bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of aortic valve replacement in moderate aortic stenosis: a 10-year outcomes study
Authors: Hariri Essa H , Badwan Osamah , Kassab Joseph , Layoun Habib , Skoza Warren , Burton Robert , Harb Serge C , Puri Rishi , Reed Grant W , Krishnaswamy Amar , Svensson Lars G , Kapadia Samir
Published: May 2024

Objective

Patients with moderate aortic stenosis (AS) exhibit high morbidity and mortality. Limited evidence exists on the role of aortic valve replacement (AVR) in this patient population. To investigate the benefit of AVR in moderate AS on survival and left ventricular function.

Methods

In a retrospective cohort study, patients with moderate AS between 2008 and 2016 were selected from the Cleveland Clinic echocardiography database and followed until 2018. Patients were classified as receiving AVR or managed medically (clinical surveillance). All-cause and cardiovascular mortality were assessed by survival analyses. Temporal haemodynamic and structural changes were assessed with longitudinal analyses using linear mixed effects models.

Results

We included 1421 patients (mean age, 75.3±5.4 years and 39.9% women) followed over a median duration of 6 years. Patients in the AVR group had lower risk of all-cause (adjusted HR (aHR)=0.51, 95% CI: 0.34 to 0.77; p=0.001) and cardiovascular mortality (aHR=0.50, 95% CI: 0.31 to 0.80; p=0.004) compared with those in the clinical surveillance group irrespective of sex, receipt of other open-heart surgeries and underlying malignancy. These findings were seen only in those with preserved left ventricular ejection fraction (LVEF) ≥50%. Further, patients in the AVR group had a significant trend towards an increase in LVEF and a decrease in right ventricular systolic pressure compared with those in the clinical surveillance group.

Conclusions

In patients with moderate AS, AVR was associated with favourable clinical outcomes and left ventricular remodelling.
Acute pain management after vaginal delivery with perineal tears or episiotomy
Authors: Luxey Xavier , Lemoine Adrien , Dewinter Geertrui , Joshi Girish P , Le Ray Camille , Raeder Johan , Van de Velde Marc , Bonnet Marie-Pierre
Published: May 2024

Background

A vaginal delivery may be associated with acute postpartum pain, particularly after perineal trauma. However, pain management in this setting remains poorly explored.

Objective

The aim of this systematic review was to evaluate the literature and to develop recommendations for pain management after a vaginal delivery with perineal trauma.

Evidence review

MEDLINE, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) and systematic reviews assessing pain after a vaginal delivery with perineal tears or episiotomy until March 2023. Cochrane Covidence quality assessment generic tool and the RoB Vis 2 tool were used to grade the quality of evidence.

Findings

Overall, 79 studies (69 RCTs and 10 systematic reviews and meta-analyses) of good quality of evidence were included. Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line treatment. Epidural morphine (≤2 mg) is recommended among women with labor epidural analgesia and severe perineal tears, with adequate respiratory monitoring. Local anesthetic infiltration, topical local anesthetic, ointment application, and pudendal nerve block are not recommended due to insufficient or lack of evidence. Ice or chemical cold packs are recommended for postpartum pain first-line treatment due to their simplicity of use. Transcutaneous nerve stimulation and acupuncture are recommended as adjuvants. When a perineal suture is indicated, a continuous suture compared with an interrupted suture for the repair of episiotomy or second-degree perineal tears is recommended for the outcome of pain. For women with first-degree or second-degree perineal tears, no suturing or glue compared with suturing is recommended for the outcome of pain.

Conclusions

Postpartum pain management after a vaginal delivery with perineal trauma should include acetaminophen, NSAIDs, and ice or chemical cold packs. Epidural morphine should be reserved for severe perineal tears. A surgical repair technique should depend on perineal tear severity.
Shutdown dose rate experiment at JET during DTE2
Authors: Fonnesu N. , Loreti S. , Villari R. , Flammini D. , Mariano G. , Batistoni P. , Colangeli A. , Moro F. , Previti A. , Klix A. ,   JET Contributors
Published: May 2024

The EUROfusion activities on the technological exploitation of deuterium–tritium (DT) operation at JET (started within the work package JET3 and continued under PrIO) were established to maximize the scientific and technological return of DTE2 campaign occurred in the second part of 2021. In particular, the aim of the NEXP sub-project was to take advantage of the expected significant neutron production during DTE2 to validate the numerical tools used for neutron streaming and shutdown dose rate (SDR) calculation for ITER through the comparison between numerical predictions and measurements. In the frame of SDR activity, a dosimetry system to measure the dose rate and based on some ionization chambers (ICs) was installed in the torus hall and upgraded both hardware and software since 2015 by exploiting the previous DD and TT campaigns. Two spherical 1-L air-vented ICs had been installed in some ex-vessel positions close to the horizontal ports of the tokamak in octants 1 and 2 and a third IC, suitable for higher dose rates, was then added in octant 1. As for SDR calculation, numerical tools employed rely on MCNP code for radiation transport and in this regard the MCNP model has been updated to include the last detector installed in octant 1. The present work is dedicated to the analysis of dose rate measurements carried out during DTE2 in the inter-pulse periods and at the shutdown. Influence quantities and error sources are analyzed to calculate the dose rate from raw signal and experimental uncertainty. Some experimental points are chosen and employed for a preliminary comparison with numerical predictions obtained from three-dimensional simulations with Advanced D1S tool. The results are presented and discussed with the major objective to contribute to the optimization of the planned SDR code validation.
Holonomic swap and controlled-swap gates of neutral atoms via selective Rydberg pumping
Authors: Sun C. F. , Chen X. Y. , Mu W. L. , Wang G. C. , You J. B. , Shao X. Q.
Published: May 2024

