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Background: Smoking induces albuminuria and accelerates progression to renal failure in persons with diabetes, but little is known about the relation between smoking and renal function in nondiabetic persons.Objective: To investigate whether smoking is related to albuminuria and abnormal renal function in nondiabetic persons.Design: Cross-sectional study.Setting: Groningen, The Netherlands.Participants: 7476 participants in the PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study.Measurements: Microalbuminuria and high normal albuminuria were defined as urinary albumin excretion of 30 to 300 mg/24 h and 15 to 30 mg/24 h, respectively. Elevated or decreased glomerular filtration rate (GFR) was defined as a creatinine clearance that exceeded or was less than two times the standard deviation of the mean value in nondiabetic, nonsmoking participants who had an albumin excretion of 0 to 15 mg/24 h, adjusted for age and sex.Results: Current smokers had a higher median albumin excretion than nonsmokers and were more likely to have microalbuminuria and high normal albuminuria with elevated or decreased GFR. After adjustment for several potential confounding factors, persons who smoked 20 or fewer cigarettes/d and persons who smoked more than 20 cigarettes/d, respectively, showed a dose-dependent association between smoking and high normal albuminuria (relative risk, 1.33 [95% CI, 1.10 to 1.61] and 1.98 [CI, 1.49 to 2.64]), microalbuminuria (relative risk, 1.92 [CI, 1.54 to 2.39] and 2.15 [CI, 1.52 to 3.03]), elevated GFR (relative risk, 1. 82 [CI, 1.31 to 2.53] and 1.84 [CI, 1.12 to 3.02]), and decreased GFR (relative risk, 1.53 [CI, 1.04 to 2.24] and 1.83 [CI, 1.05 to 3. 20]), respectively. Quitting smoking was associated only with microalbuminuria.Conclusions: Smoking is associated with albuminuria and abnormal renal function. However, these associations are less pronounced or absent in former smokers. [ABSTRACT FROM AUTHOR]

Objective: To examine if the medical disciplinary law in the Netherlands is becoming tougher., Design: Observational study., Method: We read the annual reports of the Dutch Disciplinary Committees for the Healthcare Sector 2007-2017, and registered the numbers of disciplinary cases and those cases upheld, the measures imposed and the degree of consistency in the event of an appeal. Over 400 medical disciplinary cases were reviewed in more detail. Based on these cases, we determined those variables that increase or decrease the likelihood of conviction, such as the gender of the defendants, the region in which the disciplinary case was heard, and if objective norms and professional practice guidelines had been used in arriving at the verdict., Results: Each year a disciplinary case is brought against an average of 0.4% of all health care providers - mainly physicians (an average of approximately 1400 disciplinary cases each year). One-third of all disciplinary cases were dealt with in court and about half of them were upheld. Over time, the number of disciplinary cases has increased (36%), as has the percentage of cases that are upheld (27%). Additionally, heavier measures were more often imposed and the degree of consistency between the initial ruling and the ruling on appeal also increased (56%). Those factors that increased the likelihood of a case being upheld were: being a physician of male gender, the disciplinary case being heard in The Hague or Eindhoven, and the non-implementation of an objective norm or professional practice guideline in arriving at the verdict., Conclusion: Since 2007 the Dutch medical disciplinary boards have been punishing more often and more severely. This may be because the subjective demands made on health care professionals have changed. Arriving at an opinion subjectively is not a problem when it comes to verifying compliance with standards of due care. However, if this method is used to determine the penalty, the health care system will become defensive - and this will not improve the quality of care.

Since the discovery of microRNAs (miRNAs), circulating miRNAs have been proposed as biomarkers for disease. Consequently, many groups have tried to identify circulating miRNA biomarkers for various types of diseases including cardiovascular disease and cancer. However, the replicability of these experiments has been disappointingly low. In order to identify circulating miRNA candidate biomarkers, in general, first an unbiased high-throughput screen is performed in which a large number of miRNAs is detected and quantified in the circulation. Because these are costly experiments, many of such studies have been performed using a low number of study subjects (small sample size). Due to lack of power in small sample size experiments, true effects are often missed and many of the detected effects are wrong. Therefore, it is important to have a good estimate of the appropriate sample size for a miRNA high-throughput screen. In this review, we discuss the effects of small sample sizes in high-throughput screens for circulating miRNAs. Using data from a miRNA high-throughput experiment on isolated monocytes, we illustrate that the implementation of power calculations in a high-throughput miRNA discovery experiment will avoid unnecessarily large and expensive experiments, while still having enough power to be able to detect clinically important differences.

