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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.)

Persistence of urinary incontinence (UI) after robot-assisted radical prostatectomy (RARP) is a bothersome problem because of its negative effect on the patient's quality of life (QOL). This study aimed to evaluate the effect of transperineal ultrasound (TPUS)-guided pelvic floor muscle training (PFMT) on prolonged UI after RARP. Thirty men with stress UI persisting for > 1 year after RARP underwent biofeedback PFMT using TPUS once every 2-3 weeks for 3 months. The frequency and duration of sustaining pelvic floor muscle (PFM) contractions were assessed using ultrasound imaging. The severity of UI and UI-related QOL were evaluated using a 24-hour pad test and the incontinence quality of life (I-QOL) questionnaire. Twenty-four men (mean age, 72.2 years) completed the TPUS-guided PFMT. The mean duration from RARP to PFMT was 1,228.9 days. The mean cumulative session and the total duration of TPUS-guided PFMT were 4.6 times and 73.3 days, respectively. Compared with the data before TPUS-guided PFMT, the frequency of PFM contractions and duration of sustaining contraction significantly improved after TPUS-guided PFMT (p < 0.05). Additionally, the total amount of urinary leakage after TPUS-guided PFMT was reduced significantly (248.6 ± 280.6 g vs. 397.0 ± 427.0 g, p = 0.024). The I-QOL score was significantly increased after TPUS-guided PFMT (72.1 ± 16.8 vs. 61.0 ± 19.0, p < 0.001). TPUS-guided PFMT may be effective in improving prolonged UI occurring > 1 year after RARP.

Malignant meningioma has a poor prognosis and there are currently no effective therapies. Avenaciolide is water-insoluble natural organic product produced by Aspergillus avenaceus G. Smith that can inhibit mitochondrial function. In the present study, we investigated the anti-cancer effects of avenaciolide in an isolated human malignant meningioma cell line, HKBMM. In addition, to assess the specificity of avenaciolide, its effects on normal human neonatal dermal fibroblast HDFn cells were also examined. Avenaciolide showed effective anti-cancer activity, and its cytotoxicity in HKBMM cells was greater than that in HDFn cells. The anti-cancer effects of avenaciolide were mediated by reactive oxygen species (ROS)-induced apoptosis, which may have been caused by mitochondrial disfunction. These results suggest that avenaciolide has potential as a therapeutic drug for malignant meningioma.

Background: Eribulin is a tubulin and microtubule-targeting drug that has clinical benefit in overall survival (OS) for patients with advanced soft tissue sarcoma. Eribulin's efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. We therefore sought to clarify the predictive factor of eribulin treatment, while focusing on systemic inflammation and immune response values., Methods: This study included 33 advanced STS patients treated with eribulin between March 2016 and September 2019. We evaluated the associations of clinical factors influencing the efficacy of eribulin treatment and systemic inflammatory and immune response, including the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the lymphocyte-to-monocyte ratio (LMR), the systemic inflammation response index (SIRI), and the prognostic nutrition index (PNI), with progression-free survival (PFS) and OS using the Kaplan-Meier method and log-rank test., Results: NLR, LMR, PLR, SIRI, and PNI were unassociated with PFS. Compared with patients with SIRI <1.5, those with an SIRI ≥1.5 had a significantly shorter OS [median OS 15 months (95% confidence interval [CI] 8-not reached) vs. 7 months (95% CI 3-14), P = 0.04]. Moreover, the PFS tended to be shorter for patients with SIRI ≥1.5 who received chemotherapy after eribulin treatment than in those with SIRI >1.5 [median PFS 92.5 days (95% CI 27-204) vs. 133 days (95% CI 36-507), P = 0.08]., Conclusions: High SIRI values may predict poorer overall survival and the efficacy of subsequent drugs after eribulin treatment among patients with advanced soft tissue sarcoma., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest relevant to this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Fibronectin and leucine-rich transmembrane (FLRT) proteins are necessary for various developmental processes and in pathological conditions. FLRT2 acts as a homophilic cell adhesion molecule, a heterophilic repulsive ligand of Unc5/Netrin receptors, and a synaptogenic molecule; the last feature is mediated by binding to latrophilins. Although the function of FLRT2 in regulating cortical migration at the late gestation stage has been analyzed, little is known about the expression pattern of FLRT2 during postnatal central nervous system (CNS) development. In this study, we used Flrt2-LacZ knock-in (KI) mice to analyze FLRT2 expression during CNS development. At the early postnatal stage, FLRT2 expression was largely restricted to several regions of the striatum and deep layers of the cerebral cortex. In adulthood, FLRT2 expression was more prominent in the cerebral cortex, hippocampus, piriform cortex (PIR), nucleus of the lateral olfactory tract (NLOT), and ventral medial nucleus (VM) of the thalamus, but lower in the striatum. Notably, in the hippocampus, FLRT2 expression was confined to the CA1 region and partly localized on pre- and postsynapses whereas only few expression was observed in CA3 and dentate gyrus (DG). Finally, we observed temporally limited FLRT2 upregulation in reactive astrocytes around lesion sites 7 days after thoracic spinal cord injury. These dynamic changes in FLRT2 expression may enable multiple FLRT2 functions, including cell adhesion, repulsion, and synapse formation in different regions during CNS development and after spinal cord injury., 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 © 2021 Li, Shinoda, Ogawa, Ikegaya, Li, Matsuyama, Sato and Yamagishi.)

Background: Atrial fibrillation (AF) may cause cerebral and systemic embolism. An increased D-dimer level indicates hyperactivation of secondary fibrinolysis, resulting in predilection for thrombosis. To clarify the differential effects of anticoagulation therapy, we compared the D-dimer levels in peripheral and left atrial (LA) blood of atrial fibrillation patients scheduled for ablation., Methods: We analyzed 141 patients with non-valvular AF (dabigatran, n = 30; apixaban, n = 47; edoxaban, n = 64; mean age: 68 years, male: 60%). Peripheral venous blood and LA blood was collected before pulmonary vein isolation. We examined the laboratory and echocardiographic parameters., Results: After adjusting for baseline characteristics, D-dimer level in the LA was significantly higher in patients treated with edoxaban than that in those on apixaban (0.77 ± 0.05 vs. 0.60 ± 0.05 μg/mL, P = 0.047), although there were no significant differences in peripheral D-dimer levels. We classified the D-dimer value of the LA into a normal group (< 0.9) and a high value group (≥ 1.0); the peripheral prothrombin fragment F1 + 2 level (odds ratio [OR] 1.012; 95% confidence interval [CI]: 1.003-1.022; P = 0.008) and left ventricular ejection fraction (LVEF) (OR, 0.947; 95% CI, 0.910-0.986; P = 0.008) were potential predictors of high LA D-dimer levels., Conclusions: In apixaban-treated patients, the D-dimer level in the left atrium was lower than in edoxaban-treated patients on the day of ablation, suggesting that the anticoagulant effect of apixaban on the left atrium is better than that of edoxaban in patients with AF., (© 2021. The Author(s).)

