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Abstract Connectin (also known as titin) is a giant striated muscle protein that functions as a molecular spring by providing elasticity to the sarcomere. Novex-3 is a short splice variant of connectin whose physiological function remains unknown. We have recently demonstrated using in vitro analyses that in addition to sarcomere expression, novex-3 was also expressed in cardiomyocyte nuclei exclusively during fetal life, where it provides elasticity/compliance to cardiomyocyte nuclei and promotes cardiomyocyte proliferation in the fetus, suggesting a non-sarcomeric function. Here, we analyzed novex-3 knockout mice to assess the involvement of this function in cardiac pathophysiology in vivo. Deficiency of novex-3 compromised fetal cardiomyocyte proliferation and induced the enlargement of individual cardiomyocytes in neonates. In adults, novex-3 deficiency resulted in chamber dilation and systolic dysfunction, associated with Ca2+ dysregulation, resulting in a reduced life span. Mechanistic analyses revealed a possible association between impaired proliferation and abnormal nuclear mechanics, including stiffer nuclei positioned peripherally with stabilized circumnuclear microtubules in knockout cardiomyocytes. Although the underlying causal relationships were not fully elucidated, these data show that novex-3 has a vital non-sarcomeric function in cardiac pathophysiology and serves as an early contributor to cardiomyocyte proliferation.

Abstract Background Malignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and succinylcholine, leading to a hypermetabolic reaction. The pathogenic ryanodine receptor 1 (RYR1) gene variant is critical. Patients susceptible to MH should avoid triggering agents, and total intravenous anesthesia (TIVA) is preferred. Remimazolam is safe in patients with suspected MH. Case presentation We present the first case of remimazolam treatment in a genetically confirmed patient with MH without MH development. A 72-year-old man with a family history of MH underwent remimazolam-based TIVA. After informed consent was obtained, a muscle biopsy and genetic testing were performed. Intraoperatively and postoperatively, the patient exhibited no signs of MH. An enhanced function of the RYR1 channel into releasing calcium was indicated, and the genetic testing revealed a pathogenic variant of RYR1. Conclusions Remimazolam-based TIVA is safe in patients confirming the diagnosis of MH.

Abstract Investigating ventricular diastolic properties is crucial for understanding the physiological cardiac functions in organisms and unraveling the pathological mechanisms of cardiovascular disorders. Ventricular stiffness, a fundamental parameter that defines ventricular diastolic functions in chordates, is typically analyzed using the end‐diastolic pressure–volume relationship (EDPVR). However, comparing ventricular stiffness accurately across chambers of varying maximum volume capacities has been a long‐standing challenge. As one of the solutions to this problem, we propose calculating a relative ventricular stiffness index by applying an exponential approximation formula to the EDPVR plot data of the relationship between ventricular pressure and values of normalized ventricular volume by the ventricular weight. This article reviews the potential, utility, and limitations of using normalized EDPVR analysis in recent studies. Herein, we measured and ranked ventricular stiffness in differently sized and shaped chambers using ex vivo ventricular pressure‐volume analysis data from four animals: Wistar rats, red‐eared slider turtles, masu salmon, and cherry salmon. Furthermore, we have discussed the mechanical effects of intracellular and extracellular viscoelastic components, Titin (Connectin) filaments, collagens, physiological sarcomere length, and other factors that govern ventricular stiffness. Our review provides insights into the comparison of ventricular stiffness in different‐sized ventricles between heterologous and homologous species, including non‐model organisms.

Summary: Introduction of fetal cell cycle genes into damaged adult hearts has emerged as a promising strategy for stimulating proliferation and regeneration of postmitotic adult cardiomyocytes. We have recently identified Fam64a as a fetal-specific cell cycle promoter in cardiomyocytes. Here, we analyzed transgenic mice maintaining cardiomyocyte-specific postnatal expression of Fam64a when endogenous expression was abolished. Despite an enhancement of cardiomyocyte proliferation, these mice showed impaired cardiomyocyte differentiation during postnatal development, resulting in cardiac dysfunction in later life. Mechanistically, Fam64a inhibited cardiomyocyte differentiation by repressing Klf15, leading to the accumulation of undifferentiated cardiomyocytes. In contrast, introduction of Fam64a in differentiated adult wildtype hearts improved functional recovery upon injury with augmented cell cycle and no dedifferentiation in cardiomyocytes. These data demonstrate that Fam64a inhibits cardiomyocyte differentiation during early development, but does not induce de-differentiation in once differentiated cardiomyocytes, illustrating a promising potential of Fam64a as a cell cycle promoter to attain heart regeneration.

