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Pharmacologic β-blockade is a well-established therapy for reducing adverse effects from sympathetic overactivity in cardiovascular diseases, such as heart failure. Despite decades of research efforts, in vivo cardiac functional studies using genetic animal models remain scant. We generated a mouse model of cardiomyocyte-specific deletion (cKO) of β-1 adrenergic receptor (ADRB1), the primary subtype expressed in cardiac myocytes, and demonstrated the role of ADRB1 in the maintenance of cardiac function at baseline and during exposure to increase in cardiac afterload by transient aortic occlusion and increasing heart rates (HRs) via atrial pacing. cKO hearts showed mildly depressed baseline left ventricular (LV) function, including slower HR, decreased contractility (dP/dt max/IP), and prolonged relaxation (Tau) in both sexes. Exposure to increased LV afterload depressed LV function in either genotype similarly; however, the functional recovery following the removal of the afterload was severely impaired in cKO hearts, whereas cardiac function was immediately normalized in wild-type (WT) hearts. When HR was altered from 400 to 700 beats/min, cKO hearts were deficient in HR-dependent improvement of cardiac contractility and relaxation, known as positive force-frequency relationship, that was evident in WT hearts. Enhanced phosphorylation of phospholamban by the HR increase was markedly blunted in cKO myocardium versus wild types, whereas CaMKII phosphorylation was comparable between the genotypes, suggesting the critical involvement of PKA. These results provide the first experimental evidence for the role of ADRB1 in cardiomyocytes for maintaining cardiac function at baseline and during acute stress, providing a clinical perspective relating to the management of patients on β-blockers. NEW & NOTEWORTHY Although the benefits of β-1 adrenergic receptor (ADRB1) blockade to cardiovascular disease are established, in vivo role for cardiomyocyte ADRB1 remains undetermined. Generating cardiomyocyte-specific ADRB1 knockout mice, we show that ADRB1 is pivotal to cardiac functional recovery from afterload elevation and heart rate-dependent functional enhancement as well as baseline performance. Our findings highlight the importance of cardiomyocyte ADRB1 in cardiac stress adaptability, which is of clinical importance in the management of patients on β-blockers.

Runx2 is an essential transcription factor for osteoblast differentiation and chondrocyte maturation. The spatiotemporal expression of Runx2 is regulated by enhancers. We previously identified a 1.3 kb osteoblast-specific enhancer; however, mice with this deletion showed no phenotypes. A 0.8 kb conserved region detected near the 1.3 kb enhancer did not exhibit enhancer activity in reporter assays, whereas four tandem repeats of 452 bp (452 × 4) containing the most conserved region of 0.8 kb induced strong reporter activity in chondrocyte cell lines. However, chondrocytes of enhanced green fluorescent protein (EGFP) reporter mice using 452 × 4 did not express EGFP. When 452 × 4 was combined with the 1.3 kb enhancer, hypertrophic chondrocytes highly expressed EGFP. Moreover, the 0.8 kb region combined with the 1.3 kb enhancer induced EGFP expression in prehypertrophic and hypertrophic chondrocytes. The deletion of both the 1.3 kb enhancer and the 0.8 kb conserved region slightly reduced Runx2 expression in the limbs. However, neither homozygous nor heterozygous deletions in the Runx2 +/- background showed phenotypes. The 0.8 kb conserved region itself lacked enhancer activity, but when combined with the 1.3 kb enhancer, EGFP expression was induced in chondrocytes with a similar expression pattern to Runx2. Therefore, the 0.8 kb conserved region has a novel function as a subenhancer.

Aim: Injury to and laxity of the pelvic floor muscles are highly important factors in the etiology of pelvic organ prolapse. When women with pelvic organ prolapse perform the Valsalva maneuver, progressive descent and widening of the levator ani muscle are observed on dynamic magnetic resonance images. However, physical examination of such women often reveals pelvic floor laxity, even in a relaxed state. Therefore, we aimed to verify the hypothesis that sagging of the pelvic floor can be detected on resting-state magnetic resonance images in the supine position., Methods: We retrospectively evaluated resting-state magnetic resonance imaging findings in women with (n = 193; all underwent surgical treatment) and without (controls; n = 193) pelvic organ prolapse who had at least one prior vaginal delivery. We compared the lengths of the pubococcygeal line, H-line, and M-line between the groups., Results: The median lengths (interquartile ranges) for the prolapse and control groups were 98.3 (91.9-104.0) and 95.1 (90.3-101.4) mm (p = 0.0011), respectively, for the pubococcygeal line; 61.5 (56.0-67.9) and 51.1 (47.2-55.6) mm (p < 0.0001), respectively, for the H-line; and 24.6 (20.4-29.0) and 8.6 (3.9-13.0) mm (p < 0.0001), respectively, for the M-line. Similarly, in the multiple regression analysis adjusted for age, height, body mass index, a history of operative vaginal delivery, and a history of hysterectomy, the pubococcygeal line, H-line, and M-line were significantly longer in the prolapse group., Conclusions: In women with pelvic organ prolapse, the H-line and M-line are significantly longer on resting-state magnetic resonance images, allowing for the detection of pelvic floor relaxation., (© 2025 Japan Society of Obstetrics and Gynecology.)

