bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Lower Body Negative Pressure (LBNP) on Blood Pressure in Awake Rats and Effects of Anesthesia
Authors: Nieman Michelle L , Lorenz Suzanne G , Lorenz John 
Published: May 2024

Lower body negative pressure (LBNP) has been used for decades in a variety of settings and species to model orthostatic challenge (OC) and baroreceptor unloading. However, due to physical constraints, measurements of blood pressure (BP) during LBNP have always been made in anesthetized animals, where cardiovascular reflexes are blunted or even blocked. In terminal procedures, for example, urethane is often used in an attempt to preserve some measure of autonomic reflex function during OC. More recently, investigators have used isoflurane in animals fitted with BP telemeters in order to perform longitudinal studies, but the extent to which various cardiovascular reflexes may be preserved is unknown. Here we have developed a novel method to apply lower body negative pressure in awake rats instrumented for BP measurement. Rats were placed into a tubular restraining device (5 cm diameter X 21 cm length), that is divided into an upper and lower chamber by two adjacent latex septa with small holes (~ 2 cm). Rats were positioned so that the septa form a seal at the lower margin of the thorax, thereby creating independent upper and lower chambers. Negative pressure was then applied to the lower chamber using a high-volume vacuum and the pressure controlled using an adjustable damper. BP measurements in response to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by induction of anesthesia and repetition of the LBNP protocol. The effects of pentobarbital (50mg/kg), ketamine/xylazine (70/6 mg/kg) and isoflurane (3%) were determined on separate days. BP and heart rate (HR) responses are shown in the Table. We found that BP was remarkably preserved in awake rats up to at least -9 mmHg LBNP, and thereafter (at -12 and -15 mmHg) decreased modestly. There was a robust baroreceptor-mediated increase in HR beginning at -6 mmHg. By contrast, under each anesthetic, blood pressure decreased dramatically and progressively with increasing LBNP, and the reflex increases in HR were entirely blocked (and actually inverted). These data indicate that the awake rat has robust mechanisms to preserve cardiovascular function during OC, and that these mechanisms are severely compromised during anesthesia. University of Cincinnati College of Medicine Innovation Seed Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Chronic Hyperoxia Augments the Hypercapnic Ventilatory Response in Adult Rats
Authors: Hanus Julia , Dufour Gemma , Bavis Ryan 
Published: May 2024

Rats exposed to 4 – 14 days of 60% O2 as adults exhibit a modest enhancement of their hypoxic ventilatory response (HVR) (Danielson & Bavis, Physiology 38(S1): 5730119, 2023). To determine whether this plasticity is unique to the HVR or a general increase in excitability of the respiratory control system, we tested the hypothesis that chronic hyperoxia would also enhance the hypercapnic ventilatory response (HCVR). The ventilatory response to 7% CO2 was measured by whole-body plethysmography in adult, Sprague-Dawley rats immediately after 4 and 14 days of exposure to 60% O2 or an equivalent time period in room air. Baseline ventilation and the HCVR were unchanged after 4 days of hyperoxia. The HCVR was increased after 14 days (Treatment × FICO2, P=0.004), with hypercapnic ventilation being approximately 15% greater than in control rats. However, this effect was no longer significant after accounting for variation in metabolic rate, and the HCVR was fully recovered when rats were restudied four weeks after they were returned to room air. In a follow-up experiment, pulse oximetry was performed in isoflurane-anesthetized rats breathing room air or 12% O2. Exposure to 4 – 14 days of 60% O2 did not impair gas exchange, so augmented ventilatory responses likely reflect changes in the neural control of breathing and/or metabolism rather than differences in the levels of hypoxemia and hypercapnia experienced by rats during the tests. In conclusion, chronic hyperoxia elicits plasticity in both the HVR and HCVR of adult rats, but these responses recover in less than one month after rats are returned to room air. Supported by NIH grant P20 GM-103423 (Maine INBRE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pulsatile Perfusion Therapy at 0.1 Hz Improves Survival Following Severe Hemorrhage in Rats
Authors: Dinh Viet , Farmer George , Rickards Caroline 
Published: May 2024

