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A rapid increase in the number of patients with dementia has emerged as a global health challenge. Accumulating evidence suggests that early diagnosis and timely intervention can delay cognitive decline. The diagnosis of dementia is commonly performed using neuropsychological tests, such as the Mini-Mental State Examination (MMSE), administered by trained examiners. While these traditional neuropsychological tests are valid and reliable, they are neither simple nor sufficiently short as routine screening tools for dementia. Here, we developed a brief cognitive assessment utilizing an eye-tracking technology. The subject views a series of short (178 s) task movies and pictures displayed on a monitor while their gaze points are recorded by the eye-tracking device, and the cognitive scores are determined from the gaze plots data. The cognitive scores were measured by both an eye tracking-based assessment and neuropsychological tests in 80 participants, including 27 cognitively healthy controls (HC), 26 patients with mild cognitive impairment (MCI), and 27 patients with dementia. The eye tracking-based cognitive scores correlated well with the scores from the neuropsychological tests, and they showed a good diagnostic performance in detecting patients with MCI and dementia. Rapid cognitive assessment using eye-tracking technology can enable quantitative scoring and the sensitive detection of cognitive impairment.

Background Cerebrospinal fluid (CSF) provides a close representation of pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been employed in pathogenesis research and biomarker development for CNS disorders. CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from tiny intrathecal spaces and the technical difficulties involved in CSF sampling has been a bottleneck that has hindered the detailed analysis of CSF in mouse models. Methods We developed a novel chronic dural port (CDP) method without cannulation for CSF collection of mice. This method enables easy and repeated access to the intrathecal space in a free-moving, unanesthetized mouse, thereby enabling continuous long-term CSF collection with minimal tissue damage and providing a large volume of high-quality CSF from a single mouse. When combined with chemical biosensors, the CDP method allows for real-time monitoring of the dynamic changes in neurochemicals in the CSF at a one-second temporal resolution in free-moving mice. Moreover, the CDP can serve as a direct access point for the intrathecal injection of CSF tracers and drugs. Results We established a CDP implantation and continuous CSF collection protocol. The CSF collected using CDP was not contaminated with blood and maintained physiological concentrations of basic electrolytes and proteins. The CDP method did not affect mouse’s physiological behavior or induce tissue damage, thereby enabling a stable CSF collection for up to four weeks. The spatio-temporal distribution of CSF tracers delivered using CDP revealed that CSF metabolism in different brain areas is dynamic. The direct intrathecal delivery of centrally acting drugs using CDP enabled real-time behavioral assessments in free-moving mice. Conclusions The CDP method enables the collection of a large volume of high-quality CSF and direct intrathecal drug administration with real-time behavioral assessment in free-moving mice. Combined with animal models relevant to CNS disorders, this method provides a unique and valuable platform for biomarker and therapeutic drug research.

Calcineurin is a calcium-dependent phosphatase that plays roles in a variety of biological processes including immune responses. In spermatozoa, there is a testis-enriched calcineurin composed of PPP3CC and PPP3R2 (sperm calcineurin) that is essential for sperm motility and male fertility. Because sperm calcineurin has been proposed as a target for reversible male contraceptives, identifying proteins that interact with sperm calcineurin widens the choice for developing specific inhibitors. Here, by screening the calcineurin-interacting PxIxIT consensus motif in silico and analyzing the function of candidate proteins through the generation of gene-modified mice, we discovered that SPATA33 interacts with sperm calcineurin via a PQIIIT sequence. Spata33 knockout mice exhibit reduced sperm motility because of an inflexible midpiece, leading to impaired male fertility, which phenocopies Ppp3cc and Ppp3r2 knockout mice. Further analysis reveals that sperm calcineurin disappears from the mitochondria in the Spata33 knockout testis. In addition, immunoprecipitation analysis indicates that sperm calcineurin interacts with not only SPATA33 but also the mitochondrial protein VDAC2. These results indicate that SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility.

While angiosperm clocks can be described as an intricate network of interlocked transcriptional feedback loops, clocks of green algae have been modelled as a loop of only two genes. To investigate the transition from a simple clock in algae to a complex one in angiosperms, we performed an inventory of circadian clock genes in bryophytes and charophytes. Additionally, we performed functional characterization of putative core clock genes in the liverwort Marchantia polymorpha and the hornwort Anthoceros agrestis. Phylogenetic construction was combined with studies of spatiotemporal expression patterns and analysis of M. polymorpha clock gene mutants. Homologues to core clock genes identified in Arabidopsis were found not only in bryophytes but also in charophytes, albeit in fewer copies. Circadian rhythms were detected for most identified genes in M. polymorpha and A. agrestis, and mutant analysis supports a role for putative clock genes in M. polymorpha. Our data are in line with a recent hypothesis that adaptation to terrestrial life occurred earlier than previously expected in the evolutionary history of charophyte algae. Both gene duplication and acquisition of new genes was important in the evolution of the plant circadian clock, but gene loss has also contributed to shaping the clock of bryophytes.

