Publications by authors named "Stephen J Lewis"

191 Publications

Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment.

Sci Rep 2022 Jul 18;12(1):12242. Epub 2022 Jul 18.

Division of Pulmonary, Critical Care, and Sleep Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20-30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that "low intensity intermittent" electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.
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http://dx.doi.org/10.1038/s41598-022-15761-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293925PMC
July 2022

D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood-Gas Chemistry in Freely-Moving Rats.

Front Pharmacol 2022 23;13:883329. Epub 2022 Jun 23.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States.

Cell-penetrant thiol esters including the disulfides, D-cystine diethyl ester and D-cystine dimethyl ester, and the monosulfide, L-glutathione ethyl ester, prevent and/or reverse the deleterious effects of opioids, such as morphine and fentanyl, on breathing and gas exchange within the lungs of unanesthetized/unrestrained rats without diminishing the antinociceptive or sedative effects of opioids. We describe here the effects of the monosulfide thiol ester, D-cysteine ethyl ester (D-CYSee), on intravenous morphine-induced changes in ventilatory parameters, arterial blood-gas chemistry, alveolar-arterial (A-a) gradient (i.e., index of gas exchange in the lungs), and sedation and antinociception in freely-moving rats. The bolus injection of morphine (10 mg/kg, IV) elicited deleterious effects on breathing, including depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive. Subsequent injections of D-CYSee (2 × 500 μmol/kg, IV, given 15 min apart) elicited an immediate and sustained reversal of these effects of morphine. Morphine (10 mg/kg, IV) also A-a gradient, which caused a mismatch in ventilation perfusion within the lungs, and elicited pronounced changes in arterial blood-gas chemistry, including pronounced decreases in arterial blood pH, pO and sO, and equally pronounced increases in pCO (all responses indicative of decreased ventilatory drive). These deleterious effects of morphine were immediately reversed by the injection of a single dose of D-CYSee (500 μmol/kg, IV). Importantly, the sedation and antinociception elicited by morphine (10 mg/kg, IV) were minimally affected by D-CYSee (500 μmol/kg, IV). In contrast, none of the effects of morphine were affected by administration of the parent thiol, D-cysteine (1 or 2 doses of 500 μmol/kg, IV). Taken together, these data suggest that D-CYSee may exert its beneficial effects via entry into cells that mediate the deleterious effects of opioids on breathing and gas exchange. Whether D-CYSee acts as a respiratory stimulant or counteracts the inhibitory actions of µ-opioid receptor activation remains to be determined. In conclusion, D-CYSee and related thiol esters may have clinical potential for the reversal of the adverse effects of opioids on breathing and gas exchange, while largely sparing antinociception and sedation.
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http://dx.doi.org/10.3389/fphar.2022.883329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260251PMC
June 2022

L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry.

Biomed Pharmacother 2022 Jun 17;153:113277. Epub 2022 Jun 17.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

There is an urgent need for development of drugs that are able to reverse the adverse effects of opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes the effects of bolus injections of N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) on ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) and analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion of fentanyl (1 μg/kg/min, IV). Fentanyl infusion elicited pronounced disturbances in (1) ventilatory parameters (e.g., decreases in frequency of breathing, tidal volume and minute ventilation), (2) ABG chemistry (decreases in pH, pO, sO with increases in pCO), (3) A-a gradient (increases that were consistent with reduced alveolar gas exchange), and (4) sedation and analgesia. Bolus injections of L-NAC given 60 and 90 min after start of fentanyl infusion elicited rapid and sustained reversal of the deleterious effects of fentanyl infusion on ventilatory parameters and ABG chemistry, whereas they did not affect the sedative or analgesic effects of fentanyl. Systemic L-NAC is approved for human use, and thus our findings raise the possibility that this biologically active thiol may be an effective compound to combat opioid-induced respiratory depression in human subjects.
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http://dx.doi.org/10.1016/j.biopha.2022.113277DOI Listing
June 2022

S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats.

Front Pharmacol 2022 26;13:892307. Epub 2022 May 26.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States.

Endogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO, pO, and sO) and Alveolar-arterial gradient (i.e., index of gas exchange) were markedly diminished in anesthetized Sprague Dawley rats that received a continuous intravenous infusion of the endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by showing that unanesthetized adult male Sprague Dawley rats receiving an intravenous infusion of S-nitroso-L-cysteine (100 or 200 nmol/kg/min) markedly diminished the ability of intravenous injections of the potent synthetic opioid, fentanyl (10, 25, and 50 μg/kg), to depress the frequency of breathing, tidal volume, and minute ventilation. Our study also found that the ability of intravenously injected fentanyl (10, 25, and 50 μg/kg) to disturb eupneic breathing, which was measured as a marked increase of the non-eupneic breathing index, was substantially reduced in unanesthetized rats receiving intravenous infusions of S-nitroso-L-cysteine (100 or 200 nmol/kg/min). In contrast, the deleterious effects of fentanyl (10, 25, and 50 μg/kg) on frequency of breathing, tidal volume, minute ventilation and non-eupneic breathing index were fully expressed in rats receiving continuous infusions (200 nmol/kg/min) of the parent amino acid, L-cysteine, or the D-isomer, namely, S-nitroso-D-cysteine. In addition, the antinociceptive actions of the above doses of fentanyl as monitored by the tail-flick latency assay, were enhanced by S-nitroso-L-cysteine, but not L-cysteine or S-nitroso-D-cysteine. Taken together, these findings add to existing knowledge that S-nitroso-L-cysteine stereoselectively modulates the detrimental effects of opioids on breathing, and opens the door for mechanistic studies designed to establish whether the pharmacological actions of S-nitroso-L-cysteine involve signaling processes that include 1) the activation of plasma membrane ion channels and receptors, 2) selective intracellular entry of S-nitroso-L-cysteine, and/or 3) S-nitrosylation events. Whether alterations in the bioavailability and bioactivity of endogenous S-nitroso-L-cysteine is a key factor in determining the potency/efficacy of fentanyl on breathing is an intriguing question.
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http://dx.doi.org/10.3389/fphar.2022.892307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9199495PMC
May 2022

D-cysteine ethyl ester and D-cystine dimethyl ester reverse the deleterious effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient in anesthetized rats.

Respir Physiol Neurobiol 2022 08 18;302:103912. Epub 2022 Apr 18.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA; Functinal Electrical Stimulation Center, Case Western Reserve University, Cleveland, OH 44106, USA.

