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Background: Chronic kidney disease (CKD) and coronary artery disease (CAD) are strongly associated. CAD is the most frequent cause of cardiovascular death in patients with CKD., Methods: The prospective observational nationwide multicenter Coronary Artery Disease and REnal Failure (CAD-REF) Registry enrolled 3352 patients with angiographically documented CAD classified according to their baseline estimated glomerular filtration rate (eGFR) into 5 groups according to the K/DOQI-guidelines. Patients were followed for two years. The aim of this study was the analysis of outcome and the identification of risk factors for two-year mortality in patients with both CKD and CAD., Results: With decreasing renal function, patients had more often diabetes mellitus, hypertension, peripheral artery disease, and previous cardiovascular events and interventions. The amount of diseased vessels increased with decreasing renal function. For the whole cohort, two-year mortality was 6.5%. Kaplan-Meier-curves showed highest mortality in patients with CKD stages 4 and 5 (22.4%). In multivariate Cox-regression analyses, significant risk factors for two-year all-cause mortality were lower eGFR, current smoking, left ventricular ejection fraction, diabetes mellitus treated with oral medication or insulin, age, and peripheral artery disease. Coronary status missed the level of statistical significance as a risk factor for mortality in multivariable regression analysis. An eGFR reduction of 10ml/min/1.73m 2 increased the risk of mortality by 19% regardless of other risk factors., Conclusions: Two-year morbidity and mortality increased with the degree of renal impairment. To improve survival of patients with CAD and CKD, nephroprotection is urgently needed especially for patients with atherosclerotic burden., Clinical Trial Registration Number: NCT00679419, http://clinicaltrials.gov/., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The objective of the study was to examine the educational exposure during residency in Danish orthopedic departments., Design: Questionnaire-based cross-sectional study., Setting: Data were gathered from January 1, 2014 to April 30, 2014 through a nationwide web-based questionnaire containing 15 questions within the areas of workload, surgical procedures, outpatient clinic, and research activities. The residents targeted worked at small-to-large hospitals and in tertiary care centers., Participants: Every resident in Denmark (n = 163) with at least 3 active months at a department was included. Questionnaires with less than 80% completion were excluded. In total, 152 entries were registered. Among those, 27 did not meet the inclusion criteria and 29 were excluded, leaving 96 participants, representing 22 of 26 departments, for further analysis., Results: The average number of operative procedures as primary surgeon was 16 (range: 8-35) per month. In all, 18 of 22 (81%) departments offered the possibility to participate in research facilitated by the department and 38 of 96 (40%) worked for free (an average of 10h a month [range: 3-60]) to increase the amount of surgical procedures., Conclusions: A large variation in the educational exposure was found among the Danish orthopedic departments. Numbers indicate that Danish residents, compared with their US counterparts, operate considerably less during residency. Most residents work overtime and many of them work for free to participate in more surgical procedures., (Copyright © 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Copeptin has turned out to give valuable prognostic information for future cardiovascular events. However, since its plasma concentration directly depends on renal function, the value of copeptin as a predictor for outcome also in patients with chronic kidney disease (CKD) is unknown., Methods: In this single-center substudy of the German Coronary Artery Disease-REnal Failure (CAD-REF) registry, 301 patients with an angiographically diagnosed stenosis ≥50% in at least one major coronary vessel were included. Estimated glomerular filtration rate (eGFR) was determined using the MDRD formula and patients were classified according to their CKD stage. Copeptin concentrations were measured before initial angiography. Follow-up was performed at 180days, study endpoint was all-cause mortality., Results: Of the 301 included patients, 35 (11.6%) patients had no CKD, 113 (37.5%) had CKD stage 1 or 2, 117 (38.9%) had CKD stage 3, and 36 (12.0%) had CKD stage 4 or 5. Copeptin was elevated (≥14pmol/L) in 81 (26.9%) patients and normal (<14pmol/L) in 220 (73.1%) patients. Copeptin values significantly increased with decreasing eGFR (p<0.001) and were strongly correlated with creatinine values (r=0.567, p<0.001). During 180days of follow-up, 15 patients (5.0%) died, 10 of them with elevated copeptin values. Multivariate Cox regression analysis showed that copeptin was the sole predictor for mortality (HRR 5.317 (95% CI 1.653-17.098), p=0.005), independent of serum creatinine., Conclusion: Elevated copeptin can be used as a valuable prognostic factor for intermediate-term mortality in patients with both coronary artery and renal disease., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