Holonomic quantum computing offers a promising paradigm for quantum computation due to its error resistance and the ability to perform universal quantum computations. Here, we propose a scheme for the rapid implementation of a holonomic swap gate in neutral atomic systems, based on the selective Rydberg pumping mechanism. By employing time-dependent soft control, we effectively mitigate the impact of off-resonant terms even at higher driving intensities compared to time-independent driving. This approach accelerates the synthesis of logic gates and passively reduces the decoherence effects. Furthermore, by introducing an additional atom and applying the appropriate driving field, our scheme can be directly extended to implement a three-qubit controlled-swap gate. This advancement makes it a valuable tool for quantum state preparation, quantum switches, and a variational quantum algorithm in neutral atom systems.
Investigation for AGZO RRAM using the RF Co-sputtering method
Authors: Chang Sheng-Po , Tsai Yun-Chien , Chen Jone-Fang
Published: May 2024

Recently, the Internet of Things (IOT) has rapidly developed, leading to the development of many smart devices. Moreover, artificial intelligence (AI) and 5G communication are successful, and the demand for high-performance memory is increasing. The emerging nonvolatile RRAM has many advantages, such as low power consumption, fast operation speed, simple structure and excellent scalability, compared with traditional memories; this is promising for complex computing and mass storage. Zinc oxide (ZnO) is a promising candidate for transparent conducting oxide (TCO) applications because of its abundance, high conductivity, low toxicity, and cost-effectiveness. It is currently used in various optoelectronic components including thin-film transistors (TFTs) and photodetectors. Notably, TCO has been increasingly used in the switching layers of random resistive access memory systems. In this paper, we intend to combine AGO with a large energy gap and ZnO with a high conductivity to prepare AGZO as a switching layer for RRAM by co-sputtering. By adjusting the oxygen flow ratio and power of co-sputtering, the AGZO RRAM exhibited high performance with more than 1400 switching cycles, 102–103 on/off ratio, and low operation voltage, and high- and low-resistance states could be maintained for more than 10,000[Formula: see text]s.
First-principles investigation of the thermal properties of XO (X=Be, Mg and Sr) nanosheet
Authors: Abdullah Botan Jawdat , Azeez Yousif Hussein , Abdullah Nzar Rauf
Published: May 2024

The electronic structures and thermal properties of hexagonal XO ([Formula: see text], Mg and Sr) nanosheets are studied within the density functional theory. The thermal properties are computed using the specified structural parameters of the electronic properties. Thermal properties including entropy, enthalpy, free energy and heat capacity for XO nanosheets are reported. It is found that BeO is an insulator, whereas MgO and SrO are semiconductors based on the energy gap value within GGA and HSE06. The electronegativity and bonding nature of XO nanosheets differ, resulting in considerable variations in thermodynamic parameters that follow a similar pattern as a function of temperature. Enthalpy and entropy increase with temperature whereas free energy falls, owing to a change in the binary oxide internal energy of the system and the electron density distribution. Thermal energy absorbed by the lattices grows with increasing temperature to the point at which all of their modes are activated and the systems start to display unharmonicity deviating from a linear dependence. Variable parameter ranges for XO nanosheets are useful in the development of thermoelectric nanodevices.
Parents and Children: Distinguishing Multimodal Deepfakes from Natural Images
Authors: Amoroso Roberto , Morelli Davide , Cornia Marcella , Baraldi Lorenzo , Del Bimbo Alberto , Cucchiara Rita
Published: May 2024

Recent advancements in diffusion models have enabled the generation of realistic deepfakes from textual prompts in natural language. While these models have numerous benefits across various sectors, they have also raised concerns about the potential misuse of fake images and cast new pressures on fake image detection. In this work, we pioneer a systematic study on deepfake detection generated by state-of-the-art diffusion models. Firstly, we conduct a comprehensive analysis of the performance of contrastive and classification-based visual features, respectively, extracted from CLIP-based models and ResNet or Vision Transformer (ViT)-based architectures trained on image classification datasets. Our results demonstrate that fake images share common low-level cues, which render them easily recognizable. Further, we devise a multimodal setting wherein fake images are synthesized by different textual captions, which are used as seeds for a generator. Under this setting, we quantify the performance of fake detection strategies and introduce a contrastive-based disentangling method that lets us analyze the role of the semantics of textual descriptions and low-level perceptual cues. Finally, we release a new dataset, called COCOFake, containing about 1.2 million images generated from the original COCO image–caption pairs using two recent text-to-image diffusion models, namely Stable Diffusion v1.4 and v2.0.
Multi-institutional Protocol Guidance for Pediatric Photon-counting CT
Authors: Horst Kelly K. , Cao Joseph Y. , McCollough Cynthia H. , El-Ali Alex , Frush Donald P. , Siegel Marilyn J. , Ramirez-Giraldo Juan Carlos , O’Donnell Tom , Bache Steve , Yu Lifeng
Published: May 2024

