STUDY OBJECTIVES Controversy exists as to whether elevated loop gain is a cause or consequence of... more STUDY OBJECTIVES Controversy exists as to whether elevated loop gain is a cause or consequence of obstructive sleep apnea (OSA). Upper airway surgery is commonly performed in Asian patients with OSA who have failed positive airway pressure therapy and who are thought to have anatomical predisposition to OSA. We hypothesized that high loop gain would decrease following surgical treatment of OSA due to reduced sleep apnea severity. METHODS Polysomnography was performed preoperatively and postoperatively to assess OSA severity in 30 Chinese participants who underwent upper airway surgery. Loop gain was calculated using a validated clinically-applicable method by fitting a feedback control model to airflow. RESULTS Patients were followed up for a median (interquartile range) of 130 (62, 224) days after surgery. Apnea-hypopnea index (AHI) changed from 60.8 (33.7, 71.7) to 18.4 (9.9, 42.5) events/h (P < .001). Preoperative and postoperative loop gain was 0.70 (0.58, 0.80) and 0.53 (0.46, 0.63) respectively (P < .001). There was a positive association between the decrease in loop gain and the improvement of AHI (P = .025). CONCLUSIONS High loop gain was reduced by surgical treatment of OSA in our cohort. These data suggest that elevated loop gain may be acquired in OSA and may provide mechanistic insight into improvement in OSA with upper airway surgery. CLINICAL TRIAL REGISTRATION Registry: ClinicalTrials.gov, Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea, Identifier: NCT02696629, URL: https://clinicaltrials.gov/show/NCT02696629.
Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery o... more Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery of respiratory and limb motor dysfunction. • One possible side effect of this therapy is an increase in apnea number and duration, which is particularly relevant to participants with motor disorders coupled with an increased incidence of sleep apnea. • In this study, we report that increases in apnea number and duration, following exposure to daily intermittent hypoxia, are the result of an increase in respiratory loop gain and the arousal threshold, in participants with obstructive sleep apnea. • Daily exposure to mild intermittent hypoxia also led to an increase in the ventilatory response to arousal. • Accordingly, individuals with motor disorders receiving mild intermittent hypoxia as a therapy should be screened for the presence of sleep apnea. If present, administration of intermittent hypoxia during wakefulness hours should be combined with continuous positive airway pressure treatment during sleep.
Reduced ventilatory control stability (elevated loop gain) is a key nonanatomical, pathological t... more Reduced ventilatory control stability (elevated loop gain) is a key nonanatomical, pathological trait contributing to obstructive sleep apnea (OSA), yet the mechanisms responsible remain unclear. We sought to identify the key factors contributing to elevated loop gain in OSA (controller vs. plant contributions) and to examine whether abnormalities in these factors persist after OSA treatment. In 15 males (8 OSA, 7 height, weight- and age -matched controls), we measured loop gain, controller gain, and plant gain using a pseudorandom binary CO2 stimulation method during wakefulness. Factors potentially influencing plant gain were also assessed (supine lung volume via helium dilution and spirometry). Measures were repeated 2 and 6 wk after initiating continuous positive airway pressure treatment. Loop gain (LG) was higher in OSA versus controls (LG at 1 cycle/min 0.28 ± 0.04 vs. 0.16 ± 0.04, P = 0.046, respectively), and the controller exhibited a greater peak response to CO2 and faste...
Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four k... more Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four key pathophysiological traits that contribute to cause obstructive sleep apnea (OSA). Novel treatments aimed at reducing loop gain are being investigated, with the intention that future OSA treatment may be tailored to the individual's specific cause of apnea. However, few studies have evaluated loop gain in OSA and non-OSA controls and those that have provide little evidence to support an inherent abnormality in either overall chemical loop gain in OSA patients vs. non-OSA controls, or its components (controller and plant gain). However, intermittent hypoxia may induce high controller gain through neuroplastic changes to chemoreflex control, and may also decrease plant gain via oxidative stress induced inflammation and reduced lung function. The inherent difficulties and limitations with loop gain measurements are discussed and areas where further research are required are highlighted, as only by understanding the mechanisms underlying OSA are new therapeutic approaches likely to emerge in OSA.
... Standard Article. Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research. M... more ... Standard Article. Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research. Maria S. Sepúlveda 1 ,; Kimberly J. Ralston-Hooper 2 ,; Brian C. Sanchez 3 ,; Amber Hopf-Jannasch 4 ,; Stephanie D. Baker 5 ,; Naomi Diaz 6 ,; Jiri Adamec 4. ...
Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, inc... more Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. Methodology/Results: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/ contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. Conclusion: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions.
