Search

The measurement of glycated hemoglobin (HbA1c) represents one way to detect type 1 and 2 diabetes in children at an early stage. However, to date, variations in HbA1c levels are not fully understood, even in healthy children. With this in mind, the present study aimed to establish HbA1c reference values in healthy children and to investigate the influence of various independent variables.Two thousand four hundred fifty-five healthy children and adolescents aged between 0.5 and 18 years participated in the population-based cohort study LIFE Child, Germany. Age- and gender-dependent percentiles were estimated, enabling HbA1c values to be converted into standard deviation scores (SDS). Logistic regression models were applied to assess associations between HbA1c-SDS (as outcome) and age, gender, BMI, birth weight, physical activity, pubertal status, and socioeconomic status (SES; as explanatory variables).The mean HbA1c value was 31.79 mmol/mol or 5.06% (SD = 3.3 mmol/mol, SD = 0.3%). Positive associations with HbA1c values were identified for age (b = 0.09, p 0.001), gender (b = 0.25, p = 0.007), and BMI-SDS (b = 0.06, p 0.001). In addition, obesity was related to higher HbA1c values (b = 0.29, p 0.001). Compared to prepuberty, the pubertal and postpubertal stages were associated with higher HbA1c levels. Furthermore, higher SES was associated with higher HbA1c-SDS (b = 0.01, p = 0.04).The present study established HbA1c reference values based on a large sample of healthy German children and adolescents. Age, gender, SES, pubertal stage, and BMI were found to be associated with higher HbA1c levels.

Aims We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres. Methods and results The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P Conclusions (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.

Electro-anatomical remodeling in atrial fibrillation (AF) is associated with disease initiation and progression. Troponin T (TropT) - a specific biomarker for myocardial damage - is associated with AF incidence. However, its association with AF progression is understudied. The aim of the current analysis was to investigate the association between TropT and AF progression phenotypes: persistent AF and left atrial low voltage areas (LVAs).Patients undergoing first AF ablation were included into analyses. LVAs were determined using high-density maps and defined as0.5 mV. Blood samples from femoral vein were collected before catheter ablation. The analysis of TropT serum concentrations was performed using a high-sensitive assay from Roche Diagnostics. Biomarkers, clinical, anthropometric and echocardiographic data were compared with healthy individuals from the epidemiological cohort.The study included 824 healthy individuals without overt cardiovascular disease (54 ± 10 years, 40% males) from epidemiological cohort and 241 AF patients (64 ± 11 years, 59% males, 59% persistent AF, 27% LVAs). Patients with AF had higher TropT levels and larger left atrium (LA), while healthy individuals had better renal function and ejection fraction (all p 0.001). In clinical cohort, there were significant differences between TropT levels according to AF progression groups: paroxysmal AF without/with LVAs (n = 86/12), persistent AF without/with LVAs (n = 90/53): means 7.3, 12.9, 8.4, 11.3 pg/ml, p 0.001, respectively. Similar findings were observed for LA and renal function (all p 0.001). On ROC analysis, TropT significantly predicted LVAs (AUC 0.675, 95%CI 0.598-0.752, p 0.001) in AF patients.TropT may be useful to differentiate AF progression phenotypes.

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01234220.

This study aimed to provide reliable pediatric reference values for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive Troponin T (hsTnT) obtained from a population of well children and investigate for associations with sex, pubertal status, body mass index (BMI), and serum lipid levels. We analyzed hsTnT and NT-proBNP values obtained from 4826 samples provided by 2522 children aged 0.25–18 years participating in a prospective longitudinal population-based cohort study, “LIFE child” in Leipzig, Germany (Poulain et al., Eur J Epidemiol 32:145–158, 2017). NT-proBNP values decreased throughout childhood from values over 400 ng/L at 3 months to 138 ng/L in females and 65 ng/L in males by 18 years of age. Values dropped rapidly with advancing pubertal stage. We found a strong association between lower NT-proBNP values and higher BMI or elevated serum lipids, the latter effect being more pronounced in males. For hsTnT levels, approximately half of the measurements were below the detection limit. However, 76% of those aged 3 months and 21% of those aged 6 months had values exceeding the adult cut-off limit. Females had slightly higher levels in the first 2 years of life but this was reversed during puberty. In males, there was an upward trend from pubertal stage 2 onward. We identified a positive association between hsTnT and BMI but a negative association with low-density lipoprotein (LDL) cholesterol and triglyceride levels in boys but not in girls. Based on a large number of healthy children, we have established reliable reference values for NT-proBNP and hsTnT for use in everyday clinical practice. We have also identified important associations between certain metabolic and cardiac markers.Clinical Trial Registration ClinicalTrial.gov (NCT02550236).

The majority of incidentally discovered adrenal tumors are later characterized as non-producing adrenocortical adenomas (NPA). We asked whether laboratory abnormalities in parameters that reflect glucocorticoid action can be found in patients with NPA despite their nature of being clinically unapparent. Since glucocorticoids are potent immunosuppressants we studied blood counts and differential blood counts along with corticotropin and dehydroepiandrostenedione sulfate (DHEAS) blood concentrations, as well as cortisol values before and after an overnight 1 mg dexamethasone suppression test. We compared the results of normal individuals, of patients with adrenal adenomas and normal hormone profiles and with subclinical autonomous glucocorticoid hypersecretion, as well as overt cortisol excess. We found that almost all indices of the blood counts were significantly different between the patients groups. In particular, patients with adrenal non-producing adenomas already showed signs of glucocorticoid excess, including relative lymphocytopenia, lowered DHEAS, and ACTH concentrations than control individuals. We also found that the extent of lymphocytopenia correlated with the concentrations of DHEAS and ACTH, and DHEAS correlated well with ACTH. We conclude that the basal ACTH and DHEAS values along with the differential blood counts give good information on the extent of glucocorticoid excess and that silent adrenal adenomas seem to oversecrete glucocorticoids at concentrations that already alter these parameters.

Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs. De två första författarna delar förstaförfattarskapet.

This study proposes age- and sex-specific percentiles for serum cobalamin and folate, and analyzes the effects of sex, age, body mass index (BMI), and socioeconomic status (SES) on cobalamin and folate concentrations in healthy children and adolescents. In total, 4478 serum samples provided by healthy participants (2 months-18.0 years) in the LIFE (Leipzig Research Centre for Civilization Diseases) Child population-based cohort study between 2011 and 2015 were analyzed by electrochemiluminescence immunoassay (ECLIA). Continuous age-and sex-related percentiles (2.5th, 10th, 50th, 90th, 97.5th) were estimated, applying Cole's LMS method. In both sexes, folate concentrations decreased continuously with age, whereas cobalamin concentration peaked between three and seven years of age and declined thereafter. Female sex was associated with higher concentrations of both vitamins in 13- to 18-year-olds and with higher folate levels in one- to five-year-olds. BMI was inversely correlated with concentrations of both vitamins, whilst SES positively affected folate but not cobalamin concentrations. To conclude, in the assessment of cobalamin and folate status, the age- and sex-dependent dynamic of the respective serum concentrations must be considered. While BMI is a determinant of both vitamin concentrations, SES is only associated with folate concentrations.

Context Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy. Objective This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging. Methods This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy. Results In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients. Conclusion Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.

