Refine
Has Fulltext
- yes (348)
Is part of the Bibliography
- yes (348)
Year of publication
Document Type
- Journal article (348) (remove)
Keywords
- Fabry disease (19)
- chronic kidney disease (18)
- heart failure (17)
- adrenocortical carcinoma (13)
- mortality (13)
- inflammation (12)
- echocardiography (10)
- myocardial infarction (10)
- enzyme replacement therapy (9)
- hemodialysis (9)
Institute
- Medizinische Klinik und Poliklinik I (348) (remove)
Sonstige beteiligte Institutionen
- Zentraleinheit Klinische Massenspektrometrie (4)
- Apotheke, Universitätsklinikum Würzburg (1)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (1)
- Datenintegrationszentrum Würzburg (DIZ) (1)
- Interdisziplinäre Biomaterial- und Datenbank Würzburg (ibdw) (1)
- Interdisziplinäres Amyloidosezentrum Nordbayern (1)
- Johns Hopkins School of Medicine (1)
- Johns Hopkins University School of Medicine (1)
- Klinische Studienzentrale (Universitätsklinikum) (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.
Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE).
Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness.
Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.
Background: Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. Methods: We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 +/- 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR). Results: CAC (Agatston score > 100) and any AVC were present in 65% and in 40% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 +/- 0.81 vs 0.76 +/- 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 +/- 0.84 vs 1.35 +/- 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves. Conclusion: We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.
Background: International disease management guidelines recommend the regular assessment of depression and anxiety in heart failure patients. Currently there is little data on the effect of screening for depression and anxiety on the quality of life and the prognosis of heart failure (HF). We will investigate the association between the recognition of current depression/anxiety by the general practitioner (GP) and the quality of life and the patients' prognosis.
Methods/Design: In this multicenter, prospective, observational study 3,950 patients with HF are recruited by general practices in Germany. The patients fill out questionnaires at baseline and 12-month follow-up. At baseline the GPs are interviewed regarding the somatic and psychological comorbidities of their patients. During the follow-up assessment, data on hospitalization and mortality are provided by the general practice. Based on baseline data, the patients are allocated into three observation groups: HF patients with depression and/or anxiety recognized by their GP (P+/+), those with depression and/or anxiety not recognized (P+/-) and patients without depression and/or anxiety (P-/-). We will perform multivariate regression models to investigate the influence of the recognition of depression and/or anxiety on quality of life at 12 month follow-up, as well as its influences on the prognosis (hospital admission, mortality).
Discussion: We will display the frequency of GP-acknowledged depression and anxiety and the frequency of installed therapeutic strategies. We will also describe the frequency of depression and anxiety missed by the GP and the resulting treatment gap. Effects of correctly acknowledged and missed depression/anxiety on outcome, also in comparison to the outcome of subjects without depression/anxiety will be addressed. In case results suggest a treatment gap of depression/anxiety in patients with HF, the results of this study will provide methodological advice for the efficient planning of further interventional research.
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.
Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients.
Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62).
Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.
Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{−/−}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{−/−}\) bone marrow in 5-LOX\(^{−/−}\) animals), indicating that an altered function of 5-LOX\(^{−/−}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{−/−}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{−/−}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.
Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism.
Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI.
Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.
Background-—Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results-—Prospective follow-up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women’s Health Initiative Memory Study (WHIMS). CVD was determined by self-report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini-mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow-up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
Conclusions-—CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease.
METHODS:
A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.
RESULTS:
During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.
CONCLUSION:
Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.
Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 % males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.
The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-a led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.
Objectives
The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy.
Background
Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome.
Methods
LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days.
Results
Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35% vs. compensated 78%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14%, mild 27%, intermediate 67%, and severe 64%). Mid-septum LSsys<11% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival.
Conclusions
Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy.
Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients.
Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers.
Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance.
Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.
