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The prevalence of primary osteoarthritis is higher in females than males. However, it remains unclear if there are sex differences in the incidence of post-traumatic osteoarthritis after anterior cruciate ligament (ACL) reconstruction. In this study, we aimed to investigate the effects of sex on osteoarthritic changes after ACL reconstruction using an animal model. Rats were divided into the following four groups: male control, male ACL reconstruction, female control, and female ACL reconstruction. ACL reconstruction surgery was performed on the right knees of rats in the ACL reconstruction groups, while rats in the control groups did not undergo knee surgery. At 1, 4, and 12 weeks after surgery, cartilage degeneration in the medial tibial plateau and osteophyte formation in the proximal tibia were histologically assessed. After ACL reconstruction, an increase in the Mankin score, cartilage fissures, and osteophyte formation were detected within 12 weeks in both male and female rats, with similar degrees of these changes between males and females. However, changes in cartilage thickness and chondrocyte density after ACL reconstruction differed between males and females. Cartilage thickening was observed in male rats but not in female rats. The increase in chondrocyte density in the anterior region was detected in both males and females but was more pronounced in female rats. In conclusion, osteoarthritic changes were observed after ACL reconstruction in both male and female rats, but differences in changes in cartilage thickness and chondrocyte density were observed between males and females., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background and Aims: Small ischemic lesions (SILs) accompanying intracerebral hemorrhage (ICH) might be induced by small-vessel vulnerability and hypercoagulation. Some polyunsaturated fatty acids (PUFAs) have been associated with hypercoagulation in cardiovascular diseases. Our aim here is to determine how pre-existing small-vessel disease (SVD) and PUFAs may affect SILs., Methods and Results: We screened consecutive ICH patients (October 2012-December 2021) meeting two inclusion criteria: (1) the patients were hospitalized for acute ICH and were undergoing magnetic resonance imaging and (2) the patients' PUFA measurements were available. After excluding patients with isolated intraventricular hemorrhage, we evaluated whether three SVD markers (white matter hyperintensities, old lacunes, cerebral microbleeds) and PUFAs might be associated with the development of SILs. We selected 319 participants from 377 screened consecutive ICH patients (median age = 64, males = 207 [65 %]). Of the 319 patients, 45 patients (14 %) developed SILs. In a multivariable logistic regression analysis, the factors associated with SILs were old lacunes (OR 3.255, 95 % CI 1.101-9.622, p = 0.033) and DHA/AA ratio (OR 0.180, 95 % CI 0.046-0.704, p = 0.013). Furthermore, in our multivariable analysis using DHA/AA ratio tertiles with and without SILs, we observed a linear trend between SILs and the Higher Tertile of the DHA/AA ratio (DHA/AA ratio Mid-Tertile: OR 1.330, 95%CI 0.557-3.177, p = 0.521, and DHA/AA ratio Lower Tertile: OR 2.632, 95%CI 1.124-6.162, p = 0.026)., Conclusion: The presence of old lacunes and lower DHA/AA ratios might be associated with SILs accompanying ICH., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Objective: This study's objective is to investigate whether mild aortic arch plaque is associated with the development of atrial fibrillation (AF) in stroke patients with embolic stroke of undetermined source (ESUS) during the first year following the implantation of an insertable cardiac monitor (ICM)., Methods: The participants in this cross-sectional observational study were consecutive patients with ESUS, even after transesophageal echocardiography. We assessed the relationship between the thickness of the participants' aortic arch plaque and AF detected after ICM implantation., Results: Of the 50 consecutive patients with ESUS enrolled in this study, 12 (24%) developed AF. We observed that thicker aortic arch plaque was associated with undetected AF (2.3 mm vs. 1.2 mm, p < 0.001). Aortic arch plaque thickness was independent associated with undetected AF (OR 54.00, 95% CI 2.706-1077.544, p = 0.009). When the cut-off value for aortic arch plaque thickness was 1.8 mm, the sensitivity and specificity were 71.1% and 91.7%, respectively (95% CI = 0.75-0.98, p < 0.001). Also, patients having both aortic arch plaque with a thickness < 1.8 mm and a CHADS 2 score ≥ 4 were more likely to have detectable AF than no AF (88% vs. 12%, p < 0.001)., Conclusion: A thinner aortic arch plaque was associated with the development of AF. Patients with mild aortic plaques below 4 mm but ≥1.8 mm in thickness and without other high-risk features are less likely to have paroxysmal AF on ICM, and these plaques may be a possible source of embolism for their strokes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alanyl-tRNA synthetase (AlaRS) incorrectly recognizes both a slightly smaller glycine and a slightly larger serine in addition to alanine, and the probability of incorrect identification is extremely low at 1/300 and 1/170, respectively. Alanine is the second smallest amino acid after glycine; however, the mechanism by which AlaRS specifically identifies small differences in side chains with high accuracy remains unknown. In this study, using a malachite green assay, we aimed to elucidate the alanine recognition mechanism of a fragment (AlaRS368N) containing only the amino acid activation domain of Escherichia coli AlaRS. This method quantifies monophosphate by decomposing pyrophosphate generated during aminoacyl-AMP production. AlaRS368N produced far more pyrophosphate when glycine or serine was used as a substrate than when alanine was used. Among several mutants tested, an AlaRS mutant in which the widely conserved aspartic acid at the 235th position (D235) near the active center was replaced with glutamic acid (D235E) increased pyrophosphate release for the alanine substrate, compared to that from glycine and serine. These results suggested that D235 is optimal for AlaRS to specifically recognize alanine. Alanylation activities of an RNA minihelix by the mutants of valine at the 214th position (V214) of another fragment (AlaRS442N), which is the smallest AlaRS with alanine charging activity, suggest the existence of the van der Waals-like interaction between the side chain of V214 and the methyl group of the alanine substrate., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Studies reported that knee extension strength on the operated side in patients with hip fractures was not recovered to the level on the non-operated side 6 months after surgery or later. In a cross-sectional study, we revealed that a reduction in isometric knee extension muscle strength on the operated side in patients with hip fractures approximately 6 months after surgery was associated with not only a reduction in skeletal muscle mass but also a reduction in muscle quality, characterized by a reduction in the phase angle (PhA). Furthermore, the mechanisms of knee extension strength improvement can be clarified in more detail using the minimal significant change as the index of recovery. However, no longitudinal studies have examined the factors for knee extension strength improvement based on the minimal significant change in patients with hip fractures 6 months after surgery. This study aimed to longitudinally examine the factors influencing the recovery of knee extension strength based on the minimal significant change in patients with hip fractures between 2 weeks and approximately 6 months after surgery., Methods: In this study, the outcomes used were basic and medical information, PhA, skeletal muscle index (SMI), pain, one-leg standing time, movement control during one-leg standing, and walking speed. For PhA, SMI, pain, one-leg standing time, movement control during one-leg standing, and walking speed, the amount of change was calculated by subtracting the data at 2 weeks from the data at 6 months. Group classification was determined by dividing the patients into two groups using a previous study as a reference: recovery group if the knee extension strength value approximately 6 months after surgery minus that 2 weeks after surgery was ≥3.3 kgf and non-recovery group if the value was <3.3 kgf. Logistic regression analysis was performed to explore the association between the recovery and non-recovery groups., Results: The recovery group contained 55 patients, while the non-recovery group comprised 35 patients. The only significant factor associated with knee extension muscle strength in the recovery group was the amount of change in PhA. The odds ratio for the amount of change in PhA was 2.26. The discrimination rate of the model was 62.5%., Conclusions: Our results suggest that recovery of knee extension strength in patients with hip fractures after surgery was mainly because of improvements in muscle quality, not improvements in muscle mass or pain., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims: Urinary immunoglobulin G (IgG) may be a stronger marker of atherosclerosis than microalbuminuria are because urinary IgG reflects proteinuria level and size-selectivity loss. Microalbuminuria-not urinary IgG-is associated with mild acute ischemic stroke (MAIS)., Methods: Using the Jikei University School of Medicine Stroke Registry, we selected and screened patients with symptomatic acute ischemic stroke (onset-to-door time ≤ 24 h). The exclusion criteria were (1) on-admission NIHSS scores ＞10, (2) a modified Rankin Scale (mRS) score ≥ 2 prior to stroke onset, (3) incomplete data (no urinalysis ≤ 3 days after admission or no mRS score at 90 days from stroke onset), and (4) an active malignancy. Patients at 90 days post-discharge were divided into those with favorable mRS scores of 0-1 and those with unfavorable mRS scores of 2-6. Clinical backgrounds were compared for (1) patients with positive and negative urinary IgG results, and (2) patients with favorable and unfavorable outcomes., Results: Of our study's 210 patients (164=male, median age=68, median eGFR=53.2 ml/min/1.73 m 2 ), 30 (14%) presented with positive urinary IgG, which was associated with cardiovascular risk factors. Higher BNP, higher D-dimer, lower eGFR, and higher CAVI were associated with higher positive urinary IgG. The favorable group, comprising 155 (74%) patients, had higher negative urinary IgG than the unfavorable group (89% vs 76%, P=0.026). No statistical difference emerged regarding microalbuminuria (29% vs 29%, P=1.000)., Conclusion: In MAIS, urinary IgG was associated with both the presence of atherosclerosis and an unfavorable outcome at 90 days after stroke onset.

Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) are transcriptional repressor complexes that play a fundamental role in epigenomic regulation and the cell-fate decision; these complexes are widely conserved in multicellular organisms. PRC1 is an E3 ubiquitin (ub) ligase that generates histone H2A ubiquitinated at lysine (K) 119 (H2AK119ub1), whereas PRC2 is a histone methyltransferase that specifically catalyzes tri-methylation of histone H3K27 (H3K27me3). Genome-wide analyses have confirmed that these two key epigenetic marks highly overlap across the genome and contribute to gene repression. We are now beginning to understand the molecular mechanisms that enable PRC1 and PRC2 to identify their target sites in the genome and communicate through feedback mechanisms to create Polycomb chromatin domains. Recently, it has become apparent that PRC1-induced H2AK119ub1 not only serves as a docking site for PRC2 but also affects the dynamics of the H3 tail, both of which enhance PRC2 activity, suggesting that trans-tail communication between H2A and H3 facilitates the formation of the Polycomb chromatin domain. In this review, we discuss the emerging principles that define how PRC1 and PRC2 establish the Polycomb chromatin domain and regulate gene expression in mammals., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

To develop artificial cell models that mimic living cells, cell-sized lipid vesicles encapsulating cell-free protein synthesis (CFPS) systems are useful for protein expressions or artificial gene circuits for vesicle-vesicle communications. Therefore, investigating the transcriptional and translational properties of CFPS systems in lipid vesicles is important for maximizing the synthesis and functions of proteins. Although transcription and translation using CFPS systems inside lipid vesicles are more important than that outside lipid vesicles, the former processes are not investigated by changing the lipid composition of lipid vesicles. Herein, we investigated changes in transcription and translation using CFPS systems inside giant lipid vesicles (approximately 5-20 μm in diameter) caused by changing the lipid composition of lipid vesicles containing neutral, positively, and negatively charged lipids. After incubating for 30 min, 1 h, 2 h, and 4 h, the transcriptional and translational activities in these lipid vesicles were determined by detecting the fluorescence intensities of the fluorogenic RNA aptamer on the 3'-untranslated region of mRNA (transcription) and the fluorescent protein sfCherry (translation), respectively. The results revealed that transcriptional and translational activities in a lipid vesicle containing positively charged lipids were high when the protein was synthesized using the CFPS system inside the lipid vesicle. Thus, the present study provides an experimental basis for constructing complex artificial cell models using bottom-up approaches., (© 2024. The Author(s).)

Background and Aims: Circadian variability of blood pressure (BP) and hypercoagulation in the morning have been proposed as underlying mechanisms of wake-up stroke (WUS). The aim was to determine the impact of cerebral microbleeds (CMBs), showing BP fluctuation and background hypercoagulability, on WUS., Methods: Consecutive patients with acute ischemic stroke onset-to-door time within one week were screened. WUS was defined as an ischemic stroke that occurred during sleep at night. CMBs were categorized into three: "strictly Lobar", "strictly Deep (D) and/or Infratentorial (I)", and "Mixed". Moderate to severe CMBs were defined as having more than three in total. First, whether CMBs are associated with WUS was examined. Second, the same analysis was performed according to the stroke subtype classified as large-artery atherosclerosis (LAA), cardioembolism (CE), and small-vessel occlusion (SVO)., Results: A total of 1477 patients (1059 [72%] male, median age 69 years) were included, and WUS was observed in 363 (25%) patients. On Poisson regression analysis with a robust variance estimator in the total cohort, moderate to severe strictly D and/or I CMBs (PR 1.505, 95% CI 1.154-1.962, p = 0.003) were associated with WUS. From the perspective of stroke subtype, the same result was confirmed in LAA (PR 2.223, 95% CI 1.036-4.768, p = 0.040) and CE (PR 1.668, 95% CI 1.027-2.709, p = 0.039), not SVO., Conclusions: The presence of moderate to severe strictly D and/or I CMBs might be associated with the development of WUS. By stroke subtype, the same result was confirmed in LAA and CE., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Japan has various death investigation systems; however, external examinations, postmortem computed tomography, macroscopic examinations, and microscopic examinations are performed regardless of the system used. These examinations can reveal morphological abnormalities, whereas the cause of death in cases with non-morphological abnormalities can be detected through additional examinations. Molecular autopsy and postmortem genetic analyses are important additional examinations. They are capable of detecting inherited arrhythmias or inherited metabolic diseases, which are representative non-morphological disorders that cause sudden death, especially in infants and young people. In this review, we introduce molecular autopsy reports from Japan and describe our experience with representative cases. The relationships between drug-related deaths and genetic variants are also reviewed. Based on the presented information, molecular autopsy is expected to be used as routine examinations in death investigations because they can provide information to save new lives., Competing Interests: The authors have no conflicts of interest to declare., (©2024 The Japanese Society of Toxicologic Pathology.)