We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)- 2-amino-3-sulfanylpropanoate) (D-CYSee) and D-cystine dimethyl ester (methyl (2 S)- 2-amino-3-[[(2 S)- 2-amino-3-methoxy-3-oxopropyl]disulfanyl] propanoate) (D-CYSdime), could overcome the deleterious actions of intravenous morphine on arterial blood pH, pCO, pO and sO, and Alveolar-arterial (A-a) gradient (i.e., the measure of exchange of gases in the lungs) in Sprague Dawley rats anesthetized with isoflurane. Injection of morphine (2 mg/kg, IV) caused pronounced reductions in pH, pO and sO accompanied by elevations in pCO all which are suggestive of diminished ventilation, and elevations in A-a gradient, which suggests a mismatch of ventilation-perfusion. Subsequent boluses of D-cysteine ethyl ester (2 ×100 μmol/kg, IV) or D-cystine dimethyl ester (2 ×50 μmol/kg, IV) rapidly reversed of the negative actions of morphine on pH, pCO, pO and sO and A-a gradient. Similar injections of D-cysteine (2 ×100 μmol/kg, IV) were without effect, whereas injections of D-cystine (2 ×50 μmol/kg, IV) produced a modest reversal. Our data show that D-cysteine ethyl ester and D-cystine dimethyl ester readily overcome the deleterious effects of morphine on arterial blood gas (ABG) chemistry and A-a gradient by mechanisms that may depend upon their ability to rapidly enter cells. As a result of their known ability to enter the brain, lungs, muscles of the chest wall, and most likely the major peripheral chemoreceptors (i.e., carotid bodies), the effects of the thiolesters on changes in ABG chemistry and A-a gradient elicited by morphine likely involve central and peripheral mechanisms. We are employing target prediction methods to identify an array of in vitro and in vivo methods to test potential functional proteins by which D-CYSee and D-CYSdime modulate the effects of morphine on breathing.
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http://dx.doi.org/10.1016/j.resp.2022.103912DOI Listing
August 2022

Differential immunostaining patterns of transient receptor potential (TRP) ion channels in the rat nodose ganglion.

J Anat 2022 08 9;241(2):230-244. Epub 2022 Apr 9.

Department of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Vagal afferents regulate numerous physiological functions including arterial blood pressure, heart rate, breathing, and nociception. Cell bodies of vagal afferents reside in the inferior vagal (nodose) ganglia and their stimulation by various means is being considered as a way to regulate cardiorespiratory responses and control pain sensations. Stimulation of the nodose by exposure to infrared light is recently being considered as a precise way to elicit responses. These responses would likely involve the activity of temperature-sensitive membrane-bound channels. While papers have been published to track the expression of these transient receptor potential ion channels (TRPs), further studies are warranted to determine the in situ expression of the endogenous TRP proteins in the nodose ganglia to fully understand their pattern of expression, subcellular locations, and functions in this animal model. TRP ion channels are a superfamily of Na /Ca -channels whose members are temperature- and/or mechano-sensitive and therefore represent a potential set of proteins that will be activated directly or indirectly by infrared light. Here, we report the spatial localization of six TRP channels, TRPV1, TRPV4, TRPM3, TRPM8, TRPA1, and TRPC1, from nodose ganglia taken from juvenile male Sprague-Dawley rats. The channels were detected using immunohistology with fluorescent tags on cryosections and imaged using confocal microscopy. All six TRP channels were detected with different levels of intensity in neuronal cell bodies and some were also detected in axonal fibers and blood vessels. The TRP receptors differed in their prevalence, in their patterns of expression, and in subcellular expression/localization. More specifically, TRPV1, TRPV4, TRPA1, TRPM8, TRPC1, and TRPM3 were found in vagal afferent cell bodies with a wide range of immunostaining intensity from neuron to neuron. Immunostaining for TRPV1, TRPV4, and TRPA1 appeared as fine particles scattered throughout the cytoplasm of the cell body. Intense TRPV1 immunostaining was also evident in a subset of axonal fibers. TRPM8 and TRPC1 were expressed in courser particles suggesting different subcellular compartments than for TRPV1. The localization of TRPM3 differed markedly from the other TRP channels with an immunostaining pattern that was localized to the periphery of a subset of cell bodies, whereas a scattering or no immunostaining was detected within the bulk of the cytoplasm. TRPV4 and TRPC1 were also expressed on the walls of blood vessels. The finding that all six TRP channels (representing four subfamilies) were present in the nodose ganglia provides the basis for studies designed to understand the roles of these channels in sensory transmission within vagal afferent fibers and in the responses elicited by exposure of nodose ganglia to infrared light and other stimuli. Depending on the location and functionality of the TRP channels, they may regulate the flux of Na /Ca -across the membranes of cell bodies and axons of sensory afferents, efferent (motor) fibers coursing through the ganglia, and in vascular smooth muscle.
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http://dx.doi.org/10.1111/joa.13656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296033PMC
August 2022

Development of consensus-based best practice guidelines for response to intraoperative neuromonitoring events in high-risk spinal deformity surgery.

Spine Deform 2022 07 15;10(4):745-761. Epub 2022 Mar 15.

Division of Pediatric Orthopaedic Surgery, Department of Orthopaedic Surgery, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Irving Medical Center, 3959 Broadway, CHONY 8-N, New York, NY, 10032-3784, USA.

Purpose: To expand on previously described intraoperative aids by developing consensus-based best practice guidelines to optimize the approach to intraoperative neuromonitoring (IONM) events associated with "high-risk" spinal deformity surgery.

Methods: Consensus was established among a group of experienced spinal deformity surgeons by way of the Delphi method. Through a series of iterative surveys and a final virtual consensus meeting, participants expressed their agreement (strongly agree, agree, disagree, and strongly disagree) with various items. Consensus was defined as ≥ 80% agreement ("strongly agree" or "agree"). Near-consensus was defined as ≥ 60% but < 80%. Equipoise was ≥ 20% but < 60%, and consensus to exclude was < 20%.

Results: 15 out of 15 (100%) invited surgeons agreed to participate. Final consensus supported inclusion of 105 items (53 in Response Algorithm, 13 in Ongoing Consideration of Etiology, 31 in Real-Time Data Scenarios, 8 in Patterns of IONM Loss), which were organized into a final set of best practice guidelines.

Conclusion: Detailed consensus-based best practice guidelines and aids were successfully created with the intention to help organize and direct the surgical team in exploring and responding to neurological complications during high-risk spinal deformity surgery.

Level Of Evidence: Level V.
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http://dx.doi.org/10.1007/s43390-022-00485-wDOI Listing
July 2022

Gut hormones profile after an Ivor Lewis gastro-esophagectomy and its relationship to delayed gastric emptying.