Oscillations in arterial pressure and blood flow at 0.1 Hz are associated with protection of tissue oxygenation during conditions of reduced tissue perfusion. Pulsatile Perfusion Therapy (PPT) is a method we have developed to induce these oscillations, and has been associated with increased tolerance to simulated hemorrhage via lower body negative pressure in humans. However, it is unknown how effective this therapy would be in an actual hemorrhage model. The aim for this study was to test the effcacy of PPT in a rat model of severe hemorrhage. We hypothesized that PPT at 0.1 Hz would protect arterial pressure and cerebral blood flow following severe hemorrhage in rats, subsequently improving survival. Eleven adult Sprague-Dawley rats (six female, five male) were anesthetized via isoflurane, then underwent bilateral carotid artery catheterization for assessment of arterial pressure and carotid artery blood flow, while heart rate was assessed via lead II ECG. Following a 15-min baseline period, all animals were hemorrhaged to 50% of their estimated blood volume over 30-min. Rats were then randomly assigned to the PPT group (3 female, 3 male) or the control group (CON; 3 female, 2 male). PPT was administered via inflatable cuffs attached to both hind limbs, oscillating between 0 mmHg and 250 mmHg every 5-s (10-s cycles or 0.1 Hz) for 30-min immediately following hemorrhage. For the CON group, the leg cuffs were also attached but were not inflated for this 30-min period. All animals were then monitored for an additional 150-min recovery period post-hemorrhage, or until death — defined as the absence of ventricular function on the ECG. Survival time and peak mean arterial pressure (MAP), carotid blood flow, and heart rate were assessed to determine the effectiveness of PPT in protecting hemodynamic responses following hemorrhage. PPT increased survival time ( P = 0.02), with 3 of 6 (50%) rats in the PPT group and 0 of 5 (0%) rats in the CON group surviving the entire 180-min recovery period following hemorrhage. During recovery, PPT protected MAP (PPT: −46.5 ± 12.9% vs. CON: −72.6 ± 19.5% from baseline; P = 0.07) and carotid blood flow (PPT: −61.5 ± 17.7% vs. CON: −83.7 ± 6.7% from baseline; P = 0.04), but did not affect heart rate (PPT: 0.11 ± 6.58% vs. CON: −18.70 ± 29.34% from baseline, P = 0.20), although responses were highly variable between subjects. PPT protected arterial pressure and carotid blood flow in rats following severe hemorrhage, subsequently improving survival. These data add further evidence for the use of 0.1 Hz hemodynamic oscillations as a therapeutic intervention for the treatment of hemorrhage. Physiology and Anatomy Department Seed Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effects of chronic inspiratory muscle strength training on metabolic and cardiovascular measures during a glucose tolerance test
Authors: Harbin Christina , Janssen Noah , Vranish Jennifer 
Published: May 2024

Previous work has shown that both a single session of aerobic exercise and chronic exercise training improve glucose homeostasis. Similarly, a single bout of inspiratory muscle strength training (IMST) has been shown to facilitate a greater degree of glycemic control. However, less is known about the chronic effects of IMST, particularly with respect to metabolic and cardiovascular responses to an oral glucose tolerance test (OGTT). We hypothesized that 6 weeks of IMST would promote a greater degree of glycemic control, via a reduction in fasting and peak glucose during an OGTT. To test this hypothesis, participants (n=14, 57% female, average age=21.9) completed 6 weeks of daily training at either 15% (n=7) or 75% (n=7) of their maximal inspiratory pressure. Each subject underwent a pre-IMST glucose tolerance test in which their blood glucose level, blood pressure, and heart rate were measured at baseline, 15, 30, 45, 60, and 90 minutes following glucose ingestion. A post-IMST glucose tolerance test was completed after 6 weeks of training. The results indicate no training effect on baseline glucose, peak glucose, 90-minutes post-glucose, or glucose area under the curve responses, for both training intensities (P>0.05). There was no significant effect of IMST on heart rate, nor was heart rate altered during the OGTT (P>0.5). While mean arterial pressure was not affected during the OGTT (P>0.05), baseline mean arterial pressure decreased in the 75% intensity group only (P=0.012). In summary, 6 weeks of high-intensity IMST decreases baseline blood pressure, and glucose tolerance was unaffected in both training groups. Future studies should investigate the effects of chronic IMST on other metabolic measures (e.g. lipids, triglycerides, and/or cholesterol levels) and the impact that this training has on glucose homeostasis in clinical populations. This work was supported by the Alma College CORE Summer Research Program. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Nicotine Exposure Causes Nitrosative and Oxidative Stress in Glomerular Podocytes, Resulting in Renal Damage
Authors: Jones Adam , Semenikhina Marharyta , Fedoriuk Mykhailo , Stefanenko Mariia , Cherezkova Alena , Veit Acosta Martina , Stadler Krisztian 
Published: May 2024

Introduction: Nicotine consumption is the leading cause of preventable disease and death. Patients with hypertension or kidney disease are more likely to exhibit renal pathologies associated with nicotine, such as glomerulopathy. In endothelial cells, nicotine was linked to mitochondrial oxidative stress and nitric oxide synthase (NOS) remodeling. However, there is a gap in knowledge regarding the effects of nicotine in glomerular epithelial cells, podocytes. We hypothesized that nicotine promotes nitrosative stress in the podocytes by producing peroxynitrite (ONOO-) and mitochondrial damage, thereby reducing glomerular function. Methods: We performed confocal imaging on human cultured podocytes to detect ONOO− (HPF), Ca2+ (Fluo-8) and nitric oxide NO (DAF-FM) in response to nicotine. Seahorse assay (Agilent XFe24) was used to test mitochondrial respiration. Then, nicotine was chronically infused in Dahl SS rats (0.2 mg/kg/day s.c., 0.4% NaCl, 21 days), and blood pressure was recorded with telemetry. Glomerular damage was evaluated, and electron microscopy was employed to assess mitochondrial ultrastructure. Electron paramagnetic resonance (EPR) spectroscopy was used to access the NO levels in cultured podocytes and in vivo. OriginPro was used for statistical analysis. Results: Acute application of nicotine promoted intracellular Ca2+ and ONOO− transients in podocytes. The ONOO− response was blocked in the presence of SOD, indicating that ONOO− production requires superoxide. The application of specific α7 or α4β2, α2β4, α4β4, and α3β4 nicotinic acetylcholine receptor (nAChR) agonists elicited Ca2+ transients but did not produce ONOO−, suggesting that nitrosative stress occurs independently from Ca2+ influx or nAChR activation. Incubation with nicotine (12 hrs) resulted in a decrease in podocytes’ mitochondrial respiration (two-sample t-test, p<0.05). In vivo, nicotine infusion did not affect blood pressure but promoted mitochondrial damage in podocytes, which exhibited swelling, loss of cristae, and mitophagy (t-test, p<0.05). Histopathological assessment showed higher glomerular damage in nicotine-exposed rats (t-test, p<0.05). Both EPR and confocal approaches demonstrated nicotine-mediated changes in NO bioavailability and an increase in NOS2 activity (t-test, p<0.05) Conclusion: Nicotine elicits superoxide-mediated nitrosative stress and peroxynitrite formation in podocytes, promoting mitochondrial damage and glomerular dysfunction. Revealing the mechanisms of nicotine-mediated damage in the podocytes impacts our progress towards new treatments for smoking and vaping-associated renal pathologies. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Estrogens and Olfactomedins May Induce a Feedback Loop that Increases Nicotine Consumption in Females via the Brain Reward Circuitry
Authors: Pauss Sally , Kipp Zachary , Gipson-Reichardt Cassandra , Hinds Terry 
Published: May 2024

Estrogen is associated with enhanced nicotine use in women, with enhanced vulnerability to nicotine use disorders being associated with higher levels of circulating estrogen. In ovariectomized (OVX) female rats, estradiol (E2) treatments increased estrogen receptor β (ERβ) and not ERα in a key brain reward region, the nucleus accumbens core (NAcore). Therefore, we hypothesized that ERβ might be important in the reward circuitry for regulating nicotine use in females. To determine ERβ-specific functions that might regulate nicotine use, we analyzed large sequencing datasets of estrogen-induced genes and narrowed the list to those expressed in the brain and that have a hormone function. We found one class of genes known as the olfactomedins (OLFMs), which meet these criteria. Therefore, we wanted to determine whether ERα or ERβ regulates the expression of the OLFM isoforms. We used human uterine cells (Ishikawa) that express both ER isoforms and the OLFMs and found that two-hour E2 treatments induced the expression of OLFM1 and OLFM3. However, nicotine only suppressed the E2-induction of OLFM1 and not the others. We next performed chromatin immunoprecipitation (ChIP) assays with these cells and treatments using antibodies for ERα, ERβ, or GFP control. We found that the OLFM1 promoter was only enriched by ERβ, and no binding of ERα was observed. We next treated OVX female rats with E2, nicotine, E2+nicotine, or vehicle and found that Olfm1 and Olfm2 significantly increased in the NAcore, and all three OLFM isoforms were significantly higher in the ventral tegmental area (VTA), another key region within the mesolimbic reward pathway. Nicotine suppressed the E2-induced OLFM expression in the NAcore and VTA. These new findings suggest that ERβ-induction of the olfactomedins might serve as a feedback loop for driving nicotine addiction processes, which is suppressed when nicotine is on board. These results indicate a potential new target for therapeutic cessation of nicotine use in women. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
High Resolution Reconstruction of the Proximal Tubule Apical Endocytic Pathway
Authors: Lackner Emily , Pandya Raj , Burdyniuk Mariia , Xu C. Shan , Pang Song , Caplan Michael , Weisz Ora 
Published: May 2024

Kidney proximal tubule (PT) cells are specialized for effcient apical uptake of albumin and other proteins that escape the glomerular filtration barrier. The apical endocytic pathway is uniquely organized to maintain highly dynamic retrieval of these proteins via binding to the multiligand receptors megalin and cubilin. Ultrastructural studies following the fate of internalized markers have provided a temporal model for the delivery of receptor-bound ligands and fluid phase markers to lysosomes. In this model, internalization from the apical membrane occurs via budding of irregular clathrin-coated invaginations that form at the base of microvilli. After uncoating, budded vesicles fuse with apical early endosomes (AEEs) where acidification triggers dissociation of ligands from their receptors. AEEs further mature and expand into apical vacuoles (AVs) that ultimately deliver ligands and fluid to lysosomes. Receptor recycling to the apical membrane is thought to occur via dense apical tubules (DATs) that have a uniform diameter and membrane thickness and which appear to bud from both AEEs and AVs. We used Zeiss Arivis Pro technology to annotate and reconstruct apical membrane invaginations and endocytic compartments in a 3D volume of mouse kidney with isotropic voxels of 4 nm, acquired using focused ion-beam scanning electron microscopy (FIB-SEM). Strikingly, 3D reconstruction of DATs revealed a large and highly interconnected network of tubules in the subapical region of PT cells. Connections were observed between the DAT network and endosomal compartments, as well as between DATs and apical membrane invaginations. Our data suggest the possibility that DATs exist as a stable compartment that interacts transiently with the apical membrane to enable receptor recycling. Current studies are underway to better understand how PT cells modulate endocytic entry and recycling via the same portals. National Institute of Health: 5T32GM133353-03, R01 DK118726, R01 DK125049, U54 DK137329. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Survival Predictive Nomograms for Non-Surgical Brain Metastases Patients From Non-Small Cell Lung Cancer Receiving Radiotherapy: A Population-Based Study
Authors: Li Peng , Luo Jie , Zheng Zilong , Meng Lu , Zhang Anqi , Cao Wei , Gong Xiaomei 
Published: May 2024