Background: Low arachidonic acid (AA) levels are reportedly associated with unfavorable outcomes in intracerebral hemorrhage (ICH)., Objective: We aimed to clarify whether serum AA levels might be associated with a good recovery from severe motor paralysis in the early stage of hospitalization., Methods: From among consecutive ICH patients between October 2012 and December 2021, patients with a sum of upper and lower extremity National Institutes of Health stroke scale (NIHSS) scores of 4-8 at admission (severe motor paralysis) were included. We defined good early recovery from severe motor paralysis as a sum of upper and lower extremity NIHSS scores of 0-3 on day 7 after admission, and that of individual upper and lower extremities as NIHSS scores of 0-1 on day 7 after admission. We aimed to assess whether serum AA levels might be associated with good early recovery from severe motor paralysis., Results: We screened 377 consecutive ICH patients, including 140 with severe motor paralysis (88 (63%) males, median age 64 years). Recovery from severe motor paralysis was seen in 48 (34%). Higher AA levels (PR 1.243, 95% CI 1.042 to 1.483, p = 0.016) were independently associated with good overall recovery, and good recovery of upper and lower extremities separately (upper extremity: PR 1.319, 95% CI 1.101 to 1.580, p = 0.003; lower extremity: PR 1.293, 95% CI 1.115 to 1.499, p = 0.001)., Conclusions: Higher AA levels may contribute to a good early motor recovery in patients with severe motor paralysis due to ICH., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to clarify the learning curve for robotic-assisted spine surgery. We analyzed the workflow in robotic-assisted spine surgery and investigated how much experience is required to become proficient in robotic-assisted spine surgery., Methods: The data were obtained from consecutive 125 patients who underwent robotic-assisted screw placement soon after introducing a spine robotic system at a single center from April 2021 to January 2023. The 125 cases were divided into phases 1-5 of sequential groups of 25 cases each and compared for screw insertion time, robot setting time, registration time, and fluoroscopy time., Results: There were no significant differences in age, body mass index, intraoperative blood loss, number of fused segments, operation time, or operation time per segment between the 5 phases. There were significant differences in screw insertion time, robot setting time, registration time, and fluoroscopy time between the 5 phases. The screw insertion time, robot setting time, registration time, and fluoroscopy time in phase 1 were significantly longer than those in phases 2, 3, 4, and 5., Conclusion: In an analysis of 125 cases after the introduction of the spine robotic system, the screw insertion time, robot setting time, registration time, and fluoroscopy time were significantly longer in the 25 cases in the period initially after introduction. The times were not significantly different in the subsequent 100 cases. Surgeons can be proficient in robotic-assisted spine surgery after their experience with 25 cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Objective: Mechanical thrombectomy (MT) is the gold standard treatment for acute ischemic stroke. During these interventions, a thrombus frequently obstructs a guiding catheter. The obstructed guiding catheter should be withdrawn before distal embolism occurs; however, albeit infrequently, the thrombus occludes even a sheath introducer (SI). While conventionally new SI placement is required for continuation of treatment, we propose a viable alternative for recanalization of the occluded SI, termed vacuum-assisted delivery of thrombus (VADT), with a clinical report of our cases. The usefulness of this technique was also evaluated in simulation experiments., Case Presentations: The VADT procedure is as follows: 1) insert a peel-away sheath, originally attached to a balloon-guiding catheter (BGC), into the SI to continuously open the hemostatic valve; 2) advance the BGC into the peel-away sheath while applying mechanical aspiration; and 3) remove the peel-away sheath/BGC assembly slowly. In a simulation environment using an artificial thrombus, we repeated the VADT procedure five times and reproducibly achieved SI reopening within only 10-20 seconds. From March 2013 to September 2022, 204 patients were treated with MT at our stroke center and SI occlusion occurred in three patients (1.5%). These events occurred exclusively in patients with extracranial internal carotid artery occlusion. All three patients with SI occlusion underwent successfully thrombus extraction in the SI using the VADT on the first try., Conclusion: The results of clinical experience and simulation experiments strongly support VADT as a reliable option for recanalization of an occluded SI., (©2024 The Japanese Society for Neuroendovascular Therapy.)

Purpose: Regardless of the devastating outcomes of pulmonary resection for metastases from gastric cancer, a handful of patients survive long after pulmonary metastasectomy. This study aimed to identify a good candidate for pulmonary resection for metastases from gastric cancer., Methods: Between 2005 and 2023, 564 patients underwent pulmonary metastasectomy in our department, of which 12 patients underwent pulmonary resection for metastases from gastric cancer. Variables evaluated were the number and size of metastatic lesions, surgical procedure, disease-free interval (DFI), and the serum carcinoembryonic antigen at pulmonary metastasectomy., Results: The DFI following gastrectomy ≤12.5 months group had a significantly worse overall survival (OS) than the other group (p = 0.005). A comparison between DFI following gastrectomy ≤12.5 months group and DFI following gastrectomy >12.5 months group showed a significant difference in serum carcinoembryonic antigen (CEA) value at pulmonary metastasectomy (p = 0.048). The serum CEA value at pulmonary metastasectomy >5.8 ng/ml group had a significantly worse OS than the other group (p = 0.001)., Conclusion: Pulmonary metastasectomy can be indicated in some patients with metastasis from gastric cancer who have longer DFI from gastrectomy and lower serum CEA at pulmonary metastasectomy.

It is known that sperm and seminal plasma (SP) affect uterine immunity. In cattle, artificial insemination enables breeding by depositing frozen and largely diluted sperm with a negligible amount of SP into the uterus. Thus, the present study focused on the impact of frozen-thawed sperm on bovine uterine immunity. We have previously shown that in the bovine uterus, sperm swim smoothly over the luminal epithelium and some sperm interact with uterine glands to induce a weak inflammatory response mainly via the endometrial Toll-like receptor 2 (TLR2) signaling. However, the process by which sperm is encountered in the uterine glands is not completely clear. The present study intended to evaluate the role of sperm-TLR2 in sperm-uterine mucus penetration for reaching the glandular epithelium to induce the uterine immune response. To activate and block sperm-TLR2, they were treated with TLR2 agonist and antagonist, respectively. TLR2 activation enhanced sperm hyperactivation and improved its capacity to penetrate the artificial viscoelastic fluid and estrous-uterine-mucus. In contrast, TLR2-blocked sperm showed completely opposite effects. It is noteworthy, that the TLR2-activated sperm that penetrated the uterine mucus exhibited increased motile activity with hyperactivation. In the sperm-endometrial ex-vivo model, a greater amount of TLR2-activated sperm entered the uterine glands with an immune response, which was seen as the upregulation of mRNA expression for TNFA , IL1B , IL8 , PGES , and TLR2 similar to those in control sperm. On the other hand, a lesser amount of TLR2-blocked sperm entered the uterine glands and weakened the sperm-induced increase only in PGES , suggesting that penetration of a certain number of sperm in the uterine gland is necessary enough to trigger the inflammatory response. Altogether, the present findings indicate that activation of sperm-TLR2 promotes their hyperactivation and mucus penetration with greater motility, allowing them to enter into the uterine glands more. This further suggests that the hyperactivated sperm contributes to triggering the pro-inflammatory cascade partly via TLR2 in the uterus., 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 Akthar, Kim, Umehara, Kanno, Sasaki, Marey, Yousef, Haneda, Shimada and Miyamoto.)

