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Manipulating topological states by coupled electronic orders is promising for future dissipation-less electronic devices. Here, Mitsuishi et al. report selective vanishing of Dirac-type topological surface states by the formation of coupled charge density wave in a transition-metal dichalcogenide VTe2.

Abstract High-temperature superconductivity in iron-pnictides/chalcogenides arises in balance with several electronic and lattice instabilities. Beside the antiferromagnetic order, the orbital anisotropy between Fe 3d xz and 3d yz occurs near the orthorhombic structural transition in several parent compounds. However, the extent of the survival of orbital anisotropy against the ion-substitution remains to be established. Here we report the composition (x) and temperature (T) dependences of the orbital anisotropy in the electronic structure of a BaFe2(As1−x P x )2 system by using angle-resolved photoemission spectroscopy. In the low-x regime, the orbital anisotropy starts to evolve on cooling from high temperatures above both antiferromagnetic and orthorhombic transitions. By increasing x, it is gradually suppressed and survives in the optimally doped regime. We find that the in-plane orbital anisotropy persists in a large area of the nonmagnetic phase, including the superconducting dome. These results suggest that the rotational symmetry-broken electronic state acts as the stage for superconductivity in BaFe2(As1−x P x )2.

The back bombardment (BB) effect limits wide usage of thermionic rf guns. The BB effect induces not only ramping-up of a cathode’s temperature and beam current, but also degradation of cavity voltage and beam energy during a macropulse. This paper presents a comparison of the BB effect for the case of dispenser tungsten-base (DC) and lanthanum hexaboride (LaB_{6}) thermionic rf gun cathodes. For each, particle simulation codes are used to simulate the BB effect and electron beam dynamics in a thermionic rf gun cathode. A semiempirical equation is also used to investigate the stopping range and deposited heat power of BB electrons in the cathode material. A numerical simulation method is used to calculate the change of the cathode temperature and current density during a single macropulse. This is done by solving two differential equations for the rf gun cavity equivalent circuit and one-dimensional thermal diffusion equation. High electron emission and small beam size are required for generation of a high-brightness electron beam, and so in this work the emission properties of the cathode are taken into account. Simulations of the BB effect show that, for a pulse of 6 μs duration, the DC cathode experiences a large change in the temperature compared with LaB_{6}, and a change in current density 6 times higher. Validation of the simulation results is performed using experimental data for beam current beyond the gun exit. The experimental data is well reproduced using the simulation method.

Background: Locomotive syndrome (LS) presents symptoms related to decreased mobility due to musculoskeletal disorders. Knee osteoarthritis (KOA) is a significant public health concern linked to age-related musculoskeletal issues and is among the conditions contributing to LS. Age-related lower extremity muscle weakness exacerbates knee pain in KOA, but the impact of LS on knee pain is not clear, prompting the present investigation., Methods: We conducted a cross-sectional study of 76 participants (152 knee joints) with bilateral severe KOA scheduled for total knee arthroplasty. The study investigated the association between the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale and LS using a multiple linear regression model, which included covariates and scaled estimated regression coefficients., Results: LS had a negative impact on KOOS pain (β: 0.35, 95 % confidence interval [CI]: 24.08; -6.05) (p < 0.05) and high self-efficacy had a positive impact (β: 0.25, 95%CI: 1.27; 16.34) (p < 0.05). Age, gender, BMI, Kellgren-Lawrence grade, and Central Sensitization did not influence KOOS pain., Conclusions: Our findings demonstrate that LS negatively affected knee pain while self-efficacy positively affected it. LS has been attracting attention in relation to mobility, but the fact that it also affected the knee pain in severe KOA is an important clinical finding. Further research is required to focus on the relationship between the prevention and improvement of LS, and knee pain in severe KOA., Competing Interests: Declaration of competing interest Tatsuru Sonobe, Takuya Nikaido, Miho Sekiguchi, Yoichi Kaneuchi, Tadashi Kikuchi, and Yoshihiro Matsumoto declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Decreased physical function with increasing life expectancy is a public health concern worldwide. Knee osteoarthritis (KOA) is considered one of the primary illnesses causing decreased physical function. Depression affects decreased physical function and is closely related to knee pain in KOA. However, the effect of these interacting factors on physical function is not clear., Patients and Methods: We conducted a cross-sectional analysis of the baseline data of 1106 subjects of the 2009 Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS). We determined the association between their Timed Up and Go test (TUG) scores and radiographic KOA, knee pain, and depression in a multivariate analysis., Results: Severe knee pain was significantly associated with decreased physical function (the odds ratio [OR] was 2.13, 95% confidence interval [CI]: 1.32-4.89), as was depression (OR 2.64, 95% CI 1.61-4.33). Only Kellgren-Lawrence (KL) grade 4 was significantly associated with decreased physical function in the radiographic KOA severity (OR 6.58, 95% CI 1.75-24.68)., Conclusion: Severe knee pain and depression were significantly associated with decreased physical function, but not radiographic KOA severity except for KL grade 4. The limitations of using radiographic KOA severity alone as the indicator of assessment for physical function were suggested. When assessing decreased physical function, the clinical focus tends to be on radiographic KOA severity, but it is important to consider the patient's knee pain and psychological factors., Competing Interests: The author reports no conflicts of interest in this work. This paper has a shared database with another paper published in BMC at: https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-024-07421-1. This paper has been uploaded to Research Square as a preprint: https://www.researchsquare.com/article/rs-4010731/v1., (© 2024 Sonobe et al.)

