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Aim: We aimed to elucidate the effect of a healthy diet containing adequate amounts of protein and vegetables on metabolic indices., Methods: In this randomized crossover study, twenty-two healthy Japanese participants ingested two different test meals: fish diet (F) or fish diet with adequate vegetable content (FV). Each 5-day diet load test was separated by a washout period of at least seven days. Metabolic indices were measured in fasting blood and 24-h urine samples., Results: The delta (Δ) plasma glucose and Δserum low-density lipoprotein (LDL) cholesterol concentrations were significantly larger in the participants in group FV than in group F (p=0.042, p=0.013, respectively). The urinary pH in participants in group F on day 6 was significantly lower than on day 1 (p=0.008), and the Δurinary pH and Δnet gastrointestinal absorption of alkali of participants in group FV tended to be smaller than in group F (p=0.070, p=0.075, respectively)., Conclusions: This study showed that a healthy diet containing adequate protein and vegetables reduced the dietary acid load and improved plasma glucose and serum LDL concentrations in healthy Japanese participants.

Background: Working while receiving cancer treatment is challenging for patients, with considerable impact on their quality of life (QOL). However, there have been no reports on the factors that prevent employment in patients with bone metastases. This study aimed to investigate the employment status and factors impacting the continued employment of patients with bone metastases., Methods: We analyzed clinical data from new patients consulting The University of Tokyo Hospital team for bone metastasis treatment between June 2015 and September 2017. Patients who were working at the time of cancer diagnosis (n = 124) completed four QOL questionnaires. Factors associated with work sustainability were identified via univariate analysis and a chi-squared test. Multivariate logistic regression analysis was used for significant variables. Relationships between employment and QOL scales were investigated using the Wilcoxon rank-sum test, with P < .05 considered as statistically significant., Results: Among the 124 patients, only 45 (36.3%) were still working when the questionnaire was administered. Multivariate analysis revealed temporary employment, lytic or mixed bone metastases, and lower limb or acetabular metastasis, as significant factors hindering work sustainability. The QOL scores were high in the continued employment group. However, the relationship between employment status and pain remains unclear., Conclusions: Lytic or mixed bone metastases and the lower limb and acetabular metastasis were significantly associated with employment resignation. Mobility difficulties may prevent patients with bone metastases from sustaining employment. Collaboration between rehabilitation professionals, oncologists, and workplaces is imperative to address this problem., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The impact of varying rates of pacemapping (PM) rates on QRS morphology and PM score matching in patients with scar-related ventricular tachycardia (VT) has not been systematically assessed., Objectives: In this study, we sought to assess the variability in PM score matching at different pacing rates., Methods: During substrate mapping for VT ablation, PM was performed at cycle lengths (CLs) of 600 ms, 500 ms, 400 ms, 300 ms, and VT CL. PM scores were compared for the entire QRS, the first half (H1) of QRS, and the second half (H2) of QRS to examine the influence of the preceding T wave superimposed into the onset of paced QRS complex (TR fusion)., Results: A total of 269 PMs in 40 patients undergoing scar-related VT ablation were systematically analyzed. The PM score improved at rates closer to VT with a median difference of 6% (Q1-Q3: 4%-10%; range: 0-33%) between the lowest and the highest PM scores at a given site. Greater slurring of the QRS onset was observed at faster-paced CL, corresponding to a superimposition of the preceding T wave into QRS onset, with significant differences in H1 but not H2 of the QRS complex. At faster PM rates, 32% of overall sites developed pseudo delta wave and 69% of endocardial pacing sites fulfilled epicardial criteria., Conclusions: The rate of pacemapping can significantly alter morphologic score matching, with the most optimal match observed closest to VT CL. The onset of QRS complex morphology is influenced by superimposition of the preceding T wave at faster rates, resulting in an underrecognized TR fusion phenomenon that may confound epicardial electrocardiographic criteria predicated upon the initial QRS slope and vector., Competing Interests: Funding Support and Author Disclosures Dr Tung has received speaking honoraria from Abbott, Medtronic, Boston Scientific, and Biotronik. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Microphysiological systems have attracted attention because of their use in drug screening. However, it is challenging to measure cell functions in real time using a device. In this study, we developed a cell culture device using a porous membrane electrode for in situ electrochemical glucose measurements for cell analysis. First, a porous membrane electrode was fabricated and electrochemically evaluated for enzyme-free glucose measurement. Subsequently, the glucose uptake of MCF-7 spheroids was evaluated using living spheroids, fixed spheroids, supernatants, and glucose transporter inhibitor-treated spheroids. Conventionally, the direct optical measurement of glucose uptake requires fluorescence-labeled glucose derivatives. In addition, the glucose uptake can be evaluated by measuring the glucose concentration in the medium by optical or electrochemical measurements. However, glucose needs to be consumed in the entire cell culture medium, which needs a long culture time. In contrast, our system can measure glucose in approximately 5 min without any labels because of in situ electrochemical measurements. This system can be used for in situ measurements in in vitro cell culture systems, including organ-on-a-chip for drug screening.

Background: A rotational activation pattern (RAP) around the localized line of a conduction block often correlates with sites specific to the critical zones of ventricular tachycardia (VT). The wavefront direction during substrate mapping affects manifestation of the RAP and line of block., Objective: The purpose of this study was to investigate the most optimal cardiac rhythm for identifying RAP and line of block in substrate mapping., Methods: We retrospectively evaluated 71 maps (median 3205 points/map) in 46 patients (65 ± 15 years; 33% with ischemic cardiomyopathy) who underwent high-density substrate mapping and ablation of scar-related VT. Appearance of a RAP during sinus, right ventricular (RV)-paced, left ventricular (LV)-paced, and biventricular-paced rhythms was investigated., Results: RAP was identified in 24 of 71 maps (34%) in the region where wavefronts from a single direction reached but not in the region where wavefronts from multiple directions centripetally collided. The probability of identifying the RAP depended on scar location; that is, anteroseptal and inferoseptal, inferior and apical, and basal lateral RAPs were likely to be identified during sinus/atrial, RV-paced, and LV-paced rhythms, respectively. In 13 patients, the RAP was not evident in the baseline map but became apparent during remapping in the other rhythm, in which the wavefront reached the site earlier within the entire activation time., Conclusion: The optimal rhythm for substrate mapping depends on the spatial distribution of the area of interest. A paced rhythm with pacing sites near the scar may facilitate the identification of critical VT zones., Competing Interests: Disclosures Dr Komatsu has received honoraria for lectures and advisory board activities from Johnson & Johnson. Dr Yamasaki received a scholarship fund from Johnson & Johnson. Dr. Igarashi received an endowment from Japan Lifeline, Astec Co. Ltd., Medtronic, DVX, Boston Scientific, Abbott Medical Inc., and Biotronik. Dr Nogami received honoraria from Abbott and Johnson & Johnson; and endowments from Medtronic and DVX. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The Ca 2+ -dependent activator protein for secretion (CAPS/CADPS) family protein facilitates catecholamine release through the dense-core vesicle exocytosis in model neuroendocrine cell lines. However, it remains unclear if it induces dopamine release in the central neurons. This study aimed to examine the expression and function of CADPS2, one of the two CADPS paralogs, in dopamine neurons of the mouse midbrain. This study shows that CADPS2 was expressed in tyrosine hydroxylase and the vesicular monoamine transporter 2 (VMAT2)-positive dopaminergic neurons of the midbrain samples and primary mesencephalic cell cultures. Subcellular fractions rich in dopamine were collected using immunoaffinity for CADPS2 from midbrain protein extracts. Cell imaging using fluorescent false neurotransmitter FFN511 as a substrate for VMAT2 showed decreased activity-dependent dopamine release in Cadps2 -deficient cultures, compared to that in wild-type cultures. These results suggest that CADPS2 is involved in dopamine release from the central neurons, indicating its involvement in the central dopamine pathway., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Iguchi, Katsuzawa, Saruta, Sadakata, Kobayashi, Sato, Sato, Sano, Maezawa, Shinoda and Furuichi.)