Sonic Hedgehog (Shh), encoding an extracellular signaling molecule, is vital for heart development. Shh null mutants show congenital heart disease due to left-right asymmetry defects stemming from functional anomaly in the midline structure in mice. Shh signaling is also known to affect cardiomyocyte differentiation, endocardium development, and heart morphogenesis, particularly in second heart field (SHF) cardiac progenitor cells that contribute to the right ventricle, outflow tract, and parts of the atrium. Despite extensive studies, our understanding remains incomplete. Notably, Shh signaling is suggested to promote cardiac differentiation, while paradoxically preventing premature differentiation of SHF progenitors. In this study, we elucidate the role of Shh signaling in the earliest phase of cardiac differentiation. Our meta-analysis of single-cell RNA sequencing suggests that cardiogenic nascent mesoderm cells expressing the bHLH transcription factor Mesp1 interact with axial mesoderm via Hh signaling. Activation of Hh signaling using a Smoothened agonist delayed or suppressed the differentiation of primitive streak cells expressing T-box transcription factor T to Mesp1 + nascent mesoderm cells both in vitro and ex vivo. Conversely, inhibition of Hh signaling by cyclopamine facilitated cardiac differentiation. The reduction of Eomes, an inducer of Mesp1, by Hh signaling appears to be the underlying mechanism of this phenomenon. Our data suggest that SHH secreted from axial mesoderm inhibits premature differentiation of T + cells to Mesp1 + nascent mesoderm cells, thereby regulating the pace of cardiac differentiation. These findings enhance our comprehension of Shh signaling in cardiac development, underscoring its crucial role in early cardiac differentiation., (© 2025 The Author(s). Development, Growth & Differentiation published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Developmental Biologists.)

Aim: Despite the clinical importance and significant social burden of neuropsychiatric symptoms (NPS) in dementia, the underlying neurobiological mechanism remains poorly understood. Recently, neuroimaging-derived brain-age estimation by machine-learning analysis has shown promise as an individual-level biomarker. We investigated the relationship between NPS and brain-age in amnestic mild cognitive impairment (MCI) and early dementia., Methods: In this cross-sectional study, clinical data, including neuropsychiatric inventory (NPI), and structural brain MRI of 499 individuals with clinical diagnoses of amnestic MCI (n = 185), early Alzheimer's disease (AD) (n = 258) or dementia with Lewy bodies (DLB) (n = 56) were analyzed. We established a brain-age prediction model using 694 healthy brain MRIs and a support vector regression model and applied it to the participants' data. Finally, the brain-predicted age difference (brain-PAD: predicted age minus chronological age) was calculated., Results: All groups showed significantly increased brain-PAD, and the median (IQR) brain-PAD was 4.3 (5.4) years in MCI, 6.3 (6.2) years in AD, and 5.0 (6.5) years in DLB. The NPI scores were subdivided into the following four categories: (i) Agitation and Irritability, (ii) Depression and Apathy, (iii) Delusions and Hallucinations, and (iv) Euphoria and Disinhibition. We found a significantly positive correlation between brain-PAD and the depression/apathy factor (Spearman's rs = 0.156, FDR-corrected P = 0.002), whereas no significance was shown for the other NPS factors., Conclusion: Higher brain-age may be associated with depression and apathy symptoms presented in MCI to early dementia stages, and brain-age analysis may be useful as a novel biomarker for the assessment or monitoring of NPS., (© 2025 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR + ) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR + neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA A receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR + neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.