Introduction and Importance: Meniscotibial ligament (MTL) has received attention as a major meniscus stabilizer. An MTL injury results in instability and extrusion of the meniscus. Cases of knee ganglion cyst formation due to an MTL tear and medial meniscus extrusion (ME) are extremely rare., Case Presentation: A 42-year-old female Japanese childcare worker presented painful ganglion cysts on the proximal medial side of her left tibia. An MTL tear and medial ME were thought to be involved in the ganglion formation. Joint fluid flowed through the meniscotibial side of the extruded meniscus into the space between the medial collateral ligament and tibia, where the MTL tear acted as a check valve, forming ganglion cysts. Ultrasonography-guided aspiration of the ganglion was attempted, but ganglion cysts recurred within 1 month. We used an open excision for the ganglion cysts, and arthroscopic capsulodesis was performed to repair the MTL and internalize the medial meniscus to block the inflow route from the intra-articular space., Clinical Discussion: We performed capsulodesis, which repaired the MTL and internalized the medial meniscus to prevent the recurrence of the ganglion cyst. Three months have passed since the surgery, with no recurrence of knee pain or ganglion cysts, indicating good short-term results., Conclusions: We encountered a rare case of ganglion cyst formation in the knee joint due to MTL tear and medial ME. Arthroscopic MTL repair and internalization of the meniscus by capsulodesis were effective in treating the ganglion cysts., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An ankle dislocation without an accompanying fracture is extremely rare, and an open ankle dislocation is even rarer. Due to its rarity, there is no consensus on the optimal treatment strategy. A professional basketball player (a 28-year-old male) incurred an open ankle dislocation (with no accompanying fracture) during a basketball game due to plantar flexion and inversion of his ankle during the transition from dashing to stop motion. The same day, an emergency reduction under spinal anesthesia was performed with primary closure of the wound. Considering the complications of infection and decreased ankle range of motion (ROM), primary ligament repair was not performed. He was treated conservatively with cast immobilization for four weeks, and early weight-bearing and ROM exercises were initiated. At six weeks postoperatively, stress radiography did not reveal ankle instability. After three months of conservative treatment, the patient was able to play basketball at his previous performance level. Four weeks of cast immobilization without ligament repair plus early rehabilitation with weight-bearing and ROM exercises allowed for an early return without complications. Even in high-level athletes, open ankle dislocation without an accompanying fracture can be treated adequately with conservative therapy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sonobe et al.)

Dietary diversity among children is a crucial factor influencing their nutritional status; therefore, this paper uses data from four rounds of the Cambodia Demographic and Health Survey (CDHS) to examine the minimum dietary diversity among children aged 6-23 months. Multilevel binary regression is used to evaluate the variation in minimum dietary diversity at the cluster and province levels. The results show that nearly half of Cambodian children consistently lacked access to vitamin A-rich fruits and vegetables. Although the prevalence of inadequate minimum dietary diversity (MDD) among children significantly dropped from 76% in 2005 to 51% in 2021-2022, it is still high and needs attention. A decomposition analysis (Blinder-Oaxaca decomposition) was further used to understand the drivers of this temporal change in dietary diversity. The empirical results show that clusters represented the most significant source of geographic variation with respect to all eight food groups and MDD. Nutritional policy should improve education and awareness, reduce socio-economic disparities, leverage media, and promote full antenatal care to improve dietary diversity in Cambodia. Initiatives targeting the enhancement of insufficient minimum dietary diversity intake should encompass individual aspects and be customized to suit geographic and community settings., (© 2024. The Author(s).)

Eelgrass meadows have attracted much attention not only for their ability to maintain marine ecosystems as feeding grounds for marine organisms but also for their potential to store atmospheric and dissolved CO 2 as blue carbon. This study comprehensively evaluated the bacterial and chemical data obtained from eelgrass sediments of different scales along the Japanese coast to investigate the effect on the acclimatization of eelgrass. Regardless of the eelgrass habitat, approximately 1% Anaerolineales , Babeliales , Cytophagales , and Phycisphaerales was present in the bottom sediment. Sulfate-reducing bacteria (SRB) were present at 3.69% in eelgrass sediment compared to 1.70% in bare sediment. Sulfur-oxidizing bacteria (SOB) were present at 2.81% and 1.10% in the eelgrass and bare sediment, respectively. Bacterial composition analysis and linear discriminant analysis revealed that SOB detoxified H 2 S in the eelgrass meadows and that the larger-scale eelgrass meadows had a higher diversity of SOB. Our result indicated that there were regional differences in the system that detoxifies H 2 S in eelgrass meadows, either microbial oxidation mediated by SOB or O 2 permeation via the physical diffusion of benthos. However, since bacterial flora and phylogenetic analyses cannot show bias and/or causality due to PCR, future kinetic studies on microbial metabolism are expected.

Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca 2+ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca 2+ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Sonobe and Kakinuma.)