This article addresses clinical challenges of photon-counting detector (PCD) CT in pediatric patients by outlining fundamental terminology, explaining technical aspects, and providing protocol guidance for the first commercially available PCD CT scanner.
Performance of Diffusion-weighted Imaging–based Noncontrast MRI Protocols for Diagnosis of Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Pötsch Nina , Sodano Claudia , Baltzer Pascal A. T.
Published: May 2024

Diffusion-weighted imaging–based noncontrast MRI protocols had high but variable sensitivity and specificity for breast cancer diagnosis, with modestly lower sensitivity at similar specificity compared with contrast-enhanced breast MRI.
Fear learning activated anterior basolateral amygdala neurons modulate anxiety behaviors
Authors: Hammack Robert , Daws Lynette , Toney Glenn
Published: May 2024

Traumatic events may result in development of neuropsychiatric disorders such as post-traumatic stress disorder (PTSD) with symptoms such as anxiety. While a clear connection between fear and anxiety is well established, the neuronal substrates mediating this relationship are understudied. In this study, we investigated the extent to which neurons in the anterior portion of the basolateral amygdala (aBLA), an area implicated in both fear and anxiety behavior, which are activated during fear learning, modulate anxiety-like behavior during testing in the elevated plus maze (EPM) or open field (OF). In TRAP2 transgenic mice, we permanently expressed the photoexcitatory effector channelrhodopsin or the photoinhibitory effector Jaws in aBLA neurons transcriptionally activated ( c-fos) during contextual fear learning (footshocks, fear-TRAP) or exploration of the conditioning chamber (no footshocks, context-TRAP). Three weeks later, we photoexcited or photoinhibited the fear and context-TRAPed mice during EPM or OF exploration. While photostimulation did not alter anxiety-like behavior during EPM or OF testing compared to dummy stimulation in context-TRAPed mice (n=6-10 mice/group, 8 groups), photoexcitation increased and photoinhibition decreased anxiety-like behaviors in fear-TRAPed mice (n=6-11 mice/group, 8 groups). Our results support a model in which fear learning-activated aBLA neurons are not only suffcient to exaggerate, but also contribute to, endogenous anxiety-like behaviors during exploration of novel environments. Thus, the fear learning-activated aBLA population may be a common substrate that couples fear learning to anxiety behaviors and therefore could play a vital role in development/maintenance of fear-related anxiety disorders.

MH093320 (LCD & GMT).

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.
Simulation of Conducted Responses in Microvascular Networks: Role of Current Rectification by Endothelial Cell Gap Junctions
Authors: Djurich Sara , Secomb Timothy
Published: May 2024

Neuronal activity in the brain stimulates local increases in blood flow. Such flow increases require dilation of feeding arterioles, which can be initiated by upstream conducted responses in the form of electrical currents transmitted along the endothelial lining of the vessels. One potential trigger for this response is hyperpolarization of capillary endothelial cells in active regions resulting from local elevation of extracellular K+ concentration. The conducted hyperpolarization causes arteriolar dilation. For this mechanism to be effective in delivering increased flow to a specific location, the conducted response must travel in the upstream direction only, without reentry into adjacent parallel flow pathways. Such specificity in the response to activation has been observed in skeletal muscle, and may result from partial rectification of current in gap junctions connecting adjacent endothelial cells. The goal of this work is to simulate the spread of hyperpolarizing currents along vessel walls in microvascular networks of the cerebral circulation, including the effects of rectification in gap junctions. A theoretical model was developed for the spread of electrical current in the endothelial cells of a network of microvessels in response to local K+- induced hyperpolarization. Transmembrane currents are represented in the model by a KIR-channel conductance, a non-voltage-dependent K+ conductance, and a background conductance. Currents along vessel walls are represented assuming asymmetric gap junction conductance between adjacent endothelial cells, with higher conductance for downstream currents (causing upstream hyperpolarization) than for upstream currents. The model was applied to a synthetic network of 45 segments, assuming 20 nS conductance for upstream propagation, while a range of values was used for downstream propagation. The model shows effective upstream propagation of conducted responses when the gap junction conductance for downstream propagation is 1 nS or less. This result was confirmed in a simulation of a reconstructed murine cerebral cortex network with 4881 segments. In conclusion, partial current rectification by endothelial gap junctions can result in preferential upstream propagation of conducted responses, consistent with experimental observations of local flow regulation.

Supported by NIH grant U01 HL133362.

