CONTEXT Current remission maintenance therapies for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) are limited by partial efficacy and toxicity. OBJECTIVE To compare the ...effects of mycophenolate mofetil with azathioprine on the prevention of relapses in patients with AAV. DESIGN, SETTING, AND PARTICIPANTS Open-label randomized controlled trial, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE), to test the hypothesis that mycophenolate mofetil is more effective than azathioprine for preventing relapses in AAV. The trial was conducted at 42 centers in 11 European countries between April 2002 and January 2009 (42-month study). Eligible patients had newly diagnosed AAV (Wegener granulomatosis or microscopic polyangiitis) and were aged 18 to 75 years at diagnosis. INTERVENTIONS Patients were randomly assigned to azathioprine (starting at 2 mg/kg/d) or mycophenolate mofetil (starting at 2000 mg/d) after induction of remission with cyclophosphamide and prednisolone. MAIN OUTCOME MEASURES The primary end point was relapse-free survival, which was assessed using a Cox proportional hazards model. The secondary end points were Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria. RESULTS A total of 156 patients were assigned to azathioprine (n = 80) or mycophenolate mofetil (n = 76) and were followed up for a median of 39 months (interquartile range, 0.66-53.6 months). All patients were retained in the analysis by intention to treat. Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate mofetil of 1.69 (95% confidence interval CI, 1.06-2.70; P = .03). Severe adverse events did not differ significantly between groups. There were 22 severe adverse events in 13 patients (16%) in the azathioprine group and there were 8 severe adverse events in 8 patients (7.5%) in the mycophenolate mofetil group (HR, 0.53 95% CI, 0.23-1.18; P = .12). The secondary outcomes of Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria did not differ significantly between groups. CONCLUSIONS Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00307645
Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data ...sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (
Z
lr=3.50;
P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of .037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role ...as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease.
In a double-blind, placebo-controlled randomized study, we investigated the effects of the ETA/ETB endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (P<0. 05), whereas heart rate increased slightly (P<0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (P<0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (P<0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated.
Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ETA/ETB endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease.
Summary Background The anti‐inflammatory cytokine interleukin (IL)‐10 is considered to play a major role in the pathophysiology of psoriasis, which is characterized by an IL‐10 deficiency. Systemic ...administration of IL‐10 has been shown to be an effective therapy for psoriasis. The IL‐10 promoter region contains a highly polymorphic microsatellite (IL10.G) and in a recent case–control study the IL10.G13 (144 bp) allele was found to be associated with familial early onset psoriasis (type 1 psoriasis) having a susceptible effect.
Objectives As it is essential in multifactorial diseases to replicate findings before definite conclusions can be drawn, we decided to perform a follow‐up study and to follow a genetic approach analysing allele transmission in families with a positive family history of psoriasis.
Methods We studied 137 nuclear families (trio‐design) comprising 456 individuals and genotyped the IL10.G marker. For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1). In the present study allele transmission was evaluated using the family‐based association test (FBAT) and GENEHUNTER 2.0 based on the transmission/disequilibrium test.
Results The G13 allele (144 bp) had a frequency of 24%, was present in 88 families and clearly showed an even transmission (FBAT, P = 0·753). In contrast, allele 3 (IL10.G9) (136 bp) had a frequency of 39%, was present in 110 families and was transmitted in 43 trios and remained untransmitted in 67 trios (FBAT, P = 0·026), thus showing preferential nontransmission. For the HLA‐linked tn62‐marker we obtained a P‐value of 0·000 27 for allele 4 in the same study group.
Conclusions In conclusion, we failed to confirm the susceptible effect of the G13 allele, but provide the first data for a protective effect of allele 3 (IL10.G9) for familial psoriasis. Our results suggest that the IL10.G polymorphism is not a major locus, but acts as a minor locus.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
: To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For ...this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Infection in implantable left ventricular assist device (LVAD) patients is common and has serious implications regarding permanent use of the LVAD.
Thirty-three patients had HeartMate LVAD insertion ...as a bridge to heart transplantation. The mean length of hospital stay was 8 days before LVAD insertion. Before insertion 6 patients (18%) had positive pulmonary cultures and 5 patients (15%) had bacteremia.
During LVAD support 18 patients (55%) had bloodstream infection. Of 24 patients (73%) successfully bridged to transplantation, 12 (50%) had positive blood cultures including
Staphylococcus species (n = 9),
Candida (n = 3),
Pseudomonas (n = 2), and
Enterococcus (n = 2). Infectious complications encountered in this series included driveline infection requiring surgical revision, septic embolus, “cleared” device infection, “suppressed” device infection, and LVAD infection treated by device removal in 1 patient and device exchange in another.
Infection in implantable LVAD patients is common, especially in patients in whom multiple organ failure develops, requiring prolonged stay in the intensive care unit. Strategies are needed to prevent these infections in recipients of the permanent LVADs because treatment of an established infection is difficult and expensive.
Deglaciations are characterized by the largest natural changes in methane (CH4) and nitrous oxide (N2O) concentrations of the past 800 000 years. Reconstructions of millennial- to centennial-scale ...variability within these periods are mostly restricted to the last deglaciation. In this study, we present composite records of CH4 and N2O concentrations from the EPICA Dome C ice core covering the penultimate deglaciation at temporal resolutions of ∼100 years. Our data permit the identification of centennial-scale fluctuations during the transition from glacial to interglacial levels. At ∼134000 and ∼129000 years before present (hereafter ka), both CH4 and N2O increased on centennial timescales. These abrupt rises are similar to the fluctuations associated with the Dansgaard–Oeschger events identified in the last glacial period. In addition, gradually rising N2O levels at ∼130 ka resemble a pattern of increasing N2O concentrations on millennial timescales characterizing the later part of Heinrich stadials. Overall, the events in CH4 and N2O during the penultimate deglaciation exhibit modes of variability that are also found during the last deglaciation and glacial cycle, suggesting that the processes leading to changes in emission during the transitions were similar but their timing differed.