Background: To investigate factors that have an impact on the risk of falls and determine whether radiographic knee osteoarthritis (KOA) is a factor involved in falls independent of knee pain, psychological factors, and physical function., Methods: A cross-sectional analysis was conducted on 1083 subjects for the 2009 Locomotive Syndrome and Health Outcomes in the Aizu Cohort Study (LOHAS). A logistic regression analysis was performed to examine the relationship between radiographic KOA and fall history., Results: Fall history was significantly associated with the severity of knee pain. Compared to subjects with no knee pain, the odds ratio (OR) was 1.53 times higher in the subjects with mild knee pain (95% confidence interval [CI]: 1.04-2.25), 1.69 times higher in those with moderate knee pain (95%CI: 1.03-2.79), and 2.98 times higher in those with severe knee pain (95%CI: 1.67-5.30). In subjects with depression, the OR was 1.91 (95%CI: 1.25-2.92), and in those with decreased mobility, the OR was 1.70 (95%CI: 1.08-2.69). Age, gender, knee crepitus, BMI, OLST, and sleeping pill use were not significantly associated with fall risk. In a multivariate analysis, radiographic KOA severity was not significantly associated with fall risk (OR 0.81, 95%CI 0.44-1.50 in mild OA; OR 1.10, 95%CI 0.57-2.14 in severe OA)., Conclusion: Knee pain, decreased mobility, and depression, but not the radiographic KOA severity, were significantly associated with a fall risk. Regardless of the individual's radiographic KOA severity, the risk of falls may be reduced by treating his/her knee pain, mobility problems, and/or psychological factors., (© 2024. The Author(s).)

Background: Pulmonary hypertension (PH) often leads to right ventricle (RV) failure, a significant cause of morbidity and mortality. Despite advancements in PH management, progression to RV maladaptation and subsequent failure remain a clinical challenge. This study explored the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on RV function in a rat model of PH, hypothesizing that it improves RV function by inhibiting G protein-coupled receptor kinase 2 (GRK2) and altering myofilament protein phosphorylation., Methods: The Su5416/hypoxia (SuHx) rat model was used to induce PH. Rats were treated with paroxetine and compared to vehicle-treated and control groups. Parameters measured included RV morphology, systolic and diastolic function, myofilament protein phosphorylation, GRK2 activity, and sympathetic nervous system (SNS) markers., Results: Paroxetine treatment significantly improved RV systolic function, evidenced by increased stroke volume, cardiac output, and ejection fraction, without significantly affecting RV hypertrophy, myosin heavy chain/titin isoform switching, or fibrosis. Enhanced phosphorylation of titin and myosin light chain-2 was observed, correlating positively with improved systolic function. Contrary to the hypothesis, improvements occurred independently of GRK2 inhibition or SNS modulation, suggesting an alternate mechanism, potentially involving antioxidant properties of paroxetine., Conclusion: Paroxetine improves RV systolic function in PH rats, likely through mechanisms beyond GRK2 inhibition, possibly related to its antioxidant effects. This highlights the potential of paroxetine in managing RV dysfunction in PH, warranting further investigation into its detailed mechanisms of action and clinical applicability., Competing Interests: Takeshi Ogo reports financial support was provided by Janssen Pharmaceutical KK. Takeshi Ogo reports financial support was provided by Nippon Shinyaku Co Ltd. Mark T. Waddingham reports financial support was provided by Japan Society for the Promotion of Science. Takeshi Ogo reports a relationship with Janssen Pharmaceutical KK that includes: speaking and lecture fees. Takeshi Ogo reports a relationship with Nippon Shinyaku Co Ltd. that includes: speaking and lecture fees. Takeshi Ogo reports a relationship with Bayer Yakuhin Kabushiki Kaisha that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: Several studies have investigated the factors that influence health-related quality of life in patients with knee osteoarthritis (KOA). This study aimed to identify and investigate the degree of involvement of potential factors influencing health-related quality of life (HRQOL) in an aged population with or without KOA., Methods: This multi-centered study included 651 participants who underwent health checkups in rural areas of Japan in 2010. The association between three component summary score of short-form 12 (physical component summary; PCS, mental component summary; MCS, and role-social component summary; RCS) and covariates were investigated using multiple linear regression model and calculated the scaled estimated regression coefficient., Results: Decreasing mobility, severity of knee pain, high pain-related self-efficacy (PSE), older age, high functional self-efficacy (FSE), and female gender had significant effect on PCS (p < 0.05). However, radiographic KOA had no influence on PCS. Presence of depression and body mass index had a significant influence on the MCS (p < 0.05). Decreasing mobility, presence of depression, PSE and older age had significant influence on the RCS (p < 0.05)., Conclusion: Our study results showed that physical, mental, and role/social QOL were affected by different influencing factors. Physical QOL was strongly influenced by subjective pain, physical performance, and self-efficacy, whereas radiographic KOA had no such effect. Depressive mood is associated with both mental and role/social QOL. The role/social QOL was predominantly affected by physical function and pain-related self-efficacy. Taking measure to improving functional ability and mental status might be the key factor to improve HRQOL in patient with KOA., Level of Evidence: Level 3: Epidemiologic cross-sectional study (prognostic study)., (© 2023. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: Osteochondroma is one of the most common benign bone tumors, and it may cause bone and joint deformities and limited range of motion of an adjacent joint. The pes anserinus region is one of the most frequent sites of osteochondroma, but knee locking caused by osteochondromas in the pes anserinus region is extremely rare., Case Summary: We describe a 13-year-old Japanese girl's extra-articular knee locking that occurred when the semitendinosus tendon got caught in osteochondroma that had developed in the pes anserinus region. The osteochondroma was surgically resected. The postoperative outcome has been excellent, with no recurrence of knee locking or tumor one-year post-surgery., Conclusion: When a young person develops knee locking, the possibility of extra-articular as well as intra-articular locking should be considered. Osteochondroma, one of the causes of extra-articular locking, can be treated with surgery with good postoperative results., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hypertension has been the most common non-communicable disease in low and middle-income countries for the past two decades, increasing cardiovascular and renal disease risk. Urbanization, aging, dietary and lifestyle changes, high illiteracy rates, poor access to health facilities, poverty, high costs of drugs, and social stress have contributed to an increase in the prevalence of hypertension in developing countries. Nonetheless, little is known about the comprehensive risk factors associated with prehypertension and hypertension among economically active adult populations of South Asia, such as India, Nepal, and Bangladesh. This paper uses the Demographic and Health Survey data of 637,396 individuals from India (2019-21), 8,924 from Nepal (2016), and 8,613 from Bangladesh (2017-18) to examine the prevalence and driver of prehypertension and hypertension. We analyze the prevalence of prehypertension because it leads to hypertension and is directly related to cardiovascular disease, and many people live with it for prolonged periods without realizing it. The paper finds, among other things, that the prevalence of prehypertension and hypertension among adults (18-49 years) is 43.2 and 14.9% in India, 35.1% and 19.8% in Bangladesh, and 25.2% and 13.8% in Nepal, respectively. Better educated, wealthy individuals living in urban areas of developing economies in the South Asian region are more likely to have prehypertension and hypertension. The paper suggests the urgent need to launch preventive programs to reduce prehypertension before it develops to be hypertension as a precautionary measure. Thus, such measures shall help to prevent hypertension, thereby improving the overall wellbeing of individuals and families., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rahut, Mishra, Sonobe and Timilsina.)