The widely held assumption that any important scientific information would be available in English underlies the underuse of non-English-language science across disciplines. However, non-English-language science is expected to bring unique and valuable scientific information, especially in disciplines where the evidence is patchy, and for emergent issues where synthesising available evidence is an urgent challenge. Yet such contribution of non-English-language science to scientific communities and the application of science is rarely quantified. Here, we show that non-English-language studies provide crucial evidence for informing global biodiversity conservation. By screening 419,679 peer-reviewed papers in 16 languages, we identified 1,234 non-English-language studies providing evidence on the effectiveness of biodiversity conservation interventions, compared to 4,412 English-language studies identified with the same criteria. Relevant non-English-language studies are being published at an increasing rate in 6 out of the 12 languages where there were a sufficient number of relevant studies. Incorporating non-English-language studies can expand the geographical coverage (i.e., the number of 2° × 2° grid cells with relevant studies) of English-language evidence by 12% to 25%, especially in biodiverse regions, and taxonomic coverage (i.e., the number of species covered by the relevant studies) by 5% to 32%, although they do tend to be based on less robust study designs. Our results show that synthesising non-English-language studies is key to overcoming the widespread lack of local, context-dependent evidence and facilitating evidence-based conservation globally. We urge wider disciplines to rigorously reassess the untapped potential of non-English-language science in informing decisions to address other global challenges. Please see the Supporting information files for Alternative Language Abstracts., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To evaluate whether the extent of seminal vesicle invasion of prostatic adenocarcinoma can stratify the risk of biochemical recurrence after radical prostatectomy., Methods: We carried out radical prostatectomy for 1309 patients with prostatic adenocarcinoma between 2006 and 2019; 135 (10.3%) patients had seminal vesicle invasion. After excluding patients with neo-/adjuvant therapy, we reviewed 105 patients. We analyzed the correlation of the extent of seminal vesicle invasion and biochemical recurrence-free survival after prostatectomy and adjusted by various clinicopathological factors in multivariate analyses. Seminal vesicle invasion was stratified into three groups; the proximal part from the base was defined as level 1, followed by level 2 and the distal part as level 3., Results: Among the 105 patients, 30 (29%), 54 (51%) and 21 patients (20%) had seminal vesicle invasion at levels 1, 2 and 3, respectively. Median times to biochemical recurrence were 110, 67 and 12 months in patients with levels 1, 2 and 3, respectively (P = 0.002). The extent of seminal vesicle invasion was the independent risk factor for biochemical recurrence in univariate (level 3 vs 1, P = 0.001; level 3 vs 2, P = 0.015) and multivariate analyses (level 3 vs 1, P = 0.025; level 3 vs 2, P = 0.030)., Conclusions: The extent of seminal vesicle invasion might be a significant predictor of biochemical recurrence in prostate cancer patients undergoing radical prostatectomy., (© 2021 The Japanese Urological Association.)