Background: Orthostatic hypotension (OH) is a potential modifiable risk factor for cognitive impairment in patients with Parkinson's disease (PD). Although other risk factors for dementia, hyposmia and REM sleep behavior disorder (RBD), are closely associated with autonomic dysfunction in PD, little is known about how these risk factors influence cognitive function and cerebral pathology., Objective: We investigated how these three factors contribute to gray matter atrophy by considering the interaction of OH with hyposmia and RBD., Methods: We analyzed cortical thickness, subcortical gray matter volume, and cognitive measures from 78 patients with de novo PD who underwent the head-up tilt test for the diagnosis of OH., Results: Whole-brain analyses with Monte Carlo corrections revealed that hyposmia was associated with decreased cortical thickness in a marginal branch of the cingulate sulcus among patients with OH, and cortical thickness in this area correlated with cognitive functioning only in patients with OH. Subcortical gray matter volume analysis indicated that severe RBD was associated with decreased volume in the left hippocampus and bilateral amygdala among patients with OH., Conclusion: Even in early PD, OH exerts effects on gray matter atrophy and cognitive dysfunction by interacting with RBD and hyposmia. OH might exacerbate cerebral pathology induced by hyposmia or RBD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Glioma amplified sequence 41 (GAS41), which has the Yaf9, ENL, AF9, Taf14, and Sas5 (YEATS) domain that recognizes lysine acetylation (Kac), regulates gene expression as a subunit of the SRCAP (SNF2-related CREBBP activator protein) complex that deposits histone H2A.Z at promoters in eukaryotes. The YEATS domains of the proteins AF9 and ENL recognize Kac by hydrogen bonding the aromatic cage to arginine situated just before K9ac or K27ac in the N-terminal tail of histone H3. Curiously, the YEATS domain of GAS41 binds most preferentially to the sequence that contains K14ac of H3 (H3K14ac) but lacks the corresponding arginine. Here, we biochemically and structurally elucidated the molecular mechanism by which GAS41 recognizes H3K14ac. First, stable binding of the GAS41 YEATS domain to H3K14ac required the N terminus of H3 (H3NT). Second, we revealed a pocket in the GAS41 YEATS domain responsible for the H3NT binding by crystallographic and NMR analyses. This pocket is away from the aromatic cage that recognizes Kac and is unique to GAS41 among the YEATS family. Finally, we showed that E109 of GAS41, a residue essential for the formation of the H3NT-binding pocket, was crucial for chromatin occupancy of H2A.Z and GAS41 at H2A.Z-enriched promoter regions. These data suggest that binding of GAS41 to H3NT via its YEATS domain is essential for its intracellular function.

Whenever houses are demolished or disasters occur, large quantities of building materials are discharged, which may contain asbestos. To prevent the damage caused by asbestos exposure, a rapid asbestos presence confirmation method is required at demolition sites or temporary disaster storage sites. It is difficult to confirm the presence of asbestos in waste building materials by simple observation. However, it can be confirmed by staining the materials with two dyes: methylene blue (MB) with positive charge, and erythrosine (RED-3) with negative charge, and using a stereomicroscope. The method was applied to samples collected from disaster and demolition sites. Asbestos was stained violet or reddish-purple, and the base material of the building materials remained blue. Using this method, even amateur workers can detect asbestos by means of an image in a different color than the building substrate. Furthermore, the present method detected asbestos more explicitly than the official method (JIS A 1482, 1483; detection limit is < 0.1%) recommended by the Japanese government. This cost-effective method is suitable for detecting asbestos at disaster and demolition sites. The mixture of MB and RED-3 formed nanoparticles of size 151 nm and surface charge of -34 mV that selectively stained asbestos. The staining mechanism was discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Acute aortic dissection has a high mortality rate, especially for Stanford type A with a dissected ascending aorta. Cardiac tamponade is one of the most common complications of acute type A aortic dissection (ATAAD) and can cause death. However, the pathogenesis is often unclear. We aimed to examine laboratory findings at the onset of disease and macrophage involvement., Methods: Hematological and biochemical parameters, and D-dimer, brain natriuretic peptide (BNP), and high-sensitivity troponin I (hs-cTnI) levels in 70 patients with ATAAD at our hospital were investigated. Additionally, the myocardium and aorta after autopsy of an ATAAD case with cardiac tamponade were pathologically examined., Results: Forty-four ATAAD cases were complicated by cardiac tamponade. The mean age of patients with cardiac tamponade and proportion of patients over 70 years of age were both significantly higher than for those without cardiac tamponade. Evaluable D-dimer values were higher than 0.5 μg/mL in all patients. Significantly elevated laboratory parameters in patients with cardiac tamponade included: lactate dehydrogenase, aspartate aminotransferase, C-reactive protein, lactate, BNP, and hs-cTnI. However, multivariate analysis showed only hs-cTnI was significantly associated with cardiac tamponade. Histological examination revealed numerous M2-like macrophages infiltrating the myocardium and dissecting aorta, expressing CC chemokine ligand (CCL)2 together with vascular endothelial growth factor-C and matrix metalloproteinase-9. The peripheral monocyte-to-neutrophil ratio (MNR) was also significantly higher in cardiac tamponade., Conclusions: In ATAAD patients with cardiac tamponade, hs-cTnI was significantly elevated and CCL2 expression was observed, which may be involved in the expression of M2-like macrophages via an increased MNR., Competing Interests: 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., (© 2023 The Authors.)

Background: Super-enhancers (SEs), which activate genes involved in cell-type specificity, have mainly been defined as genomic regions with top-ranked enrichment(s) of histone H3 with acetylated K27 (H3K27ac) and/or transcription coactivator(s) including a bromodomain and extra-terminal domain (BET) family protein, BRD4. However, BRD4 preferentially binds to multi-acetylated histone H4, typically with acetylated K5 and K8 (H4K5acK8ac), leading us to hypothesize that SEs should be defined by high H4K5acK8ac enrichment at least as well as by that of H3K27ac., Results: Here, we conducted genome-wide profiling of H4K5acK8ac and H3K27ac, BRD4 binding, and the transcriptome by using a BET inhibitor, JQ1, in three human glial cell lines. When SEs were defined as having the top ranks for H4K5acK8ac or H3K27ac signal, 43% of H4K5acK8ac-ranked SEs were distinct from H3K27ac-ranked SEs in a glioblastoma stem-like cell (GSC) line. CRISPR-Cas9-mediated deletion of the H4K5acK8ac-preferred SEs associated with MYCN and NFIC decreased the stem-like properties in GSCs., Conclusions: Collectively, our data highlights H4K5acK8ac's utility for identifying genes regulating cell-type specificity., (© 2023. The Author(s).)

Freezing and thawing diminish sperm motility and fertility by disrupting the cholesterol balance in sperm plasma and organelle membranes. The aim of this study was to elucidate the mechanisms through which exogeneous cholesterol treatment enhances the quality of frozen-thawed bull sperm. The incorporation of cholesterol was investigated using boron-dipyrromethene (BODIPY)-cholesterol, and BODIPY signals were detected not only in the plasma membrane but also in the midpiece region immediately after thawing. The positive signal of cholesterol in the midpiece region was inhibited by a scavenger receptor class B Type I (SR-BI) inhibitor, block lipid transport 1 (BLT-1). To comprehend the role of exogenous cholesterol in the functions of the plasma membrane, propidium iodide (PI)/Annexin V and peanut agglutinin lectin (PNA) staining were performed. The results showed that treatment with exogenous cholesterol increased the number of acrosome-intact sperm and decreased the number of sperm with damage to the plasma membrane. Moreover, since BODIPY signals were also observed in the midpiece region, mitochondrial function was evaluated using a flux analyzer and a flow cytometer with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide (JC-1) staining, revealing an increase in the number of sperm with high-mitochondrial activity and oxygen consumption. Finally, to assess sperm fertility, computer-assisted sperm analysis (CASA) and IVF were carried out. Sperm velocities and fertilization rates in IVF were significantly enhanced by the addition of cholesterol just after thawing. Thus, the treatment with cholesterol after thawing protected the plasma membrane from the stress of thawing and maintained mitochondrial function, thereby preserving the fertilization ability of frozen-thawed bull sperm for conventional IVF and artificial insemination (AI). Therefore, the application of cholesterol just after thawing is a promising option for improving the fertility of frozen-thawed sperm., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Histone acetylation is important for the activation of gene transcription but little is known about its direct read/write mechanisms. Here, we report cryogenic electron microscopy structures in which a p300/CREB-binding protein (CBP) multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for reading, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 writes by reading H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP replicates histone N-terminal tail acetylation within the H3-H4 tetramer to inherit epigenetic storage, and transcribes it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization., (© 2023. The Author(s).)

