European Journal of Clinical Investigation (Eur J Clin Investig )

Publisher: European Society for Clinical Investigation, Blackwell Publishing

Journal description

The Journal of the European Society for Clinical Investigation. The European Journal of Clinical Investigation publishes papers in the field of clinical investigation, provided they contribute to the advancement of knowledge in this field. The term 'clinical investigation' is interpreted widely and includes studies relevant to humans in health or disease, including such studies that may have taken place with animals.

Current impact factor: 3.37

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2011 Impact Factor 3.365

Additional details

5-year impact 3.05
Cited half-life 8.00
Immediacy index 0.70
Eigenfactor 0.01
Article influence 0.90
Website European Journal of Clinical Investigation website
Other titles European journal of clinical investigation (Online)
ISSN 1365-2362
OCLC 46653881
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Blackwell Publishing

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
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    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
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    • See Wiley-Blackwell entry for articles after February 2007
    • Publisher's version/PDF cannot be used
    • On author's server, institutional server or subject-based server
    • Server must be non-commercial
    • Publisher copyright and source must be acknowledged with set statement ("The definitive version is available at www.blackwell-synergy.com")
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Hepatitis C virus (HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. Methods: We characterized the distinct T-cell phenotypes based on the expression of co-stimulatory molecules CD28 and CD27, senescent markers PD-1 and CD57, chronic immune activation markers CD38 and HLA-DR, and survival marker CD127 ( IL-7R) by flow cytometry following activation of T cells by HCV peptides and phytohemagglutinin. Results: HCV-specific CD4+ and CD8+ T cells from chronic HCV (CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4+ T cells of CHC-infected subjects displayed relatively increased expression of HLA-DR and CD38 relative to HCV-specific CD8+ T cells. The CD4+ and CD8+ T cells from HCV-infected individuals showed significant increase of late-differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated to the levels of CD57 and PD-1 expressed on T cells. Conclusions: Chronic HCV infection results in increased turn-over of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection.
    European Journal of Clinical Investigation 04/2015;
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    ABSTRACT: There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational "wet" and in silico synthetic approaches and an array of biophysical, structural, and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogs that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: The threshold model represents an important advance in the field of medical decision making. It is a linchpin between evidence (which exists on the continuum of credibility) and decision making (which is a categorical exercise - we decide to act or not act). The threshold concept is closely related to the question of rational decision making. When should the physician act, i.e., order a diagnostic test, or prescribe treatment? The threshold model embodies the decision theoretic rationality that says the most rational decision is to prescribe treatment when the expected treatment benefit outweighs its expected harms. However, the well documented large variation in the way physicians order diagnostic tests or decide to administer treatments is consistent with a notion that physicians' individual action thresholds vary. We summarize the existing literature on physicians' use of a threshold strategy for decision making, concluding that the observed variation in decision action thresholds is partially due to the way people integrate benefits and harms. That is, explanation of variation in clinical practice can be reduced to a consideration of thresholds. Limited evidence suggests that non-expected utility (non-EUT) threshold models, such as regret-based and dual-processing models, may explain current medical practice better. However, inclusion of costs and recognition of risk attitudes toward uncertain treatment effects and comorbidities may improve the explanatory and predictive value of the EUT-based threshold models. We finally conclude that the medical community has not yet fully defined criteria for rational clinical decision-making. The traditional notion of rationality rooted in EUT may need to be supplemented by reflective rationality, which strives to integrate all aspects of medical practice - medical, humanistic, and socio-economic-within a coherent reasoning system. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: CKD-EPI equations estimate glomerular filtration rate more accurately than the MDRD Study equation. Our aim was to evaluate whether CKD-EPI equations based on serum creatinine and/or cystatin C predict risk for major bleeding more accurately than the MDRD Study equation in patients with non-ST-segment elevation acute coronary syndromes. 350 consecutive subjects with non-ST-segment elevation acute coronary syndrome (68±12 years, 70% male) were studied. Glomerular filtration rate was estimated using the CKD-EPI and MDRD Study equations. The primary endpoint was the occurrence of major bleeding during the follow-up, which was defined according to the Bleeding Academic Research Consortium Definition criteria as bleeding types 3 to 5. During the median follow-up of 589 days (interquartile range, 390-986), 27 patients had major bleeding (0.04% events per person-year). Patients with major bleeding had worse kidney function parameters, regardless of the estimating equation used (p<0.001). After multivariate Cox regression adjustment, both cystatin C-based CKD-EPI equations were independent predictors of major bleeding (CKD-EPIcreatinine-cystatinC per mL/min(1) /1.73m(2) , HR = 0.973 (95%CI 0.955-0.991; p=0.003) and CKD-EPIcystatinC per mL/min(1) /1.73m(2) , HR = 0.976 (95%CI 0.976-0.992; p=0.003)), while the CKD-EPIcreatinine and MDRD equations did not achieve statistical significance. Both CKD-EPIcreatine-cystatinC and CKD-EPIcystatinC were associated with a significant improvement in major bleeding risk reclassification. In this cohort of non-ST-segment elevation acute coronary syndrome patients with relatively preserved renal function, both cystatin C-based CKD-EPI equations improved ability to predict risk for major bleeding and were superior to other equations for this application. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: During exposure to high altitude the immune system is altered. During hypoxia an increase in interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP), and an increase in natural killer cells and decrease in T cells in blood was shown. However, the impact of hypoxia on dendritic cells has not been investigated yet. Twelve healthy volunteers were subjected to a transient normobaric hypoxia for 6.5 hours simulating an oxygen concentration at 5500 meters. During exposure to hypoxia blood samples were collected and analyzed by flow cytometrical cell sorting (FACS) for circulating myeloid (mDCs) and plasmacytoid (pDCs) DCs. Serum levels of IL-6 and tumor necrosis factor (TNF)-α were analyzed. In a cell culture hypoxia chamber, blood samples were subjected to the same hypoxia and analyzed regarding DCs. Exposure to normobaric hypoxia induced a significant decrease in circulating pDCs about 45% (p=0.001) but not of mDC compared to baseline normoxia. Furthermore, we observed a significant increase of TNF-α about 340% (p=0.03) and of IL-6 about 286% (p=0.002). In cell culture experiments exposure of blood to hypoxia led to no significant changes in DCs, so that a direct cytotoxic effect was excluded. During hypoxia, we observed a transient increase in stromal-derived factor 1 (SDF-1) which is important for pDC tissue recruitment. We show a significant decrease in circulating pDCs during hypoxia in parallel to a pro-inflammatory response. Further studies are necessary to evaluate if the decrease in circulating pDCs might be the result of an enhanced tissue recruitment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: Previous studies have shown that the intrauterine administration of peripheral blood mononuclear cells (PBMC) may improve pregnancy outcome of women with repeated implantation failure (RIF). We have demonstrated that, during implantation, corticotropin releasing hormone (CRH) plays a key role in facilitating endometrial decidualization and maternal-fetal immunotolerance. In the present preliminary study, we investigated whether the intrauterine administration of autologous CRH-treated PBMC can improve clinical pregnancy rates of women with RIF. Forty five (n=45) women with at least 3 failed in vitro fertilization (IVF) attempts and no previously reported clinical pregnancy were included in this crossover study. All women underwent controlled ovarian stimulation using the long GnRH-agonist protocol. PBMC were isolated at day of oocyte retrieval, treated with CRH and administered in the uterine cavity at day 2, following oocyte retrieval. Blastocyst transfer was performed on day 5. Following the CRH-PBMC intrauterine administration, a significant increase was observed in the clinical pregnancy rate of this cohort of women with RIF (20/45 women had a clinical pregnancy; 44.44%, P<10(-3) ) compared to the previous null clinical pregnancy rate prior to the intervention. The current findings support a possible role for the intrauterine administration of autologous CRH-treated PBMC in treating women with RIF. Further randomized controlled trials are needed in order to investigate the efficacy of this intervention. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: Background Smoking is a strong risk factor of metabolic syndrome. Zinc α2-glycoprotein (ZAG) is a protein involved in metabolic syndrome. This study aims to investigate the effect of smoking on plasma ZAG levels and its relations to metabolic syndrome.Materials and methodsA group of 41 cigarette smokers and 47 nonsmokers were enrolled. ZAG levels were measured to correlate to participants’ demographic and metabolic parameters.ResultsPlasma ZAG levels of smokers were higher than those of controls (p <0.0001). Plasma ZAG levels were positively correlated with male gender (p = 0.0002), number of cigarettes smoked per day (p <0.0001), smoking duration in years (p <0.0001), smoking index (p <0.0001), and nicotine dependence score (p <0.0001). In the multiple regression analysis, smoking was a strong independent factor affecting plasma ZAG levels (p = 0.0034). Plasma ZAG levels elevated progressively with the number of metabolic syndrome components (p = 0.0143). In the multiple regression analysis, plasma ZAG was an independent factor for metabolic syndrome.Conclusions Plasma ZAG levels are high in smokers and correlate with metabolic syndrome. Our results indicate ZAG is an independent risk factor, but also interacted with smoking, for the metabolic syndrome.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: Background MicroRNAs (miRNAs) are non-coding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigated whether patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) have distinct circulating and urinary miRNA expression profiles that could lead to potential development of noninvasive biomarkers of the disease.Materials and methodsExosome miRNAs were extracted from plasma and urine samples of patients with primary FSGS (n=16) or MCD (n=5) and healthy controls (n=5). Differences in miRNA abundance were examined using Affymetrix GeneChip miRNA 3.0 arrays. QRT-PCR was used to validate the findings from the array.ResultsComparison analysis of FSGS versus MCD revealed 126 and 155 differentially expressed miRNAs in plasma and in urine, respectively. Only 38 of these miRNAs were previously cited, whereas the remaining miRNAs have not been described. Comparison analysis showed that a significant number of miRNAs were down-regulated in both plasma and urine samples of FSGS patients compared to those with MCD. Plasma levels of miR-30b, miR-30c, miR-34b, miR-34c, and miR-342, and urine levels of mir-1225-5p were up-regulated in MCD patients compared to FSGS patients and controls (p<0.001). Urinary levels of mir-1915 and miR-663 were down-regulated in FSGS patients compared to MCD and controls (p<0.001), whereas the urinary levels of miR-155 were up-regulated in FSGS patients when compared to MCD patients and controls (p<0.005).Conclusions Patients with FSGS and MCD have a unique circulating and urinary miRNA profile. The diagnostic and prognostic potential of miRNAs in FSGS and MCD warrants further studies.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: Background The ability of cells to travel long distances in order to form tissues and organs is inherently connected to embryogenesis. The process in which epithelial-like embryonic cells become motile and invasive is termed “epithelial-to-mesenchymal transition” (EMT), while the reversion of this program - yielding differentiated cells and organs - is called “mesenchymal-to-epithelial transition” (MET).DesignHere, we review the processes of EMT and MET in development and cancer - and combine them with knowledge from pluripotent stem cell research.ResultsResearch has shown that these processes are activated in many cancers leading to dissemination of cancer cells throughout the body and formation of metastasis. While the regulation of EMT during cancer progression has been extensively studied for decades, many fundamental processes that govern normal development are only poorly understood. Recent discoveries, like reprograming to pluripotent stem cells and identification of ground- and primed-states of pluripotent stem cells, have redirected much attention to EMT and MET.Conclusion Findings from pluripotent stem cell research and EMT/MET should be combined in order to design future strategies aimed to improve our understanding of cancer progression and to help develop novel anticancer strategies.