Synovial hemangioma, a rare benign tumor that occurs most frequently in the knee in children and young adults, has four histological subtypes: Venous, arteriovenous, cavernous and capillary hemangiomas. Since the clinical presentation and radiological findings of synovial hemangioma are non-specific, there is frequently a long period between the onset and the diagnosis. The cases of nine patients, pathologically diagnosed with synovial hemangioma and surgically treated, were retrospectively analyzed. All nine patients had persistent knee pain. In addition, three patients also had a swollen knee with intra-articular hemorrhage. Plain radiography revealed intra-articular phleboliths in two patients. In seven patients, T1-weighted magnetic resonance imaging showed low signal intensity with small signal voids. On T2-weighted imaging, all patients showed high signal intensity containing small signal voids. All patients underwent surgical excision; there was no postoperative recurrence after the final operation, and the knee pain had disappeared at the final follow-up. From the pathological findings, the diagnoses were venous hemangioma, cavernous hemangioma and capillary hemangioma (three patients each)., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Sonobe et al.)

To investigate the roles of the serotonin (5-HT) transporter (SERT) and plasma membrane monoamine transporter (PMAT) in 5-HT uptake and its metabolism in the heart, we monitored myocardial interstitial levels of 5-HT and 5-HIAA, a metabolite of 5-HT by monoamine oxidase (MAO), in anesthetized rats using a microdialysis technique. Fluoxetine (SERT inhibitor), decynium-22 (PMAT inhibitor), or their mixture was locally administered by reverse-microdialysis for 60 min. Subsequently, pargyline (MAO inhibitor) was co-administered. Fluoxetine rapidly increased dialysate 5-HT concentration, while decynium-22 gradually increased it. The mixture induced a larger increase in dialysate 5-HT concentration compared to fluoxetine or decynium-22 alone. Fluoxetine increased dialysate 5-HIAA concentration, and this increase was abolished by pargyline. Decynium-22 and the mixture did not change dialysate 5-HIAA concentration, which were not affected by pargyline. Both SERT and PMAT regulate myocardial interstitial 5-HT levels by its uptake; however, 5-HT uptake via PMAT leads to 5-HT metabolism by MAO., (© 2022. The Author(s).)

The purpose of this retrospective study was to assess the efficacy of antimicrobial therapy for bovine acute Klebsiella pneumoniae mastitis. We evaluated data from cattle in Ehime, Japan, with naturally occurring acute mastitis due to K. pneumoniae (n=208) or Escherichia coli (n=201). Survival was significantly shorter in cattle with acute K. pneumoniae mastitis (median, 76 days) compared with the disease caused by E. coli (median 464 days). In 2004-2008, because both species were highly susceptible to cefazolin, cases of K. pneumoniae and E. coli mastitis were treated solely with cefazolin, yielding clinical cure rates of 52.8% for K. pneumoniae and 86.0% for E. coli. However, since 2009, the efficacy of treatment of K. pneumoniae mastitis with cefazolin alone has decreased. When cefazolin administered on the first disease day led to clinical improvement, treatment with cefazolin was continued. However, when cefazolin administered on the first disease day failed to yield clinical improvement, the antibiotic was switched to a fluoroquinolone on the second day, resulting in cure rates of 76.7% for K. pneumoniae and 80.0% for E. coli. These findings suggest that, when the first-line drug (e.g., cefazolin) is ineffective, promptly changing to a second-line drug (e.g., a fluoroquinolone) increases the cure rate for bovine K. pneumoniae mastitis.

Background: ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP., Methods and Results: Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell-specific Npr1 -knockout mice but not in endothelial cell-specific Npr1 -knockout mice. Moreover, ANP significantly lowered systolic blood pressure in Nos3 -knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca 2+ concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased Rgs2 mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in Rgs2 -knockout mice. Endothelial cell-specific Npr1 -overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography., Conclusions: Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.