The sympathetic nervous system is crucial for responding to environmental changes. This regulation is coordinated by the spinal sympathetic preganglionic neurons (SPNs), innervating both postganglionic neurons and the adrenal gland. Despite decades of research supporting the concept of selective control within this system, the neural circuit organization responsible for the output specificity remains poorly understood. Here, by combining recent single-cell transcriptome data with viral-genetic toolkits in mice, we identify two subtypes of SPNs in the lower thoracic spinal cord, defined at the molecular level, exhibiting nonoverlapping patterns of innervation: one specifically projecting to the celiac/superior mesenteric ganglia, and the other targeting the adrenal grand. Chemogenetic manipulations on these distinct SPN subtypes revealed selective impacts on the motility of the gastrointestinal tracts or glucose metabolism mediated by the adrenal gland, respectively. This molecularly delineated parallel labeled-line organization in sympathetic outflows presents a potential avenue for selectively manipulating organ functions., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Para-aortic lymph node metastasis(PALNM)is classified as distant metastasis in colorectal cancer(CRC). Although the benefit of para-aortic lymph node dissection(PALND)for the CRC patients with PALNM suspected radiologically remains controversial, some reports have shown that the survival benefit for PALND in CRC patients with PALNM. Moreover, the report evaluating the extent of PALND showed that the patients treated with radical lymphadenectomy had better prognosis compared to those treated with targeted lymphadenectomy defined as the dissection of only swollen lymph nodes. We have performed the laparoscopic PALND for selected CRC patients with PALNM. Three radical dissections using retroperitoneoscopy have been performed in 9 CRC patients who underwent PALND in the last 6 years. Now, we show one of the effective cases treated with the retroperitoneoscopic radical resection. We additionally mention the effectiveness of the retroperitoneoscopic radical resection for the patients with PALNM. The retroperitoneoscopic resection resulted in more blood loss and longer operative time than laparoscopic resection, however, more lymph nodes were resected. The retroperitoneoscopic radical resection may be the preferable procedure for the CRC patients with PALNM, especially for the patients with multiple or extensively spread PALNM.

Von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46 year-old man with a 35 mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55 mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36 mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6 months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22 months after primary surgery. The patient remains alive 41 months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL., (© 2024. Japanese Society of Gastroenterology.)

Introduction: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species., Materials and Methods: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan., Results: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 μg/mL) decreased from 14.7% to 7.7%., Discussion: Bacterial strains that produced extended-spectrum β-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years., Competing Interests: Declaration of competing interest Satoshi Takahashi received speaker honoraria from Fujirebio Inc. and research funding from Shino-Test Corporation, Roche Diagnostic K. K., Fujirebio Inc., and Abbott Japan Co., Ltd. Koichiro Wada received speaker honoraria from Janssen Pharmaceutical K.K., and MSD K.K. Shingo Yamamoto received speaker honoraria from MSD K.K., Fuso Pharmaceutical Industries, Ltd., Daiichi Sankyo Co., Ltd. and scholarship donations from Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd. and research funding from Takeda Pharmaceutical Co., Ltd. Tetsuya Matsumoto received speaker honoraria from MSD K.K., Pfizer Japan Inc., and Kyorin Pharmaceutical Co., Ltd., and research funding from Kewpie Corporation., Biofermin Pharmaceutical Co., Ltd. Kazumasa Matsumoto received research funding from Sysmex Corporation. Tohru Nakagawa received speaker honoraria from Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., and Janssen Pharmaceutical K.K., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: Testicular volume (TV) is known to be one of the main parameters for testicular function (TF). This study was conducted to re-evaluate the indications of a varicocelectomy based on a survey of preoperative TV results in left-side varicocele patients considered to reflect the detrimental effects of a varicocele on TF., Methods: TV results of infertile patients determined using ultrasonography by a single expert physician were retrospectively evaluated., Results: Of 590 examined patients, 424 had no varicocele findings (Group A), while 148 had a left-side varicocele (Group B). Group B was subdivided based on varicocele grade into Group B0 (subclinical), B1 (grade 1), B2 (grade 2), and B3 (grade 3). Comparisons of left-side TV showed no significant differences for grade among Group A, B0, and B1, whereas that for Group B2 and B3 was significantly lower as compared with Group A (p < 0.01, 0.02, respectively). The median TV of Group B I (composed of Groups B0 and B1) was 9.8 cm 3 , while that of Group B II (Groups B2 and B3) was significantly lower at 8.4 cm 3 (p < 0.05). In contrast, a comparison of right TV values identified no significant differences among the groups (p = 0.918)., Conclusion: A varicocelectomy should be performed for patients with a grade 2 and 3 varicocele for ameliorating testicular function., (© 2024 The Japanese Urological Association.)

