Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats.

Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7-31.2) vs. 55.9 (51.0-64.5), STZ: 83.4 (53.7-91.7) vs. 121.2 (57.0-136.0) µL·min-1·kg-1, median (1st-3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8-18.4) vs. 10.5 (2.9-19.0), STZ: 36.9 (25.7-54.9) vs. 32.8 (15.1-37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA-AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.

Effects of bilateral renal denervation on open-loop baroreflex function and urine excretion in spontaneously hypertensive rats.

Bilateral renal denervation (RDN) decreases arterial pressure (AP) or delays the development of hypertension in spontaneously hypertensive rats (SHR), but whether bilateral RDN significantly modifies urine output function during baroreflex-mediated acute AP changes remains unknown. We quantified the relationship between AP and normalized urine flow (nUF) in SHR that underwent bilateral RDN (n = 9) and compared the results with those in sham-operated SHR (n = 9). Moreover, we examined the acute effect of an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) on the AP-nUF relationship. Bilateral RDN significantly decreased AP by narrowing the response range of the total arc of the carotid sinus baroreflex. The slopes of nUF versus the mean AP (in µL·min-1·kg-1·mmHg-1) in the sham and RDN groups under baseline conditions were 0.076 ± 0.045 and 0.188 ± 0.039, respectively; and those after telmisartan administration were 0.285 ± 0.034 and 0.416 ± 0.078, respectively. The effect of RDN on the nUF slope was marginally significant (P = 0.059), which may have improved the controllability of urine output in the RDN group. The effect of telmisartan on the nUF slope was significant (P < 0.001) in the sham and RDN groups, signifying the contribution of circulating or locally produced angiotensin II to determining urine output function regardless of ongoing renal sympathetic nerve activity.

Impact of right ventricular and pulmonary vascular characteristics on Impella hemodynamic support in biventricular heart failure: A simulation study.

BACKGROUND: Impella (Abiomed, Danvers, MA, USA) is a percutaneous ventricular assist device commonly used in cardiogenic shock, providing robust hemodynamic support, improving the systemic circulation, and relieving pulmonary congestion. Maintaining adequate left ventricular (LV) filling is essential for optimal hemodynamic support by Impella. This study aimed to investigate the impact of pulmonary vascular resistance (PVR) and right ventricular (RV) function on Impella-supported hemodynamics in severe biventricular failure using cardiovascular simulation. METHODS: We used Simulink® (Mathworks, Inc., Natick, MA, USA) for the simulation, incorporating pump performance of Impella CP determined using a mock circulatory loop. Both systemic and pulmonary circulation were modeled using a 5-element resistance-capacitance network. The four cardiac chambers were represented by time-varying elastance with unidirectional valves. In the scenario of severe LV dysfunction (LV end-systolic elastance set at a low level of 0.4 mmHg/mL), we compared the changes in right (RAP) and left atrial pressures (LAP), total systemic flow, and pressure-volume loop relationship at varying degrees of RV function, PVR, and Impella flow rate. RESULTS: The simulation results showed that under low PVR conditions, an increase in Impella flow rate slightly reduced RAP and LAP and increased total systemic flow, regardless of RV function. Under moderate RV dysfunction and high PVR conditions, an increase in Impella flow rate elevated RAP and excessively reduced LAP to induce LV suction, which limited the increase in total systemic flow. CONCLUSIONS: PVR is the primary determinant of stable and effective Impella hemodynamic support in patients with severe biventricular failure.

Predicting Workers' Stress: Application of a High-Performance Algorithm Using Working-Style Characteristics.