Dis Esophagus 2022 Mar 8. Epub 2022 Mar 8.

Department of Gastroenterology, University Hospital Plymouth, Plymouth, UK.

Delayed gastric emptying (DGE) is common after an Ivor Lewis gastro-esophagectomy (ILGO). The risk of a dilated conduit is the much-feared anastomotic leak. Therefore, prompt management of DGE is required. However, the pathophysiology of DGE is unclear. We proposed that post-ILGO patients with/without DGE have different gut hormone profiles (GHP). Consecutive patients undergoing an ILGO from 1 December 2017 to 31 November 2019 were recruited. Blood sampling was conducted on either day 4, 5, or 6 with baseline sample taken prior to a 193-kcal meal and after every 30 minutes for 2 hours. If patients received pyloric dilatation, a repeat profile was performed post-dilatation and were designated as had DGE. Analyses were conducted on the following groups: patient without dilatation (non-dilated) versus dilatation (dilated); and pre-dilatation versus post-dilatation. Gut hormone profiles analyzed were glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) using radioimmunoassay. Of 65 patients, 24 (36.9%) had dilatation and 41 (63.1%) did not. For the non-dilated and dilated groups, there were no differences in day 4, 5, or 6 GLP-1 (P = 0.499) (95% confidence interval for non-dilated [2822.64, 4416.40] and dilated [2519.91, 3162.32]). However, PYY levels were raised in the non-dilated group (P = 0.021) (95% confidence interval for non-dilated [1620.38, 3005.75] and dilated [821.53, 1606.18]). Additionally, after pyloric dilatation, paired analysis showed no differences in GLP-1, but PYY levels were different at all time points and had an exaggerated post-prandial response. We conclude that DGE is associated with an obtunded PYY response. However, the exact nature of the association is not yet established.
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http://dx.doi.org/10.1093/dote/doac008DOI Listing
March 2022

Systemic Administration of Tempol, a Superoxide Dismutase Mimetic, Augments Upper Airway Muscle Activity in Obese Zucker Rats.

Front Pharmacol 2022 9;13:814032. Epub 2022 Feb 9.

Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, School of Medicine, Case Western Reserve University, Cleveland, OH, United States.

Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMG) and diaphragmatic (EMG) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1-100 mg/kg) increased EMG without changing EMG in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1-25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.
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http://dx.doi.org/10.3389/fphar.2022.814032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864283PMC
February 2022

Establishing consensus: determinants of high-risk and preventative strategies for neurological events in complex spinal deformity surgery.

Spine Deform 2022 07 23;10(4):733-744. Epub 2022 Feb 23.

The Daniel and Jane Och Spine Hospital at New York-Presbyterian/Allen, New York, NY, USA.

Purpose: To establish expert consensus on various parameters that constitute elevated risk during spinal deformity surgery and potential preventative strategies that may minimize the risk of intraoperative neuromonitoring (IONM) events and postoperative neurological deficits.

Methods: Through a series of surveys and a final virtual consensus meeting, the Delphi method was utilized to establish consensus among a group of expert spinal deformity surgeons. During iterative rounds of voting, participants were asked to express their agreement (strongly agree, agree, disagree, strongly disagree) to include items in a final set of guidelines. Consensus was defined as ≥ 80% agreement among participants. Near-consensus was ≥ 60% but < 80% agreement, equipoise was ≥ 20% but < 60%, and consensus to exclude was < 20%.

Results: Fifteen of the 15 (100%) invited expert spinal deformity surgeons agreed to participate. There was consensus to include 22 determinants of high-risk (8 patient factors, 8 curve and spinal cord factors, and 6 surgical factors) and 21 preventative strategies (4 preoperative, 14 intraoperative, and 3 postoperative) in the final set of best practice guidelines.

Conclusion: A resource highlighting several salient clinical factors found in high-risk spinal deformity patients as well as strategies to prevent neurological events was successfully created through expert consensus. This is intended to serve as a reference for surgeons and other clinicians involved in the care of spinal deformity patients.

Level Of Evidence: Level V.
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http://dx.doi.org/10.1007/s43390-022-00482-zDOI Listing
July 2022

Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer's disease.

Alzheimers Res Ther 2022 01 10;14(1). Epub 2022 Jan 10.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.

Background: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful.

Methods: To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein-protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells.

Results: Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861-0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862-0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD.

Conclusions: In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.
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http://dx.doi.org/10.1186/s13195-021-00951-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751379PMC
January 2022

Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in unanesthetized rats.

Biomed Pharmacother 2022 Feb 22;146:112571. Epub 2021 Dec 22.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

There is an urgent need to understand the intracellular mechanisms by which synthetic opioids, such as fentanyl, depress breathing. We used L-NAME (N-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor, to provide evidence for a role of nitric oxide (NO) and nitrosyl factors, including S-nitrosothiols, in fentanyl-induced suppression of breathing in rats. We measured breathing parameters using unrestrained plethysmography to record the changes produced by bolus administration of fentanyl (25 μg/kg, IV) in male Sprague Dawley rats that were pretreated with vehicle (saline), L-NAME (50 μmol/kg, IV) or the inactive D-isomer, D-NAME (50 μmol/kg, IV), 15 min previously. L-NAME produced a series of ventilatory changes that included (i) sustained elevations in breathing frequency, due to the reductions in the durations of inspiration and expiration, (ii) sustained elevations in minute ventilation, accompanied by minimal changes in tidal volume, and (iii) increases in inspiratory drive and expiratory drive, and peak inspiratory flow and peak expiratory flow. Subsequent administration of fentanyl in rats pretreated with vehicle produced negative effects on breathing, including decreases in frequency, tidal volume and therefore minute ventilation. Fentanyl elicited markedly different responses in rats that were pretreated with L-NAME, and conclusively, the negative effects of fentanyl were augmented by the NOS inhibitor. D-NAME did not alter ventilatory parameters or modulate the effects of fentanyl on breathing. Our study fully characterized the effects of L-NAME on ventilation in rats and is the first to suggest a potential role of nitrosyl factors in the ventilatory responses to fentanyl. Our data shows that nitrosyl factors reduce the expression of fentanyl-induced changes in ventilation.
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http://dx.doi.org/10.1016/j.biopha.2021.112571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776621PMC
February 2022

Research Practices and Needs Among Spine Surgeons Worldwide.

Global Spine J 2021 Dec 6:21925682211058158. Epub 2021 Dec 6.

Department of Orthopaedic Surgery, 2468Rush University Medical Center, Chicago, IL, USA.

Objective: Resource allocation to research activities is challenging and there is limited evidence to justify decisions. Members of AO Spine were surveyed to understand the research practices and needs of spine surgeons worldwide.

