Respiratory Drive Research Articles

Long lasting degradation of all alkanes in soil by Pseudomonas activated after Fenton pre-oxidation

This study investigated the function and mechanism of Fenton pre-oxidation on the long lasting degradation of all alkanes in soil contaminated by petroleum. The findings demonstrated that the biological removal amount of all alkanes in the respiratory regulation group reached 4083.46 mg/kg, which was twice that of the non-regulation group, and the removal amount gradually increased in the four stages of bioremediation. In addition, the removal amount of all alkanes in the non-regulated group did not change much and showed a downward trend, indicating that long lasting degradation of all alkanes could be achieved by the respiratory regulation group, and the biodegradation cycle was saved by 251 days compared with the non-regulated group. Furthermore, the total number of bacteria in the respiratory regulation group (6.73 log CFU/g) was significantly higher than that in the non-regulation group (2.25 log CFU/g). Pseudomonas became the dominant genus in the respiratory regulation group with an average relative abundance of 32.17 %. In the respiratory regulation group, a large amount of ammonia nitrogen (1703.62 mg/kg) was consumed during the degradation process, which stimulated the tricarboxylic acid cycle respiratory metabolism process of Pseudomonas and accelerated the hydrocarbon conversion. This may be the reason why the long lasting degradation of all alkanes in soil could be achieved by the respiratory regulation group.

Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors

P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor’s ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3’s physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3β domain of the ICD. PSFL77 modulated pain perception in P2rx3+/+, but not in P2rx3−/−, mice, indicating that the 1α3β, a “tunable” region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors.

Sensing, feeling and regulating: investigating the association of focal braindamage with voluntary respiratoryand motor control.

Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire, and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia and left medial temporal lobe showed reduced performance relative to individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnoea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

Effect of adenosinergic manipulations on amygdala-kindled seizures in mice: Implications for sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) results in more years of potential life lost than any neurological condition with the exception of stroke. It is generally agreed that SUDEP happens due to some form of respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, the mechanistic cause of these perturbations is unclear. One possible explanation lies with adenosinergic signaling. Extracellular levels of the inhibitory neuromodulator adenosine rapidly rise during seizures, a countermeasure that is necessary for seizure termination. Previous evidence has suggested that excessive adenosinergic inhibition could increase the risk of SUDEP by silencing brain areas necessary for life, such as the respiratory nuclei of the brainstem. The goal of this investigation was to further clarify the role of adenosine in seizure-induced respiratory and electrocerebral dysfunction. To determine the role of adenosine in postictal physiological dysregulation, we pharmacologically manipulated adenosine signaling prior to amygdala-kindled seizures in mice while recording electroencephalogram (EEG), electromyogram, and breathing using whole body plethysmography. The adenosinergic drugs used in this study included selective and nonselective adenosine receptor antagonists and inhibitors of adenosine metabolism. We found that high doses of adenosine receptor antagonists caused some seizures to result in seizure-induced death; however, counterintuitively, animals in these conditions that did not experience seizure-induced death had little or no postictal generalized EEG suppression. Inhibitors of adenosine metabolism had no effect on postictal breathing but did worsen some postictal electrocerebral outcomes. The unexpected effect of high doses of adenosine antagonists on seizure-induced death observed in this study may be due to the increase in seizure severity, vasoconstriction, or phosphodiesterase inhibition caused by these drugs at high doses. These findings further clarify the role of adenosine in seizure-induced death and may have implications for the consumption of caffeine in epilepsy patients and the prevention of SUDEP.