Purpose: Antral pulmonary vein isolation (PVI) using a radiofrequency hot balloon catheter (RHB) is a feasible therapeutic option for treating atrial fibrillation (AF). Lesion durability after antral RHB-PVI remains unknown. This study aimed to evaluate lesion durability and the associations between procedural characteristics after antral RHB-PVI., Methods: A total of 200 patients received antral RHB-PVI using the single-shot technique between April 2016 and March 2018. Antral RHB-PVI was performed following a pre-specified protocol and RHB energy application was performed for a maximum of two times for each PV. Consecutive patients who underwent repeated procedures for recurrence of any type of atrial tachyarrhythmia were enrolled., Results: Twenty-six (13%) patients underwent repeated ablation and 20 patient documented AF recurrence (AF group) and 6 patients documented non-AF recurrence (non-AF group). Repeated ablation was performed at a median (25th, 75th percentiles) of 378 days (217, 487) after the initial procedure and durable PVI was observed in 86 (83.5%) PVs. Durability reached 89.7% when PVI was achieved only using an RHB. In the AF group (79 PVs), durable PVI was observed in 62 (78.5%) PVs, whereas all 24 PVs were still isolated in the non-AF group. The majority of reconnection sites were around the superior PVs., Conclusions: Antral RHB-PVI shows high lesion durability, especially with both inferior PVs., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study investigates the effect of stellate ganglion (SG) phototherapy in healthy participants and assesses its efficacy in suppressing electrical storm (ES) refractory to antiarrhythmic drugs and catheter ablation., Background: Modulation of the autonomic nervous system has been shown to be an effective adjunctive therapy for ES., Methods: Ten-minute SG phototherapy was performed twice weekly for 4 weeks in 20 healthy volunteers. To evaluate the acute and chronic effects of SG phototherapy, heart rate variability and serum concentrations of adrenaline, noradrenaline, and dopamine were obtained before phototherapy, immediately after the first phototherapy session, after 8 sessions of phototherapy, and 3 months after the first phototherapy session. In addition, the efficacy of SG phototherapy was evaluated in 11 patients with ES refractory to medication, sedation, and catheter ablation., Results: In healthy participants, serum adrenaline concentration significantly decreased after phototherapy, whereas low-frequency power/high-frequency power significantly decreased during phototherapy. Moreover, the effect on heart rate variability did not last beyond 3 months. In the clinical pilot study, 7 patients had a suppression of ES after SG phototherapy; however, without maintenance therapy, 2 patients had a recurrence of ventricular arrhythmias. Furthermore, it did not control ES in 4 patients., Conclusions: SG phototherapy reduced sympathetic activity and may be a safe and effective adjunctive therapy to control ES in some patients, but its long-term efficacy remains unknown. Chronic phototherapy might help reduce ES recurrence., Competing Interests: Funding Support and Author Disclosures Dr Soejima has received honoraria for lectures from Abbott Japan and Medtronic Japan. Dr Nogami has received honoraria from Abbott Japan and Boston Scientific; and endowments from Medtronic Japan and Johnson & Johnson. Drs Ueda and Sato have endowments from Biotronik Japan and Abbott Japan. Dr Togashi has endowments from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The severity of diastolic dysfunction is assessed using a combination of several indices of left atrial (LA) volume overload and LA pressure overload. We aimed to clarify which overload is more associated with the prognosis in patients with heart failure and preserved ejection fraction (HFpEF)., Setting: A prospective, multicenter observational registry of collaborating hospitals in Osaka, Japan., Participants: We enrolled hospitalised patients with HFpEF showing sinus rhythm (men, 79; women, 113). Blood tests and transthoracic echocardiography were performed before discharge. The ratio of diastolic elastance (Ed) to arterial elastance (Ea) was used as a relative index of LA pressure overload., Primary Outcome Measures: All-cause mortality and admission for heart failure were evaluated at >1 year after discharge., Results: In the multivariable Cox regression analysis, Ed/Ea, but not LA volume index, was significantly associated with all-cause mortality or admission for heart failure (HR 2.034, 95% CI 1.059 to 3.907, p=0.032), independent of age, sex, and the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level. In patients with a higher NT-proBNP level, the effect of higher Ed/Ea on prognosis was prominent (p=0.015)., Conclusions: Ed/Ea, an index of LA pressure overload, was significantly associated with the prognosis in elderly patients with HFpEF showing sinus rhythm., Trial Registration Number: UMIN000021831., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Phosphaturic mesenchymal tumors primarily cause tumor-induced osteomalacia, a rare paraneoplastic syndrome, and half occur in soft tissues. There are few reports about the surgical margins of these tumors. This study aimed to clarify the optimal surgical margin for phosphaturic mesenchymal tumors by analyzing radiological and histopathological features., Methods: This study included eight cases, seven primary and one recurrent, of tumor-induced osteomalacia caused by soft-tissue phosphaturic mesenchymal tumors that were surgically treated between January 2000 and January 2019. We evaluated the radiological and histopathological features of all tumors and investigated the correlation of these features, the surgical margin, and recurrence of hypophosphatemia., Results: The tumors were located in superficial (n = 5) and deep (n = 3) tissues. Six of the eight tumors had a clear boundary, but five had an irregular margin. Three tumors had a hypointense rim on T2-weighted images, indicating fibrous tumor encapsulation. Histopathological analysis revealed infiltrative growth in six of the eight tumors, which correlated with an irregular margin seen on imaging. Although there was no recurrence in patients treated with an intended wide margin >1 cm, one of the three patients treated with marginal tumor resection experienced a recurrence of hypophosphatemia, with histopathological analysis showing infiltration of subcutaneous fat. In contrast, two tumors with clear boundaries, regular margins, and fibrous capsule seen on imaging, had no infiltrative growth and were cured by marginal resection. In one recurrent case, tumor infiltration was observed in the previous surgical scar, which was not detected on preoperative imaging., Conclusions: Soft-tissue phosphaturic mesenchymal tumors with an irregular boundary seen on imaging tend to be infiltrative, especially into subcutaneous fat, and should be treated by at least a 1-cm wide margin resection. Tumors with a fibrous capsule with clear and regular margins are cured by marginal margin resection. These findings could inform surgeons' decisions regarding the resection of soft-tissue phosphaturic mesenchymal tumors., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is characterized by the invariably progressive deposition of fibrotic tissue in the lungs and overall poor prognosis. TG2 (transglutaminase 2) is an enzyme that crosslinks glutamine and lysine residues and is involved in IPF pathogenesis. Despite the accumulating evidence implicating TG2 as a critical enzyme, the causative function and direct target of TG2 relating to this pathogenesis remain unelucidated. Here, we clarified the distributions of TG2 protein/activity and conducted quantitative proteomics analyses of possible substrates crosslinked by TG2 on unfixed lung sections in a mouse pulmonary fibrosis model. We identified 126 possible substrates as markedly TG2-dependently increased in fibrotic lung. Gene ontology analysis revealed that these identified proteins were mostly enriched in the lipid metabolic process, immune system process, and protein transport. In addition, these proteins were enriched in 21 pathways, including phagosome, lipid metabolism, several immune responses, and protein processing in endoplasmic reticulum. Furthermore, the network analyses screened out the six clusters and top 20 hub proteins with higher scores, which are related to endoplasmic reticulum stress and peroxisome proliferator-activated receptor signals. Several enriched pathways and categories were identified, some of which were the same terms based on transcription analysis in IPF. Our results provide novel pathological molecular networks driven by protein crosslinking via TG2, which can lead to the development of new therapeutic targets for IPF.

Background: Surgical procedure for symptomatic spinal metastasis is expected to improve the quality of life. Factors related to short-term perioperative mortality after surgery for spinal metastasis may be different from those related to long-term mortality, which have classically been used to determine the indication for surgery. The purposes of this study were to evaluate factors related to the 30-day mortality after surgery for spinal metastasis and create an integer risk scoring system., Methods: Using the Diagnosis Procedure Combination database from 2010 to 2016, we extracted data of patients who underwent surgical procedure for spinal metastasis. Multivariable logistic regression analysis was performed to clarify the association between patient backgrounds and the 30-day postoperative mortality. We created a risk scoring system using regression coefficients to estimate the 30-day mortality for each patient., Results: Among 3524 patients, the 30-day mortality was 2.6%. Factors associated with a higher 30-day mortality were male sex (odds ratio, 2.50 [95% confidence interval, 1.45-4.31]), emergency admission (1.80 [1.11-2.92]), rapid growth tumors (3.83 [2.49-5.90]), and non-skeletal metastasis (2.27 [1.42-3.64]). In patients with the maximum risk score of five, the 30-day mortality was 16.2%., Conclusions: Factors related to the 30-day mortality were male sex, emergency admission, rapid growth tumors, and non-skeletal metastasis. These findings provide spine surgeons and patients knowledge of the potential risk of short-term perioperative mortality and allow them to consider the risk of surgery., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Homer is a postsynaptic scaffold protein, which has long and short isoforms. The long form of Homer consists of an N-terminal target-binding domain and a C-terminal multimerization domain, linking multiple proteins within a complex. The short form of Homer only has the N-terminal domain and likely acts as a dominant negative regulator. Homer2a, one of the long form isoforms of the Homer family, expresses with a transient peak in the early postnatal stage of mouse cerebellar granule cells (CGCs); however, the functions of Homer2a in CGCs are not fully understood yet. In this study, we investigated the physiological roles of Homer2a in CGCs using recombinant adenovirus vectors. Overexpression of the Homer2a N-terminal domain construct, which was made structurally reminiscent with Homer1a, altered NMDAR1 localization, decreased NMDA currents, and promoted the survival of CGCs. These results suggest that the Homer2a N-terminal domain acts as a dominant negative protein to attenuate NMDAR-mediated excitotoxicity. Moreover, we identified a novel short form N-terminal domain-containing Homer2, named Homer2e, which was induced by apoptotic stimulation such as ischemic brain injury. Our study suggests that the long and short forms of Homer2 are involved in apoptosis of CGCs.