Methods: An 84-item survey was distributed to the AO Spine community in September of 2020. Respondent demographics and insights regarding research registries, training and education, mentorship, grants and financial support, and future directions were collected. Responses were anonymous and compared among regions.

Results: A total of 333 spine surgeons representing all geographic regions responded; 52.3% were affiliated with an academic/university hospital, 91.0% conducted clinical research, and 60.9% had 5+ years of research experience. There was heterogeneity among research practices and needs across regions. North American respondents had more research experience ( = .023), began conducting research early on ( < .001), had an undergraduate science degree ( < .001), and were more likely to have access to a research coordinator or support staff ( = .042) compared to other regions. While all regions expressed having the same challenges in conducting research, Latin America, and Middle East/Northern Africa respondents were less encouraged to do research ( < .001). Despite regional differences, there was global support for research registries and research training and education.

Conclusion: To advance spine care worldwide, spine societies should establish guidelines, conduct studies on pain management, and support predictive analytic modeling. Tailoring local/regional programs according to regional needs is advised. These results can assist spine societies in developing long-term research strategies and provide justified rationale to governments and funding agencies.
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http://dx.doi.org/10.1177/21925682211058158DOI Listing
December 2021

Clinical Efficacy and Safety of Controlled Distraction-Compression Technique Using Expandable Titanium Cage in Correction of Posttraumatic Kyphosis.

J Korean Neurosurg Soc 2022 Jan 15;65(1):84-95. Epub 2021 Nov 15.

Department of Neurosurgery, School of Medicine, Gyeongsang National University, Jinju, Korea.

Objective: To investigate the clinical efficacy and safety of the controlled distraction-compression technique using an expandable titanium cage (ETC) in posttraumatic kyphosis (PTK).

Methods: We retrospectively studied and collected data on 20 patients with PTK. From January 2014 to December 2017, the controlled distraction-compression technique using ETC was consecutively performed in 20 patients with PTK of the thoracolumbar zone (range, 36-82 years). Among them, nine were males and 11 were females and the mean age was 61.5 years. The patients were followed regularly at 1, 3, 6, and 12 months, and the last follow-up was more than 2 years after surgery.

Results: The mean follow-up period was 27.3±7.3 months (range, 14-48). The average operation time was 286.8±33.1 minutes (range, 225-365). The preoperative regional kyphotic angle (RKA) ranged from 35.6° to 70.6° with an average of 47.5°±8.1°. The immediate postoperative mean RKA was 5.9°±3.8° (86.2% correction rate, p=0.000), and at the last follow-up more than 2 years later, the mean RKA was 9.2°±4.9° (80.2% correction rate, p=0.000). The preoperative mean thoracolumbar kyphosis was 49.1°±9.2° and was corrected to an average of 8.8°±5.3° immediately after surgery (p=0.000). At the last follow-up, a correction of 11.9°±6.3° was obtained (p=0.000). The preoperative mean back visual analog scale (VAS) score was 7.9±0.8 and at the last follow-up, the VAS score was improved to a mean of 2.3±1.0 with a 70.9% correction rate (p=0.000). The preoperative mean Oswestry disability index (ODI) score was 32.3±6.9 (64.6%) and the last follow-up ODI score was improved to a mean of 6.85±2.9 (3.7%) with a 78.8% correction rate (p=0.000). The overall complication was 15%, with two of distal junctional fractures and one of proximal junctional kyphosis and screw loosening. However, there were no complications directly related to the operation.

Conclusion: Posterior vertebral column resection through the controlled distraction-compression technique using ETC showed safe and good results in terms of complications, and clinical and radiologic outcomes in PTK. However, to further evaluate the efficacy of this surgical procedure, more patients need long-term follow-up and there is a need to apply it to other diseases.
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http://dx.doi.org/10.3340/jkns.2021.0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752882PMC
January 2022

Ventilatory responses during and following hypercapnic gas challenge are impaired in male but not female endothelial NOS knock-out mice.

Sci Rep 2021 10 18;11(1):20557. Epub 2021 Oct 18.

Department of Pediatrics, Case Western Reserve University, Biomedical Research Building BRB 319, 10900 Euclid Avenue Mail Stop 1714, Cleveland, OH, 44106-1714, USA.

The roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO, 21% O, 74% N) were assessed in freely-moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background using whole body plethysmography. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was similar in both male and female WT mice. However, the post-HCC increases in frequency of breathing (with decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory drive (i.e., tidal volume/inspiratory time) and expiratory drive (i.e., tidal volume/expiratory time), and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.
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http://dx.doi.org/10.1038/s41598-021-99922-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523677PMC
October 2021

Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats.

Front Pharmacol 2021 22;12:749084. Epub 2021 Sep 22.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United states.

We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts the cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective of the present study was to determine whether Tempol is able to reverse the effects of morphine on arterial blood-gas (ABG) chemistry in freely-moving Sprague Dawley rats. The intravenous injection of morphine (10 mg/kg) elicited substantial decreases in pH, pO and sO that were accompanied by substantial increases in pCO and Alveolar-arterial gradient, which results in diminished gas-exchange within the lungs. Intravenous injection of a 60 mg/kg dose of Tempol 15 min after the injection of morphine caused minor improvements in pO and pCO but not in other ABG parameters. In contrast, the 100 mg/kg dose of Tempol caused an immediate and sustained reversal of the negative effects of morphine on arterial blood pH, pCO, pO, sO and Alveolar-arterial gradient. In other rats, we used pulse oximetry to determine that the 100 mg/kg dose of Tempol, but not the 60 mg/kg dose elicited a rapid and sustained reversal of the negative effects of morphine (10 mg/kg, IV) on tissue O saturation (SpO). The injection of morphine caused a relatively minor fall in mean arterial blood pressure that was somewhat exacerbated by Tempol. These findings demonstrate that Tempol can reverse the negative effects of morphine on ABG chemistry in freely-moving rats paving the way of structure-activity and mechanisms of action studies with the host of Tempol analogues that are commercially available.
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http://dx.doi.org/10.3389/fphar.2021.749084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493249PMC
September 2021

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome.

Respir Physiol Neurobiol 2022 02 6;296:103800. Epub 2021 Oct 6.

Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, OH, 44106, USA; Department of Physiology, Case Western Reserve University, Cleveland, OH, 44106, USA. Electronic address:

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.
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http://dx.doi.org/10.1016/j.resp.2021.103800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742781PMC
February 2022

Short-term facilitation of breathing upon cessation of hypoxic challenge is impaired in male but not female endothelial NOS knock-out mice.