Butyrylcholinesterase Is Not Required for the Neonatal Autoresuscitation Reflex

Sudden Infant Death Syndrome (SIDS) is the leading cause of infant death under the age of one year of age, taking the lives of more than 1,400 infants annually, and comprising approximately 41% of all Sudden Unexpected Infant Death (SUID) cases. SIDS etiology remains vastly unknown but is best explained via a triple risk model that proposes SIDS occurs in a vulnerable infant during a critical developmental period when triggered by an external stressor. In SIDS it is hypothesized that there is first a failure in arousal followed by failure in the protective autoresuscitation reflex; a defense mechanism for an infant that is in a hypoxic coma, that promotes deep gasping to attempt to restart cardiovascular function. Many SIDS case studies reveal associations with genetic variants and abnormal biomarkers; however, it is unclear whether these variants are causal. Recently a case study identified a broad association between reduced blood BChE activity and SIDS cases, yet the functional relationship between BChE and respiratory regulation remains to be investigated. We aimed to functionally test the relationship between BChE and the neonatal autoresuscitation reflex utilizing a rapid pipeline for precision genetic modeling and high-throughput functional testing developed by the Ray Lab. BChE loss of function mice, generated through targeted genetic editing, were tested for neonatal autoresuscitation on our automated closed loop phenotyping platform, Looper. Postnatal day 7-8 mice were exposed to 3% CO2 and 97% N2 stimuli to induce a state of hypoxia resulting in detection of bradycardia, initial hyperventilation, hypoventilation, and apnea followed by restoration of room air conditions to facilitate the autoresuscitation reflex and cardio-respiratory recovery. Male and female mice were exposed to repeated anoxic gas challenges and allowed to autoresuscitate until death occurred. Data suggest that loss of BChE function does not affect neonatal autoresuscitation. BChE knockout mice and heterozygous mice survived similar amounts of anoxic challenges as wild type controls. No sex differences were observed between the number of anoxic challenges survived in males and females for all genotypes. Our data demonstrate the first functional assessment of BChE in neonatal cardio-respiratory regulation and the autoresuscitation response and highlight that BChE is not required for successful neonatal autoresuscitation. Additional analyses of respiratory parameters from respiratory trace data for BChE loss of function mice will aid in a further understanding if BChE loss of function is implicated in other aspects respiratory regulation. Funding: Precision Core funding U54 OD030165. NIH/NHLBI R01HLN161142-01 and R01HL130249-07. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of OPRM1 in the Neonatal Autoresuscitation Reflex and Sudden Infant Death Syndrome

Opioid receptors are widely expressed throughout the brain and integral in nociception as well as homeostatic regulation of autonomic processes including respiration through modulation of respiratory rhythmogenesis and chemosensory responses. Perturbations to homeostatic mu opioid receptor (MOR) signaling via opiate overdose results in respiratory depression, aberrant breathing, and often death. With the rise of opioid use over the last two decades, many infants are being diagnosed with Neonatal Abstinence Syndrome (NAS), a congenital cardio-respiratory disorder resulting from prenatal exposure to opioids. Infants born with NAS have a fourfold increased risk for Sudden Infant Death Syndrome (SIDS). SIDS and related Sudden Unexpected Infant Death takes the lives of approximately 3,400 infants annually under the age of one and its etiology remains mostly unknown. Currently SIDS is explained via the triple risk model that proposes that SIDS occurs in a vulnerable infant during a critical developmental period when triggered by an external stressor, converging on the failure of the neonate autoresuscitation reflex in most cases. Recently a study identified an association between a mutation in the OPRM1 gene encoding MORs and SIDS cases. However, how this gene and perturbations in its native function modulates respiratory regulation are poorly understood. We hypothesize that native OPRM1 function is integral to protective neonate respiratory reflexes and that perturbation of native OPRM1 signaling negatively affects the neonatal autoresuscitation reflex. Male and female OPRM1 loss of function mice were assayed for their autoresuscitation reflex on our novel testbed, Looper. Mice were exposed to repeated bouts of anoxia and allowed to autoresuscitate until death occurred. Preliminary data suggest that loss of OPRM1 function results in a higher mortality rate on the autoresuscitation assay with OPRM1 KO mice surviving significantly less anoxic challenges compared to wild type controls. No sex differences were observed between male and female survival for all genotype groups. Results indicate that perturbation of the native function of OPRM1 produces a vulnerability to autoresuscitation dysfunction and mitigated survival. Our data demonstrate the first functional assessment of OPRM1 in neonatal cardiovascular function and autoresuscitation and reveal an important risk factor that may be implicated in perpetuating SIDS and NAS phenotypes. Additional analyses of distinct parameters from respiratory trace data for OPRM1 loss of function mice will aid in a deeper, mechanistic understanding of features implicated in autoresuscitation dysfunction. Future studies aim to characterize specific splice variants of OPRM1, known to produce neomorphic function and model the SIDS associated VUS, to further characterize the implication of OPRM1 and its variants in congenital respiratory diseases. Funding sources NIH/NHLBI R01HLN161142-01 and R01HL130249-07. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alternative Oxidase: From Molecule and Function to Future Inhibitors.