Background: The clinical signs of adrenal cortical insufficiency (incidence, ca. 25 per million per year; prevalence, ca. 400 per million) are nonspecific, and misdiagnoses are therefore common. Glucocorticoid substitution therapy has been in use for 50 years but is not a wholly adequate treatment. Our understanding of this disease remains incomplete in many ways.
Methods: We selectively searched the Medline database for publications on adrenal cortical insufficiency, with particular attention to studies from the year 2000 onward (search terms: "adrenal insufficiency" or "Addison's disease" or "hypopituitarism"). Results: Hydrocortisone substitution therapy is often given in doses of 10-25 mg/day, timed according to the circadian rhythm. Gastrointestinal and other, febrile infections account for 30-50% of life-threatening adrenocortical crises. Such crises affect 8 of 100 persons with adrenal cortical insufficiency per year and must be treated by the immediate administration of glucocorticoids and fluids. When persons with adrenal cortical insufficiency are acutely ill or are otherwise under unusual stress, they may need additional amounts of hydrocortisone, often in the range of 5-10 mg but occasionally as high as 200 mg. The sustained administration of excessive amounts of steroid can shorten patients' lives by several years. Inappropriate substitution therapy can cause other major medical conditions, such as metabolic syndrome and osteoporosis.
Conclusion: Important measures for the prevention of adrenocortical crises include improved care by treating physicians, education of patients and their families, the provision of emergency identifying documents, and the prescription of glucocorticoid emergency kits.
Background: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD).
Methods: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease.
Results: Study participants were at baseline on average 47 \(\pm\)13 years old and 65% were male. Mean \(\pm\) standard deviation of homoarginine concentrations were \(2.5 \pm 1.1 \mu mol/L\) and concentrations were incrementally lower at lower levels of GFR with mean concentrations of \(2.90 \pm 1.02 \mu mol/L\) (GFR. 90 ml/min), \(2.64 \pm 1.06 \mu mol/L\) (GFR 60-90 ml/min), \(2.52 \pm 1.24 \mu mol/L\) (GFR 30-60 ml/min) and \(2.05 \pm 0.78 \mu mol/L\) (GFR, 30 ml/min), respectively (p = 0.002). The age-and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (\(1.1 \mu mol/L\)) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06).
Conclusions: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.
PDZ (PSD-95/Disc large/Zonula occludens-1) protein interaction domains bind to cytoplasmic protein C-termini of transmembrane proteins. In order to identify new interaction partners of the voltage-gated L-type \(Ca^{2+}\) channel Cav1.2 and the plasma membrane \(Ca^{2+}\) ATPase 4b (PMCA4b), we used PDZ domain arrays probing for 124 PDZ domains. We confirmed this byGST pulldowns and immunoprecipitations. In PDZ arrays, strongest interactionswith \(Ca_v1.2\) and PMCA4b were found for the PDZ domains of SAP-102, MAST-205, MAGI-1, MAGI-2, MAGI-3, and ZO-1. We observed binding of the \(Ca_v1.2\) C-terminus to PDZ domains of NHERF1/2, Mint-2, and CASK. PMCA4b was observed to interact with Mint-2 and its known interactions with Chapsyn-110 and CASK were confirmed. Furthermore, we validated interaction of \(Ca_v1.2\) and PMCA4b with NHERF1/2, CASK,MAST-205 and MAGI-3 viaimmunoprecipitation. We also verified the interaction of \(Ca_v1.2\) and nNOS and hypothesized that nNOS overexpression might reduce \(Ca^{2+}\) influx through \(Ca_v1.2\). To address this, we measured \(Ca^{2+}\) currents in HEK 293 cells co-expressing \(Ca_v1.2\) and nNOS and observed reduced voltage-dependent \(Ca_v1.2\) activation. Taken together, we conclude that \(Ca_v1.2\) and PMCA4b bind promiscuously to various PDZ domains, and that our data provides the basis for further investigation of the physiological consequences of these interactions.
Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF). Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. Methods and Results. Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17%of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. Conclusion. Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure.
Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined.
Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality.
Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.
Background
Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies.
Methods
Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition.