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation., Competing Interests: Declaration of interests M.-M.Z. is a scientific founder, director, and shareholder of Parkside Scientific Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/aim: Dendritic cells (DCs) are difficult to evaluate in lung regional lymph nodes because of region-specific structures, such as abundant trabeculae connecting the medullary and subcapsular sinuses, the latter of which contains few anthracotic macrophages. Therefore, DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DCsign)-positive DCs and CD68-positive macrophages are unlikely to show a typical distribution. The present study therefore explored quantitative factors connecting the nodal DC morphology to the patient outcome., Materials and Methods: Lymph nodes from 34 non-small-cell lung cancer patients who underwent complete resection were used for immunohistochemical assessments of DCsign and CD68 and terminal deoxynucleotidyl transferase dUTP nick-end labeling. Preoperative patient blood samples were used for the quantitative evaluation of monocytes., Results: The nodal DCs showed a complementary distribution with macrophages, thus few DCs were seen in clusters of macrophages. DCs often presented as a mesh-like rosette that was solitary or connected to a DC cluster. DCs disappeared, and some macrophages were apoptotic when surrounded by cancer cells that have metastasized to lymph nodes. The proportional area of a DC cluster was significantly associated with the histological differentiation of cancer (p=0.013), with a higher ratio tending to lead to a better overall survival (p=0.059), and significantly so in adenocarcinoma (p=0.007). The rosette number was significantly correlated with the smoking index and blood monocyte number (p=0.013 and p=0.005, respectively)., Conclusion: The nodal DC morphology appears useful as a prognostic factor and may lead to a new phase of clinicopathological studies of solid cancers., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Individuals with Parkinson's disease (PD) may present with rapid eye movement sleep behavior disorder (RBD). We therefore investigated the association between RBD and quality of life (QOL) in people with PD., Methods: Individuals with PD and a Mini-Mental State Examination score ≥ 24 were divided into two groups using the RBD screening questionnaire (RBDSQ): those with an RBDSQ score ≥ 5 were assigned to the "probable RBD" (pRBD) group, and those with a score < 5 to the "non-pRBD" group. Participants were then evaluated for motor symptoms (Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and modified Hoehn and Yahr Scale), cognitive functions (Montreal Cognitive Assessment and Frontal Assessment Battery [FAB]), anhedonia (Snaith-Hamilton Pleasure Scale), and QOL (Parkinson's Disease Questionnaire [PDQ]-39 total and subscores for mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort). Each measure was compared between the two groups (Mann-Whitney U test/χ 2 test). Multiple regression analyses were performed to identify factors contributing to the total score and the subscore of the stigma domain of the PDQ-39., Results: Ninety-three individuals with PD were recruited (mean ± standard deviation age, 67.0 ± 10.6 years). The pRBD group exhibited a longer disease duration (P = 0.006), worse FAB (P = 0.015) and PDQ-39 total (P = 0.032) scores. RBDSQ scores correlated with higher scores in the PDQ-39 stigma domain (B = 2.44, P = 0.033)., Conclusion: RBD is associated with worse QOL and stigma in people with PD. The RBDSQ is a useful tool for the prediction of such disturbances in QOL., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Study Design: Multicenter retrospective study., Objectives: To investigate adverse events (AEs) in patients with neuropathic pain related to lumbar disease who switched to mirogabalin from pregabalin., Methods: This study surveyed the records of 82 patients with peripheral neuropathic leg pain related to lumbar disease who switched to mirogabalin from pregabalin. We evaluated AEs associated with pregabalin and mirogabalin, the continuation rate of mirogabalin, and the pain-relieving effect at 4 weeks after switching from pregabalin to mirogabalin. We compared patients who switched due to lack of efficacy (LoE group) and patients who switched due to AEs (AE group)., Results: The incidence rates of somnolence and dizziness with pregabalin were 12.2% and 14.6%, respectively, while the incidence rates with mirogabalin were reduced to 7.3% for somnolence and 4.9% for dizziness. The incidence of AEs with pregabalin was significantly higher in the AE group (LoE group: 11.1%, AE group 100%), especially for somnolence (LoE group: 3.2%, AE group: 47.1%) and dizziness (LoE group: 4.8%, AE: 52.9%). After switching, the incidences of AEs with mirogabalin were not significantly different between the 2 groups (LoE group: 15.9%, AE group: 23.5%), including for somnolence (LoE group: 7.9%, AE group: 5.9%) and dizziness (LoE group: 4.8%, AE group: 5.9%). There were no significant differences in continuation rate of mirogabalin or the pain-relieving effect between groups., Conclusions: The patients who experience somnolence and dizziness with pregabalin might be able to continue safely receiving treatment for their pain by switching to mirogabalin.

Our results revealed that the decrease in isometric knee extension muscle strength on the operated and nonoperated sides in patients with hip fractures was associated with not only a decrease in skeletal muscle mass but also a decrease in muscle quality, characterized by a decreased PhA., Purpose: This study aimed to assess the relationship between isometric knee extension muscle strength on the operated or nonoperated sides and PhA in patients with hip fractures at approximately 6 months postoperatively., Methods: This study was a cross-sectional study. Skeletal muscle index (SMI), PhA, knee extension muscle strength on the operated and nonoperated sides, and other physical function variables were assessed at approximately 6 months postoperatively. To identify predictors of knee extension muscle strength on the operated and nonoperated sides, hierarchical multiple regression analysis was performed., Results: A total of 90 patients with hip fractures were included (mean age, 80.1 ± 6.9 years). SMI (0.45) and PhA on the operated side (0.27) were the significant associated factors extracted for isometric knee extension muscle strength on the operated side (standardized partial regression coefficients), independent of age, sex, and body mass index (BMI). Movement control during one-leg standing on the nonoperated side (0.26), SMI (0.32), and PhA on the nonoperated side (0.40) were the significant associated factors extracted for isometric knee extension muscle strength on the nonoperated side, independent of age, sex and BMI., Conclusions: Our results revealed that the decrease in isometric knee extension muscle strength on the operated and nonoperated sides in patients with hip fractures at approximately 6 months postoperatively was associated with not only a decrease in skeletal muscle mass but also a decrease in muscle quality, characterized by a decreased PhA., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

TEAD transcription factors are responsible for the transcriptional output of Hippo signaling. TEAD activity is primarily regulated by phosphorylation of its coactivators, YAP and TAZ. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity. Here, we report lysine long-chain fatty acylation as a posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a "stable active form." Significantly, lysine fatty acylation of TEAD increased upon Hippo signaling activation despite a decrease in cysteine acylation. Our results provide insight into the role of fatty-acyl modifications in the regulation of TEAD activity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the relationships between phase angle and muscle mass, strength, and physical function in patients with heart failure., Methods: This study used a cross-sectional design. The analysis included 51 patients with heart failure. The Short Physical Performance Battery, one-leg standing time, handgrip strength, phase angle, and skeletal muscle index were measured. To identify explanatory variables of phase angle, hierarchical multiple regression analysis was performed., Results: Handgrip strength was found to be an explanatory variable of phase angle independent of age, sex, and body mass index. This model was able to explain 30.4% of the model variance for phase angle., Conclusion: In patients with heart failure, improving muscle strength rather than muscle mass or physical function might be more important for improving phase angle. Handgrip strength is an important outcome for improving prognosis in patients with heart failure.