Ventricular diastolic mechanical properties are important determinants of cardiac function and are optimized by changes in cardiac structure and physical properties. Oncorhynchus masou masou is an anadromous migratory fish of the Salmonidae family, and several ecological studies on it have been conducted; however, the cardiac functions of the fish are not well known. Therefore, we investigated ventricular diastolic function in landlocked (masu salmon) and sea-run (cherry salmon) types at 29-30 months post fertilization. Pulsed-wave Doppler echocardiography showed that the atrioventricular inflow waveforms of cherry salmon were biphasic with early diastolic filling and atrial contraction, whereas those of masu salmon were monophasic with atrial contraction. In addition, end-diastolic pressure-volume relationship analysis revealed that the dilatability per unit myocardial mass of the ventricle in cherry salmon was significantly suppressed compared to that in masu salmon, suggesting that the ventricle of the cherry salmon was relatively stiffer (relative ventricular stiffness index; p = 0.0263). Contrastingly, the extensibility of cardiomyocytes, characterized by the expression pattern of Connectin isoforms in their ventricles, was similar in both types. Histological analysis showed that the percentage of the collagen accumulation area in the compact layer of cherry salmon increased compared with that of the masu salmon, which may contribute to ventricle stiffness. Although the heart mass of cherry salmon was about 11-fold greater than that of masu salmon, there was no difference in the morphology of the isolated cardiomyocytes, suggesting that the heart of the cherry salmon grows by cardiomyocyte proliferation, but not cell hypertrophy. The cardiac physiological function of the teleosts varies with differences in their developmental processes and life history. Our multidimensional analysis of the O. masou heart may provide a clue to the process by which the heart acquires a biphasic blood-filling pattern, i.e., a ventricular diastolic suction.

In CBA/CaJ mice, confocal analysis has shown that acoustic overexposure can immediately destroy synapses between auditory-nerve fibers (ANFs) and their peripheral targets, the inner hair cells (IHCs), and that years later, a corresponding number of ANF cell bodies degenerate. In guinea pig, post-exposure disappearance of pre-synaptic ribbons can be equally dramatic, however, post-exposure recovery to near-baseline counts has been reported. Since confocal counts are confounded by thresholding issues, the fall and rise of synaptic ribbon counts could represent “regeneration,” i.e., terminal retraction, re-extension and synaptogenesis, or “recovery,” i.e., down- and subsequent up-regulation of synaptic markers. To clarify, we counted pre-synaptic ribbons, assessed their juxtaposition with post-synaptic receptors, measured the extension of ANF terminals, and quantified the spatial organization and size gradients of these synaptic elements around the hair cell. Present results in guinea pigs exposed as adults (14 months), along with prior results in juveniles (1 month), suggest there is post-exposure neural regeneration in the guinea pig, but not the CBA/CaJ mouse, and that this regenerative capacity extends into adulthood. The results also show, for the first time, that the acute synaptic loss is concentrated on the modiolar side of IHCs, consistent with a selective loss of the high-threshold ANFs with low spontaneous rates. The morphological similarities between the post-exposure neurite extension and synaptogenesis, seen spontaneously in the guinea pig, and in CBA/CaJ only with forced overexpression of neurotrophins, suggest that the key difference may be in the degree of sustained or injury-induced expression of these signaling molecules in the cochlea.

Abstract Noise exposures causing only transient threshold shifts can destroy auditory-nerve synapses without damaging hair cells. Here, we asked whether virally mediated neurotrophin3 (NT3) overexpression can repair this damage. CBA/CaJ mice at 6 wks were injected unilaterally with adeno-associated virus (AAV) containing either NT3 or GFP genes, via the posterior semicircular canal, 3 wks prior to, or 5 hrs after, noise exposure. Controls included exposed animals receiving vehicle only, and unexposed animals receiving virus. Thresholds were measured 2 wks post-exposure, just before cochleas were harvested for histological analysis. In separate virus-injected animals, unexposed cochleas were extracted for qRT-PCR. The GFP reporter showed that inner hair cells (IHCs) were transfected throughout the cochlea, and outer hair cells mainly in the apex. qRT-PCR showed 4- to 10-fold overexpression of NT3 from 1–21 days post-injection, and 1.7-fold overexpression at 40 days. AAV-NT3 delivered prior to noise exposure produced a dose-dependent reduction of synaptopathy, with nearly complete rescue at some cochlear locations. In unexposed ears, NT3 overexpression did not affect thresholds, however GFP overexpression caused IHC loss. In exposed ears, NT3 overexpression increased permanent threshold shifts. Thus, although NT3 overexpression can minimize noise-induced synaptic damage, the forced overexpression may be harmful to hair cells themselves during cochlear overstimulation.