In this experimental study we film the landings of Aedes aegypti mosquitoes to characterize landing behaviors and kinetics, limitations, and the passive physiological mechanics they employ to land on a vertical surface. A typical landing involves 1–2 bounces, reducing inbound momentum by more than half before the mosquito firmly attaches to a surface. Mosquitoes initially approach landing surfaces at 0.1–0.6 m/s, decelerating to zero velocity in approximately 5 ms at accelerations as high as 5.5 gravities. Unlike Dipteran relatives, mosquitoes do not visibly prepare for landing with leg adjustments or body pitching. Instead mosquitoes rely on damping by deforming two forelimbs and buckling of the proboscis, which also serves to distribute the impact force, lessening the potential of detection by a mammalian host. The rebound response of a landing mosquito is well-characterized by a passive mass-spring-damper model which permits the calculation of force across impact velocity. The landing force of the average mosquito in our study is approximately 40 $$\upmu$$ μ N corresponding to an impact velocity of 0.24 m/s. The substrate contact velocity which produces a force perceptible to humans, 0.42 m/s, is above 85% of experimentally observed landing speeds.

In patients suffering from multiple sclerosis (MS), intrathecal injection of triamcinolone acetonide (TCA) has been shown to improve symptoms of spasticity. Although repeated intrathecal injection of TCA has been used in a number of studies in late-stage MS patients with spinal cord involvement, no clinical-chemical data are available on the distribution of TCA in cerebrospinal fluid (CSF) or serum. Moreover, the effects of intrathecal TCA administration on the concentrations of endogenous steroids remain poorly understood. Therefore, we have quantified TCA and selected endogenous steroids in CSF and serum of TCA-treated MS patients suffering from spasticity. Concentrations of steroids were quantified by LC-MS, ELISA, or ECLIA and compared with the blood-brain barrier status, diagnosed with the Reibergram. The concentration of TCA in CSF significantly increased during each treatment cycle up to >5 μg/ml both in male and female patients (p < 0.001). Repeated TCA administration also evoked serum concentrations of TCA up to >30 ng/ml (p < 0.001) and severely depressed serum levels of cortisol and corticosterone (p < 0.001). In addition, concentrations of circulating estrogen were significantly suppressed (p < 0.001). Due to the potent suppressive effects of TCA on steroid hormone concentrations both in the brain and in the periphery, we recommend careful surveillance of adrenal function following repeated intrathecal TCA injections in MS patients.

Objective Patients with adrenal insufficiency (AI) suffer from impaired quality of life and are at risk of adrenal crisis (AC) despite established replacement therapy. Patient education is regarded an important measure for prevention of AC and improvement of AI management. A standardized education programme was elaborated for patients with chronic AI in Germany. Design Longitudinal, prospective, questionnaire-based, multi-centre study. Methods During 2-h sessions, patients (n = 526) were provided with basic knowledge on AI, equipped with emergency cards and sets and trained in self-injection of hydrocortisone. To evaluate the education programme, patients from eight certified centres completed questionnaires before, immediately after and 6–9 months after training. Results 399 completed data sets were available for analysis. Questionnaire score-values were significantly higher after patient education, indicating successful knowledge transfer (baseline: 17 ± 7.1 of a maximum score of 29; after training: 23 ± 4.2; P Conclusion Patient group education in chronic AI represents a helpful tool for the guidance of patients, their self-assurance and their knowledge on prevention of adrenal crises. Repeated training and adaptation to specific needs, for example, of older patients is needed.

Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality globally, with the burden largely borne by people living in low- and middle-income countries. Adolescents are central to NCD control through the potential to modify risks and alter the trajectory of these diseases across the life-course. However, an absence of epidemiological data has contributed to the relative exclusion of adolescents from policies and responses. This paper documents the design of a study to measure the burden of metabolic syndrome (a key risk for NCDs) and poor mental health (a key outcome) amongst Indonesian adolescents. Using a mixed-method design, we sampled 16–18-year-old adolescents from schools and community-based settings across Jakarta and South Sulawesi. Initial formative qualitative enquiry used focus group discussions to understand how young people conceptualise mental health and body weight (separately); what they perceive as determinants of these NCDs; and what responses to these NCDs should involve. These findings informed the design of a quantitative survey that adolescents self-completed electronically. Mental health was measured using the Centre for Epidemiologic Studies Depression Scale-Revised (CESD-R) and Kessler-10 (both validated against formal psychiatric interview in a subsample), with the metabolic syndrome measured using biomarkers and anthropometry. The survey also included scales relating to victimisation, connectedness, self-efficacy, body image and quality of life. Adolescents were sampled from schools using a multistage cluster design, and from the community using respondent-driven sampling (RDS). This study will substantially advance the field of NCD measurement amongst adolescents, especially in settings like Indonesia. It demonstrates that high quality, objective measurement is acceptable and feasible, including the collection of biomarkers in a school-based setting. It demonstrates how comparable data can be collected across both in-school and out of school adolescents, allowing a more comprehensive measure of NCD burden, risk and correlates.

Any surgical procedure develops a stress situation for the patient, which can modulate the individual outcome. At present, there is only limited information about stress response in colorectal resections by laparoscopic compared to conventional surgery. Therefore, our objectives were the feasibility and the investigation of stress biomarkers including copeptin and steroid hormones before, during and after colorectal surgery.Eleven patients underwent minimally invasive and ten patients conventionally open colorectal surgery. Blood samples were collected before, during and 24 h after surgery and copeptin, NT-proBNP, cortisol, cortisone, interleukin-6 and glucose were analyzed.Both, minimally invasive and conventional-open colorectal surgery caused a fast but heterogeneous response of stress biomarkers. However, the postoperative decrease of cortisol, cortisone and glucose differed between both groups. The stress biomarkers decreased faster down to baseline after minimally invasive surgery, while in open surgery cortisol, cortisone and glucose did not return to baseline within 24 h after operation.We show in this feasibility study for the first time an increase of copeptin in combination with glucocorticoids as stress biomarkers by open surgery compared to minimally invasive procedures in patients undergoing colorectal surgery. Exceeding an individual threshold of 'stress burden' may have unfavorable effects on the long-time clinical outcome.

Peptide receptor radionuclide therapy (PRRT) with lutetium-177 (Lu)-DOTATATE is regarded as a safe treatment option with promising results for patients with neuroendocrine neoplasia (NEN). We aimed to study the absorbed organ and tumor doses, the renal and hematological toxicity as well as their mutual interaction. Another aim was the identification of adverse effects as possible predictors which may affect survival.A total of 30 (14 female and 16 male) patients with inoperable/metastatic NEN were treated with 7.4 GBq of Lu-DOTATATE. Occurrence of renal and hematological toxicity wasretrospectively studied. Morever, we examined the effects of hematological toxicity on survival after Lu-DOTATATE-PRRT.In 49 treatment cycles, the mean absorbed dose to the kidneys was 5.13±2.12, 4.49±2.49 Gy to the liver, and 14.44±8.97 Gy to the spleen, whereas tumor lesions absorbed a mean dose of 31.43±36.86 Gy. Comparing different localizations of metastases, no significant differences in absorbed dose were observed. Clinical response status revealed regressive disease in 47.6%, stable disease in 38.1%, and progressive disease in 14.3% of cases (n=21). Biochemically, 81.3% of patients showed reduced serotonin values (n=16; P0.05) following Lu-DOTATATE-PRRT. No severe subacute renal or hematological toxicity occurred (one Common Terminology Criteria for Adverse Events-grade 3 for thrombocytopenia and another one for leukocytopenia). No statistically significant relation between baseline kidney function and post-therapeutic hematological changes was identified.The findings indicate that Lu-DOTATATE-PRRT is a safe and effective treatment method for patients with NEN. Moreover, these data strongly suggest that hematological parameters may affect survival so a further re-evaluation in prospective studies is warranted.