Aim: Numerous recent reports have highlighted the association between mental disorders and electrocardiographic findings. The early repolarization pattern (ERP) on electrocardiogram has been linked with a history of suicide attempts and attention deficit hyperactivity disorder, and associations with impulsivity have also been reported. It is known that suicidal intent is more common at night. Patients who have a mental disorder and ERP may have a higher likelihood of impulsivity, potentially increasing the risk of suicide at night., Methods: The subjects were 43 patients with a history of suicide attempts who had undergone electrocardiographic examination at Jikei University School of Medicine Kashiwa Hospital and received intervention from our department. Due to the diurnal variation in electrocardiographic findings, only patients who underwent the examination during the daytime were included. Patients' clinical backgrounds were compared according to the presence or absence of ERP, and the association between nocturnal suicide attempts and ERP was examined using multivariate analysis., Results: The frequency of nocturnal suicidal behavior was 76.2% in patients with ERP and 31.8% in those without ERP, but the difference was not significant after Bonferroni correction. In the multivariate analysis, there was a significant association of ERP with nocturnal suicide attempts (p = 0.018)., Conclusion: The finding of an association between ERP and nocturnal suicide attempts indicates that ERP is a biological indicator that can predict nocturnal suicide attempts., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Cognitive behavioral therapy for insomnia (CBT-I) is among the recommended non-pharmacological treatments for patients with insomnia. While there are multiple reports on the effects of CBT-I treatment, few studies evaluating the factors associated with the treatment response to CBT-I have been reported. The present study aimed to confirm the effects of CBT-I in patients with insomnia and to examine the clinico-demographic factors that can predict the outcomes of CBT-I in these patients., Methods: Overall, 62 patients were included in the present study. To confirm the effectiveness of CBT-I, we compared the pre- and post-CBT-I therapy values of several sleep parameters. Furthermore, to identify the clinico-demographic factors that could be predictive of the treatment response to CBT-I, we performed generalized linear model (GLM) analysis., Results: The values of several sleep parameters were significantly lower after treatment than at baseline. The results of the GLM analysis revealed that sex and occupation were significantly associated with the treatment response to CBT-I., Conclusions: The present results suggest that several clinico-demographic factors should be considered in the treatment of patients with insomnia., (© 2024. The Author(s).)

Background Screening tests reveal the early signs of cognitive decline, enabling better self-care and preparation for the future. We developed and evaluated the accuracy of a rapid (20 s) and easy-to-use tool called ONSEI, assessing the cognitive decline equivalent to dementia in actual clinical practice by correlating clinical diagnoses with the ONSEI classification. Methods In this retrospective observational study, data were collected from individuals who visited three neurosurgical clinics in neighboring prefectures of Tokyo, Japan. ONSEI analysis was performed using a smartphone or tablet. The tool adopts a machine-learning algorithm using the speaker's age, time-orientation task score, and acoustic features of spoken responses to that task. Significant differences in accuracy, sensitivity, and specificity were evaluated by Fisher's exact test. Results The overall classification accuracy of ONSEI was 98.1% (p<0.001). The sensitivity and specificity were 97.3% (p<0.001) and 98.5% (p<0.001), respectively. The proportion of correct classifications was consistent across different age groups. Conclusion ONSEI showed high classification accuracy for dementia in cognitively normal individuals in actual clinical practice, regardless of the facility at which the tests were conducted or the age of the participants. Thus, ONSEI can be useful for dementia screening and self-care., Competing Interests: Japanese Patent No. 6804779, issued in 2019, to Tadashi Masuoka and Norihide Maikusa., (Copyright © 2024, Asano et al.)

Toward a regioselective method for the synthesis of β-halovinyl amides, we developed a transition-metal-free nucleophilic addition reaction of amides to haloalkynes. The regioselective nucleophilic addition was achieved under solvent-free conditions using phosphonates to protonate the intermediate alkylidene carbenoids, thus suppressing their decomposition. Furthermore, we demonstrate that β-halovinyl amides can serve as dual precursors of allyl halides and alkylidene carbenes to obtain functionalized indoles and pyrrolidones.