Results
Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease.
Conclusion
Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients.
The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.
Background Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results: Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
Conclusions: CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.
Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
Background
Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP).
Methods
In this case–control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function.
Results
All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients.
Conclusion
Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.
A 74-year-old man was admitted to the cardiac catheterization laboratory with acute myocardial infarction. After successful angioplasty and stent implantation into the right coronary artery, he developed cardiogenic shock the following day. Echocardiography showed ventricular septal rupture. Cardiac magnet resonance imaging (MRI) was performed on the critically ill patient and provided detailed information on size and localization of the ruptured septum by the use of fast MRI sequences. Moreover, the MRI revealed that the ventricular septal rupture was within the myocardial infarction area, which was substantially larger than the rupture. As the patient’s condition worsened, he was intubated and had intra-aortic balloon pump implanted, and extracorporeal membrane oxygenation was initiated. During the following days, the patient’s situation improved, and surgical correction of the ventricular septal defect could successfully be performed. To the best of our knowledge, this case report is the first description of postinfarction ventricular septal rupture by the use of cardiac MRI in an intensive care patient with cardiogenic shock and subsequent successful surgical repair.
Background
The aortic pulse-wave velocity (PWV) is an important indicator of cardiovascular risk. In recent studies MRI methods have been developed to measure this parameter noninvasively in mice. Present techniques require additional hardware for cardiac and respiratory gating. In this work a robust self-gated measurement of the local PWV in mice without the need of triggering probes is proposed.
Methods
The local PWV of 6-months-old wild-type C57BL/6J mice (n=6) was measured in the abdominal aorta with a retrospectively triggered radial Phase Contrast (PC) MR sequence using the flow-area (QA) method. A navigator signal was extracted from the CMR data of highly asymmetric radial projections with short repetition time (TR=3 ms) and post-processed with high-pass and low-pass filters for retrospective cardiac and respiratory gating. The self-gating signal was used for a reconstruction of high-resolution Cine frames of the aortic motion. To assess the local PWV the volume flow Q and the cross-sectional area A of the aorta were determined. The results were compared with the values measured with a triggered Cartesian and an undersampled triggered radial PC-Cine sequence.
Results
In all examined animals a self-gating signal could be extracted and used for retrospective breath-gating and PC-Cine reconstruction. With the non-triggered measurement PWV values of 2.3±0.2 m/s were determined. These values are in agreement with those measured with the triggered Cartesian (2.4±0.2 m/s) and the triggered radial (2.3±0.2 m/s) measurement. Due to the strong robustness of the radial trajectory against undersampling an acceleration of more than two relative to the prospectively triggered Cartesian sampling could be achieved with the retrospective method.
Conclusion
With the radial flow-encoding sequence the extraction of a self-gating signal is feasible. The retrospective method enables a robust and fast measurement of the local PWV without the need of additional trigger hardware.
Background
Published models predicting nasal colonization with Methicillin-resistant Staphylococcus aureus among hospital admissions predominantly focus on separation of carriers from non-carriers and are frequently evaluated using measures of discrimination. In contrast, accurate estimation of carriage probability, which may inform decisions regarding treatment and infection control, is rarely assessed. Furthermore, no published models adjust for MRSA prevalence.
Methods
Using logistic regression, a scoring system (values from 0 to 200) predicting nasal carriage of MRSA was created using a derivation cohort of 3091 individuals admitted to a European tertiary referral center between July 2007 and March 2008. The expected positive predictive value of a rapid diagnostic test (GeneOhm, Becton & Dickinson Co.) was modeled using non-linear regression according to score. Models were validated on a second cohort from the same hospital consisting of 2043 patients admitted between August 2008 and January 2012. Our suggested correction score for prevalence was proportional to the log-transformed odds ratio between cohorts. Calibration before and after correction, i.e. accurate classification into arbitrary strata, was assessed with the Hosmer-Lemeshow-Test.
