Abstract Background Uncontrolled resistant hypertension (URH) is defined as PAS ≥140mmHg despite the adherence to at least 3 maximally tolerated doses of antihypertensive medications. In the adult population URH is a common condition with a prevalence that ranges between 10–15% and is related with poor prognosis and higher risk of major adverse cardiovascular events. Renal sympathetic denervation (RDN) has recently proved efficacy in different hypertensive subsets of patients. However, patients with chronic kidney disease (CKD) IIIB-V stages (i.e. glomerular filtrate rate <45 ml/min) have been systematically excluded from randomized clinical trials (RCT). Purpose To evaluate the safety and the efficacy of RDN in a daily practice population of patients with URH on top of medical therapy, including patients with renal function impairment (GFR<45ml/min). Methods Consecutive unselected patients with URH undergoing RDN were enrolled. Indication of RDN was assessed in a multidisciplinary team involving cardiologist, nephrologist and hypertension specialists, after secondary forms of hypertension had been excluded. Efficacy was defined as the inter-individual change of office (OBP) and ambulatory blood pressure monitoring (ABPM) at 3, 6 and 12 months after RDN. Safety as the absence of any device-related major complication (BARC classification), end-stage renal disease, stroke, acute myocardial infarction and any cause of death within 1 month of the procedure. Safety and efficacy profile was assessed in patients with an estimated GFR below 45 ml/min/1.73 m2. Results Seventy-two patients underwent RDN for URH from 2012 to 2022. The population presented with multiple comorbidities and target organ damage: almost 50% were smoker, 43% diabetic, 33% PAD, 25% CAD and 60% CKD. Isolated systolic hypertension prevalence was 53%. The average number of antihypertensive medications at baseline was 5.3±1.1. Baseline OBP and ABPM were 158.8/86.6±23.4/15.3 mmHg and 151.4/87.6±18.8/14.2 mmHg, respectively. The vast majority of the procedures were performed with tetrapolar radio-frequency catheter (91.7%), with 37.3±14.3 number of ablations per procedure. The average amount of contrast medium was 72.1±38.1 ml. At 12-month follow-up a significant reduction of office and ambulatory systolic BP, respectively by −15.66±29.73 mmHg (P<0.01) and by −11.3±23.1mmHg (P<0.05), was noticed. BP reduction at 12-month follow-up among patients with eGFR <45 ml/min was similar to that obtained in patients with higher eGFR. No major complications were observed and renal function was stable up to 12 months, even in patients with lowest eGFR at baseline. Conclusion(s) RDN is safe and feasible in patients with URH on top of medical therapy, even in a high-risk CKD population with multiple comorbidities. Our experience underlines the central role of multidisciplinary team evaluation for the targeted management of uncontrolled resistant hypertension. Funding Acknowledgement Type of funding sources: None.

Abstract Rationale In the clinical setting, and particularly in the cardiovascular field, an exponential increase of non–invasive diagnostic tests has been observed. Between these, the exercise stress test represents a low–sensitivity and low–specificity diagnostic approach and its use has been less and less recommended in national and international guidelines. However, in the Italian clinical common practice it continues to be extensively prescribed both for chronic coronary syndrome (CCS) follow–up and for screening of coronary artery disease (CAD) in asymptomatic patients with multiple cardiovascular risk factors. Materials and Methods A retrospective cohort single–center study was conducted and 968 consecutives patients undergoing ECG stress test at our Department between October 2018 and March 2019 were included. Appropriateness of prescription and impact on the following diagnostic and therapeutic pathway has been analyzed. Results In this series, the main indication for exercise stress test was subclinical ischemia detection in CCS follow–up (312 pts, 32.3%). 181 tests (18.2%) were undertaken for CAD detection in patients symptomatic for chest pain and 171 (17.7%) for CAD detection in asymptomatic patients with multiple cardiovascular risk factors. At last, 97 tests (10%) were prescribed for arrhythmic burden evaluation and exercise response in patients with documented hyperkinetic arrhythmias. 590 tests (61%) were considered significative for reaching heart rate significance threshold (85% of target heart rate); between these 53 (9%) were positives for symptoms or ECG modifications. Among the positive tests, 25 patients (2.6%) went to the catheterization laboratory for coronary angiography: the indications for the exercise stress testing were chest pain for 14 of these patients while 7 undertook the examination for CCS follow–up. No asymptomatic patient presented for CAD screening undertook coronary angiography. At the end of the diagnostic pathway, 9 patients (0.9% of the complete cohort) received percutaneous or surgical revascularization. Conclusions Routinary and extensive use of exercise stress test can lead to dispersion of resources with many inappropriate examinations. Accurate clinical evaluation and appropriate prescription, especially regarding chest pain evaluation, are the foundations for a significative impact on clinical history of patients.