Background: Metabolically healthy obesity (MHO) refers to those individuals who do not show cardiometabolic abnormalities. Our aim was to identify potential clinical and metabolic indicators that may help to distinguish between metabolically healthy and unhealthy individuals amongst overweight and obese children and adolescents. Methods: The study involved 246 overweight/obese and 212 normal-weight individuals enrolled in the LIFE Child study, aged between 6 and 18 years. Overweight/obese individuals without cardiovascular risk factors (fasting serum lipids, blood pressure, and glucose) were classified as MHO. Individuals meeting 1 or more criteria of cardiovascular risk factors were classified as metabolically unhealthy obesity (MUO). Results: Among the 246 overweight/obese individuals, 173 (70%) were MHO and 73 (30%) were MUO. The MHO individuals were younger, more likely to be male, and had lower BMI SDS. In the logistic regression models, uric acid (UA) SDS (OR 1.61, 95% CI 1.1–2.6, p = 0.004), waist circumference SDS (OR 2.50, 95% CI 1.2–6.4, p = 0.017), and C-peptide (OR 4.05, 95% CI 3.5–91, p = 0.003) were significant indicators of MUO. Conclusion: Our results suggest that nearly one-third of overweight/obese children are already identified as MUO. Serum levels of UA can be used as an indicator of unhealthy obesity in youth, where lower levels of UA indicate a lower risk and higher levels suggest a higher risk of MUO. We note that the relevance of identifying potential indicators remains the first most important step in future clinical research.

Effectively controlling vector mosquito populations while avoiding the development of resistance remains a prevalent and increasing obstacle to integrated vector management. Although, metallic nanoparticles have previously shown promise in controlling larval populations via mechanisms which are less likely to spur resistance, the impacts of such particles on life history traits and fecundity of mosquitoes are understudied. Herein, we investigate the chemically well-defined cerium oxide nanoparticles (CNPs) and silver-doped nanoceria (AgCNPs) for larvicidal potential and effects on life history traits and fecundity of Aedes (Ae.) aegypti mosquitoes. When 3rd instar larvae were exposed to nanoceria in absence of larval food, the mortality count disclosed significant activity of AgCNPs over CNPs (57.8±3.68% and 17.2±2.81% lethality, respectively) and a comparable activity to Ag+ controls (62.8±3.60% lethality). The surviving larvae showed altered life history traits (e.g., reduced egg hatch proportion and varied sex ratios), indicating activities of these nanoceria beyond just that of a larvicide. In a separate set of experiments, impacts on oocyte growth and egg generation resulting from nanoceria-laced blood meals were studied using confocal fluorescence microscopy revealing oocytes growth-arrest at 16-24h after feeding with AgCNP-blood meals in some mosquitoes, thereby significantly reducing average egg clutch. AgCNPs caused ~60% mortality in 3rd instar larvae when larval food was absent, while CNPs yielded only ~20% mortality which contrasts with a previous report on green-synthesized nanoceria and highlights the level of detail required to accurately report and interpret such studies. Additionally, AgCNPs are estimated to contain much less silver (0.22 parts per billion, ppb) than the amount of Ag+ needed to achieve comparable larvicidal activity (2.7 parts per million, ppm), potentially making these nanoceria ecofriendly. Finally, this work is the first study to demonstrate the until-now-unappreciated impacts of nanoceria on life history traits and interference with mosquito egg development., Author summary Viral diseases like Zika and dengue fevers that are vectored by mosquitoes cause illness and death in populations worldwide. Chemical pesticides are the frontline tools used to control mosquitoes, however, development of resistance by the vectors to these agents overtime ultimately reduces effectiveness. Hence, the development of new pesticides that do not spur the development of resistance is of paramount importance. We therefore developed and characterized various types of well-defined cerium oxide nanoparticles (nanoceria) and studied the impacts on Aedes (Ae.) aegypti mosquitoes resulting from exposure to these novel agents. We found that nanoceria not only have larvicidal potential, but also alter the life history traits (e.g., reduced egg hatch proportion and altered sex ratio) of the subsequent adult mosquitoes exposed to these nanoparticles during the larval stage. One of the most interesting and important findings of our study is that exposure of female Ae. aegypti mosquitoes to nanoceria via blood meals significantly reduced egg clutches apparently via arresting oocyte growth, thereby interfering with the ultimate development and production of eggs. Thus, this study reveals until-now-unappreciated impacts of nanoceria exposure on Ae. aegypti mosquitoes and helps inform how these kinds of agents can be potentially deployed in control strategies.

Catecholamines stimulate renin-secretion in the juxtaglomerular cells of the kidney and a number of case reports suggest an association between pheochromocytoma and activation of the RAAS. Therefore, it could be asked whether patients suffering from pheochromocytoma with high concentrations of circulating catecholamines present with oversecretion of renin and aldosterone. We identified twelve patients with excessive catecholamine secretion due to pheochromocytoma and compared them to a group of twelve patients with essential hypertension (EH) with regard to the activation of the renin-angiotensin-aldosterone-system (RAAS). The PubMed database was screened for studies that investigate the association between pheochromocytoma and activation of the RAAS. The plasma concentrations of metanephrines (19.9-fold) and normetanephrines (29.5-fold) were significantly higher in the pheochromocytoma group than in the EH group. Renin and aldosterone levels were 1.3-fold and 1.6-fold higher, respectively, as compared to the EH group, whereas the differences were not statistically significant. There was no significant correlation between plasma metanephrine or normetanephrine levels and the plasma renin concentration (rs=0.077, rs=0.049, respectively) in our patients. The data from our institution and from review of literature suggest that an association between pheochromocytoma in the context of high plasma catecholamine levels and activation of the RAAS is present. However, results have not been consistent. Thus, other causes of RAAS-activation should be considered also in the presence of pheochromocytoma or reinvestigation for aldosteronism should be offered to such patients after removal of the catecholamine-producing tumour.

Essentials Acute iliofemoral deep vein thrombosis can be treated with catheter-directed thrombolysis (CDT). We performed a randomized trial comparing conventional CDT versus ultrasound-assisted CDT (USAT). Clinical and duplex sonographic outcomes at 12 months were similar in the CDT and USAT groups. In both groups, incidence of postthrombotic syndrome was very low with good quality of life.Background In patients with acute iliofemoral deep vein thrombosis (IFDVT), catheter-directed thrombolysis (CDT) aims to prevent the postthrombotic syndrome (PTS). Adding intravascular high-frequency, low-power ultrasound energy to CDT does not seem to improve the immediate thrombolysis results but its impact on clinical outcomes at 12 months is not known. Patients/Methods In this randomized-controlled trial, 48 patients (mean age 50 ± 21 years; 52% women) with acute IFDVT were randomized to conventional CDT (n = 24) or ultrasound-assisted CDT (USAT; n = 24). In both groups, a fixed-dose thrombolysis regimen (20 mg r-tPA over 15 h) was used, followed by routine stenting of residual venous obstruction. At 12 months, PTS and venous disease severity (Villalta score and revised Venous Clinical Severity Score [rVCSS]), disease-specific quality of live (QOL; CIVIQ-20) and duplex-sonographic outcomes were assessed. Results Among the 45 surviving patients, 40 (89%; 95% confidence interval [CI] 76-96%) patients were free from PTS (defined as Villalta score5 points; 83%, 95% CI 61-95% in the USAT and 96%, 95% CI 77-100% in the CDT group), with a similar mean total Villalta score of 2.3 ± 2.9 vs. 1.7 ± 1.6, and a mean total rVCSS of 3.0 ± 3.5 vs. 2.7 ± 2.9 in the USAT and the CDT groups, respectively. Both groups had good disease-specific QOL with a CIVIQ-20 score of 29.4 ± 11.8 vs. 26.1 ± 7.8, respectively. Primary (100% vs. 92%) and secondary (100% vs. 96%) iliofemoral patency rates and presence of femoro-popliteal venous reflux (39% vs. 33%) were similar in both groups. Conclusion The addition of intravascular ultrasound energy to conventional CDT for the treatment of acute IFDVT did not have any impact on relevant clinical or duplex sonographic outcomes, which were favorable in both study groups. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier:NCT01482273.

