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The development of efficient immunosuppressants may bring significant benefits to patients after organ/stem transplantation and those with allergies or autoimmune diseases. MEK inhibitors were originally developed as anticancer reagents, but recent reports have suggested that they may have the potential to be immunosuppressants. Trametinib is a first-in-class MEK inhibitor. Here, we examined the effects of trametinib on the immune system and revealed its mechanism. Trametinib suppressed both CD4 and CD8 T-cell proliferation and activated T cells, which expressed CD25 and TIM3, in a dose-dependent manner in vitro. Trametinib also suppressed T cell-related cytokine secretion in a dose-dependent manner. Notably, trametinib suppressed T cell proliferation through the induction of G1 arrest and apoptosis in stimulated T cells. In addition, trametinib induced regulatory T cells (Tregs). We confirmed that low concentrations of trametinib (1 and 10 nM) were not toxic toward splenic naïve T cells and normal mouse liver cells. In this study, we demonstrated whether trametinib suppressed CD4 and CD8 T cell proliferation by inducing G1 arrest and apoptosis along with suppression of cytokine secretion., (© 2025 Wiley‐VCH GmbH.)

Introduction: Recent studies have reported that essential tremor (ET) presents with not only motor symptoms but also cognitive dysfunction. However, detailed pathological mechanisms remain unclear. Here, we evaluate the characteristics of cognitive changes in older patients., Methods: Eighty-five patients aged 65 years or older with ET but without dementia were evaluated for cognitive function using the Addenbrooke Cognitive Examination Revised (ACE-R). The patients were compared with healthy controls (HCs), and the characteristics of cognitive dysfunction were examined. Age at onset and correlations with tremor severity were also investigated. Moreover, we performed resting-state network (RSNs) analysis in a subset of these patients, and the functional connectivity (FC) within the networks was compared with age-matched controls., Results: Compared to HCs, older patients with ET showed a clear reduction in the total (p = 0.001), attention (p = 0.005), verbal fluency (p = 0.001), and memory (p = 0.001) ACE-R scores. Older-onset patients showed significant cognitive dysfunction compared with younger-onset patients. Verbal fluency correlated with tremor severity in the multiple regression analysis (p < 0.001). RSNs showed an increase in FC in the frontal lobes within the language network in patients with ET compared to HCs (p < 0.05, FWE-corrected)., Conclusion: Older patients with ET showed obvious cognitive dysfunction compared to HCs, indicating that cognitive dysfunction varies by age of onset and correlates with tremor severity. The results of the RSNs analysis suggest that the pathological mechanism of cognitive dysfunction in ET patients involves network changes similar to those in the early stages of Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Vitamin D is an essential nutrient for maintaining blood calcium and phosphorus levels and controlling bone density. Deficiency in it leads to rickets, osteomalacia, osteoporosis, and various other diseases. Recently, it has gained attention for reportedly reducing the risk of COVID-19 severity. However, there are no reports evaluating pregnant women in the Hokkaido region of Japan. This study aims to elucidate the current status of vitamin D levels in pregnant women in the Hokkaido region., Methods: This study measured the serum concentrations of Vitamin D2 and D3 in 206 pregnant women participating in the Japan Environment and Children's Study-Hokkaido sub-cohort at the Hokkaido Regional Center. It analyzed the relationship between these concentrations and the months, seasons, and sunshine hours., Results: The mean maternal age was 31.7 ± 4.7 years, and the mean prepregnancy BMI was 21.0 ± 2.5 kg/m2. Only two women have given birth at least once. Regarding sunscreen use, 65 participants (31.6%) responded "often" or "sometimes." Five women used the supplement containing Vitamin D. The value of 25(OH)D2 was above 1 ng/ml in four of them. The average 25(OH)D3 level was 12.1 ng/ml, with a median of 11.0 ng/ml. Four participants (1.9%) had levels below 5 ng/ml. The highest median of 25(OH)D3 was in July, and the lowest was in April. The concentration of 25(OH)D3 was significantly higher in summer than in winter. A correlation was found between 25(OH)D3 and sunshine hours, with 25(OH)D3 concentrations gradually increasing as sunshine hours increase., Conclusion: It was found that almost all pregnant women in Hokkaido were deficient in vitamin D. It is necessary to implement measures to enhance vitamin D levels in pregnant women to safeguard the health of women and fetuses in Hokkaido., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakanishi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Abrupt discontinuation of overused medications is standard treatment for medication overuse headache (MOH), but discontinuation is difficult to maintain. The aim was to evaluate the real-world clinical results of anti-calcitonin gene-related peptide monoclonal antibody (CGRP-mAb) treatment for migraine with MOH without abrupt drug discontinuation and no hospitalization., Methods: Data were collected before starting CGRP-mAb injections (baseline) and 1 month after each injection. The following items were compared between baseline