bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resuscitating Learner Satisfaction: Enhancing ACLS Pharmacology Education Through a Case‐Based Escape Room Simulation
Authors: Conway Nicholas B. , Daniele Alexander L. , Uchiyama Emiri , Saunders John M. , Athauda Gagani , Toonkel Rebecca L. 
Published: May 2022

BackgroundTraining in Advanced Cardiac Life Support (ACLS) is a vital component of medical education. However, data suggests that learners are not satisfied with traditional ACLS learning formats and quickly lose mastery of the pharmacologic knowledge obtained. Prior studies have shown high learner satisfaction and knowledge mastery related to the ‘gamification’ of learning sessions. We hypothesize that the utilization of an online pre‐session learning module followed by a case‐based escape room simulation will lead to high levels of learner knowledge, satisfaction, and confidence in ACLS pharmacology.MethodsAll fourth‐year medical students (n=112) in the Class of 2021 participated in an online pre‐session module and escape room activity. Initially, all students completed a short (16‐minute) online learning module designed to teach the basics of ACLS pharmacology. After this module, students completed a 28‐item pre‐session MCQ quiz to assess baseline knowledge and to ensure preparation for the escape room activity. Students then completed a high‐fidelity case‐based escape room activity consisting of six ten‐minute stations incorporating simulators, puzzles, and clues related to ACLS relevant pharmacologic concepts and algorithms. After the activity, students completed the same 28‐items as a post‐session MCQ quiz and a 14‐item satisfaction/confidence survey. Pre‐ and post‐session results were compared via paired t‐tests.ResultsAll 112 participants (RR=100%) completed both the pre‐ and post‐session knowledge assessments. Overall mean performance on pre‐ and post‐session assessments was 87.6% (SD 8.4) vs. 95.7% (SD 5.0), respectively (Table 1, p<0.0001). Mean pre‐ and post‐session performance on pharmacology specific items was 77.7% (SD 11%) and 92.8% (SD 9.5%), respectively (Table 1, p<0.0001). 111 participants (RR=99%) completed the post‐session confidence survey. On a 7‐point Likert scale (1‐“Strongly Disagree” through 7‐“Strongly Agree, ”Figure 1), mean agreement with the statement “The ACLS module improved my knowledge of medical decision making for patients in cardiac arrest” was 6.6 (SD 0.8). On a 10‐point Likert scale, students rated their pre‐ and post‐session confidence in “Addressing a patient in cardiac arrest” at 7.7 (SD 2.1) and 8.4 (SD 1.6), respectively (p=0.0019).ConclusionParticipation in the online pre‐session module and escape room activity led to significant knowledge gains in ACLS pharmacology along with high levels of learner confidence and satisfaction. This innovative approach may be used to teach ACLS pharmacology to fourth‐year medical students and to supplement traditional ACLS certification courses.
Soluble Guanylyl Cyclase Stimulator Improves Contracting Skeletal Muscle Oxygen Pressures in Heart Failure Rats
Authors: Weber Ramona E. , Schulze Kiana , Hageman K. S. , Sandner Peter , Musch Timothy , Poole David 
Published: May 2022

IntroductionImpaired convective and diffusive oxygen (O2) transport is a hallmark of heart failure with reduced ejection fraction (HFrEF), largely attributed to nitric oxide‐soluble guanylyl cyclase (sGC)‐cyclic guanosine monophosphate pathway dysfunction. sGC stimulators were synthesized to independently and synergistically (with endothelial derived‐NO) promote vasodilation, thereby demonstrating the potential to improve skeletal muscle oxygenation in HFrEF. We tested the hypotheses that 2 weeks of administration of sGC stimulator BAY 41‐2272 would increase the O2 delivery (Q̇O2)‐to‐O2uptake (V̇O2) ratio in the skeletal muscle interstitial space (PO2is) of HFrEF rats at rest and during twitch contractions.MethodsHFrEF was induced in adult male Sprague‐Dawley (3‐4 mo. old) rats via myocardial infarction (MI). Following 5 weeks of HFrEF progression, rats were treated with 1.0 mg/kg of BAY 41‐2272 via oral gavage twice per day (HFrEF + BAY; n=6) for 2 weeks prior to the contraction protocol. The control heart failure group (HFrEF; n=5) received vehicle only. Phosphorescence quenching protocols determined the partial pressure of O2 in the spinotrapezius muscle interstitial space at rest and during twitch contractions, reflecting the dynamic relationship between Q̇O2 and V̇O2.ResultsThe degree of HFrEF was not different between groups as evidenced by left ventricular end‐diastolic pressure (16 ± 1 mmHg, both groups) and MI size (27 ± 1 vs. 29 ± 1%) (all P>0.05). There were no differences in blood gases following contractions (P>0.05). Kinetic analyses revealed no difference in PO2is at rest, however immediately following the onset of contractions and throughout the contraction steady‐state, HFrEF+BAY rats maintained a ~5‐7 mmHg higher PO2is (32‐180s of contractions, P<0.05). Furthermore, HFrEF+BAY rats had an attenuated undershoot, decreased tau (time constant), and increased end PO2is (all P<0.05) in comparison to HFrEF rats.ConclusionsDuring the rest‐contraction transient and throughout the contractions steady‐state BAY 41‐2272 increases PO2isin rats with moderate HFrEF. By improving O2delivery and relieving the HF‐induced O2‐dependence of V̇O2 kinetics these findings support the therapeutic potential for sGC stimulators to reduce vasomotor dysfunction and improve exercise tolerance in HFrEF.
Overexpression of Multiple E3 Ubiquitin Ligases in Gastrocnemius Muscles from Mice
Authors: Hughes David C. , Baehr Leslie M. , Waddell David S. , Bodine Sue C. 
Published: May 2022