BACKGROUND: Work characteristics, such as teleworking rate, have been studied in relation to stress. However, the use of work-related data to improve a high-performance stress prediction model that suits an individual's lifestyle has not been evaluated. OBJECTIVE: This study aims to develop a novel, high-performance algorithm to predict an employee's stress among a group of employees with similar working characteristics. METHODS: This prospective observational study evaluated participants' responses to web­based questionnaires, including attendance records and data collected using a wearable device. Data spanning 12 weeks (between January 17, 2022, and April 10, 2022) were collected from 194 Shionogi Group employees. Participants wore the Fitbit Charge 4 wearable device, which collected data on daily sleep, activity, and heart rate. Daily work shift data included details of working hours. Weekly questionnaire responses included the K6 questionnaire for depression/anxiety, a behavioral questionnaire, and the number of days lunch was missed. The proposed prediction model used a neighborhood cluster (N=20) with working-style characteristics similar to those of the prediction target person. Data from the previous week predicted stress levels the following week. Three models were compared by selecting appropriate training data: (1) single model, (2) proposed method 1, and (3) proposed method 2. Shapley Additive Explanations (SHAP) were calculated for the top 10 extracted features from the Extreme Gradient Boosting (XGBoost) model to evaluate the amount and contribution direction categorized by teleworking rates (mean): low: <0.2 (more than 4 days/week in office), middle: 0.2 to <0.6 (2 to 4 days/week in office), and high: ≥0.6 (less than 2 days/week in office). RESULTS: Data from 190 participants were used, with a teleworking rate ranging from 0% to 79%. The area under the curve (AUC) of the proposed method 2 was 0.84 (true positive vs false positive: 0.77 vs 0.26). Among participants with low teleworking rates, most features extracted were related to sleep, followed by activity and work. Among participants with high teleworking rates, most features were related to activity, followed by sleep and work. SHAP analysis showed that for participants with high teleworking rates, skipping lunch, working more/less than scheduled, higher fluctuations in heart rate, and lower mean sleep duration contributed to stress. In participants with low teleworking rates, coming too early or late to work (before/after 9 AM), a higher/lower than mean heart rate, lower fluctuations in heart rate, and burning more/fewer calories than normal contributed to stress. CONCLUSIONS: Forming a neighborhood cluster with similar working styles based on teleworking rates and using it as training data improved the prediction performance. The validity of the neighborhood cluster approach is indicated by differences in the contributing features and their contribution directions among teleworking levels. TRIAL REGISTRATION: UMIN UMIN000046394; https://www.umin.ac.jp/ctr/index.htm.

Molecular dynamics simulations of head-on low-velocity collisions between particles.

The particle contact model is important for powder simulations. Although several contact models have been proposed, their validity has not yet been well established. Therefore, we perform molecular dynamics (MD) simulations to clarify the particle interaction. We simulate head-on collisions of two particles with impact velocities less than a few percent of the sound velocity to investigate the dependence of the interparticle force and the coefficient of restitution on the impact velocity and particle radius. In this study, we treat particles with a radius of 10-100 nm and perform simulations with up to 0.2 billion atoms. We find that the interparticle force exhibits hysteresis between the loading and unloading phases. Larger impact velocities result in strong hysteresis and plastic deformation. For all impact velocities and particle radii, the coefficient of restitution is smaller than that given by the Johnson-Kendall-Robert theory, which is a contact model that gives the force between elastic spherical particles. A contact model of inelastic particles cannot reproduce our MD simulations. In particular, the coefficient of restitution is significantly reduced when the impact velocity exceeds a certain value. This significant energy dissipation cannot be explained even by the contact models including plastic deformation. We also find that the coefficient of restitution increases with increasing particle radius. We also find that the previous contact models including plastic deformation cannot explain the strong energy dissipation obtained in our MD simulations, although they agree with the MD results for very low impact velocities. Accordingly, we have constructed a new dissipative contact model in which the dissipative force increases with the stress generated by collisions. The new stress-dependent model successfully reproduces our MD results over a wider range of impact velocities than the conventional models do. In addition, we proposed another, simpler, dissipative contact model that can also reproduce the MD results.

Novel closed-loop control system of dual rotary blood pumps in total artificial heart based on the circulatory equilibrium framework: a proof-of-concept in vivo study.