Abstract
Background
A symptomatic and prognostic benefit by Transcatheter edge-to-edge repair (TEER) for mitral regurgitation (MR) has been proven. A variety of individual factors including female ...sex has been suggested to be associated with adverse outcome in cardio-surgical procedures.
Purpose
While gender is factored in common risk factor models for adverse outcome, evidence on sex-specific differences in long-term outcome after TEER for MR is limited. We aimed to investigate the impact of gender on prognosis in a large monocentric cohort with long-term follow-up.
Methods
We analyzed survival stratified for gender after successful isolated edge-to-edge repair of MR in the period between 06/2010 and 03/2018 (exclusion of combined forms of TMVR) in a monocentric retrospective cohort by performing survival analyses and cox regression analyses.
Results
Consecutively, 627 patients (47.0% females, 57.4% functional MR; survival status was available in 96.7%) entered the study and were followed for a median follow-up period of 462 days IQR 142–945 days. Survival rates were 97.6% at discharge, 75.7% after 1, 54.5% after 3, 37.6% after 5 and 21.7% after 7 years. Risk score as calculated by the Logistic Euroscore I did not differ significantly between females and males (at baseline: 25.0 IQR 18.0/34.8 vs. 27.0 18.4/40.1%, p=0.093) and no relevant differences were found for in-hospital (2.0 vs. 2.7%, p=0.613), 30 days (4.8 vs. 6.5%, p=0.473) and 1-year mortality (27.0 vs. 25.3%, p=0.675). At the time of procedure, women were older (79.9 IQR 75.6/84.4 vs. 78.3 72.9/83.4 years, p<0.001), were less often affected by coronary artery disease (53.1% vs. 75.0% p<0.001), diabetes mellitus (23.7% vs. 31.3%, p=0.040) and impaired left ventricular function (44.5±12.9% vs. 38.9±13.4%, p<0.001). Regarding long-term survival, women had a better prognosis after MR-therapy, especially in functional etiology: e.g., 4-year survival in FMR 65.7 vs. 35.7%, p=0.006 (Figure 1). Remarkably, female sex was associated with a lower risk for long-term mortality in the Cox-regression models, especially in the FMR subgroup (total cohort: univariate HR 0.81 0.62–1.04, p=0.101; FMR: univariate HR 0.68 0.49–0.96, p=0.028).
Conclusion
In our cohort of patients undergoing TEER for MR, we found no evidence for an impaired short- and mid-term prognosis for female patients. In contrary and not as indicated by Logistic Euroscore, female sex was associated with better long-term survival in comparison to men despite higher median age, which might be partly explained by a slightly more favorable cardiovascular risk profile.
Funding Acknowledgement
Type of funding sources: None. Figure 1
Abstract
Introduction
Diabetes mellitus (DM) represents a notable risk factor after surgical and interventional procedures but data on the influence of DM on long-term survival after Transcatheter ...Edge-to-edge Repair (TEER) for Mitral valve Regurgitation (MR) are sparse.
Purpose
To compare the outcome of patients with and without DM after TEER.
Methods
Retrospective monocentric assessment of patients after successful treatment of MR by TEER (exclusion of combined forms of transcatheter repair) between 06/2010 and 03/2018. Patients were stratified for DM at baseline and observed regarding mortality during follow-up. Cox regression analyses were performed for survival analyses.
Results
627 patients (47.0% females, 88.2% aged ≥70 years) and among these 174 subjects with DM (27.3%) were included with a median follow-up period of 486 days IQR 157–916 days). Within the investigation period, 20 patients (3.2%) were lost to follow-up. Patients with DM more often presented severe comorbidities like obesity (27.3% vs. 9.2%, p<0.001), arterial hypertension (91.4% vs. 83.7%, p=0.013), renal insufficiency (63.8% vs. 43.9%, p<0.001), coronary artery disease (77.0% vs. 59.8%, p<0.001) or peripheral artery disease (14.4% vs. 8.4%, p=0.026) and had a higher median logistic Euroscore I (29.4% 20.0/43.0 vs. 25.0% 16.7/36.6, p=0.001) as well as reduced systolic function (LVEF 35% 30/50 vs. 45% 30/55, p<0.001). No statistical differences in short- and long-term survival were detected between patients with and without DM (in-hospital mortality 1.7 vs. 2.6%, p=0.771; at 30-days 5.0 vs. 6.0%, p=0.842, 1-year 28.7 vs. 25.0%, p=0.419, 3-years 49.2 vs. 44.1%, p=0.554, 5-years 69.0 vs. 68.3%, p=0.497). By calculating cox regression analyses, DM was not predictive for a higher mortality, even after adjustment for other risk factors (HR 1-year 1.17 95% CI 0.80–1.71, p=0.419; HR long-term 1.13 95% CI 0.86–1.49, p=0.373) in the total cohort, as well as after stratification for the underlying mitral valve pathology (functional MR: 1-year HR 0.99 95% CI 0.01–1.62, p=0.969, long-term HR 0.903 95% CI 0.63–1.29, p=0.571; primary MR: 1-year HR 1.48 95% CI 0.66–3.35, p=0.344, long-term HR1.66 95% CI 0.89–3.09, p=0.110).
Conclusions
Even though DM-patients presented with a more vulnerable clinical profile, no relevant differences in short- and long-term mortality after TEER for MR were found. Although being factored in most common risk scores, DM could not be associated with an adverse prognosis after transcatheter therapy of MR.
Funding Acknowledgement
Type of funding sources: None.
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