In the respiratory chain of the majority of aerobic organisms, the enzyme alternative oxidase (AOX) functions as the terminal oxidase and has important roles in maintaining metabolic and signaling homeostasis in mitochondria. AOX endows the respiratory system with flexibility in the coupling among the carbon metabolism pathway, electron transport chain (ETC) activity, and ATP turnover. AOX allows electrons to bypass the main cytochrome pathway to restrict the generation of reactive oxygen species (ROS). The inhibition of AOX leads to oxidative damage and contributes to the loss of adaptability and viability in some pathogenic organisms. Although AOXs have recently been identified in several organisms, crystal structures and major functions still need to be explored. Recent work on the trypanosome alternative oxidase has provided a crystal structure of an AOX protein, which contributes to the structure-activity relationship of the inhibitors of AOX. Here, we review the current knowledge on the development, structure, and properties of AOXs, as well as their roles and mechanisms in plants, animals, algae, protists, fungi, and bacteria, with a special emphasis on the development of AOX inhibitors, which will improve the understanding of respiratory regulation in many organisms and provide references for subsequent studies of AOX-targeted inhibitors.

Pathophysiological mechanisms and clinical consequences of exposure to new psychoactive substances (“salts”) on a newborn

Background. The usage of new psychoactive substances (NPAS) is increasing every year among various social groups around the world. According to various authors, the use of abused drugs during pregnancy remains at a high level — from 2.8 to 7% of pregnant women. The usage of NPAS, as well as other groups of abused drugs, during pregnancy is fraught with intrauterine multi-organ damage, however, any organ and tissue specificity for NPAS has not been described. In intervention trials conducted on laboratory animals, negative pathophysiological mechanisms triggered by synthetic cathinones have been demonstrated in the form of increased proapoptotic activity, the formation of autophagolysosomes and reactive oxygen intermediates in cells of nervous tissue, and the pro-inflammatory orientation of cells of the immune system.Case report describes a predominant lesion of the nervous system (developmental brain malformations, damage to the inspiratory center) and the musculoskeletal system (pronounced miotonical syndrome, congenital pathological fractures of the femurs), leading to multiorgan dysfunction, uncontrolled inflammatory response and, as a result, to the development of severe disablement of such children and an increase in the cohort of palliative pediatric patients. In the article, the authors focus on the pathophysiological mechanisms of NPAS for a deeper and more holistic understanding of the pathological process occurring in the body, in order to form and improve the medical judgment of specialist doctors and cite their own clinical observation as an illustration of the consequences of using NPAS during pregnancy. The authors believe that this review describing the case report is valuable from the point of view of practical applicability both for clinicians of various fields and for researchers.Conclusion. In addition, it is necessary to pay attention to the fact that the use of NPAS is of great social and economic significance, the description of such clinical observations, as well as in vitro studies, is relevant, and the expansion of ideas about the short-term and long-term negative consequences of the use of NPAS should serve as an initiating stage for the development of rehabilitation strategies for these patients

Whole-brain inputs and outputs of Phox2b and GABAergic neurons in the nucleus tractus solitarii.

The nucleus tractus solitarii (NTS) plays a critical role in the homeostatic regulation of respiration, blood pressure, sodium consumption and metabolic processes. Despite their significance, the circuitry mechanisms facilitating these diverse physiological functions remain incompletely understood. In this study, we present a whole-brain mapping of both the afferent and efferent connections of Phox2b-expressing and GABAergic neurons within the NTS. Our findings reveal that these neuronal populations not only receive monosynaptic inputs primarily from the medulla oblongata, pons, midbrain, supra-midbrain and cortical areas, but also mutually project their axons to these same locales. Moreover, intense monosynaptic inputs are received from the central amygdala, the paraventricular nucleus of the hypothalamus, the parasubthalamic nucleus and the intermediate reticular nucleus, along with brainstem nuclei explicitly engaged in respiratory regulation. In contrast, both neuronal groups extensively innervate brainstem nuclei associated with respiratory functions, although their projections to regions above the midbrain are comparatively limited. These anatomical findings provide a foundational platform for delineating an anatomical framework essential for dissecting the specific functional mechanisms of these circuits.