OBJECTIVE: Total artificial heart (TAH) using dual rotary blood pumps (RBPs) is a potential treatment for end-stage heart failure. A well-noted challenge with RBPs is their low sensitivity to preload, which can lead to venous congestion and ventricular suction. To address this issue, we have developed an innovative closed-loop control system of dual RBPs in TAH. This system emulates the Frank-Starling law of the heart in controlling RBPs while monitoring stressed blood volume (V) based on the circulatory equilibrium framework. We validated the system in in-vivo experiments. METHODS: In 9 anesthetized dogs, we prepared a TAH circuit using 2 centrifugal-type RBPs. We first investigated whether the flow and inlet atrial pressure in each RBP adhered to a logarithmic Frank-Starling curve. We then examined whether the RBP flows and atrial pressures were maintained stably during aortic occlusion (AO) and pulmonary cannula stenosis (PS), whether averaged flow of dual RBPs and bilateral atrial pressures were controlled to their predefined target values for a specific V, and whether this system could maintain the atrial pressures within predefined control ranges under significant changes in V. RESULTS: This system effectively emulated the logarithmic Frank-Starling curve. It robustly stabilized the flow and atrial pressures during AO and PS without venous congestion or ventricular suction, accurately achieved target values in averaged flow and atrial pressures, and efficaciously maintained these pressures within the control ranges. CONCLUSION: This system controls dual RBPs in TAH accurately and stably. SIGNIFICANCE: This system may accelerate clinical application of TAH with dual RBPs.

EGFR-TKI-induced Factor V deficiency in a patient with advanced non-small cell lung cancer: The first case report.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is routinely prescribed as first-line therapy for advanced non-small cell lung cancer, regardless of the presence of the T790M resistance mutation. This study reports a rare case of Factor V inhibitor detection during osimertinib therapy in a patient with lung adenocarcinoma. These findings underscore the importance of vigilant monitoring for coagulation abnormalities during EGFR-TKI therapy.

Verification of acromion marker cluster and scapula spinal marker cluster methods for tracking shoulder kinematics: a comparative study with upright four-dimensional computed tomography.

BACKGROUND: This study validated the accuracy of the acromion marker cluster (AMC) and scapula spinal marker cluster (SSMC) methods compared with upright four-dimensional computed tomography (4DCT) analysis. METHODS: Sixteen shoulders of eight healthy males underwent AMC and SSMC assessments. Active shoulder elevation was tracked using upright 4DCT and optical motion capture system. The scapulothoracic and glenohumeral rotation angles calculated from AMC and SSMC were compared with 4DCT. Additionally, the motion of these marker clusters on the skin with shoulder elevation was evaluated. RESULTS: The average differences between AMC and 4DCT during 10°-140° of humerothoracic elevation were - 2.2° ± 7.5° in scapulothoracic upward rotation, 14.0° ± 7.4° in internal rotation, 6.5° ± 7.5° in posterior tilting, 3.7° ± 8.1° in glenohumeral elevation, - 8.3° ± 10.7° in external rotation, and - 8.6° ± 8.9° in anterior plane of elevation. The difference between AMC and 4DCT was significant at 120° of humerothoracic elevation in scapulothoracic upward rotation, 50° in internal rotation, 90° in posterior tilting, 120° in glenohumeral elevation, 100° in external rotation, and 100° in anterior plane of elevation. However, the average differences between SSMC and 4DCT were - 7.5 ± 7.7° in scapulothoracic upward rotation, 2.0° ± 7.0° in internal rotation, 2.3° ± 7.2° in posterior tilting, 8.8° ± 7.9° in glenohumeral elevation, 2.0° ± 9.1° in external rotation, and 1.9° ± 10.1° in anterior plane of elevation. The difference between SSMC and 4DCT was significant at 50° of humerothoracic elevation in scapulothoracic upward rotation and 60° in glenohumeral elevation, with no significant differences observed in other rotations. Skin motion was significantly smaller in AMC (28.7 ± 4.0 mm) than SSMC (38.6 ± 5.8 mm). Although there was smaller skin motion in AMC, SSMC exhibited smaller differences in scapulothoracic internal rotation, posterior tilting, glenohumeral external rotation, and anterior plane of elevation compared to 4DCT. CONCLUSION: This study demonstrates that AMC is more accurate for assessing scapulothoracic upward rotation and glenohumeral elevation, while SSMC is preferable for evaluating scapulothoracic internal rotation, posterior tilting, glenohumeral external rotation, and anterior plane of elevation, with smaller differences compared to 4DCT.