Sci Rep 2021 09 15;11(1):18346. Epub 2021 Sep 15.

Department of Pediatrics, Biomedical Research Building BRB 319, Case Western Reserve University, 10900 Euclid Avenue Mail Stop 1714, Cleveland, OH, 44106-1714, USA.

Decreases in arterial blood oxygen stimulate increases in minute ventilation via activation of peripheral and central respiratory structures. This study evaluates the role of endothelial nitric oxide synthase (eNOS) in the expression of the ventilatory responses during and following a hypoxic gas challenge (HXC, 10% O, 90% N) in freely moving male and female wild-type (WT) C57BL6 and eNOS knock-out (eNOS-/-) mice. Exposure to HXC caused an array of responses (of similar magnitude and duration) in both male and female WT mice such as, rapid increases in frequency of breathing, tidal volume, minute ventilation and peak inspiratory and expiratory flows, that were subject to pronounced roll-off. The responses to HXC in male eNOS-/- mice were similar to male WT mice. In contrast, several of the ventilatory responses in female eNOS-/- mice (e.g., frequency of breathing, and expiratory drive) were greater compared to female WT mice. Upon return to room-air, male and female WT mice showed similar excitatory ventilatory responses (i.e., short-term potentiation phase). These responses were markedly reduced in male eNOS-/- mice, whereas female eNOS-/- mice displayed robust post-HXC responses that were similar to those in female WT mice. Our data demonstrates that eNOS plays important roles in (1) ventilatory responses to HXC in female compared to male C57BL6 mice; and (2) expression of post-HXC responses in male, but not female C57BL6 mice. These data support existing evidence that sex, and the functional roles of specific proteins (e.g., eNOS) have profound influences on ventilatory processes, including the responses to HXC.
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http://dx.doi.org/10.1038/s41598-021-97322-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443732PMC
September 2021

The Scoli-RISK 1 results of lower extremity motor function 5 years after complex adult spinal deformity surgery.

Eur Spine J 2021 11 30;30(11):3243-3254. Epub 2021 Aug 30.

University of Virginia, Charlottesville, VA, USA.

Introduction: Neurologic complications after complex adult spinal deformity (ASD) surgery are important, yet outcomes are heterogeneously reported, and long-term follow-up of actual lower extremity motor function is unknown.

Objective: To prospectively evaluate lower extremity motor function scores (LEMS) before and at 5 years after surgical correction of complex ASD.

Design: Retrospective analysis of a prospective, multicenter, international observational study.

Methods: The Scoli-RISK-1 study enrolled 272 ASD patients undergoing surgery from 15 centers around the world. Inclusion criteria were Cobb angle of > 80°, corrective osteotomy for congenital or revision deformity and/or 3-column osteotomy. Among patients with 5-year follow-up, comparisons of LEMS to baseline and within each follow-up period were made via documented neurologic exams on each patient.

Results: Seventy-seven (28.3%) patients had 5-year follow-up. Among these 77 patients with 5-year follow-up, rates of postoperative LEMS deterioration were: 14.3% hospital discharge, 10.7% at 6 weeks, 6.5% at 6 months, 9.5% at 2 years and 9.3% at 5 years postoperative. During the 2-5 year window, while mean LEMS did not change significantly (-0.5, p = 0.442), eight (11.1%) patients deteriorated (of which 3 were ≥ 4 motor points), and six (8.3%) patients improved (of which 2 were ≥ 4 points). Of the 14 neurologic complications, four (28.6%) were surgery-related, three of which required reoperation. While mean LEMS were not impacted in patients with a major surgery-related complication, mean LEMS were significantly lower in patients with neurologic surgery-related complications at discharge (p = 0.041) and 6 months (p = 0.008) between the two groups as well as the change from baseline to 5 years (p = 0.041).

Conclusions: In 77 patients undergoing complex ASD surgery with 5-year follow-up, while mean LEMS did not change from 2 to 5 years, subtle neurologic changes occurred in approximately 1 in 5 patients (11.1% deteriorated; 8.3% improved). Major surgery-related complication did not result in decreased LEMS; however, those with neurologic surgery-related complications continued to have decreased lower extremity motor function at 5 years postoperative. These results underscore the importance of long-term follow-up to 5 years, using individual motor scores rather than group averages, and comparing outcomes to both baseline and last follow-up.
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http://dx.doi.org/10.1007/s00586-021-06969-zDOI Listing
November 2021

Characterization of endothelium-dependent and -independent processes in occipital artery of the rat: relevance to control of blood flow to nodose sensory cells.

J Appl Physiol (1985) 2021 09 29;131(3):1067-1079. Epub 2021 Jul 29.

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.

Circulating factors access cell bodies of vagal afferents in nodose ganglia (NG) via the occipital artery (OA). Constrictor responses of OA segments closer in origin from the external carotid artery (ECA) differ from segments closer to NG. Our objective was to determine the role of endothelium in this differential vasoreactivity in rat OA segments. Vasoreactivity of OA segments (proximal segments closer to ECA, distal segments closer to NG) was examined in wire myographs. We evaluated ) vasoconstrictor effects of 5-hydroxytryptamine (5-HT) in intact and endothelium-denuded OA segments in absence/presence of soluble guanylate cyclase (SGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), ) vasodilator responses elicited by the endothelium dependent vasodilator, acetylcholine (ACh), in intact or endothelium-denuded OA segments in absence/presence of ODQ, and ) vasodilator responses elicited by NO-donor MAHMA NONOate, in intact OA segments in absence/presence of ODQ. Intact distal OA responded more to 5-HT than intact proximal OA. Endothelium denudation increased 5-HT potency in both OA segments, especially proximal OA. ODQ increased maximal responses of 5-HT in both segments, particularly proximal OA. ACh similarly relaxed both OA segments, effects abolished by endothelial denudation and attenuated by ODQ. MAHMA NONOate elicited transient vasodilation in both segments. Effects of ODQ against ACh were segment dependent whereas those against MAHMA NONOate were not. The endothelium regulates OA responsiveness in a segment-dependent fashion. Endothelial cells at the OA-ECA junction more strongly influence vascular tone than those closer to NG. Differential endothelial regulation of OA tone may play a role in controlling blood flow and access of circulating factors to NG. This study demonstrates that the endothelium-dependent regulation of smooth muscle tone of occipital arteries is segment-dependent. Endothelial cells at the occipital artery-external carotid artery junction (entryway of blood flow to the nodose ganglia) more strongly influence vascular tone than those closer to the nodose ganglia. This differential endothelial regulation of occipital artery tone may control blood flow and access of circulating factors to the nodose ganglia.
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http://dx.doi.org/10.1152/japplphysiol.00221.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461804PMC
September 2021

Stratifying outcome based on the Oswestry Disability Index for operative treatment of adult spinal deformity on patients 60 years of age or older: a multicenter, multi-continental study on Prospective Evaluation of Elderly Deformity Surgery (PEEDS).