E3 ubiquitin ligases are commonly studied in skeletal muscle under atrophy‐inducing conditions. MuRF1 is a recognized marker of muscle atrophy and we have recently identified Fbxl22 to be involved in the process of denervation‐induced muscle atrophy. Thus, we sought to investigate the role of MuRF1 and Fbxl22 together in the process of skeletal muscle atrophy. Male C57BL/6 mice (16 to 20‐week old) were subjected to in vivo electroporation with either a mouse specific MuRF1 or Fbxl22 plasmid (20ug) in the gastrocnemius (GA) muscles with the contralateral leg serving as a vector control (EV). An additional cohort of mice was electroporated with MuRF1 and Fbxl22 plasmids simultaneously. After 7 days, lateral (LGA) and medial (MGA) gastrocnemius muscles were collected, weighed and sectioned for cross‐sectional area (CSA) and GFP visualization. Western blotting was performed on sarcoplasmic and myofibrillar fractions to determine levels of ubiquitin and sarcomeric proteins in the transfected GA muscles.MuRF1 overexpression (OE) resulted in significant loss of total GA muscle mass (‐8.8%) after 7 days alone. In comparison, Fbxl22 OE led to no loss in total GA muscle mass, although significant reductions in LGA mass (‐3.4%) were observed. Combined OE of MuRF1 and Fbxl22 together resulted in significant loss of GA muscle mass (‐5.5%) but the level of atrophy was not as great as compared to MuRF1 OE alone. In transfected LGA muscles, total ubiquitin levels were significantly elevated in the Fbxl22 OE and combined E3 ligase group for the sarcoplasmic fraction. In the myofibrillar fraction of LGA transfected muscles, only the combined E3 ligase group displayed increased total ubiquitin levels after 7 days. In transfected Fbxl22 LGA muscles, we observed significant increases in vimentin, alpha‐actinin and Troponin T in the sarcoplasmic fractions. Gene manipulation of the E3 ubiquitin ligases, MuRF1 and Fbxl22 in basal skeletal muscle resulted in skeletal muscle atrophy and divergent changes in ubiquitination and sarcomeric proteins were observed following E3 overexpression. Future studies will seek to identify potential unique and shared substrates targeted by Fbxl22 and MuRF1 for ubiquitination.
nTS Glutamate Signaling in the Chemoreflex Axis of an Alzheimer's Disease Rat Model
Authors: Tipton Robert K. , Humphrey Chuma M. , Scales Dorothy M. , Ostrowski Daniela , Ostrowski Tim D. 
Published: May 2022