Extracorporeal Closed-Loop Respiratory Regulation for Patients With Respiratory Difficulty Using a Soft Bionic Robot.

Respiratory regulation is critical for patients with respiratory dysfunction. Clinically used ventilators can lead to long-term dependence and injury. Extracorporeal assistance approaches such as iron-lung devices provide a noninvasive alternative, however, artificial actuator counterparts have not achieved marvelous biomimetic ventilation as human respiratory muscles. Here, we propose a bionic soft exoskeleton robot that can achieve extracorporeal closed-loop respiratory regulation by emulating natural human breath. For inspiration, a soft vacuum chamber is actuated to produce negative thoracic pressure and thus expand lung volume by pulling the rib cage up and outward through use of external negative pressure. For expiration, a soft origami array under positive pressure pushes the abdominal muscles inward and the diaphragm upward. To achieve in vitro measurement of respiratory profile, we describe a wireless respiratory monitoring device to measure respiratory profiles with high accuracy, validated by quantitative comparisons with spirometer as gold-standard reference. By constructing a human-robot coupled respiratory mechanical model, a model-based proportional controller is designed for continuous tracking of the target respiratory profile. In experiments with ten healthy participants and ten patients with respiratory difficulty, the robot can adjust its assistive forces in real time and drive human-robot coupling respiratory system to track the target profile. The biomimetic robot can achieve extracorporeal closed-loop respiratory regulation for a diverse population. The soft robot has important potential to assist respiration for people with respiratory difficulty, whether in a hospital or a home setting.

A neural circuit for vocal production responds to viscerosensory input in the songbird.

Motor performance is monitored continuously by specialized brain circuits and used adaptively to modify behavior on a moment-to-moment basis and over longer time periods. During vocal behaviors, such as singing in songbirds, internal evaluation of motor performance relies on sensory input from the auditory and vocal-respiratory systems. Sensory input from the auditory system to the motor system, often referred to as auditory feedback, has been well studied in singing zebra finches (Taeniopygia guttata), but little is known about how and where nonauditory sensory feedback is evaluated. Here we show that brief perturbations in air sac pressure cause short-latency neural responses in the higher-order song control nucleus HVC (used as proper name), an area necessary for song learning and song production. Air sacs were briefly pressurized through a cannula in anesthetized or sedated adult male zebra finches, and neural responses were recorded in both nucleus parambigualis (PAm), a brainstem inspiratory center, and HVC, a cortical premotor nucleus. These findings show that song control nuclei in the avian song system are sensitive to perturbations directly targeted to vocal-respiratory, or viscerosensory, afferents and support a role for multimodal sensory feedback integration in modifying and controlling vocal control circuits.NEW & NOTEWORTHY This study presents the first evidence of sensory input from the vocal-respiratory periphery directly activating neurons in a motor circuit for vocal production in songbirds. It was previously thought that this circuit relies exclusively on sensory input from the auditory system, but we provide groundbreaking evidence for nonauditory sensory input reaching the higher-order premotor nucleus HVC, expanding our understanding of what sensory feedback may be available for vocal control.

Effect of the NLRP3 inflammasome on increased hypoxic ventilation response after CIH exposure in mice

BackgroundChronic intermittent hypoxia (CIH) increases the hypoxic ventilation response (HVR). The downstream cytokine IL-1β of the NLRP3 inflammasome regulates respiration by acting on the carotid body (CB) and neurons in the respiratory center, but the effect of the NLRP3 inflammasome on HVR induced by CIH remains unclear. ObjectiveTo investigate the effect of NLRP3 on the increased HVR and spontaneous apnea events and duration induced by CIH, the expression and localization of NLRP3 in the respiratory regulatory center of the rostral ventrolateral medulla (RVLM), and the effect of CIH on the activation of the NLRP3 inflammasome in the RVLM. MethodsEighteen male, 7-week-old C57BL/6 N mice and eighteen male, 7-week-old C57BL/6 N NLRP3 knockout mice were randomly divided into CON-WT, CON-NLRP3-/-, CIH-WT and CIH-NLRP3-/- groups. Respiratory changes in mice were continuously detected using whole-body plethysmography. The expression and localization of the NLRP3 protein and the formation of apoptosis-associated speck-like protein containing CARD (ASC) specks were detected using immunofluorescence staining. ResultsNLRP3 knockout reduced the increased HVR and the incidence and duration of spontaneous apnea events associated with CIH. The increase in HVR caused by CIH partially recovered after reoxygenation. After CIH, NLRP3 inflammasome activation in the RVLM, which is related to respiratory regulation after hypoxia, increased, which was consistent with the trend of the ventilation response. ConclusionThe NLRP3 inflammasome may be involved in the increase in the HVR and the incidence and duration of spontaneous apnea induced by CIH. NLRP3 inhibitors may help reduce the increase in the HVR after CIH, which is important for ensuring sleep quality at night in patients with obstructive sleep apnea.