In resistance arteries, endothelium-dependent hyperpolarization (EDH)-mediated vasodilatation is depressed in diabetes. We hypothesized that downregulation of KCa channel derived EDH reduces exercise-induced vasodilatation and blood flow redistribution in diabetes. To test this hypothesis, we evaluated vascular function in response to hindlimb muscle contraction, and the contribution of KCa channels in anaesthetised ZFDM, metabolic disease rats with type 2 diabetes. We also tested whether exercise training ameliorated the vascular response. Using in vivo microangiography, the hindlimb vasculature was visualized before and after rhythmic muscle contraction (0.5 s tetanus every 3 s, 20 times) evoked by sciatic nerve stimulation (40 Hz). Femoral blood flow of the contracting hindlimb was simultaneously measured by an ultrasonic flowmeter. The contribution of KCa channels was investigated in the presence and absence of apamin and charybdotoxin. We found that vascular and blood flow responses to muscle contraction were significantly impaired at the level of small artery segments in ZFDM fa/fa rats compared to its lean control fa/+ rats. The contribution of KCa channels was also smaller in fa/fa than in fa/+ rats. Low-intensity exercise training for 12 weeks in fa/fa rats demonstrated minor changes in the vascular and blood flow response to muscle contraction. However, the KCa-derived component in the response to muscle contraction was much greater in exercise trained than in sedentary fa/fa rats. These data suggest that exercise training increases the contribution of KCa channels among endothelium-dependent vasodilatory mechanisms to maintain vascular and blood flow responses to muscle contraction in this metabolic disease rat model. KEY POINTS: Microvascular dysfunction in type 2 diabetes impairs blood flow redistribution during exercise and limits the performance of skeletal muscle and may cause early fatigability. Endothelium-dependent hyperpolarization (EDH), which mediates vasodilatation in resistance arteries, is known to be depressed in animals with diabetes. Here, we report that low-intensity exercise training in ZFDM rats increased the KCa channel-derived component in the vasodilator responses to muscle contraction compared to that in sedentary rats, partly as a result of the increase in KCNN3 expression. These results suggest that low-intensity exercise training improves blood flow redistribution in contracting skeletal muscle in metabolic disease with diabetes via upregulation of EDH., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

The creation of low-dimensional heterostructures for intelligent devices is a challenging research topic; however, macro- and atomic-scale connections in one-dimensional (1D) electronic systems have not been achieved yet. Herein, we synthesize a heterostructure comprising a 1D Mott insulator [Ni(chxn) 2 Br]Br 2 (1; chxn = 1R-2R-diaminocyclohexane) and a 1D Peierls or charge-density-wave insulator [Pd(chxn) 2 Br]Br 2 (2) using stepwise electrochemical growth. It can be considered as the first example of electrochemical liquid-phase epitaxy applied to molecular-based heterostructures with a macroscopic scale. Moreover, atomic-resolution scanning tunneling microscopy images reveal a modulation of the electronic state in the heterojunction region with a length of five metal atoms (~ 2.5 nm), that is a direct evidence for the atomic-scale connection of 1 and 2. This is the first time that the heterojunction in the 1D chains has been shown and examined experimentally at macro- and atomic-scale. This study thus serves as proof of concept for heterojunctions in 1D electronic systems., (© 2022. The Author(s).)

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever and serositis. Periodic febrile attack can be managed with biologic medication in colchicine-resistant FMF patients, however, no reports or guidelines exist regarding the postoperative management of elective joint surgery in these patients. Although it is not clear how FMF attacks are triggered, they may be precipitated by stress including anesthesia or surgery. This study reports the case of a 51-year-old FMF patient who received total hip replacement under canakinumab (a specific interleukin-1β monoclonal antibody) treatment. He had highly active FMF, which was resistant to colchicine; however, his recurrent febrile attack with serositis was successfully controlled with canakinumab. Four months later from the start of canakinumab treatment, his hip osteoarthritis was required for total hip replacement (THR) because of the traumatic fracture. THR was successfully done and FMF attack was not occurred after this elective surgery. Discontinuation of canakinumab 3 weeks before surgery and resumption 6 weeks after led to favorable outcome without complications. This case addresses the differential management concerning stopping and restating of canakinumab in the perioperative setting in contrast to the other biologics such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) blocking agents. This case report suggests that canakinumab may represent a safe and effective therapy for the colchicine-resistant FMF, even in the patients requiring THR therapy.

The majority of the conventional techniques that are utilized for investigating the pathogenesis of cardiovascular disease in preclinical animal models do not permit microlevel assessment of in situ cardiomyocyte and microvascular functions. Therefore, it has been difficult to establish whether cardiac dysfunction in complex multiorgan disease states, such as heart failure with preserved ejection fraction and pulmonary hypertension, have their origins in microvascular dysfunction or rather in the cardiomyocyte. Herein, we describe our approach of utilizing synchrotron radiation microangiography to, first, ascertain whether the growth hormone secretagogue (GHS) hexarelin is a vasodilator in the coronary circulation of normal and anesthetized Sprague-Dawley rats, and next investigate if hexarelin is able to prevent the pathogenesis of right ventricle (RV) dysfunction in pulmonary hypertension in the sugen chronic hypoxia model rat. We show that acute hexarelin administration evokes coronary microvascular dilation through GHS-receptor 1a and nitric oxide, and through endothelium-derived hyperpolarization. Previous work indicated that chronic exogenous administration of ghrelin largely prevented the pathogenesis of pulmonary hypertension in chronic hypoxia and in monocrotaline models. Unexpectedly, chronic hexarelin administration prior to sugen chronic hypoxia did not prevent RV hypertrophy or RV cardiomyocyte relaxation impairment. Small-angle X-ray scattering revealed that super relaxed myosin filaments contributed to diastolic dysfunction, and that length-dependent activation might contribute to sustained contractility of the RV. Thus, synchrotron-based imaging approaches can reveal novel insights into cardiac and coronary functions in vivo ., Competing Interests: MW, RA, and TO belong to a department endowed by Nippon Shinyaku Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Waddingham, Tsuchimochi, Sonobe, Asano, Jin, Ow, Schwenke, Katare, Aoyama, Umetani, Hoshino, Uesugi, Shirai, Ogo and Pearson.)