Rubber hand illusion (RHI), a kind of body ownership illusion, is sometimes atypical in individuals with autism spectrum disorder; however, the brain regions associated with the illusion are still unclear. We previously reported that mice responded as if their own tails were being touched when rubber tails were grasped following synchronous stroking to rubber tails and their tails (a "rubber tail illusion", RTI), which is a task based on the human RHI; furthermore, we reported that the RTI response was diminished in Ca 2+ -dependent activator protein for secretion 2- knockout ( Caps2 -KO) mice that exhibit autistic-like phenotypes. Importance of the posterior parietal cortex in the formation of illusory perception has previously been reported in human imaging studies. However, the local neural circuits and cell properties associated with this process are not clear. Therefore, we aimed to elucidate the neural basis of the RTI response and its impairment by investigating the c-Fos expression in both wild-type (WT) and Caps2 -KO mice during the task since the c-Fos expression occurred soon after the neural activation. Immediately following the delivery of the synchronous stroking to both rubber tails and actual tails, the mice were perfused. Subsequently, whole brains were cryo-sectioned, and each section was immunostained with anti-c-Fos antibody; finally, c-Fos positive cell densities among the groups were compared. The c-Fos expression in the posterior parietal cortex was significantly lower in the Caps2 -KO mice than in the WT mice. Additionally, we compared the c-Fos expression in the WT mice between synchronous and asynchronous conditions and found that the c-Fos-positive cell densities were significantly higher in the claustrum and primary somatosensory cortex of the WT mice exposed to the synchronous condition than those exposed to the asynchronous condition. Hence, the results suggest that decreased c-Fos expression in the posterior parietal cortex may be related to impaired multisensory integrations in Caps2 -KO mice., 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 © 2021 Wada, Takano, Ide, Sano, Shinoda, Furuichi and Kansaku.)

Ca 2+ -dependent activator protein for secretion 2 (CAPS2) regulates dense-core vesicle (DCV) exocytosis to facilitate peptidergic and catecholaminergic transmitter release. CAPS2 deficiency in mice has mild neuronal effects but markedly impairs social behavior. Rare de novo Caps2 alterations also occur in autism spectrum disorder, although whether CAPS2-mediated release influences social behavior remains unclear. Here, we demonstrate that CAPS2 is associated with DCV exocytosis-mediated release of the social interaction modulatory peptide oxytocin (OXT). CAPS2 is expressed in hypothalamic OXT neurons and localizes to OXT nerve projection and OXT release sites, such as the pituitary. Caps2 KO mice exhibited reduced plasma albeit increased hypothalamic and pituitary OXT levels, indicating insufficient release. OXT neuron-specific Caps2 conditional KO supported CAPS2 function in pituitary OXT release, also affording impaired social interaction and recognition behavior that could be ameliorated by exogenous OXT administered intranasally. Thus, CAPS2 appears critical for OXT release, thereby being associated with social behavior. SIGNIFICANCE STATEMENT The role of the neuropeptide oxytocin in enhancing social interaction and social bonding behavior has attracted considerable public and neuroscientific attention. A central issue in oxytocin biology concerns how oxytocin release is regulated. Our study provides an important insight into the understanding of oxytocin-dependent social behavior from the perspective of the CAPS2-regulated release mechanism., (Copyright © 2021 the authors.)

Although systemic therapy is the standard treatment for metastatic prostate cancer, a randomized controlled trial showed radiotherapy to the prostate improved overall survival of metastatic prostate cancer patients with the low metastatic burden. Additionally, a randomized phase II trial showed that metastasis-directed therapy for oligo-recurrent prostate cancer improved androgen-deprivation therapy (ADT)-free survival. Therefore, administering radiotherapy to both prostate and metastatic regions might result in better outcomes. Thus, we report the treatment results of radiotherapy to both prostate and metastatic regions. Our institutional database was searched for patients who received radiotherapy to the prostate and metastatic regions. We summarized patient characteristics and treatment efficacy and performed statistical analysis to find possible prognostic factors. A total of 35 patients were included in this study. The median age was 66 years, and the median initial prostate-specific antigen (PSA) level was 32 ng/ml. The Gleason score was 7 in 10 patients, 8 in 13 patients, and 9 in 12 patients. The median radiotherapy dose was 72 Gy to the prostate and 50 Gy to the metastatic bone region. The 8-year overall survival, cause-specific survival, progression-free survival, and freedom from biochemical failure rate were 81, 85, 53, and 57%. Among the 35 patients, 12 were disease-free even after ADT was discontinued. In selected patients with metastatic prostate cancer, ADT and radiotherapy to the prostate and metastatic sites were effective. Patients with good response to ADT may benefit from radiotherapy to both prostate and metastatic regions., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This article is dedicated to the memory of Masao Ito. Masao Ito made numerous important contributions revealing the function of the cerebellum in motor control. His pioneering contributions to cerebellar physiology began with his discovery of inhibition and disinhibition of target neurons by cerebellar Purkinje cells, and his discovery of the presence of long-term depression in parallel fiber-Purkinje cell synapses. Purkinje cells formed the nodal point of Masao Ito's landmark model of motor control by the cerebellum. These discoveries became the basis for his ideas regarding the flocculus hypothesis, the adaptive motor control system, and motor learning by the cerebellum, inspiring many new experiments to test his hypotheses. This article will trace the achievements of Ito and colleagues in analyzing the neural circuits of the input-output organization of the cerebellar cortex and nuclei, particularly with respect to motor control. The article will discuss some of the important issues that have been solved and also those that remain to be solved for our understanding of motor control by the cerebellum., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Soft tissue metastasis is rarer than bone metastasis. Patients with soft tissue metastasis generally have a dismal prognosis. The treatment for metastatic lesions is sometimes difficult, because the prognostic factors of patients with soft tissue metastasis remain unelucidated. Therefore, this study aimed to identify these prognostic factors., Methods: Thirty-one patients with soft tissue metastasis were included in the study. We evaluated associations of overall survival with clinical parameters and inflammatory markers using Kaplan-Meier curves and Cox proportional hazards models., Results: Twelve patients received surgery for soft tissue metastasis, while radiation therapy was performed in six cases. The median overall survival after the detection of soft tissue metastasis was 11 months. Univariate analysis revealed that detection of soft tissue metastasis after the multidisciplinary treatment (P = 0.01); solitary metastasis (P = 0.0003); and pretreatment C-reactive protein (CRP) level < 0.4 mg/dL (P < 0.0001), white blood cell count < 8500 × 10 3 /μL (P = 0.0003), and neutrophil-to-lymphocyte ratio < 5 (P = 0.02) were significant good prognostic factors. Multivariate analysis revealed that a CRP value < 0.4 mg/dL (P = 0.07) and solitary metastasis (P = 0.09) were possible significant predictors of survival. Furthermore, in case of CRP levels <0.4 mg/dL and metastatic tumor resection, patients had a good prognosis; however, when the CRP levels increased to 0.4 mg/dL and above, patients had a poor prognosis, irrespective of tumor resection., Conclusions: CRP is potentially useful for determining the indication of radical metastasectomy in soft tissue metastasis., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest relevant to this manuscript., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) accounts for the majority of dementia among the elderly. In addition to cognitive impairment, behavioral and psychological symptoms (BPSD) such as depression tendency and increased aggression impose a great burden on the patient. However, there is still no rational therapeutic drug for BPSD. Recently, we developed a novel AD therapeutic candidate, SAK3, and demonstrated that it improved cognitive dysfunction in AppNL-G-F/NL-G-F knock-in (NL-G-F) mice. In this study, we investigated whether acute SAK3 administration improved BPSD in addition to cognitive improvement. Acute SAK3 administration improved BPSD, including anxiolytic and depressive-like behaviors, and ameliorated aggressive behaviors. Furthermore, continuous SAK3 administration improved anxiolytic and depressive-like behaviors. Intriguingly, the anti-anxiolytic and cognitive improvement lasted two weeks after the withdrawal of SAK3, whereas the anti-depressive action did not. Taken together, SAK3 had comprehensive beneficial effects on BPSD behavior., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Calcium-dependent activator protein for secretion 1 (CAPS1) is a key molecule in vesicular exocytosis, probably in the priming step. However, CAPS1's role in synaptic plasticity and brain function is elusive. Herein, we showed that synaptic plasticity and learning behavior were impaired in forebrain and/or hippocampus-specific Caps1 conditional knockout (cKO) mice by means of molecular, physiological, and behavioral analyses. Neonatal Caps1 cKO mice showed a decrease in the number of docked vesicles in the hippocampal CA3 region, with no detectable changes in the distribution of other major exocytosis-related molecules. Additionally, long-term potentiation (LTP) was partially and severely impaired in the CA1 and CA3 regions, respectively. CA1 LTP was reinforced by repeated high-frequency stimuli, whereas CA3 LTP was completely abolished. Accordingly, hippocampus-associated learning was severely impaired in adeno-associated virus (AAV) infection-mediated postnatal Caps1 cKO mice. Collectively, our findings suggest that CAPS1 is a key protein involved in the cellular mechanisms underlying hippocampal synaptic release and plasticity, which is crucial for hippocampus-associated learning.