Only one nasal spray antihistamine is currently marketed in the U.S. and there is limited information available on systemic levels of antihistamines administered via the nasal versus the oral routes. A model was developed to characterize epinastine systemic exposure after nasal administration and then compare and evaluate it to previously modeled data for a 20 mg tablet for potential therapeutic effectiveness due to known systemic exposure. A total of 420 plasma samples were utilized from the PK subset of SAR subjects (12M, 18F) participating in a Phase 2, randomized, double-blind, placebo-controlled study assigned to either epinastine nasal spray 0.05% or 0.1% (0.14 mg/dose or 0.28 mg/dose). The data from Day 1, 196 samples from 28 subjects, were analyzed using the WinNonlin® program according to a one-compartment model with first-order absorption and elimination. In addition, the final PK model was evaluated for fit to the Day 14 observed exposure. A one-compartment model with Levenberg modification best fit the data and the following noncompartmental parameters were generated for Cmax, Tmax and AUC for the 0.14 mg and 0.28 mg doses respectively: 0.205 ± 0.023, 0.459 ± 0.042 ng/mL; 65 ± 7, 84 ± 9 min; 129 ± 22, 269 ± 73 min.ng/mL (mean±SE). A PK model for epinastine was established and confirms that systemic exposure from intranasal dosages at 0.14 mg and 0.28 mg is linear, reaches steady state by Day 3 and based on Cmax and AUC is minimally 58-fold below the 20 mg oral dose modeling. Thus, the effectiveness of epinastine delivered as a nasal solution is due to local activity and not systemic exposure.

In patients with Alzheimer's disease, hippocampal cells are among the first neuronal cells of the brain to degenerate. Both rat primary hippocampal neurons and cells of the clonal mouse hippocampal cell line HT22 express endogenous functional glucocorticoid receptors (GRs), as shown by transient transfection of cells with a luciferase reporter plasmid containing GR-responsive elements. The influence of activated GRs on oxidative stress-induced neuronal cell death in vitro was investigated employing these hippocampal model systems. Two oxidative stressors were investigated, the free radical-inducing Alzheimer's disease-associated amyloid beta-protein, which is toxic to hippocampal neurons, and the excitatory amino acid glutamate, which induces oxidative cell death in HT22 cells via an increase in intracellular peroxides. Cellular viability was assessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide test and trypan exclusion staining, followed by microscopical cell counting. Glucocorticoids strongly increased the vulnerability of the hippocampal cells to amyloid beta-protein and glutamate. This increase could be blocked by the specific GR antagonist RU486. Our data suggest that changes in hippocampal GR homeostasis and regulation may render hippocampal neurons more vulnerable to oxidative stress-induced neuronal degeneration.