Spine J 2021 11 15;21(11):1775-1783. Epub 2021 Jul 15.

Department of Neurosurgery and Orthopaedic Surgery, University of California, San Francisco, CA, USA.

Background Context: Patients with adult spinal deformity suffer from disease related disability as measured by the Oswestry Disability Index (ODI) for which surgery can result in significant improvements.

Purpose: The purpose of this study was to show the change in overall and individual components of the ODI in patients aged 60 years or older following multi-level spinal deformity surgery.

Study Design: Prospective, multicenter, multi-continental, observational longitudinal cohort study PATIENT SAMPLE: Patients ≥60 years undergoing primary spinal fusion surgery of ≥5 levels for coronal, sagittal or combined deformity.

Outcome Measures: Oswestry Disability Index (ODI) METHODS: : Patients completed the ODI pre-operatively for baseline, then at 10 weeks, 12 months and 24 months post-operatively. ODI scores were grouped into deciles, and change was calculated with numerical score and improvement or worsening was further categorized from baseline as substantial (≥20%), marginal (≥10-<20%) or no change (within 10%).

Results: Two-hundred nineteen patients met inclusion criteria for the study. The median number of spinal levels fused was 9 [Q1=5.0, Q3=12.0]. Two-year mean (95% CI) ODI improvement was 19.3% (16.7%; 21.9%; p<.001) for all age groups, with mean scores improved from a baseline of 46.3% (44.1%; 48.4%) to 41.1% (38.5%; 43.6%) at 10 weeks (p<.001), 28.1% (25.6%; 30.6%) at 12 months (p<.001), and 27.0% (24.4%; 29.5%) at 24 months (p<.001). At 2 years, 45.5% of patients showed 20% or greater improvement in ODI, 23.7% improved between 10% and 20%, 26.3% reported no change (defined as±10% from baseline), 4.5% of patients reported a worsening between 10% to 20%, and none reported worsening greater than 20%. 59.0% of patients were severely disabled (ODI >40%) pre-operatively, which decreased to 20.2% at 2 years. Significant improvement was observed across all 10 ODI items at 12 and 24 months. The largest improvements were seen in pain, walking, standing, sex life, social life and traveling.

Conclusions: In this prospective, multicenter, multi-continental study of patients 60 years or older undergoing multi-level spinal deformity surgery, almost 70% of patients reported significant improvements in ODI without taking into account surgical indications, techniques or complications. Clear data is presented demonstrating the particular change from baseline for each decile of pre-operative ODI score, for each sub-score, and for each age group.
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http://dx.doi.org/10.1016/j.spinee.2021.07.007DOI Listing
November 2021

Carotid sinus nerve transection abolishes the facilitation of breathing that occurs upon cessation of a hypercapnic gas challenge in male mice.

J Appl Physiol (1985) 2021 08 8;131(2):821-835. Epub 2021 Jul 8.

Department of Pediatrics, Case Western University, Cleveland, Ohio.

Arterial pCO elevations increase minute ventilation via activation of chemosensors within the carotid body (CB) and brainstem. Although the roles of CB chemoafferents in the hypercapnic (HC) ventilatory response have been investigated, there are no studies reporting the role of these chemoafferents in the ventilatory responses to a HC challenge or the responses that occur upon return to room air, in freely moving mice. This study found that an HC challenge (5% CO, 21% O, 74% N for 15 min) elicited an array of responses, including increases in frequency of breathing (accompanied by decreases in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives in sham-operated (SHAM) adult male C57BL6 mice, and that return to room air elicited a brief excitatory phase followed by gradual recovery of all parameters toward baseline values over a 15-min period. The array of ventilatory responses to the HC challenge in mice with bilateral carotid sinus nerve transection (CSNX) performed 7 days previously occurred more slowly but reached similar maxima as SHAM mice. A major finding was responses upon return to room air were dramatically lower in CSNX mice than SHAM mice, and the parameters returned to baseline values within 1-2 min in CSNX mice, whereas it took much longer in SHAM mice. These findings are the first evidence that CB chemoafferents play a key role in initiating the ventilatory responses to HC challenge in C57BL6 mice and are essential for the expression of post-HC ventilatory responses. This study presents the first evidence that carotid body chemoafferents play a key role in initiating the ventilatory responses, such as increases in frequency of breathing, tidal volume, and minute ventilation that occur in response to a hypercapnic gas challenge in freely moving C57BL6 mice. Our study also demonstrates for the first time that these chemoafferents are essential for the expression of the ventilatory responses that occur upon return to room air in these mice.
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http://dx.doi.org/10.1152/japplphysiol.01031.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409918PMC
August 2021

The superior cervical ganglia modulate ventilatory responses to hypoxia independently of preganglionic drive from the cervical sympathetic chain.

J Appl Physiol (1985) 2021 08 1;131(2):836-857. Epub 2021 Jul 1.

Division of Pulmonology, Allergy and Immunology, Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.

Superior cervical ganglia (SCG) postganglionic neurons receive preganglionic drive via the cervical sympathetic chains (CSC). The SCG projects to structures like the carotid bodies (e.g., vasculature, chemosensitive glomus cells), upper airway (e.g., tongue, nasopharynx), and to the parenchyma and cerebral arteries throughout the brain. We previously reported that a hypoxic gas challenge elicited an array of ventilatory responses in sham-operated (SHAM) freely moving adult male C57BL6 mice and that responses were altered in mice with bilateral transection of the cervical sympathetic chain (CSCX). Since the CSC provides preganglionic innervation to the SCG, we presumed that mice with superior cervical ganglionectomy (SCGX) would respond similarly to hypoxic gas challenge as CSCX mice. However, while SCGX mice had altered responses during hypoxic gas challenge that occurred in CSCX mice (e.g., more rapid occurrence of changes in frequency of breathing and minute ventilation), SCGX mice displayed numerous responses to hypoxic gas challenge that CSCX mice did not, including reduced total increases in frequency of breathing, minute ventilation, inspiratory and expiratory drives, peak inspiratory and expiratory flows, and appearance of noneupneic breaths. In conclusion, hypoxic gas challenge may directly activate subpopulations of SCG cells, including subpopulations of postganglionic neurons and small intensely fluorescent (SIF) cells, independently of CSC drive, and that SCG drive to these structures dampens the initial occurrence of the hypoxic ventilatory response, while promoting the overall magnitude of the response. The multiple effects of SCGX may be due to loss of innervation to peripheral and central structures with differential roles in breathing control. We present data showing that the ventilatory responses elicited by a hypoxic gas challenge in male C57BL6 mice with bilateral superior cervical ganglionectomy are not equivalent to those reported for mice with bilateral transection of the cervical sympathetic chain. These data suggest that hypoxic gas challenge may directly activate subpopulations of superior cervical ganglia (SCG) cells, including small intensely fluorescent (SIF) cells and/or principal SCG neurons, independently of preganglionic cervical sympathetic chain drive.
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http://dx.doi.org/10.1152/japplphysiol.00216.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409919PMC
August 2021

D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.