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: Background Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, i.e. higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD).Materials and methodsThis narrative review, which includes results from previously published systematic reviews and meta-analyses, is based on clinical and basic research papers, obtained via MEDLINE and Pubmed up to November 2014.ResultsLow-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far.Conclusions Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain. The extent to which low-normal thyroid function prospectively predicts cardio-metabolic disorders has been insufficiently established so far.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 02/2015;
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    ABSTRACT: Djulbegovic et al's paper “Modern health care as a game theory problem” ought to be promulgated to all policy makers, health professionals and patients to make them realize that “self-interest” is “a near perfect” recipe for poor outcomes for all. I wholeheartedly agree with the paper's conclusion that successful encounters require ‘clinical interactions within a framework of trust in the healthcare system’ but that ‘the medical profession does not currently enjoy much trust as it has historically’. Whilst the paper highlights the problems it omits to explore potential solutions.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Osteoarthritis (OA) and cardiovascular disease (CVD) are the two most prevalent conditions in the population aged over 70 in developed countriesBoth conditions share common risk factors, in particular age and body mass index. However, the very high level of co-occurrence of both diseases cannot be accounted by common risk factors aloneOn the one hand, the disability caused by OA increases the risk of CVD and in particular of ischemic events and mortality beyond what can be explained by known common risk factors, such as ageing and obesity. Moreover, the presence of OA has a synergistic effect on CVD symptoms considerably worsening themOn the other hand, at least in women, there appears to be a common pathogenic mechanism underlying atherosclerosis (but not hypertension) and actual joint damageWe present current knowledge in the fields and possible molecular mechanisms underlying the data available to date. We also discuss future directions that need to be taken to address these highly prevalent, costly and disabling morbiditiesThis article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Background Autoantibodies have been shown to play a critical role in predicting major adverse cardiovascular events in atherosclerotic patients. We aimed to assess the diagnostic accuracy of autoantibodies to apolipoprotein A-1 (anti-apoA-1 IgG), and to phosphorylcholine (anti-PC IgM) for non-ST segment elevation acute myocardial infarction (NSTEMI) and to explore their potential prognostic value.Methods This prospective multicenter study included 1072 patients presenting to the emergency department for suspected NSTEMI. The final diagnosis was adjudicated by two independent cardiologists. For both antibodies alone or expressed as a ratio (anti-apoA-1 IgG/anti-PC IgM) we determined their i) diagnostic accuracy for NSTEMI, and ii) prognostic accuracy for major adverse cardiovascular events (MACE) during 1-year follow-up.ResultsA total of 154 patients (14%) had a final diagnosis of NSTEMI. Diagnostic accuracy for the diagnosis of NSTEMI as quantified by the area under the receiver-operating characteristics curve (AUC) was very low for both autoantibodies separately as well as combined as a ratio: AUC anti-apoA-1 IgG 0.50 (95%CI, 0.47-0.53, p=0.99), AUC anti-PC IgM 0.53 (95%CI, 0.50-0.56, p=0.30), and AUC of the ratio 0.52 (95%CI, 0.49-0.55, p=0.47). Adding the anti-apoA-1 IgG/Anti-PC IgM ratio to hs-cTnT did not provide incremental diagnostic value over hs-cTnT alone. MACE occurred in 221 patients (21%) during follow-up. The autoantibodies, separately or expressed as ratio, also had very low accuracy to predict MACE (p=ns).Conclusions Anti-apoA-1 IgG, and anti-PC IgM autoantibodies did not have diagnostic or prognostic value in patients with NSTEMI.