Background Office workers spend much of their time sitting, which is now understood to be a risk factor for several chronic diseases. This qualitative study examined participants’ perspectives following their involvement in a cluster randomised controlled trial of a multi-component intervention targeting prolonged workplace sitting (Stand Up Victoria). The intervention incorporated a sit-stand workstation, individual health coaching and organisational support strategies. The aim of the study was to explore the acceptability of the intervention, barriers and facilitators to reducing workplace sitting, and perceived effects of the intervention on workplace culture, productivity and health-related outcomes. Methods Semi-structured interviews (n = 21 participants) and two focus groups (n = 7) were conducted with intervention participants at the conclusion of the 12 month trial and thematic analysis was used to analyse the data. Questions covered intervention acceptability, overall impact, barriers and facilitators to reducing workplace sitting, and perceived impact on productivity and workplace culture. Results Overall, participants had positive intervention experiences, perceiving that reductions in workplace sitting were associated with improved health and well-being with limited negative impact on work performance. While sit-stand workstations appeared to be the primary drivers of change, workstation design and limited suitability of standing for some job tasks and situations were perceived as barriers to their use. Social support from team leaders and other participants was perceived to facilitate behavioural changes and a shift in norms towards increased acceptance of standing in the workplace. Conclusions Multi-component interventions to reduce workplace sitting, incorporating sit-stand workstations, are acceptable and feasible; however, supportive social and environmental conditions are required to support participant engagement. Best practice approaches to reduce workplace sitting should address the multiple levels of influence on behaviour, including factors that may act as barriers to behavioural change. Electronic supplementary material The online version of this article (doi:10.1186/s12966-017-0530-y) contains supplementary material, which is available to authorized users.

A fracture is a clinical manifestation of osteoporosis and is one of the main causes of functional limitations and chronic pain in patients with osteoporosis. Muscle and coordination training are recommended to the patients as general measures. We inquired whether sling training is better than traditional physiotherapy in relieving pain and improving abilities of daily living. Fifty patients with osteoporosis were divided into two groups. Group A performed conventional physiotherapy, while Group B performed sling training exercises. Data were collected before and after the intervention and after 3 months. The registered parameters were stamina, posture, and pain. Posture, torques, and the associated strength of spinal muscles were studied in a biomechanical model in order to estimate the forces acting on the spine. Furthermore, the factors that exerted a positive impact on the success of therapy were registered. Forty-four patients (88%) completed the study. Positive effects of the training were noted in both groups, but significantly better effects were observed in the group that performed sling training. A reduction of pain independent of the number of fractures, significantly reduced torques, and reduced muscle strength were registered. Specific training programs helped to increase muscle strength and straightening the back thereby reducing the force needed on a permanent basis and decreasing torque in the spine. Sling training was more effective in that than traditional physiotherapy.

Purpose Young men who have sex with men (YMSM) in Myanmar are disproportionately affected by HIV, with prevalence five times that of the general population. The Link Up project implemented an intervention using peer education and outreach providing education and counseling on health seeking around sexually transmitted infections and reproductive health, combined with focused clinic capacity building to improve the sexual and reproductive health of YMSM. This study aimed to evaluate the effectiveness and acceptability of the intervention. Methods Using a mixed-methods approach, and employing a quasi-experimental design, we conducted two quantitative repeat cross-sectional surveys in purposively selected control (no intervention) and intervention townships, before and after implementation of the Link Up intervention. Respondent-driven sampling was used to recruit YMSM aged 15–24 years, and study participants were administered a structured questionnaire assessing intervention exposure, health service access, knowledge of HIV, and sexual risk behavior. Focus group discussions were held to elicit perspectives on the use and acceptability of the health services and peer outreach. Results At baseline, 314 YMSM were recruited in the intervention townships and 309 YMSM in the control townships. At end line, 267 (intervention) and 318 (control) YMSM were recruited. Coverage of the program was relatively low, with one-third of participants in the intervention townships having heard of the Link Up program by the end line. Comparing changes between baseline and end line, a greater proportion of HIV-negative or unknown status YMSM accessed HIV testing in the past 3 months in intervention townships (from 45.0% to 57.1%) compared with those in control townships (remained at 29.0%); however, this difference in the effect over time was not statistically significant in multivariate modeling (adjusted odds ratio: 1.45; 95% confidence interval: .66–3.17). Qualitative findings showed that the intervention was acceptable to YMSM. Conclusions Overall, the intervention was perceived as acceptable. Although not statistically significant, results showed some trends toward improvements among YMSM in accessing HIV testing services and HIV-related knowledge. The modest coverage and short time frame of the evaluation likely limits the ability for any significant behavioral improvements.

Item does not contain fulltext BACKGROUND: Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome. METHODS: The Primary Aldosteronism Surgical Outcome (PASO) study was an international project to develop consensus criteria for outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism. An international panel of 31 experts from 28 centres, including six endocrine surgeons, used the Delphi method to reach consensus. We then retrospectively analysed follow-up data from prospective cohorts for outcome assessment of patients diagnosed with unilateral primary aldosteronism by adrenal venous sampling who had undergone a total adrenalectomy, consecutively included from 12 referral centres in nine countries. On the basis of standardised criteria, we determined the proportions of patients achieving complete, partial, or absent clinical and biochemical success in accordance with the consensus. We then used logistic regression analyses to identify preoperative factors associated with clinical and biochemical outcomes. FINDINGS: Consensus was reached for criteria for six outcomes (complete, partial, and absent success of clinical and biochemical outcomes) based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin concentrations or activities. Consensus was also reached for two recommendations for the timing of follow-up assessment. For the international cohort analysis, we analysed clinical data from 705 patients recruited between 1994 and 2015, of whom 699 also had biochemical data. Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients. Female patients had a higher likelihood of complete clinical success (odds ratio [OR] 2.25, 95% CI 1.40-3.62; p=0.001) and clinical benefit (complete plus partial clinical success; OR 2.89, 1.49-5.59; p=0.002) than male patients. Younger patients had a higher likelihood of complete clinical success (OR 0.95 per extra year, 0.93-0.98; p

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men ( P P =0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications ( P P The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01234220.