BackgroundPneumonia is a common cause of illness and death of the elderly in Japan. Its prevalence is escalating globally with the aging of population. To describe the latest trends in pneumonia hospitalizations, especially aspiration pneumonia (AP) cases, we assessed the clinical records of pneumonia patients admitted to core acute care hospitals in Miyagi prefecture, Japan.MethodsA retrospective multi-institutional joint research was conducted for hospitalized pneumonia patients aged ≥20 years from January 2019 to December 2019. Clinical data of patients were collected from the medical records of eight acute care hospitals.ResultsOut of the 1,800 patients included in this study, 79% of the hospitalized pneumonia patients were aged above 70 years. The most common age group was in the 80s. The ratio of AP to total pneumonia cases increased with age, and 692 out of 1,800 patients had AP. In univariate analysis, these patients had significantly older ages, lower body mass index (BMI), a lower ratio of normal diet intake and homestay before hospitalization, along with more AP recurrences and comorbidities. During hospitalization, AP patients had extended fasting periods, more swallowing assessments and interventions, longer hospitalization, and higher in-hospital mortality rate than non-AP patients. A total of 7% and 2% AP patients underwent video endoscopy and video fluorography respectively. In multivariate analysis, lower BMI, lower C-reactive protein, a lower ratio of homestay before hospitalization, a higher complication rate of cerebrovascular disease, dementia, and neuromuscular disease were noted as a characteristic of AP patients. Swallowing interventions were performed for 51% of the AP patients who had been hospitalized for more than two weeks. In univariate analysis, swallowing intervention improved in-hospital mortality. Lower AP recurrence before hospitalization and a lower ratio of homestay before hospitalization were indicated as characteristics of AP patients of the swallowing intervention group from multivariate analysis. Change in dietary pattern from normal to modified diet was observed more frequently in the swallowing intervention group.ConclusionAP accounts for 38.4% of all pneumonia cases in acute care hospitals in Northern Japan. The use of swallowing evaluations and interventions, which may reduce the risk of dysphagia and may associate with lowering mortality in AP patients, is still not widespread.

Haiti announced in 2018 its aim to achieve universal health coverage. In this paper, we discuss what this objective means for the country and what next steps should be taken. To contextualize the notion, we framed Haiti en route to the 2030 goal and analyzed qualitatively the status quo in terms of geographic, financial, and service access. For each dimension, we focused on the context, the government’s policies and political agendas, their implementation progress, and key influential factors. Our analysis found little progress and numerous challenges. Geographic access was limited due principally to the insufficient number of facilities, difficulties in reaching health facilities, and local customs. Financial coverage was low because of the government’s insufficient budgets, inefficient budget allocation, and ineffective management. Service access also had room for significant improvement for a lack of basic infrastructure and resources, gaps between the essential service package guidelines, health professionals’ skills, and the needs, as well as deficiencies in people-centered care. These factors affected not only health service coverage but also its quality. We found that the root causes of these issues were composed of unstable financing mechanisms, opportunistic resource allocation, and ineffective management control systems. We suggest that to overcome these issues and achieve universal health coverage with decent service quality, Haiti’s health system needs to be reformed by implementing strategic financing, decentralized management systems, and community engagement in primary health care.

