Temporary threshold shift after noise exposure in hypobaric hypoxia at high altitude: results of the ADEMED expedition 2011.

OBJECTIVES: To evaluate whether there is an increased risk for noise-induced hearing loss at high altitude rsp. in hypobaric hypoxia. METHODS: Thirteen volunteers got standard audiometry at 125, 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, and 8000 Hz before and after 10 min of white noise at 90 dB. The system was calibrated for the respective altitude. Measurements were performed at Kathmandu (1400 m) and at Gorak Shep (5300 m) (Solo Khumbu/Nepal) after 10 days of acclimatization while on trek. Temporary threshold shift (TTS) was analyzed by descriptive statistics and by factor analysis. RESULTS: TTS is significantly more pronounced at high altitudes. Acclimatization does not provide any protection of the inner ear, although it increases arterial oxygen saturation. CONCLUSION: The thresholds beyond which noise protection is recommended (> 80 dB) or necessary (> 85 dB) are not sufficient at high altitudes. We suggest providing protective devices above an altitude of 1500 m ("ear threshold altitude") when noise level is higher than 75 dB and using them definitively above 80 dB. This takes the individual reaction on hypobaric hypoxia at high altitude into account.

[Interventional treatment of high blood pressure-Current state]. / Interventionelle Therapien bei Hypertonie ­ aktueller Stand.

Arterial hypertension is a real global burden with a very high prevalence. In the last decades, many pharmaceutical approaches have been successfully developed for treating hypertension. Currently, novel medications for influencing blood pressure are not in sight. In recent years alternatives, such as interventional procedures for reducing blood pressure, have been developed and tested. Ablation of the renal sympathetic nerves (renal denervation, RDN), which are wrapped around the renal arteries in particular, has been intensively investigated as a procedure. After the first RDN studies a clear influence on the blood pressure could be shown; however, in the first sham-controlled studies the reduction in blood pressure by RDN could no longer consistently be shown. In very systematic sham-controlled, blinded studies in patients with hypertension but without medication a robust blood pressure reducing effect of RDN could be shown, which corresponded to the effect of a blood pressure-reducing drug. It is obvious that larger studies and also long-term studies have to sustainably confirm this effect. In recent years, active and passive stimulation of the baroreceptors could also be established as a blood pressure reducing principle, at least in studies but the evidence is still very low.

Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells.

Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism.

[Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. / Barorezeptorakivierungstherapie bei therapierefraktärer Hypertonie: Indikation und Patientenselektion : Empfehlungen der BAT-Konsensusgruppe 2017.

Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3.

Endothelial nitric oxide synthase (eNOS) plays a crucial role in vascular homeostasis. Lysophospholipid interaction with sphingosine 1-phosphat (S1P) receptors results in eNOS activation in different cells. In endothelial cells, eNOS activation via S1P1 or S1P3 was shown controversially. The aim of this study is to investigate the meaning of both S1P receptors for eNOS activation in human endothelial cells. Therefore, several S1P1 and S1P3 agonists in combination with antagonists and specific RNAi approach were used. eNOS activation was measured in human umbilical vein endothelial cells (HUVEC) via DAF2-DA-based fluorescence microscopy. For investigation of the signaling pathway, agonists/antagonist studies, RNAi approach, Luminex™ multiplex, and Western Blot were used. In HUVEC, both the S1P1 agonist AUY954 as well as the S1P1,3 agonist FTY720P induced eNOS activation in a time- and dose-dependent manner. Other S1P1 agonists activated eNOS to a lesser extent. The AUY954-induced eNOS activation was blocked by the S1P1 antagonist W146, the combination of W146 and the S1P3 antagonist CAY10444 and the S1P1,3 antagonist VPC23019, but not by CAY10444 indicating the meaning of S1P1 for the AUY954-induced eNOS activation. The FTY720P-induced eNOS activation was blocked only by the combination of W146 and CAY10444 and the combined S1P1,3 antagonist VPC23019, but not by W146 or CAY10444 indicating the importance of both S1P1 and S1P3 for FTY720-induced eNOS activation. These results were confirmed using specific siRNA against S1P1 and S1P3. The S1P1,3 activation results in Akt phosphorylation and subsequent activation of eNOS via phosphorylation at serine(1177) and dephosphorylation at threonine(495). Beside former investigations with rather unspecific S1P receptor activation these data show potent selective S1P1 activation by using AUY954 and with selective S1P receptor inhibition evidence was provided that both S1P1 and S1P3 lead to downstream activation of eNOS in HUVEC in the same experimental setting. Inhibition or knockdown of one of these receptor subtypes did not abolish the eNOS activation and subsequent NO production.