Study Design: Retrospective study., Objective: The aim was to clarify the health-related quality of life (QOL) of patients who had adolescent idiopathic scoliosis (AIS) at a minimum of 40 years after surgery., Summary of Background Data: The postoperative health-related QOL of middle-aged patients with AIS has been reported to be good, but that of middle-aged and older patients with AIS has yet to be completely explored., Materials and Methods: We included 179 patients with AIS who underwent spinal fusion(s) between 1968 and 1982. We conducted three surveys in 2009, 2014, and 2022. Patients self-administered both the Scoliosis Research Society-22 and the Roland-Morris Disability questionnaires three times (in 2009, 2014, and 2022) and the Oswestry Disability Index (ODI) questionnaire was self-administered in 2014 and 2022. We considered patients who responded to all three surveys in 2009, 2014, and 2022., Results: For the Scoliosis Research Society-22 questionnaires, no significant differences were detected among the three time points (2009, 2014, and 2022) for total scores, function domain, pain domain, self-image domain, mental domain, or satisfaction domain. The results of the Roland-Morris Disability Questionnaire were also not significantly different among the surveys over time. The ODI questionnaires revealed a significant worsening of the 2022 results compared with the 2014 results. Eight patients (29.6%) who had an ODI deterioration of 10% or more had numerically fewer mobile lumbar disks than those with <10% deterioration of the ODI, although the difference did not reach statistical significance., Conclusion: Among patients with AIS who underwent spinal fusion(s) between 1968 and 1982, we found health-related QOL to be maintained over the last 13 years. Relatively good QOL was appreciated in this population of patients who are now middle-aged and older., Competing Interests: T.A. declares research grants from Medtronic and Globus Medical. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of this study is to clarify the feasibility of left atrial (LA) volume measurement and CHA 2 DS 2 -VASc score for predicting the development of pulmonary vein (PV) stump thrombus after left upper lobectomy (LUL). The study population comprised 50 patients who underwent LUL for pulmonary lesions. All patients were evaluated for the development of PV stump thrombus at 7 days after LUL. LA volume was measured using preoperative CT and the CHA 2 DS 2 -VASc score was evaluated. LA volume and CHA 2 DS 2 -VASc score were compared between patients with and without the development of PV stump thrombus using the Mann-Whitney U test. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate the accuracy of prediction of PV stump thrombus development. PV stump thrombus was detected in 17 (33.4%) of the 50 patients. LA volume was significantly greater in patients who developed PV stump thrombus than in those without thrombus (79.7 ± 19.4 vs. 66.6 ± 17.0 mL, p = 0.040). CHA 2 DS 2 -VASc score was significantly higher in patients with PV stump thrombosis than in those without thrombus (3.4 ± 1.5 vs. 2.5 ± 1.5, p = 0.039). Area under the ROC curve values for predicting PV stump thrombus were 0.679, 0.676, and 0.714 for LA volume, CHA 2 DS 2 -VASc score, and their combination, respectively. In conclusion, LA volume measured using preoperative CT and CHA 2 DS 2 -VASc score may help predict the development of PV stump thrombus after LUL., (© 2023. The Author(s).)

Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit rac - 10a obtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure-activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand-protein interaction. Further optimization of the in vitro characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of 26j (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC 50 = 27/53 nM). Compound 26j exhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cells in vitro . Moreover, compound 26j showed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC) in vivo mouse model without overt acute toxicity.

The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent studies in epigenomics and chemical biology have led to the development of a series of small-molecule demethylase inhibitors that are potent, specific, and have in vivo efficacy. In this review, we highlight emerging small-molecule inhibitors targeting the histone lysine demethylases and their progress toward drug discovery.

Background: Monotherapy with monoamine oxidase B (MAO-B) inhibitors enhances the level of endogenous dopamine in treatment for Parkinson's disease (PD) and provides some benefits. Certain neuropsychiatric functions are also regulated by central dopaminergic activity., Aim: To investigate the relationship of the efficacy of monotherapy with MAO-B inhibitors on motor symptoms in PD with baseline cognitive function., Patients and Methods: Outcomes were examined for 27 consecutive drug-naïve PD patients who received initial treatment with a MAO-B inhibitor (selegiline: 11, rasagiline: 16). Selegiline was titrated to an optimal dose. The dose of rasagiline was fixed at 1 mg/day. Motor symptoms were assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III before treatment and after the efficacy reached a plateau within 19 weeks after drug initiation, and the % improvement in motor symptoms was calculated. Pre-treatment cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). Correlations of % improvement in motor symptoms and baseline cognitive assessments were examined using Spearman correlation coefficients and multiple regression analysis., Results: In all patients, the mean % improvement in motor symptoms was 46.5% (range 0-83.3%). Spearman correlation coefficients showed the % improvement in motor symptoms was correlated with FAB (r = 0.631, p < 0.001). In multiple regression analysis with patient background factors as independent variables, only FAB was associated with improvement in motor symptoms in the MAO-B group., Conclusion: Better FAB scores predict a significant improvement in motor symptoms with treatment with MAO-B inhibitors, suggesting high activity of endogenous dopamine., (© 2022. Fondazione Società Italiana di Neurologia.)