Background: Neuromodulation through spinal cord stimulation (SCS) is a therapeutic option for relieving leg pain and improving the chances of limb salvage in patients with intractable chronic limb-threatening ischemia (CLTI); however, there is no consensus on its indications., Objective: The aim of this study was to assess the clinical outcomes of SCS in patients with intractable leg pain caused by various diseases treated in the department of cardiovascular medicine in Japan., Methods: This was a retrospective study of patients who underwent SCS for pain management. Patients were considered eligible for the therapy if they met the following criteria: (1) intractable leg pain (numerical rating scale [NRS] score of 10), (2) no revascularization option, and (3) no septicemia., Results: Twenty patients (mean age: 77 years; men/women: 11/9) were included in this study. The NRS score of the patients significantly reduced from 10 ± 0 before procedure to 4 ± 3 at discharge (p < 0.001). The clinical response rate of the entire cohort was 65% (13/20) at 17 ± 14 months after implantation; however, patients with intractable CLTI showed a low response rate (45%), whereas those with subacute limb ischemia showed a high response rate (100%). A multivariable regression analysis showed that hemoglobin level was significantly associated with treatment response, even after adjusting for age and sex (p = 0.026). The area under the receiver operating characteristic curve for the correlation between hemoglobin level (cutoff, 11.4 g/dL) and clinical response to SCS was 0.824 (0.619-1)., Conclusions: SCS can reduce clinical symptoms in majority of patients with intractable leg pain. Although implantation of an SCS device has been shown to improve microvascular perfusion insufficiency, the correlation between hemoglobin level and the clinical effect of SCS indicates that a preserved microcirculatory vascular bed is essential for the therapy to be effective., (© 2024 World Institute of Pain.)

Objectives: To determine the outcomes for elderly patients with de novo metastatic germ cell tumors and the influence of patient age on adherence to standard chemotherapy., Methods: A total of 150 patients who were initially diagnosed with metastatic germ cell tumors and treated at our institution between 2007 and 2021 were included. Patients were classified according to three age groups: aged <40, 40-49, and ≥50 years. Clinicopathological features, adherence to standard first-line chemotherapy, overall survival, and disease-free survival were compared between these groups. We also analyzed the outcomes of patients who received low-intensity induction chemotherapy due to adverse events and/or comorbidities., Results: There was no significant difference in any of the survival outcomes and in the rate of adherence to standard first-line chemotherapy between the three age groups, although elderly patients with intermediate/poor prognosis group tended to receive less-intense chemotherapies. The rate of febrile neutropenia as a chemotherapy-related adverse event was significantly higher in patients aged ≥50 years. No statistical significance in survival outcomes was detected between the group of patients who received relatively low-intensity induction chemotherapy and those who received adequately intensive planned chemotherapy., Conclusions: The adherence rate of standard fist-line chemotherapy of elderly patients is almost comparable to that of younger patients, although some adverse events should be carefully managed. Even elderly patients with metastatic germ cell tumors can aim for equivalently good survival outcome like younger populations, with effort to adhere to standard chemotherapy., (© 2024 The Japanese Urological Association.)

Background: Limited research has evaluated the long-term outcomes of prospective audit and feedback (PAF) led by pharmacists. We assessed pharmacist-led PAF processes and outcome measures over 8 years., Methods: This study was conducted at a single public hospital in Japan. Between 2014 and 2021, pharmacists conducted weekday PAFs for hospitalized patients and annually evaluated the process and outcome measures. The endpoints included detection of drug-resistant bacteria, drug susceptibility rates, duration of antimicrobial therapy, and proportion of long-term administration., Results: Among inpatients, methicillin-resistant Staphylococcus aureus significantly decreased from 50.9% in 2014 to 32.8% in 2021 (P < .001). The susceptibility rate of Pseudomonas aeruginosa to meropenem significantly increased from 91.2% in 2014 to 94.4% in 2021 (P < .001) and levofloxacin increased from 84.9% in 2014 to 89.3% in 2021 (P < .001). Antimicrobial therapy duration did not differ significantly between 2014 and 2016, but decreased significantly from 2017 onwards (P < .001), except in 2018. The number of patients receiving intravenous antimicrobials for >10 days decreased significantly between 2014 and 2021 (P < .001)., Conclusions: Long-term continuous PAF interventions by pharmacists contribute to improving and maintaining process and outcome indicators and prevent the spread of drug-resistant bacteria., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

The alveoli, critical sites for gas exchange in the lungs, comprise alveolar epithelial cells and pulmonary capillary endothelial cells. Traditional experimental models rely on porous polyethylene terephthalate or polycarbonate membranes, which restrict direct cell-to-cell contact. To address this limitation, we developed AlveoMPU, a new foam-based mortar-like polyurethane-formed alveolar model that facilitates direct cell-cell interactions. AlveoMPU features a unique anisotropic mortar-shaped configuration with larger pores at the top and smaller pores at the bottom, allowing the alveolar epithelial cells to gradually extend toward the bottom. The underside of the film is remarkably thin, enabling seeded pulmonary microvascular endothelial cells to interact with alveolar epithelial cells. Using AlveoMPU, it is possible to construct a bilayer structure mimicking the alveoli, potentially serving as a model that accurately simulates the actual alveoli. This innovative model can be utilized as a drug-screening tool for measuring transepithelial electrical resistance, assessing substance permeability, observing cytokine secretion during inflammation, and evaluating drug efficacy and pharmacokinetics.

Background: Cryoballoon ablation for atrial fibrillation (AF) requires adequate contact between the pulmonary vein (PV) antrum and cryoballoon. The surge of intraballoon pressure during the initial phase of ablation may change the balloon's shape and compliance, resulting in balloon dislodgement and loss of PV occlusion. Without continuous monitoring, this phenomenon is often undetected but can be associated with incomplete PV isolation (PVI)., Methods: Primary cryoablation of AF was performed in 15 patients. PV occlusion status pre- and post-freezing were analyzed with intracardiac echocardiography (ICE) and dielectric imaging-based occlusion tool (DIOT) to calculate the incidence of expansion dislodgement of cryoballoon., Results: A total of 105 cryoablation applications were performed on 57 veins, including three common ostiums of left pulmonary veins. In the evaluation of PV occlusion, both modalities reported consistent results in 86.7% of the assessments. Despite complete PV occlusion before ablation, peri-balloon leak after initiation of freezing was detected by ICE in 5/22 (22.7%) applications and by DIOT in 8/25 (32%) applications., Conclusion: Incidence of expansion dislodgement of the cryoballoon was detected in one-fourth to one-third of cryoablation applications depending on the imaging modality used, which was clinically frequent and significant., (© 2023 Wiley Periodicals LLC.)