Central blood pressure assessment using oscillometry is feasible for everyday clinical practice.

The benefit of the central systolic blood pressure (cSBP) has already been recognized, but its general measurement in the everyday routine is still limited mainly because available established non-invasive assessment devices are not suitable for everyday use. In this study, we investigated the performance of an oscillometric device Tel-O-GRAPH for cSBP assessment in terms of suitability for everyday clinical use. One hundred and three patients were prospectively included. cSBP was computed by Tel-O-GRAPH compared with Sphygmocor using applanation tonometry. There was a good agreement between Tel-O-GRAPH and Sphygmocor for cSBP (mean difference±s.d.: -0.3±6.7 mm Hg; Pearson's R=0.95; P<0.0001). Recorded cSBP values in the supine vs seated position and for the experienced vs non-experienced user did not significantly differ (mean cSBPsupine 122.1±13.9 mm Hg vs cSBPseated 120.7±15.7 mmHg; cSBPnon-experienced 120.6±20.5 mm Hg and cSBPexperienced 119.2±19.9 mm Hg). The mean difference of cSBP between supine and seated positions was 1.5±6.8 and -1.4±5.0 mm Hg between experienced and non-experienced users. This study showed good accuracy in assessing cSBP with an oscillometric BP measurement device Tel-O-GRAPH compared with a Sphygmocor. Furthermore, the calculation of cSBP by Tel-O-GRAPH appears to be easy and can be done during the routine brachial BP measurement. Computed cSBP values seem to remain reliable independently of the patient body position and experience of the operator. Consequently, the easiness of utilization and reliability of the device may open the opportunity for its extended use in everyday clinical practice, as well as reliable alternative for clinical studies, making complex applanation tonometry dispensable.

In vivo TLR9 inhibition attenuates CpG-induced myocardial dysfunction.

The involvement of toll-like receptor 9 (TLR9), a receptor for bacterial DNA, in septic cardiac depression has not been clarified in vivo. Thus, the aim of the study was to test possible TLR9 inhibitors (H154-thioate, IRS954-thioate, and chloroquine) for their ability to protect the cardiovascular system in a murine model of CpG oligodeoxynucleotide- (ODN-) dependent systemic inflammation. Sepsis was induced by i.p. application of the TLR9 agonist 1668-thioate in C57BL/6 wild type (WT) and TLR9-deficient (TLR9-D) mice. Thirty minutes after stimulation TLR9 antagonists were applied i.v. Survival was monitored up to 18 h after stimulation. Cardiac mRNA expression of inflammatory mediators was analyzed 2 h and 6 h after stimulation with 1668-thioate and hemodynamic parameters were monitored at the later time point. Stimulation with 1668-thioate induced a severe sepsis-like state with significant drop of body temperature and significantly increased mortality in WT animals. Additionally, there was a time-dependent increase of inflammatory mediators in the heart accompanied by development of septic heart failure. These effects were not observed in TLR9-D mice. Inhibition of TLR9 by the suppressive ODN H154-thioate significantly ameliorated cardiac inflammation, preserved cardiac function, and improved survival. This suppressive ODN was the most efficient inhibitor of the tested substances.

Renal denervation for refractory hypertension - technical aspects, complications and radiation exposure.