Polycomb repressive complex 1 (PRC1) and PRC2 are responsible for epigenetic gene regulation. PRC1 ubiquitinates histone H2A (H2Aub), which subsequently promotes PRC2 to introduce the H3 lysine 27 tri-methyl (H3K27me3) repressive chromatin mark. Although this mechanism provides a link between the two key transcriptional repressors, PRC1 and PRC2, it is unknown how histone-tail dynamics contribute to this process. Here, we have examined the effect of H2A ubiquitination and linker-DNA on H3-tail dynamics and H3K27 methylation by PRC2. In naïve nucleosomes, the H3-tail dynamically contacts linker DNA in addition to core DNA, and the linker-DNA is as important for H3K27 methylation as H2A ubiquitination. H2A ubiquitination alters contacts between the H3-tail and DNA to improve the methyltransferase activity of the PRC2-AEBP2-JARID2 complex. Collectively, our data support a model in which H2A ubiquitination by PRC1 synergizes with linker-DNA to hold H3 histone tails poised for their methylation by PRC2-AEBP2-JARID2., Competing Interests: Conflict Interest Statement The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: The study aimed to determine the current status of face mask use, deep body temperature measurement, and active cooling in patients suffering from heat stroke and heat exhaustion in Japan., Methods: This was a prospective, observational, multicenter study using data from the Heatstroke STUDY 2020-2021, a nationwide periodical registry of heat stroke and heat exhaustion patients. Based on the Bouchama heatstroke criteria, we classified the patients into two groups: severe and mild-to-moderate. We compared the outcomes between the two groups and reclassified them into two subgroups according to the severity of the illness, deep body temperature measurements, and face mask use. Cramer's V was used to determine the effect sizes for a comparison between groups., Results: Almost all patients in this study were categorized as having degree III based on the Japanese Association for Acute Medicine heatstroke criteria (JAAM-HS). However, the severe group was significantly worse than the mild-to-moderate group in outcomes like in-hospital death and modified Rankin Scale scores, when discharged. Heat strokes had significantly higher rates of active cooling and lower mortality rates than heat stroke-like illnesses. Patients using face masks often use them during labor, sports, and other exertions, had less severe conditions, and were less likely to be young male individuals., Conclusions: It is suggested that severe cases require a more detailed classification of degree III in the JAAM-HS criteria, and not measuring deep body temperature could have been a factor in the nonperformance of active cooling and worse outcomes., (© 2023 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Purpose: To compare the accuracy of pedicle screw placement in adolescent idiopathic scoliosis (AIS) between robotics and navigation and clarify the factors that cause screw deviation when robotics is used., Methods: Fifty consecutive patients who underwent posterior spinal fusions with computer-assisted pedicle screw placement including robotics and navigation for AIS were included. A total of 741 pedicle screws (250: Robot group, 491: Navi group) were evaluated on postoperative CT images. A rate of penetration of ≥ 2 mm was calculated as the deviation rate. After propensity score matching, we examined vertebral levels, the distance from the reference frame (RF), and the pedicle channel grade as factors for deviation., Results: The deviation rate was significantly lower in the Robot group than in the Navi group (Robot group: 1.6%, Navi group: 7.5%). After propensity score matching, 22 cases were extracted. At T5-T8, the deviation rate of the Robot group was significantly lower than that of the Navi group. In the Robot group, the T2-T4 deviation rate was significantly higher than at the other vertebral levels. The distance from the RF didn't affect the deviation rate. The deviation rate of pedicle channel Grade 4 (inner diameter of less than 1 mm) was significantly higher than for the other grades., Conclusion: The deviation rate of robotics was 1.6%, lower than that of navigation. The narrow pedicles with an inner diameter of less than 1 mm (deviation rate: 22.2%) and the upper thoracic level (deviation rate: 14.3%) were factors related to screw deviation even when using robotics., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine the impact of old lacunes and their sites on the prognosis of one-sided supratentorial intracerebral hemorrhage (ICH) by classifying lacunes sites in relation to anatomical structures using MRI., Methods: Consecutive patients with one-sided supratentorial ICH ≤72 h from onset to door who underwent MRI were retrospectively included. The sites of old lacunes were categorized as follows: deep subcortical white matter, caudate head, lentiform, posterior limb and genu of the internal capsule, thalamus, and brainstem. We also evaluated all other cerebral small vessel disease markers. An unfavorable outcome was defined as a modified Rankin Scale score of 3 to 6 at 3 months after onset. We investigated whether old lacunes in particular locations were related to unfavorable outcomes., Results: We included 186 patients with one-sided supratentorial ICH (126 [68%] males, median age 62 years). Of 186 patients, 65 (35%) patients had unfavorable outcomes. Factors associated with unfavorable outcomes were age (OR 2.261, 95% CI 1.332-3.839, p = 0.003), National Institutes of Health Stroke Scale [NIHSS] score at admission (OR 1.175, 95% CI 1.090-1.267, p < 0.001), and old thalamic lacunes contralateral to the hematoma (OR 3.805, 95% CI 1.009-14.340, p = 0.048). Patients with old thalamic lacunes contralateral to the hematoma tended to have arm (p = 0.006) and leg (p = 0.011) motor impairment on the paralyzed side at discharge as estimated by the NIHSS score., Conclusions: Old thalamic lacunes contralateral to the hematoma may be related to unfavorable outcomes in ICH., Competing Interests: Declaration of Competing Interest Motohiro Okumura reports no disclosures. Takeo Sato reports no disclosures. Takahiro Maku reports no disclosures. Tomomichi Kitagawa reports no disclosures. Hiroki Takatsu reports no disclosures. Teppei Komatsu reports no disclosures. Kenichi Sakuta reports no disclosures. Kenichiro Sakai reports no disclosures. Tadashi Umehara reports no disclosures. Hidetaka Mitsumura reports no disclosures. Hidetomo Murakami reports no disclosures. Yasuyuki Iguchi reports personal fees from Bayer Healthcare Co. Ltd., grants and personal fees from Pfizer Japan Inc., grants and personal fees from Nippon Boehringer Ingelheim Co. Ltd., grants and personal fees from Takeda Pharmaceutical Co. Ltd., grants and personal fees from Otsuka Pharmaceutical Co. Ltd., and grants and personal fees from Daiichi Sankyo Co. Ltd. outside the submitted work., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sickle cell disease (SCD) is a heritable disorder caused by β-globin gene mutations. Induction of fetal γ-globin is an established therapeutic strategy. Recently, epigenetic modulators, including G9a inhibitors, have been proposed as therapeutic agents. However, the molecular mechanisms whereby these small molecules reactivate γ-globin remain unclear. Here we report the development of a highly selective and non-genotoxic G9a inhibitor, RK-701. RK-701 treatment induces fetal globin expression both in human erythroid cells and in mice. Using RK-701, we find that BGLT3 long non-coding RNA plays an essential role in γ-globin induction. RK-701 selectively upregulates BGLT3 by inhibiting the recruitment of two major γ-globin repressors in complex with G9a onto the BGLT3 gene locus through CHD4, a component of the NuRD complex. Remarkably, BGLT3 is indispensable for γ-globin induction by not only RK-701 but also hydroxyurea and other inducers. The universal role of BGLT3 in γ-globin induction suggests its importance in SCD treatment., (© 2023. The Author(s).)

Background: The readmission rate of heart failure (HF) patients has not decreased during the past few years., Objectives: The purpose of this study was to examine whether factors such as left ventricular ejection fraction (LVEF) and frailty are associated with readmission and number of readmissions in HF patients., Methods: First, a propensity score matching method was used to adjust for confounding factors for readmission. Cox regression analysis was conducted to determine the factors that influenced readmission. Finally, multiple regression analysis was conducted to determine the factors that influenced the number of readmissions. The independent variables were basic and medical information, physical structure, physical functions, and activity for both Cox regression analysis and multiple regression analysis., Results: After matching based on the propensity score, 18 out of 18 (100.0%) patients in the readmission group (age: 85.0 ± 6.9 years, female rate: 50.0%, body mass index: 21.7 ± 3.4 kg/m 2 ) and 18 out of 51 (35.3%) patients in the nonreadmission group (age: 84.3 ± 8.6, female rate: 50.0%, body mass index: 21.8 ± 4.5 kg/m 2 ) were eligible for analysis. Cox regression analysis (hazard ratios) showed that sex (0.16), geriatric nutritional risk index (1.02), and degree of frailty (11.44) were extracted as significant factors. Multiple regression analysis (standardized regression coefficients) showed that the estimated glomerular filtration rate (-0.40), LVEF (-0.32), and degree of frailty (0.29) were extracted as significant factors., Conclusion: Our results suggest that frailty is important to reduce the readmission rate and number of readmissions of the acute HF patients., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: This study aimed to characterize the muscle strength and skeletal muscle mass of patients with heart failure by investigating hand-grip strength, five times sit-to-stand (5STS) results, and skeletal muscle mass index (SMI). Materials and Methods: Muscle strength was assessed based on hand-grip strength and 5STS, while skeletal muscle mass was assessed using a bioelectrical impedance analyzer. Hierarchical logistic regression analysis was performed to explore the association between patients with heart failure and healthy elderly individuals. Results: Hierarchical logistic regression analysis was performed to examine the muscle strength and skeletal muscle mass characteristics in patients with heart failure. Hand-grip strength and 5STS responses but not SMI outcomes differed significantly between the two groups. The results of the hierarchical logistic regression analysis revealed that the hand-grip strength and 5STS were significant predictors of heart failure. The odds ratios for hand-grip strength and 5STS were 1.44 and 0.53, respectively. Conclusion: Our results suggested that upper and lower limb muscle strengths (handgrip strength and 5STS) in elderly patients with heart failure worsened significantly without a decrease in skeletal muscle mass., Competing Interests: The authors declare that there are no conflicts of interest., (©2023 The Japanese Association of Rural Medicine.)