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.
Increases of renal sodium transporters before and after the occurrence of the hypertension in spontaneously hypertensive rats
Authors: Xue Ying , Ren Zhiyun , Wang Ping , Liu Mingda , Wang Weiwan , Wang Xiaoyan
Published: May 2024

Background: Adult spontaneously hypertensive rats (SHR) have increases of renal sodium transporters associated with hypertension. It remains to be determined whether the increases of renal sodium transporters are precede by occurrence of hypertension and reflected by urine exosomal sodium transporters that may serve as non-invasive biomarkers for the effcacy of anti-hypertensive drugs. Methods: 1. Male WKY rats and SHRs were aged of 4, 7 and 10 weeks respectively (n=5/group). 2. Additional 3 sets of 10-week-old rat (n=5/group) were administered by a 7-day intraperitoneal injections of furosemide (NKCC2 inhibitor, 5mg/kg), hydrochlorothiazide (NCC2 inhibitor, 30mg/kg) and amiloride (ENaC inhibitor, 10mg/kg) respectively. 3. The systolic blood pressure (SBP) was measured with a catheter in carotid artery of rats under anesthesia. Tail-cuff methods were used to monitor the drug responses. 4. All rats were rationally fed 0.4% NaCl agar-gelled diet for 7 days. 5. Exosomes were extracted with ultracentrifuge from the urines. Results: SHRs (4 weeks) exhibited similar SBP. The renal NKCC2, the major apical sodium transporters in thick ascending limb, was more than doubled in SHRs (215±14 % of WKY, student t-test, p<0.05, same as below) while the other sodium transporters were normal. However, SHRs had a higher SBP than WKY at ages of 7 (157±10 vs 125±14, mmHg) and 10 weeks (192±8 vs 128±12). There were no differences for the all age groups in heart rate, body weight, urine volume, urine Na+ and Cl− excretion, and serum Cr, K+, Na+, and Cl− concentration between rat strains. At 10-weeks old, renal (161±24) and urine exosomal (159±21, corrected by UCr, same as below) NKCC2 were higher in SHR than WKY. Frusemide normalized SBP on day 1 (day 0: 190±18 vs 138±13; day 1: 149±13 vs 128±16) in SHR; Renal (129±9) and urine-exosomal (137±12) NCC were higher in SHR than WKY. Hydrochlorothiazide normalized SBP in SHR on day 1 (day 0: 206±4 vs 140±9; day 1: 159±11 vs 144±11). Renal (α:134±16; β:137±25) and urine-exosomal (α:153±13; β:158±12) ENaCs were higher in SHR than WKY. Amiloride diminished the difference in SBP between rat strains on day 1 (day 0: 188±18 vs 138±11; day 1: 164±16 vs 147±7). Conclusions: The increase of renal NKCC2 precedes the elevation of SBP in SHRs. Urine exosomal NKCC2, NCC, ENaCs may reflect their renal levels and be indicative of the corresponding inhibitors on the hypertension model.

Natural Science Foundation of China 81970605.

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.
Long-term intermittent fasting induces sex-dependent changes in small intestine from SAMP8 aged mice
Authors: Vroegop Spencer , Smith Nicholas , Sudler Sydney , Potter Ross , Shim Minsub , Broderick Tom , Aziz Ann-Marie
Published: May 2024

Background: Intermittent fasting (IF) is a popular and effective method to decrease body weight. Yet, the effects of IF on aged intestine is unknown. SAMP8 (Senescence Accelerated Mouse-Prone 8) mice are used as a model for studying aging. This study aimed to examine the potential for IF to ameliorate age-associated disturbances in murine jejunum. Methods: Two-month-old male and female SAMP8 mice were randomly assigned to either an IF protocol or an ad-libitum diet (AL) for the 8-month study (n=7-10 group). Fasted mice followed a 24-hour alternate day fasting protocol. At the end of the study mice were euthanized and jejunum stored at −80°C until use for western blot or other assay, and a segment was fixed for histology. Results: IF resulted in significantly less weight gain in both males (22% less, n=7-10, p<0.05) and females (33% less, n=7-8, p<0.05) and response to glucose load (glucose tolerance testing) was comparable in both sexes: area under curve for AL > IF. Interestingly, IF significantly reduced fasting serum glucose levels in males (30% less, n=6, p<0.05), but IF had no effect on fasting serum glucose in females. In jejunum, we assessed: protein expression, health, and morphology. In females, IF led to a 57% decrease in GLUT2 expression (n=5-6, p<0.05) versus AL. GLUT2 moves glucose/galactose and fructose out of the enterocyte into the blood, suggesting restructuring of monosaccharide transport due to IF. IF had no effect on jejunum GLUT5 or SGLT1 expression. Cleaved Caspase-3 expression was decreased by IF in both sexes versus AL. This reduction was greater in females, suggesting a sex-dependent protective role of IF against apoptosis. Moreover, IF induced a significant increase 1.4-fold (n=5=6, p<0.05) in jejunum superoxide dismutase (SOD) activity in both sexes. Jejunum morphology was significantly changed in females only: IF induced both a decrease in villi length (by 21%, n=4/group, p<0.05) and a decrease in wall thickness (by 7%, n=4/group, p<0.05). Conclusions: In both sexes, IF decreased body weight, yet in females resting glucose levels were unchanged by IF. In females, IF reduced monosaccharide absorption out of intestines, yet improved overall intestinal health, increasing antioxidant levels with SOD. These findings collectively highlight the complex effects of IF on cellular processes and demonstrate significant sex-dependent aged intestinal responses. Unraveling the underlying molecular mechanisms driving these sex-dependent IF-induced effects is currently under evaluation.