Computers based on physical systems are increasingly anticipated to overcome the impending limitations on digital computer performance. One such computer is a coherent Ising machine (CIM) for solving combinatorial optimization problems. Here, we report a CIM with 100,512 degenerate optical parametric oscillator pulses working as the Ising spins. We show that the CIM delivers fine solutions to maximum cut problems of 100,000-node graphs drastically faster than standard simulated annealing. Moreover, the CIM, when operated near the phase transition point, provides some extremely good solutions and a very broad distribution. This characteristic will be useful for applications that require fast random sampling such as machine learning.

Vagal nerve stimulation (VNS) has been explored as a potential therapy for chronic heart failure. The contribution of the afferent pathway to myocardial interstitial acetylcholine (ACh) release during VNS has yet to be clarified. In seven anesthetized Wistar-Kyoto rats, we implanted microdialysis probes in the left ventricular free wall and measured the myocardial interstitial ACh release during right VNS with the following combinations of stimulation frequency (F in Hz) and voltage readout (V in volts): F0V0 (no stimulation), F5V3, F20V3, F5V10, and F20V10. F5V3 did not affect the ACh level. F20V3, F5V10, and F20V10 increased the ACh level to 2.83 ± 0.47 ( P < 0.01), 4.31 ± 1.09 ( P < 0.001), and 4.33 ± 0.82 ( P < 0.001) nM, respectively, compared with F0V0 (1.76 ± 0.22 nM). After right vagal afferent transection (rVAX), F20V3 and F20V10 increased the ACh level to 2.90 ± 0.53 ( P < 0.001) and 3.48 ± 0.63 ( P < 0.001) nM, respectively, compared with F0V0 (1.61 ± 0.19 nM), but F5V10 did not (2.11 ± 0.24 nM). The ratio of the ACh levels after rVAX relative to before was significantly <100% in F5V10 (59.4 ± 8.7%) but not in F20V3 (102.0 ± 8.7%). These results suggest that high-frequency and low-voltage stimulation (F20V3) evoked the ACh release mainly via direct activation of the vagal efferent pathway. By contrast, low-frequency and high-voltage stimulation (F5V10) evoked the ACh release in a manner dependent on the vagal afferent pathway.

At present nearly half of the world's population is under some form of government restriction to curb the spread of COVID-19, an extremely contagious disease. In Bangladesh, in the wake of five deaths and 48 infections from COVID-19, between March 24 and May 30, 2020, the government imposed a nationwide lockdown. While this lockdown restricted the spread of COVID-19, in the absence of effective support, it can generate severe food and nutrition insecurity for daily wage-based workers. Of the 61 million employed labor force in Bangladesh, nearly 35% of them are paid on a daily basis. This study examines the food security and welfare impacts of the COVID-19 induced lockdown on daily wage workers both in the farm and nonfarm sectors in Bangladesh. Using information from more than 50,000 respondents complied with the 2016-17 Household Income and Expenditure Survey (HIES) in Bangladesh, this study estimates daily wage rates as Bangladesh Taka (BDT) 272.2 in the farm sector and BDT 361.5 in the nonfarm sector. Using the estimated daily wage earnings, this study estimates that a one-day complete lockdown generates a US$64.2 million equivalent economic loss only considering the wage loss of the daily wage workers. After estimating the daily per capita food expenditure separately for farm and nonfarm households, this study estimates a minimum compensation package for the daily wage-based farm and nonfarm households around the US $ 1 per day per household to ensure minimum food security for the daily wage-based worker households., Competing Interests: The authors have declared that no competing interests exist.

Background: As severe acute hypoxemia produces a rapid inhibition of the respiratory neuronal activity through a nonopioid mechanism, we have investigated in adult rats the effects of hypoxemia after fentanyl overdose-induced apnea on (1) autoresuscitation and (2) the antidotal effects of naloxone., Methods: In nonsedated rats, the breath-by-breath ventilatory and pulmonary gas exchange response to fentanyl overdose (300 µg · kg · min iv in 1 min) was determined in an open flow plethysmograph. The effects of inhaling air (nine rats) or a hypoxic mixture (fractional inspired oxygen tension between 7.3 and 11.3%, eight rats) on the ability to recover a spontaneous breathing rhythm and on the effects of naloxone (2 mg · kg) were investigated. In addition, arterial blood gases, arterial blood pressure, ventilation, and pulmonary gas exchange were determined in spontaneously breathing tracheostomized urethane-anesthetized rats in response to (1) fentanyl-induced hypoventilation (7 rats), (2) fentanyl-induced apnea (10 rats) in air and hyperoxia, and (3) isolated anoxic exposure (4 rats). Data are expressed as median and range., Results: In air-breathing nonsedated rats, fentanyl produced an apnea within 14 s (12 to 29 s). A spontaneous rhythmic activity always resumed after 85.4 s (33 to 141 s) consisting of a persistent low tidal volume and slow frequency rhythmic activity that rescued all animals. Naloxone, 10 min later, immediately restored the baseline level of ventilation. At fractional inspired oxygen tension less than 10%, fentanyl-induced apnea was irreversible despite a transient gasping pattern; the administration of naloxone had no effects. In sedated rats, when PaO2 reached 16 mmHg during fentanyl-induced apnea, no spontaneous recovery of breathing occurred and naloxone had no rescuing effect, despite circulation being maintained., Conclusions: Hypoxia-induced ventilatory depression during fentanyl induced apnea (1) opposes the spontaneous emergence of a respiratory rhythm, which would have rescued the animals otherwise, and (2) prevents the effects of high dose naloxone.