2'-ß-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3'-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2'-ß-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3'-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3'-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.

Comparative study on muscle function in two different streptozotocin-induced diabetic models.

AIMS: Streptozotocin (STZ) is widely used to study diabetic complications. Owing to the nonspecific cytotoxicity of high-dose STZ, alternative models using moderate-dose or a combination of low-dose STZ and a high-fat diet have been established. This study aimed to investigate the effects of these models on muscle function. METHODS: The muscle function of two STZ models using moderate-dose STZ (100 mg/kg, twice) and a combination of low-dose STZ and high-fat diet (50 mg/kg for 5 consecutive days + 45% high-fat diet) were examined using in vivo electrical stimulation. Biochemical and gene expression analysis were conducted on the skeletal muscles of the models immediately after the stimulation. RESULTS: The contractile force did not differ significantly between the models compared to respective controls. However, the moderate-dose STZ model showed more severe fatigue and blunted exercise-induced glycogen degradation possibly thorough a downregulation of oxidative phosphorylation- and vasculature development-related genes expression. CONCLUSIONS: Moderate-dose STZ model is suitable for fatigability assessment in diabetes and careful understanding on the molecular signatures of each model is necessary to guide the selection of suitable models to study diabetic myopathy.

Computer-controlled closed-loop norepinephrine infusion system for automated control of mean arterial pressure in dogs under isoflurane-induced hypotension: a feasibility study.

Introduction: Intra-operative hypotension is a common complication of surgery under general anesthesia in dogs and humans. Computer-controlled closed-loop infusion systems of norepinephrine (NE) have been developed and clinically applied for automated optimization of arterial pressure (AP) and prevention of intra-operative hypotension in humans. This study aimed to develop a simple computer-controlled closed-loop infusion system of NE for the automated control of the mean arterial pressure (MAP) in dogs with isoflurane-induced hypotension and to validate the control of MAP by the developed system. Methods: NE was administered via the cephalic vein, whereas MAP was measured invasively by placing a catheter in the dorsal pedal artery. The proportional-integral-derivative (PID) controller in the negative feedback loop of the developed system titrated the infusion rate of NE to maintain the MAP at the target value of 60 mmHg. The titration was updated every 2 s. The performance of the developed system was evaluated in six laboratory Beagle dogs under general anesthesia with isoflurane. Results: In the six dogs, when the concentration [median (interquartile range)] of inhaled isoflurane was increased from 1.5 (1.5-1.5)% to 4 (4-4)% without activating the system, the MAP was lowered from 95 (91-99) to 41 (37-42) mmHg. In contrast, when the concentration was increased from 1.5 (1.0-1.5)% to 4 (4-4.8)% for a 30-min period and the system was simultaneously activated, the MAP was temporarily lowered from 92 (89-95) to 47 (43-49) mmHg but recovered to 58 (57-58) mmHg owing to the system-controlled infusion of NE. If the acceptable target range for MAP was defined as target MAP ±5 mmHg (55 ≤ MAP ≤65 mmHg), the percentage of time wherein the MAP was maintained within the acceptable range was 96 (89-100)% in the six dogs during the second half of the 30-min period (from 15 to 30 min after system activation). The median performance error, median absolute performance error, wobble, and divergence were - 2.9 (-4.7 to 1.9)%, 2.9 (2.0-4.7)%, 1.3 (0.8-1.8)%, and - 0.24 (-0.34 to -0.11)%·min-1, respectively. No adverse events were observed during the study period, and all dogs were extubated uneventfully. Conclusion: This system was able to titrate the NE infusion rates in an accurate and stable manner to maintain the MAP within the predetermined target range in dogs with isoflurane-induced hypotension. This system can be a potential tool in daily clinical practice for the care of companion dogs.

Transcriptome analysis of the tardigrade Hypsibius exemplaris exposed to the DNA-damaging agent bleomycin.