Acute purulent pericarditis is a rare infection in developed countries. We herein report a case with diabetic nephropathy under maintenance hemodialysis who suffered from acute purulent pericarditis caused by methicillin-resistant Staphylococcus aureus (MRSA). The treatment of purulent pericarditis mainly involves rapid administration of appropriate antibiotics and drainage. However, in this case, the patient was unresponsive to vancomycin and performing early surgical intervention was challenging due to highly pathogenic MRSA. Therefore, we performed pericardial fenestration in the chronic phase to suppress the risk of fatal secondary infections after daily irrigation for one month to reduce bacterial load mechanically., Learning Objective: In a case of purulent pericarditis caused by highly pathogenic methicillin-resistant Staphylococcus aureus resistant to antibiotics and resulting in constrictive pericarditis, it was possible to perform pericardial fenestration in the chronic phase, while mitigating the risk of fatal secondary infections, by controlling the inflammation through daily irrigation for a long time to reduce the bacterial load mechanically., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Japanese College of Cardiology. Published by Elsevier Ltd.)

Background: Even terminal cancer patients desire to walk to the toilet by themselves until the very last day. This study aimed to describe the walking ability of patients with spinal metastases at the end-of-life stage and identify the factors affecting this ability., Methods: Among 527 patients who first visited our multidisciplinary team for bone metastasis between 2013 and 2016, 56 patients who had spinal metastases with a Spinal Instability Neoplastic Score ≥7 and died during follow-up were included. We collected general clinical data, performance status, Frankel classification, epidural spinal cord compression scale and Spinal Instability Neoplastic Score at the first consultation. Patients' last day of walking and date of death were also examined. Univariate analyses (chi-squared tests) were performed to identify the factors that impacted walking ability 30 and 14 days before patients' death., Results: A total of 56 patients were extracted, and 57.1% (32/56) and 32.7% (16/49) of patients were ambulatory 30 and 14 days before death, respectively. Their performance status (P = 0.0007), Frankel grade (P = 0.012) and epidural spinal cord compression grade (P = 0.006) at the first examination, and administration of bone modifying agents during follow-up period (P = 0.029) were significantly related to walking ability 30 days before death. Among ambulatory patients 30 days before death, those with Spinal Instability Neoplastic Score ≥10 (P = 0.005), especially with high scores of collapse (P = 0.002) and alignment (P = 0.002), were less likely to walk 14 days before death. The walking period in the last month of their life was significantly longer in patients with total Spinal Instability Neoplastic Score 7-9 (P = 0.009) and in patients without collapse (P = 0.040) by the Wilcoxon test., Conclusion: The progression of spinal metastasis, especially neurological deficit, at the initial consultation were associated with walking ability 30 days before death, and spinal stability might be crucial for preserving walking ability during the last month. Early diagnosis and implementation of appropriate bone management might be important for the end-of-life walking ability., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neurons in the nucleus raphe interpositus have tonic activity that suppresses saccadic burst neurons (BNs) during eye fixations, and that is inhibited before and during saccades in all directions (omnipause neurons, OPNs). We have previously demonstrated via intracellular recording and anatomical staining in anesthetized cats of both sexes that OPNs are inhibited by BNs in the medullary reticular formation (horizontal inhibitory BNs, IBNs). These horizontal IBNs receive monosynaptic input from the caudal horizontal saccade area of the superior colliculus (SC), and then produce monosynaptic inhibition in OPNs, providing a mechanism to trigger saccades. However, it is well known that the neural circuits driving horizontal components of saccades are independent from the circuits driving vertical components. Thus, our previous results are unable to explain how purely vertical saccades are triggered. Here, we again apply intracellular recording to show that a disynaptic vertical IBN circuit exists, analogous to the horizontal circuit. Specifically, we show that stimulation of the SC rostral vertical saccade area produces disynaptic inhibition in OPNs, which is not abolished by midline section between the horizontal IBNs. This excludes the possibility that horizontal IBNs could be responsible for the OPN inhibition during vertical saccades. We then show that vertical IBNs in the interstitial nucleus of Cajal, which receive monosynaptic input from rostral SC, are responsible for the disynaptic inhibition of OPNs. These results indicate that a similarly functioning SC-IBN-OPN circuit exists for both the horizontal and vertical oculomotor pathways. These two IBN-mediated circuits are capable of triggering saccades in any direction. Significance Statement Saccades shift gaze to objects of interest, moving their image to the central retina, where it is maintained for detailed examination (fixation). During fixation, high gain saccade burst neurons (BNs) are tonically inhibited by omnipause neurons (OPNs). Our previous study showed that medullary horizontal inhibitory BNs (IBNs) activated from the caudal superior colliculus (SC) inhibit tonically active OPNs in order to initiate horizontal saccades. The present study addresses the source of OPN inhibition for vertical saccades. We find that OPNs monosynaptically inhibit vertical IBNs in the interstitial nucleus of Cajal during fixation. Those same vertical IBNs are activated by the rostral SC, and inhibit OPN activity to initiate vertical saccades., (Copyright © 2023 the authors.)

Background/aim: We evaluated the incidence of radiation-induced hypothyroidism and its risk factors in patients with head and neck cancer who underwent radiotherapy using simultaneous integrated boost-volumetric-modulated arc therapy (SIB-VMAT)., Patients and Methods: This retrospective study included 86 patients who received definitive radiotherapy using SIB-VMAT for head and neck cancer. The incidence of ≥ grade 2 hypothyroidism was evaluated. We also evaluated the relationships between hypothyroidism development and clinical factors and thyroid dose-volume parameters., Results: During a median follow-up period of 17 months (range=3-65 months), 31 patients (36.0%, 31/86) developed grade 2 hypothyroidism requiring hormone replacement therapy. No patients experienced ≥ grade 3 hypothyroidism. The cumulative incidences of hypothyroidism at 1 and 2 years after radiation therapy were 24.5% and 38.7%, respectively, with a median onset time of 10.0 months (range=3.0-35.0 months). Thyroid volume (p=0.003), volume of the thyroid spared at 60 Gy (VS60; cut-off value, 5.16 ml; p=0.009), VS70 (cut-off value, 8.0 ml; p=0.007), VS60 equivalent dose in 2 Gy fraction (EQD2; cut-off value, 7.78 ml; p=0.001), and VS70EQD2 (cut-off value, 10.59 ml; p=0.008) were significantly associated with the development of radiation-induced hypothyroidism., Conclusion: Radiation-induced hypothyroidism is not rare in patients with head and neck cancer undergoing radiotherapy using SIB-VMAT. Radiation dose-volume parameters detected in this study may be useful indicators to prevent this complication., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Vascular endothelial cells serve as barriers between blood components and subendothelial tissue and regulate the blood coagulation-fibrinolytic system. Ionizing radiation is a common physical stimulant that induces a bystander effect whereby irradiated cells influence neighboring cells through signalings, including purinergic receptor signaling, activated by adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), and adenosine as secondary soluble factors. Human vascular endothelial EA.hy926 cells were cultured and irradiated with γ-rays or treated with ATP, ADP, or adenosine under non-toxic conditions. RNA-seq, gene ontology, and hierarchical clustering analyses were performed. The transcriptome analysis of differentially expressed genes in vascular endothelial cells after γ-ray irradiations suggests that the change of gene expression by γ-irradiation is mediated by ATP and ADP. In addition, the expression and activity of the proteins related to blood coagulation and fibrinolysis systems appear to be secondarily regulated by ATP and ADP in vascular endothelial cells after exposure to γ-irradiation. Although it is unclear whether the changes of the gene expression related to blood coagulation and fibrinolysis systems by γ-irradiation affected the increased hemorrhagic tendency through the exposure to γ-irradiation or the negative feedback to the activated blood coagulation system, the present data indicate that toxicity associated with γ-irradiation involves the dysfunction of vascular endothelial cells related to the blood coagulation-fibrinolytic system, which is mediated by the signalings, including purinergic receptor signaling, activated by ATP and ADP.