Background: Cerebral microbleeds (CMBs) detected on susceptibility-weighted imaging (SWI) are associated with cerebral small vessel disease. Chronic kidney disease and microalbuminuria have been associated with the presence of CMBs in stroke patients. Urinary immunoglobulin G (IgG) is measured to document glomerular injury; however, the relationship between urinary IgG and CMBs is unknown., Methods: We retrospectively enrolled consecutive patients who had been admitted with transient ischemic attack (TIA) or ischemic stroke and identified those who had undergone SWI and a spot urine test. The location of CMBs was classified on magnetic resonance imaging as strictly lobar, deep/infratentorial (D/I), or mixed areas. We analyzed the association between urinary IgG and the presence and location of CMBs., Results: We included 298 patients (86 female, median age 70 years, median eGFR 65.8 mL/min/1.73 m2). Positive urinary IgG and CMB results were found in 58 (19%) and 160 patients (54%), respectively. Urinary IgG positivity was significantly associated with CMBs compared with non-CMBs (28% vs. 9%, p < 0.001), and with D/I or mixed CMBs compared with non-D/I or mixed CMBs (34% vs. 10%, p < 0.001). Multivariate analysis revealed that urinary IgG and hypertension positivity were strongly associated with D/I or mixed CMBs (OR 3.479, 95% CI: 1.776-6.818, p < 0.001; OR 3.415, 95% CI: 1.863-6.258, p < 0.001)., Conclusions: Urinary IgG was associated with the prevalence of D/I or mixed location CMBs in TIA or ischemic stroke patients. Our findings provide new insights into the association between urinary IgG and the distribution of CMBs., (© 2022 S. Karger AG, Basel.)

Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor and non-motor symptoms. Current treatment mainly relies on medication as a symptomatic therapy modulating neurotransmitters. Dopamine replacement therapy has been established, and levodopa is the gold standard for treatment of PD. However, the emergence of motor complications, such as a wearing-off phenomenon, is a clinical problem. Both primary symptoms and motor complications have been targets for the development of treatments for PD. Recent progression in the management of motor complications is supported by newly developed agents and advances in device and formulation technology to deliver drugs continuously. Elucidation of the pathophysiology of PD and the development of disease-modifying therapy that affects the underlying fundamental pathophysiology of the disease are also progressing. In this review, we introduce current knowledge on developments concerning medications for patients with PD.

Objective: Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in chronic intracerebral hemorrhage (ICH) is beneficial, it has been poorly investigated in rTMS for acute ICH. Our aim is to investigate the effects and safety of rTMS in acute spontaneous ICH., Methods: We prospectively performed HF-rTMS on consecutive patients with ICH within 24 h from onset between April 2019 and August 2021. The inclusion criterion was (1) persistent paralysis, with an NIHSS scale of 1 or higher for at least 3 days after onset. The exclusion criteria were (1) cortical, subcortical, and cerebellar ICH, (2) disturbance of consciousness, and (3) over 80 years of age. For the purpose of comparison, we used a conventional rehabilitation group whose patients met the same criteria between April 2016 and March 2019. We evaluated incidence of epilepsy and exacerbation of the NIHSS score in the rTMS group. We also compared the two groups regarding clinical background and outcome., Results: Enrolled in the study were a total of 44 patients. Of the patients, 22 (50%) were in the rTMS group. The median (IQR) time from onset to the start of rTMS was 9 (6-12) days. There were no cases of epilepsy or exacerbation of NIHSS after the start of rTMS. Favorable outcome (modified Rankin Scale score of between 0 and 2) at 3 months was frequently observed in the rTMS group (73% vs 27%, p = 0.006). HF-rTMS was independently associated with favorable outcome at 3 months (OR = 11.5, 95% CI = 2.194-60.447, p = 0.004)., Conclusions: HF-rTMS may be safe and effective in acute ICH patients., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction The purpose of this study was to evaluate robotic-assisted cortical bone trajectory (CBT) screw placement. Early, middle, and late phases of robotic-assisted CBT screw placement were compared for accuracy and screw insertion time by comparing time and accuracy in every phase.  Methods A retrospective review was conducted on the initial 40 patients who underwent spinal fusion using CBT screws in one institution from September 2021 to September 2022 utilizing a spine surgery robot system (Mazor X Stealth Edition, Medtronic Inc., Dublin, Ireland). The inclusion criterion was one- or two-level posterior lumbar interbody fusion (PLIF). Exclusion criteria were 1) patients who underwent posterior-lateral fusion in other segments, 2) patients who underwent additional decompression in other segments, 3) patients who underwent reoperation, and 4) patients with spondylolysis. The deviation of the CBT screw was evaluated on computed tomography (CT) one week after surgery using the Gertzbein-Robbins grade system. The rate of Grade A was considered the perfect accuracy rate, and the rate of penetration of 2 mm or more (Grades C, D, and E) was calculated as the deviation rate. To assess the learning curve, patients were divided into three groups. The first 10 cases were in the early phase group, the subsequent 10 cases were in the middle phase group, and the last 10 cases were in the late phase group. We compared the perfect accuracy rate, deviation rate, operative time, operative time per segment, intraoperative blood loss, registration time, and screw insertion time among the three groups. Results Thirty patients met the criteria. Overall, the perfect accuracy (Grade A) rate of the screw was 95.3% and the deviation rate was 1.4%. The perfect accuracy rate was 90.4% in the early phase, 95.5% in the middle phase, and 100% in the late phase. The deviation rate was 3.8% in the early phase, 0% in the middle phase, and 0% in the late phase, and there was no statistically significant difference between the three groups. Among the three groups, the operative time, the operative time per segment, the intraoperative blood loss, and the registration time were not significantly different. There was no significant difference in the screw insertion time among the three groups, but it decreased with experience (early phase: 156.9 ± 54.7 sec, middle phase: 139.9 ± 41.6 sec, and late phase: 106.4 ± 39.9 sec, p=0.060). The screw insertion time of the late phase tended to be shorter than that of the early phase (p=0.052). Conclusions The deviation rate of robotic-assisted CBT screw placement with one- or two-level PLIF was 1.4%, which was highly accurate. The deviation rate was 3.8% in the early phase, 0% in the middle phase, and 0% in the late phase. Although the deviation rate was low even in the early period, the screw insertion time in the early 10 cases tended to be longer than that in the late 10 cases. After passing the experience of 10 cases, this study concluded that robotic-assisted CBT screw placement was proficient., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Ueno et al.)