Midwestern-Arizona Alzheimer’s Consortium Grant, Midwestern University Intramural 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.
CD8 Cell PHD2 Deficiency Amplifies Pressure Overload-Induced Cardiac Inflammation through Metabolic Reprogramming of CD8 Cells
Authors: Pan Lihong , Bhattarai Umesh , He Xiaochen , Niu Ziru , Zeng Heng , Chen Jianxiong , Chen Yingjie
Published: May 2024

Prolyl hydroxylase domain (PHD) proteins function as oxygen sensors and regulate various cellular metabolism. PHD2 is well-known for its role in oxygen sensing and has been implicated in cardiac hypertrophy and fibrosis through HIF-2α. However, the specific impact and the mechanism of CD8 cell PHD2 deficiency on cardiac inflammation and heart failure (HF) development remains unclear. Here, we explored the role of CD8 cell-specific PHD2 deficiency (CD8-PHD2 KO) in HF development by using transverse aortic constriction (TAC) mouse model. Our findings reveal that CD8 PHD2 knockout exacerbated TAC-induced left ventricular (LV) hypertrophy, as evidenced by increased LV weight relative to bodyweight or tibial length. CD8-PHD2 KO also leads to a significant increase in lung and right ventricular weight relative to bodyweight or tibial length following TAC. Furthermore, CD8-PHD2 KO worsens TAC-induced reductions in LV ejection fraction, LV fractional shortening, and LV dilatation. Additionally, CD8-PHD2 KO exacerbates TAC-induced LV cardiomyocyte hypertrophy, fibrosis, and immune cell infiltration. Moreover, our study demonstrated that CD8-PHD2 KO amplified the infiltration and activation of antigen-presenting cells, CD4 T cells, and CD8 T cells in the heart and lungs after TAC. At the molecular level, we characterized the PHD2-deficient CD8 cells showed typical features of anaerobic glycolysis, which were paralleled by augmented hypoxia-inducible factor 1α (HIF-1α) protein levels. Collectively, these results highlight the critical role of PHD2 in CD8 cells in regulating cardiac inflammation and HF development in response to systolic overload.

National Institutes of Health Project Number 5R01HL161085-02.

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.
Urocortin 2 Gene Transfer in Mice Improves Diastolic Function in Heart Failure with Preserved Ejection Fraction
Authors: Lai N. Chin , Gao Mei Hua , Lai Yin Jie , Suarez Jorge , Hammond H. Kirk
Published: May 2024

Patients with heart failure and preserved ejection fraction (HFpEF) comprise about 50% of patients with heart failure in the US (>3 million people). There are currently no treatments for HFpEF that prolong life, and few that reduce HF hospitalization rates. The Schlager BPH (Blood Pressure-High) mouse is a genetic model of hypertension, a major contributing factor in left ventricular (LV) diastolic dysfunction and HFpEF. This study test the hypothesis that intravenous (i.v.) delivery of a long-term expression vector encoding murine urocortin 2 (AAV8.m Ucn2) can improve LV diastolic function in mice with impaired LV diastolic function. Twelve male and 12 female BPH mice (21.3±0.5 g; 3.1±0.1 months-old) with an ejection fraction (EF) of 60±2% (echocardiography) were studied. Prior to Ucn2 gene transfer their unsedated systolic/diastolic blood pressures (tail cuff) were (183/146±2/7 mmHg, n=24), conforming the presence of severe hypertension. The BPH mice were separated into two groups (6M & 6F in each group). One group (BPH + Ucn2) received AAV8.m Ucn2 (2x1013 gc/kg, i.v) and the other group (BPH) received saline, i.v. Seven weeks after randomization, LV EF showed a group difference (BPH: 54±2%, n=12; BPH+Ucn2: 74±2%, n=12; p<.0001) that was same as with systolic/diastolic blood pressure (BPH: 183/154±4/4 mmHg, n=12; BPH +Ucn2: 142/117±4/4 mmHg; p<0.0001). In addition, physiological studies conducted in vivo showed accelerated cardiac relaxation in the Ucn2-treated mice (see Tau in Table), indicating superior LV relaxation after Ucn2 gene transfer. Conclusion: Ucn2 gene transfer improves LV diastolic and systolic function in mice with HFpEF, indicating that such a strategy may be applicable in clinical settings.

[Formula: see text]

Merit grant from the Department of Veterans Affairs (I01 BX003774).