The relation between coagulation and atherosclerosis has been extensively described, pointing towards a hypercoagulable state in patients with atherosclerosis, especially in young individuals. However, not all studies were conclusive. It is known that the metabolic syndrome (MetS), a risk factor for coronary artery disease (CAD), is related to a higher incidence of thrombo-embolic events. We hypothesised that individuals with CAD at a young age and MetS have an increased prothrombotic potential. It was the study objective to analyse the endogenous thrombin potential (ETP) and related thrombin generation parameters in patients with CAD before the age of 51 in men and 56 in women with and without MetS features and their healthy first-degree relatives. In this case-control study we included 118 CAD patients and 50 first-degree relatives (controls). Parameters of thrombin generation were obtained with calibrated automated thrombinography. An adjusted general linear model (GLM) showed a positive association between the peak thrombin levels and the presence of CAD at a young age. Based on the NCEP criteria we divided our patient group in CAD patients with and without MetS, and compared them to the controls without MetS. We showed that CAD patients with MetS have increased ETP levels, both in comparison with healthy first-degree relatives and with CAD patients without MetS. There were no differences in ETP between patients without MetS and healthy controls. In conclusion, this study shows that individuals with CAD at a young age and MetS features have an increased prothrombotic potential, compared to CAD patients without MetS.

Objective: We report a novel lamin A/C (LMNA) mutation, p.Glu223Lys, in a family with extensive atherosclerosis, diabetes mellitus and steatosis hepatis., Methods: Sequence analysis of LMNA (using Alamut version 2.2), co-segregation analysis, electron microscopy, extensive phenotypic evaluation of the mutation carriers and literature comparison were used to determine the loss of function of this mutation., Results: The father of three siblings died at the age of 45 years. The three siblings and the brother and sister of the father were referred to the cardiovascular genetics department, because of the premature atherosclerosis and dysmorphic characteristics observed in the father at autopsy. The novel LMNA mutation, p.Glu223Lys, was identified in the proband and his two sons. Clinical evaluation revealed atherosclerosis, insulin resistance and hypertension in the proband and dyslipidemia and hepatic steatosis in all the patients with the mutation., Conclusion: Based on the facts that in silico analysis predicts a possibly pathogenic mutation, the mutation co-segregates with the disease, only fibroblasts from mutation carriers show nuclear blebbing and a similar phenotype was reported to be due to missense mutations in LMNA we conclude that we deal with a pathogenic mutation. We conclude that the phenotype is similar to Dunnigan-type familial partial lipodystrophy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

We present the case of a patient with clinical features of familial dysbetalipoproteinaemia (FD) including high levels of total cholesterol, hypertriglyceridaemia and the presence of palmar xanthomas. Whereas genotype analysis identified the APOE3E3 isoform, sequence analysis revealed the presence of one APOE1 allele due to a mutation, p.Lys164Glu, which leads to loss of function of apolipoprotein E (ApoE), a rare cause of dominant FD.

Microalbuminuria is associated with both an increased prevalence of cardiovascular risk factors and greater renal and cardiovascular morbidity. We questioned whether in the general population such associations can be found at lower levels of urinary albumin excretion than that of classically defined microalbuminuria. To that purpose urinary albumin concentration was measured in 40619 subjects aged 28 to 75 years. The subjects filled in a questionnaire on cardiovascular risk factors and events and were divided in deciles according to their urinary albumin concentration. Smoking was associated with albuminuria in the fifth or higher decile of urinary albumin concentration, that is with an albumin concentration of 5.1 mg/l and higher. The lower cut-off point for a positive association with hypertension was 8.8 mg/l, and for diabetes 11.2 mg/l. Family history for cardiovascular disease and hyperlipidaemia were not associated with albuminuria. We conclude that urinary albumin concentrations far below the microalbuminuric range are associated with increased prevalence of established cardiovascular risk factors. Family history for cardiovascular disease and hyperlipidaemia seems to behave differently. These data emphasize the need for more studies on the impact of albuminuria on the prediction of cardiovascular and renal disease in the general population.