and after the first, second, and third CGRP-mAb injections, monthly headache days (MHD), monthly migraine days (MMD), monthly acute medication use (AMU) days, monthly total amount of AMU tablets, headache impact test-6 (HIT-6), and the migraine-specific quality of life questionnaire (MSQ). Achieving reduction rates ≥50 % in the frequency of each headache and migraine was defined as a good response. Achieving reduction rates of both AMU days and tablets ≥50 % was defined as effective in reducing AMU., Results: This study included 33 patients with migraine with MOH. After the third CGRP-mAb injection, MHD and MMD were significantly decreased from median 30.0 to 9.5 days, and 10.0 to 1.5 days, respectively. In addition, monthly AMU days and tablets were significantly decreased from median 28.0 to 8.0 days, and 30.0 to 9.5 tablets, respectively. After the third CGRP-mAb injection, the good MHD and MMD responder rates were 75.0 % and 85.7 %, respectively. The rate of reducing AMU was 78.6 %. HIT-6 and MSQ scores decreased significantly from baseline to after each CGRP-mAb injection., Conclusions: When CGRP-mAb was administered to migraine with MOH, frequency of headache symptoms and AMU were reduced without abrupt drug discontinuation and no hospitalization., Competing Interests: TT received speaking fees from Daiichi Sankyo, Otsuka Pharmaceutical, and Amgen. YF reports no conflict of interest. SM reports no conflict of interest. YN reports no conflict of interest. TI reports no conflict of interest. YN reports no conflict of interest. MM reports no conflict of interest. YI reports no conflict of interest. MH reports no conflict of interest. TS reports no conflict of interest. SY reports no conflict of interest. TW reports no conflict of interest. RS received speaking fees from Daiichi Sankyo., (© 2024 The Authors.)

Background: In familial adenomatous polyposis (FAP) patients, fundic gland polyps (FGPs) have been considered a risk factor for gastric neoplasms. We speculated that FGPs in FAP patients spread directionally from the greater to the lesser curvature of the gastric body and investigated the relationship between the distribution of FGPs and gastric neoplasm development., Methods: We extracted 195 FAP patients from two institutions and reviewed their medical records. Gastric polyposis was classified based on the FGP distribution (P0, no FGPs; P1, localized in the fundus or greater curvature of the gastric body; P2, spreading to the anterior or posterior wall; P3, involving the proximal half of the lesser curvature; and P4, spreading from P3 to the anal side of the lesser curvature)., Results: The 195 eligible patients were divided into the neoplasm group (n = 54, 28%) and the non-neoplasm group (n = 141, 72%). Overall, 24% of the patients were Helicobacter pylori (H. pylori)-positive. In the FGP distribution, the rate of patients with gastric neoplasm tended to increase significantly with each step towards an increasingly wide distribution from P0 to P4 in H. pylori-negative patients, but not in H. pylori-positive ones. In addition, in H. pylori-negative patients, the likelihood of neoplasm increased consistently from P0 to P4, with the highest odds ratio (95% confidence interval) at P4 of 14.1 (2.5-154.4). Furthermore, multivariate analysis showed P4 and Spigelman stage ≥III were significantly associated with gastric neoplasm development., Conclusion: FGP distribution was correlated with gastric neoplasm development in FAP patients., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Hypertrophic cardiomyopathy (HCM) is often concomitant with sleep-disordered breathing (SDB), which can cause adverse cardiovascular events. Although an appropriate approach to SDB prevents cardiac remodelling, detection of concomitant SDB in patients with HCM remains suboptimal. Thus, we aimed to develop a machine learning-based discriminant model for SDB in HCM., Methods: In the present multicentre study, we consecutively registered patients with HCM and performed nocturnal oximetry. The outcome was a high Oxygen Desaturation Index (ODI), defined as 3% ODI >10, which significantly correlated with the presence of moderate or severe SDB. We randomly divided the whole participants into a training set (80%) and a test set (20%). With data from the training set, we developed a random forest discriminant model for high ODI based on clinical parameters. We tested the ability of the discriminant model on the test set and compared it with a previous logistic regression model for distinguishing SDB in patients with HCM., Results: Among 369 patients with HCM, 228 (61.8%) had high ODI. In the test set, the area under the receiver operating characteristic curve of the discriminant model was 0.86 (95% CI 0.77 to 0.94). The sensitivity was 0.91 (95% CI 0.79 to 0.98) and specificity was 0.68 (95% CI 0.48 to 0.84). When the test set was divided into low-probability and high-probability groups, the high-probability group had a higher prevalence of high ODI than the low-probability group (82.4% vs 17.4%, OR 20.9 (95% CI 5.3 to 105.8), Fisher's exact test p<0.001). The discriminant model significantly outperformed the previous logistic regression model (DeLong test p=0.03)., Conclusions: Our study serves as the first to develop a machine learning-based discriminant model for the concomitance of SDB in patients with HCM. The discriminant model may facilitate cost-effective screening tests and treatments for SDB in the population with HCM., Competing Interests: Competing interests: YM received an unrestricted research grant from the Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Astellas Pharma, Ono Pharmaceutical Co, Daiichi-Sankyo Co, Nippon Boehringer Ingelheim Co, Pfizer Japan, Takeda Pharmaceutical Co and Teijin Pharma. YM reports receipt of Scholarship funds or Donations Scholarship funds from Abbott Medical Japan and BIOTRONIK JAPAN., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Prevalence of colonoscopy (CS) is an important countermeasure against colorectal cancer (CRC). In this study, we used large-scale data for a comparison of CS with esophagogastroduodenoscopy (EGD) in Japan., Methods: This was a retrospective descriptive study. Commercially anonymized patient data were collected from various health insurance societies (JMDC, Inc. Tokyo, Japan) generated from the insurance registry, receipts (inpatient, outpatient, and prescription), and health checkup data. The data also included healthy subjects who had never been examined in a hospital. The data of 2,760,048 persons who were 50-75 years old during January 2012-December 2019 were extracted from the original data source. The annual rate, the prevalence rate (frequency of those undergoing at least one endoscopy during the period), and the percentage of repeaters (undergoing endoscopy at least twice during the period) of CS were calculated and compared to those of EGD., Results: The annual rates in 2012/2015/2019 were 3.4%/4.5%/5.3% for CS, respectively, and increased gradually from 2012 to 2019. Those rates were 7.0%/7.9%/7.4% for EGD, respectively, and did not increase. The prevalence rates of CS and EGD were 25.3% and 36.2%, respectively, among the 137,246 participants over 8 years. The prevalence rates of individuals in their 50 s/60 s/70 s were 23.0%/25.9%/31.4% for CS and 33.0%/37.6%/40.7% for EGD, respectively. The proportions of males/females were 27.9%/20.7% for CS, and 36.4%/35.8% for EGD, respectively. The repeat rates of CS and EGD were 40.3% and 44.8%, respectively, over 8 years., Conclusions: Using large-scale data, we determined the status of CS and EGD in Japan., (© 2024. Japanese Society of Gastroenterology.)

Introduction: Familial adenomatous polyposis (FAP), a hereditary disorder of the gastrointestinal tract, is an autosomal dominant inherited condition caused by germline mutations in the adenomatous polyposis coli ( APC ) gene. It is characterized by the development of hundreds to thousands of colorectal adenomatous polyps, which, if left untreated, can eventually develop into colorectal carcinomas. Representative extracolonic tumors in FAP include multiple duodenal adenomas and desmoid tumors. Moreover, multiple fundic gland polyps are frequently identified in the stomachs of patients with FAP., Case Presentation: Herein, we report the two cases. A 52-year-old woman who underwent total colectomy for FAP, and pancreatoduodenectomy was initiated on esomeprazole for the treatment of anastomotic erosion. Esophagogastroduodenoscopy performed 42 months later showed an increased number and size of gastric fundic gland polyps, which subsequently decreased after replacing esomeprazole with ranitidine. Similarly, a 39-year-old woman with FAP was initiated on vonoprazan for the treatment of reflux symptoms. Esophagogastroduodenoscopy and colonoscopy performed 14 months later indicated an increase in the number of gastric fundic gland polyps and colorectal polyps, which subsequently decreased after vonoprazan discontinuation. In these two cases, the increase and decrease in the number and size of fundic gland polyps and colon adenoma were associated with serum gastrin levels., Conclusion: Gastric fundic gland polyps and colon polyps may rapidly increase in number and size due to increased gastrin levels induced by proton pump inhibitor/potassium-competitive acid blocker use. Hence, these drugs should be prescribed with caution., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for essential tremor (ET). However, its long-term outcomes and prognostic factors remain unclear. This study aimed to retrospectively investigate 38 patients with ET who underwent MRgFUS thalamotomy and were followed up for >2 years. The improvement in tremor was evaluated using the Clinical Rating Scale for Tremor (CRST). Adverse events were documented, and correlations with factors, such as skull density ratio (SDR), maximum mean temperature (T-max), and lesion size, were examined. Furthermore, the outcomes were compared between two groups, one that met the cutoff values, which was previously reported (preoperative CRST-B ≤ 25, T-max ≥ 52.5°C, anterior-posterior size of lesion ≥ 3.9 mm, superior-inferior [SI] size of lesion > 5.5 mm), and the other that did not. The improvement rate was 59.4% on average at the 2-year follow-up. Adverse events, such as numbness (15.8%), dysarthria (10.5%), and lower extremity weakness (2.6%), were observed even after 2 years, although these were mild. The factors correlated with tremor improvement were the T-max and SI size of the lesion (p < 0.05), whereas the SDR showed no significance. Patients who met the aforementioned cutoff values demonstrated a 69.8% improvement at the 2-year follow-up, whereas others showed a 43.6% improvement (p < 0.05). In conclusion, MRgFUS is effective even after 2 years. The higher the T-max and the larger the lesion size, the better the tremor control. Previously reported cutoff values clearly predict the 2-year prognosis, indicating the usefulness of MRgFUS.