We investigated the effects of regrowth interval and first-cut timing on the dietary characteristics of second-cut orchardgrass silage and feed intake and milk production in dairy cows fed second-cut orchardgrass silage. The second-cut grasses were harvested 7w after the first-cut at the early stage (E7w) or at the heading stage (H7w), or harvested 6w after the first-cut at the early stage (E6w) from orchardgrass sward, and then ensiled. We evaluated the effect of regrowth interval by comparing E7w and E6w, and the effect of first-cut timing by comparing E7w and H7w. Six multiparous Holstein cows were used in a replicated 3 × 3 Latin square design, with three dietary treatments: diets containing E7w, E6w, or H7w silage at 30% dietary dry matter. We observed that feeding E6w silage instead of E7w silage increased fiber digestibility, dry matter intake, and milk production; however, the first-cut timing (E7w vs. H7w) did not affect nutrient content and digestibility, feed intake, or lactation performance. These results show that harvesting at short regrowth intervals for second-cut orchardgrass can be an effective strategy for improving feed utilization and milk yield; however, the first-cut timing for second-cut orchardgrass has little impact., (© 2024 Japanese Society of Animal Science.)

Methylmercury is an environmental polluting organometallic compound that exhibits neurotoxicity, as observed in Minamata disease patients. Methylmercury damages peripheral nerves in Minamata patients, causing more damage to sensory nerves than motor nerves. Peripheral nerves are composed of three cell types: dorsal root ganglion (DRG) cells, anterior horn cells (AHCs), and Schwann cells. In this study, we compared cultured these three cell types derived from the rat for susceptibility to methylmercury cytotoxicity, intracellular accumulation of mercury, expression of L-type amino acid transporter 1 (LAT1), which transports methylmercury into cells, and expression of multidrug resistance-associated protein 2 (MRP2), which transports methylmercury-glutathione conjugates into the extracellular space. Of the cells examined, we found that DRG cells were the most susceptible to methylmercury with markedly higher intracellular accumulation of mercury. The constitutive level of LAT1 was higher and that of MRP2 lower in DRG cells compared with those in AHC and Schwann cells. Additionally, decreased cell viability caused by methylmercury was significantly reduced by either the LAT1 inhibitor, JPH203, or siRNA-mediated knockdown of LAT1. On the other hand, an MRP2 inhibitor, MK571, significantly intensified the decrease in the cell viability caused by methylmercury. Our results provide a cellular basis for sensory neve predominant injury in the peripheral nerves of Minamata disease patients.

Intermittent docetaxel therapy (IDT) is rarely used nowadays as a treatment option for men with metastatic castration-resistant prostate cancer (mCRPC) because of the widespread availability of androgen receptor axis-targeted therapy, which is less toxic. Therefore, there is limited information available on whether IDT has a clinical benefit in the treatment of men with mCRPC. This report describes the case of a 66-year-old man with a diagnosis of cT2N1M0 prostate cancer who underwent neoadjuvant combined androgen blockade and whole-pelvis radiation therapy. However, the tumor had progressed to mCRPC with metastasis to the bladder and a left pelvic lymph node within 2 years. Docetaxel had been administered as first-line chemotherapy, and the patient achieved a complete response in terms of the bladder metastasis. Docetaxel was stopped after 15 cycles. When a durable response had been maintained for more than 2 years, during which only androgen deprivation therapy was administered, the patient was switched to observation only. However, his prostate-specific antigen level gradually increased. Abiraterone was started as second-line therapy, during which there was a rapid increase in the PSA level. Computed tomography revealed further enlargement of the left pelvic lymph node, bladder metastasis, metastasis to the left common iliac lymph nodes, and several disseminated nodules around the bladder. Docetaxel was reintroduced as IDT for third-line therapy, and a complete response was achieved for all metastases, with the exception of the metastasis in the left pelvic lymph node. Thus far, the patient has survived for more than 7 years after starting docetaxel as first-line therapy for mCRPC. IDT is potentially useful in a subgroup of patients with mCRPC and could achieve long-term survival. Comprehensive genomic profiling may help physicians to select patients with mCRPC who are more likely to benefit from docetaxel than other systemic therapy., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interests., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aims: The first-generation radiofrequency HotBalloon (RHB) is a size-adjustable single-shot device used in atrial fibrillation. The energy output is determined by its central temperature and not by its balloon surface temperature (BST), thus limiting its efficacy and safety. Therefore, a second-generation RHB was developed to monitor BST and enable BST-controlled ablation. This animal study aims to evaluate the accuracy of a newly developed BST-monitoring system and validate the optimal BST for ablation., Methods and Results: In Protocol 1, thermocapsules were attached to the superior vena cava (SVC) epicardium. The accuracy of BST monitoring was examined during SVC isolation. In Protocol 2, the efficacy and safety of different BST-controlled ablations were examined. In the acute model, electrophysiological and pathological findings were assessed after energy applications with BST at 51, 54, 57, and 60°C. In the chronic model, the lesion durability and pathological findings were assessed 8 weeks after BST-controlled ablation (57 and 60°C). A significant positive correlation was found between the epicardial temperature and the BST-monitoring value (r = 0.98). In the acute model, all target veins were electrically isolated with BST-controlled ablation at ≥57°C (18/18, 100%). In the chronic model, durable lesions were observed in all veins at 60°C, while 44% of the veins showed reconnection at 57°C. In both pathological analyses, significantly greater lesions were observed at 60°C than at 57°C. There were no significant differences in adverse events between the two groups., Conclusion: Balloon surface temperature-controlled ablation at 60°C using the second-generation RHB may be optimal for creating durable lesions without compromising safety., Competing Interests: Conflict of interest: H.Y. received a consultant fee from Toray Industries, Inc. T.Y. received speaker honoraria from Medtronic Japan and BEG Co., Ltd and research grants from Japan Lifeline Co., Ltd. The other authors report no conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca 2+ -dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2 -/- ) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2 -/- mice than that in WT mice. The area of fibrin deposition and the proportion of CD41 + CD31 + cells were lower in TG2 -/- mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41 + CD31 + cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) is an intractable chronic pain syndrome with various signs and symptoms including allodynia/hyperalgesia, edema, swelling, and skin abnormalities. However, a definitive therapeutic treatment for CRPS has not been established. In CRPS patients, inflammatory cytokines such as TNF-α and IL-1β have been shown to increase in affected areas, suggesting that these molecules may be potential therapeutic targets for CRPS. Here, we first created a novel CRPS mouse model (CRPS-II-like) via sciatic nerve injury and cast immobilization, which was characterized by mechanical allodynia, local edema, and skin abnormalities, to evaluate the pathophysiology and pharmacotherapy of CRPS. When an anti-TNF-α antibody was consecutively administered near the injured sciatic nerve of CRPS model mice, persistent allodynia and CRPS-related signs in the ipsilateral hindpaw were markedly attenuated to control levels. Perineural administration of anti-TNF-α antibody also suppressed the upregulation of inflammatory cytokines as well as the activation of macrophages and Schwann cells in the injured sciatic nerve. These findings indicate that persistent allodynia and CRPS-related signs in CRPS models are primarily associated with TNF-α-mediated immune responses in injured peripheral nerves, suggesting that perineural treatment with anti-TNF-α antibody might be therapeutically useful., Competing Interests: Declaration of competing interest The authors have no conflict of interest regarding this manuscript., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: To conduct an exploratory examination of caregiver burden involving toilet problems in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) and related characteristics., Methods: We included 50 outpatients with amnestic MCI and AD and their caregivers. Patients were subclassified into three groups: MCI, mild AD, and moderate/severe AD. We used the Japanese version of the Zarit Burden Interview (J-ZBI) to evaluate caregiver burden and conducted a questionnaire on the frequency of lower urinary tract symptoms and related caregiver burden. We compared the frequency of questionnaire items with the level of burden in each group and subsequently determined the J-ZBI correlation coefficient., Results: Among the questionnaire items, the caregiver's burden of "increased daytime urinary frequency," "nocturia," "urinary incontinence," and "they cannot clean the toilet" statistically significantly correlated with J-ZBI scores (ρ = 0.52, 0.65, 0.79, and 0.83, respectively). Items including "they cannot clean the toilet," "the smell of excrement is bothersome," "assistance for transfer is necessary," "they soil the clothes and bed," and "they cannot clean the genital region" were significantly more common in the patient group with moderate/severe AD., Conclusions: Lower urinary tract symptoms and toilet problems were significantly correlated with caregiver burden. Toilet problems differ depending on the severity of dementia. Therefore, a support system based on dementia severity is required to address toilet problems., (© 2023 The Japanese Urological Association.)