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Background Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are potentially life-threatening disorders. Materials and methods Even though immunosuppressive therapy improves the prognosis, adverse events, either attributable to persistent disease activity or side effects of treatment remain a challenge. Infectious complications are the leading cause of death in the first year after diagnosis and a major cause of morbidity and mortality thereafter. Results Their incidence in clinical trials varies considerably but opportunistic and life-threatening infections, such as Pneumocystis jirovecii pneumonia or systemic cytomegalovirus infections, are frequent and thus predisposing/risk factors need to be defined. Pneumocystis jirovecii pneumonia has been associated with a lymphocyte count below 300/mm3. Additionally, besides the aggressiveness of the immunosuppressive regimen administered (especially the cumulative dose of steroids and cyclophosphamide), an elevated serum creatinine or dialysis dependency, older age and pulmonary involvement increase the rate of infectious omplications. Conclusions We suggest to routinely prescribe trimethoprim–sulfamethoxazole or antimicrobial agents such as pentamidine in case of intolerance or contraindication in the early phase of induction therapy irrespective of the immunosuppressive strategy used and to continue therapy, together with other targeted measures (antiviral, antimycotic or antibiotic) in the presence of risk factors for a prolonged period of time. Finally, there is an urgent need to standardize the reporting of infectious complications in clinical trials to enable comparing the adverse event spectrum of distinct treatment approaches more appropriately. Keywords ANCA-associated vasculitis, granulomatosis with polyangiitis, immunosuppression, infections, Pneumocystis jirovecii, trimethoprim–sulfamethoxazole.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Renal hypoxia is known to play an important role in the pathophysiology of acute renal injury as well as in other chronic kidney diseases. The mediators of hypoxia are the transcription factors HIF (hypoxia-inducible factors), that are highly regulated. Under normoxic conditions constitutively expressed HIF-α subunits are hydroxylated by prolyl hydroxylases (PHD1, PHD2, and PHD3) and subsequently degraded by proteasomes. The MAPK organizer 1 (Morg1) has been identified to act as a scaffold protein of PHD3 and suppression of Morg1 leads to the stabilization of HIF-α, which forms in the absence of oxygen a heterodimer with HIF-β, translocates to the nucleus and promotes the transcription of HIF target genes. This review summarizes the current knowledge regardingthe role of hypoxia, HIF signalling, and Morg1 in acute and chronic renal injury. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Despite advancements from balloon angioplasty to drug-eluting stents, primary patency rates after endovascular revascularization of peripheral artery disease have remained inferior compared to surgery. Endovascular revascularization has been limited by restenosis and mechanical stent failure. Thus, there is increased research into other non-stent based local drug delivery modalities, which can provide an active drug to inhibit restenosis focally and avoid the risk of systemic adverse effects. This can be accomplished by direct drug application to the vessel wall either mechanically or via a local drug infusion. Paclitaxel has several chemical properties, which make it an ideal drug candidate for these novel delivery techniques. This paper will summarize the unique properties of paclitaxel and studies on paclitaxel local delivery for the treatment of peripheral artery disease.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Prognostic impact of procedure-related bleeding in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI) remains incompletely investigated. The aim of this study was to investigate the association between peri-PCI bleeding and one-year outcome of patients with stable CAD. The study included 9035 patients with stable CAD who underwent elective PCI. Bleeding within 30 days of PCI was defined using the Bleeding Academic Research Consortium (BARC) criteria. The primary outcome was one-year mortality. Bleeding occurred in 844 patients (9.3%). Actionable bleeding (BARC class ≥2) occurred in 442 patients (4.9%). There were 210 deaths (2.3%) at 1 year following PCI: 41 deaths among patients with bleeding and 169 deaths among patients without bleeding (Kaplan-Meier estimates of mortality, 4.9% and 2.1%; odds ratio = 2.41, 95% confidence interval [CI] 1.73 to 3.36, P<0.001). The association between bleeding and mortality remained significant after adjustment for baseline risk variables (adjusted hazard ratio = 1.87, 95% CI 1.27 to 2.76, P=0.002). Bleeding increased the discriminatory power of the model regarding prediction of one-year mortality (absolute and relative integrated discrimination improvement, 0.006 and 16.3%, respectively, P=0.001). In patients with stable CAD undergoing elective PCI, the occurrence of bleeding within 30 days of the procedure was associated with increased risk of death at 1 year after PCI. These findings suggest that procedure-related bleeding may contribute to less than optimal results of PCI in terms