Objective: Patients with epilepsy have high risk of experiencing uncommon causes of death. This study aimed to evaluate patients who underwent unusual deaths related to epilepsy and identify factors that may contribute to these deaths and may also include sudden unexpected death in epilepsy (SUDEP)., Methods: We analyzed 5291 cases in which a postmortem imaging (PMI) study was performed using plane CT, because of an unexplained death. A rapid troponin T assay was performed using peripheral blood samples. Clinical information including the cause of death suspected by the attending physician, body position, place of death, medical history, and antiseizure medications was evaluated., Results: A total of 132 (2.6%) patients had an obvious history of epilepsy, while 5159 individuals had no history of epilepsy (97.4%). Cerebrovascular disease was the cause of death in 1.6% of patients in the group with epilepsy, and this was significantly lower than that in the non-epilepsy group. However, drowning was significantly higher (9.1% vs. 4.4%). Unspecified cause of death was significantly more frequent in the epilepsy group (78.0% vs. 57.8%). Furthermore, the proportion of patients who demonstrated elevation of troponin T levels without prior cardiac disease was significantly higher in the epilepsy group (37.9% vs. 31.1%). At discovery of death, prone position was dominant (30.3%), with deaths occurring most commonly in the bedroom (49.2%). No antiseizure medication had been prescribed in 12% of cases, while 29.5% of patients were taking multiple antiseizure medications., Significance: The prevalence of epilepsy in individuals experiencing unusual death was higher than in the general population. Despite PMI studies, no definitive cause of death was identified in a significant proportion of cases. The high troponin T levels may be explained by long intervals between death and examination or by higher incidence of myocardial damage at the time of death., Plain Language Summary: This study investigated unusual deaths in epilepsy patients, analyzing 5291 postmortem imaging cases. The results showed that 132 cases (2.6%) had a clear history of epilepsy. In these cases, only 22% cases were explained after postmortem examination, which is less than in non-epilepsy group (42.2%). Cerebrovascular disease was less common in the epilepsy group, while drowning was more common. Elevated troponin T levels, which suggest possibility of myocardial damage or long intervals between death and examination, were also more frequent in the epilepsy group compared to non-epilepsy group., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Connector hubs are specialized brain regions that connect multiple brain networks and therefore have the potential to affect the functions of multiple systems. This study aims to examine the involvement of connector hub regions in essential tremor., Methods: We examined whole-brain functional connectivity alterations across multiple brain networks in 27 patients with essential tremor and 27 age- and sex-matched healthy controls to identify affected hub regions using a network metric called functional connectivity overlap ratio estimated from resting-state functional MRI. We also evaluated the relationships of affected hubs with cognitive and tremor scores in all patients and with motor function improvement scores in 15 patients who underwent postoperative follow-up evaluations after focused ultrasound thalamotomy., Results: We have identified affected connector hubs in the cerebellum and thalamus. Specifically, the dentate nucleus in the cerebellum and the dorsomedial thalamus exhibited more extensive connections with the sensorimotor network in patients. Moreover, the connections of the thalamic pulvinar with the visual network were also significantly widespread in the patient group. The connections of these connector hub regions with cognitive networks were negatively associated (FDR q < 0.05) with cognitive, tremor, and motor function improvement scores., Conclusion: In patients with essential tremor, connector hub regions within the cerebellum and thalamus exhibited widespread functional connections with sensorimotor and visual networks, leading to alternative pathways outside the classical tremor axis. Their connections with cognitive networks also affect patients' cognitive function., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gen Sobue reports a relationship with Mitsubishi Tanabe Pharma Corporation that includes: paid expert testimony and speaking and lecture fees. Gen Sobue reports a relationship with Cyberdine, Inc that includes: speaking and lecture fees. Gen Sobue reports a relationship with Takeda Pharmaceutical Company Limited that includes: paid