Macrophages are important components in modulating homeostatic and inflammatory responses and are generally categorized into two broad but distinct subsets: classical activated (M1) and alternatively activated (M2) depending on the microenvironment. Fibrosis is a chronic inflammatory disease exacerbated by M2 macrophages, although the detailed mechanism by which M2 macrophage polarization is regulated remains unclear. These polarization mechanisms have little in common between mice and humans, making it difficult to adapt research results obtained in mice to human diseases. Tissue transglutaminase (TG2) is a known marker common to mouse and human M2 macrophages and is a multifunctional enzyme responsible for crosslinking reactions. Here we sought to identify the role of TG2 in macrophage polarization and fibrosis. In IL-4-treated macrophages derived from mouse bone marrow and human monocyte cells, the expression of TG2 was increased with enhancement of M2 macrophage markers, whereas knockout or inhibitor treatment of TG2 markedly suppressed M2 macrophage polarization. In the renal fibrosis model, accumulation of M2 macrophages in fibrotic kidney was significantly reduced in TG2 knockout or inhibitor-administrated mice, along with the resolution of fibrosis. Bone marrow transplantation using TG2-knockout mice revealed that TG2 is involved in M2 polarization of infiltrating macrophages derived from circulating monocytes and exacerbates renal fibrosis. Furthermore, the suppression of renal fibrosis in TG2-knockout mice was abolished by transplantation of wild-type bone marrow or by renal subcapsular injection of IL4-treated macrophages derived from bone marrow of wild-type, but not TG2 knockout. Transcriptome analysis of downstream targets involved in M2 macrophages polarization revealed that ALOX15 expression was enhanced by TG2 activation and promoted M2 macrophage polarization. Furthermore, the increase in the abundance of ALOX15-expressing macrophages in fibrotic kidney was dramatically suppressed in TG2-knockout mice. These findings demonstrated that TG2 activity exacerbates renal fibrosis by polarization of M2 macrophages from monocytes via ALOX15., (© 2023. The Author(s).)

The Sigma-1 receptor (Sigmar1) is downregulated in heart failure model mice with mitochondrial dysfunction. However, the mechanism in detail has not been investigated. In this study, we investigated the role of Sigmar1 in ER-mitochondria proximity using Sigmar1-knockdown or -overexpressed neonatal rat ventricular myocytes (NRVMs). The endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy was aggravated with the dysregulation of mitochondrial function and ER-mitochondrial junctional formation in Sigmar1-knockdown NRVMs, whereas improved in Sigmar1 overexpressed NRVMs. Our data suggests that the reduction of the cardiac Sigmar1 results in decrease mitochondrial Ca 2+ influx and promotes mitochondrial fission, followed by reduced ER-mitochondria proximity, exacerbating ET-1-induced cardiomyocyte injury., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

This study examined the effect of an imposed equibiaxial pre-stress (EBPS) on the evaluation of mechanical properties, using the depth-sensing indentation method with a point-sharp indenter, through a numerical analysis of indentations simulated with the 3D finite element method. The predicted elastic modulus, E * , and yield stress, Y * , were used as elastic and plastic deformation resistances under the indentation, respectively. It was found that both increased nominally with the increase in compressive EBPS and decreased with the increase in tensile EBPS, even though the induced change in the piling-up or sinking-in around the indentations was not significant. The effect of EBPS on E * was described by the Hooke's law for an isotropic elastoplastic material, whereas that on Y * was accounted for by the change in the von Mises stress due to EBPS.

Granule cell-selective toxicity of methylmercury in the cerebellum is one of the main unresolved issues in the pathogenesis of Minamata disease. Rats were orally administered methylmercury chloride (10 mg/kg/day) for 5 consecutive days, and their brains were harvested on days 1, 7, 14, 21, or 28 after the last administration for histological examination of the cerebellum. It was found that methylmercury caused a marked degenerative change to the granule cell layers but not to the Purkinje cell layers. The generative change of the granule cell layer was due to cell death, including apoptosis, which occurred at day 21 and beyond after the methylmercury administration. Meanwhile, cytotoxic T-lymphocytes and macrophages had infiltrated the granule cell layer. Additionally, granule cells are shown to be a cell type susceptible to TNF-α. Taken together, these results suggest that methylmercury causes small-scale damage to granule cells, triggering the infiltration of cytotoxic T-lymphocytes and macrophages into the granule cell layer, which secrete tumor necrosis factor-α (TNF-α) to induce apoptosis in granule cells. This chain is established based on the susceptibility of granule cells to methylmercury, the ability of cytotoxic T lymphocytes and macrophages to synthesize and secrete TNF-α, and the sensitivity of granule cells to TNF-α and methylmercury. We propose to call the pathology of methylmercury-induced cerebellar damage the "inflammation hypothesis."

Methylmercury (MeHg) is the causal substrate of Minamata disease and a major environmental toxicant. MeHg is widely distributed, mainly in the ocean, meaning its bioaccumulation in seafood is a considerable problem for human health. MeHg has been intensively investigated and is known to induce inflammatory responses and neurodegeneration. However, the relationship between MeHg-induced inflammatory responses and neurodegeneration is not understood. In the present review, we first describe recent findings showing an association between inflammatory responses and certain MeHg-unrelated neurological diseases caused by neurodegeneration. In addition, cell-specific MeHg-induced inflammatory responses are summarized for the central nervous system including those of microglia, astrocytes, and neurons. We also describe MeHg-induced inflammatory responses in peripheral cells and tissue, such as macrophages and blood. These findings provide a concept of the relationship between MeHg-induced inflammatory responses and neurodegeneration, as well as direction for future research of MeHg-induced neurotoxicity.