BackgroundSleep disorders and vitamin D deficiency are among the most common health problems. Few studies investigated the effect of vitamin D on objectively recorded sleep with sound methodological quality and reasonable temporal proximity.ObjectiveTo investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) concentrations and objective sleep parameters assessed within close temporal proximity in a population-based sample. It is expected that higher serum 25(OH)D concentrations are associated with 1) better objective sleep outcomes (longer sleep duration, higher sleep efficiency, earlier mid-sleep time) and 2) more positive subjective sleep evaluations.MethodsA subset of participants (n = 1045) from the LIFE-Adult-Study was analysed. Measurement of serum 25(OH)D vitamin was performed using an electrochemiluminescence immunoassay. Actigraphic assessments were performed using SenseWear Pro 3 devices. The following objective sleep parameters were calculated: total sleep duration, night sleep duration, night sleep efficiency, midsleep time and wake after sleep onset (WASO). Subjective sleep evaluations were assessed via questionnaire (sleep quality (PSQI), daytime sleepiness (ESS)). Data were analysed applying a multiple linear regression model with a stepwise approach.ResultsThe regression models revealed significant associations of serum 25(OH)D concentration with night sleep duration and midsleep time. No association was found for total sleep duration and night sleep efficiency. Higher serum 25(OH)D concentration was further associated with shorter WASO in males but longer WASO in females. Moreover, serum 25(OH)D concentration did not show any significant association with subjective sleep quality and daytime sleepiness.ConclusionThe results indicate that a higher concentration of serum 25(OH)D is associated with longer and earlier night sleep. Although the present study was able to demonstrate an association between serum 25(OH)D concentration and objective sleep parameters, no conclusion about underlying mechanisms or causal inferences can be drawn.

Lipoprotein apheresis reliably reduces low-density lipoprotein (LDL) cholesterol in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). Besides lowering lipoproteins and triglycerides, apheresis also decreases levels of essential omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) in blood plasma. In contrast, heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) lipid apheresis might increase the formation of potentially pro-inflammatory and pro-thrombotic lipid mediators derived from n-6 and n-3 PUFAs. The study presented here analyzed lipid mediator profiles in the plasma of patients with hyperlipidemia treated by one of three different apheresis methods, either HELP, direct absorption (DA), or membrane filtration (MDF), in a direct pre- and post-apheresis comparison. Using gas chromatography and liquid chromatography tandem mass spectrometry (LC-MS/MS) we were able to analyze fatty acid composition and the formation of lipid mediators called oxylipins. Our data illustrate—particularly in HELP-treated patients—significant decreases of essential omega-6 and omega-3 polyunsaturated fatty acids in blood plasma but significant increases of PUFA-derived lipoxygenase-, as well as cyclooxygenase- and cytochrome P450-derived lipid mediators. Given that n-3 PUFAs in particular are presumed to be cardioprotective and n-3 PUFA-derived lipid mediators might limit inflammatory reactions, these data indicate that n-3 PUFA supplementation in the context of lipid apheresis treatment might have additional benefits through apheresis-triggered protective n-3 PUFA-derived lipid mediators.

This study aimed to evaluate the initial and long-term effectiveness of a workplace intervention compared with usual practice, targeting the reduction of sitting on activity outcomes.Office worksites (≥1 km apart) from a single organization in Victoria, Australia, were cluster randomized to intervention (n = 7) or control (n = 7). Participants were 231 desk-based office workers (5-39 participants per worksite) working at least 0.6 full-time equivalent. The workplace-delivered intervention addressed organizational, physical environment, and individual behavioral changes to reduce sitting time. Assessments occurred at baseline, 3 months, and 12 months, with the primary outcome participants' objectively measured (activPAL3 device) workplace sitting time (minutes per 8-h workday). Secondary activity outcomes were workplace time spent standing, stepping (light, moderate to vigorous, and total), and in prolonged (≥30 min) sitting bouts (hours per 8-h workday); usual duration of workplace sitting bouts; and overall sitting, standing, and stepping time (minutes per 16-h day). Analysis was by linear mixed models, accounting for repeated-measures and clustering and adjusting for baseline values and potential confounders.At baseline, on average, participants (68% women; mean ± SD age = 45.6 ± 9.4 yr) sat, stood, and stepped for 78.8% ± 9.5%, 14.3% ± 8.2%, and 6.9% ± 2.9% of work hours, respectively. Workplace sitting time was significantly reduced in the intervention group compared with the controls at 3 months (-99.1 [95% confidence interval = -116.3 to -81.8] min per 8-h workday) and 12 months (-45.4 [-64.6 to -26.2] min per 8-h workday). Significant intervention effects (all favoring intervention) were observed for standing, prolonged sitting, and usual sitting bout duration at work, as well as overall sitting and standing time, with no significant or meaningful effects observed for stepping.This workplace-delivered multicomponent intervention was successful at reducing workplace and overall daily sitting time in both the short term and the long term.

Context: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Aldosterone excess can cause DNA damage in vitro and in vivo. Single case reports have indicated a coincidence of PA with renal cell carcinoma and other tumors. However, the prevalence of benign and malignant neoplasms in patients with PA has not yet been studied. Patients and Design: In the multicenter MEPHISTO study, the prevalence of benign and malignant tumors was investigated in 335 patients with confirmed PA. Matched hypertensive subjects from the population-based Study of Health in Pomerania cohort served as controls. Results: Of the 335 PA patients, 119 (35.5%) had been diagnosed with a tumor at any time, and 30 had two or more neoplasms. Lifetime malignancy occurrence was reported in 9.6% of PA patients compared to 6.0% of hypertensive controls (P = .08). PA patients with a history of malignancy had higher baseline aldosterone levels at diagnosis of PA (P = .009), and a strong association between aldosterone levels and the prevalence of malignancies was observed (P = .03). In total, 157 neoplasms were identified in the PA patients; they were benign in 61% and malignant in 25% of the cases (14% of unknown dignity). Renal cell carcinoma was diagnosed in five patients (13% of all malignancies) and was not reported in controls. Conclusion: Compared to hypertensive controls, the prevalence of malignancies was positively correlated with aldosterone levels, tended to be higher in PA patients, but did not differ significantly.

DesignAbnormalities in glucose homeostasis have been described in patients with primary aldosteronism (PA) but most studies show inconsistent results. Therefore, we aimed to compare the prevalence of type 2 diabetes mellitus and metabolic syndrome (MetS) in newly diagnosed PA patients to a matched control cohort of the background population.MethodsIn total, 305 PA patients of the prospective German Conn's Registry were compared to the population-based Study of Health In Pomerania (SHIP1;n=2454). A 1:1 match regarding sex, age, and BMI resulted in 269 matched pairs regarding type 2 diabetes and 183 matched pairs regarding MetS. Of the total, 153 PA patients underwent oral glucose tolerance testing (OGTT) at diagnosis and 38 PA patients were reevaluated at follow-up.ResultsType 2 diabetes and MetS were significantly more frequent in PA patients than in the control population (17.2% vs 10.4%,P=0.03; 56.8% vs 44.8%,P=0.02 respectively). Also, HbA1c levels were higher in PA patients than in controls (PP=0.01) at follow-up. We detected a negative correlation between 2 h OGTT glucose levels and serum potassium (PConclusionsType 2 diabetes and MetS are more prevalent in patients with PA than in controls matched for sex, age, BMI, and blood pressure. This may explain in part the increased cardiovascular disease morbidity and mortality in PA patients.

Background This study aimed to culturally verify and examine the empirical psychometric properties of the Indonesian versions of the Centre for Epidemiologic Studies Depression Scale – Revised (CESD-R), the Kessler Psychological Distress Scale – 10 items (K10) and a subset of 6 items of the K10, the K6 to detect depressive and anxiety disorders among older adolescents in Indonesia. Methods The empirical psychometric properties were examined formally among students aged 16–18 years attending high schools in Jakarta. The scales were validated against the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-Kid) modules for major depressive episode, dysthymia, panic disorder, separation anxiety disorder, and generalized anxiety disorder. Results In total, 196 students contributed complete data. All of the scales had Cronbach's alpha >0.8. The areas under the ROC Curve of CESD-R against MINI depressive disorders and K10/K6 against MINI depressive and anxiety disorders were at moderate to high accuracy levels (0.78 to 0.86). The optimal cut-off value of CESD-R (scores ranging: 0–60) to screen for any depressive disorder is ≥20 (sensitivity 75.0%; specificity 79.9%). The optimal cut-off value of K10 to detect any depressive/anxiety disorders is ≥18 (sensitivity 85.7%; specificity 74.7%); and K6 is ≥12 (sensitivity 81.0%; specificity 76.6%); Limitations The school-based sample limits the generalisability of the findings to this group. Conclusions This study suggests that the CESD-R I is a useful tool for screening for depressive disorders and both the K10 I and K6 I are useful for screening for any depressive or anxiety disorders among Indonesian adolescents.