Sci Rep 2021 05 11;11(1):10038. Epub 2021 May 11.

Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44106, USA.

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of D-cystine diethyl ester (D-cystine diEE) or D-cystine dimethyl ester (D-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of D-cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO and sO accompanied by pronounced increases in pCO (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by D-cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by D-cystine diEE. D-cystine diEE and D-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the D-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.
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http://dx.doi.org/10.1038/s41598-021-89455-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113454PMC
May 2021

Loss of Cervical Sympathetic Chain Input to the Superior Cervical Ganglia Affects the Ventilatory Responses to Hypoxic Challenge in Freely-Moving C57BL6 Mice.

Front Physiol 2021 22;12:619688. Epub 2021 Apr 22.

Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, Case Western Reserve University, Cleveland, OH, United States.

The cervical sympathetic chain (CSC) innervates post-ganglionic sympathetic neurons within the ipsilateral superior cervical ganglion (SCG) of all mammalian species studied to date. The post-ganglionic neurons within the SCG project to a wide variety of structures, including the brain (parenchyma and cerebral arteries), upper airway (e.g., nasopharynx and tongue) and submandibular glands. The SCG also sends post-ganglionic fibers to the carotid body (e.g., chemosensitive glomus cells and microcirculation), however, the function of these connections are not established in the mouse. In addition, nothing is known about the functional importance of the CSC-SCG complex (including input to the carotid body) in the mouse. The objective of this study was to determine the effects of bilateral transection of the CSC on the ventilatory responses [e.g., increases in frequency of breathing (Freq), tidal volume (TV) and minute ventilation (MV)] that occur during and following exposure to a hypoxic gas challenge (10% O and 90% N) in freely-moving sham-operated (SHAM) adult male C57BL6 mice, and in mice in which both CSC were transected (CSCX). Resting ventilatory parameters (19 directly recorded or calculated parameters) were similar in the SHAM and CSCX mice. There were numerous important differences in the responses of CSCX and SHAM mice to the hypoxic challenge. For example, the increases in Freq (and associated decreases in inspiratory and expiratory times, end expiratory pause, and relaxation time), and the increases in MV, expiratory drive, and expiratory flow at 50% exhaled TV (EF) occurred more quickly in the CSCX mice than in the SHAM mice, although the overall responses were similar in both groups. Moreover, the initial and total increases in peak inspiratory flow were higher in the CSCX mice. Additionally, the overall increases in TV during the latter half of the hypoxic challenge were greater in the CSCX mice. The ventilatory responses that occurred upon return to room-air were essentially similar in the SHAM and CSCX mice. Overall, this novel data suggest that the CSC may normally provide inhibitory input to peripheral (e.g., carotid bodies) and central (e.g., brainstem) structures that are involved in the ventilatory responses to hypoxic gas challenge in C57BL6 mice.
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http://dx.doi.org/10.3389/fphys.2021.619688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100345PMC
April 2021

Operative versus nonoperative treatment for adult symptomatic lumbar scoliosis at 5-year follow-up: durability of outcomes and impact of treatment-related serious adverse events.

J Neurosurg Spine 2021 Apr 30:1-13. Epub 2021 Apr 30.

2Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri.

Objective: Although short-term adult symptomatic lumbar scoliosis (ASLS) studies favor operative over nonoperative treatment, longer outcomes are critical for assessment of treatment durability, especially for operative treatment, because the majority of implant failures and nonunions present between 2 and 5 years after surgery. The objectives of this study were to assess the durability of treatment outcomes for operative versus nonoperative treatment of ASLS, to report the rates and types of associated serious adverse events (SAEs), and to determine the potential impact of treatment-related SAEs on outcomes.

Methods: The ASLS-1 (Adult Symptomatic Lumbar Scoliosis-1) trial is an NIH-sponsored multicenter prospective study to assess operative versus nonoperative ASLS treatment. Patients were 40-80 years of age and had ASLS (Cobb angle ≥ 30° and Oswestry Disability Index [ODI] ≥ 20 or Scoliosis Research Society [SRS]-22 subscore ≤ 4.0 in the Pain, Function, and/or Self-Image domains). Patients receiving operative and nonoperative treatment were compared using as-treated analysis, and the impact of related SAEs was assessed. Primary outcome measures were ODI and SRS-22.

Results: The 286 patients with ASLS (107 with nonoperative treatment, 179 with operative treatment) had 2-year and 5-year follow-up rates of 90% (n = 256) and 74% (n = 211), respectively. At 5 years, compared with patients treated nonoperatively, those who underwent surgery had greater improvement in ODI (mean difference -15.2 [95% CI -18.7 to -11.7]) and SRS-22 subscore (mean difference 0.63 [95% CI 0.48-0.78]) (p < 0.001), with treatment effects (TEs) exceeding the minimum detectable measurement difference (MDMD) for ODI (7) and SRS-22 subscore (0.4). TEs at 5 years remained as favorable as 2-year TEs (ODI -13.9, SRS-22 0.52). For patients in the operative group, the incidence rates of treatment-related SAEs during the first 2 years and 2-5 years after surgery were 22.38 and 8.17 per 100 person-years, respectively. At 5 years, patients in the operative group who had 1 treatment-related SAE still had significantly greater improvement, with TEs (ODI -12.2, SRS-22 0.53; p < 0.001) exceeding the MDMD. Twelve patients who received surgery and who had 2 or more treatment-related SAEs had greater improvement than nonsurgically treated patients based on ODI (TE -8.34, p = 0.017) and SRS-22 (TE 0.32, p = 0.029), but the SRS-22 TE did not exceed the MDMD.