Objective: It remains unclear which factors contribute to dysphagia recovery after an acute stroke. This study aimed to identify factors associated with complete oral intake recovery in patients with post-stroke dysphagia., Methods: Data were obtained from the Diagnosis Procedure Combination database, which is a nationwide database of administrative claims and discharge abstracts in Japan. We selected patients admitted within 3 days of stroke onset and conducted multivariable logistic regression analysis. Total oral intake within 30 days of admission was the primary outcome measure., Results: A total of 151,302 patients were included, and total oral intake was observed in 48% of them within 30 days of admission. Total oral intake was significantly associated with age, sex, stroke subtype, consciousness disturbance, low body mass index, multiple comorbidities, and the modified Rankin Scale before stroke onset. In addition, males had worse outcomes than females (odds ratio, 0.75; 95% confidence interval, 0.73-0.77, p < 0.001), and intracerebral and subarachnoid hemorrhagic stroke subtypes were associated with non-recovery., Conclusion: This study identified several prognostic factors for total oral intake in patients with acute stroke. These results may be useful for predicting a patient's dysphagia prognosis at the time of admission and designing a nutritional management plan for patients with acute stroke., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The type 2 Ca 2+ -dependent activator protein for secretion (CAPS2/CADPS2) regulates dense-core vesicle trafficking and exocytosis and is involved in the regulated release of catecholamines, peptidergic hormones, and neuromodulators. CAPS2 is expressed in the pancreatic exocrine acinar cells that produce and secrete digestive enzymes. However, the functional role of CAPS2 in vesicular trafficking and/or exocytosis of non-regulatory proteins in the exocrine pancreas remains to be determined. Here, we analyzed the morpho-pathological indicators of the pancreatic exocrine pathway in Cadps2 -deficient mouse models using histochemistry, biochemistry, and electron microscopy. We used whole exosome sequencing to identify CADPS2 variants in patients with chronic pancreatitis (CP). Caps2/Cadps2 -knockout (KO) mice exhibited morphophysiological abnormalities in the exocrine pancreas, including excessive accumulation of secretory granules (zymogen granules) and their amylase content in the cytoplasm, deterioration of the fine intracellular membrane structures (disorganized rough endoplasmic reticulum, dilated Golgi cisternae, and the appearance of empty vesicles and autophagic-like vacuoles), as well as exocrine pancreatic cell injury, including acinar cell atrophy, increased fibrosis, and inflammatory cell infiltration. Pancreas-specific Cadps2 conditional KO mice exhibited pathological abnormalities in the exocrine pancreas similar to the global Cadps2 KO mice, indicating that these phenotypes were caused either directly or indirectly by CAPS2 deficiency in the pancreas. Furthermore, we identified a rare variant in the exon3 coding region of CADPS2 in a non-alcoholic patient with CP and showed that Cadps2-dex3 mice lacking CAPS2 exon3 exhibited symptoms similar to those exhibited by the Cadps2 KO and cKO mice. These results suggest that CAPS2 is critical for the proper functioning of the pancreatic exocrine pathway, and its deficiency is associated with a risk of pancreatic acinar cell pathology., 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 © 2022 Sato, Tsuyusaki, Takahashi-Iwanaga, Fujisawa, Masamune, Hamada, Matsumoto, Tanaka, Kakuta, Yamaguchi-Kabata, Furuse, Wakana, Shimura, Kobayashi, Shinoda, Goitsuka, Maezawa, Sadakata, Sano and Furuichi.)

Objective: We aim to clarify the differences in the association between re-admission for heart failure (HF) and left atrial (LA) overload indices by sex in heart failure and a preserved ejection fraction (HFpEF)., Methods: We analyzed 898 HFpEF patients hospitalized for acute decompensated HF. Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for HF during the first year., Results: The ratio of diastolic elastance to arterial elastance ( p = 0.014), a relative index of LA pressure overload, in men and LA volume index (LAVI, p = 0.020) in women were significant for re-admission for HF during the first year in the multivariable Fine-Gray analysis. Stroke volume (SV)/LA volume (LAV), another index for LAV overload, was not a significant prognostic factor of re-admission for HF during this time., Conclusion: LA overload was an important prognostic factor for HF re-readmission during the first year after enrolment in patients with HFpEF, but the indices relating to LA overload differed by sex.

Background: A prospective audit with intervention and feedback (PAF) by pharmacists is important for the appropriate use of antimicrobials. Clinically, Escherichia coli (E. coli) bacteremia is a common condition, but only few researchers have examined the role of PAF in its appropriate use of antimicrobials., Methods: We started PAF by pharmacists in 2017 for all injectable antibiotics. This study included cases of E. coli bacteremia that resulted in hospitalization over a 4 year period from 2016 to 2019. Patients were grouped by year (Period 0-3), and clinical outcomes were examined., Results: The pharmacists had 12 and 54 suggestions in Periods 0 and 3, respectively. The most common suggestion was de-escalation. The median duration of antimicrobial use was 12 (interquartile range: 8-15) days in Periods 0-2. The duration of antimicrobial use was significantly reduced to 9 (7-12) days in Period 3. In Period 3, the duration of antimicrobial use was reduced by 29%, while anti-pseudomonal drug use was reduced by 42% compared with that in period 0. The 30 day mortality rates were not significantly different between the groups., Conclusions: PAF by pharmacists promotes the appropriate use of antimicrobials in patients with E. coli bacteremia; it is important to continue the program for several years., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Hibernoma is an uncommon benign tumor of brown fat cells that consistently expresses uncoupling protein 1 (UCP1). Herein, we clinicopathologically characterized 16 liposarcomas, for which histology, at least focally, closely resembled that of hibernoma, including sheets of brown fat-like, finely multivacuolated-to-eosinophilic tumor cells with no or minimal nuclear atypia. The cohort consisted of 4 well-differentiated liposarcomas (WDLSs), 6 dedifferentiated liposarcomas with a concomitant WDLS component, and 6 myxoid liposarcomas (MLSs). For all dedifferentiated liposarcoma cases, hibernoma-like histology was present only in the WDLS component. All tumors presented as large, deep-seated masses. Hibernoma-like histology resembled the pale cell, mixed cell, eosinophilic cell, or spindle cell subtypes of hibernoma, and it was a focal observation, with conventional liposarcoma histology coexisting in all cases. However, a few biopsy samples were predominated by hibernoma-like patterns, and 1 case was initially interpreted as hibernoma. Hibernoma-like components in WDLS immunohistochemically coexpressed MDM2 and CDK4 in most cases and harbored MDM2 amplification in tested cases, whereas half of the cases expressed UCP1. The hibernoma-like components of MLS expressed DDIT3, and DDIT3 rearrangements were present in the tested cases, whereas only negative or equivocal UCP1 expression was observed. In summary, WDLS and MLS focally demonstrate hibernoma-like histology on rare occasions. These elements are neoplastic, and some such areas in WDLS likely represent true brown fat differentiation, as supported by UCP1 expression. This pattern requires recognition to avoid the misdiagnosis as hibernoma, especially in biopsies. A careful search for classic liposarcoma histology and additional work-ups for the MDM2/CDK4 or DDIT3 status will be helpful for an accurate diagnosis., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by JSPS KAKENHI (Grant Number JP21K06919, A.Y.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To describe the operation of an outpatient rehabilitation practice at a Japanese hospital severely affected by the coronavirus disease 2019 (COVID-19) pandemic., Design: Analytical observational study., Setting: Outpatient rehabilitation department in Saitama, Japan., Participants: Number (N=953) of outpatients from January 2019 to July 2021., Interventions: Not applicable., Main Outcome Measures: This paper begins with a review of the infection control measures that were initiated after declaration of a state of emergency in April 2020. The effects of the pandemic were then examined by comparing the daily average number of outpatients from January 2020 to July 2021 with that noted for the same duration during 2019., Results: In April 2020, the average daily number of patients decreased by 77.1% compared with the number in 2019 and was further decreased by 65.7% and 63.7% in May and June 2020, respectively. The time limitations on rehabilitation were lifted in June, and the number of patients increased by 82.3% in July 2020. Thereafter, it remained at approximately 80% throughout the rest of the year compared with that noted in 2019. From January 2021 to July 2021, the number of patients approached the number noted during normal practice or was even higher., Conclusions: The implementation of infection control measures, adjustments to procedures, and widespread vaccination permitted the continuation of our outpatient practice., (© 2022 The Authors.)