Results
Treating culture as reference, the rapid diagnostic test had positive predictive values of 64.8% and 54.0% in derivation and internal validation corhorts with prevalences of 2.3% and 1.7%, respectively. In addition to low prevalence, low positive predictive values were due to high proportion (> 66%) of mecA-negative Staphylococcus aureus among false positive results. Age, nursing home residence, admission through the medical emergency department, and ICD-10-GM admission diagnoses starting with “A” or “J” were associated with MRSA carriage and were thus included in the scoring system, which showed good calibration in predicting probability of carriage and the rapid diagnostic test’s expected positive predictive value. Calibration for both probability of carriage and expected positive predictive value in the internal validation cohort was improved by applying the correction score.
Conclusions
Given a set of patient parameters, the presented models accurately predict a) probability of nasal carriage of MRSA and b) a rapid diagnostic test’s expected positive predictive value. While the former can inform decisions regarding empiric antibiotic treatment and infection control, the latter can influence choice of screening method.
Background
Laxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated.
Methods
This prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3-year follow-up visit on everyone. Data on self-reported falls (≥2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI.
Results
Age-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate-adjusted hazard ratios for any laxative use were 1.06 (95% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95% CI, 0.85-1.22) for hip fractures and 1.01 (95% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake.
Conclusion
These findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use.
Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner’s diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, ‘GOLD-COPD’ misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.
Nephrogenic Systemic Fibrosis is a rare condition appearing only in patients with severe renal impairment or failure and presents with dermal lesions and involvement of internal organs. Although many cases are mild, an estimated 5 % have a progressive debilitating course. To date, there is no known effective treatment thus stressing the necessity of ample prevention measures. An association with the use of Gadolinium based contrast agents (GBCA) makes Nephrogenic Systemic Fibrosis a potential side effect of contrast enhanced magnetic resonance imaging and offers the opportunity for prevention by limiting use of gadolinium based contrast agents in renal failure patients. In itself toxic, Gadolinium is embedded into chelates that allow its safe use as a contrast agent. One NSF theory is that Gadolinium chelates distribute into the extracellular fluid compartment and set Gadolinium ions free, depending on multiple factors among which the duration of chelates exposure is directly related to the renal function. Major medical societies both in Europe and in North America have developed guidelines for the usage of GBCA. Since the establishment of these guidelines and the increased general awareness of this condition, the occurrence of NSF has been nearly eliminated. Giving an overview over the current knowledge of NSF pathobiochemistry, pathogenesis and treatment options this review focuses on the guidelines of the European Medicines Agency, the European Society of Urogenital Radiology, the FDA and the American College of Radiology from 2008 up to 2011 and the transfer of this knowledge into every day practice.
Magnetic resonance imaging can be used for preprocedural assessment of complex anatomy for radiofrequency (RF) ablations, e.g., in a univentricular heart. This case report features the treatment of a young patient with a functionally univentricular heart who suffered from persistent sudden onset tachycardia with wide complexes that required RF ablation as treatment.
Background
Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting.
Methods
Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary.
Results
120 patients were screened, 109 enrolled (median age 71; range 26–90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23–6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8. 15.7 ± 14.3% of the dialysis filters’ visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400–6000) and 4200 (3000–6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95%CI 0.21–0.27], 0.33 [0.27–0.40] and 0.38 [0.33–0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01–0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19–3.24] and 3.66 [3.00–4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected.
Conclusions
Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.
One of the main shortcomings of interventional electrophysiology (EP) is its inability to generate sufficient soft tissue contrast for intra-procedural visualization of the myocardium and the surrounding tissue, using conventional imaging techniques. Interventional cardiovascular magnetic resonance imaging (MRI) aims at bringing about significant improvements to the complex and decisive EP interventions far beyond the capabilities of currently available supportive imaging techniques used to surmount the drawbacks of fluoroscopy, as MRI not only allows of precise three-dimensional exposure of the cardiovascular morphology, but also proves to be a promising technique exclusively suitable for direct visualization of arrhythmogenic substrate and therapeutic effects. The major challenge posed by clinical …
Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta.
Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression.
Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year).
Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5x10\(^{-32}\) 3x10\(^{-10}\), with heterogeneity detected only at the PSMB9/TAP1 locus (I\(^{-2}\) = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5x10\(^{-4}\)). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3x10\(^{-128}\)). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.
Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60 min). Following 24 h of reperfusion, inulin-and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury.
Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial-(L/E) and platelet/endothelial-(P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme.
Principal Findings: Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE\(^{-/-}\)/eNOS\(^{-/-}\)), while P/E-interactions did not differ, compared to apoE\(^{-/-}\). eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE\(^{-/-}\) vessels.
Conclusion: Overt plaque formation, increased vascular inflammation and L/E-interactions are associated with significant reduction of superoxide production in apoE\(^{-/-}\)/eNOS\(^{-/-}\) vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE\(^{-/-}\) atherosclerosis but does not negate the enzyme's strong protective effects.
Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures
(2012)
Background: One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating.
Methods: A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip. Results: A maximum temperature rise of 22.4 degrees C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2 degrees C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8 degrees C.
Conclusion: Up to a maximum of 22.4 degrees C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner.
The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>= 20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.
Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting.
Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary.
Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23-6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8.15.7 +/- 14.3% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected.
Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.
Background: It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins. Methods and Findings: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78-1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72-1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76-1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82-1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80-1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Conclusions: The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out. Please see later in the article for the Editors' Summary.
Context:
Adrenal tumors have a prevalence of around 2% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2–11% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values.
Objective:
Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy.
Design:
Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19–84 yr) and 45 ACC patients (20–80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26–201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids.
Results:
Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88% (area under the curve = 0.96) when using only the nine most differentiating markers.
Conclusions:
Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas.
Background:
Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo.
Methods:
In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection.
Results:
We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection.
Conclusions:
Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection.
Aim
To investigate whether diagnostic data from implanted cardiac resynchronization therapy defibrillators (CRT-Ds) retrieved automatically at 24 h intervals via a Home Monitoring function can enable dynamic prediction of cardiovascular hospitalization and death.
Methods and results
Three hundred and seventy-seven heart failure patients received CRT-Ds with Home Monitoring option. Data on all deaths and hospitalizations due to cardiovascular reasons and Home Monitoring data were collected prospectively during 1-year follow-up to develop a predictive algorithm with a predefined specificity of 99.5%. Seven parameters were included in the algorithm: mean heart rate over 24 h, heart rate at rest, patient activity, frequency of ventricular extrasystoles, atrial–atrial intervals (heart rate variability), right ventricular pacing impedance, and painless shock impedance. The algorithm was developed using a 25-day monitoring window ending 3 days before hospitalization or death. While the retrospective sensitivities of the individual parameters ranged from 23.6 to 50.0%, the combination of all parameters was 65.4% sensitive in detecting cardiovascular hospitalizations and deaths with 99.5% specificity (corresponding to 1.83 false-positive detections per patient-year of follow-up). The estimated relative risk of an event was 7.15-fold higher after a positive predictor finding than after a negative predictor finding.
Conclusion
We developed an automated algorithm for dynamic prediction of cardiovascular events in patients treated with CRT-D devices capable of daily transmission of their diagnostic data via Home Monitoring. This tool may increase patients’ quality of life and reduce morbidity, mortality, and health economic burden, it now warrants prospective studies.
Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death.
Background:
Competing risks methodology allows for an event-specific analysis of the single components of composite time-to-event endpoints. A key feature of competing risks is that there are as many hazards as there are competing risks. This is not always well accounted for in the applied literature.
Methods:
We advocate a simulation point of view for understanding competing risks. The hazards are envisaged as momentary event forces. They jointly determine the event time. Their relative magnitude determines the event type. 'Empirical simulations' using data from a recent study on cardiovascular events in diabetes patients illustrate subsequent interpretation. The method avoids concerns on identifiability and plausibility known from the latent failure time approach.