Respiratory dysfunction is commonly observed in Alzheimer’s disease (AD) and likely due to neuronal alterations of the respiratory network in the brain. The streptozotocin (STZ) ‐induced AD model mimics respiratory problems seen in humans and exhibits neuronal hyperactivity in the nucleus tractus solitarii (nTS), the central integration site for respiratory afferents in the brainstem. This ongoing study looks at the changes of glutamate signaling within the chemoreflex axis as a possible mechanism for nTS hyperactivity and respiratory dysfunction in STZ‐AD.AD was induced by intracerebroventricular injection of 2 mg/kg STZ in 6‐week old male Sprague Dawley rats. After 14 days, caudal nTS neurons within close proximity of DiI‐labeled chemoafferent terminals were recorded using the patch clamp technique. Electrical stimulation of the tractus solitarii (TS) generated glutamatergic excitatory postsynaptic currents (EPSCs) that were compared between experimental groups. Consistent with enhanced glutamatergic signaling, TS‐EPSC amplitude was increased in STZ‐AD. High TS stimulation frequency induced a time and frequency dependent depression that was similar between groups, indicating no change in presynaptic vesicle turnover or postsynaptic receptor desensitization. On the other hand, asynchronous EPSCs following high frequency stimulation seemed enhanced in STZ‐AD, supporting an increased excitatory tone in the nTS. Immunohistochemical analysis of the caudal nTS revealed no change in neuron number but showed a reduced synaptic density in the AD model. Astrocyte number and morphology were unchanged between groups. However, microglia, which are able to influence glutamate‐handling of astrocytes, showed an activated phenotype.Overall, our data show enhanced glutamatergic signaling in the chemoreflex axis contributing to nTS hyperactivity of the STZ‐AD model. nTS hyperactivity may lead to the observed respiratory dysfunction in this model and potentially constitutes a mechanism for sleep disordered breathing in AD patients.
Non‐invasively derived human induced mesenchymal stem cells demonstrate an enhanced protection of cardiomyocytes from injuries
Authors: Gurusamy Narasimman , Sigamani Vinoth , Perales Selene G. , Rajasingh Sheeja , Rajasingh Johnson 
Published: May 2022

BackgroundMesenchymal stem are multipotent stem cells used for treating various diseases including cardiomyopathy. However, their heterogeneity, limited proliferation and low retention in the transplanted tissue restricts their application for cell therapy. Recently, induced pluripotent stem cells (iPSCs)‐derived mesenchymal stem cells (iMSCs) have created an exciting source of cells for autologous therapy.ObjectiveIn this study, we have compared the therapeutic potential of non‐invasively derived iMSCs with adult umbilical cord MSCs (hereafter referred as MSCs) for the protection of cardiomyocytes from injury.Methods and ResultsThe urinary epithelial cells obtained from adult human urine were safely reprogrammed into iPSCs using a mixture of mRNA of pluripotency genes (Oct4, Nanog, Sox2, Klf4, cMyc and Lin28) along with a cocktail of miRNAs. The generated iPSCs were subsequently differentiated into iMSCs, which had the capacity to differentiate into osteocytes, chondrocytes and adipocytes. Our comparative qRT‐PCR and Western blot analysis showed that the mesenchymal‐specific CD73, CD90 and CD105 gene transcripts and proteins were highly expressed in both iMSCs and MSCs. But the iMSCs maintained their mesenchymal markers even at a late passage (P18), during which the MSCs started losing their characteristics. Scratch assay and transwell migration assay demonstrated that iMSCs had a greater wound healing property compared to MSCs. Furthermore, the cardioprotective properties of iMSCs and their exosomes (obtained from the conditioned media by precipitation method) were evaluated using human skin fibroblast‐derived induced‐cardiomyocytes, treated with 50 µg of exosomes 1 hr before subjecting them to either 24 hrs of angiotensin II treatment (10 µM) or 6 hrs of 1% hypoxia and 24 hrs of reoxygenation. In comparison with MSCs, iMSCs and their exosomes elicited an enhanced cardiomyocyte protection studied through measurement of mitochondrial membrane potentials (JC1 dye), intracellular reactive oxygen species (CM‐H2DCFDA), in situ cell death by apoptosis, and qRT‐PCR expression of survival genes. Further studies are underway to evaluate the specific role of exosomal RNA and protein in mediating the cardioprotection.ConclusionIn this study, we have demonstrated a non‐invasive method of generating iMSCs for regenerative therapy. This homogeneous and highly proliferative iMSCs may provide an alternative source of cells or cell‐free exosomes for treating ischemic cardiomyopathy.
Analgesic and Antinociceptive Effects of (2R,6R)‐hydroxynorketamine (HNK) in Mice
Authors: Yost Jonathan G. , Browne Caroline A. , Lucki Irwin 
Published: May 2022