Abstract Fetal cardiomyocytes actively proliferate to form the primitive heart in utero in mammals, but they stop dividing shortly after birth. The identification of essential molecules maintaining this active cardiomyocyte proliferation is indispensable for potential adult heart regeneration. A recent study has shown that this proliferation depends on a low fetal oxygen condition before the onset of breathing at birth. We have established an isolation protocol for mouse fetal cardiomyocytes, performed under strict low oxygen conditions to mimic the intrauterine environment, that gives the highest proliferative activities thus far reported. Oxygen exposure during isolation/culture markedly inhibited cell division and repressed cell cycle-promoting genes, and subsequent genome-wide analysis identified Fam64a as a novel regulatory molecule. Fam64a was abundantly expressed in hypoxic fetal cardiomyocyte nuclei, but this expression was drastically repressed by oxygen exposure, and in postnatal cardiomyocytes following the onset of breathing and the resulting elevation of oxygen tension. Fam64a knockdown inhibited and its overexpression enhanced cardiomyocyte proliferation. Expression of a non-degradable Fam64a mutant suggested that optimum Fam64a expression and subsequent degradation by anaphase-promoting complex/cyclosome (APC/C) during the metaphase-to-anaphase transition are required for fetal cardiomyocyte division. We propose that Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice.

Aging is associated with motor disorders that decrease the quality of life (QOL). Royal jelly (RJ), used as a dietary supplement, has shown various health benefits and, therefore, it has the potential to improve the QOL during aging. We have previously developed protease enzyme-treated RJ to avoid the anaphylactic response induced by RJ supplementation. However, the effects of a lifelong treatment with RJ on normal aging have not been fully clarified. In this study, we investigated the effects of enzyme-untreated RJ (NRJ) and enzyme-treated RJ (ERJ) on the aging process focusing on motor functions, by using a genetically heterogeneous (HET) mouse model experimentally endowed with genetic diversity. We performed four different physical performance tests (grip strength, wire hang, horizontal bar, and rotarod). We showed that the age-related impairment of the motor functions was significantly delayed in RJ-treated mice. Both NRJ and ERJ were similarly effective against these types of aging-associated declines. Histological analyses revealed that the RJ treatment affected the muscle fiber size at an advanced age. We also demonstrated that age-related changes in muscle satellite cell markers and catabolic genes were affected in RJ-treated mice. These results suggest that non-protein components of RJ improved the motor function in aging mice. These findings indicate that RJ has the potential to change the QOL during aging by regulating the motor function.

On March 11, 2011, Japan's northeast Pacific coast was hit by a gigantic earthquake and subsequent tsunami. Soma City in Fukushima Prefecture is situated approximately 44 km north of Fukushima Daiichi Nuclear Power Plant. Soma General Hospital is the only hospital in Soma City that provides full-time otolaryngological medical care. We investigated the changes in new patients from one year before to three years after the disaster. We investigated 18,167 new patients treated at our department during the four years from April 1, 2010 to March 31, 2014. Of the new patients, we categorized the diagnoses into Meniere's disease, acute low-tone sensorineural hearing loss, vertigo, sudden deafness, tinnitus, and facial palsy as neuro-otologic symptoms. We also investigated the changes in the numbers of patients whom we examined at that time concerning other otolaryngological disorders, including epistaxis, infectious diseases of the laryngopharynx, and allergic rhinitis. The total number of new patients did not change remarkably on a year-to-year basis. Conversely, cases of vertigo, Meniere's disease, and acute low-tone sensorineural hearing loss increased in number immediately after the disaster, reaching a plateau in the second year and slightly decreasing in the third year. Specifically, 4.8% of patients suffering from these neuro-otologic diseases had complications from depression and other mental diseases. With regard to new patients in our department, there was no apparent increase in the number of patients suffering from diseases other than neuro-otologic diseases, including epistaxis, and allergic rhinitis. Patients suffering from vertigo and/or dizziness increased during the first few years after the disaster. These results are attributed to the continuing stress and tension of the inhabitants. This investigation of those living in the disaster area highlights the need for long-term support.