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.
Doxorubicin treatment reduces expression of cardiac iron transporters
Authors: Lapierre-Nguyen Stephanie , Morales Marianna , Doerr Vivian , Dowllah Imtiaz , Jacintho Moritz Cesar , Smuder Ashley
Published: May 2024

Doxorubicin (DOX) is an effective anticancer therapy. Unfortunately, the toxicity of DOX is not limited to cancerous cells, with the heart particularly prone to DOX-induced damage. While the mechanisms of DOX cardiotoxicity remain unclear, accumulation of iron within the heart may exacerbate the detrimental effects of DOX. Thus, understanding the effects of DOX on iron transport and storage protein expression would provide further insight on the mechanisms of disrupted iron handling and may lead to potential therapeutic targets for cardioprotection. Our goal was to investigate changes in gene expression of iron transporters in a preclinical model of DOX-induced cardiotoxicity. Female Sprague Dawley rats (2-3 month-old) were randomly divided to receive DOX or saline consistent with standard clinical treatment (i.e., intravenous infusion once every 3 weeks for 4 total cycles and a cumulative dose of ~160 mg/m2). One week following the fourth cycle measures of cardiac function, assessed by echocardiography, and cardiorespiratory capacity, determined by a graded exercise tolerance test, were completed. Cardiac tissue was also collected and cardiac mitochondria were isolated for measurement of reactive oxygen species production. At endpoint, DOX treatment resulted in a lower heart weight to tibia length ratio, reduced cardiorespiratory capacity, impaired ventricular fractional shortening and greater cardiac mitochondrial hydrogen peroxide emission. We found significant reductions in expression of transmembrane/cytoplasmic iron transporters (transferrin receptor 1 and divalent metal transporter 1) and the inner mitochondrial membrane transporter mitoferrin-2 with DOX treatment compared to saline. Expression of genes encoding for ferroportin-1, mitoferrin-1, ABCB8 and ferrochelatase were also downregulated in the DOX-treated group compared to saline, but these did not reach statistical significance. These findings are the first to describe changes in gene expression of proteins involved in iron homeostasis in a clinically relevant model of DOX-induced cardiotoxicity. Further studies are needed to investigate interventional approaches that improve cardiac iron handling to determine if they provide cardioprotection during DOX treatment.

This research was funded by the National Institute of Health (NIH), R01 HL144858.

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.
Eplerenone Reduces Blood Pressure and Improves Vascular Function in a Mouse Model of Leptin-induced Preeclampsia
Authors: Mellott Elisabeth , Moronge Desmond , Cooper Gibson , Ogbi Safia , Faulkner Jessica
Published: May 2024

Preeclampsia is a hypertensive pregnancy disease that increases the risks for adverse outcomes of pregnancy for both mother and baby, notably by reducing fetal growth in utero. We have shown that mid-late gestation leptin infusion induces preeclampsia characteristics in pregnant mice in inducing hypertension, endothelial dysfunction, and fetal growth restriction, which is ablated in mice with endothelial mineralocorticoid receptor deletion (ECMR). However, there is a lack of preclinical data and rationale for MR antagonism for use in preeclampsia in the existing literature. Therefore, we hypothesized that leptin increases ECMR expression and that MR antagonism decreases hypertension, endothelial dysfunction, and fetal growth restriction in leptin-induced preeclamptic mice. We infused timed-pregnant Balb/C mice with saline (sham) or leptin (LEP, 0.9 mg/kg/day) via s.c. osmotic minipump and administered vehicle or eplerenone (EPL, 200mg/kg/day) in drinking water from gestation day (GD)11-18 (n=7-12). We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in 2nd order mesenteric arteries by wire myography, and pup/placental weights on GD18. We isolated endothelial cells from placentas of our mice via magnetic cell sorting. Pairwise comparisons were by student’s t test and myography curves analyzed by 2-W ANOVA w/RM. Leptin increased ECMR mRNA expression (3.1±0.32 WT LEP vs 1.1±0.48 WT sham, fold change, *p<0.05) compared to WT sham mice in placenta indicating a direct role for leptin to upregulate ECMR in pregnancy. EPL ablated leptin-induced increases in BP (98±4 LEP/EPL vs 113±3 lep/veh mmHg, *p<0.05), and when treated with EPL leptin did not induce endothelial dysfunction, as assessed as a lack of decrease in vascular relaxation to acetylcholine (p>0.05 LEP/EPL vs sham/EPL). Interestingly, EPL treatment did not prevent leptin from decreasing placental effciency in pregnant mice (7.42±0.17 LEP/veh vs 6.71±0.15 LEP/EPL, pup/placenta weight ratio, p>0.05). Collectively, these data show that leptin infusion from GD11-18 in pregnant mice increases ECMR activation by increasing expression. Furthermore, MR antagonism by eplerenone ablates the maternal hypertension and endothelial dysfunction in leptin-induced preeclampsia mice, however, fetal growth is not restored by eplerenone. Therefore, eplerenone may be a promising therapeutic for the maternal cardiovascular syndrome of preeclampsia patients, however, MR antagonism therapies may need additional agents to improve fetal outcomes.

1R01HL169576, 4R00HL146948.