In the Netherlands, risk assessment of contaminated soils is based on determining the total contaminant concentration. If this measured soil concentration exceeds the Soil Quality Standards (SQS) a higher tier risk evaluation must be performed. Experiences from the field have given rise to the perception that performing risk evaluations based on (measured) total concentrations may lead to an inaccurate assessment of the actual risks. Assuming that only the bioavailable fraction is capable of exerting adverse effects in the soil ecosystem, it is suggested, that by taking bioavailability into account in a (higher tier) risk evaluation, a more effect-based risk assessment can be performed. Bioavailability has been a subject of research for several decades. However up to now bioavailability has not been implemented in the Dutch Soil Quality Assessment Framework. First actions were taken in the Netherlands to determine whether the concept of bioavailability could be implemented in the risk assessment of contaminated soils and to find out how bioavailability can become part of the Dutch Soil Quality Assessment Framework. These actions have led to a concrete proposal for implementation of bioavailability methods in the risk assessment of organic contaminants in soils. This paper focuses on the chemical prediction of bioavailability for ecological risk assessment of contaminated soils., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: In whole genome and single gene analyses, genetic variation at the vascular cell adhesion molecule-1 (VCAM-1) locus has been associated with inflammatory disease and stroke in sickle cell anaemia. In the current work, we investigated the functional impact of VCAM-1 missense variants and their effect on cell-cell adhesion., Methods and Results: To determine the functional in vitro relevance of five missense VCAM-1 variants (S318F; T384A; G413A; L555V; I716L), we generated wild type and single variant VCAM-1 forms [318F, 384A, 413A, 555V, 716L] in EA.hy926 endothelial cells. Real-time PCR, western blot and ELISA analyses revealed significant differences in mRNA and protein levels for VCAM-1 variants. Monocytic cell lines THP-1 and U937 showed significantly increased adhesion to endothelial cells overexpressing VCAM-1 forms 318F, 555V and 716L compared to those overexpressing wild type VCAM-1 (p < 0.05)., Conclusions: VCAM-1-dependent cell adhesion to endothelial cells in vitro is significantly increased when expressing VCAM-1 missense mutations 318F, 555V and 716L. The underlying mechanism involves altered VCAM-1 protein levels and function. This observation may be of particular relevance for chronic inflammatory pathophysiologic conditions involving cell-cell adhesion such as atherosclerosis and other proinflammatory conditions., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

1. Masters athletes may experience low back pain from multiple sources. Masters athletes with discogenic back pain should avoid or modify sports with combined rotational and compressive forces; individuals with facet-mediated pain should avoid or modify sports with excessive extension and rotation. 2. Optimization of flexibility, strength, endurance, and core control is critical. Sports specific training, realistic goal setting, and counseling are of maximal importance. 3. Overall, the health benefits of continued sports and athletic participation outweigh the potential risks of spinal degeneration in middle-aged athletes. There is little correlation between radiographic appearance of the spine and symptoms; therefore, symptoms should serve as the primary guide when determining activity modifications. Overall, masters athletes should be encouraged to remain active and fit to enhance their quality of life and reduce the risk of cardiovascular disease.

This paper presents the policy framework of contaminated site management in The Netherlands and the corresponding risk assessment tools, including innovations that have taken place since an overview was published in 1999. According to the Dutch Soil Protection Act assessment framework, soils are subdivided into three quality classes: clean, slightly contaminated and seriously contaminated. Historic cases of slightly contaminated soils are managed in a sustainable way by re-use of soil material within a region on the basis of risk-based and land use specific Maximal Values and Background Values. In case of serious soil contamination remediation is in principle necessary and the urgency of remediation has to be determined based on site-specific risks for human health, the ecosystem and groundwater. The major risk assessment tools in The Netherlands are the CSOIL exposure model (human health risks and food safety), Species Sensitivity Distributions and the Soil Quality Triad (ecological risks), along with a procedure to assess the risks due to contaminant spreading to and in the groundwater. Following the principle 'simple if possible, complex when necessary', tiered approaches are used. Contaminated site practices are supported with web-based decision support systems., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case-control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GENIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels (P=0.044 [ECTIM] P=0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20-0.74], P=0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques (P=0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants.

Adrenomedullin (ADM) is a vasodilator and inhibits salt appetite. An A-to-G substitution at position -1984 in the promoter region of the ADM gene likely increases transcription. We therefore investigated this polymorphism in relation to blood pressure and urinary sodium in a Chinese population. We genotyped 427 Chinese enrolled in a family-based population study. We measured blood pressure by conventional sphygmomanometry and ambulatory monitoring. The frequencies of the ADM AA, AG, and GG genotypes were 50.6, 38.2, and 11.2%, respectively. In adjusted analyses, G allele carriers, compared to AA homozygotes, had significantly lower conventional (45.3 versus 48.5 mm Hg, P = 0.004) and 24-h (42.6 versus 44.3 mm Hg, P = 0.03) pulse pressures and urinary sodium excretion (143.8 versus 159.4 mmol/day, P = 0.03). In parents, but not offspring, both systolic pressure and pulse pressure were significantly (P<0.01) lower in G allele carriers. The genotypic difference in sodium excretion was consistent across the age range. In 68 informative offspring, transmission of the G allele was associated with lower urinary sodium excretion (effect size, 40.1 mmol/day, P = 0.01). In 81 healthy volunteers, the plasma ADM concentration was 15.2% higher in GG homozygotes than in sex- and age-matched AA subjects (11.4 versus 9.9 pmol/l, P = 0.10). In conclusion, in Chinese, the ADM -1984G allele is associated with lower sodium excretion and in older subjects also with lower systolic pressure and narrower pulse pressure.