Advances in fluorescence microscopy and tissue-clearing have revolutionised 3D imaging of fluorescently labelled tissues, organs and embryos. However, the complexity and high cost of existing software and computing solutions limit their widespread adoption, especially by researchers with limited resources. Here, we present Acto3D, an open-source software, designed to streamline the generation and analysis of high-resolution 3D images of targets labelled with multiple fluorescent probes. Acto3D provides an intuitive interface for easy 3D data import and visualisation. Although Acto3D offers straightforward 3D viewing, it performs all computations explicitly, giving users detailed control over the displayed images. Leveraging an integrated graphics processing unit, Acto3D deploys all pixel data to system memory, reducing visualisation latency. This approach facilitates accurate image reconstruction and efficient data processing in 3D, eliminating the need for expensive high-performance computers and dedicated graphics processing units. We have also introduced a method for efficiently extracting lumen structures in 3D. We have validated Acto3D by imaging mouse embryonic structures and by performing 3D reconstruction of pharyngeal arch arteries while preserving fluorescence information. Acto3D is a cost-effective and efficient platform for biological research., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background and Hypothesis: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance., Study Design: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis., Study Results: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009)., Conclusions: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Pharmacotherapy such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors is recommended for the treatment of anxiety disorders. Although there are patients with persisted symptoms of anxiety disorders who are treated with monotherapy of benzodiazepine anxiolytics without SSRIs, the characteristics of these patients are unclear. In the present study, we investigated the characteristics of patients with persisted symptoms of anxiety disorder without SSRI prescription., Methods: From a prescription dataset covering 2018 and 2020, the prescriptions of 243 patients with anxiety disorder were analyzed. Patients were classified into two groups: SSRI non-prescription and prescription groups., Results: The SSRI non-prescription group had a higher ratio of females than did the SSRI prescription group (60.1% vs. 44.6%, respectively, p = 3.12 × 10 -2 ), but statistically not significant after the Bonferroni correction. No significant differences in age, body mass index, or duration of outpatient visits were found between groups. Among the independent variables, sex (female) was the only variable identified that predicted SSRI non-prescription., Conclusion: The present study showed that among patients with anxiety disorders, sex (female) was the only variable that predicted SSRI non-prescription., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

The heritability of major depressive disorder (MDD) is reportedly 30-50%. However, the genetic basis of its heritability remains unknown. Within SITH-1, a risk factor for MDD in human herpesvirus 6B (HHV-6B), we discovered a gene polymorphism with a large odds ratio for an association with MDD. It was a sequence whose number of repeats was inversely correlated with SITH-1 expression. This number was significantly lower in MDD patients. Rates for 17 or fewer repeats of the sequence were 67.9% for MDD and 28.6% for normal controls, with an odds ratio of 5.28. For patients with 17 or less repeats, the rate for presence of another MDD patient in their families was 47.4%, whereas there were no MDD patients in the families of patients with more than 17 repeats. Since HHV-6B is transmitted primarily mother to child and within families and persists for life, this gene polymorphism could potentially influence heritability of MDD., Competing Interests: K.K. and N.K. have submitted a patent application entitled “Factor involved in latent infection with herpesvirus, and use thereof,” US patent application publication 2010/0281550 A1. N.O., K.K., and N.K. have submitted a patent application entitled “Method for detecting antibody against SITH-1 in biological sample,” US patent application publication 2012/0107842 A1. K.K. has stock in Virus Ikagaku Kenkyusho Inc., (© 2024 The Author(s).)

Mucociliary clearance (MCC) is a host defense mechanism of the respiratory system. Beating cilia plays a crucial role in the MCC process and ciliary beat frequency (CBF) is activated by several factors including elevations of the intracellular cAMP concentration ([cAMP] i ), intracellular Ca 2+ concentration ([Ca 2+ ] i ), and intracellular pH (pH i ). In this study, we investigated whether an artichoke-extracted component cynaropicrin could be a beneficial compound for improving MCC. We found that cynaropicrin increased [cAMP] i using A549 cells bearing Pink Flamindo. Then, we also confirmed that cynaropicrin elevates CBF using airway epithelial ciliated cells (AECCs). We next investigated the effects of cynaropicrin on the alternation of [Ca 2+ ] i , and pH i . Cynaropicrin increased [Ca 2+ ] i , but not pH i . Further experiments also found that cynaropicrin increased [cAMP] i primarily by raising [Ca 2+ ] i . To elucidate the mechanisms of cynaropicrin to increase [Ca 2+ ] i , we investigated the alternation of the effects of cynaropicrin on [Ca 2+ ] i using several compounds. BTP-2 and ruthenium red (RuR) inhibited cynaropicrin-induced [Ca 2+ ] i increase and RuR reduced also [cAMP] i . These results suggest that cynaropicrion increased [Ca 2+ ] i by augmenting the Ca 2+ influx and that the increase of [cAMP] i by cynaropicrin was induced by [Ca 2+ ] i elevation. Interestingly, cynaropicrin decreased the Ca 2+ concentration in the endoplasmic reticulum following inhibition of sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA). SERCA activator CDN1163 abolished this effect. Furthermore, RuR and Ca 2+ -free conditions suppressed the increase of CBF. In conclusion, cynaropicrin inhibits SERCA, induces store-operated calcium entry, and thereby increases CBF.

