bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infrared Laser Light Elicits Cardiorespiratory Responses when Applied to the Nucleus Tractus Solitarius in the In Situ Rat Brainstem Preparation
Authors: Kola Gjinovefa , Dick Thomas E , Dutschmann Mathias , Chiel Hillel , Jenkins Michael , Lewis Stephen J 
Published: November 2023

The application of infrared laser (IR) light has been shown to alter central and peripheral neural activity. We hypothesized that cardiorespiratory activity would be an ideal system to test the effects of IR on spontaneous activity that is generated by a complex neural circuit. In the present study, we examined the responses elicited by IR stimuli delivered unilaterally to the intermediate subnucleus of the nucleus of the solitary tract (NTSINT) in the in situ brainstem preparation. The data show that IR light evoked changes in cardiorespiratory motor activity in a stimulus intensity‐dependent manner.These studies used the in situ arterially perfused brainstem preparation of male Sprague‐Dawley rat pups (P15–P25). We recorded outputs from the phrenic nerve, the cervical vagus nerve, and thoracic sympathetic nerve and monitored heart rate and perfusion pressure. A 200 mm optic fiber was positioned on the dorsal surface of the brainstem above the NTSINT. The IR light (1450nm) stimulus was 200 Hz pulse frequency, 200 ms pulses duration for 30 s. In order to gain an insight into the potential neurochemistry associated with the IR light‐induced responses, we also examined the effects elicited by the microinjection of the excitatory neurotransmitter, glutamate (20 to 30 nL of a 10 mM solution) into the NTSINT.Low radiant exposure levels of IR light stimuli (4.78 J/cm2 per pulse) decreased phrenic nerve activity (consistent with a decrease in breathing frequency), decreased bursting of vagal activity, inhibition of thoracic sympathetic nerve, a decrease in heart rate and a decrease in perfusion pressure. Upon cessation of IR light application was often followed by a post‐stimulus response. This delayed effect consisted of a further decrease in breathing rate, thoracic sympathetic bursting and perfusion pressure. Increasing the radiant exposure to 5.57 J/cm2 per pulse evoked a strong baroreflex‐like response but only during IR light stimulation. Further, increases in radiant exposure levels evoked the immediate effect, other behaviors like swallowing; and a post‐stimulus response (10 to 30 seconds) such increases in breathing frequency. However, the cardiorespiratory patterning had changed and returning to a 4.78 J/cm2 per pulse IR light stimulus did not evoked comparable response in cardiorespiratory patterning as before. The microinjections of glutamate into the NTSINT elicited cardiorespiratory responses that were similar to those elicited by the lower intensity IR light stimuli.These data indicate that the even though IR light stimuli are focally applied they are strong enough to elicit network effects on respiratory and sympathetic activities. The mechanisms by which IR light elicits these profound changes in cardiorespiratory circuit function remain to be elucidated.Support or Funding InformationGlaxoSmithKline (GSK) FundingCWRU Internal Number: RES510692
Basal Ventilatory Activity in Conscious Freely‐moving Spontaneously Breathing 6‐OHDA SN‐lesioned Parkinson's Disease Rat Model
Authors: Wadolowski Robert M , Wadolowski Steven B , Collins William F , Solomon Irene C 
Published: November 2023

Respiratory dysfunction in Parkinson's Disease (PD) patients manifests as a variety of altered breathing patterns that are suggested to result from impairment of central respiratory control. Ongoing work in our laboratory has recently identified time‐dependent alterations in basal inspiratory motor output and chemical control of breathing in the 6‐hydroxydopamine (6‐OHDA) neurotoxin‐induced unilateral substantia nigra (SN) lesion rat model. Our studies, however, have been limited to examination of these ventilatory behaviors at specified time points in acute terminal experiments; thus, the time course underlying the progression of the changes observed is not known. Here, we begin to address this issue by examining the basal respiratory phenotype using whole body plethysmography before and weekly for 4‐weeks after administration of 6‐OHDA into the SN of adult female Sprague‐Dawley rats; vehicle injected rats served as a control. Our preliminary data from 6‐OHDA SN‐lesioned rats (compared to vehicle control rats) suggest that there is a progressive reduction in tidal volume (TV) with a slight decrease in peak expiratory flow as indicated by a reduced EF50 and relaxation time albeit these changes are fairly modest. In addition, 6‐OHDA SN‐lesioned rats appear to exhibit a progressive reduction in variability in most of the time series respiratory parameters examined (e.g., TV, expiratory volume, EF, PIF, PEF, MV). These observations suggest that in conscious freely‐moving 6‐OHDA SN‐lesioned rats, ventilatory behaviors undergo a progressive alteration; however, the 4‐week time course studied here was only able to identify limited changes. We suggest that additional experiments examine a longer post‐lesion time period in order to more fully characterize the time course underlying the progression of ventilatory impairment in this PD rat model.Support or Funding InformationThomas Hartman Center for Parkinson's Disease Research at Stony Brook University
Gasotransmitters in Sleep Apnea
Authors: Zhang Xiuli , Peng Yingjie , Irina Chupikova , Gridina Anna , Nanduri Jayasri , Kumar Ganesh , Snyder Solomon H. , Nanduri Prabhakar 
Published: November 2023

Sleep apnea is a highly prevalent respiratory disease, affecting an estimated 10% of adult human population. Sleep apneas are characterized by periodic cessations of breathing during sleep and are associated with several sequelae including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity is one of the major drivers of sleep apnea. Because gaseous molecules, carbon monoxide (CO) and hydrogen sulfide (H2S) are important determinants of CB activity we hypothesized that aberrations in their signaling could lead to sleep apnea. We tested this possibility in mice deficient in heme oxygenase‐2 (HO‐2), which catalyzes the endogenous production of CO. Basal breathing was monitored in unsedated 6‐to‐9 months old wild‐type and HO‐2−/− mice by plethysmography. A majority of the HO‐2−/− mice (40/70 mice, 57%) had 20 or more apnea events per hour. In contrast, only 2/40 wild‐type mice (5%) exhibited such frequent apneas. The apnea index was higher in 6–9 month old mice compared to 6–9 weeks old HO‐2−/− mice. Fifty‐six percent of the HO‐2−/− mice (39/70) had a hypopnea index of > 80 (breathing events with ≥ 30% reduction in tidal volume per hour), whereas only 2.5% of the wild‐type mice (1/40 mice) displayed a similar hypopnea index. Apneas and hyponeas were remarkably higher in non‐rapid eye movement (NREM) and REM sleep. Further characterization of apneas revelead that HO‐2−/− mice experience both obstructive and central apneas, and the incidence of former was greater than the latter. Hyperoxia, which inhibits the CB activity reduced, whereas hypoxia, which stimulates the CB activity increased the incidence of apneas. We identified hydrogen sulfide (H2S), as a major molecule driving apneas. Genetically ablating the H2S‐synthesizing enzyme cystathionine‐g‐lyase (CSE) or pharmacologic blockade of CSE normalized breathing in HO‐2−/− mice. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas.Support or Funding InformationSupported by NIH‐UH3‐HL90554 and PO1‐HL90554
The Norepinephrine‐dependent ‘Postinspiratory Complex’ is NOT an Autonomous Generator of the Postinspiratory Rhythm
Authors: Poon Chi‐Sang , Song Gang 
Published: November 2023

Previous studies have identified a defined population of postinspiratory (post‐I) driver neurons in pontine Kölliker‐Fuse nucleus which send an excitatory input to post‐I interneurons and motoneurons in medulla1. In contrast, a recent report2 suggests that a group of norepinephrine (NE)‐dependent cholinergic neurons localized within a medullary area dubbed the ‘post‐I complex’ (PiCo) may produce post‐I bursts as well as ectopic bursts that outpace the inspiratory rhythm in vitro. Because the inspiratory and post‐I rhythms are always phase‐locked in vivo, we tested whether the spontaneous post‐I rhythm was dependent on NE by injecting i.v. in rats an α1‐adrenergic receptor antagonist known to block the excitatory effect of NE on respiratory‐related neurons. Remarkably, systemic α1‐adrenergic blockade resulted in a significant decrease of arterial blood pressure but postinspiration at rest and during hypoxic chemostimulation persisted. Next, we suppressed NE facilitation of respiratory‐related neurons by injecting i.v. an α2‐adrenergic receptor agonist known to block the release of NE from pontine noradrenergic neurons. Systemic α2‐adrenergic blockade resulted in a significant decrease of hypoglossal nerve activity but postinspiration at rest and during hypoxic chemostimulation again persisted, indeed with a significant prolongation of the post‐I period. These data strongly suggest that NE‐facilitated PiCo neurons are not necessary for generating post‐I activity, although other NE‐inhibited neurocircuits could play a role. This is in contrast to the reported suppression of vagal post‐I activity after bilateral injections of the peptide somatostatin or the μ‐opioid receptor agonist DAMGO into the mouse PiCo in vivo2. This discrepancy may be attributed to the excessively large volume of injection (reportedly 250 nl) in mice2—which would inevitably invade the neighboring Bötzinger complex where similar injections at a much smaller volume (20–50 nl) has been shown sufficient to produce similar effects in rats. Interestingly, post‐I PiCo neurons are phenotypically akin to post‐I laryngeal motoneurons which (1) are cholinergic; (2) receive catecholamine inputs; (3) receive simultaneous excitatory and GABAA receptor‐mediated inhibitory inputs during inspiration followed by a postinhibitory rebound postinspiration; (4) mediate the laryngeal adductor reflex resetting of inspiratory rhythm; (5) do not generate the post‐I rhythm. The NE‐dependent ectopic PiCo neuronal bursts in vitro are reminiscent of fictive rhythmic bursting in motoneurons and are non‐autonomous and nonphysiologic. Finally, available functional and histologic data do not support the notion that cholinergic PiCo neurons are also glutamatergic.Support or Funding InformationHL093225, HL127258 and NS094178
Eupnea, Tachypnea, and Autoresuscitation in a Closed‐Loop Respiratory Control Model
Authors: Diekman Casey O , Wilson Christopher G , Thomas Peter J 
Published: November 2023

The mechanisms underlying oscillations in a central pattern generator (CPG) may differ fundamentally in the intact organism versus an isolated CPG preparation. We investigate this aspect of rhythmogenesis in a computational model of closed‐loop respiratory control, incorporating minimal models of the brainstem CPG, lung mechanics, oxygen handling, metabolism, and chemosensation. We analyze the model behavior using fast/slow dynamical systems analysis and open‐loop/closed‐loop control analysis. We show that eupnea‐like bursting oscillations arise from a distinct mechanism in the intact (closed loop) versus isolated (open loop) systems. The closed‐loop model exhibits bistability between eupnea‐like bursting and tachypnea‐like tonic spiking, and we demonstrate that imposed bouts of hypoxia can induce a dramatic transition from eupnea to tachypnea. For moderate bouts of hypoxia, the endogenous properties of the ionic conductances in the Butera‐Rinzel‐Smith CPG model can lead to spontaneous autoresuscitation and recovery to eupnea. We also find that chemosensory feedback gives the closed‐loop control system greater robustness to changes in metabolic demand than the open‐loop control system.Support or Funding InformationThis work was partially supported by grants from the National Science Foundation (DMS 1413770, 1412877, and 1555237) and by an intramural grant from Loma Linda University.
Effects of Inhaled Erythropoietin on Canine Post‐pneumonectomy Compensatory Lung Growth
Authors: Dane Dan Merrill , Yilmaz Cuneyt , Gyawali Dipendra , Ravikumar Priya , Estrera Aaron S , Menon Jyothi , Nguyen Kytai , Tustison Nicholas J , Gee James C , Hsia Connie C.W. 
Published: November 2023