Angiotensin II recruits transforming growth factor beta(1) (TGFbeta(1)) and is related to left ventricular fibrosis. However, it is unclear whether chronic in vivo reduction in left ventricular TGFbeta(1) expression blunts fibrosis and improves outcome in angiotensin II-dependent hypertension. Four-week-old male hypertensive TGR(mRen2)27 (Ren2) rats received either normal food, low-dose losartan (0.5 mg. kg(-1). d(-1)), or tranilast (a nonspecific TGFbeta inhibitor; 400 mg. kg(-1). d(-1)) (n=10 for each group) for 12 weeks and were compared with Sprague-Dawley control rats. The effect of tranilast on survival was evaluated in 34 additional untreated homozygous Ren2 rats. Tranilast or low-dose losartan did not lower blood pressure. However, the increase in left ventricular weight (Ren2 versus SD 3.1+/-0.16 versus 2.1+/- 0.06 mg/g body wt; P<0.05) was significantly (P<0.05) blunted by both tranilast (2.7+/-0.05) and losartan (2.7+/-0.07). Both drugs prevented the increase in left ventricular TGFbeta(1) mRNA and fibronectin mRNA and blunted the increase in hydroxyproline content and the increase in perivascular fibrosis. The perivascular fibrosis score correlated significantly with the level of expression of TGFbeta(1) (r=0.62; P=0.019). In situ hybridization demonstrated increases in TGFbeta(1) mRNA, predominantly in perivascular and nonmyocyte areas. Both drugs did not prevent the decrease in systolic or diastolic dP/dt, but tranilast significantly improved the survival of untreated Ren2 rats (P=0.029). In conclusion, TGFbeta(1) mRNA expression is increased predominantly in nonmyocyte regions in the hypertrophied left ventricle in this angiotensin II-dependent model of hypertension. This increase is probably due to high angiotensin II levels rather than to hypertension. This is the first study to suggest that chronic inhibition of TGFbeta(1) expression attenuates left ventricular hypertrophy and fibrosis, even without lowering blood pressure.

Endothelin-1 (ET-1) was discovered 10 years ago. Because it is one of the most potent vasoconstrictors in vivo, a pathophysiological role for the peptide as a mediator of hypertension has been postulated. Several clinical studies, however, have been unable to identify elevated ET levels in the plasma of hypertensive patients, suggesting that it does not play a prominent role in this disease. More recently, evidence has been presented that ETs act predominantly at the autocrine/paracrine level and that measurements of plasma levels can give only an indirect view of the activity of the system. In addition, transgenic technology has uncovered new actions of the peptide systems in recent years, which point to a key function of the system in prenatal development. Moreover, investigation of conditions associated with hypertensive end-organ damage, such as chronic renal failure, has led to a re-evaluation of the role of the ET system in hypertension. This article discusses this recent evidence and defines the exact role of the ET system in hypertension and hypertensive end-organ damage.

Amplification and over-expression of oncogenes of the myc family are related to the prognosis of certain solid tumors such as small cell lung cancer (SCLC). For SCLC, c-myc is the oncogene most consistently found to correlate with the end stage behaviour of the tumour, in particular with survival after chemotherapeutic treatment. C-myc is important in many cellular processes such as proliferation, differentiation and apoptosis. In the present study the relationship between c-myc and differentiation was analyzed by down-regulation of endogenous c-myc protein, using two approaches: first by coculturing with antisense (AS) oligodeoxynucleotides (ODN) in the human SCLC cell line GLC4 and its 6-fold cisplatin resistant subline GLC4-CDDP, second by stable transfection of GLC4-CDDP with a dexamethasone-inducible AS c-myc expression vector. Basic characterization of the differentiation status of GLC4 and GLC4-CDDP showed a decrease in neuroendocrine differentiation in GLC4-CDDP compared to GLC4 Cytokeratin was absent in both cell lines. No significant differences in expression of adhesion molecules or myeloid antigens were observed between the lines. Vimentin expression was higher in GLC4-CDDP compared to GLC4 (AS c-myc ODN)-induced growth inhibition and down-regulation of endogenous c-myc protein further decreased neuroendocrine differentiation (CD57 positive cells) in GLC4-CDDP without affecting the expression of other antigens such as vimentin (intermediate filament),CD15 (myeloid antigen) and VLA-alpha 4 (adhesion molecule) and did not alter the expression of these antigens in GLC4 (AS c-myc RNA)-induced growth inhibition did not significantly affect the expression of the tested antigens in the AS c-myc transfected GLC4-CDDP/AS cell line. No effect of nonsense c-myc ODN or dexamethasone-induced control RNA (controls) was observed.