Aim: An easy-to-use tool that can detect cognitive decline in mild cognitive impairment (MCI) is required. In this study, we aimed to construct a machine learning model that discriminates between MCI and cognitively normal (CN) individuals using spoken answers to questions and speech features., Methods: Participants of ≥50 years of age were recruited from the Silver Human Resource Center. The Japanese Version of the Mini-Mental State Examination (MMSE-J) and Clinical Dementia Rating (CDR) were used to obtain clinical information. We developed a research application that presented neuropsychological tasks via automated voice guidance and collected the participants' spoken answers. The neuropsychological tasks included time orientation, sentence memory tasks (immediate and delayed recall), and digit span memory-updating tasks. Scores and speech features were obtained from spoken answers. Subsequently, a machine learning model was constructed to classify MCI and CN using various classifiers, combining the participants' age, gender, scores, and speech features., Results: We obtained a model using Gaussian Naive Bayes, which classified typical MCI (CDR 0.5, MMSE ≤26) and typical CN (CDR 0 and MMSE ≥29) with an area under the curve (AUC) of 0.866 (accuracy 0.75, sensitivity 0.857, specificity 0.712)., Conclusions: We built a machine learning model that can classify MCI and CN using spoken answers to neuropsychological questions. Easy-to-use MCI detection tools could be developed by incorporating this model into smartphone applications and telephone services.

Background: Neuropsychiatric symptoms (NPS) in patients with dementia lead to caregiver burdens and worsen the patient's prognosis. Although many neuroimaging studies have been conducted, the etiology of NPS remains complex. We hypothesize that brain structural asymmetry could play a role in the appearance of NPS., Objective: This study explores the relationship between NPS and brain asymmetry in patients with Alzheimer's disease (AD)., Methods: Demographic and MRI data for 121 mild AD cases were extracted from a multicenter Japanese database. Brain asymmetry was assessed by comparing the volumes of gray matter in the left and right brain regions. NPS was evaluated using the Neuropsychiatric Inventory (NPI). Subsequently, a comprehensive assessment of the correlation between brain asymmetry and NPS was conducted., Results: Among each NPS, aggressive NPS showed a significant correlation with asymmetry in the frontal lobe, indicative of right-side atrophy (r = 0.235, p = 0.009). This correlation remained statistically significant even after adjustments for multiple comparisons (p < 0.01). Post-hoc analysis further confirmed this association (p < 0.05). In contrast, no significant correlations were found for other NPS subtypes, including affective and apathetic symptoms., Conclusions: The study suggests frontal lobe asymmetry, particularly relative atrophy in the right hemisphere, may be linked to aggressive behaviors in early AD. These findings shed light on the neurobiological underpinnings of NPS, contributing to the development of potential interventions.

Purpose: The risk of pelvic floor muscle injury is commonly considered to be higher in vaginal than in cesarean delivery. This study aimed to compare levator ani muscle (LAM) elasticity after vaginal and cesarean delivery using shear wave elastography (SWE)., Methods: Postpartum women who underwent a single SWE evaluation 1 month after their first delivery were divided into vaginal and cesarean delivery groups. The elastic moduli of both sides of the LAM were measured in a horizontal section and compared between the groups. In addition, a subgroup analysis was performed to compare LAM elasticity according to the delivery method within the vaginal delivery group-normal vaginal delivery, episiotomy, and operative vaginal delivery., Results: Sixty-two women were included (vaginal delivery, n = 47; elective cesarean section, n = 15). Multiple regression analysis revealed that the LAM elastic modulus was significantly lower in the vaginal delivery group than in the cesarean delivery group (right LAM: 44.2 vs. 72.7 kPa, p = 0.0036; left LAM 40.4 vs. 82.7 kPa, p < 0.0001). In the subgroup analysis, the right LAM elastic modulus was significantly lower in the operative vaginal delivery subgroup than in the normal vaginal delivery subgroup (p = 0.0131). However, there was no significant difference in the left LAM elastic modulus between the three subgroups., Conclusion: LAM elasticity was significantly lower after vaginal delivery than after cesarean delivery. Furthermore, the elasticity of the right LAM was lower after operative vaginal delivery than after normal vaginal delivery. SWE has the potential to provide an objective quantitative assessment of postpartum pelvic floor muscle recovery., (© 2023. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Introduction: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) in Japan has not been adequately investigated. Furthermore, the relationship between stimulation-site pain and the antidepressant effects of rTMS has not been thoroughly examined. Therefore, this study aimed to clarify (1) the real-world efficacy and safety of rTMS for TRD in Japan and (2) the relationship between stimulation-site pain and clinical improvement of depressive symptoms., Methods: We conducted a retrospective observational study involving 50 right-handed patients with TRD. All patients received high-frequency rTMS for up to 6 weeks. Depressive symptoms were assessed using the Montgomery-Åsberg depression rating scale (MADRS). Pain at the stimulation site was reported by the patients using a visual analog scale (VAS) after each session. Remission and response rates at 3 and 6 weeks were calculated based on the MADRS scores. The correlation between changes in the MADRS and VAS scores was examined., Results: Remission and response rates were 36% and 46%, respectively, at the end of 3 weeks, and 60% and 70%, respectively, at 6 weeks. At the end of the treatment, there was significant correlation between the reduction of MADRS and VAS scores (r = 0.42, p = 0.003)., Conclusion: This study demonstrates the clinical efficacy of rTMS in Japan and the correlation between its antidepressant effects and stimulation-site pain., (© 2024 S. Karger AG, Basel.)