of mortality reduction in patients with stable CAD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Background Following wider acceptance of “the thrifty phenotype” hypothesis and the convincing evidence that early life exposures can influence adult health even decades after the exposure, much interest has been placed on the mechanisms through which early life exposures become biologically embedded.Methods In this review, we summarize the current literature regarding biological embedding of early life experiences. To this end we conducted a literature search to identify studies investigating early life exposures in relation to DNA methylation changes. In addition, we summarize the challenges faced in investigations of epigenetic effects, stemming from the peculiarities of this emergent and complex field. A proper systematic review and meta-analyses were not feasible given the nature of the evidence.ResultsWe identified 7 studies on early life socioeconomic circumstances, 10 studies on childhood obesity, and 6 studies on early life nutrition all relating to DNA methylation changes that met the stipulated inclusion criteria. The pool of evidence gathered, albeit small, favours a role of epigenetics and DNA methylation in biological embedding, but replication of findings, multiple comparison corrections, publication bias, and causality are concerns remaining to be addressed in future investigations.Conclusions Based on these results, we hypothesize that epigenetics, in particular DNA methylation, is a plausible mechanism through which early life exposures are biologically embedded. This review describes the current status of the field and acts as a stepping stone for future, better designed investigations on how early life exposures might become biologically embedded through epigenetic effects.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: A proportion of phenotypic type 2 diabetes (T2D) patients produce pancreatic autoantibodies and a majority of T2D patients develop serious life-disabling complications over time despite the implementation of adequate clinical interventions. This study determined whether the presence of pancreatic autoantibodies (GADA, IA-2A, anti-ZnT8, or ICA) were associated with serious complications or concomitant diseases of adult patients diagnosed with T2D (N=305). In the study population, 22.3% (N=68) of subjects were positive for at least 1 of the 4 of the markers associated with autoimmune diabetes (presence of pancreatic autoantibody - pAb), followed by GADA (14.1%, N=43), ICA (8.9%, N=27), anti-ZnT8 (5.6%, N=17), and IA-2A (2.0%, N=6). Logistic regression analysis adjusted for patient's age, gender and duration of T2D revealed that: (i) pAb was associated with higher prevalence of adiposity (odds ratio of adjusted regression model (adOR) 2.51, p=0.032); (ii) pAb, GADA, and anti-ZnT8 were associated with autoimmune thyroid disease (adORs 3.07, p=0.012; 6.29, p<0.001 and 3.52, p=0.052, respectively); (iii) pAb and GADA, in particular, were risk factors for neurological complications (adORs 2.10, p=0.036; 2.76, p=0.009, respectively) and polyneuropathy in particular (adORs 2.60, p=0.012; 3.10, p=0.007, respectively); and (iv) anti-ZnT8 was a risk factor for developing nephropathy (adOR 4.61, p=0.022). In addition, adiposity was associated with 5.3-year earlier onset of disease (adjusted linear regression model, p=0.006). These results suggest that GADA and anti-ZnT8 are associated with progression of serious T2D complications, including polyneuropathy and nephropathy. In addition, adiposity represents a significant risk for autoimmunity development in T2D patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;
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    ABSTRACT: Methylation of DNA and modifications of histones have emerged as intricately involved in gene regulation since they crosstalk and respond in multiple ways to the activity of transcription factors. Measuring these epigenome components has become a powerful tool to identify regulatory principles and biomarkers that predict cellular state during development or disease. Here I will focus on DNA methylation as a reversible epigenetic modification of DNA that has been studied in great detail at the level of the genome. Recent advances in sequencing have identified unexpected dynamics of this modification, which are tightly linked to gene regulation. Understanding how DNA methylation patterns are read and how they contribute to regulation will be critical to interpret and utilize genomic maps of DNA methylation. Since these patterns are dynamic during cellular differentiation and perturbed in disease they present an opportunity to use DNA methylation as a biomarker.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 01/2015;