Tardigrades are microscopic animals that are renowned for their capabilities of tolerating near-complete desiccation by entering an ametabolic state called anhydrobiosis. However, many species also show high tolerance against radiation in the active state as well, suggesting cross-tolerance via the anhydrobiosis mechanism. Previous studies utilized indirect DNA damaging agents to identify core components of the cross-tolerance machinery in species with high anhydrobiosis capacities. However, it was difficult to distinguish whether transcriptomic changes were specific to DNA damage or mutual with anhydrobiosis. To this end, we performed transcriptome analysis on bleomycin-exposed Hypsibius exemplaris. We observed induction of several tardigrade-specific gene families, including a previously identified novel anti-oxidative stress family, which may be a core component of the cross-tolerance mechanism. We also identified enrichment of the tryptophan metabolism pathway, for which metabolomic analysis suggested engagement of this pathway in stress tolerance. These results provide several candidates for the core component of cross-tolerance, as well as possible anhydrobiosis machinery.

Real-World Effectiveness of Ensitrelvir in Reducing Severe Outcomes in Outpatients at High Risk for COVID-19.

INTRODUCTION: This study aimed to evaluate the effectiveness of ensitrelvir, an oral antiviral, in reducing hospitalization risk in outpatients at high-risk for severe COVID-19 during the Omicron era. METHODS: This was a retrospective study using a large Japanese health insurance claims database. It included high-risk outpatients for severe symptoms who received their first COVID-19 diagnosis between November 2022 and July 2023. The study included outpatients aged ≥ 18 years. The primary endpoint was all-cause hospitalization during the 4-week period from the date of outpatient diagnosis and medication, comparing the ensitrelvir group (n = 5177) and the no antiviral treatment group (n = 162,133). The risk ratio and risk difference were evaluated after adjusting patient background distribution by the inverse probability of treatment weight (IPTW) method. Secondary endpoints were incidence of respiratory and heart rate monitoring, oxygen therapy, ventilator use, intensive care admission, and all-cause death. RESULTS: The risk ratio for all-cause hospitalization between the ensitrelvir group (n = 167,385) and the no antiviral treatment group (n = 167,310) after IPTW adjustment was 0.629 [95% confidence interval (CI) 0.420, 0.943]. The risk difference was - 0.291 [95% CI - 0.494, - 0.088]. The incidence of both respiratory and heart rate monitoring and oxygen therapy was lower in the ensitrelvir group. Ventilator use, intensive care admission, and all-cause death were difficult to assess because of the limited events. CONCLUSIONS: The incidence of all-cause hospitalization was significantly lower in the ensitrelvir group than in the no antiviral treatment group, suggesting ensitrelvir is an effective treatment in patients at risk of severe COVID-19.

COVID-19 still poses a risk for patients with serious health conditions and weakened immune systems, who are more likely to develop severe illness. Several studies have indicated that some oral antiviral medications might be effective in preventing severe disease. This study aimed to evaluate if ensitrelvir, an oral antiviral medication, can help prevent hospitalization in outpatients who are at risk of developing severe symptoms from the Omicron variant of the SARS-CoV-2 virus. The hospitalization rates of patients who received ensitrelvir was compared with those who did not receive any antiviral treatment, using medical records from a large health insurance database in Japan focused on outpatients who were at risk of severe symptoms and were diagnosed with COVID-19 between November 2022 and July 2023. Respiratory and heart rate monitoring, oxygen therapy, ventilator use, intensive care admission, and all-cause death were also evaluated. The study found that patients who received ensitrelvir had a lower risk of being hospitalized compared to those who did not receive any antiviral treatment. The ensitrelvir group also had lower rates of respiratory and heart rate monitoring and oxygen therapy. However, it was challenging to assess the effects on ventilator use, intensive care admission, and all-cause death due to the small number of events in the population under evaluation. Based on these findings, ensitrelvir appears to be an effective treatment for reducing the risk of hospitalization in patients at risk of severe COVID-19.

Sexual dimorphism in the tardigrade Paramacrobiotus metropolitanus transcriptome.