Purpose: Over 50% of patients with early-stage glaucoma discontinue topical therapy within the first 6 months of treatment initiation. This risk of discontinuation could be reduced by how the ophthalmologist explains the treatment plan. Ophthalmologists can explain the treatment plan to patients in either positive or negative contexts. Although explanations in a negative context can be selected depending on the medical situation, identification of patients who will choose the treatment with explicit statistical prediction after an explanation in a negative context is important; personality traits are related to these emotional decisions. Therefore, in the present study, we examined the personality traits associated with choice of treatment with explicit statistical prediction after an explanation in a negative context., Patients and Methods: A total of 147 patients with glaucoma were recruited for this study. The questionnaire booklets used contained positively framed or negatively framed versions of an "Asian disease problem" to enable examination of the influence of the way in which a problem is framed (framing effect) on the participants' decision-making. The Japanese version of the Ten-Item Personality Inventory was used to estimate the personality traits of the participants., Results: Low conscientiousness was identified as the only variable that was strongly predictive of the choice of treatment with explicit statistical prediction (β = -0.44, z = 2.19, p = 0.03). In addition, while the association was not statistically significant, low neuroticism was found to be weakly predictive of the choice of uncertain treatment (β = -0.37, z = 1.73, p = 0.08)., Conclusion: In conclusion, we showed that low levels of conscientiousness predict the choice of treatment with explicit statistical prediction (ie, topical treatment) for glaucoma after an explanation in a negative context., Competing Interests: Dr Fumitoshi Kodaka reports grants and/or personal fees from Janssen Pharmaceutical K.K., Lundbeck, MEIJI Seika Pharma Co., Ltd., Santen Pharmaceutical, and Mochida Pharmaceutical Co., Ltd., outside the submitted work. KH is an employee of Santen Pharmaceutical Co., Ltd. The authors report that they have no other conflicts of interest in this work., (© 2023 Kodaka et al.)

Late recurrence of stage ⅠB gastric cancer with high microsatellite instability(MSI-high)is rare. Here, we report a case of MSI-high StageⅠB gastric cancer recurring more than 5 years after surgery. A 78-yaer-old man was admitted to our hospital for gastric cancer surgery. Laparoscopic distal gastrectomy was performed. Histologic examination revealed a T2(MP) N0M0, HER2-negative, StageⅠB gastric tubular adenocarcinoma. Postoperatively, the patient received chemotherapy with S-1 for 1 year. He developed liver and para-aortic lymph node metastases 5 years 1 month after surgery. Pathological genetic examination revealed a high microsatellite instability. He received pembrolizumab therapy for the recurrence. This case suggests that late recurrence occurs in patients with gastric cancer with high microsatellite instability.

Aim: The objective of this study was to reveal risk factors for incident of frontotemporal dementia (FTD) compared with Alzheimer disease (AD) in Japan., Method: Fifty consecutive subjects diagnosed with FTD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) under 75 years old were included retrospectively. As a control group, 48 subjects who were diagnosed with AD according to the DSM-5 and matched by age, sex, educational history, and Mini-Mental State Examination were also included. In order to examine the distinctive risk factors of FTD, we compared the relationship between symptomatologic features, Clinical Dementia Rating, clinical factors, and sociopsychological factors in the two groups., Result: Patients with FTD were more likely than patients with AD to have meticulous premorbid personality and less likely to have a history of diabetes than patients with AD. Although the regression analysis was not significant, a history of psychiatric disorders tends to affect the incidence of FTD., Conclusions: These findings regarding the risk of FTD are expected to lead to early diagnosis and care of FTD. Geriatr Gerontol Int 2023; 23: 932-937., (© 2023 Japan Geriatrics Society.)