PURPOSE: To analyze procedural details, complications and radiation exposure in renal denervation (RDN) using the Medtronic Symplicity® device in the treatment of refractory hypertension. MATERIALS AND METHODS: Fifty three consecutive patients underwent RDN. The number of ablations per artery, peri-procedural complications, procedure time (PT), fluoroscopy time (FT), dose-area product (DAP) and procedure-related complications were documented. Additionally, the radiation dose was compared between obese (body mass index ≥ 30 kg/m(2)) and non-obese patients. RESULTS: Bilateral RDN was performed in 50/53 (94 %) cases and with a minimum of 4 ablations per artery in 33/50 (66 %), the mean count being 5.4 (range R: 2 - 13) on the right and 4.3 (R: 1 - 10) on the left. The FT and DAP decreased significantly over the first 12 procedures, reaching a steady state with a median FT of 11.2 min (R: 7.5 - 27) and a median DAP of 4796 cGy × cm(2) (R: 1076 - 21 371), resulting in an effective dose of 15.7 mSv. The median PT was 57 min (R: 40 - 70). Obese patients had a 3.3-fold higher radiation dose (p < 0.001). We observed one severe spasm and one imminent respiratory depression, both resolved without sequelae. CONCLUSION: For an experienced interventionalist, RDN has a short learning curve with a low risk profile. The radiation dose does not exceed that of other renal artery interventions, but is explicitly higher in obese patients, who account for a large portion of patients with refractory hypertension.

Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine.

BACKGROUND: Recurrent urinary tract infections (UTIs) increase mortality and reduce graft survival after renal transplantation. Strategies to prevent recurrent UTIs include L-methionine, cranberry juice, and antibiotics. Data on the efficacy of cranberry and L-methionine, however, are controversial in the general population; there are few data in renal transplant recipients. METHODS: We performed a retrospective analysis of 82 transplant recipients with recurrent UTIs, who underwent prophylaxis with cranberry juice (2 × 50 mL/d, n = 39, 47.6%), or L-methionine (3 × 500 mg/d, n = 25, 30.5%), or both modalities (n = 18, 21.9%). Thirty patients without prophylaxis served as controls. We analyzed symptoms, pyuria/nitrituria, and incidence of UTI events during 1 year before versus after initiation of prophylaxis. RESULTS: Prophylaxis highly significantly decreased the annual UTI incidence by 58.3% (P < .001) in the study population with no change in the control group (P = .85); in addition, 53.7% of symptomatic patients reported relief of symptoms and pyuria/nitrituria disappeared in 42.4% of the dipstick-positive patients (P < .001 each). Cranberry reduced the annual number of UTI episodes by 63.9% from 3.6 ± 1.4 to 1.3 ± 1.3/year (P < .001) and L-methionine by 48.7% from 3.9 ± 1.8 to 2.0 ± 1.3/year (P < .001). CONCLUSION: Cranberry juice and L-methionine successfully reduced the incidence of UTI after renal transplantation.

Intraoperative assessment of kidney allograft perfusion by laser-assisted indocyanine green fluorescence videography.

BACKGROUND: Kidney allograft function crucially depends on the quality of organ perfusion. Duplex sonography, however, frequently reveals hypoperfused segments that remained undetectable to visual inspection intraoperatively. To date, no imaging system supplementing the surgeon's experience has achieved clinical acceptance. The present work examines whether laser-assisted indocyanine green (ICG) fluorescence-videography can be used as a safe and sensitive technique for the intraoperative assessment of renal allograft perfusion. METHODS: Intraoperative assessment of organ perfusion by laser-assisted ICG fluorescence videography (IC-VIEW) was performed in 10 consecutive de novo renal transplantations. The IC-VIEW system allows the visualization of graft perfusion by the fluorescein dye ICG that emits infrared light after exposure to laser light. RESULTS: Perfusion measurements were successful in all 10 transplant recipients. Fluorescence videography produced brilliant, sharply contrasted images of the organs, allowing the detection of even small perfusion deficits. Remarkably, this technique detected 1 large perfusion defect that had remained imperceptible to visual inspection. Repositioning of the graft led to a homogeneous overall perfusion. There were no complications with the ICG injection or the imaging device. CONCLUSION: Laser-assisted ICG fluorescence videography is a feasible and safe technique for the intraoperative assessment of renal allograft perfusion.