STUDY OBJECTIVES Controversy exists as to whether elevated loop gain is a cause or consequence of... more STUDY OBJECTIVES Controversy exists as to whether elevated loop gain is a cause or consequence of obstructive sleep apnea (OSA). Upper airway surgery is commonly performed in Asian patients with OSA who have failed positive airway pressure therapy and who are thought to have anatomical predisposition to OSA. We hypothesized that high loop gain would decrease following surgical treatment of OSA due to reduced sleep apnea severity. METHODS Polysomnography was performed preoperatively and postoperatively to assess OSA severity in 30 Chinese participants who underwent upper airway surgery. Loop gain was calculated using a validated clinically-applicable method by fitting a feedback control model to airflow. RESULTS Patients were followed up for a median (interquartile range) of 130 (62, 224) days after surgery. Apnea-hypopnea index (AHI) changed from 60.8 (33.7, 71.7) to 18.4 (9.9, 42.5) events/h (P < .001). Preoperative and postoperative loop gain was 0.70 (0.58, 0.80) and 0.53 (0.46, 0.63) respectively (P < .001). There was a positive association between the decrease in loop gain and the improvement of AHI (P = .025). CONCLUSIONS High loop gain was reduced by surgical treatment of OSA in our cohort. These data suggest that elevated loop gain may be acquired in OSA and may provide mechanistic insight into improvement in OSA with upper airway surgery. CLINICAL TRIAL REGISTRATION Registry: ClinicalTrials.gov, Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea, Identifier: NCT02696629, URL: https://clinicaltrials.gov/show/NCT02696629.
Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery o... more Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery of respiratory and limb motor dysfunction. • One possible side effect of this therapy is an increase in apnea number and duration, which is particularly relevant to participants with motor disorders coupled with an increased incidence of sleep apnea. • In this study, we report that increases in apnea number and duration, following exposure to daily intermittent hypoxia, are the result of an increase in respiratory loop gain and the arousal threshold, in participants with obstructive sleep apnea. • Daily exposure to mild intermittent hypoxia also led to an increase in the ventilatory response to arousal. • Accordingly, individuals with motor disorders receiving mild intermittent hypoxia as a therapy should be screened for the presence of sleep apnea. If present, administration of intermittent hypoxia during wakefulness hours should be combined with continuous positive airway pressure treatment during sleep.
Reduced ventilatory control stability (elevated loop gain) is a key nonanatomical, pathological t... more Reduced ventilatory control stability (elevated loop gain) is a key nonanatomical, pathological trait contributing to obstructive sleep apnea (OSA), yet the mechanisms responsible remain unclear. We sought to identify the key factors contributing to elevated loop gain in OSA (controller vs. plant contributions) and to examine whether abnormalities in these factors persist after OSA treatment. In 15 males (8 OSA, 7 height, weight- and age -matched controls), we measured loop gain, controller gain, and plant gain using a pseudorandom binary CO2 stimulation method during wakefulness. Factors potentially influencing plant gain were also assessed (supine lung volume via helium dilution and spirometry). Measures were repeated 2 and 6 wk after initiating continuous positive airway pressure treatment. Loop gain (LG) was higher in OSA versus controls (LG at 1 cycle/min 0.28 ± 0.04 vs. 0.16 ± 0.04, P = 0.046, respectively), and the controller exhibited a greater peak response to CO2 and faste...
Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four k... more Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four key pathophysiological traits that contribute to cause obstructive sleep apnea (OSA). Novel treatments aimed at reducing loop gain are being investigated, with the intention that future OSA treatment may be tailored to the individual's specific cause of apnea. However, few studies have evaluated loop gain in OSA and non-OSA controls and those that have provide little evidence to support an inherent abnormality in either overall chemical loop gain in OSA patients vs. non-OSA controls, or its components (controller and plant gain). However, intermittent hypoxia may induce high controller gain through neuroplastic changes to chemoreflex control, and may also decrease plant gain via oxidative stress induced inflammation and reduced lung function. The inherent difficulties and limitations with loop gain measurements are discussed and areas where further research are required are highlighted, as only by understanding the mechanisms underlying OSA are new therapeutic approaches likely to emerge in OSA.
... Standard Article. Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research. M... more ... Standard Article. Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research. Maria S. Sepúlveda 1 ,; Kimberly J. Ralston-Hooper 2 ,; Brian C. Sanchez 3 ,; Amber Hopf-Jannasch 4 ,; Stephanie D. Baker 5 ,; Naomi Diaz 6 ,; Jiri Adamec 4. ...
Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, inc... more Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. Methodology/Results: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/ contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. Conclusion: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions.
Uploads
Papers by Naomi Diaz