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.
Increase in Plasma S100B Concentration Is Associated With Decrements in Spatial Processing During Acute High-Altitude Exposure
Authors: Figueiredo Peter , Karl James Philip , Landspurg Steven , Femling Jon , Williams Jason , Buller Mark , Staab Janet
Published: May 2024

Vasogenic edema consequent to blood-brain barrier (BBB) permeability may contribute to cognitive performance decrements during acute exposure to high altitude. S100B is a putative marker of BBB permeability, but S100B responses to high altitude are poorly characterized and the relation to cognitive performance is unknown. To test the hypothesis that S100B increases upon ascent to high altitude and that increase is associated with changes in cognitive performance, 41 healthy Soldiers (mean±SD; age=26±5yr) were tested at their baseline residence (SL, 331m), transported to Taos, NM (2845m), then immediately hiked (n=21) or were driven (n=20) to a high-altitude (HA, 3600m) facility. Plasma S100B was measured at 06:00 throughout the study; twice at SL and again after the first night at HA (16h exposure). The automated neuropsychological assessment metric (ANAM) was administered four times at SL and once at HA to assess sustained attention, working memory, spatial processing, computation, executive function, and reaction time. ANAM performance was assessed using throughput scores, a metric considering both response speed and accuracy. The last SL morning assessment and the HA morning assessment (19h exposure) were used to generate ΔANAM scores. Correlations between ΔS100B and ΔANAM scores were significant for 1 of 9 modules, simultaneous spatial processing (SPD; r=-0.401; p=0.009). S100B increased (5.3%, p=0.02) from SL to HA while SPD scores decreased (8.2%, p=0.05). Using the reliable change index (RCI) to dichotomize individuals into those demonstrating a decrease in performance that exceeded measurement error and day-to-day variability (responders; RCI <-1.64; n=7) and those who did not (non-responders; RCI >-1.64; n=34) revealed that responders experienced a greater increase (+12.3%, p=0.01) in S100B from SL to HA relative to non-responders (+3.4%, p=0.14) Findings suggest that acute exposure to 3600m may increase BBB permeability, as indicated from plasma S100B concentrations, and the increased BBB permeability may be mechanistically associated with spatial processing decrements.

Funding: USAMRDC, PRMRP. Authors’ views not offcial U.S. Army or DoD policy.

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.
Galantamine Reduces Blood Pressure and Renal Injury in Female Angiotensin II-induced Hypertensive Mice
Authors: Chaudhari Sarika K. , Young-Stubbs Cassandra M. , Dinh Viet Q. , Mathis Keisa W.
Published: May 2024

Inflammation is a known culprit in the development and progression of hypertension. The autoimmune disease, systemic lupus erythematosus (SLE), is an important model of hypertension in the setting of chronic kidney inflammation. We have shown that administration of an acetylcholinesterase inhibitor, galantamine, attenuates the hypertension, kidney inflammation, and kidney injury in female SLE mice by activating the vagally-mediated cholinergic anti-inflammatory pathway. Although SLE hypertension represents a specific population of patients, we hypothesized that galantamine would have similar anti-inflammatory effects in the angiotensin II (AngII)-induced hypertensive mouse, which more commonly models essential hypertension. Female C57BL/6 mice were implanted with minipumps at 9 weeks of age for subcutaneous delivery of either AngII (1000 ng/kg/min) or saline (controls), and galantamine hydrobromide (4 mg/kg/day) or vehicle, for 21 days. At 12 weeks, carotid catheters were implanted and mean arterial pressure (MAP) was measured in conscious mice for two consecutive days. Mice were then euthanized, and kidneys collected. Markers of kidney inflammation and injury, including interleukin (IL)-6 and kidney injury molecule (KIM)-1, were measured by ELISA and normalized to total kidney protein. MAP (mmHg) was higher in AngII-treated mice compared to controls (174±4 vs. 133±3; n=4-5, p=0.0023). Galantamine lowered MAP in AngII mice (157±8; n=7, p=0.2567) without altering MAP in controls (133±4; n=5, p=0.9999). Renal IL-6 (pg/μg) was not different between AngII and control mice (0.004±0.0001 vs. 0.005±0.0006; p=0.6685). Although galantamine lowered IL-6 in both groups, it was only significant in controls (0.003±0.0002; p=0.0134) and not AngII mice (0.003±0.0003; p=0.4677). Renal cortical KIM-1 (pg/μg) trended higher in AngII mice compared to controls (2.53±0.50 vs 0.63±0.16; p=0.0741). Galantamine lowered KIM-1 in AngII mice (1.18±0.39, p=0.2064), but not controls (1.45 ± 0.59; p=0.6285). In summary, galantamine protected female mice from hypertension and renal injury in a model of AngII hypertension. This suggests that acetylcholinesterase inhibitor therapy may be effective in patients with hypertension.

Studies funded by NIH R01HL153703 and K01HL139859 for KWM.