Conclusions: The significantly greater improvement of operative versus nonoperative treatment for ASLS at 2 years was durably maintained at the 5-year follow-up. Patients in the operative cohort with a treatment-related SAE still had greater improvement than patients in the nonoperative cohort. These findings have important implications for patient counseling and future cost-effectiveness assessments.
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http://dx.doi.org/10.3171/2020.9.SPINE201472DOI Listing
April 2021

Recognition of posterior thoracolumbar instrumentations used in spinal deformity surgery and techniques for implant removal.

J Clin Neurosci 2021 Apr 10;86:217-222. Epub 2021 Feb 10.

Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

Spinal surgeries requiring implant removals/revisions are becoming more common, as a long time has passed since contemporary spinal instrumentation was developed and utilized. Recognizing implants and manufacturers preoperatively from radiographs and preparing appropriate instruments for removal are mandatory. The objective of the present paper was to review the various designs of contemporary posterior thoracolumbar spinal implants along with their radiographic features to facilitate the identification of previously used systems in removal or revision surgeries. We focused on contemporary spinal implants that have been commonly used in spinal deformity surgery since the development of screw-and-rod constructs up to 2005. The pertinent information was requested from three major manufacturers (DePuy Synthes, Medtronic and Stryker). Characteristics of each system are reviewed with radiographic features, and the instruments needed for revision are summarized. We propose a systematic identification diagram. Rod loading can be categorized as offset-loading, side-loading or top-loading. Screw design can be cylindrical, conical or dual-core threading. Each system has unique features that can facilitate identification. Identifying the materials and diameters of the rod is also imperative. When removal of an unidentified system is needed or removal of an identified system fails, the short rod has to remain loaded on the screw and the implant removed en bloc as an isolated piece. Understanding the radiographic features of spinal implants used in previous surgeries will help surgeons prepare for the increasing incidence of revision surgeries.
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http://dx.doi.org/10.1016/j.jocn.2021.01.045DOI Listing
April 2021

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.

Sci Rep 2021 03 26;11(1):6985. Epub 2021 Mar 26.

Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106-4984, USA.

There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO and sO and increases in pCO (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
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http://dx.doi.org/10.1038/s41598-021-86458-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997982PMC
March 2021

Patient-Reported Outcomes After Complex Adult Spinal Deformity Surgery: 5-Year Results of the Scoli-Risk-1 Study.

Global Spine J 2021 Feb 9:2192568220988276. Epub 2021 Feb 9.

University of Virginia, Charlottesville, VA, USA.

Study Design: Prospective cohort.

Objective: To prospectively evaluate PROs up to 5-years after complex ASD surgery.

Methods: The Scoli-RISK-1 study enrolled 272 ASD patients undergoing surgery from 15 centers. Inclusion criteria was Cobb angle of >80°, corrective osteotomy for congenital or revision deformity, and/or 3-column osteotomy. The following PROs were measured prospectively at intervals up to 5-years postoperative: ODI, SF36-PCS/MCS, SRS-22, NRS back/leg. Among patients with 5-year follow-up, comparisons were made from both baseline and 2-years postoperative to 5-years postoperative. PROs were analyzed using mixed models for repeated measures.

Results: Seventy-seven patients (28.3%) had 5-year follow-up data. Comparing baseline to 5-year data among these 77 patients, significant improvement was seen in all PROs: ODI (45.2 vs. 29.3, < 0.001), SF36-PCS (31.5 vs. 38.8, < 0.001), SF36-MCS (44.9 vs. 49.1, = 0.009), SRS-22-total (2.78 vs. 3.61, < 0.001), NRS-back pain (5.70 vs. 2.95, < 0.001) and NRS leg pain (3.64 vs. 2.62, = 0.017). In the 2 to 5-year follow-up period, no significant changes were seen in any PROs. The percentage of patients achieving MCID from baseline to 5-years were: ODI (62.0%) and the SRS-22r domains of function (70.4%), pain (63.0%), mental health (37.5%), self-image (60.3%), and total (60.3%). Surprisingly, mean values ( > 0.05) and proportion achieving MCID did not differ significantly in patients with major surgery-related complications compared to those without.

Conclusions: After complex ASD surgery, significant improvement in PROs were seen at 5-years postoperative in ODI, SF36-PCS/MCS, SRS-22r, and NRS-back/leg pain. No significant changes in PROs occurred during the 2 to 5-year postoperative period. Those with major surgery-related complications had similar PROs and proportion of patients achieving MCID as those without these complications.
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http://dx.doi.org/10.1177/2192568220988276DOI Listing
February 2021

The Role of Carotid Sinus Nerve Input in the Hypoxic-Hypercapnic Ventilatory Response in Juvenile Rats.

Front Physiol 2020 17;11:613786. Epub 2020 Dec 17.

Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, Case Western Reserve University, Cleveland, OH, United States.

In juvenile rats, the carotid body (CB) is the primary sensor of oxygen (O) and a secondary sensor of carbon dioxide (CO) in the blood. The CB communicates to the respiratory pattern generator via the carotid sinus nerve, which terminates within the commissural nucleus tractus solitarius (cNTS). While this is not the only peripheral chemosensory pathway in juvenile rodents, we hypothesize that it has a unique role in determining the interaction between O and CO, and consequently, the response to hypoxic-hypercapnic gas challenges. The objectives of this study were to determine (1) the ventilatory responses to a poikilocapnic hypoxic (HX) gas challenge, a hypercapnic (HC) gas challenge or a hypoxic-hypercapnic (HH) gas challenge in juvenile rats; and (2) the roles of CSN chemoafferents in the interactions between HX and HC signaling in these rats. Studies were performed on conscious, freely moving juvenile (P25) male Sprague Dawley rats that underwent sham-surgery (SHAM) or bilateral transection of the carotid sinus nerves (CSNX) 4 days previously. Rats were placed in whole-body plethysmographs to record ventilatory parameters (frequency of breathing, tidal volume and minute ventilation). After acclimatization, they were exposed to HX (10% O, 90% N), HC (5% CO, 21% O, 74% N) or HH (5% CO, 10% O, 85% N) gas challenges for 5 min, followed by 15 min of room-air. The major findings were: (1) the HX, HC and HH challenges elicited robust ventilatory responses in SHAM rats; (2) ventilatory responses elicited by HX alone and HC alone were generally additive in SHAM rats; (3) the ventilatory responses to HX, HC and HH were markedly attenuated in CSNX rats compared to SHAM rats; and (4) ventilatory responses elicited by HX alone and HC alone were not additive in CSNX rats. Although the rats responded to HX after CSNX, CB chemoafferent input was necessary for the response to HH challenge. Thus, secondary peripheral chemoreceptors do not compensate for the loss of chemoreceptor input from the CB in juvenile rats.
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http://dx.doi.org/10.3389/fphys.2020.613786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773764PMC
December 2020
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