Objective A high number of Non-Small Cell Lung Cancer (NSCLC) patients with brain metastasis who have not had surgery often have a negative outlook. Radiotherapy remains a most common and effective method. Nomograms were developed to forecast the cancer-specific survival (CSS) and overall survival (OS) in NSCLC individuals with nonoperative brain metastases who underwent radiotherapy. Methods Information was gathered from the Surveillance, Epidemiology, and End Results (SEER) database about patients diagnosed with NSCLC who had brain metastases not suitable for surgery. Nomograms were created and tested using multivariate Cox regression models to forecast CSS and OS at intervals of 1, 2, and 3 years. Results The research involved 3413 individuals diagnosed with NSCLC brain metastases who had undergone radiotherapy but had not experienced surgery. These participants were randomly divided into two categories. The analysis revealed that gender, age, ethnicity, marital status, tumor location, tumor laterality, tumor grade, histology, T stage, N stage, chemotherapy, tumor size, lung metastasis, bone metastasis, and liver metastasis were significant independent predictors for OS and CSS. The C-index for the training set for predicting OS was .709 (95% CI, .697-.721), and for the validation set, it was .705 (95% CI, .686-.723), respectively. The C-index for predicting CSS was .710 (95% CI, .697-.722) in the training set and .703 (95% CI, .684-.722) in the validation set, respectively. The nomograms model, as suggested by the impressive C-index, exhibits outstanding differentiation ability. Moreover, the ROC and calibration curves reveal its commendable precision and distinguishing potential. Conclusions For the first time, highly accurate and reliable nomograms were developed to predict OS and CSS in NSCLC patients with non-surgical brain metastases, who have undergone radiotherapy treatment. The nomograms may assist in tailoring counseling strategies and choosing the most effective treatment method.
Evaluating the diagnostic accuracy of heat shock proteins and their combination with Alpha-Fetoprotein in the detection of hepatocellular carcinoma: a meta-analysis
Authors: Xiang Dan , Fu Lifang , Yang Ying , Liu ChengJiang , He Yong 
Published: May 2024

Abstract
Background
A growing body of research suggests that heat shock proteins (HSPs) may serve as diagnostic biomarkers for hepatocellular carcinoma (HCC), but their results are still controversial. This meta-analysis endeavors to evaluate the diagnostic accuracy of HSPs both independently and in conjunction with alpha-fetoprotein (AFP) as novel biomarkers for HCC detection.

Methods
Pooled statistical indices, including sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) with 95% confidence intervals (CI), were computed to assess the diagnostic accuracy of HSPs, AFP, and their combinations. Additionally, the area under the summary receiver operating characteristic (SROC) curve (AUC) was determined.

Results
A total of 2013 HCC patients and 1031 control subjects from nine studies were included in this meta-analysis. The summary estimates for HSPs and AFP are as follows: sensitivity of 0.78 (95% CI: 0.69–0.85) compared to 0.73 (95% CI: 0.65–0.80); specificity of 0.89 (95% CI: 0.81–0.95) compared to 0.86 (95% CI: 0.77–0.91); PLR of 7.4 (95% CI: 3.7–14.9) compared to 5.1 (95% CI: 3.3–8.1); NLR of 0.24 (95% CI: 0.16–0.37) compared to 0.31 (95% CI: 0.24–0.41); DOR of 30.19 (95% CI: 10.68–85.37) compared to 16.34 (95% CI: 9.69–27.56); and AUC of 0.90 (95% CI: 0.87–0.92) compared to 0.85 (95% CI: 0.82–0.88). The pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.90 (95% CI: 0.82–0.95), 0.94 (95% CI: 0.82–0.98), 14.5 (95% CI: 4.6–45.4), 0.11 (95% CI: 0.06–0.20), 133.34 (95% CI: 29.65–599.61), and 0.96 (95% CI: 0.94–0.98) for the combination of HSPs and AFP.

Conclusion
Our analysis suggests that HSPs have potential as a biomarker for clinical use in the diagnosis of HCC, and the concurrent utilization of HSPs and AFP shows notable diagnostic effectiveness for HCC.