Results:
The 'empirical simulations' served as a proof of concept. Additionally manipulating baseline hazards and treatment effects illustrated both scenarios that require greater care for interpretation and how the simulation point of view aids the interpretation. The simulation algorithm applied to real data also provides for a general tool for study planning.
Conclusions:
There are as many hazards as there are competing risks. All of them should be analysed. This includes estimation of baseline hazards. Study planning must equally account for these aspects.
Background:
To assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function.
Methods:
3304 patients with heart failure from 9 different studies were included (mean age 63 +/- 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (>= 50%) and 994 patients in the whole cohort suffered from diabetes.
Results:
The majority (>90%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function.
Conclusions:
Diabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function.
Aims
Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients.
Methods and results
This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95% CI 2.0–4.9), attenuating slightly in multivariate models (HR 2.4; 95% CI 1.5–3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected.
Conclusion
Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.
Background:
Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs).
Objective:
We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice.
Methods:
Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers.
Results:
Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5% vs 3.4 +/- 1.5%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5%; * p < 0.05).
Conclusion:
Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.
Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and naı¨ve mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.861.86104 cells/ml vs. 336116104 in control mice) and spleen (dexamethasone: 2.861.96105/spleen vs. 956226105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.061.5% vs 3.461.5%*; AITR+: 0.660.4 vs 0.560.3%, CD127low: 4.061.3 vs 5.063.0%* and CTLA4+: 13.8611.5 vs 15.6612.5%; * p,0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers.
Background
The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-naïve population.
Methods and Findings
HIVDR was determined in 88 sequentially enrolled ART-naïve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25–63 years. The frequency of HIVDR in the study population was 14.8% (95%; CI 0.072–0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1%; 95% CI 0.095–0.28) versus 0%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma.
Conclusions
ART-naïve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-naïve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-naïve HIV-infected population.
Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.
Background
Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far.
Methods and results
The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p < 0.001) and higher SF-36 PF score (54.4 ± 28.3 vs. 54.4 ± 27.7, p < 0.001). All comorbidities were significantly (p < 0.05) more frequent in HFrEF, except hypertension and obesity, which were more frequent in HFpEF (p < 0.001). Adjusting for age and gender, COPD, anemia, hyperuricemia, atrial fibrillation, renal dysfunction, cerebrovascular disease and diabetes had a similar (p for interaction > 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r 2) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF.
Conclusion
The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF.
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Thermodynamics of Competitive Molecular Channel Transport: Application to Artificial Nuclear Pores
(2010)
In an analytical model channel transport is analyzed as a function of key parameters, determining efficiency and selectivity of particle transport in a competitive molecular environment. These key parameters are the concentration of particles, solvent-channel exchange dynamics, as well as particle-in-channel- and interparticle interaction. These parameters are explicitly related to translocation dynamics and channel occupation probability. Slowing down the exchange dynamics at the channel ends, or elevating the particle concentration reduces the in-channel binding strength necessary to maintain maximum transport. Optimized in-channel interaction may even shift from binding to repulsion. A simple equation gives the interrelation of access dynamics and concentration at this transition point. The model is readily transferred to competitive transport of different species, each of them having their individual in-channel affinity. Combinations of channel affinities are determined which differentially favor selectivity of certain species on the cost of others. Selectivity for a species increases if its in-channel binding enhances the species’ translocation probablity when compared to that of the other species. Selectivity increases particularly for a wide binding site, long channels, and fast access dynamics. Recent experiments on competitive transport of in-channel binding and inert molecules through artificial nuclear pores serve as a paradigm for our model. It explains qualitatively and quantitatively how binding molecules are favored for transport at the cost of the transport of inert molecules.
Background: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany.
Methods: Data from the German ACC registry were analyzed with regard to the patients’ preoperative diagnostic evaluation, histopathological reporting, and clinical followup. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT).
Results: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21% of them underwent no hormonal evaluation before surgery, and 59% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all.
Conclusion: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers.