bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Gestational Chronic Intermittent Hypoxia and Hypertension on the Serotonergic System and Autoresuscitation in the Developmental Rat
Authors: Harvey Drayton , Leal Angel Carrillo , Li Aihua 
Published: November 2023

Sudden infant death syndrome (SIDS) is characterized by the sudden death of a seemingly healthy infant during a sleep period under the age of 12 months. Abnormalities in the medullary serotonin (5HT) system, e.g. decreased tissue levels of 5HT and 5HTT, and increased immature 5HT neurons, have been identified in approximately 70% of infants that died of SIDS. Failed autoresuscitation (inability to recover breathing and heart rate following hypoxic apnea) is considered a possible mechanism of SIDS deaths, and animal studies have shown that 5HT neurons are critical for neonatal mice and rats to survive repeated episodes of severe hypoxia/asphyxia. Gestational chronic intermittent hypoxia (CIH) and preeclampsia both are risk factors for SIDS. In this study we asked whether the stressors, e.g. gestational/prenatal chronic intermittent hypoxia (CIH) and/or hypertension, would increase stress hormone levels, impair the maturity and integrity of medullary 5HT neurons and the ability to autoresuscitate from repetitive asphyxia in developing rat pups. The pregnant dams of normotensive Sprague Dawley (SD) rats and spontaneously hypertensive rats (SHR) were exposed to CIH or room air (RA) from gestation E4‐21, and then the serum corticosterone level (ELISA), the number and integrity of the medullary serotonin neurons (immunostainings), and in vivo autoresuscitation were assessed in the offspring pups at Postnatal (P) days 5–15.We found 1) SHR‐CIH pups have significantly higher serum corticosterone levels than SHR‐RA and SD‐RA pups at P7 (11,485 vs. 8078 & 8970 pg/mL respectively, P<0.05) and P10 (11,708 vs. 9040 & 6,529 pg/mL respectively, P<0.05). At P15 SD‐CIH, SHR‐CIH and SHR‐RA pups all have significantly higher corticosterone levels than SD‐RA pups; 2) Relative to the SD‐RA pups, SD‐CIH pups have a significantly higher total number of 5HT neurons and primarily due to increased number of Ki67/5HT‐ir positive neurons in the medulla. When compared to SD rats, we noticed that SHR pups appear to have more Ki67/5HT‐ir neurons which contribute to an increase in total number of 5HT neurons in the medulla than SD‐CIH & SD‐RA (P<0.01); and 3) the offspring pups of SHRs have the highest mortality rate during repetitive exposure of anoxia at all ages tested. Our data suggest that both gestational CIH and uncontrolled hypertension may lead to an impaired 5HT system in the offspring pups. The uncontrolled high blood pressure during pregnancy may cause placental insufficiency and contribute to failed autoresuscitation in response to repetitive anoxia in early postnatal life.Support or Funding InformationDartmouth UGAR, NIH HD036379, NIH HL28066
Intermittent Hypoxia during Gestation Disrupts Respiratory Rhythm and Neuroplasticity in Newborn Rat Brainstem‐spinal cord Preparations In Vitro
Authors: Johnson Stephen Mark , Watters Jyoti , Randhawa Karanbir 
Published: November 2023

Pregnant women with sleep‐disordered breathing experience intermittent hypoxia, especially during late pregnancy. To test whether intermittent hypoxia exposures during pregnancy (G‐IH; gestational intermittent hypoxia) alter breathing in newborn rats, pregnant rats were exposed to intermittent hypoxia (2 min 10.5% oxygen / 2 min normoxia for 8 h) from gestational day 10 to 21 (exposures completed prior to birth). Newborn rats (P0–P3) were anesthetized and their brainstem‐spinal cords isolated under in vitro conditions. Spontaneous respiratory motor bursts were recorded on cervical spinal roots (C4–C5). G‐IH preparations from P0–P1 rats had a lower baseline burst frequency (8.2 +/− 0.6 bursts/min; n=10) compared to normoxic controls (11.0 +/− 0.3 bursts/min; n=21). After 90 min, burst frequency decreased with time nearly 2× times greater in G‐IH preparations compared to controls. In most G‐IH preparations, there were frequent “pauses” in the rhythm, which resembled spontaneous apneas. With respect to respiratory neuroplasticity, dihydroxyflavone (DHF) application (5 micromolar, 9 min; TrkB receptor agonist) induced long‐lasting 19% increase in respiratory motor burst amplitude in control preparations (n=5) after 90 min. However, only 2/4 G‐IH preparations expressed a DHF‐dependent increase in motor burst amplitude. Also, episodic substance‐P application (100 nanomolar, 3 min on / 7 min wash ×3) induced a long‐lasting (60‐min) increase in respiratory burst frequency in control preparations. However, there was no substance‐P induced frequency plasticity in any G‐IH preparations (n=4). These data suggest that gestational intermittent hypoxia disrupts respiratory rhythm generation and reduces the capacity for expressing respiratory neuroplasticity in newborn rats.Support or Funding InformationNIH Grant: NS085226
Effects of cervical spinal cord injury on cough
Authors: Pitts Teresa , Huff Alyssa , Greene Clint , Cheffer Kimberly A , O'Steen Wilbur A , Howland Dena R 
Published: November 2023

Action of the diaphragm is necessary for negative force production during breathing and cough. However, the effect of cervical spinal cord injury on action of the diaphragm during cough is not known. It was hypothesized that C2 hemisection would result in a loss of cough excitability and depression of the diaphragm during breathing and cough. Electromyograms (EMGs) of the crural diaphragm, abdominal oblique complex, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus, cricopharyngeus and thyrohyoid muscles were measured along with esophageal and stomach pressures were recorded in spontaneously breathing (non‐paralyzed) anesthetized (sodium pentobarbital) cats. Cough was elicited by mechanical stimulation of the lumen of the intrathoracic trachea. Following acute C2 hemisection there was an ~50% reduction in cough number from 1:1 sec to 1:2 sec; additionally there was a bilateral reduction in crural diaphragm recruitment with a significant increase in upper airway EMG activity. Temporal progression of changes in cough characteristics was captured for up to 2 hours following acute hemisection. Lesion levels were verified post‐mortem and histology was used to assess lesion extent in each animal. Of note the blood pressure and pCO2 remained relatively consistent, and the animals were not placed on a ventilator. We conclude that there is a balance of excitation and inhibition from the spinal cord to the brainstem regulating the excitability of airway protective behaviors and cranial/spinal motor drive during coughing.Support or Funding InformationSupported by R00‐HL 111215, The Kentucky Spinal Cord and Head injury Trust, The Commonwealth of Kentucky Challenge for Excellence, the Rebecca F Hammond Trust and RCS‐VA RR&D B9249S. The contents of this abstract do not represent the views of the DVA or US government.
In vivo Studies of Brainstem Neurons with Respiratory Rhythm Activity in a Rat Model of Rett Syndrome
Authors: Wu Yang , Cui Ningren , Xing Hao , Zhong Weiwei , Johnson Christopher M. , Jiang Chun 
Published: November 2023

People with Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations of the MECP2 gene, show breathing abnormalities that are attributable to the high incidence of sudden death. To understand the underlying mechanisms for the breathing disorders, direct in vivo recordings from brainstem neurons with respiratory rhythm are needed, which is a challenge in mouse RTT models. The newly available rat model may allow such a study. Therefore, we performed electrophysiological recording from individual neurons of the medullary ventral respiratory group (VRG) in decerebrate Mecp2‐null and wild‐type (WT) rats. In both groups of rats, neurons with expiratory rhythm were recorded from the rostral and caudal VRG, and cells with inspiratory rhythm were found in between. Firing frequency of the inspiratory neurons was significantly lower in null rats than in WT rats, while expiratory neurons in both rostral and caudal VRG did not show such a difference. Firing durations of both expiratory and inspiratory neurons were elongated in null rats compared with the WT. The ratio of inspiratory to expiratory firing duration (Ti/Te) was lower in null rats. A large number of cells showed E‐I phase‐spanning in null rats. The null rats had a frequent breathing pattern of apneusis followed by apnea, during which inspiratory neurons showed increased firing frequency and caudal expiratory neurons showed decreased firing frequency, whereas no significant change was observed in rostral expiratory neurons. Although this breathing pattern of apneusis followed by apnea was also seen in WT rats, the firing frequency of either respiratory neurons did not seem to change. These findings suggest that Mecp2 disruption appears to cause a large scale of changes in firing activity and pattern of medullary respiratory neurons consistent with the broad range of breathing abnormalities seen in people with RTT and animal models.Support or Funding InformationThis work was supported by NIH grant R01‐NS‐073875 and International Rett Syndrome Foundation.
The differential effect of systemic inflammation and chronic intermittent hypoxia on the respiratory networks generating Inspiration and Postinspiration.
Authors: Agosto Ibis M , Ramirez Sanja , Garcia Alfredo J , Ramirez Jan‐Marino 
Published: November 2023

Novel evidence suggests that the neural control of breathing is controlled by three distinct, yet interacting oscillators. These rhythm‐generating networks have been identified as the Pre‐Bötzinger complex (preBötC), the Post‐inspiratory complex (PiCo) and the parafacial respiratory group (pFRG). Each rhythmic network has a specify function and together they are thought to control the three distinct phases of breathing, inspiration, post‐insipration and active expiration, respectively. The “three‐oscillator hypothesis” is a novel concept, and emerging evidence suggests that each oscillator differentially responds to endogenous and exogenously applied neuromodulators. Yet, little is known whether these networks also respond in a differential manner to clinically relevant conditions such as inflammation or chronic intermittent hypoxia (CIH). In this study we explore how CIH and systemic inflammation elicited by lipopolysaccharide (LPS, 2μg/g) affects two of the oscillators, the PreBötC and PiCo, in young mice (P5‐8). Systemic inflammation elicited by LPS induces a neuroinflammation by indirect pathways resulting in an upregulation of proinflammatory cytokines (IL‐β, IL‐6, TNF‐α), and oxidative stress. IL‐6 and TNF‐a have been shown to alter the CNS by decreasing inhibition/excitation ratio that can lead to a hyper‐excitable state. We extracellularly recorded spontaneous rhythmic population activity in horizontal slices containing preBötC and PiCo 24hrs after an LPS insult. Our data suggest that PiCo becomes hyper excited, while the PreBötC burst frequency remains unchanged to control (saline). This data complements our CIH data, in which young mice that receive CIH from P0‐8, also revealed increased excitability in PiCo, while the preBötC characterized in transverse slices becomes less active and more desynchronized. The decreased activity in the PreBötC, after prolonged CIH, results in irregular bursting patterns and failed transmission to the hypoglossal nucleus, which can contribute to apneas at the level of the hypoglossus. By contrast, the increased excitability in PiCo may contribute to an increased activation of postinspiratory activity following CIH and inflammation. Thus, we hypothesize that inflammation and CIH differentially affects the two phases of breathing, inspiration and postinspiration, by differentially acting on the rhythm generating networks that provide excitatory drive for inspiration and postinspiration, the preBötC and PiCo.Support or Funding InformationNIH: R01HL126523, P01 HL090554
Modulation of KCNQ Channels is a Potential Mechanism for Controlling Inspiratory Burst Duration
Authors: Revill Ann L , Katzell Alexis , Funk Gregory D 
Published: November 2023

The preBötzinger Complex (preBötC) is a key site of inspiratory rhythm generation in mammals and significant progress has been made toward defining the mechanisms underlying inspiratory burst generation. In contrast, the mechanisms that control burst duration have received relatively little attention. Here we test the hypotheses that KCNQ channels help determine inspiratory burst duration and contribute to burst termination. KCNQ channels mediate a slow, voltage‐gated outward K+ current that is active at resting membrane potential and becomes larger with membrane depolarization. This current helps determine resting membrane potential and also acts to stabilize membrane potential. Using rhythmically‐active brainstem spinal cord (BSSC) and rhythmic medullary slice preparations from neonatal rats (postnatal day 0–4), we examined the role of KCNQ in controlling inspiratory behavior by assessing the effects of KCNQ inhibitors and activators on inspiratory burst duration and inspiratory frequency recorded from the C4 ventral nerve root in BSSC preparations and the XII nerve in slices. Bath application of the KCNQ channel blockers XE991 (0.1 μM and 1 μM) and linopirdine (6 μM, BSSC; 3 μM, slice) caused a time‐ and concentration‐dependent increase in burst duration (XE991, 1 μM: BSSC: 1.35 ± 0.05 fold increase, n = 6, p < 0.05; slice: 3.59 ± 0.20 fold increase, n = 5, p < 0.05; linopirdine: BSSC: 1.22 ± 0.04 fold increase, n = 8, p < 0.05 slice: 1.94 ± 0.13 fold increase, n = 6, p < 0.05), but only XE991 caused a decrease in burst frequency (1 μM: 0.52 ± 0.03 of control levels, p < 0.05). Local microinjection of XE991 (10 μM) directly into the preBötC produced very similar effects on burst duration (3.65 ± 0.86 fold increase, n = 3, p < 0.05) and burst frequency (0.59 ± 0.04 of control, p < 0.05). In contrast, potentiation of the KCNQ current via bath application of retigabine (2 μM) caused a significant decrease in inspiratory burst duration (BSSC: 0.62 ± 0.05 times control, n = 5, p < 0.05; slice: 0.72 ± 0.06 times control, n = 8, p < 0.05) and a decrease in burst frequency. Inspiratory burst generation ceased when retigabine concentration was increased to 3 μM. These data suggest that activation of KCNQ channels specifically within the preBötC contributes to inspiratory burst termination and that their modulation may provide a mechanism for controlling inspiratory burst duration.Funding: CIHR, NSERC, WCHRI, AIHS, CFI.Support or Funding InformationCIHR, NSERC, WCHRI, AIHS, CFI
Cigarette Smoke Induced Alterations in Bone Microarchitecture: Regional Differences in a Mouse Model
Authors: Calendo Gennaro , Stapor Daniel T , Baker Sandy T , Amin Mamta , Barbe Mary F. , Wolfson Marla R. 
Published: November 2023

BackgroundOxidative stress from prolonged exposure to tobacco smoke plays a major role in the pathogenic process leading to COPD. An increased respiratory load due to altered lung and airway mechanics increases the demand on respiratory muscles and contributes to difficulties in maintaining body weight. Theoretically, the increased muscle demand, by imposing additional stress on the muscular‐skeletal insertion, may alter bone characteristics of the rib cage and contribute to rib fracture in patients with respiratory disease. There is growing evidence that smoking delays or inhibits vertebral and long bone healing after surgery or trauma. Finally, the incidence of osteoporosis is increased in humans with poor nutrition as well as a history of current smoking, with female gender an additional risk factor in developing osteoporosis. However, direct linkage between CS exposure and bone health has proven elusive due to co‐morbidities and/or therapeutics. Here, we sought to test the hypothesis that CS smoke‐exposure alone, in the absence of glucocorticoid use, will cause alterations in bone structure.MethodsFemale C57BL/6J mice (17–21 g;12–14 weeks) were randomly assigned to either whole body exposure to filtered room air (n=15) or cigarette smoke (CS; n =15, SciReq; In‐Expose; 3R4F University of Kentucky reference cigarettes; ISO 1991 standard exposure; 1 hr/2× daily, 5 days/week; total particulate matter was 100 mg/m3 for the first 3 days then 300 mg/m3 for a total of 6 weeks). Mouse carcasses were imaged with microCT (Skyscan 1176; 9 um). Reconstruction with volume rendering and 3D model creation was performed. Morphometric analyses were performed on cortical bone of the 1st, 6th, and 10th ribs and sternum, and on trabecular bone of the sternum, femur and 6th lumbar vertebrae (LV6).ResultsCortical bone thickness was significantly (p < 0.05) reduced in the 1st and 10th rib in CS‐exposed relative to RA‐exposed mice, but was unchanged in the sternum and 6th rib. Percent trabecular bone/tissue volume, a reflection of bone mass, was significantly reduced in femurs of CS‐exposed animals (p< 0.05) but comparable in sternum and LV6 between exposure groups.ConclusionsThese data demonstrate in a mouse model, that chronic CS exposure alone results in thinning of the ribs that experience the greatest torque, and reduced trabecular bone mass in the femur. This profile is likely to predispose to fracture and impaired bone healing, consistent with observations in actively smoking humans.Support or Funding InformationN0014‐10‐0761; N00014‐13‐1‐0742
Influence of Learning Paradigms on the Retention of Anatomical Knowledge in Medical Students
Authors: Ahmed Mohammed , Dykowski Sara , Tooley Trevor , Helland Timothy , Barremkala Malli 
Published: November 2023

IntroductionPracticing clinicians today, especially surgical specialists, feel that medical students' anatomical knowledge is inadequate and does not meet the minimum threshold for safe practice. Culprits for this loss of knowledge are not exactly understood, however, key contributors include inadequacies during initial learning, lack of reinforcement in later phases, and non‐adaptive teaching methods for a growingly diverse population of learners. The primary goal of this study is to describe or suggest patterns of learning, learning tools, and teaching methods that promote retention of learned anatomical knowledge in medical students. A secondary goal is to compare and assess perceptions of students on anatomy learning and retention in pre‐clerkship years (i.e. years 1 and 2), and during clerkships (i.e. years 3 and 4).MethodsAn online survey was sent to all medical students (i.e. years 1 to 4) at the Oakland University William Beaumont School of Medicine (OUWB), approximately 450 students. Information collected included demographics, learning style preferences, learning tool preferences, perceived level of anatomical knowledge retained, and opinions on curricular structure.ResultsNinety‐five students (52.1% male; 73.7% from years 1 and 2) responded to the survey. Fifty‐one students (54.8%) stated having no prior experience with anatomy, or having taken an anatomy class, while 42.9% of respondents reported utilizing anatomical principles less than 50% of the time. Seven respondents (10.6%) stated having retained 20% anatomical knowledge learned in first‐year medical school, 22 (33.3%) stated 21–39% retention, 29 (43.9%) stated 40–59% retention, and 8 (12.1%) stated greater than 60% retention. Each category of students was asked to provide a rank order of utilized studying resources. Students who reported <60% retention utilized dissection labs and professor‐written notes as their main resources. Students with >60% reported primarily using also the latter but with less frequency, atlases, and multiple‐choice questions. When re‐prompted to select resources for optimal retention, in both groups (<60% and >60% retention), there was an increase in frequency of students selecting dissection labs most pronounced in the >60% group. There was also an increase in frequency of students selecting atlases in the 21–39% and >60% groups. Across all groups, professor‐written notes were selected less frequently.ConclusionAnatomy education and retention relies on a major visual and kinesthetic (experiential) component, as seen in the preferences and perceived retention levels of students at OUWB. The use of written notes may be initially important for establishing context, but does not seem to be a significant contributor to long‐term retention. As more data is collected, these selections may show concrete trends in the way students are retaining anatomical information.
Everything Old Is New Again: An Alternate Approach to Human Hip Dissection Inspired by a Classic 19th Century Experiment
Authors: D'Abarno Anthony , Singleton Michelle 
Published: November 2023

Disarticulation of the human hip is among the most arduous joint dissections routinely performed in gross anatomy laboratories. The force required to distract the femoral head can fracture the femur or acetabulum, especially when applied by inexperienced student dissectors to a geriatric donor. We conducted a literature review to better understand the factors that contribute to passive stabilization of the hip in hopes of minimizing use of force and averting hard and soft tissue damage during hip dissection. We found that early experiments by Weber and Weber (1837) first demonstrated the role of atmospheric pressure differentials in resisting distraction of the femoral head. Subsequent experimental research has clarified the relationship among three factors that contribute to this phenomenon: 1) the cross‐sectional area of the femoral head; 2) the saturated vapor pressure of synovial fluid at body temperature; and 3) the integrity of the acetabular labrum and the zona orbicularis of the joint capsule, the latter being necessary to maintain intra‐articular pressure levels. The force F required to distract the hip is given by F = (πD2/4) * (Pa − Pi), where D is the diameter of the femoral head (m), Pa is atmospheric pressure (mBar), and Pi is the saturated vapor pressure of synovial fluid at body temperature (mBar). Thus, equilibration of atmospheric and intra‐articular pressures should minimize or eliminate the force required for hip distraction. As a practical application to anatomical education, we have performed multiple standard hip dissections (Grant's Dissector, 16th ed.) with the additional step—following the example of Weber and Weber (1837)—of drilling a 3 mm hole in the acetabulum ~2 cm superior to the acetabular notch. Using this procedure, the femoral head slides easily from the socket with no need for the complex maneuvers described in many dissection manuals. Adoption of this technique should provide human anatomy students with a less stressful dissection experience, as well as the opportunity to directly observe the interplay of factors contributing to normal human hip function.Support or Funding InformationThis research was supported by the Midwestern University Department of Anatomy, and did not require IRB approval.