Effect of Acute Ozone Induced Airway Inflammation on Human Sympathetic Nerve Traffic: A Randomized, Placebo Controlled, Crossover Study

Background: Ozone concentrations in ambient air are related to cardiopulmonary perturbations in the aging population. Increased central sympathetic nerve activity induced by local airway inflammation may be one possible mechanism. Methodology/Principal Findings: To elucidate this issue further, we performed a randomized, double-blind, cross-over study, including 14 healthy subjects (3 females, age 22-47 years), who underwent a 3 h exposure with intermittent exercise to either ozone (250 ppb) or clean air. Induced sputum was collected 3 h after exposure. Nineteen to 22 hours after exposure, we recorded ECG, finger blood pressure, brachial blood pressure, respiration, cardiac output, and muscle sympathetic nerve activity (MSNA) at rest, during deep breathing, maximum-inspiratory breath hold, and a Valsalva maneuver. While the ozone exposure induced the expected airway inflammation, as indicated by a significant increase in sputum neutrophils, we did not detect a significant estimated treatment effect adjusted for period on cardiovascular measurements. Resting heart rate (clean air: 59 +/- 62, ozone 60 +/- 62 bpm), blood pressure (clean air: 121 +/- 3/71 +/- 2 mmHg; ozone: 121 +/- 2/71 +/- 2mmHg), cardiac output (clean air: 7.42 +/- 0.29 mmHg; ozone: 7.98 +/- 0.60 l/min), and plasma norepinephrine levels (clean air: 213 +/- 21 pg/ml; ozone: 202 +/- 16 pg/ml), were similar on both study days. No difference of resting MSNA was observed between ozone and air exposure (air: 2362, ozone: 2362 bursts/min). Maximum MSNA obtained at the end of apnea (air: 44 +/- 4, ozone: 48 +/- 4 bursts/min) and during the phase II of the Valsalva maneuver (air: 64 +/- 5, ozone: 57 +/- 6 bursts/min) was similar. Conclusions/Significance: Our study suggests that acute ozone-induced airway inflammation does not increase resting sympathetic nerve traffic in healthy subjects, an observation that is relevant for environmental health. However, we can not exclude that chronic airway inflammation may contribute to sympathetic activation

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Do programmed death 1 (PD-1) and its ligand (PD-L1) play a role in patients with non-clear cell renal cell carcinoma?

Clinical trials targeting programmed death 1 (PD-1) and its ligand PD-L1 (PD-L1) for metastatic renal cell cancer (RCC) are ongoing. The aim of this study is to validate their roles as prognostic markers in non-clear cell (non-cc) RCC. Sixty-four non-cc RCC tissue specimens were collected from patients undergoing renal tumor surgery. Expressions of biomarkers were assessed using immunohistochemistry and compared with clinical characteristics. Survival analyses were performed with a median follow-up of 77.5 (range: 0-176) months. No significant correlations were found for PD-1(+) tumor-infiltrating mononuclear cells (TIMC) or PD-L1(+) expression and clinical attributes in patients with non-cc RCC. Kaplan-Meier analysis revealed no differences in 5- and 10-year cancer-specific survival (CSS) for PD-1-TIMC compared to PD-1(+) TIMC (71.4 and 63 % versus 72.2 and 61.9 %; p = 0.88). Intratumoral expression of PD-L1 did not appear to influence the 5-and 10-year CSS significantly, even though a trend was identified (68 and 53.6 % versus 80.1 and 75.7 %; p = 0.08). In multivariate analysis, neither PD-1(+) TIMC nor intratumoral PD-L1(+) expression proved to be independent predictors of CSS (p = 0.99 and p = 0.68, respectively). Our study demonstrates that PD-1(+) TIMC and intratumoral PD-L1(+) expression did not significantly impact tumor aggressiveness or clinical outcome in non-ccRCC specimens. Due to rare incidence of non-cc RCC in particular according to PD-L1 expression, further analyzes are warranted

Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial

Background Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. Methods In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. Results In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 mu g/L, P<0.001) and cyclosporin A (47.4 versus 64.1 mu g/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. Conclusions Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs

Individual values of muscle sympathetic nerve activity (burst frequency in bursts/min) measured after clean air and ozone exposure at rest (top), at the end of maximum inspiratory apnea (middle) and during late phase II of the Valsalva maneuver (bottom) for subjects exposed first to clean air (empty circles, n = 4) and for subjects exposed first to ozone (filled circles, n = 7).

<p>Individual values of muscle sympathetic nerve activity (burst frequency in bursts/min) measured after clean air and ozone exposure at rest (top), at the end of maximum inspiratory apnea (middle) and during late phase II of the Valsalva maneuver (bottom) for subjects exposed first to clean air (empty circles, n = 4) and for subjects exposed first to ozone (filled circles, n = 7).</p

Normobaric Hyperoxia for Treatment of Pneumocephalus after Posterior Fossa Surgery in the Semisitting Position: A Prospective Randomized Controlled Trial

<div><p>Background</p><p>Supratentorial pneumocephalus after posterior fossa surgery in the semisitting position may lead to decreased alertness and other symptoms. We here aimed to prove the efficacy of normobaric hyperoxia on the absorption of postoperative pneumocephalus according to a standardized treatment protocol.</p><p>Methods and Findings</p><p>We enrolled 44 patients with postoperative supratentorial pneumocephalus (> 30 ml) after posterior fossa surgery in a semisitting position. After randomisation procedure, patients received either normobaric hyperoxia at FiO₂ 100% over an endotracheal tube for 3 hours (treatment arm) or room air (control arm). Routine cranial CT scans were performed immediately (CT1) and 24 hours (CT2) after completion of surgery and were rated without knowledge of the therapy arm. Two co-primary endpoints were assessed: (i) mean change of pneumocephalus volume, and (ii) air resorption rate in 24 hours. Secondary endpoints were subjective alertness (Stanford Sleepiness Scale) postoperatively and attention (Stroop test), which were evaluated preoperatively and 24 hours after surgery. The mean change in pneumocephalus volume was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.001). The air resorption rate was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.0015). Differences were more pronounced in patients aged 52 years and older. No difference between patients in treatment arm and control arm was observed for the Stroop test. The distribution of scores in the Stanford Sleepiness Scale differed in the treatment arm as compared to the control arm, and there was a difference in mean values (p = 0.015).</p><p>Conclusions</p><p>Administration of normobaric hyperoxia at FiO₂ 100% via an endotracheal tube for 3 hours is safe and efficacious in the treatment of pneumocephalus after posterior fossa surgery in the semisitting position. Largest benefit was found in elderly patients and particularly in older men.</p><p>Trial Registration</p><p>German Clinical Trials Register <a href="https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00006273" target="_blank">DRKS00006273</a></p></div

Results of Stroop test of patients in treatment and control arm.

<p>SD = standard deviation</p><p>* p<0.05 = significant; ANCOVA</p><p>Results of Stroop test of patients in treatment and control arm.</p

Baseline characteristics of the study population.

<p>SD = standard deviation</p><p>* p<0.05 = significant</p><p>¹ two-sided t-test</p><p>² χ²-test</p><p>Baseline characteristics of the study population.</p

Trial profile.

<p>Trial profile.</p