent past, PEG/PEJ has found worldwide acceptance. The uncomplicated nature of the method has resulted in a considerable increase in endoscopic gastrostomies. Provided that the method is properly applied, and appropriate aftercare is offered, complications rarely occur. In principle, the indications are chronic diseases requiring tube feeding for longer than one month, such as cachexia in patients with cancer or stenotic tumors of the mouth and throat, or of the upper gastrointestinal tract.