Background This study aims to establish age- and gender-specific cystatin C (CysC) reference values for healthy infants, children, and adolescents and to relate them to pubertal stage, height, weight, and body mass index (BMI). Methods Serum CysC and creatinine levels of 6217 fasting, morning venous blood samples from 2803 healthy participants of the LIFE Child study (age 3 months to 18 years) were analyzed by an immunoassay. Recruitment started in 2011; 1636 participants provided at least one follow-up measurement. Percentiles for CysC were calculated. Age- and gender-related effects of height, weight, BMI, and puberty status were assessed through linear regression models. Results Over the first 2 years of life, median CysC levels decrease depending on height (ß = − 0.010 mg/l/cm, p

OBJECTIVES: This study aimed to assess the economic credentials of a workplace-delivered intervention to reduce sitting time among desk-based workers. METHODS: We performed within-trial cost-efficacy analysis and long-term cost-effectiveness analysis (CEA) and recruited 231 desk-based workers, aged 24–65 years, across 14 worksites of one organization. Multicomponent workplace-delivered intervention was compared to usual practice. Main outcome measures including total device-measured workplace sitting time, body mass index (BMI), self-reported health-related quality of life (Assessment of Quality of Life-8D, AQoL-8D), and absenteeism measured at 12 months. RESULTS: Compared to usual practice, the intervention was associated with greater cost (AU$431/person), benefits in terms of reduced workplace sitting time [-46.8 minutes/8-hour workday, 95% confidence interval (CI): -69.9– -23.7] and increased workplace standing time (42.2 minutes/8-hour workday, 95% CI 23.8–60.6). However, there were no significant benefits for BMI [0.148 kg/m^2 (95% CI-1.407–1.703)], QoL-8D [-0.006 (95% CI -0.074–0.063)] and absenteeism [2.12 days (95% CI -2.01–6.26)]. The incremental cost-efficacy ratios (ICER) ranged from AU$9.94 cost/minute reduction in workplace sitting time to AU$13.37/minute reduction in overall sitting time. CEA showed the intervention contributed to higher life year (LY) gains [0.01 (95% CI 0.009–0.011)], higher health-adjusted life year (HALY) gains [0.012 (95% CI 0.0105 – 0.0135)], and higher net costs [AU$344 (95% CI $331–358)], with corresponding ICER of AU$34 443/LY and AU$28 703/HALY if the intervention effects were to be sustained for five-years. CEA results were sensitive to assumptions surrounding intervention-effect decay rate and discount rate. CONCLUSIONS: The intervention was cost-effective over the lifetime of the cohort when scaled up to the national workforce and provides important

The SHINE home injection service is part of a patient support program run by Novartis. SHINE is for people prescribed octreotide long-acting release (Sandostatin LAR) for neuroendocrine tumours (NETs) and acromegaly. SHINE has been running in Australia since 2009. The service is run by a third-party and administered by homecare (SHINE) nurses. Five hundred people with NETs or acromegaly have been involved since the service started. We review our collective experience of the benefits of SHINE, and make recommendations for future development. We hope this review provides guidance for developing future home injection service.

Introduction The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI). Methods In this double-blind, randomized controlled trial, 60 elderly participants (60–79 years) with a wide body-mass index (BMI) range of 21–37 kg/m2 were randomized to receive either resveratrol (200 mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7 T, and questionnaires to assess confounding factors. Results Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p = 0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1 at follow-up, which were partly more pronounced after resveratrol. Discussion This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.

Tocotrienols, a vitamin E subgroup, exert potent anticancer effects, but easily degrade due to oxidation. Eight vitamin E reference compounds, α-, β-, γ-, or δ-tocopherols or -tocotrienols, were thermally oxidized in n-hexane. The corresponding predominantly dimeric oxidation products were separated from the parent compounds by diol-modified normal-phase HPLC-UV and characterized by mass spectroscopy. The composition of test compounds, that is, α-tocotrienol, γ-tocotrienol, or palm tocotrienol-rich fraction (TRF), before and after thermal oxidation was determined by HPLC-DAD, and MCF-7 cells were treated with both nonoxidized and oxidized test compounds for 72 h. Whereas all nonoxidized test compounds (0-100 μM) led to dose-dependent decreases in cell viability, equimolar oxidized α-tocotrienol had a weaker effect, and oxidized TRF had no such effect. However, the IC50 value of oxidized γ-tocotrienol was lower (85 μM) than that of nonoxidized γ-tocotrienol (134 μM), thereby suggesting that γ-tocotrienol oxidation products are able to reduce tumor cell viability in vitro.

Background: Many patients present to emergency departments (EDs) with an altered state of consciousness. Fast exclusion of gamma hydroxybutyrate (GHB)-associated intoxication in these patients may optimize diagnostic and therapeutic algorithms and decisions in the ED. Methods: Between January and March 2014, a novel enzymatic test system was used to quantify GHB in blood and urine samples of suspected intoxicated patients in the ED of the University Hospital. The underlying causes for suspected intoxication and the diagnostic and therapeutic measures were documented and analysed retrospectively. Results: GHB measurements were performed in 13 patients with suspected ingestion during a 3-month study period. GHB was positive in six patients showing serum levels between 61.8 mg/l and 254.8 mg/l, and GHB was tested negative in seven patients with a range of 0.3–6.2 mg/l (upper reference limit 6.1 mg/l). Additional intoxication was found in five of six GHB positive (83%, alcohol n = 2 and other drugs n = 5) and in six of seven negative-tested patients (86%, alcohol n = 5 and other drugs n = 1). Conclusion: GHB quantification in the ED provides specific additional information for intoxication, which can lead to more precise diagnostic and therapeutic decisions and may also be important for legal aspects. We believe that GHB analysis in unconscious patients with suspected intoxication may improve the efficient treatment of intoxicated patients.

Background Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. Methods Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65 ± 7 years) and 18 healthy control subjects (44% men, 57 ± 7 years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CV I ) and between-subject (CV G ) coefficients of variation and intra-class correlation coefficient (ICC). Results Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls ( P ≤ .05 for all). CV I and CV G of the different biomarkers varied considerably in both groups. An ICC ≥ 0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. Conclusions Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

BackgroundReports conflict concerning measurements of plasma metanephrines (MNs) for diagnosis of pheochromocytomas/paragangliomas (PPGLs) by immunoassays compared with other methods. We aimed to compare the performance of a commercially available enzyme-linked immunoassay (EIA) kit with liquid chromatography–tandem mass spectrometric (LC–MS/MS) measurements of MNs to diagnose PPGLs.MethodsIn a substudy of a prospective, multicenter trial to study the biochemical profiles of monoamine-producing tumors, we included 341 patients (174 males and 167 females) with suspected PPGLs (median age 54 years), of whom 54 had confirmed PPGLs. Plasma MNs were measured by EIA and LC–MS/MS, each in a specialized laboratory.ResultsPlasma normetanephrine (NMN) and MN were measured 60 and 39% lower by EIA than by LC–MS/MS. Using upper cut-offs stipulated for the EIA, diagnostic sensitivity was only 74.1% at a specificity of 99.3%. In contrast, use of similar cut-offs for MN and overall lower age-adjusted cut-offs for NMN measured by LC–MS/MS returned a diagnostic sensitivity and specificity of 98.1 and 99.7%. Areas under receiver-operating characteristic curves, nevertheless, indicated comparable diagnostic performance of the EIA (0.993) and LC–MS/MS (0.985). Diagnostic sensitivity for the EIA increased to 96.2% with a minimal loss in specificity (95.1%) following use of cut-offs for the EIA adapted to correct for the negative bias.ConclusionsThe EIA underestimates plasma MNs and diagnostic sensitivity is poor using commonly stipulated cut-offs, resulting in a high risk for missing patients with PPGLs. Correction of this shortcoming can be achieved by appropriately determined cut-offs resulting in comparable diagnostic performance of EIA and LC–MS/MS assays.