Background: There is no consensus on whether proton pump inhibitor (PPI) or vonoprazan (VPZ) is superior in preventing delayed bleeding (DB) after endoscopic submucosal dissection (ESD) of the stomach. Objectives: This study aimed to compare the efficacy of combined intravenous and oral PPI versus oral VPZ alone therapy in preventing DB after gastric ESD in a consecutive and large case series. Design: Retrospective study. Methods: This study included consecutive patients who underwent gastric ESD at Chiba University Hospital from January 2017 to July 2023. Before 2019, patients received intravenous omeprazole 20 mg in the morning and evening on the day of ESD and the day after. Thereafter, esomeprazole 20 mg was administered orally once daily, which was continued for generally 28 days (defined as the PPI group). From 2020 onward, patients received oral VPZ 20 mg once daily starting on the day of ESD, also typically continued for 28 days (defined as the VPZ group). DB rates between the PPI and VPZ groups were compared using propensity score matching. Results: There were 720 cases (856 tumors) of gastric ESD during the study period, of which 352 (409 tumors) were in the PPI group and 368 (447 tumors) in the VPZ group. Propensity score matching for 9 covariates related to DB rates for gastric ESD ultimately produced 329 best matches. There was no significant difference in DB rates between the two groups (4.3% vs 3.6%, p = 0.84). Conclusion: Though further prospective studies are needed to draw definitive conclusions, it was suggested that the easily administered oral VPZ can be an important option for acid suppression after gastric ESD.

Background/Objectives: Mesalazine agents are essential drugs for treating ulcerative colitis (UC). Biomarkers that can differentiate mesalazine intolerance from exacerbated UC are needed because of the similarity of their symptoms and increasing prevalence of mesalazine intolerance. The study aim was to assess the usefulness of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) to identify mesalazine intolerance in patients with UC. Methods: In this single-center retrospective study, patients with UC in whom serum PR3-ANCA was measured were included, and the serum levels were compared between the mesalazine-intolerant and -tolerant patient groups. The predictability of the marker to discriminate between these patients was analyzed. Results: Among 406 patients with UC with measured serum PR3-ANCA levels, 68 (17%) had mesalazine intolerance. The PR3-ANCA levels were significantly higher in the intolerance group than in the tolerance group [4.5 U/mL (0.8–26.2 U/mL) vs. 1.5 U/mL (0.0–8.5 U/mL), p = 0.001]. The area under the curve of the receiver operating characteristic curve analysis of the predictability of PR3-ANCA in differentiating mesalazine-intolerant patients from clinically active patients with UC was 0.755 (95% confidence interval: 0.634–0.876, cutoff value: 15.05 U/mL; sensitivity: 0.625, specificity: 0.813). Multivariate logistic regression analysis using various clinical factors revealed that serum PR3-ANCA > 15.0 U/mL was an independent risk factor of mesalazine intolerance (odds ratio: 8.25, 95% confidence interval: 2.52–27.02, p < 0.001). Conclusions: Serum PR3-ANCA could be a useful marker to identify mesalazine-intolerant patients with UC.

Background Metastasis of infradiaphragmatic tumors to the left supraclavicular lymph node is reported to be rare. When metastasis is detected in the left supraclavicular node in patients with head and neck carcinoma, locating the primary cancer remains a difficult and time-consuming challenge despite the dramatic development of screening technologies and treatment methods. Case presentation We report three cases of malignant infradiaphragmatic tumor diagnosed following an initial finding of left supraclavicular node metastasis after surgery for tongue squamous cell carcinoma (follow-up period, range 18–62 months). In these cases, adenocarcinoma was diagnosed based on left supraclavicular node biopsies, and a second primary tumor was found, in a 78-year-old Japanese woman with a diagnosis of cholangiocarcinoma, a 64-year-old Japanese man with a diagnosis of bladder carcinoma, and a 61-year-old Japanese man with a diagnosis of prostate carcinoma. In the cholangiocarcinoma case, carbohydrate antigen 19-9 and alpha-fetoprotein levels helped to diagnose cholangiocarcinoma. Palliative care only was given, with survival for 11 months after diagnosis of lymph node metastasis. In the bladder carcinoma case, pathological analysis of fine-needle aspiration biopsy specimen of the metastatic cervical lymph node showed atypical cells with slight squamous differentiation. Hematoxylin–eosin staining of the bladder lesion did not identify a clear glandular or squamous component, and we could not make a definitive diagnosis of whether the lesion was poorly differentiated squamous cell carcinoma, adenocarcinoma, or high-grade urothelial carcinoma. GATA3 staining aided in the diagnosis of urothelial bladder cancer with left supraclavicular node metastasis. He survived for 2 months after diagnosis of left supraclavicular lymph node metastasis. In the prostate carcinoma case, 18 F‐fluorodeoxyglucose uptake was weak. Prostate-specific antigen levels and magnetic resonance imaging findings aided the diagnostic process. This patient underwent bilateral orchiectomy and adjuvant hormonal therapy and survived for 47 months after diagnosis of left supraclavicular node metastasis. Conclusions Pathological diagnosis on the basis of immunohistochemistry and specific diagnosis methods such as radiological and serological assessments are important for providing rapid diagnosis and appropriate treatment.