BACKGROUND:Central American countries face a major challenge in the control of Triatoma dimidiata, a widespread vector of Chagas disease that cannot be eliminated. The key to maintaining the risk of transmission of Trypanosoma cruzi at lowest levels is to sustain surveillance throughout endemic areas. Guatemala, El Salvador, and Honduras integrated community-based vector surveillance into local health systems. Community participation was effective in detection of the vector, but some health services had difficulty sustaining their response to reports of vectors from the population. To date, no research has investigated how best to maintain and reinforce health service responsiveness, especially in resource-limited settings. METHODOLOGY/PRINCIPAL FINDINGS:We reviewed surveillance and response records of 12 health centers in Guatemala, El Salvador, and Honduras from 2008 to 2012 and analyzed the data in relation to the volume of reports of vector infestation, local geography, demography, human resources, managerial approach, and results of interviews with health workers. Health service responsiveness was defined as the percentage of households that reported vector infestation for which the local health service provided indoor residual spraying of insecticide or educational advice. Eight potential determinants of responsiveness were evaluated by linear and mixed-effects multi-linear regression. Health service responsiveness (overall 77.4%) was significantly associated with quarterly monitoring by departmental health offices. Other potential determinants of responsiveness were not found to be significant, partly because of short- and long-term strategies, such as temporary adjustments in manpower and redistribution of tasks among local participants in the effort. CONCLUSIONS/SIGNIFICANCE:Consistent monitoring within the local health system contributes to sustainability of health service responsiveness in community-based vector surveillance of Chagas disease. Even with limited resources, countries can improve health service responsiveness with thoughtful strategies and management practices in the local health systems.

Aims: Although increased Na+/Ca2+ exchanger 1 (NCX1) expression is observed during heart failure (HF), the pathological role of NCX1 during the progression of HF remains unclear. We examined alterations of NCX1 expression and activity in hearts after transverse aortic constriction (TAC) surgery and explored whether NCX1 influences pressure overloadinduced pathological cardiac remodelling. Methods and results: We generated novel transgenic mice in which NCX1 expression is controlled by a cardiac-specific, doxycycline (DOX)- dependent promoter. In the absence of DOX, TAC surgery caused substantial chamber dilation with a gradual decrease in contractility by 16 weeks. Cardiomyocytes showed a decline in contractility with abnormal Ca2+ handling during excitation- contraction (E-C) coupling. Reduced NCX1 activity was observed 8 weeks after TAC and was still apparent at 17 weeks. Induced NCX1 overexpression by DOX treatment starting 8 weeks after TAC returned NCX1 activity to pre-TAC levels and prevented chamber dilation with cardiac dysfunction. DOX treatment not only upregulated NCX1 expression in TAC-operated hearts but also returned L-type Ca2+ channel and sarcoplasmic reticulum (SR) Ca2+ ATPase expression levels to those in sham-operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca2+ release from the SR, and Ca2+ handling during E-C coupling was preserved 16 weeks after TAC surgery. In addition, DOX treatment attenuated the down-regulation of survival signalling and up-regulation of apoptosis signalling 16 weeks after TAC surgery. Conclusion: Induced overexpression of NCX1 attenuated pressure overload-induced pathological cardiac remodelling. Thus, maintaining NCX1 activity may be a potential therapeutic strategy for preventing the progression of HF. [ABSTRACT FROM AUTHOR]

Background: Integration of disease-specific programmes into the primary health care (PHC) service has been attempted mostly in clinically oriented disease control such as HIV/AIDS and tuberculosis but rarely in vector control. Chagas disease is controlled principally by interventions against the triatomine vector. In Honduras, after successful reduction of household infestation by vertical approach, the Ministry of Health implemented community-based vector surveillance at the PHC services (health centres) to prevent the resurgence of infection. This paper retrospectively analyses the effects and process of integrating a Chagas disease vector surveillance system into health centres. Methods: We evaluated the effects of integration at six pilot sites in western Honduras during 2008-2011 on; surveillance performance; knowledge, attitude and practice in schoolchildren; reports of triatomine bug infestation and institutional response; and seroprevalence among children under 15 years of age. The process of integration of the surveillance system was analysed using the PRECEDE-PROCEED model for health programme planning. The model was employed to systematically determine influential and interactive factors which facilitated the integration process at different levels of the Ministry of Health and the community. Results: Overall surveillance performance improved from 46 to 84 on a 100 point-scale. Schoolchildren's attitude (risk awareness) score significantly increased from 77 to 83 points. Seroprevalence declined from 3.4% to 0.4%. Health centres responded to the community bug reports by insecticide spraying. As key factors, the health centres had potential management capacity and influence over the inhabitants' behaviours and living environment directly and through community health volunteers. The National Chagas Programme played an essential role in facilitating changes with adequate distribution of responsibilities, participatory modelling, training and, evaluation and advocacy. Conclusions: We found that Chagas disease vector surveillance can be integrated into the PHC service. Health centres demonstrated capacity to manage vector surveillance and improve performance, children's awareness, vector report-response and seroprevalence, once tasks were simplified to be performed by trained non-specialists and distributed among the stakeholders. Health systems integration requires health workers to perform beyond their usual responsibilities and acquire management skills. Integration of vector control is feasible and can contribute to strengthening the preventive capacity of the PHC service. [ABSTRACT FROM AUTHOR]