Pharmacological inhibition of mineralocorticoid receptor (MR) signaling in patients with primary aldosteronism (PA) reestablishes aldosterone synthesis by nondiseased zona glomerulosa cells through activation of the renin-angiotensin-aldosterone system. In this context, current guidelines recommend discontinuing MR blockade for diagnostic procedures, including adrenal vein sampling (AVS). Discontinuation of MR blockade in high-risk patients may be harmful because of uncontrolled hypertension and severe hypokalemia. We hypothesize that MR antagonist therapy can be continued during AVS as long as renin levels remain suppressed.The objective of this study was to assess the validity of AVS results in the context of MR antagonistic therapy.We retrospectively analyzed all AVS studies in Munich (since 2008) and Düsseldorf (since 2011) and identified four of 237 (1.7%) patients with PA who underwent AVS while treated with an MR antagonist. Adrenalectomy was recommended based on the results of AVS in all four patients. After adrenalectomy, follow-up data were obtained to confirm improvement or remission of PA. Main outcome measures included blood pressure values, daily defined doses of antihypertensive medication, as well as levels of aldosterone, renin, and potassium, and the aldosterone/renin ratio.In all patients, renin remained low or suppressed during AVS despite MR antagonist treatment. AVS clearly demonstrated unilateral aldosterone excess in each case. After adrenalectomy, all patients showed remission of PA as demonstrated by blood pressure values, potassium levels, and the aldosterone/renin ratio.In selected cases of PA, MR antagonist therapy might be continued during AVS, provided that renin values remain low.

Background Obesity is a risk factor for chronic venous insufficiency and venous thromboembolism. The aim of this study was to compare venous flow parameters of the lower limbs assessed by duplex ultrasound scanning in obese and nonobese individuals according to body mass index (BMI). Methods Venous hemodynamics were studied in a prospective cohort study in nonobese (BMI 2 ) and obese individuals (BMI >30 kg/m 2 ). Diameter, flow volume, peak, mean, and minimum velocities were assessed. Results The study examined 36 limbs in 23 nonobese individuals and 44 limbs in 22 obese individuals. The diameter of the femoral vein was significantly greater in obese (8.5 ± 2.2 mm) vs nonobese (7.1 ± 1.6 mm; P = .0009) limbs. Venous peak and minimum velocities differed between nonobese and obese individuals (14.8 ± 7.2 vs 10.8 ± 4.8 cm/s [ P = .0071] and 4.0 ± 3.6 vs 1.7 ± 6.3 cm/s [ P = .056]). Calculation of venous amplitude and shear stress showed significantly higher values in nonobese vs obese (18.8 ± 9.4 vs 12.5 ± 9.3 cm/s [ P = .003] and 2.13 ± 2.2 dyn/cm 2 vs 1.6 ± 2.7 dyn/cm 2 [ P = .03]). Spearman rank correlation revealed a significant inverse correlation between waist-to-hip ratios and waist circumference and venous peak velocity, mean velocity, velocities amplitude (peak velocity-minimum velocity), and shear stress. Conclusion Lower limb venous flow parameters differ significantly between healthy obese and nonobese individuals. These findings support the mechanical role of abdominal adipose tissue potentially leading to elevated risk for both venous thromboembolism and chronic venous insufficiency.

ObjectivePlatinum-based chemotherapy (PBC) is the most effective cytotoxic treatment for advanced adrenocortical carcinoma (ACC). Excision repair cross complementing group 1 (ERCC1) plays a critical role in the repair of platinum-induced DNA damage. Two studies investigating the role of ERCC1 immunostaining as a predictive marker for the response to PBC in ACC had reported conflicting results. Both studies used the ERCC1-antibody clone 8F1 that later turned out to be not specific. The aim of this study was to evaluate the predictive role of ERCC1 with a new specific antibody in a larger series of ACC.Design and methods146 ACC patients with available FFPE slides were investigated. All patients underwent PBC (median cycles = 6), including cisplatin (n = 131) or carboplatin (n = 15), in most cases combined with etoposide (n = 144), doxorubicin (n = 131) and mitotane (n = 131). Immunostaining was performed with the novel ERCC1-antibody clone 4F9. The relationship between ERCC1 expression and clinicopathological parameters, as well as best objective response to therapy and progression-free survival (PFS) during PBC was evaluated.ResultsHigh ERCC1 expression was observed in 66% of ACC samples. During PBC, 43 patients experienced objective response (29.5%), 49 stable disease (33.6%), 8 mixed response (5.5%) and 46 progressive disease (31.5%) without any relationship with the ERCC1 immunostaining. No significant correlation was also found between ERCC1 expression and progression-free survival (median 6.5 vs 6 months,P = 0.33, HR = 1.23, 95% CI = 0.82–2.0).ConclusionERCC1 expression is not directly associated with sensitivity to PBC in ACC. Thus, other predictive biomarkers are required to support treatment decisions in patients with ACC.

The development of parasitic nematodes proceeds via multiple stages, often implicating the necessity to adapt to different environments. Especially the transition from free-living to parasitic stages is accompanied by a significant change in the environmental conditions. To shed light on possible adaptations to these transitions, the fatty acid composition of different developmental stages of the bovine lungworm Dictyocaulus viviparus was investigated. Fatty acids of D. viviparus eggs, the free-living first, second and third larval stage (L1-L3) as well as the parasitic preadult stage and adult male and female worms residing in the lungs of infected hosts were quantified by gas chromatography after transesterification to their fatty acid methyl esters. The fatty acid content and diversity were higher in parasitic stages compared to those of free-living larvae. The most prevalent fatty acids in both parasitic and free-living stages were stearic (C18:0), palmitic (C16:0), palmitoleic (C16:1) and caprylic acid (C8:0). A variety of (poly-)unsaturated FAs was found in the parasitic stages and in the eggs, which was similar to the variety of FAs found in bovine surfactant. This finding indicates that parasitic stages of D. viviparus take up FAs from their environment. While eggs contained the highest concentration of fatty acids, a decrease was observed from eggs to L1 and further from L2 to L3. The lowest concentration was found in 38-days-old L3, which suggests that FAs serve as an energy reserve for the free-living, non-feeding larval stages. The free-living larvae contained mainly saturated fatty acids and only traces of unsaturated fatty acids, which is in contrast to the phospholipid saturation hypothesis of cold tolerance. Instead, a trade-off between desiccation stress and temperature adaptation may favour a higher amount of saturated FAs in the free-living larval stages. Further studies explicitly examining the FA composition of the different classes of lipids are necessary to better describe the adaptative responses of the FA metabolism to different environmental conditions.