The peroxisome proliferator-activated receptor gamma (PPARgamma) Pro12Ala polymorphism affects plasma lipids, but to what extent alcohol intake interferes with this association remains unknown. We randomly recruited 251 nuclear families (433 parents and 493 offspring) in the framework of the European Project on Genes in Hypertension study and genotyped 926 participants in whom all serum lipid variables and information on alcohol consumption were available for PPARgamma2 Pro12Ala. Genotype-phenotype relations were assessed using generalized estimating equations (GEE) and a quantitative transmission disequilibrium test (QTDT). The Ala12 allele was more frequent in Novosibirsk (0.17) than in Cracow (0.12) and Mirano (0.11) (P < 0.01). Using GEE (P = 0.03) or QTDT (P = 0.007), Italian offspring carrying the Ala12 allele had higher serum HDL cholesterol than noncarriers. HDL cholesterol levels were on average 0.086 mmol/l (P = 0.001) higher in drinkers than in nondrinkers. Compared with Pro12 homozygotes, Ala12 allele carriers consuming alcohol had higher serum total and HDL cholesterol, with the opposite trend occurring in nondrinkers. This genotype-alcohol interaction was independent of the type of alcoholic beverage and more pronounced in moderate than in heavy drinkers. We conclude that alcohol intake modulates the relation between the PPARgamma2 Pro12Ala and HDL cholesterol level and that, therefore, the Pro12Ala polymorphism, pending confirmation of our findings, might affect cardiovascular prognosis.

Background/aims: Interferon-based regimens (alone or with ribavairin) are standard therapies for chronic hepatitis C. The aim of this study was to compare a 24-week regimen of interferon alpha-2b + ribavirin (IFN + RIBA) to interferon alpha-2b + amantadine (IFN + AMANT) in non-responders to previous interferon monotherapy., Methods: In a multi-center, double-blind clinical trial, 118 patients (non-responders to previous interferon monotherapy) were equally randomized into the two arms: interferon alpha-2b (3 MU thrice weekly) and ribavirin (800 mg daily) vs. interferon alpha-2b (3 MU thrice weekly) and amantadine (200 mg daily)., Results: After 24 weeks of therapy, HCV RNA became undetectable in 34.8% (95% CI: 23.7-49.2) of IFN + RIBA and 19.6% (95% CI: 10.6-34.7) of IFN + AMANT (P = 0.10). This response was sustained in 3.9% (95% CI: 1.0-14.9) of IFN + RIBA and 0% of IFN + AMANT (P = 0.16). Ten patients from IFN + AMANT (17%) and 12 patients (20%) from IFN + RIBA were discontinued before completion of therapy. Of these, 7% in IFN + AMANT and 12% in IFN + RIBA were discontinued due to adverse effects., Conclusions: Re-treatment of interferon non-responders with a 24-week course of IFN + AMANT was not associated with any sustained viral eradication. Although IFN + RIBA in this group was associated with a reasonable end of treatment response, relapses were common and sustained responses were low.

Objective: To identify individual, parent/family, and treatment follow-through predictors of outcome for adolescent psychiatric inpatients 6 months after hospital discharge., Method: Eighty-nine adolescents participated in a comprehensive baseline evaluation during psychiatric hospitalization. Baseline measures included the Diagnostic Interview Schedule for Children, Social Adjustment Inventory for Children and Adolescents, Reynolds Adolescent Depression Scale (RADS), and Suicidal Ideation Questionnaire-Junior (SIQ-Jr). Structured telephone follow-up interviews assessed treatment follow-through, suicidal behaviors, rehospitalizations, living changes, and social adaptive functioning. The RADS and SIQ-Jr were also readministered., Results: Baseline indices of adolescent functioning emerged as the strongest predictors of outcomes. Hierarchical multiple regression analyses indicated that baseline depression severity, a cluster of parent/family indices, and medication follow-through were significant predictors of outcome depression severity. Baseline social adaptive functioning, presence/absence of conduct disorder, and medication follow-through were significant predictors of outcome social adaptive functioning., Conclusions: The nature and course of adolescent psychopathology was difficult to disrupt, with baseline characteristics as the strongest predictors of outcome. Nevertheless, the significance of medication follow-through as a predictor suggests that treatment-related gains are possible.