Background: Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl)., Methods: Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting., Results: We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably., Conclusions: In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.

Hydrogen sulfide (H 2 S) remains a chemical hazard in the gas and farming industry. It is easy to manufacture from common chemicals and thus represents a potential threat for the civilian population. It is also employed as a method of suicide, for which incidence has recently increased in the US. H 2 S is a mitochondrial poison and exerts its toxicity through mechanisms that are thought to result from its high affinity to various metallo-proteins (such as - but not exclusively- the mitochondrial cytochrome c oxidase) and interactions with cysteine residues of proteins. Ion channels with critical implications for the cardiac and the brain functions appear to be affected very early during and following H 2 S exposure, an effect which is rapidly reversible during a light intoxication. However, during severe H 2 S intoxication, a coma, associated with a reduction in cardiac contractility, develops within minutes or even seconds leading to death by complete electro-mechanical dissociation of the heart. If the level of intoxication is milder, a rapid and spontaneous recovery of the coma occurs as soon as the exposure stops. The risk, although probably very small, of developing long-term debilitating motor or cognitive deficits is present. One of the major challenges impeding our effort to offer an effective treatment against H 2 S intoxication after exposure is that the pool of free/soluble H 2 S almost immediately disappears from the body preventing agents trapping free H 2 S (cobalt or ferric compounds) to play their protective role. This paper (1) presents and discusses the neurological symptoms and lesions observed in various animals models and in humans following an acute exposure to sub-lethal or lethal levels of H 2 S, (2) reviews the potential interest of methylene blue (MB), a potent cyclic redox dye - currently used for the treatment of methemoglobinemia - which has potential rescuing effects on the mitochondrial activity, as an antidote against sulfide intoxication., (Copyright © 2019. Published by Elsevier Inc.)

Serotonin (5-HT) accumulates in the heart during myocardial ischemia and induces deleterious effects on the cardiomyocytes through receptor-dependent and monoamine oxidase-dependent pathways. We aimed to clarify the involvement of extra-neuronal monoamine transporters in the clearance of 5-HT during ischemia and reperfusion in the heart. Using a microdialysis technique in the anesthetized Wistar rat heart, we monitored myocardial interstitial 5-HT and 5-hydroxyindole acetic acid (5-HIAA) concentration by means of electro-chemical detection coupled with high-performance liquid chromatography (HPLC-ECD). Effects of inhibitors of the plasma membrane monoamine transporter (PMAT) and the organic cation transporter 3 (OCT3) (decynium-22 and corticosterone) on the 5-HT and 5-HIAA concentrations during baseline, coronary occlusion, and reperfusion were investigated. Basal dialysate 5-HT concentration were increased by local administration of decynium-22, but not by corticosterone. Addition of fluoxetine, a serotonin transporter (SERT) inhibitor further increased the 5-HT concentration upon during administration of decynium-22. Decynium-22 elevated the background level of 5-HT during coronary occlusion and maintained 5-HT concentration at a high level during reperfusion. Production of 5-HIAA in the early reperfusion was significantly suppressed by decynium-22. These results indicate that PMAT and SERT independently regulate basal level of interstitial 5-HT, and PMAT plays a more important role in the clearance of 5-HT during reperfusion. These data suggest the involvement of PMAT in the monoamine oxidase-dependent deleterious pathway in the heart., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Ghrelin is a small peptide with important roles in the regulation of appetite, gut motility, glucose homeostasis as well as cardiovascular protection. This review highlights the role that acyl ghrelin plays in maintaining normal endothelial function by maintaining the balance of vasodilator-vasoconstrictor factors, inhibiting inflammatory cytokine production and immune cell recruitment to sites of vascular injury and by promoting angiogenesis., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review., (© 2019 The authors.)

Aim: To investigate and compare the efficacy of two machine-learning technologies with deep-learning (DL) and support vector machine (SVM) for the detection of branch retinal vein occlusion (BRVO) using ultrawide-field fundus images., Methods: This study included 237 images from 236 patients with BRVO with a mean±standard deviation of age 66.3±10.6y and 229 images from 176 non-BRVO healthy subjects with a mean age of 64.9±9.4y. Training was conducted using a deep convolutional neural network using ultrawide-field fundus images to construct the DL model. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the curve (AUC) were calculated to compare the diagnostic abilities of the DL and SVM models., Results: For the DL model, the sensitivity, specificity, PPV, NPV and AUC for diagnosing BRVO was 94.0% (95%CI: 93.8%-98.8%), 97.0% (95%CI: 89.7%-96.4%), 96.5% (95%CI: 94.3%-98.7%), 93.2% (95%CI: 90.5%-96.0%) and 0.976 (95%CI: 0.960-0.993), respectively. In contrast, for the SVM model, these values were 80.5% (95%CI: 77.8%-87.9%), 84.3% (95%CI: 75.8%-86.1%), 83.5% (95%CI: 78.4%-88.6%), 75.2% (95%CI: 72.1%-78.3%) and 0.857 (95%CI: 0.811-0.903), respectively. The DL model outperformed the SVM model in all the aforementioned parameters ( P <0.001)., Conclusion: These results indicate that the combination of the DL model and ultrawide-field fundus ophthalmoscopy may distinguish between healthy and BRVO eyes with a high level of accuracy. The proposed combination may be used for automatically diagnosing BRVO in patients residing in remote areas lacking access to an ophthalmic medical center.

