Browsing by Subject "nitric oxide"
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Item Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis(ATS, 2017-07) Shapiro, Adam J.; Josephson, Maureen; Rosenfeld, Margaret; Yilmaz, Ozge; Davis, Stephanie D.; Polineni, Deepika; Guadagno, Elena; Leigh, Margaret W.; Lavergne, Valery; Pediatrics, School of MedicineRationale: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. Objectives: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. Data Sources: Ten databases were searched for reference sources from database inception through July 29, 2016. Data Extraction: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. Synthesis: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7–99.2) and specificity was 96.0% (87.9–98.7), with a positive likelihood ratio of 24.3 (7.6–76.9), a negative likelihood ratio of 0.03 (0.01–0.08), and a diagnostic odds ratio of 956.8 (141.2–6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7–98.9) and specificity of 96.4% (85.1–99.2), with a positive likelihood ratio of 26.5 (5.9–119.1), a negative likelihood ratio of 0.04 (0.01–0.12), and a diagnostic odds ratio of 699.3 (67.4–7256.0). Certainty of the evidence was graded as moderate. Conclusions: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.Item Dietary Nitrate Increases VO2peak and Performance but Does Not Alter Ventilation or Efficiency in Patients With Heart Failure With Reduced Ejection Fraction(Elsevier, 2017) Coggan, Andrew R.; Broadstreet, Seth R.; Mahmood, Kiran; Mikhalkova, Deana; Madigan, Michael; Bole, Indra; Park, Soo; Leibowitz, Joshua L.; Kadkhodayan, Ana; Thomas, Deepak P.; Thies, Dakkota; Peterson, Linda R.; Kinesiology, School of Physical Education and Tourism ManagementBackground Patients with heart failure with reduced ejection fraction (HFrEF) exhibit lower efficiency, dyspnea, and diminished peak oxygen uptake (VO2peak) during exercise. Dietary nitrate (NO3−), a source of nitric oxide (NO), has improved these measures in some studies of other populations. We determined the effects of acute NO3− ingestion on exercise responses in 8 patients with HFrEF using a randomized, double-blind, placebo-controlled, crossover design. Methods and Results Plasma NO3−, nitrite (NO2−), and breath NO were measured at multiple time points and respiratory gas exchange was determined during exercise after ingestion of beetroot juice containing or devoid of 11.2 mmol of NO3−. NO3− intake increased (P < .05–0.001) plasma NO3− and NO2− and breath NO by 1469 ± 245%, 105 ± 34%, and 60 ± 18%, respectively. Efficiency and ventilation during exercise were unchanged. However, NO3− ingestion increased (P < .05) VO2peak by 8 ± 2% (ie, from 21.4 ± 2.1 to 23.0 ± 2.3 mL.min−1.kg−1). Time to fatigue improved (P < .05) by 7 ± 3 % (ie, from 582 ± 84 to 612 ± 81 seconds). Conclusions Acute dietary NO3− intake increases VO2peak and performance in patients with HFrEF. These data, in conjunction with our recent data demonstrating that dietary NO3− also improves muscle contractile function, suggest that dietary NO3− supplementation may be a valuable means of enhancing exercise capacity in this population.Item Dietary nitrate's effects on exercise performance in heart failure with reduced ejection fraction (HFrEF)(Elsevier, 2018) Mulkareddy, Vinaya; Racette, Susan B.; Coggan, Andrew R.; Peterson, Linda R.; Kinesiology, School of Physical Education and Tourism ManagementHeart failure with reduced ejection fraction (HFrEF) is a deadly and disabling disease. A key derangement contributing to impaired exercise performance in HFrEF is decreased nitric oxide (NO) bioavailability. Scientists recently discovered the inorganic nitrate pathway for increasing NO. This has advantages over organic nitrates and NO synthase production of NO. Small studies using beetroot juice as a source of inorganic nitrate demonstrate its power to improve exercise performance in HFrEF. A larger-scale trial is now underway to determine if inorganic nitrate may be a new arrow for physicians' quiver of HFrEF treatments.Item Dietary nitrate‐induced increases in human muscle power: high versus low responders(Wiley, 2018-01-25) Coggan, Andrew R.; Broadstreet, Seth