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.
Evidence of Premature Vascular Dysfunction in Young Adults who Regularly Use E-cigarettes and the Impact of Usage Length
Authors: Simovic Tijana , Matheson Chloe , Heefner Allison , Colon Marisa , Tunon Enrique , Cobb Kolton , Thode Christopher
Published: May 2024

Background: Electronic (e-) cigarettes are increasingly popular novel tobacco products on the US market. Traditional tobacco products are well known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. Despite the popularity of e-cigarettes, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. Methods: Twenty-one regular users of e-cigarettes (ECU, age: 23±3 y.) and twenty-one demographically matched non-users (NU, age: 25±5 y.) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality as well as endothelium-dependent vasodilation (EDD) and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). Results: Our results suggest that regular users of e-cigarettes present with premature microvascular impairment compared to non-users. Specifically, they exhibit lower hyperemic ( p=0.003), thermal ( p=0.010), and EDD ( p=0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than three years also present with systemic manifestations, as observed by significantly reduced macrovascular ( p=0.002) and microvascular ( p≤0.044) function. Conclusions: Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than three years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes.

Supported in part by a Rapid Response Project NIDA/FDA (PRM).

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.
Does zinc deficiency promote renal inflammation?
Authors: Barrett Hannah , Rockwood Jananie , Wenegieme Tara-Yesomi , McMichael Kelia , Hasrat Khanzada , Waite Aston , Nshuti Adeline
Published: May 2024

Background: Renal inflammation is implicated in the pathogenesis of CKD and plays a critical role in kidney damage. CKD-associated tubular damage stimulates the secretion of proinflammatory cytokines (e.g. IL-1β, IL-6, and TNF-α) which expedite CKD progression, further instigating kidney damage and inflammation. Studies have shown that zinc deficiency (ZnD) elevates oxidative stress and affects proinflammatory cytokine abundance. Based on these findings, we hypothesize that ZnD will promote renal inflammation. Experimental Design: To examine if ZnD promotes renal inflammation, wild-type adult mice (C57BL/6J) were placed on a zinc-adequate (ZnA) or zinc-deficient (ZnD) diet for 10 weeks. At week 8, a subset of the ZnD mice were placed back on a ZnA diet (ZnR) for 2 weeks. The kidneys were harvested, embedded in paraffn, and both immunohistochemistry and immunofluorescence were performed to assess morphological changes and proinflammatory cytokine abundance. Results: Compared to ZnA kidneys, morphological changes were observed in ZnD kidneys, such as loss of endothelial cells in the glomerulus and abnormalities in nuclei arrangement in tubular cells. However, these changes were mitigated with the replenishment of zinc. There were no significant changes in TNF-α expression between the ZnA and ZnD kidneys, but there was decreased expression in the ZnR kidney. Conclusions: Based on preliminary findings, we can conclude that ZnD (1) promotes abnormalities in glomerular and tubular morphology and (2) does not have a significant impact on TNF-α expression in the renal cortex. Zinc repletion was shown to mitigate the glomerular and tubular abnormalities instigated by zinc deficiency. Significance: These findings provide evidence for Zn’s influence on renal inflammation, and advocate for zinc supplementation as a plausible therapeutic strategy for CKD.

Funding: R21 DK119879, R01 DK-133698.

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.
Age-associated impairment in swallow function is concomitant with nucleus ambiguus motor neuron death in Fischer 344 rats
Authors: Fogarty Matthew
Published: May 2024

The nucleus ambiguus contains motor neurons (MNs) innervating the muscles of the larynx, pharynx and oesophagus. Many of the motor units these muscles are comprised of are fast fatigueable units — highly vulnerable to neurodegeneration. Loss of the MNs or damage to the nerves innervating the muscles of the larynx, pharynx and oesophagus may impair swallow, vocalization and/or respiratory functions. Of particular importance, human patients with deficits in swallow are at risk of sequelae such as aspiration pneumonia and malnutrition. In aged male Fischer 344-Brown Norway crosses, age-associated loss of nucleus ambiguus MNs contributes to vocalisation deficits. Here, we use female and male Fischer 344 (F344) at young (6-months old) and old (24-months old) to evaluate swallow function and nucleus ambiguus MN survival. Swallow function was evaluated under anesthesia by delivering an 0.3 mL bolus of water to the base of the tongue and videoing the number of subsequent swallows. A pressure catheter was inserted into the oesophagus to evaluate the incidence and duration of wallow-associated apneas and the magnitude of the schluckatmung in 30 s following bolus delivery. Following functional evaluations, rats were euthanized, perfused with paraformaldehyde and brainstem tissue cryopreserved, sectioned and stained with Nissl to stereologically evaluate the number of nucleus ambiguus MNs. In old age, we observed an ~30% reduction in the number of swallows per delivery of the water bolus and an increased incidence and duration of swallow apnea. Schluckatmung was not affected by age. The number of nucleus ambiguus MNs was reduced by ~20% in old F344 rats, with MN size unaffected. We propose that swallow evaluations are a robust readout of oropharyngeal behaviour, with deficits concomitant with MN death. These findings are similar to age-associated weakness in other skeletal muscle being related to MN death. It is likely that the mechanisms underpinning fast fatigue motor unit MN death in brainstem and spinal pools are similar.

This research was funded by HL166204.

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.