The aim of this study is to assess the performance of two machine-learning technologies, namely, deep learning (DL) and support vector machine (SVM) algorithms, for detecting central retinal vein occlusion (CRVO) in ultrawide-field fundus images. Images from 125 CRVO patients ( n =125 images) and 202 non-CRVO normal subjects ( n =238 images) were included in this study. Training to construct the DL model using deep convolutional neural network algorithms was provided using ultrawide-field fundus images. The SVM uses scikit-learn library with a radial basis function kernel. The diagnostic abilities of DL and the SVM were compared by assessing their sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic curve for CRVO. For diagnosing CRVO, the DL model had a sensitivity of 98.4% (95% confidence interval (CI), 94.3-99.8%) and a specificity of 97.9% (95% CI, 94.6-99.1%) with an AUC of 0.989 (95% CI, 0.980-0.999). In contrast, the SVM model had a sensitivity of 84.0% (95% CI, 76.3-89.3%) and a specificity of 87.5% (95% CI, 82.7-91.1%) with an AUC of 0.895 (95% CI, 0.859-0.931). Thus, the DL model outperformed the SVM model in all indices assessed ( P < 0.001 for all). Our data suggest that a DL model derived using ultrawide-field fundus images could distinguish between normal and CRVO images with a high level of accuracy and that automatic CRVO detection in ultrawide-field fundus ophthalmoscopy is possible. This proposed DL-based model can also be used in ultrawide-field fundus ophthalmoscopy to accurately diagnose CRVO and improve medical care in remote locations where it is difficult for patients to attend an ophthalmic medical center.

It has been shown that the size of myocardial infarction in rats created by coronary ligation technique is not uniform, varying from 4% to 65%. We hypothesized that infarct size variability induced by coronary artery ligation might be caused by coronary artery branching pattern. Coronary artery angiography was performed in 50 normal Lewis rats and in chronic myocardial infarction models in which coronary artery was ligated immediately below the left atrial appendage or 2mm distal to the left atrial appendage (n = 25 for each), followed by histological analysis. Unlike the human, the rats had a single major septal artery arising from the proximal part of the left coronary artery (n = 30) or right coronary artery (n = 20). There were three branching patterns of left circumflex artery (LCX): 33 (66%) had LCX branching peripherally from a long left main coronary artery (LMCA), while the remainder 17 (34%) had the LCX branching from the proximal part of the septal artery or a short LMCA. The rats with distal coronary ligation presented myocardial infarction localized to an anterior territory irrespective of LCX branching pattern. In the rats with proximal coronary ligation, 64% (n = 16) had broad myocardial infarction involving the anterior and lateral territories, while the remainder (36%, n = 9) had myocardial infarction localized to an anterior territory with the intact LCX arising proximally from a short LMCA. The interventricular septum was spared from infarction in all rats because of its anatomical location. Infarct size variations were caused not only by ligation site but also by varying LCX branching patterns. There are potential risks to create different sizes of myocardial infarction, particularly when targeting a broad range of myocardial infarction. The territory of the septal artery always appears to be spared from myocardial infarction induced by the coronary ligation technique.

Our objective was to determine how circulatory failure develops following systemic administration of potassium cyanide (KCN). We used a noninhaled modality of intoxication, wherein the change in breathing pattern would not influence the diffusion of CN into the blood, akin to the effects of ingesting toxic levels of CN. In a group of 300 to 400 g rats, CN-induced coma (CN i.p., 7 mg/kg) produced a central apnea within 2 to 3 min along with a potent and prolonged gasping pattern leading to autoresuscitation in 38% of the animals. Motor deficits and neuronal necrosis were nevertheless observed in the surviving animals. To clarify the mechanisms leading to potential autoresuscitation versus asystole, 12 urethane-anesthetized rats were then exposed to the lowest possible levels of CN exposure that would lead to breathing depression within 7 to 8 min; this dose averaged 0.375 mg/kg/min i.v. At this level of intoxication, a cardiac depression developed several minutes only after the onset of the apnea, leading to cardiac asystole as PaO2 reached value approximately 15 Torr, unless breathing was maintained by mechanical ventilation or through spontaneous gasping. Higher levels of KCN exposure in 10 animals provoked a primary cardiac depression, which led to a rapid cardiac arrest by pulseless electrical activity (PEA) despite the maintenance of PaO2 by mechanical ventilation. These effects were totally unrelated to the potassium contained in KCN. It is concluded that circulatory failure can develop as a direct consequence of CN-induced apnea but in a narrow range of exposure. In this "low" range, maintaining pulmonary gas exchange after exposure, through mechanical ventilation (or spontaneous gasping), can reverse cardiac depression and restore spontaneous breathing. At higher level of intoxication, cardiac depression is to be treated as a specific and spontaneously irreversible consequence of CN exposure, leading to a PEA., Competing Interests: The authors declare that they have no conflict of interest.