R.; Mikhalkova, Deana; Bole, Indra; Leibowitz, Joshua L.; Kadkhodayan, Ana; Park, Soo; Thomas, Deepak P.; Thies, Dakkota; Peterson, Linda R.; Kinesiology, School of Health and Human SciencesMaximal neuromuscular power is an important determinant of athletic performance and also quality of life, independence, and perhaps even mortality in patient populations. We have shown that dietary nitrate (NO 3 −), a source of nitric oxide (NO), improves muscle power in some, but not all, subjects. The present investigation was designed to identify factors contributing to this interindividual variability. Healthy men (n = 13) and women (n = 7) 22–79 year of age and weighing 52.1–114.9 kg were studied using a randomized, double‐blind, placebo‐controlled, crossover design. Subjects were tested 2 h after ingesting beetroot juice (BRJ) either containing or devoid of 12.3 ± 0.8 mmol of NO 3 −. Plasma NO 3 − and nitrite (NO 2 −) were measured as indicators of NO bioavailability and maximal knee extensor speed (V max), power (P max), and fatigability were determined via isokinetic dynamometry. On average, dietary NO 3 − increased (P < 0.05) P max by 4.4 ± 8.1%. Individual changes, however, ranged from −9.6 to +26.8%. This interindividual variability was not significantly correlated with age, body mass (inverse of NO 3 − dose per kg), body mass index (surrogate for body composition) or placebo trial V max or fatigue index (in vivo indicators of muscle fiber type distribution). In contrast, the relative increase in Pmax was significantly correlated (r = 0.60; P < 0.01) with the relative increase in plasma NO 2 − concentration. In multivariable analysis female sex also tended (P = 0.08) to be associated with a greater increase in Pmax. We conclude that the magnitude of the dietary NO 3 −‐induced increase in muscle power is dependent upon the magnitude of the resulting increase in plasma NO 2 − and possibly female sex.Item Effect of dietary nitrate on human muscle power: a systematic review and individual participant data meta-analysis(Journal of the International Society of Sports Nutrition, 2021) Coggan, Andrew R.; Baranauskas, Marissa N.; Hinrichs, Rachel J.; Liu, Ziyue; Carter, Stephen J.Background: Previous narrative reviews have concluded that dietary nitrate (NO3−) improves maximal neuromuscular power in humans. This conclusion, however, was based on a limited number of studies, and no attempt has been made to quantify the exact magnitude of this beneficial effect. Such information would help ensure adequate statistical power in future studies and could help place the effects of dietary NO3− on various aspects of exercise performance (i.e., endurance vs. strength vs. power) in better context. We therefore undertook a systematic review and individual participant data meta-analysis to quantify the effects of NO3− supplementation on human muscle power. Methods: The literature was searched using a strategy developed by a health sciences librarian. Data sources included Medline Ovid, Embase, SPORTDiscus, Scopus, Clinicaltrials.gov, and Google Scholar. Studies were included if they used a randomized, double-blind, placebo-controlled, crossover experimental design to measure the effects of dietary NO3− on maximal power during exercise in the non-fatigued state and the within-subject correlation could be determined from data in the published manuscript or obtained from the authors. Results: Nineteen studies of a total of 268 participants (218 men, 50 women) met the criteria for inclusion. The overall effect size (ES; Hedge’s g) calculated using a fixed effects model was 0.42 (95% confidence interval (CI) 0.29, 0.56; p = 6.310 × 10− 11). There was limited heterogeneity between studies (i.e., I2 = 22.79%, H2 = 1.30, p = 0.3460). The ES estimated using a random effects model was therefore similar (i.e., 0.45, 95% CI 0.30, 0.61; p = 1.064 × 10− 9). Subgroup analyses revealed no significant differences due to subject age, sex, or test modality (i.e., small vs. large muscle mass exercise). However, the ES in studies using an acute dose (i.e., 0.54, 95% CI 0.37, 0.71; p = 6.774 × 10− 12) was greater (p = 0.0211) than in studies using a multiple dose regimen (i.e., 0.22, 95% CI 0.01, 0.43; p =0.003630). Conclusions: Acute or chronic dietary NO3− intake significantly increases maximal muscle power in humans. The magnitude of this effect–on average, ~ 5%–is likely to be of considerable practical and clinical importance.Item Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial(Elsevier, 2019-03) Kline, Jeffrey A.; Puskarich, Michael A.; Jones, Alan E.; Mastouri, Ronald A.; Hall, Cassandra L.; Perkins, Anthony; Gundert, Emily; Lahm, Tim; Emergency Medicine, School of MedicineObjective To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. Methods This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. Results We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). Conclusions In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography.Item Loss of Endothelial Nitric Oxide Synthase Exacerbates Intestinal and Lung Injury in Experimental Necrotizing Enterocolitis(Elsevier, 2018) Drucker, Natalie A.; Jensen, Amanda R.; te Winkel, Jan P.; Ferkowicz, Michael J.; Markel, Troy A.; Surgery, School of MedicineBackground Necrotizing enterocolitis (NEC) continues to be a devastating condition among preterm infants. Nitric oxide, which is synthesized in the intestine by endothelial nitric oxide synthase (eNOS), acts as a potent vasodilator and antioxidant within the mesentery and may play a role in prevention of NEC. We hypothesized that loss of endothelial nitric oxide would worsen both intestinal and associated lung injury and increase local and systemic inflammation during experimental NEC. Methods NEC was induced in five-day-old wild type (WT) and eNOS-knockout (eNOSKO) mouse pups. Experimental groups (n = 10) were formula fed and subjected to intermittent hypoxic and hypothermic stress, while control groups (n = 10) remained with their mother to breastfeed. Pups were monitored by daily clinical assessment. After sacrifice on day nine, intestine and lung were assessed for injury, and cytokines were measured in tissue homogenates by ELISA. Data were compared with Mann–Whitney, and p < 0.05 was significant. Results Each NEC group was compared to its respective strain’s breastfed control to facilitate comparisons between the groups. Both NEC groups were significantly sicker than their breastfed controls. eNOSKO NEC animals had a median clinical assessment score of 3 (IQR = 1–5), and the WT NEC animal’s median score was 3 (IQR = 2–5). Despite similar clinical scores, intestinal injury was significantly worse in the eNOSKO NEC groups compared to WT NEC groups (median injury scores of 3.25 (IQR = 2.25–3.625) and 2 (IQR = 1–3), respectively (p = 0.0474). Associated lung injury was significantly worse in the eNOSKO NEC group as compared to the WT NEC group (median scores of 8.5 (IQR = 6.75–11.25) and 6.5 (IQR = 5–7.5), respectively, p = 0.0391). Interestingly, cytokines in both tissues were very different between the two groups, with varying effects noted for each cytokine (IL-6, IL-1β, VEGF, and IL-12) in both tissues. Conclusion Nitric oxide from eNOS plays a key role in preventing the development of NEC. Without eNOS function, both intestinal and lung injuries are more severe, and the inflammatory cascade is significantly altered. Further studies are needed to determine how eNOS-derived nitric oxide facilitates these beneficial effects.Item Nitric oxide and skeletal muscle contractile function(Elsevier, 2022-05) Kumar, Ravi; Coggan, Andrew R.; Ferreira, Leonardo F.; Kinesiology, School of Health and Human SciencesNitric oxide (NO) is complex modulator of skeletal muscle contractile function, capable of increasing or decreasing force and power output depending on multiple factors. This review explores the effects and potential mechanisms for modulation of skeletal muscle contractile function by NO, from pharmacological agents in isolated muscle preparations to dietary nitrate supplementation in humans and animals. Pharmacological manipulation in vitro suggests that NO signaling diminishes submaximal isometric force, whereas dietary manipulation in vivo suggest that NO enhances submaximal force. The bases for these different responses are unknown but could reflect dose-dependent effects. Maximal