Paracrine erythropoietin (Epo) signaling via its receptor (EpoR) recruits endothelial progenitor cells and promotes angiogenesis. Epo‐EpoR axis is upregulated during canine post‐pneumonectomy (PNX) compensatory lung growth (CLG). To determine whether exogenous Epo augments endogenous CLG, adult male canines (age 1 year, 25.1± 3.4 kg, mean±SD) underwent right PNX and received either recombinant human Epo (100 units/kg) encapsulated within poly‐lactic‐co‐glycolic acid (PLGA) nanoparticles (NPs, 0.5 mg/kg) or empty NPs (n=4 animals each), suspended in phosphate buffered saline, nebulized (4μm droplets) and delivered via a previously constructed permanent tracheal stoma. Treatment was repeated weekly for 14 weeks. High resolution CT (HRCT) was performed at two transpulmonary pressures (10 and 30 cmH2O) and lung function was measured using established techniques under anesthesia pre‐PNX and post‐PNX following treatment. HRCT images were analyzed to quantify lobar air and tissue volumes, fractional tissue volume (FTV), parenchymal strain magnitude along 3D coordinate axes, principal strains and shear distortion using established deformation analysis. The remaining lobes were fixed at 25 cm H2O airway pressure for morphometric analysis.Compared to control treatment, Epo delivery increased serum Epo concentration by 6–13% (p<0.05) without increasing systemic hematocrit. Epo delivery selectively increased the magnitude and reduced the coefficient of variation of in vivo FTV (10–20%, p<0.05) of the remaining lobes without altering lobar air and tissue volumes, principal strains or shear distortion measured by HRCT. Epo treatment increased the prevalence of alveolar double capillary profiles measured at postmortem by 12–28% (p=0.06), indicating mild enhancement of new capillary formation. However, resting lung diffusing capacity (DLCO), pulmonary blood flow, lung compliance, and postmortem extravascular alveolar tissue volume and alveolar surface area, were not significantly different from control. We conclude that targeted inhalational delivery of exogenous Epo improved post‐PNX pulmonary microvascular blood volume distribution and modestly augmented alveolar angiogenesis. Treatment did not significantly alter extravascular alveolar tissue growth, regional lung mechanics or physiological function measured at rest.Support or Funding InformationSupported by NHLBI R01 HL40070 and U01 HL111146.
Development of a Poly(Lactic Acid) and Fibrin Device for Use in Bone Regenerative Medicine
Authors: Carvalho Renata Aquino , Júnior Valmir Vieira Rocha , Silva Eraldo Jannone , Trovatti Eliane , da Costa Iemma Monica Rosas , Amaral André Capaldo 
Published: November 2023

Bone regenerative medicine aims to overcome the limitations of the conventional treatments for bone repair in attempt to develop therapeutic strategies based on biomaterials capable of acting as temporary substitutes for guiding and stimulating the tissue repair, in order to reduce or eliminate the need for autologous donor tissues. The aim of this study was develop a Poly(lactic acid) (PLA) and fibrin cellularized bioactive scaffold to establish a new strategy with potential to use in bone regenerative medicine. For this purpose, three‐dimensional PLA scaffolds were initialy produced by Fused Deposition Modeling (FDM) 3D printing technique, using computer aided drawing (CAD) software. These scaffolds were embedded in the suspension containing human pure platelet‐rich plasma (hP‐PRP) and human infrapatellar fat pad derived mesenchymal stem cells. Then, the platelets were exogenously activated by thrombin and calcium chloride, leading the fibrin to polymerize and form a cellularized device. The scaffolds were maintained in serum‐free Dulbecco's Modified Eagle Medium for 5 days. Scanning electron microscopy and fluorescence microscopy demonstrated that cells kept viable and in tree‐dimensional conformation during the experimental period of time. The results suggest that PLA scaffolds, associated with hP‐PRP fibrin matrix, generated a rigid bioactive scaffold capable of mantain cellular viability and represent a promising strategy for bone regenerative medicine.Support or Funding InformationFUNADESP‐ Fundação Nacional de Desenvolvimento do Ensino Superior Particular
Isolation and Expansion of “Youthful” Bone Marrow Mesenchymal Stem Cells from Elderly Individuals
Authors: Block Travis Jackson , Marinkovic Milos , Tran Olivia , Dean David D , Chen Xiao‐Dong 
Published: November 2023

Due to increased life expectancy, age‐related degenerative diseases are becoming an important public health concern. Although researchers have actively pursued stem cell‐based therapies for retarding or reversing age‐related degeneration, the results of clinical trials aimed at demonstrating stem cell efficacy have been inconsistent. Unfortunately, progress in developing autologous mesenchymal stem cell (MSC)‐based therapies has been impeded by the fact that MSC quantity and quality decline with aging. Since elderly patients are the main target population for cell‐based treatment of age‐related diseases, it is essential that a reproducible strategy for providing sufficient quantities of high‐quality autologous cells be developed and rigorously tested. In the present study, we propose that the ratio of young to old (aged) stem cells in the BM‐MSC population reverses with aging and that old MSCs not only lose their self‐renewal and differentiation capacity, but also release harmful factors that damage and/or suppress the younger “healthy” sub‐population of MSCs. These changes result in an inexorable functional decline of the overall elderly MSC population. Here, we test the hypothesis that MSCs from elderly patients can be rejuvenated by: 1) isolating a sub‐population of more “youthful” cells, using biomarkers (size and SSEA‐4 expression), from the original population of elderly MSCs; and 2) preserving and expanding this “youthful” sub‐population by culture on a “young microenvironment” using our established technology (BM‐ECM produced by young cells). We demonstrate that it is possible to obtain large quantities of MSCs that are functionally and phenotypically similar to MSCs from young donors from elderly donors whose overall cell populations are highly compromised. The results are provocative and suggest that it may be feasible to bank large quantities of high‐quality autologous MSCs for treatment of age‐related diseases.Support or Funding InformationThis study was supported by a VA Merit Review (1I01BX002145‐01) to X‐D Chen the National Institutes of Health, National Center for Advancing Translational Sciences (NIH/NCATS, UL1 TR001119).
Angiotensin‐(1‐7) Treatment Aids in the Recovery of Skeletal Muscle Function After Acute Injury in Rats
Authors: Criswell Tracy , Zhou Yu , Yoseph Benyam 
Published: November 2023