The HapMap Project is a major international research effort to construct a resource to facilitate the discovery of relationships between human genetic variations and health and disease. The Ser19Stop single nucleotide polymorphism (SNP) of human phytanoyl-CoA hydroxylase-interacting protein-like (PHYHIPL) gene was detected in HapMap project and registered in the dbSNP. PHYHIPL gene expression is altered in global ischemia and glioblastoma multiforme. However, the function of PHYHIPL is unknown. We generated PHYHIPL Ser19Stop knock-in mice and found that PHYHIPL impacts the morphology of cerebellar Purkinje cells (PCs), the innervation of climbing fibers to PCs, the inhibitory inputs to PCs from molecular layer interneurons, and motor learning ability. Thus, the Ser19Stop SNP of the PHYHIPL gene may be associated with cerebellum-related diseases.

5-Aminolevulinic acid (5-ALA) is an amino acid derivative and a precursor of protoporphyrin IX (PpIX). The photophysical feature of PpIX is clinically used in photodynamic diagnosis (PDD) and photodynamic therapy (PDT). These clinical applications are potentially based on in vitro cell culture experiments. Thus, conducting a systematic review and meta-analysis of in vitro 5-ALA PDT experiments is meaningful and may provide opportunities to consider future perspectives in this field. We conducted a systematic literature search in PubMed to summarize the in vitro 5-ALA PDT experiments and calculated the effectiveness of 5-ALA PDT for several cancer cell types. In total, 412 articles were identified, and 77 were extracted based on our inclusion criteria. The calculated effectiveness of 5-ALA PDT was statistically analyzed, which revealed a tendency of cancer-classification-dependent sensitivity to 5-ALA PDT, and stomach cancer was significantly more sensitive to 5-ALA PDT compared with cancers of different origins. Based on our analysis, we suggest a standardized in vitro experimental protocol for 5-ALA PDT.

Purpose: Fatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/β-catenin signaling that enhances proliferation in melanoma cells., Methods: Skmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/β-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/β-catenin signaling were examined., Results: FABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/β-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells., Conclusion: These results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.

Objects: We aimed to clarify the differences in the of the ratio of diastolic elastance (Ed) to arterial elastance (Ea), [Ed/Ea=(E/e')/(0.9×systolic blood pressure)], anafterload-integrateddiastolic index that reflects left atrial pressure overload, on prognosis between patients with heart failure with preserved ejection fraction (HFpEF) with and without atrial fibrillation (AF)., Methods: We studied 552 HFpEF patients hospitalized for acute decompensated heart failure (sinus rhythm/AF:352/200).Blood testing and transthoracic echocardiography were performed before discharge. Primary endpoint was all-cause mortality after discharge., Results: During a median follow-up of 508 days, 88 patients (sinus rhythm/AF: 54/34) had all-cause mortality. In the subgroup with sinus rhythm, but not AF, Ed/Ea was significantly higher in patients with than without all-cause mortality. In a multivariate Cox hazard analysis, Ed/Ea was significantly associated with all-cause mortality independent of N-terminal pro-brain natriuretic peptide level in patients with sinus rhythm, but not with AF., Conclusions: Ed/Ea providedlesser important information for predicting all-cause mortality in HFpEF patients with AF than with sinus rhythm. The prognostic risk factors may differ between elderly HFpEF patients with and without AF.

The accumulation of α-synuclein (αSyn) has been implicated as a causal factor in the pathogenesis of Parkinson's disease (PD). There is growing evidence that supports mitochondrial dysfunction as a potential primary cause of dopaminergic neuronal death in PD. Here, we focused on reciprocal interactions between αSyn aggregation and mitochondrial injury induced by oxidative stress. We further investigated whether epidermal fatty acid-binding protein 5 (FABP5) is related to αSyn oligomerization/aggregation and subsequent disturbances in mitochondrial function in neuronal cells. In the presence of rotenone, a mitochondrial respiratory chain complex I inhibitor, co-overexpression of FABP5 with αSyn significantly decreased the viability of Neuro-2A cells compared to that of αSyn alone. Under these conditions, FABP5 co-localized with αSyn in the mitochondria, thereby reducing mitochondrial membrane potential. Furthermore, we confirmed that pharmacological inhibition of FABP5 by its ligand prevented αSyn accumulation in mitochondria, which led to cell death rescue. These results suggested that FABP5 is crucial for mitochondrial dysfunction related to αSyn oligomerization/aggregation in the mitochondria induced by oxidative stress in neurons.

Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory impairment in the four extremities; however, the sensitivity of individual sensory modalities to MeHg has not been investigated extensively. In the present study, we performed stimulus-response behavioral experiments in MeHg-exposed rats to compare the sensitivities to pain, heat, cold, and mechanical sensations. MeHg (6.7 mg/kg/day) was orally administered to 9-week-old Wistar rats for 5 days and discontinued for 2 days, then administered daily for another 5 days. The four behavioral experiments were performed daily on each rat from the beginning of MeHg treatment for 68 days. The pain sensation decreased significantly from day 11 onwards, but recovered to control levels on day 48. Other sensory modalities were not affected by MeHg exposure. These findings suggest that the pain sensation is the sensory modality most susceptive to MeHg toxicity and that this sensitivity is reversible following discontinuation of the exposure.

Objective: Malignant fungating wounds are ulcerating tumors that infiltrate the overlying skin. Little evidence exists regarding the prognosis or treatment of malignant fungating wound in soft tissue sarcoma. This study aimed to reveal the prognosis and outcome of surgical treatment of malignant fungating wound in soft tissue sarcoma., Methods: We retrospectively reviewed 26 patients with malignant fungating wound in high-grade soft tissue sarcoma between 2005 and 2018. The patients' characteristics, treatments, surgical wound complications, local recurrences and prognoses were analyzed. Overall survival was analyzed using the Kaplan-Meier method and compared with that of the control cohort, consisting of 236 consecutive patients with non-malignant fungating wound high-grade soft tissue sarcoma treated during the same period., Results: Among the 26 patients, undifferentiated pleomorphic sarcoma was the most common subtype. Twenty-three patients, including 20 (87%) and 3 (13%), underwent limb-salvage surgery and amputation, respectively. Among the 20 patients who underwent limb-salvage surgery, 4 (20%) had surgical wound complications, which required additional surgical procedures. Excluding the patients who underwent palliative surgery, local recurrence occurred in 2 patients (11%). The 5-year overall survival rate for all high-grade malignant fungating wound and non-malignant fungating wound patients was 26.0 and 67.3% (P < 0.0001), respectively., Conclusions: Malignant fungating wounds in soft tissue sarcoma were significantly associated with a poor prognosis; however, the incidence of surgical complications and local recurrence after limb-salvage surgery was comparable to that of general soft tissue sarcoma cases. Limb-salvage surgery should be considered, if possible, to preserve the patient's quality of life because of the dismal prognosis of patients with malignant fungating wound in soft tissue sarcoma., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

α-synuclein (αSyn) is a protein known to form intracellular aggregates during the manifestation of Parkinson's disease. Previously, it was shown that αSyn aggregation was strongly suppressed in the midbrain region of mice that did not possess the gene encoding the lipid transport protein fatty acid binding protein 3 (FABP3). An interaction between these two proteins was detected in vitro, suggesting that FABP3 may play a role in the aggregation and deposition of αSyn in neurons. To characterize the molecular mechanisms that underlie the interactions between FABP3 and αSyn that modulate the cellular accumulation of the latter, in this report, we used in vitro fluorescence assays combined with fluorescence microscopy, transmission electron microscopy, and quartz crystal microbalance assays to characterize in detail the process and consequences of FABP3-αSyn interaction. We demonstrated that binding of FABP3 to αSyn results in changes in the aggregation mechanism of the latter; specifically, a suppression of fibrillar forms of αSyn and also the production of aggregates with an enhanced cytotoxicity toward mice neuro2A cells. Because this interaction involved the C-terminal sequence region of αSyn, we tested a peptide derived from this region of αSyn (αSynP130-140) as a decoy to prevent the FABP3-αSyn interaction. We observed that the peptide competitively inhibited binding of αSyn to FABP3 in vitro and in cultured cells. We propose that administration of αSynP130-140 might be used to prevent the accumulation of toxic FABP3-αSyn oligomers in cells, thereby preventing the progression of Parkinson's disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Tolvaptan (TLV) carries the risk of serious side effects, and its introduction requires hospitalization. Therefore, it is important from the viewpoints of safety and medical economics to predict in advance, the patients for whom it will be effective and introduce it. The purpose of this study was to investigate the noninvasive and simple predictors for identifying TLV responders. We conducted a retrospective observational study of patients with heart failure who had TLV introduced at our hospital from January 1, 2017, to December 31, 2018. By using the body weight and BNP reduction as the effect indices, predictors of body weight and BNP reduction were extracted by logistic analysis. The sensitivity and specificity at the cutoff value obtained by ROC analysis were also examined. Among 85 subjects, urine sodium concentration >63 mEq/L [odds ratio (OR): 6.11, 95% confidence interval (CI): 1.36-27.4] was detected as a predictor of body weight reduction. The sensitivity at this cutoff value was 81%, and the specificity was 70%. Serum osmolarity>291 mOsm/L (OR: 3.76, 95% CI: 1.00-14.2), urine potassium concentration<21 mEq/L (OR: 4.45, 95% CI: 1.09-18.2), and urine sodium concentration>71 mEq/L (OR: 7.38, 95% CI: 2.05-26.6) were detected as predictors of BNP reduction. The sensitivities were 62%, 53%, and 73%, and the specificities were 58%, 68%, and 68%, respectively. Therefore, it was suggested that urine sodium concentration may be useful as a predictor of body weight and BNP decrease after TLV induction.

For diurnal nonhuman primates, shifting among different sleeping sites may provide multiple benefits such as better protection from predators, reduced risk of parasitic infection, and closer proximity to spatially and temporally heterogeneous food and water. This last benefit may be particularly important in sleeping site selection by primates living in savanna-woodlands where rainfall is more limited and more seasonally pronounced than in rainforests. Here, we examined the influence of rainfall, a factor that affects food and water availability, on the use of sleeping sites by anubis baboons (Papio anubis) over two 13-month study periods that differed in rainfall patterns. We predicted that during wet periods, when food and water availability should be higher, the study group would limit the number of sleeping sites and would stay at each one for more consecutive nights than during dry periods. Conversely, we predicted that during dry periods the group would increase the number of sleeping sites and stay at each one for fewer consecutive nights as they searched more widely for food and water. We also predicted that the group would more often choose sleeping sites closer to the center of the area used during daytime (between 07:00 and 19:00) during wet months than during dry months. Using Global Positioning System data from collared individuals, we found that our first prediction was not supported on either monthly or yearly timescales, although past monthly rainfall predicted the use of the main sleeping site in the second study period. Our second prediction was supported only on a yearly timescale. This study suggests that baboons' choice of sleeping sites is fluid over time while being sensitive to local environmental conditions, one of which may be rainfall., (© 2020 Wiley Periodicals LLC.)