isometric force is unaffected by physiologically relevant levels of NO, which do not induce overt protein oxidation. Pharmacological and dietary manipulation of NO signaling enhances the maximal rate of isometric force development, unloaded shortening velocity, and peak power. We hypothesize that these effects are mediated by post-translational modifications of myofibrillar proteins that modulate thick filament regulation of contraction (e.g., mechanosensing and strain-dependence of cross-bridge kinetics). NO effects on contractile function appear to have some level of fiber type and sex-specificity. The mechanisms behind NO-mediated changes in skeletal muscle function need to be explored through proteomics analysis and advanced biophysical assays to advance the development of small molecules and open intriguing therapeutic and ergogenic possibilities for aging, disease, and athletic performance.Item Photolytic Measurement of Tissue S-Nitrosothiols in Rats and Humans In Vivo(MDPI, 2022-02) Neidigh, Noah; Alexander, Alyssa; van Emmerik, Parker; Higgs, Allison; Plack, Logan; Clem, Charles; Cater, Daniel; Marozkina, Nadzeya; Gaston, Benjamin; Pediatrics, School of MedicineS-nitrosothiols are labile thiol-NO adducts formed in vivo primarily by metalloproteins such as NO synthase, ceruloplasmin, and hemoglobin. Abnormal S-nitrosothiol synthesis and catabolism contribute to many diseases, ranging from asthma to septic shock. Current methods for quantifying S-nitrosothiols in vivo are suboptimal. Samples need to be removed from the body for analysis, and the S-nitrosothiols can be broken down during ex vivo processing. Here, we have developed a noninvasive device to measure mammalian tissue S-nitrosothiols in situ non-invasively using ultraviolet (UV) light, which causes NO release in proportion to the S-nitrosothiol concentration. We validated the assay in vitro; then, we applied it to measure S-nitrosothiols in vivo in rats and in humans. The method was sensitive to 0.5 µM, specific (did not detect other nitrogen oxides), and was reproducible in rats and in humans. This noninvasive approach to S-nitrosothiol measurements may be applicable for use in human diseases.Item Reducing Unnecessary Nitric Oxide Use: A Hospital-Wide, Respiratory Therapist-Driven Quality Improvement Project(Daedalus Enterprises, 2021-01) Rogerson, Colin M.; Tori, Alvaro J.; Hole, Acrista J.; Summitt, Elizabeth; Allen, Jayme D.; Abu-Sultaneh, Samer; Valentine, Kevin M.; Pediatrics, School of MedicineBACKGROUND: We sought to evaluate the institutional use of inhaled nitric oxide (INO) and to create a pathway to reduce waste using the Institute for Healthcare Improvement's model for improvement. Our aim was to reduce the use of INO by 20% within 8 months. METHODS: This was a prospective, respiratory therapist-driven, quality improvement project. We implemented a hospital-wide INO utilization protocol that was developed by neonatology, pediatric critical care, cardiac critical care, and respiratory therapy. INO use and respiratory therapist input for protocol failures were derived from the electronic medical record and were used to generate improvement opportunities. Monthly total hospital use of INO (in hours) was used as the primary outcome measure. Median hourly use per subject (evaluated in groups of 7 subjects) was used as a secondary outcome measure. New sildenafil dosing was tabulated for pre- and post-INO weaning protocol intervention as a balancing measure. Subjects included all patients in the hospital who were given INO therapy during the specified timeframe. RESULTS: Hospital-wide total hours were reduced from 1,515 h/month to 930 h/month. This hospital-wide reduction of 39% equates to a cost-avoidance of approximately $912,000 per year based on 2018 costs of INO of $130 per hour. Median hours of INO per subject decreased from 88 h to 50 h. Sildenafil was started in 18 of 98 subjects (18%) in the pre-intervention period and in 12 of 109 subjects (11%) in the post-intervention period (P = .27). CONCLUSIONS: A hospital-wide, multi-professional initiative led to a reduction in unnecessary INO use, resulting in decreased subject exposure and associated cost avoidance.