Genetic characteristics of North Pacific loggerhead turtles captured as bycatch in pound nets operating inMuroto, Kochi, Japan were sampled to identify and estimate stock structure of coastal foraging aggregations. Tissue samples were obtained from juvenile, subadult and adult turtles from 2005-2006 and 2008-2010. For each of the years, 100 samples were processed and approximately 820 bp of mitochondrial DNA control region were sequenced. Straight carapace length of the turtles ranged from 56.3-99.1 cmand their life stages were identified based on previous estimates of the size at puberty (66.0cm) and maturity (82.1cm). A total of 487 out of the 500 samples yielded sequences of sufficient quality to identify five different haplotypes. We conducted mixed stock analysis (MSA) using Bayesian approaches to estimate the contributions of three potential source nesting Management Units (MU) to the Muroto foraging aggregation. There were no significant differences between haplotype frequencies among the different size classes and life stages, nor among the different years, thus the haplotype frequencies were combined for the MSA. The MSA was runwith and without consideration of MUsize and distance, which resulted in similar MSA estimates. A >50% contribution was estimated from the Yakushima MU, and 40% from the Mainland MU, with only minor contribution from the Ryukyu MU. The estimated contribution from Mainland MU and Yakushima MU were disproportionately larger than the relative abundance of nesting at these MUs compared with Ryukyu MU, demonstrating that closer MUs had a greater contribution than those from further away. The lack of differences found in haplotype frequency among life stages, suggests that both juvenile and mature loggerhead turtles that remigrate to Japanese waters have the tendency to utilize foraging grounds and migration routes near their natal waters. [ABSTRACT FROM AUTHOR]

Connectin (also known as titin) is a giant striated muscle protein that functions as a molecular spring by providing elasticity to the sarcomere. Novex-3 is a short splice variant of connectin whose physiological function remains unknown. We have recently demonstrated using in vitro analyses that in addition to sarcomere expression, novex-3 was also expressed in cardiomyocyte nuclei exclusively during fetal life, where it provides elasticity/compliance to cardiomyocyte nuclei and promotes cardiomyocyte proliferation in the fetus, suggesting a non-sarcomeric function. Here, we analyzed novex-3 knockout mice to assess the involvement of this function in cardiac pathophysiology in vivo. Deficiency of novex-3 compromised fetal cardiomyocyte proliferation and induced the enlargement of individual cardiomyocytes in neonates. In adults, novex-3 deficiency resulted in chamber dilation and systolic dysfunction, associated with Ca2+ dysregulation, resulting in a reduced life span. Mechanistic analyses revealed a possible association between impaired proliferation and abnormal nuclear mechanics, including stiffer nuclei positioned peripherally with stabilized circumnuclear microtubules in knockout cardiomyocytes. Although the underlying causal relationships were not fully elucidated, these data show that novex-3 has a vital non-sarcomeric function in cardiac pathophysiology and serves as an early contributor to cardiomyocyte proliferation. [ABSTRACT FROM AUTHOR]

Background: Malignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and succinylcholine, leading to a hypermetabolic reaction. The pathogenic ryanodine receptor 1 (RYR1) gene variant is critical. Patients susceptible to MH should avoid triggering agents, and total intravenous anesthesia (TIVA) is preferred. Remimazolam is safe in patients with suspected MH. Case presentation: We present the first case of remimazolam treatment in a genetically confirmed patient with MH without MH development. A 72-year-old man with a family history of MH underwent remimazolam-based TIVA. After informed consent was obtained, a muscle biopsy and genetic testing were performed. Intraoperatively and postoperatively, the patient exhibited no signs of MH. An enhanced function of the RYR1 channel into releasing calcium was indicated, and the genetic testing revealed a pathogenic variant of RYR1. Conclusions: Remimazolam-based TIVA is safe in patients confirming the diagnosis of MH. [ABSTRACT FROM AUTHOR]