Objectives: The prognostic significance of an afterload-integrated diastolic index, the ratio of diastolic elastance (Ed) to arterial elastance (Ea) (Ed/Ea=[E/e']/[0.9×systolic blood pressure]), is valid for 1 year after discharge in older patients with heart failure with preserved ejection fraction (HFpEF). We aimed to clarify the association with changes in Ed/Ea from enrolment to 1 year and prognosis thereafter in patients with HFpEF., Setting: A prospective, multicentre observational registry of collaborating hospitals in Osaka, Japan., Participants: We enrolled 659 patients with HFpEF hospitalised for acute decompensated heart failure (men/women: 296/363). Blood tests and transthoracic echocardiography were performed before discharge and at 1 year after., Primary Outcome Measures: All-cause mortality and/or re-admission for heart failure were evaluated after discharge., Results: High Ed/Ea assessed before discharge was a significant prognostic factor during the first, but not the second, year after discharge in all-cause mortality or all-cause mortality and/or re-admission for heart failure. When re-analysis was performed using the value of Ed/Ea at 1 year after discharge, high Ed/Ea was significant for the prognosis during the second year for both end points (p=0.012 and p=0.033, respectively). The poorest mortality during 1‒2 years after enrolment was observed in those who showed a worsening Ed/Ea during the first year associated with larger left ventricular mass index and reduced left ventricular ejection fraction. In all-cause mortality and/or re-admission for heart failure, the event rate during 1‒2 years was highest in those with persistently high Ed/Ea even after 1 year., Conclusions: Time-sensitive prognostic performance of Ed/Ea, an afterload-integrated diastolic index, was observed in older patients with HFpEF., Trial Registration Number: UMIN000021831., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Spinal metastases can cause intractable pain and neurological deficits, which can markedly worsen both patients' activities of daily living (ADL) and their health-related quality of life (QOL). Early intervention is essential to prevent irreversible neurological deficits and pain associated with spinal metastases. We investigated the imaging features of spinal metastases that led to neurological deficits., Methods: We analyzed axial cross-sectional computed tomography (CT) images of cervical and thoracic spinal metastases in patients with and without lower limb motor paralysis, neuropathic pain, and local nociceptive pain. We distinguished regions of the spine associated with these respective symptoms, and explored their inferable performance using images obtained before symptom onset. In addition, we analyzed the imaging features and type of bone metastasis (osteolytic and osteoblastic)., Results: Spinal lesions occupied the area in and around the spinal canal and around the pedicle in patients with motor paralysis. Lesions around the pedicle and in the most posterior vertebral body part before symptom onset were inferable. In patients with neuropathic pain, spinal metastases spread along the pedicle before symptom onset, and had surrounded the spinal canal circumferentially at symptom onset. Local nociceptive pain was more common near the center of the vertebral body either at or before symptom onset. There was no difference in the imaging features according to the type of bone metastasis., Conclusions: Lesions in certain regions in the asymptomatic metastatic spine can indicate the onset of spinal metastasis-related symptoms in the next few months. Early therapeutic intervention might be applied to prevent neurological disorder.

Background: The prognostic factors of retroperitoneal soft tissue sarcoma (STS) have been explored but not yet certain. This study evaluated the prognostic impact of various preoperative clinical parameters and inflammatory indices in primary STS, with a particular focus on the transition of inflammatory index before and after tumor resection in de-differentiated liposarcoma (DD-LPS)., Methods: The clinical data of 113 patients with primary retroperitoneal STS receiving tumor resection were reviewed. Six variables (neutrophils, platelets, C-reactive protein (CRP), lymphocytes, albumin, and hemoglobin) in the blood samples were measured and nine inflammatory indices (neutrophil-lymphocyte ratio (NLR), CRP-lymphocyte ratio (CLR), platelet-lymphocyte ratio (PLR), neutrophil-albumin ratio (NAR), CRP-albumin ratio (CAR), platelet-albumin ratio (PAR), HALP (hemoglobin, albumin, lymphocyte and platelet), prognostic nutrition index (PNI), and modified Glasgow Prognostic Score (mGPS)) were calculated. The prognostic value of the indices was analyzed by univariate and multivariate analyses., Results: Elevated NLR, CLR, PLR, NAR, CAR, PAR, and mGPS were associated with a worse overall survival (p = 0.0124, 0.0011, 0.049, 0.0047, 0.0085, 0.0332, and 0.0086, respectively) in univariate analysis. Multivariate analysis showed that elevated CLR and DD-LPS were associated with poor overall survival (p = 0.0267 and 0.0218, respectively) in all retroperitoneal STS. In DD-LPD, patients with preoperative high CLR, whose postoperative CLR was normalized, demonstrated a favorable survival rate similar to those with preoperative low CLR., Conclusions: Elevated CLR before surgery as well as DD-LPS were poor prognostic markers for overall survival in primary retroperitoneal STS. Perioperative CLR normalization may be related to a favorable prognosis in DD-LPS., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: Catheter ablation is a therapeutic option to suppress ventricular tachycardia (VT) in the setting of dilated-phase hypertrophic cardiomyopathy (DHCM). However, the characteristics of the arrhythmogenic substrate and the ablation outcome are not fully illustrated., Method: A total of 23 ablation procedures for drug-refractory sustained monomorphic VTs in 13 DHCM patients (60 ± 11 years, one female, the left ventricular [LV] ejection fraction 39% ± 9%, the LV mass index 156 ± 39 g/m 2 ) were performed. The distribution of VT substrate as endocardial or epicardial/intramural was based on detailed mapping and ablation response during VT., Result: Two patients underwent ablation of sustained monomorphic VT that was not scar-mediated tachycardia. Of the remaining 11 patients, eight (73%) patients had VT substrate in the basal regions, most frequently at the epicardial and/or intramural basal antero-septum. None of the patients had VT substrate located at the LV inferolateral region. Ablation at the right ventricular septum and the aortic cusps was done in four and five patients, respectively. Other approaches including bipolar and chemical ablations, were done in three and two patients, respectively. Six (55%) out of 11 patients (two patients lost follow-up) had VT recurrence. All the six patients had basal substrate. However, anti-tachycardia pacing was sufficient for VT termination except in one patient., Conclusion: Catheter ablation of VT in patients with DHCM is challenging because of the predominant basal anteroseptal epicardial/intramural location of arrhythmogenic substrate. An ablation approach from multiple sites and/or adjunctive interventional techniques are often required., (© 2022 Wiley Periodicals LLC.)

Purpose: Enzalutamide is a potent inducer of cytochrome P450 substrates. Hence, it induces major metabolizing enzyme effects in some of the concomitant drugs, raising the possibility of decreased efficacy. We investigated the actual status of drugs for which precautions for co-administration are indicated during concomitant use with enzalutamide., Methods: We retrospectively investigated the duration of enzalutamide use, concomitant medications, laboratory values, and events using the medical records of patients prescribed enzalutamide for castration-resistant prostate cancer at the National Cancer Center Hospital from May 2014 to May 2017., Results: The median age of the 107 studied patients was 74 years[range: 53-93], median duration of enzalutamide prescriptions was 120 days[range: 14-1,008], and the median number of concomitant medications(components)was 6[range: 0-16]. Sixty nine patients(64%)were taking drugs that could be affected by enzyme induction. The medications listed in the concomitant use section of the package insert were warfarin(3 patients) and omeprazole(2 patients). In this study, 4 patients(except for 1 on warfarin)were taking other drugs that could be affected by enzyme induction. Events considered to possibly reduce their efficacy during concomitant use with enzalutamide were elevated blood pressure and blood clots., Conclusions: When enzalutamide is used in combination with other drugs, there exists the possibility that the effect of concomitant medications may be weakened by enzyme induction.

