Search

Dynamin plays an essential role in maintaining the structure and function of the glomerular filtration barrier. Specifically, dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, and knocking down dynamin expression causes proteinuria. Moreover, promoting dynamin oligomerization with Bis-T-23 restores podocyte function and reduces proteinuria in several animal models of chronic kidney disease. Thus, dynamin is a promising therapeutic target for treating chronic kidney disease. Here, we investigated the pathophysiological role of dynamin under proteinuric circumstances in a rat model and in humans. We found that glomerular Dnm2 and Dnm1 mRNA levels are increased prior to the onset of proteinuria in a rat model of spontaneous proteinuria. Also, in zebrafish embryos, we confirm that knocking down dynamin translation results in proteinuria. Finally, we show that the glomerular expression of dynamin and cathepsin L protein is increased in several human proteinuric kidney diseases. We propose that the increased expression of glomerular dynamin reflects an exhausted attempt to maintain and/or restore integrity of the glomerular filtration barrier. These results confirm that dynamin plays an important role in maintaining the glomerular filtration barrier, and they support the notion that dynamin is a promising therapeutic target in proteinuric kidney disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Brain health plays a central role in wellbeing and in the management of chronic diseases. Stroke and dementia pose the two greatest threats to brain health, but recent developments suggest the possibility that preventing stroke may also prevent some dementias: 1. A large population study showed a 32% decrease in the incidence of stroke and a concomitant 7% reduction in the incidence of dementia; 2. Treatment of atrial fibrillation resulted not only in stroke reduction, but a 48% decrease in dementia; 3. A hypothesis free analyses has shown that the first phase of Alzheimer disease involves vascular dysregulation, opening the door to new therapeutic approaches; 4. Cognitive impairment, often treatable and reversible, accompanies heart and kidney failure. These developments, combined with the knowledge that stroke, dementia and heart disease share the same major treatable risk factors, particularly hypertension, offers an opportunity for their joint prevention. This aspiration is expressed by a Proclamation of the World Stroke Organization on Stroke and Potentially Preventable Dementias and endorsed by the World Heart Federation, the World Hypertension League, Alzheimer Disease International and 18 other international, regional and national organizations as a call for action.

Aim Evidence on antithrombotic therapy use in centenarians diagnosed with atrial fibrillation (AF) is sparse. Our objective was to investigate a possible underprescribing in centenarians relative to younger cohorts of the oldest-old. We assumed lower AF rates; and, within AF patients, lower use of anticoagulants in those who died as centenarians (aged ≥100 years) than in those who died aged in their 80s (≥80 years) or 90s (≥90 years). Methods The present study was a quarterly structured cohort study over the 6 years before death using administrative data from German institutionalized and non-institutionalized insured patients (whole sample n = 1398 and subsample of AF patients n = 401 subclassified according to age-of-death groups [≥80, ≥90, ≥100 years]). AF, medication, stroke risk (Congestive heart failure; Hypertension; 2 × Age ≥75 years; Diabetes mellitus; 2 × Stroke; Vascular disease; Age 65-74 years; Sex [female] (CHA2 DS2 -VASc)) and risk of major bleeding (Hypertension; Abnormal renal and liver function; Stroke; Bleeding; Labile International Normalized Ratio [omitted in the present analysis]; Elderly; Drugs or alcohol (HAS-BLED)) were calculated. Generalized estimation equations were used to model the trajectories. Results Half a year before death (T1), AF rates were higher in patients aged ≥80 years (31.8%) and ≥90 years (30.6%) compared with patients aged ≥100 years (22.4%), whereas there were no significant differences between age groups 6 years before death (T0). Of all AF patients with AF at T1, 26.7% received anticoagulants; 11.2% vitamin K antagonists; 15.7% non-vitamin K antagonist oral anticoagulants; and 17.5% platelet inhibitors; yet 58.1% received none of these drugs. Centenarians received significantly fewer anticoagulants compared with the other age groups. Prescriptions of anticoagulants were not associated with CHA2 DS2 -VASc with and without adjustment for HAS-BLED. Conclusions The present findings highlight the need for more appropriate use of anticoagulation therapy in older patients, as well as for new treatment guidelines taking the heterogeneity of very old patients into account. Geriatr Gerontol Int 2018; 18: 1634-1640.

Purpose Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. Methods Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications. Results Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P = .026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P = .046) were independently associated with the occurrence of thromboembolic events. Conclusions Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.