Chronic pain can be challenging to treat and increases the risk of developing psychological disorders such as depression. Identifying novel treatment modalities that effectively alleviate pain is essential to improve clinical treatment and rehabilitation for patients with pain conditions. Ketamine is an effective analgesic for many types of pain. However, its widespread use is limited by its side effect profile and requirement for intranasal/intravenous administration under medical supervision. (2R,6R)‐hydroxynorketamine (HNK) is a ketamine metabolite that lacks the psychotomimetic effects of its parent drug but retains ketamine’s anti‐stress effects. Therefore, it is natural to question whether (2R,6R)‐HNK may also possess analgesic activity.Administration of (2R,6R)‐HNK produced antinociception in healthy mice exposed to a noxious, painful stimulus 24 hours after injection. The dose response for the delayed‐yet‐persistent antinociception revealed an inverted U shape with significant antinociception at doses of 10‐18 mg/kg for both sexes and 30 mg/kg in female mice. Mice pretreated with different receptor antagonists to examine the potential mechanism for (2R,6R)‐HNK mediated antinociception revealed a mechanism dependent on AMPA receptors and not opioid receptors. In contrast, ketamine antinociception was not dependent on AMPA receptors and partially dependent on opioid receptors. These results demonstrate that both (2R,6R)‐HNK and the parent drug ketamine produce antinociception but work via different neural mechanisms.In separate studies, (2R,6R)‐HNK administration reversed mechanical allodynia associated with localized inflammatory pain induced in mice by injecting λ‐carrageenan into the hind paw. The onset for this analgesia‐like activity was less than 1 hour with a duration greater than 24 hours following a single administration. (2R,6R)‐HNK was effective at reversing mechanical allodynia at doses of 10 & 30 mg/kg in both male and female animals. These results demonstrate (2R,6R)‐HNK exhibits great promise for treating inflammatory pain in addition to other pain types. Overall, these data suggest that (2R,6R)‐HNK may be a safe alternative therapy for pain that could be made widely available to patients and support the need for continued investigation and development of (2R,6R)‐HNK as a novel non‐opioid pain treatment.
Lipid phosphate phosphatase‐3 dysfunction exaggerates neointimal hyperplasia following diabetic vascular injury
Authors: Subedi Utsab , Bhattarai Susmita , Sharma Sudha , Ara Hosne , murov Milena , Bhuiyan Md Shenuarin , Miriyala Sumitra , Panchatcharam Manikandan 
Published: May 2022

IntroductionDiabetes mellitus is a major risk factor for cardiovascular diseases and promotes neointimal hyperplasia characterized by occlusive disorders such as atherosclerosis and stenosis, caused by excessive proliferation and migration of vascular smooth muscle cells (VSMCs) following endovascular interventions such as balloon angioplasty and stent placement. Lipid phosphate phosphatase‐3 (LPP3) is an enzyme that regulates the availability of lysophosphatidic acid (LPA) and has been reported to play a significant role in vascular genesis, cellular permeability, tumor progression, vascular remodeling, and myocardial infarction. However, the functional role and mechanism of LPP3 in diabetic neointimal hyperplasia is unclear. LPP3 dysfunction may lead to LPA accumulation at the vascular injury site, leading to vascular inflammation, proliferation, and migration, causing restenosis. Recently, the Receptor for Advanced Glycation End product (RAGE) has been presented as a potential receptor for LPA leading to downstream signaling in vascular smooth muscle cells (VSMCs).MethodsIn this study, we used a streptozocin‐induced diabetes mice model. We made SM‐22 specific LPP3 knock‐out mice and performed endothelial denudation surgery in the carotid artery to induce neointima hyperplasia to tease out the role of LPP3 in restenosis. We isolated aortic VSMCs from LPP3 floxed and LPP3 knock‐out mice and cultured them under normal or high glucose media. The immunoblotting was performed and probed with antibodies for total extracellular signal‐regulated kinase (ERK) and phosphorylated‐ERK. The cell proliferation and migration assay was performed using the Electric Cell substrate Impedance Sensing (ECIS) with or without LPP3 in VSMC under normal or high glucose conditions. Data are mean ± SEM; P‐values were determined by Student t‐test or one‐way ANOVA with Tukey's post‐hoc tests.ResultWe observed a significant increase in proliferation (P<0.01) and exaggerated migration (p<0.01) of VSMC that lack LPP3 under the hyperglycemic condition in real‐time using ECIS. These effects are at least partially a consequence of decreased lysophosphatidic acid hydrolysis due to lack of LPP3 activity. Furthermore, VSMC that lack LPP3 showed increased phospho‐ERK expression (P<0.01) under hyperglycemic conditions. The diabetic LPP3 knock‐out mice exhibited exaggerated neo‐intimal areas after the carotid injury compared to LPP3 floxed mice.ConclusionThese findings implicate that LPP3 plays a vital role as a negative regulator of smooth muscle phenotypic modulation. We speculate that changes in LPP3 expression control the development of neo‐intima by limiting smooth muscle cell proliferation, migration, and vascular inflammation in diabetic restenosis.
Variations in the bony architecture of the greater palatine canal: An anatomical report
Authors: Hafeez Sahar , Ansari Ali , Johnson Marjorie , Khadry Galil A. 
Published: May 2022