BACKGROUND: In gonochoristic animals, the sex determination pathway induces different morphological and behavioral features that can be observed between sexes, a condition known as sexual dimorphism. While many components of this sex differentiation cascade show high levels of diversity, factors such as the Doublesex-Mab-3-Related Transcription factor (DMRT) are widely conserved across animal taxa. Species of the phylum Tardigrada exhibit remarkable diversity in morphology and behavior between sexes, suggesting a pathway regulating this dimorphism. Despite the wealth of genomic and zoological knowledge accumulated in recent studies, the sexual differences in tardigrades genomes have not been identified. In the present study, we focused on the gonochoristic species Paramacrobiotus metropolitanus and employed omics analyses to unravel the molecular basis of sexual dimorphism. RESULTS: Transcriptome analysis between sex-identified specimens revealed numerous differentially expressed genes, of which approximately 2,000 male-biased genes were focused on 29 non-male-specific genomic loci. From these regions, we identified two Macrobiotidae family specific DMRT paralogs, which were significantly upregulated in males and lacked sex specific splicing variants. Furthermore, phylogenetic analysis indicated all tardigrade genomes lack the doublesex ortholog, suggesting doublesex emerged after the divergence of Tardigrada. In contrast to sex-specific expression, no evidence of genomic differences between the sexes was found. We also identified several anhydrobiosis genes that exhibit sex-biased expression, suggesting a possible mechanism for protection of sex-specific tissues against extreme stress. CONCLUSIONS: This study provides a comprehensive analysis for analyzing the genetic differences between sexes in tardigrades. The existence of male-biased, but not male-specific, genomic loci and identification of the family specific male-biased DMRT subfamily provides the foundation for understanding the sex determination cascade. In addition, sex-biased expression of several tardigrade-specific genes which are involved their stress tolerance suggests a potential role in protecting sex-specific tissue and gametes.

The Inhibition of TREK-1 K+ Channels via Multiple Compounds Contained in the Six Kamikihito Components, Potentially Stimulating Oxytocin Neuron Pathways.

Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.

Effects of nitric oxide inhalation on pulmonary arterial impedance: differences between normal and pulmonary hypertension male rats.

Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.

Proposal for structure revision of pinofuranoxin A through total syntheses of stereoisomers.

The relative configuration of the epoxide functionality in pinofuranoxin A (1), α-alkylidene-ß-hydroxy-γ-methyl-γ-butyrolactone with trans-epoxy side chain isolated by Evidente et al. in 2021, was revised by DFT-based spectral reinvestigations and stereo-controlled synthesis. The present investigation demonstrates the difficulty of the configurational elucidation of the stereogenic centers on the conformationally flexible acyclic side-chains. Sharpless's enantioselective epoxidations and dihydroxylations were quite effective in the reinvestigations of the configurations. As our syntheses made all diastereomers available, these would be quite effective in the next structure-biological activity relationship studies.

CHARGE syndrome with both primary and secondary hypogonadism.

Introduction: CHARGE syndrome is a rare disorder that causes congenital abnormalities in multiple organs, including secondary hypogonadism. We report, herein, a unique case of CHARGE syndrome with both primary and secondary hypogonadism and discuss the possible causes and pathogenesis in this patient. Case presentation: A 15-year-old boy with delayed secondary sexual characteristics and non-palpable testes was referred to our hospital. Physical examination and detection of a chromodomain-helicase-deoxyribonucleic acid-binding protein 7 gene mutation confirmed CHARGE syndrome. Hormone stimulation tests suggested both primary and secondary hypogonadism. Laparoscopic bilateral orchiectomy was performed because of decreased testosterone production and atrophy in both testes. Pathological examination of the testes revealed maturation arrest, germ cell neoplasm in situ, and decreased expression of steroid synthase. Conclusion: This appears to be the first report of CHARGE syndrome with both primary and secondary hypogonadism demonstrated in endocrinological and histological examinations.

Association of IL-33 in modeling type-2 airway inflammation and pulmonary emphysema in mice.

We developed pulmonary emphysema and a type 2 airway inflammation overlap mouse model. The bronchoalveolar lavage (BAL) interleukin 13 (IL-13), IL-4, and IL-5 levels in the overlap model were higher than in the pulmonary emphysema model and lower than in the type 2 airway inflammation model, but IL-33 level in the lung was higher than in other models. IL-33 and interferon-γ (IFNγ) in lungs may control the severity of a type 2 airway inflammation in lung.