Genetic mutations related to ALS, a progressive neurological disease, have been discovered in the gene encoding σ-1 receptor (σ1R). We previously reported that σ1RE102Q elicits toxicity in cells. The σ1R forms oligomeric states that are regulated by ligands. Nevertheless, little is known about the effect of ALS-related mutations on oligomer formation. Here, we transfected NSC-34 cells, a motor neuronal cell line, and HEK293T cells with σ1R-mCherry (mCh), σ1RE102Q-mCh, or nontagged forms to investigate detergent solubility and subcellular distribution using immunocytochemistry and fluorescence recovery after photobleaching. The oligomeric state was determined using crosslinking procedure. σ1Rs were soluble to detergents, whereas the mutants accumulated in the insoluble fraction. Within the soluble fraction, peak distribution of mutants appeared in higher sucrose density fractions. Mutants formed intracellular aggregates that were co-stained with p62, ubiquitin, and phosphorylated pancreatic eukaryotic translation initiation factor-2-α kinase in NSC-34 cells but not in HEK293T cells. The aggregates had significantly lower recovery in fluorescence recovery after photobleaching. Acute treatment with σ1R agonist SA4503 failed to improve recovery, whereas prolonged treatment for 48 h significantly decreased σ1RE102Q-mCh insolubility and inhibited apoptosis. Whereas σ1R-mCh formed monomers and dimers, σ1RE102Q-mCh also formed trimers and tetramers. SA4503 reduced accumulation of the four types in the insoluble fraction and increased monomers in the soluble fraction. The σ1RE102Q insolubility was diminished by σ1R-mCh co-expression. These results suggest that the agonist and WT σ1R modify the detergent insolubility, toxicity, and oligomeric state of σ1RE102Q, which may lead to promising new treatments for σ1R-related ALS., (Copyright © 2020 © 2020 Shinoda et al. Published by Elsevier Inc. All rights reserved.)

Objective: During follow-up time, the value of prognostic factors may change, especially in the elderly patients, and the altered extent may affect the prognosis. We aimed to clarify the significance of the ratio of diastolic elastance (Ed) to arterial elastance (Ea), (Ed/Ea=(E/e')/(0.9×systolic blood pressure)), an afterload-integrated diastolic index, in relation to follow-up periods and other laboratory factors, on the prognosis of elderly patients with heart failure with preserved ejection fraction (HFpEF)., Methods: We studied 552 HFpEF patients hospitalised for acute decompensated heart failure (men/women: 255/297). Blood testing and transthoracic echocardiography were performed before discharge. The primary endpoint was all-cause mortality., Results: During a median follow-up of 508 days, 88 patients (men/women: 39/49) had all-cause mortality. During the first year after discharge, Ed/Ea (p=0.045) was an independent prognostic factor in association with albumin (p<0.001) and N-terminal pro-brain natriuretic peptide (NT-proBNP, p=0.005) levels after adjusting for age and sex in the multivariate Cox hazard analysis. However, at 1 to 3 years after discharge, no other significant prognostic factors, except for albumin level (p=0.046), were detected. In the subgroup analysis, albumin, but not NT-proBNP level, showed a significant interaction with Ed/Ea for prognosis (p=0.047)., Conclusion: The prognostic significance of a haemodynamic parameter such as Ed/Ea may be valid only during a short-term period, but that of albumin was persisting during the entire follow-up period in the elderly patients. The clinical significance of prognostic factors in HFpEF patients may differ according to the follow-up period., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: We previously demonstrated that heme oxygenase-1 (HO-1) induction may contribute to a protective response against photodynamic therapy (PDT) using talaporfin sodium (TS) in rat malignant meningioma KMY-J cells. In the present study, we examined the mechanism of HO-1 induction by PDT with TS (TS-PDT) in KMY-J cells., Methods: KMY-J cells were incubated with 25 μM TS for 2 h and then exposed to 664 nm diode laser irradiation at 1 J/cm 2 . The gene and protein expression levels of HO-1 and hypoxia-inducible factor-1α (HIF-1α) were determined by real-time RT-PCR and western blot analysis, respectively. Cell viability was measured using the cell counting kit-8 assay., Results: mRNA and protein levels of HO-1 in KMY-J cells were increased significantly at 3, 6, and 9 h after laser irradiation and the increased mRNA level of HO-1 was decreased by antioxidant N-acetyl cysteine treatment. The protein level of HIF-1α, which mediates transcriptional activation of the HO-1 gene, was increased significantly at 1 h after laser irradiation. Additionally, induction of mRNA expression of HO-1 by TS-PDT was diminished by HIF-1α inhibitor echinomycin. We also demonstrated that echinomycin significantly augmented the cytotoxic effect of TS-PDT., Conclusions: Our findings indicate that TS-PDT may induce HO-1 expression via reactive oxygen species production and then HIF-1 pathway activation in KMY-J cells, and the HO-1 induction may cause attenuation of the therapeutic effect of TS-PDT., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: His-bundle pacing (HBP) alone may become an alternative to conventional cardiac resynchronization therapy (CRT) utilizing right ventricular apical (RVA) and left ventricular (LV) pacing (BiV RVA+LV ) in selected patients, but the effects of CRT utilizing HBP and LV pacing (BiV HB+LV ) on cardiac resynchronization and heart failure (HF) are unclear., Case Summary: We presented two patients with inotrope-dependent end-stage HF in whom the upgrade from conventional BiV RVA+LV to BiV HB+LV pacing by the addition of a lead for HBP improved their HF status. Patient 1 was a 32-year-old man with lamin A/C cardiomyopathy, atrial fibrillation, and complete atrioventricular (AV) block. Patient 2 was a 70-year-old man with ischaemic cardiomyopathy complicated by AV block and worsening of HF resulting from ablation for ventricular tachycardia storm. The HF status of both patients improved dramatically following the upgrade from BiV RVA+LV to BiV HB+LV pacing., Discussion: End-stage HF patients suffer from diffuse intraventricular conduction defect not only in the LV but also in the right ventricle (RV). The resulting dyssynchrony may not be sufficiently corrected by conventional BiV RVA+LV pacing or HBP alone. Right ventricular apical pacing itself may also impair RV synchrony. An upgrade to BiV HB+LV pacing could be beneficial in patients who become non-responsive to conventional BiV pacing as the His-Purkinje conduction defect progresses., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Achieving a favorable pacing threshold with a Micra transcatheter pacing system (Micra-TPS) is needed to reduce battery depletion. In some cases, the threshold increases shortly after the device is implanted, and a higher pacing threshold may be required. This study aims to identify the causes and predictors of the increase in pacing threshold observed shortly after Micra-TPS implantation., Methods: The study included 64 consecutive patients who underwent Micra-TPS implantation between 2017 and 2020. The patients were divided into two groups depending on their pacing threshold: the increased pacing threshold (IPT) group (threshold increased by ≥0.5 V/0.24 ms within 1 month of implantation) and the stable pacing threshold (SPT) group., Results: Excluding four patients who could not be followed up, of the 60 remaining patients, nine (15%) were in the IPT group and 51 (85%) were in the SPT group. The IPT group had significantly lower implant impedance values and higher implant thresholds than the SPT group (582 ± 59 vs 755 ± 167 Ω [P < .001] and 1.29 ± 0.87 vs 0.71 ± 0.40 V/0.24 ms [P = .014]). Implant impedance and threshold may serve as predictors of a threshold increase after implantation (area under the curve: 0.737-0.943 and 0.586-0.926, respectively)., Conclusions: An IPT was noted shortly after Micra-TPS implantation owing to micro-dislodgement because of insufficient anchoring of the device to the myocardium. Impedance >660 Ω and threshold <1.0 V/0.24 ms may predict an increase in pacing threshold., (© 2020 Wiley Periodicals LLC.)