Transluminal coronary angioplasty has become an established form of treatment for coronary artery disease. The dilatation time is normally restricted by the ischaemic tolerance. Until today passive perfusion catheters have been used to maintain coronary blood flow to the distal segment. However, such continuous perfusion has often been insufficient to retain myocardial function. Active perfusion catheters, instead, have not been introduced so far for technical reasons. Active coronary perfusion via dilatation catheters with an intracorporal rotary micropump was the objective of investigations by Fraunhofer-IPA and the University of Essen. The result of the development activities was an internal geared pump with an outer diameter of 2.5 mm. Several design studies were undertaken to integrate the micropump in a PTCA catheter. The most important aspect of the integrated micropump is that the dilatation time can be prolonged. First in vitro tests with whole-blood showed acceptable mechanical haemolysis of the pump system. Further in vitro tests will lead to an optimized pump design with low mechanical haemolysis and a high flow rate.

Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases; one such ailment is Alzheimer's disease. Using the Alzheimer's disease-associated amyloid beta protein, glutamate, hydrogen peroxide, and buthionine sulfoximine, we investigated the neuroprotective potential of estrogen against oxidative stress-induced cell death. We show that 17-beta-estradiol, its nonestrogenic stereoisomer, 17-alpha-estradiol, and some estradiol derivatives can prevent intracellular peroxide accumulation and, ultimately, the degeneration of primary neurons, clonal hippocampal cells, and cells in organotypic hippocampal slices. The neuroprotective antioxidant activity of estrogens is dependent on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule but is independent of an activation of estrogen receptors.

The neuroleptic drug haloperidol is cytotoxic to cells of different origin in high doses. The mechanism of haloperidol toxicity may involve oxidative stress resulting in necrosis. In the present study, we show that rat pheochromocytoma PC12 cell clones which were selected for resistance to the toxicity of the oxidative stressor amyloid β-protein (A β), were also resistant to haloperidol toxicity. This data strongly supports the causative involvement of free radicals in haloperidol-induced cell death.

THE pineal hormone melatonin has been suggested to be a very effective antioxidant in the brain. Oxidative stress may play a role in certain neuropathological conditions and the hippocampus is an early target of neurodegeneration. Using cells of the clonal hippocampal cell line HT22 and organotypic hippocampal rat brain slice cultures, we investigated a possible protective role of melatonin against oxidative stress-induced hippocampal cell death. Glutamate alone induced oxidative apoptotic cell death in HT22 cells as detected with Hoechst staining and DNA fragmentation analysis. Preincubation with 1 mM melatonin protected HT22 cells against glutamate-induced cell death and protected organotypic hippocampal slices against H2O2-induced cell death. These findings suggest that this neurohormone may be useful in the prevention of neurodegenerative diseases.

Article Neue Werkzeuge für die minimalinvasive Therapie auf der Basis eines fluidisch angetriebenen, rotatorischen Mikromotors bzw. einer Mikropumpe was published on January 1, 1996 in the journal Biomedical Engineering / Biomedizinische Technik (volume 41, issue s1).

The potential antioxidant activity of 17-beta estradiol and other steroid hormones in neuronal cells was investigated by studying oxidative stress-induced cell death caused by the neurotoxins amyloid beta protein, hydrogen peroxide and glutamate in the clonal mouse hippocampal cell line HT22. Preincubation of the cells with 10(-5) M 17-beta estradiol prior to addition of the neurotoxins prevented oxidative stress-induced cell damage and ultimately cell death, as detected with cell viability (MTT) and cell lysis (trypan blue exclusion/cell counting; propidium iodide staining) assays. At the DNA level, 17-beta estradiol blocked the DNA degradation caused by glutamate. Other steroid hormones, such as progesterone, aldosterone, corticosterone and the steroid precursor cholesterol, did not protect the cells. The neuronal protection afforded by 17-beta estradiol was estrogen receptor-independent. These data demonstrate a potent neuroprotective activity of the antioxidant 17-beta estradiol, which may have implications for the prevention and treatment of Alzheimer's disease.

A patient with an intraluminal duodenal diverticulum causing the onset of symptoms at age 76 is reported. The features of roentgen diagnosis are illustrated. The embryological, clinical, and pathological characteristics of this rare anomaly are described.