Background and Aim The treatment strategy for patients with ulcerative colitis (UC) in clinical remission who have not achieved mucosal healing is unclear. This study aimed to determine the risk factors of relapse in patients in clinical remission with endoscopic activity. Methods This retrospective, single‐center study included patients with UC who underwent colonoscopy (CS) and were in clinical remission with endoscopic activity. Characteristics were compared between patients who relapsed within 2 years after CS and those who did not. A Cox proportional hazards regression model was used to identify risk factors contributing to clinical relapse. Recent worsening in bowel symptoms was defined as increase in bowel frequency and/or increase in abdominal pain within approximately 1 month based on the descriptions in the medical charts. Results This study regarded 142 patients in clinical remission with an endoscopic activity of Mayo endoscopic subscore (MES) of ≥1 as eligible, and 33 (23%) patients relapsed during the observation period. Recent worsening of bowel symptoms was a significant risk factor for clinical relapse (hazard ratio [HR]: 3.02, 95% confidence interval [CI]: 1.34–6.84). This was particularly evident in patients with MES of 2 (HR: 5.16, 95% CI: 1.48–18.04), whereas no risk factors were identified in patients with MES of 1. The presence or absence of therapeutic intervention just after CS did not significantly affect clinical relapse. Conclusion Recent worsening in bowel symptoms was a significant risk factor for clinical relapse in patients with UC who were in clinical remission with endoscopic activity. This study revealed that recent worsening in bowel symptoms was a significant risk factor for clinical relapse in ulcerative colitis [UC] patients in clinical remission but without mucosal healing. This trend is particularly evident in patients with higher endoscopic activity (Mayo endoscopic subscore [MES] of 2) but not in those with lower endoscopic activity (MES of 1). Therefore, patients in clinical remission should be thoroughly interviewed for symptoms and therapeutic intervention should be cautiously considered for those with endoscopic activity.

Background: Patients with inflammatory bowel diseases (IBD) can develop extraintestinal manifestations (EIMs) during the disease course, which sometimes impact their quality of life. Objectives: This study aimed to clarify the prevalence and types of EIMs using a hospital-based IBD cohort in Japan. Methods: A patient cohort with IBD was established in 2019, as participated by 15 hospitals in Chiba Prefecture of Japan. Using this cohort, the prevalence and types of EIMs, which are defined based on previous reports and the Japanese guidelines, were investigated. Results: This cohort enrolled 728 patients, including 542 ulcerative colitis (UC) and 186 Crohn’s disease (CD). Of these patients with IBD, 10.0% were identified with one or more EIMs (57 (10.5%) with UC and 16 (8.6%) with CD). Arthropathy and arthritis were the most common EIM in 23 (4.2%) patients with UC, followed by primary sclerosing cholangitis (PSC) (2.6%). Arthropathy and arthritis were also the most common in patients with CD, but no cases of PSC were observed. EIMs were more frequently observed in patients with IBD treated by specialists than in those treated by non-specialists (12.7% vs. 5.5%, p = 0.011). The incidence of EIMs in patients with IBD was not significantly different over time. Conclusions: The prevalence and types of EIMs in our hospital-based cohort in Japan did not significantly differ from those reported in previous or Western studies. However, the incidence might be underestimated due to the limited ability of non-IBD specialists to discover and describe EIMs in patients with IBD.

Background and Aim Endoscopic retrograde cholangiopancreatography (ERCP) may help detect cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC), but it may be associated with complications. This study was aimed at determining the prognostic impact of ERCP on patients with PSC without cholangitis. Methods Patients with PSC without cholangitis were divided into two groups: those who underwent ERCP within three years after diagnosis (ERCP-performed group) and those who did not (non-ERCP group). These groups were compared in terms of clinical outcomes (liver-related death or liver transplantation, endoscopic treatment requirement and repeated cholangitis) and the composite outcome. Results Of 99 patients with PSC with detailed medical history, 49 were included in the ERCP-performed group and 21 in the non-ERCP group. In Kaplan-Meier analysis, the non-ERCP group was less likely to achieve the three outcomes and the composite outcome, showing statistical significance (endoscopic treatment requirement; p  = 0.017 and composite outcome; p  = 0.014). A Cox proportional hazards model indicated that ERCP in the asymptomatic state was a significant predictor of endoscopic treatment requirement (hazard ratio [HR]: 4.37, 95% confidence interval [CI]: 1.03–18.59) and the composite outcome (HR: 4.54, 95% CI: 1.07–19.28). Conclusion ERCP in patients with PSC without cholangitis is likely to require further endoscopic treatment and may be associated with poor prognosis. Graphical Abstract