Orotate, a nutritional compound typically utilized as an intermediate in pyrimidine synthesis, has been suggested to undergo renal reabsorption. However, the detailed mechanisms involved in the process remain unclear, with only urate transporter 1 (URAT1/SLC22A12) being indicated as a transporter involved in its tubular uptake. As an attempt to identify transporters involved in that to help clarify the mechanisms, we examined a possibility that organic anion transporter 10 (OAT10/SLC22A13), which is present at the brush border membrane in renal tubular epithelial cells, could transport orotate. The operation of human OAT10 for orotate transport was demonstrated indeed and analyzed in detail in Madin-Darby canine kidney II cells introduced with this transporter by stable transfection. Orotate transport by OAT10 was found to be kinetically saturable with a biphasic characteristic and dependent on Cl - . These are unique characteristics previously unknown in its operation for the other substrates. Orotate transport by OAT10 was, on the other hand, inhibited by several anionic compounds known as OAT10 inhibitors. Finally, the rat ortholog of OAT10 was found not to be able to transport orotate, indicating animal species differences in that function. Thus, human OAT10 has been demonstrated to operate for orotate transport with unique characteristics., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by repetitive behaviors and social impairments, often accompanied by learning disabilities. It has been documented that the neuropeptide oxytocin (OXT) ameliorates core symptoms in patients with ASD. We recently reported that chronic administration of intranasal OXT reversed social and learning impairments in prenatally valproic acid (VPA)-exposed rats. However, the underlying molecular mechanisms remain unclear. Here, we explored molecular alterations in the hippocampus of rats and the effects of chronic administration of intranasal OXT (12 μg/kg/d). Microarray analyses revealed that prenatal VPA exposure altered gene expression, a part of which is suggested as a candidate in ASD and is involved in key features including memory, developmental processes, and epilepsy. OXT partly improved the expression of these genes, which were predicted to interact with those involved in social behaviors and hippocampal-dependent memory. Collectively, the present study documented molecular profiling in the hippocampus related to ASD and improvement by chronic treatment with OXT., 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 © 2022 Matsuo, Shinoda, Abolhassani, Nakabeppu and Fukunaga.)

We previously show that fatty acid-binding protein 3 (FABP3) triggers α-synuclein (Syn) accumulation and induces dopamine neuronal cell death in Parkinson disease mouse model. But the role of fatty acid-binding protein 7 (FABP7) in the brain remains unclear. In this study we investigated whether FABP7 was involved in synucleinopathies. We showed that FABP7 was co-localized and formed a complex with Syn in Syn-transfected U251 human glioblastoma cells, and treatment with arachidonic acid (100 M) significantly promoted FABP7-induced Syn aggregation, which was associated with cell death. We demonstrated that synthetic FABP7 ligand 6 displayed a high affinity against FABP7 with K d value of 209 nM assessed in 8-anilinonaphthalene-1-sulfonic acid (ANS) assay; ligand 6 improved U251 cell survival via disrupting the FABP7-Syn interaction. We showed that activation of phospholipase A2 (PLA2) by psychosine (10 M) triggered oligomerization of endogenous Syn and FABP7, and induced cell death in both KG-1C human oligodendroglia cells and oligodendrocyte precursor cells (OPCs). FABP7 ligand 6 (1 M) significantly decreased Syn oligomerization and aggregation thereby prevented KG-1C and OPC cell death. This study demonstrates that FABP7 triggers α-synuclein oligomerization through oxidative stress, while FABP7 ligand 6 can inhibit FABP7-induced Syn oligomerization and aggregation, thereby rescuing glial cells and oligodendrocytes from cell death., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Omnipause neurons (OPNs) in the nucleus raphe interpositus have tonic activity while the eyes are stationary ("fixation") but stop firing immediately before and during saccades. To locate the source of suppression, we analyzed synaptic inputs from the rostral and caudal superior colliculi (SCs) to OPNs by using intracellular recording and staining, and investigated pathways transmitting the inputs in anesthetized cats of both sexes. Electrophysiologically or morphologically identified OPNs received monosynaptic excitation from the rostral SCs with contralateral dominance, and received disynaptic inhibition from the caudal SCs with ipsilateral dominance. Cutting the tectoreticular tract transversely between the contralateral OPN and inhibitory burst neuron (IBN) regions eliminated inhibition from the caudal SCs, but not excitation from the rostral SCs in OPNs. In contrast, a midline section between IBN regions eliminated disynaptic inhibition in OPNs from the caudal SCs but did not affect the monosynaptic excitation from the rostral SCs. Stimulation of the contralateral IBN region evoked monosynaptic inhibition in OPNs, which was facilitated by preconditioning SC stimulation. Three-dimensional reconstruction of HRP-stained cells revealed that individual OPNs have axons that terminate in the opposite IBN area, while individual IBNs have axon collaterals to the opposite OPN area. These results show that there are differences in the neural circuit from the rostral and caudal SCs to the brainstem premotor circuitry and that IBNs suppress OPNs immediately before and during saccades. Thus, the IBNs, which are activated by caudal SC saccade neurons, shut down OPN firing and help to trigger saccades and suppress ("latch") OPN activity during saccades. SIGNIFICANCE STATEMENT Saccades are the fastest eye movements to redirect gaze to an object of interest and bring its image on the fovea for fixation. Burst neurons (BNs) and omnipause neurons (OPNs) which behave reciprocally in the brainstem, are important for saccade generation and fixation. This study investigated unsolved important questions about where these neurons receive command signals and how they interact for initiating saccades from visual fixation. The results show that the rostral superior colliculi (SCs) excite OPNs monosynaptically for fixation, whereas the caudal SCs monosynaptically excite inhibitory BNs, which then directly inhibit OPNs for the initiation of saccades. This inhibition from the caudal SCs may account for the omnipause behavior of OPNs for initiation and maintenance of saccades in all directions., (Copyright © 2022 the authors.)

We report a 64-year-old Japanese woman with a history of progressive loss of motor function and painful swelling of large joints. At the age of 54, profound calcification appeared around the shoulder and hip joints, which did not heal after repeated surgical resections. Iliac bone biopsy revealed osteomalacic changes. Laboratory data showed low serum alkaline phosphatase (ALP) activity and a high urine phosphoethanolamine (PEA) concentration with normal serum calcium, phosphate, and fibroblast growth factor 23 (FGF23) levels. Subsequent genetic analysis of the ALPL gene confirmed the diagnosis of hypophosphatasia (HPP) with the identification of a heterozygous single nucleotide deletion, c.1559delT (p.Leu520ArgfsX86). We started a mineral-targeted enzyme replacement therapy, asfotase alfa (AA), to treat the patient's musculoskeletal symptoms. A follow-up bone biopsy after 12 months of AA treatment showed improvement of osteomalacia. Calcified deposits around the large joints were unchanged radiographically. To our knowledge, this is the first report of a patient with an adult-onset HPP who presented with profound calcification around multiple joints. Nonspecific clinical signs and symptoms in patients with adult-onset HPP often result in delayed diagnosis or misdiagnosis. We propose that bone biopsy and genetic analysis should be considered along with laboratory analysis for all patients with ectopic calcification around joints of unknown etiology for accurate diagnosis and better treatment., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)