Engineering ATP activated reversible nanochannel for gating of ion transport

Adenosine triphosphate (ATP) is an important purine molecule. It widely exists in cells and is closely related to a variety of significant physiological and pathological processes, such as energy metabolism, respiratory regulation, inflammation, and so forth. In vivo, ATP not only provides energy for organisms at the molecular level but also activates intracellular ion channels and regulates signaling pathways. Therefore, it is of great significance to construct ATP-responsive nanochannels for understanding complex biological processes. In this work, we designed and fabricated multi-amino conjugated rhodamine B (NH2-RhB) functionalized artificial nanochannels, which exhibited high performance for ATP response with current and fluorescence dual signals. Significantly, owing to the non-covalent bonding of NH2-RhB and ATP, the system performed reversible properties for regulating ion transport and behaved as an ionic gate that can flexibly switch between the "on" and "off" state under the condition of ATP and pH. The platform showed high selectivity for ATP and the detection limit can be as low as 48.2 fM. Moreover, finite-element theoretical simulation was employed to reveal the mechanism of ATP-activated nanochannel regulating ion flux. It proved that the surface charge density of the NH2-RhB functionalized nanochannels can be regulated by dealing with ATP and pH. This work shows promising applications of biomimetic nanochannel with gating properties and offers prospects for the development of biosensing, nanodevice, and nanofluidic logic gates.

Interaction between Kölliker-Fuse/A7 and the parafacial respiratory region on the control of respiratory regulation

Respiration is regulated by various types of neurons located in the pontine-medullary regions. The Kölliker-Fuse (KF)/A7 noradrenergic neurons play a role in modulating the inspiratory cycle by influencing the respiratory output. These neurons are interconnected and may also project to brainstem and spinal cord, potentially involved in regulating the post-inspiratory phase. In the present study, we hypothesize that the parafacial (pF) neurons, in conjunction with adrenergic mechanisms originating from the KF/A7 region, may provide the neurophysiological basis for breathing modulation. We conducted experiments using urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Injection of L-glutamate into the KF/A7 region resulted in inhibition of inspiratory activity, and a prolonged and high-amplitude genioglossal activity (GGEMG). Blockade of the α1 adrenergic receptors (α1-AR) or the ionotropic glutamatergic receptors in the pF region decrease the activity of the GGEMG without affecting inspiratory cessation. In contrast, blockade of α2-AR in the pF region extended the duration of GG activity. Notably, the inspiratory and GGEMG activities induced by KF/A7 stimulation were completely blocked by bilateral blockade of glutamatergic receptors in the Bötzinger complex (BötC). While our study found a limited role for α1 and α2 adrenergic receptors at the pF level in modulating the breathing response to KF/A7 stimulation, it became evident that BötC neurons are responsible for the respiratory effects induced by KF/A7 stimulation.

Evaluation of vestibular functions in patients with obstructive sleep apnea syndrome