Defects in nephrogenesis can have detrimental effects on cardiovascular and renal health in adult life. This is confirmed by observations in the Munich Wistar Fromter (MWF) rat that exhibits a congenital nephron deficit and renal failure with age. Here, we performed genome-wide transcriptome analysis in embryonic kidneys to identify candidate genes for the reduced nephron number in MWF. We compared MWF rats at embryonic day (E)15.5 with stage-matched spontaneously hypertensive rats (SHR) at E16. Microarray analysis revealed 311 transcripts representing 253 known genes with differential expression between MWF and SHR (fold change >+1.5 or

Background and Purpose The Munich Wistar Fromter (MWF) rat strain represents an experimental model to study cardiovascular alterations under conditions of progressive albuminuria. The aim of this study was to evaluate the association between genetic predisposition to albuminuria and the development of arterial stiffness and/or vascular remodelling. Experimental Approach Experiments were performed in mesenteric arteries from 12-week-old MWF, Wistar Kyoto (WKY) and consomic MWF-6SHR and MWF-8SHR rats in which chromosomes 6 or 8 associated with albuminuria from MWF were replaced by the respective chromosome from spontaneously hypertensive rats (SHR). Key Results Incremental distensibility, wall stress and strain were reduced, and arterial stiffness was significantly increased in albuminuric MWF compared with WKY. Albuminuria suppression in both consomic strains was associated with lower β-values in MWF-8SHR and MWF-6SHR compared with MWF. Moreover, elastin content was significantly lower in MWF external elastic lamina compared with WKY and both consomic strains. In addition, a reduction in arterial external and internal diameter and cross-sectional area was detected in MWF compared with WKY, thus exhibiting an inward hypotrophic remodelling. However, these alterations remained unchanged in both consomic strains. Conclusion and Implications These data demonstrate that albuminuria in MWF is associated with increased arterial stiffness due to a reduction of elastin content in the external elastic lamina. Moreover, inward hypotrophic remodelling in MWF is not directly associated with albuminuria. In contrast, we demonstrated that two major genetic loci affect both the development of albuminuria and arterial stiffness, thus linking albuminuria and impairment of mechanical properties of resistance arteries.

Aim Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case–control study to determine the hepatotoxic risk of a wide range of drugs. Methods The Berlin Case–Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case–control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. Results The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. Conclusions Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic.

Recognizing the ageing of populations and expected increase in prevalence of dementia, the necessity of research involving persons with dementia is widely agreed upon. Autonomy is key to nursing home residents' well-being and quality of life, but this phenomenon has not been thoroughly assessed from the residents' perspective. The aim of this cross-sectional study was to investigate perceived autonomy of nursing home residents. Data on 560 randomly selected residents in 40 nursing homes in two German federal states were generated by face-to-face interviews, psychological and physical assessments, analysis of nursing records, and acquisition of institutional parameters. This paper reports on a subsample (n = 179) that met screening requirements, including subjects with and without mild cognitive impairment (Mini Mental Status Examination score 30-18), who completed the Hertz Perceived Enactment of Autonomy Scale (HPEAS). The mean score of HPEAS was 101.1 ± 14.5 (range 54-122). In our population, Cronbach's alpha was 0.89. Scores in HPEAS were not related to demographical factors but positively associated with increasing self-efficacy and absence of pain. The novel findings contribute to an understanding of autonomy from the residents' perspective.

Background Current knowledge about the quality and appropriateness of pharmacological pain treatment in nursing home residents (NHR), particularly in NHR with moderate to severe cognitive impairment, is poor. Methods This observational cross-sectional study assessed pain treatment in a random sample of NHR with or without cognitive impairment from nursing homes in Germany. Prescribed drugs, pain intensity and frequency, diagnoses, and surgical procedures and injuries during the last 4 weeks were documented. Quality and appropriateness of pain medication were assessed by analysis of pain medications and the Pain Medication Appropriateness Scale (PMAS) score (SPMAS), with a cut-off value of >67% indicating appropriate pain treatment. Results A total of 321 residents (62% women) were studied, including 152 (47%) with severe cognitive impairment. The most frequently prescribed analgesics were dipyrone, fentanyl, tramadol and ibuprofen. The mean SPMAS was 48.5 ± 1.5 (range, −33 to +100). Residents with prescribed scheduled analgesics had a significantly better SPMAS than patients without such treatment (SPMAS 58 ± 1.5 vs. 37 ± 2.5, p