Investigating ventricular diastolic properties is crucial for understanding the physiological cardiac functions in organisms and unraveling the pathological mechanisms of cardiovascular disorders. Ventricular stiffness, a fundamental parameter that defines ventricular diastolic functions in chordates, is typically analyzed using the end‐diastolic pressure–volume relationship (EDPVR). However, comparing ventricular stiffness accurately across chambers of varying maximum volume capacities has been a long‐standing challenge. As one of the solutions to this problem, we propose calculating a relative ventricular stiffness index by applying an exponential approximation formula to the EDPVR plot data of the relationship between ventricular pressure and values of normalized ventricular volume by the ventricular weight. This article reviews the potential, utility, and limitations of using normalized EDPVR analysis in recent studies. Herein, we measured and ranked ventricular stiffness in differently sized and shaped chambers using ex vivo ventricular pressure‐volume analysis data from four animals: Wistar rats, red‐eared slider turtles, masu salmon, and cherry salmon. Furthermore, we have discussed the mechanical effects of intracellular and extracellular viscoelastic components, Titin (Connectin) filaments, collagens, physiological sarcomere length, and other factors that govern ventricular stiffness. Our review provides insights into the comparison of ventricular stiffness in different‐sized ventricles between heterologous and homologous species, including non‐model organisms. [ABSTRACT FROM AUTHOR]

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Macrophages are ancient, phagocytic immune cells thought to have their origins 500 million years ago in metazoan phylogeny. The understanding of macrophages has evolved to encompass their foundational roles in development, homeostasis, tissue repair, inflammation, and immunity. Notably, macrophages display high plasticity in response to environmental cues, capable of a strikingly wide variety of dynamic gene signatures and phenotypes. Macrophages are also involved in many pathological states including neural disease, asthma, liver disease, heart disease, cancer, and others. In cancer, most tumor-associated immune cells are macrophages, coined tumor-associated macrophages (TAMs). While some TAMs can display anti-tumor properties such as phagocytizing tumor cells and orchestrating an immune response, most macrophages in the tumor microenvironment are immunosuppressive and pro-tumorigenic. Macrophages have been implicated in all stages of cancer. Therefore, interest in manipulating macrophages as a therapeutic strategy against cancer developed as early as the 1970s. Companion dogs are a strong comparative immuno-oncology model for people due to documented similarities in the immune system and spontaneous cancers between the species. Data from clinical trials in humans and dogs can be leveraged to further scientific advancements that benefit both species. This review aims to provide a summary of the current state of knowledge on macrophages in general, and an in-depth review of macrophages as a therapeutic strategy against cancer in humans and companion dogs. [ABSTRACT FROM AUTHOR]

Ventricular diastolic mechanical properties are important determinants of cardiac function and are optimized by changes in cardiac structure and physical properties. Oncorhynchus masou masou is an anadromous migratory fish of the Salmonidae family, and several ecological studies on it have been conducted; however, the cardiac functions of the fish are not well known. Therefore, we investigated ventricular diastolic function in landlocked (masu salmon) and sea-run (cherry salmon) types at 29–30 months post fertilization. Pulsed-wave Doppler echocardiography showed that the atrioventricular inflow waveforms of cherry salmon were biphasic with early diastolic filling and atrial contraction, whereas those of masu salmon were monophasic with atrial contraction. In addition, end-diastolic pressure–volume relationship analysis revealed that the dilatability per unit myocardial mass of the ventricle in cherry salmon was significantly suppressed compared to that in masu salmon, suggesting that the ventricle of the cherry salmon was relatively stiffer (relative ventricular stiffness index; p = 0.0263). Contrastingly, the extensibility of cardiomyocytes, characterized by the expression pattern of Connectin isoforms in their ventricles, was similar in both types. Histological analysis showed that the percentage of the collagen accumulation area in the compact layer of cherry salmon increased compared with that of the masu salmon, which may contribute to ventricle stiffness. Although the heart mass of cherry salmon was about 11-fold greater than that of masu salmon, there was no difference in the morphology of the isolated cardiomyocytes, suggesting that the heart of the cherry salmon grows by cardiomyocyte proliferation, but not cell hypertrophy. The cardiac physiological function of the teleosts varies with differences in their developmental processes and life history. Our multidimensional analysis of the O. masou heart may provide a clue to the process by which the heart acquires a biphasic blood-filling pattern, i.e., a ventricular diastolic suction. [ABSTRACT FROM AUTHOR]