Background and Aims: Protein C is a plasma protein, and its active form regulates blood coagulation. The recommended unit of protein C activity is IU/mL; however, some laboratories use percentage. Some deficiencies cannot be detected owing to measurement principles. This study sought to quantify protein C activity levels and overcome the limitations of the current measurements., Materials and Methods: Our protein C activity measurement method mimicked the blood coagulation cascade and used a thrombin-specific chromogenic reagent. The control was prepared by adding protein C to the protein C deficient plasma. The calibration curve was plotted as the increase in the absorbance per minute and the concentration of protein C in the control. Statistical tests were performed to compare our method with the current chromogenic method., Results: A calibration curve was constructed ( y  = -0.0132 x  + 0.14, R 2  = 0.9987, n  = 10). The statistical results of our method suggested non-inferiority when compared to the current chromogenic method (α = 0.05)., Conclusion: The quantitative measurement was performed using plasma samples. Our method provides the possibility of expressing protein C activity quantitatively and detecting deficiencies that cannot be detected using the current chromogenic method., Competing Interests: The all 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., (© 2023 The Authors.)

Introduction: A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection in specific brain regions remain unclear., Methods: To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [ 18 F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected., Results: Transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [ 18 F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [ 18 F]DPA-714 in the DR, RPC and A5 was positively correlated with subsequent fatigue-like behavior, and that in the A7 tended to positively correlate with fever., Discussion: These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Hu, Ochi, Arakaki, Mawatari, Shigeta, Wu, Hayashinaka, Neyama, Tahara, Wada, Li, Doi, Watanabe and Cui.)

A 60-year-old woman was undergoing chemotherapy for triple-negative breast cancer and multiple liver metastases. One year and 3 months after the start of treatment, blood tests showed worsening liver function and a decrease in the platelet count. Multiple liver metastases tend to shrink on computed tomography, but pseudocirrhosis was suspected because the right lobe of the liver had atrophied and the marginal irregularities were conspicuous. The platelet count decreased because of hypersplenism, and continuing chemotherapy was difficult. Splenic artery embolization was performed by the internal medicine department, and chemotherapy was resumed once the platelet count recovered. Imaging findings consistent with cirrhosis without the typical cirrhosis histopathology are considered as pseudocirrhosis. This phenomenon has been reported for breast cancer. During chemotherapy for liver metastases, attention should be paid to its appearance. Furthermore, liver cirrhosis should be controlled, and chemotherapy should be continued in coordination with the internal medicine department.

Human induced pluripotent stem (iPS) cells initiate hepatocyte differentiation in a medium without glucose and supplemented with galactose, oncostatin M and small molecules [hepatocyte differentiation inducer (HDI)]. To clarify the metabolic differences between iPS cells in HDI and ReproFF (undifferentiated state), a metabolome analysis was performed. iPS cells were cultured in a medium without glucose and supplemented with galactose, as well as 1 mM of calcium lactate, sodium lactate or lactic acid. After 7 days of culture, the cells were subjected to reverse transcription-quantitative PCR analysis. The galactose-1-phosphate concentration was significantly higher in cells cultured in HDI than in those cultured with ReproFF. The lactate concentration in the HDI group was significantly lower than that in the ReproFF group. The expression levels of α-feto protein and albumin were significantly higher in the groups cultured with calcium lactate, sodium lactate and lactic acid as compared with ReproFF. It was suggested that lactate promoted the survival of iPS cells cultured in a medium without glucose and supplemented with galactose. Under these conditions, iPS cells begin to differentiate into a hepatocyte lineage. Lactate may be applied to produce hepatocytes from iPS cells more efficiently., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023, Spandidos Publications.)

Morita therapy (MT) has been re-evaluated and has attracted much attention internationally to date. However, it is not known what kinds of experiences inpatients with mood disorders undergo during the process of recovery through MT. The purpose of this study was therefore to empirically clarify what subjective experiences influence the recovery from depression when it is treated with MT. Patients with mood disorders who were admitted to the Jikei University Center for Morita Therapy were included. Successive assessments of depression were performed using rating scales. Semi-structured interviews were conducted at the time of discharge regarding factors contributing to improvement, and were analyzed using qualitative data analysis methods to identify factors contributing to the recovery from depression among inpatients treated with MT. There were 24 subjects, 19 of whom completed treatment. The completers had significantly lower severity of depression severity upon discharge. Remarkably, qualitative analysis revealed that nine categories of experiences contributed to recovery from depression. In particular, experiences of "isolation bed-resting of MT", "getting stuck in doing things one's way", "identifying maladaptive behavior patterns", "modifying maladaptive behavior patterns", "restoring self-evaluation", and "change in negative emotions" were considered as the key experiences for recovery.