Rivaroxaban, an oral, direct factor Xa inhibitor, is a small molecule drug capable of inhibiting not only free factor Xa with high selectivity but also prothrombinase-bound and clot-associated factor Xa in a concentration-dependent manner. Clinical studies have demonstrated predictable anticoagulation and confirmed dose-proportional effects for rivaroxaban in humans with a rapid onset (within 2-4 h) and a half-life of 7-11 h and 11-13 h for young and elderly subjects, respectively. For a 10 mg dose, the oral bioavailability of rivaroxaban is high (80-100%) and is not affected by food intake. These favourable pharmacological properties underpin the use of rivaroxaban in fixed dosing regimens, with no need for dose adjustment or routine coagulation monitoring. Rivaroxaban has a dual mode of excretion with the renal route accounting for one-third of the overall elimination of unchanged active drug. Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein and therefore not recommended for concomitant use with strong inhibitors of both pathways, e.g. most azole antimycotics and protease inhibitors. Rivaroxaban is currently approved for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Studies using 10 mg rivaroxaban once daily in this indication demonstrated its suitability for a wide range of patients regardless of age, gender or body weight. Further studies in the treatment of VTE, prevention of cardiovascular events in patients with acute coronary syndrome, prevention of stroke in those with atrial fibrillation and prevention of VTE in hospitalized medically ill patients have been reported or are ongoing.

Purpose The current use of inappropriate medication in elderly nursing home residents (NHRs) in Germany is unclear. We therefore set out to analyse the frequency and patterns of potentially inappropriate drug prescriptions in elderly NHRs in Germany. Methods We utilised prescription data for NHRs 65 years or older from a large German health insurance company during a period of 3 months. Inappropriate drugs were identified from a recently reported French consensus list. Results Data for 7271 (83.7%) females and 1414 (16.3%) males were available for analysis. The average age was 83.6 ± 7.3 years. Overall 48 inappropriate drugs were prescribed resulting in a total of 3825 inappropriate drug prescriptions which accounted for 4.3% of all documented prescriptions (n = 88 695). One thousand nine hundred and three (21.9%) residents received at least one inappropriate drug prescription. Using logistic regression we detected no significant influence of gender or level of care on frequency of inappropriate prescriptions. However, age had a significant influence; with increasing age the frequency of residents receiving inappropriate medications decreased steadily (r = −0.92, p = 0.003) and ranged from a maximum of 32.8% in the group between 65 and 69 years to a minimum of 15.2% in residents older than 94 years. This observation was paralleled by a significant and continuous decrease of drug prescription rates with increasing age (r = −0.88, p = 0.009). Conclusion The present analysis demonstrates that about one out of five elderly NHRs received at least one inappropriate drug prescription. Additional studies may aim to establish a list of frequently prescribed inappropriate drugs for Germany. Copyright © 2010 John Wiley & Sons, Ltd.

We used YC-1 as a pharmacological tool to investigate the short-term blood pressure effects of NO-independent activation of sGC in normotensive and hypertensive rats. Four groups of normotensive Wistar-Kyoto rats were treated by i.v. injection with vehicle (V), YC-1 (YC-1), sodium nitroprusside (SNP), or YC-1 and SNP (YC-1+SNP). Hypertension was induced in four additional groups of WKY rats by 3 weeks of oral treatment with L-NAME. These animals were investigated with the same protocol as the normotensive animals: L-NAME/V, L-NAME/YC-1, L-NAME/SNP, L-NAME/YC-1+SNP. YC-1 lowered mean arterial blood pressure (MAP) in normotensive and hypertensive animals similarly to SNP alone (P

The purpose of this study was to evaluate the effects of short-term sympathetic inhibition with clonidine on blood pressure and renal responses to central hypervolaemia induced by thermoneutral head-out water immersion. Eleven healthy subjects were randomly studied on two occasions, during a 1 h pre-immersion period, 2 h of water immersion and a 1 h post-immersion period, after either placebo or clonidine treatment. Clonidine caused a significant suppression of plasma adrenaline, plasma noradrenaline, urinary noradrenaline excretion and mean arterial blood pressure. Blood pressure remained constant during water immersion after both placebo and clonidine, compared with the respective pre-immersion control values. The suppression pattern of plasma catecholamines and urinary noradrenaline in response to water immersion during placebo was similar after clonidine treatment. Renal volume excretion was not affected by clonidine. In contrast, clonidine caused a significant attenuation of the immersion-induced stimulation of natriuresis (maximum -33 +/- 12%, P < 0.01, compared with placebo). These data indicate that the renal capacity to excrete sodium is impaired during moderate blood pressure reduction by short-term sympathetic inhibition with clonidine, whereas the regulation of arterial blood pressure in response to central hypervolaemia is maintained.