A new oscillometric method for pulse wave analysis: comparison with a common tonometric method.

In the European Society of Cardiology-European Society of Hypertension guidelines of the year 2007, the consequences of arterial stiffness and wave reflection on cardiovascular mortality have a major role. But the investigators claimed the poor availability of devices/methods providing easy and widely suitable measuring of arterial wall stiffness or their surrogates like augmentation index (AIx) or aortic systolic blood pressure (aSBP). The aim of this study was the validation of a novel method determining AIx and aSBP based on an oscillometric method using a common cuff (ARCSolver) against a validated tonometric system (SphygmoCor). aSBP and AIx measured with the SphygmoCor and ARCSolver method were compared for 302 subjects. The mean age was 56 years with an s.d. of 20 years. At least two iterations were performed in each session. This resulted in 749 measurements. For aSBP the mean difference was -0.1 mm Hg with an s.d. of 3.1 mm Hg. The mean difference for AIx was 1.2% with an s.d. of 7.9%. There was no significant difference in reproducibility of AIx for both methods. The variation estimate of inter- and intraobserver measurements was 6.3% for ARCSolver and 7.5% for SphygmoCor. The ARCSolver method is a novel method determining AIx and aSBP based on an oscillometric system with a cuff. The results agree with common accepted tonometric measurements. Its application is easy and for widespread use.

The impact of pulse pressure on the accuracy of wrist blood pressure measurement.

There is an increasing number of wrist blood pressure measurement devices that successfully passed the validation procedures of the British Hypertension Society (BHS) and the European Society of Hypertension (ESH). It remains unknown, however, whether pulse pressure as a marker of arterial stiffness and vascular ageing affects the accuracy of these devices. An ESH protocol validated wrist device was compared with the upper arm mercury sphygmomanometry in a study population (33 patients, 99 measurements) including a relevant number of subjects with pulse pressure >50 mm Hg (84.8%) and isolated systolic hypertension (27.3%). Mean systolic bias was 10.2 mm Hg with 95% limits of agreement of -13.1 and 33.6 mm Hg, mean diastolic bias was 4.8 mm Hg with limits of agreement of -11.0 and 20.7 mm Hg. The impact of body mass index, age, systolic blood pressure and pulse pressure on the absolute value of blood pressure bias was tested by stepwise multiple regression analysis. The systolic bias significantly depended on pulse pressure, whereas there was no significant effect of the independent variables on the diastolic bias. Separate correlation analysis showed a significant correlation between pulse pressure and both absolute systolic bias (Pearson r=0.48, P<0.001) and relative systolic bias (systolic bias divided by systolic blood pressure, Pearson r=0.29, P=0.003). Even well-validated wrist blood pressure devices can show a clinically relevant bias in patients with elevated pulse pressure. Increased arterial stiffness may impair the accuracy of oscillometric blood pressure measurement at the wrist.

Oxidative stress markers in young hemodialysis patients - a pilot study.

AIMS: Studies in young hemodialysis patients without significant comorbidities might increase the understanding of incipient vascular pathology in uremia. We investigated whether a specific pattern of oxidative stress markers with potential prognostic significance could be identified in this population. MATERIAL AND METHODS: We performed a cross-sectional matched case control study of 25 young hemodialysis patients (age 18 - 40 years) without known comorbidity factors. Patients were matched pairwise to healthy controls, and markers of oxidative stress were analyzed for associations with surrogate parameters of vascular structure and function. RESULTS: Oxidized low-density lipoproteins (OxLDL) were similar in patients and controls whereas conjugated dienes were increased in the very low-density lipoproteins (VLDL) fraction (20 +/- 6 vs. 12 +/- 5 micromol/l, p < 0.0001), but not in the low-density lipoproteins (LDL) fraction (16 +/- 6 vs. 18 +/- 6 micromol/l). Superoxide dismutase (SOD) activity was diminished in patients (1,117 +/- 151 vs. 1,299 +/- 88 U/g Hb, p < 0.0001), but there was no difference in glutathione peroxidase (GPx) activity. Oxidative stress expressed as the ratio of oxidized and reduced glutathione (GSSG/GSH) was increased in patients (0.25 +/- 0.18 vs. 0.13 +/- 0.04, p = 0.0048). Intima-media thickness (IMT) of the common carotid artery (0.70 +/- 0.12 vs. 0.62 +/- 0.08 mm, p = 0.0007) was significantly increased, and postischemic peak flow (PIPF) by venous occlusion plethysmography was severely diminished in patients (632 +/- 319 vs. 1,057 +/- 543% of basal flow, p < 0.0001). None of the markers of oxidative stress was independently associated with IMT or PIPF or a significant discriminator between patients and controls by multivariate regression. CONCLUSIONS: In this pilot study of exclusively young patients on hemodialysis, oxidative stress markers were of limited clinical value in identifying young patients at risk for vascular complications.

Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives.

Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (P<0.05 each). The extent of ABP reduction did not significantly differ in the presence or absence of beta-blockade (Delta systolic ABP 10.6+/-10.5 vs 10.6+/-8.8 mm Hg, Delta diastolic ABP 5.7+/-8.6 vs 5.8+/-4.0 mm Hg). Mean training heart rate was significantly lower in the patients on beta-blockers (97.2+/-7.7 vs 118.3+/-7.5/min, P<0.001). Lactate-based aerobic endurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.

Sphingosine-1-phosphate and FTY720 as anti-atherosclerotic lipid compounds.

All stages of atherosclerosis have been identified as a chronic vascular inflammatory disease. In the last few years there is increasing evidence that endogenous lysophospholipids such as sphingosine-1-phosphate (S1P) have potent anti-inflammatory properties. The S1P analogue FTY720 that has been developed as a potent, orally active, immunosuppressant in the field of transplantation and autoimmune disease has interesting effects on inflammatory processes in the arterial vessel wall. S1P targets five specific S1P receptors (S1P(1-5)), which are ubiquitously expressed. S1P(1-3) receptor expression is identified in arterial vessels. S1P and FTY720 show potent silencing effects on some vascular proinflammatory mechanisms in endothelial and vascular smooth muscle cells. In addition, the interaction of monocytes with the vessel wall is inhibited. As shown recently, FTY720 can effectively reduce the progression of atherosclerosis in apolipoprotein E-deficient mice having a high-cholesterol diet. It is not entirely clear which S1P receptor subtype is mainly involved in this process. However, it is currently speculated that the S1P(3) and probably the S1P(1) is involved in the anti-atherosclerotic effects of FTY720. This review summarizes the current knowledge about S1P- and FTY720-effects on mechanisms of vascular inflammatory disease. In addition S1P receptor subtypes are identified which might be interesting for molecular drug targeting.

Paracrine stimulation of vascular smooth muscle proliferation by diadenosine polyphosphates released from proximal tubule epithelial cells.

The purinergic receptor system plays an important role in the regulation of both vascular and tubular functions within the kidney; however, the release of purinergic agonists other than ATP by renal tissue is not known. In this investigation, we determine if kidney tissue is a source of diadenosine polyphosphates, which have high affinity for the P(2X) and P(2Y) receptors. Both diadenosine pentaphosphate and hexaphosphate were identified by matrix-assisted laser desorption ionization-mass spectrometry in extracts purified from both whole porcine kidney and from cloned cells of the LLC-PK1 cell line. Both polyphosphates in nanomolar concentrations were found to significantly stimulate the proliferation of vascular smooth muscle cells derived from rat thoracic aortas. The purinergic-receptor antagonist, suramin, did not significantly affect the growth-stimulatory properties of the polyphosphates. The growth stimulation of vascular smooth muscle cells by platelet-derived growth factor was potentiated by both diadenosine polyphosphates. We conclude that diadenosine polyphosphates are endogenous purinergic agonists of the kidney that have physiologic and pathophysiologic relevance. These epithelial cell metabolic products have vasoregulatory properties while linking the energy supply and tubular function.