Backgrounds: Tolvaptan significantly increases urine volume in acute decompensated heart failure (ADHF); serum sodium level increases due to aquaresis in almost all cases. We aimed to elucidate clinical factors associated with hypernatremia in ADHF patients treated with tolvaptan., Methods: We enrolled 117 ADHF patients treated with tolvaptan in addition to standard therapy. We examined differences in clinical factors at baseline between patients with and without hypernatremia in the initial three days of hospitalization., Results: Systolic (p = 0.045) and diastolic (p = 0.004) blood pressure, serum sodium level (p = 0.002), and negative water balance (p = 0.036) were significantly higher and serum potassium level (p = 0.026) was significantly lower on admission day in patients with hypernatremia (n = 22). In multivariate regression analysis, hypernatremia was associated with low serum potassium level (p = 0.034). Among patients with serum potassium level ≤ 3.8 mEq/L, the cutoff value obtained using receiver operating characteristic curve analysis, those with hypernatremia related to tolvaptan treatment showed significantly higher diastolic blood pressure on admission day (p = 0.004)., Conclusion: In tolvaptan treatment combined with standard therapy in ADHF patients, serum potassium level ≤ 3.8 mEq/L may be a determinant factor for hypernatremia development. Among hypokalemic patients, those with higher diastolic blood pressure on admission may be carefully managed to prevent hypernatremia.

A photosensitizer is a molecular drug for photodynamic diagnosis and photodynamic therapy (PDT) against cancer. Many studies have developed photosensitizers, but improvements in their cost, efficacy, and side effects are needed for better PDT of patients. In the present study, we developed a novel photosensitizer β-mannose-conjugated chlorin e6 (β-M-Ce6) and investigated its PDT effects in human glioblastoma U251 cells. U251 cells were incubated with β-M-Ce6, followed by laser irradiation. Cell viability was determined using the Cell Counting Kit-8 assay. The PDT effects of β-M-Ce6 were compared with those of talaporfin sodium (TS) and our previously reported photosensitizer β-glucose-conjugated chlorin e6 (β-G-Ce6). Cellular uptake of each photosensitizer and subcellular distribution were analyzed by fluorescence microscopy. β-M-Ce6 showed 1000× more potent PDT effects than those of TS, and these were similar to those of β-G-Ce6. β-M-Ce6 accumulation in U251 cells was much faster than TS accumulation and distributed to several organelles such as the Golgi apparatus, mitochondria, and lysosomes. This rapid cellular uptake was inhibited by low temperature, which suggested that β-M-Ce6 uptake uses biological machinery. β-M-Ce6 showed potent PDT anti-cancer effects compared with clinically approved TS, which is a possible candidate as a next generation photosensitizer in cancer therapy.

The relationship between alterations in left ventricular (LV) diastolic function and the incidence of recurrence, as well as the associated factors after cryoballoon (CB) and radiofrequency (RF) catheter ablation in patients with paroxysmal atrial fibrillation (Paf), require clarification. We enrolled 138 patients with Paf (RF/CB 69/69) who underwent the first catheter ablation and follow-up for 12 months. Transthoracic echocardiography was performed before and after ablation. An afterload-integrated index of LV diastolic function was calculated as diastolic elastance (Ed)/arterial elastance (Ea), Ed/Ea. No significant increases were observed in Ed/Ea 3 days after RF ablation in patients with (n=12) and without (n=57) recurrence. However, a significant increase was observed in recurrence-free patients with CB ablation (n=59; P<0.05), although this level was restored after 6 months. Ed/Ea 3 days after CB ablation was correlated with left atrial pressure immediately after (r=0.630, P<0.001), but not before (r=0.290, P=0.159), ablation. The increment of creatine kinase- myocardial band release was positively associated with that of Ed/Ea (r=0.388, P<0.05) after CB ablation. Thus, the transient manifestation of LV diastolic dysfunction after CB ablation, evaluated by a new echocardiographic index, was observed only in recurrence-free patients with Paf. Protracted impairment of left atrial compliance due to ablation-induced myocardial injury may be related to the lack of recurrence in patients after CB ablation., Competing Interests: None., (AJCD Copyright © 2020.)

Background: Myocardial perfusion single-photon emission computed tomography (SPECT) imaging with stress is a useful examination for detecting coronary artery disease. Since the presence of artifacts is remaining challenges, we aimed to define the minimum intensity of low-grade exercise stress levels combined with drug stress to reduce undesired artifacts and their related factors., Methods: We divided patients with suspicious coronary artery disease into 4 groups as follows: group A, adenosine triphosphate (ATP) for 6 min; group A + 25 W, ATP + 25 W exercise for 6 min; group A + 35 W, ATP + 35 W exercise for 6 min; group A + 45 W, ATP + 45 W exercise for 6 min) and enrolled only those whose summed stress scores were < 3. Undesired artifacts were evaluated on the basis of heart-to-liver activity (H/L) ratio and heart-to-10 pixels below the heart (H/below the H) ratio., Results: The logarithmic values of H/L and H/below the H ratios were significantly higher in groups A + 35 W and A + 45 W than in group A (p < 0.05, each). In all the patients, the logarithmic values of H/L and H/below the H ratios positively correlated with the increment of rate pressure product (RPP, p = 0.002 and p = 0.005, respectively) after stress in the univariate analysis. The left ventricular end-diastolic volume (LVEDV) after stress (p = 0.002) negatively correlated with the logarithmic value of H/below the H ratio, but not H/L ratio. Although the increment of RPP was independently associated with the logarithmic values of both H/L (p = 0.001) and H/below the H ratios (p = 0.005), LVEDV was also independently associated with the logarithmic value of H/below the H ratio (p < 0.001) in multivariate regression analysis under adjusting with age and sex., Conclusion: ATP plus ≥35 W exercise stress for 6 min was useful for reducing undesired artifacts after stress in myocardial perfusion SPECT. LVEDV after stress in addition to the increment of RPP was independently associated with the H/below the H ratio, but not the H/L ratio.