IntroductionThe greater palatine canal route has been well‐described in adults for the purposes of anesthetizing the branches of the maxillary division of trigeminal nerve for the relief of sphenopalatine neuralgia [11]. The canal also provides direct access to the contents of the PPF [12]. A complex array of vascular and neural structures characterizes this posterior maxillary region where the GPC is located. Its surgical anatomy can get further complicated by any anatomic variations and identification of vital structures becomes difficult, especially when bleeding during surgery obscures the region. Accurate knowledge of normal anatomy and common anatomical variations therefore remain crucial in minimizing intraoperative and postoperative complications associated with invasive microsurgical approaches to this region. The aim of this study was to explore the architecture of the GPC for any anatomic variations.Material & MethodIn total, 30 adult dried and intact skull specimens were selected. The selection criteria included an intact hard palate with erupted 3rd molars and an intact lateral nasal wall on both sides. The exclusion criteria included any major craniofacial deformities, excessive bone resorption, very old specimens. The bony walls of the GPC were observed by passing a black wire.Findings4 out of 30 specimens showed marked variations in the bony medial wall of the greater palatine canal (GPC). Partial to complete malfusion between the posterior surface of the maxilla and the perpendicular plate of palatine bone was observed. This might be the result of embryological malformation.ConclusionThe present study provided information regarding the existence of some degree of anatomical variation in the bony architecture of greater palatine canal.SignificanceThis might help surgeons visualize over the possibility of the existence of any such variation while performing any surgical procedure in the posterior maxillary area. In order to establish the embryological basis of these findings, investigation on a larger number of specimens is highly suggested by the authors.
Cell‐free Hemoglobin‐Oxidized LDL Axis Contributes to Microvascular Endothelial Barrier Dysfunction and Poor Outcomes During Sepsis
Authors: Meegan Jamie E. , Tomasek Toria , Desco Alex , Ware Lorraine B. , Bastarache Julie A. 
Published: May 2022

IntroductionSepsis, a dysregulated host response to infection with high morbidity and mortality, is characterized by a systemic inflammatory response and widespread vascular hyperpermeability leading to edema, organ dysfunction, and death with no specific treatments. Disruption of the microvascular endothelial barrier is a critical pathological feature of sepsis‐induced organ dysfunction driven by circulating inflammatory mediators, oxidants, and proteolytic enzymes. Cell‐free hemoglobin (CFH) is one such factor, released from damaged red blood cells during sepsis due to their increased deformability and fragility. Though CFH is not detectable in healthy subjects, plasma CFH is elevated in patients with sepsis and independently associated with mortality. CFH contributes to endothelial dysfunction, but the signaling mechanisms are incompletely understood. CFH can oxidize circulating low‐density lipoproteins (oxLDL), which could potentiate endothelial barrier disruption. We hypothesized that elevated levels of CFH during sepsis are associated with increased oxLDL and contribute to microvascular endothelial barrier dysfunction through the oxLDL receptor, lectin‐like oxidized LDL receptor 1 (LOX‐1).MethodsCirculating levels of CFH and oxLDL were measured in sepsis patients. In human lung microvascular endothelial cells (HLMVECs), transendothelial electrical resistance (TER), a measure of barrier dysfunction, was assessed by Electric Cell‐substrate Impedance Sensing (ECIS).Results (Figure)In sepsis patients, plasma oxLDL levels correlated with CFH (r=0.686; p=0.016, n=12) and were higher in patients who died in hospital (33.24 U/L [IQR 28.08, 48.28] vs. 27.19 U/L [IQR 16.24, 38.24]; p=0.045, n=25). HLMVEC barrier dysfunction induced by CFH (p<0.0001, n=6‐7) or oxLDL (p=0.002, n=4‐6) was attenuated by blocking the LOX‐1 receptor with small molecule inhibitor BI‐0115 (Boehringer Ingelheim, 20 µM; p=0.018 vs CFH, n=5; p=0.0002 vs oxLDL, n=6).ConclusionIncreased plasma CFH and oxLDL are associated with HLMVEC barrier dysfunction and poor clinical outcomes during sepsis; one mechanism by which CFH may cause vascular hyperpermeability during sepsis is through oxidation of LDL which can drive signaling through the LOX‐1 receptor.