Objective: Our goal was to determine whether toxicity of the diphtheria toxin A-chain gene regulated by the human chorionic gonadotropin promoter can be directed to malignant ovarian cell lines., Study Design: Plasmids containing diphtheria toxin A-chain gene linked to the regulatory elements of the metalloergothioneine and human chorionic gonadotropin promoters were transfected into the cell lines. Expression of diphtheria toxin A-chain gene was determined by the inhibition of a cotransfected luciferase reporter gene., Results: Cytotoxicity of the diphtheria toxin A-chain gene is shown in a dose-responsive manner. Transfection of a plasmid expressing the diphtheria toxin A-chain gene controlled by a constitutive promoter readily inhibits protein synthesis. Specific inhibition of luciferase protein synthesis occurs in ovarian cancer cells transfected with the diphtheria toxin A-chain gene under the control of the human chorionic gonadotropin promoters when compared with normal ovarian epithelial cells or fibroblasts., Conclusions: These data demonstrate the preferential expression of the diphtheria toxin A-chain gene, regulated by the human chorionic gonadotropin promoter, to ovarian cancer cell lines. This provides an avenue for targeting such cells for suicide, toxin, or cytokine genes.

Objective: To help determine optimal strategies for treating suicidal adolescents, the authors studied family predictors of compliance with recommended psychotropic medication monitoring, individual therapy, and parent guidance/family therapy sessions., Method: Sixty-six hospitalized, suicidal adolescents participated in a comprehensive diagnostic evaluation and depression/suicidality assessment. Family/parental assessment measures were the Family Assessment Device, Social Adjustment Inventory for Children and Adolescents (parent-adolescent subscales), Symptom Checklist-90-Revised, and Social Adjustment Scale-Self Report. Follow-up evaluation, 6 months posthospitalization, consisted of structured telephone interviews assessing treatment follow-through., Results: Compliance with recommended medication follow-up (66.7%) and individual therapy (50.8%) was better than compliance with parent guidance/family therapy (33.3%) sessions. The most dysfunctional families and those with the least involved/affectionate father-adolescent relationships had the poorest follow-through with parent guidance/family therapy. Mothers' depressive and paranoid symptoms were linked with less adolescent individual therapy and family therapy follow-through. Mothers' hostility was associated with less medication follow-up., Conclusions: Follow-through was best for medication and individual therapy. Multiple family/parental predictors of poor follow-through suggest the need for alternative or supplemental treatment strategies.

Objective: To identify clinical profiles discriminating depressed adolescents on the basis of comorbid alcohol/substance use disorders and to determine whether or not profiles with high predictive power are gender-specific., Method: One hundred three adolescent inpatients with major depression (65 girls, 38 boys) participated in a comprehensive diagnostic evaluation. Independent assessments of depression, suicidality, and psychosocial adjustment were conducted using well-validated instruments., Results: Gender-specific clinical profiles were identified that predicted alcohol/substance abuse in depressed adolescents with high levels of sensitivity (90%). The significant discriminant function for depressed girls included the following predictors: longer depressive episodes, more conduct problems and psychosocial impairment, and more active involvement in relationships with boys. The significant discriminant function for depressed boys included conduct disorder, older age, and schoolwork problems. These profiles correctly identified most depressed adolescents with comorbid alcohol/substance abuse., Conclusions: Given that alcohol abuse and depression are associated with highly impaired social functioning and increased risk of self-harm, sensitivity in case identification is critical. Clinicians should conduct comprehensive assessments of alcohol/substance abuse in depressed adolescents with the identified clinical profiles.

Objective: To determine the nature of comorbid psychopathology and suicidality associated with a history of sexual abuse in depressed adolescents., Method: Twenty-four depressed adolescent inpatients with a history of sexual abuse were compared with a matched control group of 24 depressed adolescent inpatients on measures of depression, suicidal ideation and behavior, and posttraumatic stress disorder (PTSD) symptoms., Results: Depressed adolescents with a history of sexual abuse had a higher prevalence of comorbid PTSD than did those without such a history. Chronicity and severity of abuse were significant contributors to a PTSD diagnosis. No differences were found in depression severity, specific depressive symptoms, or suicidal behavior., Conclusion: Comorbidity of depressive disorders and PTSD are common among adolescent inpatients with a history of chronic sexual abuse. The need for thorough assessment of depression and PTSD with appropriate interventions for sexually abused adolescents is clear.

Sex hormone binding globulin in blood is quantitated by ammonium sulphate precipitation technique with two radioactive ligands, [3H]testosterone and [3H5dihydrotestosterone. Plasma levels in normal men, normal women, women taking oral contraceptives containing oestrogens, and pregnant women are presented, measured with both ligands. Binding experiments with these ligands and several competing steroids show marked differences in displacement ability. For cyproterone acetate 100-500 ng per tube is required to obtain even a slight displacement of the radioactive ligands.