Background To determine the anatomical proximity of the vestibular nuclei to the respiratory nuclei and the effect of susceptibility of the posterior labyrinth to a hypoxic state on the vestibular system. Objective It was aimed to evaluate the possible effects of periodic hypoxia on vestibular reflexes and proprioceptive perception in patients with obstructive sleep apnea syndrome (OSAS). Material and methods The study was conducted with 40 patients diagnosed with moderate and severe OSAS and 21 healthy individuals. All individuals were evaluated with Dizziness Handicap Inventory, ocular vestibular evoked myogenic potential (oVEMP), cervical vestibular evoked myogenic potential (cVEMP), video head impulse test (vHIT), videonystagmography (VNG) and sportKAT 3000. Results In the vHIT, a statistically significant difference was found between the groups in terms of anterior and posterior semicircular canal vestibulo-ocular reflex gains (p < .05). A negative correlation was found between the lateral gain asymmetry and RALP gain asymmetry and the awake blood oxygen level in the OSAS groups. There was a statistically significant difference between the groups in terms of wave response rates cVEMP 100 dB nHL and oVEMP 100–110 dB nHL (p < .05). Conclusion and Significance It was concluded that vestibular reflexes and proprioceptive perception were affected due to periodic/chronic hypoxia in patients with moderate and severe OSAS.

Modification of Endotypic Traits in OSA by the Carbonic Anhydrase Inhibitor Sulthiame

The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation. How does sulthiame treatment modify endotypic traits in OSA? Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI,≥ 20 to≤ 35kg/m2; age, 18-75 years; apnea-hypopnea index (AHI)≥ 15 events/h; Epworth sleepiness scale score,≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n= 22), sulthiame 200mg (n= 12), or sulthiame 400mg (n= 24) during 4weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson (r) or Spearman correlations (rs). Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG1; mean, -0.16 [95%CI, -0.18 to -0.13]; P< .05) in addition to increased ventilation at lowest decile of ventilatory drive (Vmin; median,+12 [95%CI, 4-20]; P< .05) and median ventilation at eupneic ventilatory drive (Vpassive; median,+4 [95%CI, 0-5]; P< .05). ΔLG1 correlated with ΔAHI percentage (200mg: r= 0.65; P< .05). Vmin and Vpassive correlated with ΔAHI (all sulthiame: rs= -0.59 and rs= -0.65; P< .05 for all). The reduction of LG1 was seen already in the lower sulthiame concentration range, whereas changes in Vmin peaked in the higher range. The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG1) as well as upper airway collapsibility (Vmin and Vpassive). European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu.

Dynamics of ventilatory pattern variability and Cardioventilatory Coupling during systemic inflammation in rats.

Introduction: Biometrics of common physiologic signals can reflect health status. We have developed analytics to measure the predictability of ventilatory pattern variability (VPV, Nonlinear Complexity Index (NLCI) that quantifies the predictability of a continuous waveform associated with inhalation and exhalation) and the cardioventilatory coupling (CVC, the tendency of the last heartbeat in expiration to occur at preferred latency before the next inspiration). We hypothesized that measures of VPV and CVC are sensitive to the development of endotoxemia, which evoke neuroinflammation. Methods: We implanted Sprague Dawley male rats with BP transducers to monitor arterial blood pressure (BP) and recorded ventilatory waveforms and BP simultaneously using whole-body plethysmography in conjunction with BP transducer receivers. After baseline (BSLN) recordings, we injected lipopolysaccharide (LPS, n = 8) or phosphate buffered saline (PBS, n =3) intraperitoneally on 3 consecutive days. We recorded for 4-6h after the injection, chose 3 epochs from each hour and analyzed VPV and CVC as well as heart rate variability (HRV). Results: First, the responses to sepsis varied across rats, but within rats the repeated measures of NLCI, CVC, as well as respiratory frequency (fR), HR, BP and HRV had a low coefficient of variation, (<0.2) at each time point. Second, HR, fR, and NLCI increased from BSLN on Days 1-3; whereas CVC decreased on Days 2 and 3. In contrast, changes in BP and the relative low-(LF) and high-frequency (HF) of HRV were not significant. The coefficient of variation decreased from BSLN to Day 3, except for CVC. Interestingly, NLCI increased before fR in LPS-treated rats. Finally, we histologically confirmed lung injury, systemic inflammation via ELISA and the presence of the proinflammatory cytokine, IL-1β, with immunohistochemistry in the ponto-medullary respiratory nuclei. Discussion: Our findings support that NLCI reflects changes in the rat's health induced by systemic injection of LPS and reflected in increases in HR and fR. CVC decreased over the course to the experiment. We conclude that NLCI reflected the increase in predictability of the ventilatory waveform and (together with our previous work) may reflect action of inflammatory cytokines on the network generating respiration.