IntroductionPathologic fibrosis is a major impedance to the recovery of muscle function after injury, and is augmented in the elderly population. Angiotensin‐(1‐7) [Ang‐(1‐7)] is an endogenous, 7‐amino acid peptide hormone of the renin‐angiotensin system, which has been shown to reduce fibrosis in the heart, lung and kidney. The objective of this research was to examine the effect of Ang‐(1‐7) treatment on the recovery of muscle function in older rats after compression injury.MethodsCompression injury was induced in the hind limbs of 12 month old male Lewis rats as previously described1. Ang‐(1‐7) was delivered at a dose of 24 μg/kg/hr by an osmotic pump implanted immediately after injury. Muscle function was measured via peroneal nerve stimulation. The tibialis anterior (TA) muscles were collected at day 14 after injury and processed for histological analyses and quantitative PCR (qPCR) analyses.ResultsOur data showed that treatment with Ang‐(1‐7) significantly increased muscle function 7 and 14 days after injury. However, we did not find any significant changes in fibrosis with Ang‐(1‐7) treatment.ConclusionsOur data suggests that Ang‐(1‐7) may be acting directly on the muscle tissue and/or the local microenvironment in order to promote restoration of muscle function.Support or Funding InformationSupported by pilot funding from the Wake Forest Baptist Health Hypertension and Vascular Research Center
Interprofessional Education in Anatomy: Using Q Methodology to Determine Student Perceptions
Authors: Mackinnon Chelsea , Akhtar‐Danesh Noori , Palombella Andrew , Wainman Bruce 
Published: November 2023

Interprofessional education (IPE) is critical for preparing healthcare students for the collaborative components of their future careers. Anatomic dissection is an ideal IPE activity because all healthcare professionals require anatomy training and dissection demands extensive student interaction in a sensitive environment. The purpose of this study was to determine which aspects healthcare students perceived to contribute to the development of their (individual) interprofessional skillset within the context of McMaster University's 10‐week IPE gross anatomy dissection course.We used Q‐methodology to identify the students' common viewpoints regarding the course. A total of 26 students from the Medical, Nursing, Midwifery, Physician Assistants, Occupational Therapy and Physiotherapy programs participated in this study. Students were asked to sort a Q‐sample of 43 statements based on their viewpoints regarding the IPE dissection course. The 43 statements were developed from interviews with students who had previously completed the course.Using the centroid factor extraction and varimax rotation, three salient factors (groups) emerged. The groups were named based on distinguishing statements as follows: 1) Anatomy IPE Enthusiasts; 2) Practical IPE Advocates; 3) Skeptical IPE Anatomists. The Anatomy IPE Enthusiasts believed that students from different disciplines brought unique anatomical knowledge and each group member guided others through difficult material. The Practical IPE Advocates expressed that they would be much stronger advocates for interprofessional teams in the future as a result of taking the course. The Skeptical IPE Anatomists strongly disagree that learning with students from different disciplines helped them gain a solid understanding of their roles in the context of other healthcare professionals, and felt that there was not much benefit from the IPE program compared to other non‐interdisciplinary programs.It is critical to understand student perceptions of IPE programs in order to best prepare these students for their future collaborative careers. These findings can help the course developers make further adjustments in the course structure, content and delivery to address some of the issues highlighted by the students, and to further emphasize the topics that were well‐received by the students. Finally, we hope that these results will be helpful to other interprofessional educators, especially those whose program has an anatomy framework.