expert testimony and speaking and lecture fees. Gen Sobue reports a relationship with Biogen Japan Ltd that includes: paid expert testimony. Ryuta Saito reports a relationship with Idorsia Pharmaceuticals Japan Co Ltd that includes: funding grants. Ryuta Saito reports a relationship with Kaneka Corporation that includes: funding grants. Ryuta Saito reports a relationship with Eisai Inc that includes: speaking and lecture fees. Ryuta Saito reports a relationship with Daiichi Sankyo Co Ltd Tokyo that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The use of anchor bolts to secure electrodes to the skull can be difficult in some clinical situations. Herein, we present the boltless technique to secure electrodes to the scalp using nylon sutures to overcome the problems associated with anchor bolts. We investigated the safety, accuracy errors, and patient-related and operative factors affecting errors in the boltless technique., Methods: This single-institution retrospective series analyzed 103 electrodes placed in 12 patients. The target-point localization error (TPLE), entry-point localization error (EPLE), radial error (RE), and depth error (DE) of the electrodes were calculated., Results: The median of the mean operative time per electrode was 9.3 min. The median TPLE, EPLE, RE, and absolute DE value were 4.1 mm, 1.6 mm, 2.7 mm, and 1.9 mm, respectively. Positive correlations were observed between the preoperative scalp thickness, mean operative time per electrode, EPLE, RE, and the absolute value of DE versus TPLE (r = .228, p = .02; r = .678, p = .015; r = .228, p = .02; r = .445, p < .01; r = .630, p < .01, respectively), and electrode approach angle versus EPLE (r = .213, p = .031). Multivariate analysis revealed that the absolute value of DE had the strongest influence on the TPLE, followed by RE and preoperative scalp thickness, respectively (β = .938, .544, .060, respectively, p < .001). No complications related to SEEG insertion and monitoring were encountered., Conclusion: The boltless technique using our unique planning and technical method is a safe, effective, and low-cost alternative in cases where anchor bolts are contraindicated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Aspirin, a nonsteroidal anti-inflammatory drug, has been proven effective in a clinical trial of carcinogenesis blockade. However, various modes of action have been reported for these effects. Thus, in this study, we aimed to present reasonable mode of actions as a proof of concept for human trials, especially trials for patients with familial adenomatous polyposis (FAP). Aspirin treatment at 1000 ppm inhibited intestinal tumorigenesis in FAP model Min mice. As a mode of action, aspirin regulated β-catenin signaling, inflammation, and oxidative stress both in vivo and in vitro. Furthermore, we examined novel markers predictive of aspirin treatment based on liquid biopsy. Here, we demonstrated that aspirin reduced the levels of reactive carbonyl species in the serum of Min mice. These data are expected to be of use for proof of concept of aspirin human trials and implied for the prediction of aspirin efficacy., (© 2023. The Author(s).)

Background/aim: We previously reported a decrease in prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer treated with angiotensin II receptor blockers (ARBs). However, no studies have reported the effect of ARBs on PSA variability in patients without a history of prostate cancer. Therefore, we conducted a population-based, retrospective study to determine whether ARBs have an inhibitory effect on elevated PSA levels in Japanese patients without a history of prostate cancer., Patients and Methods: This study was conducted using a large-scale Japanese claim database, including male patients aged ≥60 years who had two or more PSA measurements with an interval between measurements of 3 months to 2 years between April 2008 and June 2019. Patients who had been prescribed ARBs were grouped into the ARB group, and those who were prescribed antihypertensive drugs other than ARBs were grouped into the non-ARB group. We compared the proportions of patients with second PSA levels greater than the first. The numbers of eligible patients in the ARB and non-ARB groups were 777 and 527, respectively., Results: Multivariate logistic regression analysis revealed that the proportion of patients with elevated PSA levels was significantly lower in the ARB group than in the non-ARB group (adjusted odds ratio=0.80, 95% confidence interval=0.64-0.99, p=0.047)., Conclusion: ARBs may suppress elevated PSA levels in patients without a history of prostate cancer. This contributes to the prevention of prostate cancer., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)