Theophylline reverses oxycodone's but not fentanyl's respiratory depression in mice while caffeine is ineffective against both opioids

RationaleThe opioid epidemic remains a pressing public health crisis in the United States. Most of these overdose deaths are a result of lethal respiratory depression. In recent years the increasing incidence of opioid-involved overdose deaths has been driven by fentanyl, which is more resistant to adequate reversal by naloxone (NARCAN ®) than semi-synthetic or classical morphinan predecessors like oxycodone and heroin. For this and other reasons (e.g., precipitating withdrawal) non-opioidergic pharmacotherapies to reverse opioid-depressed respiration are needed. Methylxanthines are a class of stimulant drugs including caffeine and theophylline which exert their effects primarily via adenosine receptor antagonism. Evidence suggests methylxanthines can stimulate respiration by enhancing neural activity in respiratory nuclei in the pons and medulla independent of opioid receptors. This study aimed to determine whether caffeine and theophylline can stimulate respiration in mice when depressed by fentanyl and oxycodone. MethodsWhole-body plethysmography was used to characterize fentanyl and oxycodone's effects on respiration and their reversal by naloxone in male Swiss Webster mice. Next, caffeine and theophylline were tested for their effects on basal respiration. Finally, each methylxanthine was evaluated for its ability to reverse similar levels of respiratory depression induced by fentanyl or oxycodone. Results and conclusionsOxycodone and fentanyl dose-dependently reduced respiratory minute volume (ml/min; MVb) that was reversible by naloxone. Caffeine and theophylline each significantly increased basal MVb. Theophylline, but not caffeine, completely reversed oxycodone-depressed respiration. In contrast, neither methylxanthine elevated fentanyl-depressed respiration at the doses tested. Despite their limited efficacy for reversing opioid-depressed respiration when administered alone, the methylxanthines safety, duration, and mechanism of action supports further evaluation in combination with naloxone to augment its reversal of opioid-depressed respiration.

Multifunctional changes in the athletes’ body during the formation of autonomic regulations’ overstrain under the influence of training load

Purpose: the purpose of this study was to generalize polysystemic changes that occur in the body of highly qualified athletes with signs of autonomic regulation overstrain under the influence of training load and during the recovery period after it. Material &amp; Methods: test subjects were qualified male athletes (N=202) aged 22.6±2.8 years, who were examined by means of spiroarteriocardiorhythmography (SACR) and computerized motion meter (CMM). In accordance with the design the examinations with the aid of SACR and CMM were carried out three times: in the morning, on an empty stomach, in a sitting position on the day of training (G1), immediately after training (during the first 5-7 minutes) (G2) and the next day in the morning after sleep (G3). Results: according to the data of the examination of athletes in the dynamics of recovery after the training load, options of changes in HRV indicators were determined, which indicated the formation of sympathetic and parasympathetic overstrain in athletes. Two groups were created. The first included 10 athletes, the second included 9 athletes. The analysis of changes in indicators, the research methods used, allowed us to establish differences in their dynamics during the formation of sympathetic and parasympathetic overstrain. Differences were noted among 18 indicators. Among them are indicators of HRV – ABI (c.u.), SRAI (c.u.), ARI (c.u.), RMSSD (ms), VLF (ms2), LFHF (ms2/ms2); variability of arterial pressure – LFSBPn (n.u.), HFSBPn (n.u.), LFHFSBP (mmHg2), TPDBP (mmHg2), LFDBP, (mmHg2), ICDBP (mmHg2/mmHg2); hemodynamics – CO (dm3), GPVR, (dyn/s/cm−5), CI (dm3/m2); respiratory variability – TPR (L×min–1)2; of sensorimotor function – SCSleft (s), SMleft (%). Conclusions: the obtained results on the formation of sympathetic and parasympathetic overstrain under the influence of intense physical activity indicate that changes in the autonomic regulation of the heart rate, which determine the type of heart rate regulation, are accompanied by a number of changes in hemodynamics, autonomic regulation of the pumping function of the heart, vascular tone, respiratory regulation, and sensorimotor function. The determined differential dynamics of changes in cardiorespiratory and sensorimotor indicators will allow further algorithmization of the assessment of the functional state of the athletes’ body in order to detect early states of non-functional overstrain and overtraining.

Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms.

Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms-somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla-all of which could contribute to opioid-induced respiratory depression.