Introduction Biomedical research towards an HIV cure is advancing in the United States and elsewhere, yet little is known about perceptions of risks and benefits among potential study participants and other stakeholders. We conducted a qualitative study to explore perceived risks and benefits of investigational HIV cure research among people living with HIV (PLWHIV), biomedical HIV cure researchers, policy-makers and bioethicists. Methods We conducted a qualitative research study using in-depth interviews with a purposive sample of PLWHIV, biomedical HIV cure researchers, policy-makers and bioethicists in 2015–2016. We analysed interview transcripts using thematic analysis anchored in grounded theory. Results We conducted and analyzed 36 key informant interviews. Qualitative analysis revealed four main findings. 1) Potential HIV cure study volunteers noted needing more information and education about the potential risks of HIV cure research. 2) Biomedical HIV cure researchers, policy-makers and bioethicists showed less awareness of social and financial risks of HIV cure research than PLWHIV. 3) Most respondents across the different categories of informants identified some risks that were too great to be acceptable in HIV cure research, although a subset of PLWHIV did not place an upper limit on acceptable risk. 4) PLWHIV showed a better awareness of potential psychological benefits of participating in HIV cure research than other groups of stakeholders. Conclusion Our research suggests that PLWHIV have a variable understanding of the individual risks, sometimes substantial, associated with participating in biomedical HIV cure research studies. Community engagement and increased research literacy may help improve community understanding. Intensive informed consent procedures will be necessary for ethical study implementation. The current state of HIV cure research offers greater potential benefits to society than to participants. There is likely to be disagreement among regulators, researchers, clinicians, and potential participants about what constitutes acceptable risk for HIV cure studies.

ContextThe Li–Fraumeni tumor syndrome is strongly associated with adrenocortical carcinoma (ACC) and is caused by germline mutations in TP53 in 70% of cases. Also, TP53 polymorphisms have been shown to influence both cancer risk and clinical outcome in several tumor entities. We, therefore, investigated TP53 polymorphisms in a cohort of adult patients with ACC.ObjectiveEvaluation of the role of TP53 polymorphisms in adult patients with ACC.Subjects and methodsPeripheral blood for DNA extraction was collected from 72 ACC patients. Polymorphism analysis was carried out by amplification and sequencing of exons and adjacent intron sections of TP53. Results were correlated with clinical data and the distribution of the polymorphisms was compared with published Caucasian control groups.ResultsCompared with control groups, genotype frequencies of analyzed TP53 polymorphisms among ACC patients were significantly different in three out of four polymorphisms: IVS2+38G>C (G/G, P=0.0248), IVS3ins16 (NoIns/NoIns, PPG (G/G, PPn=23), was significantly inferior (median survival: 81.0 months in patients with the common homozygous genotypes vs 20.0 months in patients with the less frequent genotypes, HR 2.56, 95% CI 1.66–7.07; P=0.001). These results were confirmed by multivariable regression analysis (HR 2.84, 95% CI 1.52–7.17; P=0.037).ConclusionSome TP53 polymorphisms seem to influence overall survival in ACC patients. This effect was observed for a combination of polymorphic changes rather than for single polymorphisms.

PURPOSE To assess the extent of early recoil in patients with critical limb ischemia (CLI) undergoing conventional tibial balloon angioplasty. METHODS Our hypothesis was that early recoil, defined as lumen compromise >10%, is frequent and accounts for considerable luminal narrowing after tibial angioplasty, promoting restenosis. To test this theory, 30 consecutive CLI patients (18 men; mean age 76.2±12.1 years) were angiographically evaluated immediately after tibial balloon angioplasty and 15 minutes later. Half the patients were diabetics. Target lesions included anterior and posterior tibial arteries and the peroneal artery with / without the tibioperoneal trunk. Mean tibial lesion length was 83.8 mm. Early elastic recoil was determined on the basis of minimal lumen diameter (MLD) measurements at baseline (MLDbaseline), immediately after tibial balloon angioplasty (MLDpostdilation), and 15 minutes thereafter (MLD15min). RESULTS Elastic recoil was observed in 29 (97%) patients with a mean luminal compromise of 29% according to MLD measurements (MLDbaseline 0.23 mm, MLD postdilation 2.0 mm, and MLD15min 1.47 mm). CONCLUSION Early recoil is frequently observed in CLI patients undergoing tibial angioplasty and may significantly contribute to restenosis. These findings support the role of dedicated mechanical scaffolding approaches for the prevention of restenosis in tibial arteries.

Aim This cross-sectional study was repeated at two time points and investigated the influence of gingivitis, smoking and body mass index (BMI) on the systemic inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL6) in 10- and 15-year-olds. Materials and Methods The study sample of two birth cohorts, i.e. GINIplus and LISAplus, from the Munich centre consisted of 806 and 846 subjects who were evaluated at 10- and 15-year follow-ups respectively. Children and their parents completed questionnaires on participant-related lifestyle information. Gingivitis was measured at the sextant level using a simplified sulcus-bleeding index. Serum hs-CRP and IL6 levels were obtained from blood samples. Multiple logistic regressions adjusting for lifestyle-related factors and other confounders were performed to assess associations between the specified variables. Results There were no associations between gingivitis and the inflammatory markers hs-CRP and IL6 in 10-year-olds. In 15-year-olds, gingivitis (aOR: 2.17; 95% CI: 1.25–3.77); daily smoking (aOR: 6.27; 95% CI: 1.39–28.39); and being overweight/obese (aOR: 4.95; 95% CI: 0.73–33.68) were identified as significantly influencing factors for elevated hs-CRP values. Oral hygiene did not influence hs-CRP. Conclusion In this study, hs-CRP was positively associated with gingivitis, smoking daily and overweight/obesity among 15-year-olds.

Obesity is a risk factor for chronic venous disease. However, the mechanisms behind this association are poorly understood. We tested the hypothesis that obese subjects have a higher diurnal leg volume increase compared with non-obese subjects.In this prospective cohort study including obese (body mass index, BMI ≥30 kg m(-)(2)) and non-obese (BMI ≤25 kg m(-)(2)) subjects without venous insufficiency, lower leg volume was assessed by optoelectronic volumetry in the morning and in the evening. All subjects underwent duplex ultrasound and light reflection rheography (venous pump power and venous refill time, VRT) to investigate lower extremity venous function. A pedometer was carried between the morning and evening visit to assess the daily number of footsteps. A backward multivariable linear regression model was used to determine factors associated with diurnal lower leg volume increase.Forty-two limbs in 24 obese subjects and 29 limbs in 15 non-obese subjects were analyzed. Obese subjects had larger common femoral vein diameters (17.1±2.4 vs 15.5±2.4 mm, P0.01) and slower peak, mean and minimal velocities (25.1±10.6 vs 44.3±14.3 cm s(-1); 6.8±2.4 vs 12.7±5.6 cm s(-1); -0.2±6.4 vs -6.3±11.9 cm s(-1); P0.01 for all) than non-obese subjects. VRT was shorter in obese subjects (40.5±15.0 vs 51.0±12.1 s, P0.01) and decreased significantly in the course of the day only in obese subjects (P0.01). Obesity, male gender, CEAP (Clinical-Etiology-Anatomy-Pathophysiology) class, total time between the two visits and difference between morning and evening VRT were positively associated with higher lower leg volume increase; morning VRT and the total number of footsteps showed a negative association (P0.04 for all).Obesity was found to be an independent predictor of higher diurnal leg volume increase. One potential mechanism is a progressive failure of venous valve function in the course of the day in obese subjects.