Search

Competing Interests: Declaration of Competing Interest The all authors declare that they have no conflict of interest.

Background and Aims: Hypertension is a risk factor for developing chronic kidney disease (CKD). Studies of adult participants in the USA reported that hypertension increased the risk of developing CKD even in the non-diabetic population. However, studies in non-diabetic populations are limited and additional studies in other races are required. This study aimed to examine the relationship between hypertension and the development of CKD in non-diabetic Asian adults., Methods and Results: In this longitudinal study, non-diabetic Japanese adults who took annual checkups from 1998 to 2023 were included. CKD was defined as <60 mL/min/1.73 m 2 , and hypertension was classified into four levels according to the guidelines of the American College of Cardiology/American Heart Association. The Weibull accelerated failure time model was selected because the proportional hazards assumption was violated. Of the 7363 (men: 40.3%) people in the final cohort, 2498 (men: 40.1%) developed CKD after a mean follow-up of 7.99 years. Elevated blood pressure (BP) and hypertension stage 2 had a 9% (95% confidence interval [CI]: 1%-16%) and 11% (95% CI: 5%-17%) shorter survival time to CKD onset, respectively, than normal BP. Hypertension stage 1 also had a shorter survival to CKD onset by point estimate, but all 95% CIs crossed 1 in all models., Conclusions: In a relatively healthy Asian population without diabetes, controlling BP to an appropriate range reduces the risk of developing CKD., Competing Interests: Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Yukari Okawa declares a relationship with Zentsuji City that includes employment. Toshiharu Mitsuhashi declares no potential conflict of interest associated with this manuscript., (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.)

Objective: In tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance., Methods: Patients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts., Results: Elevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76., Conclusions: Optimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways., Significance: This study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Introduction: Obesity (i.e., body mass index [BMI] of 30 kg/m 2 or more) is one of the risk factors for severe COVID-19, but the findings may not be directly applicable to Asians, who have a different cutoff point for defining obesity. We thus examined the association between obesity/overweight (BMI of 25 kg/m 2 or more and less than 30 kg/m 2 ) and the risk of COVID-19 severity., Methods: The study population included COVID-19 patients who had been enrolled in the registry of the Okayama City Public Health Center in Okayama, Japan, between March 2020 and June 2022. We included 27 820 patients who had information on BMI and prognosis, and we conducted Poisson regression analysis with robust error variance to estimate risk ratios (RRs) with 95% confidence intervals (CIs) for severe outcomes., Results: Obesity and overweight were associated with the increased risk of severe COVID-19 in all age categories. The RRs (95% CI) for COVID-19 induced respiratory failure compared to the normal weight category were 1.57 (1.31-1.88) for overweight and 2.45 (1.90-3.15) for obesity., Conclusions: Both obesity and overweight were associated with increased risk of severe COVID-19. This study suggests the importance of the overweight category to predict the risk of severe COVID-19 in Asians., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Twisted carotid bifurcation (TCB) is a well-known anatomical variation of the carotid bifurcation in patients undergoing carotid endarterectomy. However, few investigations of TCB have focused on patients without internal carotid artery (ICA) stenosis. This study was performed to analyze the characteristics of TCB in patients with ICA stenosis and other diverse pathologies., Methods: All conventional cerebral angiographies performed in our institute for any reason from January 2012 to December 2018 were reviewed. The patients were divided into two groups, the TCB group and the anatomically normal non-TCB group, and the basic characteristics of the groups were analyzed., Results: Both sides of the carotid bifurcation were clearly visualized in 457 patients. TCB was found in 89 of 457 patients (19.5%); among these 89 patients, 74 (83.1%) had TCB only on the right side, 8 (9.0%) only on the left side, and 7 (7.9%) bilaterally. TCB was found more frequently on the right than left [81 (17.7%) and 15 (3.3%), respectively, on each of the 457 sides (p < 0.0001)]. TCB was significantly more frequent in older patients (p = 0.02), female patients (p < 0.001), and patients with ICA stenosis or occlusion at the bifurcation (p = 0.005). The prevalence of TCB was 19.5%, and 84.4% of cases were on the right side in patients with diverse pathologies., Conclusions: Older patients, female patients, and patients with ICA stenosis or occlusion are more prone to have TCB., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze chronological changes in phase-amplitude coupling (PAC) and verify whether PAC analysis can diagnose epileptogenic zones during seizures., Methods: We analyzed 30 seizures in 10 patients with mesial temporal lobe epilepsy who had ictal discharges with preictal spiking followed by low-voltage fast activity patterns on intracranial electroencephalography. We used the amplitude of two high-frequency bands (ripples: 80-200 Hz, fast ripples: 200-300 Hz) and the phase of three slow wave bands (0.5-1 Hz, 3-4 Hz, and 4-8 Hz) for modulation index (MI) calculation from 2 minutes before seizure onset to seizure termination. We evaluated the accuracy of epileptogenic zone detection by MI, in which a combination of MI was better for diagnosis and analyzed patterns of chronological changes in MI during seizures., Results: MI Ripples/3-4 Hz and MI Ripples/4-8 Hz in the hippocampus were significantly higher than those in the peripheral regions from seizure onset. Corresponding to the phase on intracranial electroencephalography, MI Ripples/3-4 Hz decreased once and subsequently increased again. MI Ripples/4-8 Hz showed continuously high values., Conclusions: Continuous measurement of MI Ripples/3-4 Hz and MI Ripples/4-8 Hz could help identify epileptogenic zones., Significance: PAC analysis of ictal epileptic discharges can help epileptogenic zone identification., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: To mitigate the COVID-19 pandemic, many countries have recommended the use of booster vaccinations. The relationship between the degree of adverse vaccine reactions and elevated antibody titers is of interest; however, no studies have investigated the temporal changes in antibody titers based on repeated measurements after a third dose of the BNT162b2 vaccine., Methods: This prospective longitudinal cohort study was conducted with 62 healthcare workers who received a third dose of the BNT162b2 at Okayama University Hospital, Japan. Venous blood draw and fingertip whole blood test sample collection were conducted at the early (3-13 days) and 1-month time points; only FWT sample collection was conducted at the 2-month time point. Information on adverse reactions within 1 week after vaccination was also obtained. The association between fever of 37.5 °C or higher and antibody titers after the third dose of BNT162b2 was examined using a mixed-effects model and Poisson regression with robust variance., Results: A trend toward higher antibody titers in the early period after vaccination was observed in the febrile individuals, but the differences were not significant at 1 and 2 months post-vaccination (the partial regression coefficient for fever was 8094.3 [-1910.2, 18,098.8] at 1 month after vaccination, and 1764.1 [-4133.9, 7662.1] at 2 months after vaccination in the adjusted models)., Conclusion: The findings suggest that the presence of fever after the third vaccine does not predict a sustained elevation in serum antibody titers., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We assessed the diagnostic utility of the occurrence rate of high-frequency oscillations and modulation index (MI) from intraoperative electrocorticography (ioECoG) in determining the extent of epileptogenicity in mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS)., Methods: We enrolled 17 patients who underwent selective amygdalohippocampectomy (SelAH) for TLE due to HS. We analyzed the occurrence rate of ripples (80-200 Hz) and fast ripples (200-300 Hz); and MI between ripples and 3-4 Hz (MI Ripples/3- 4   Hz ) and fast ripples and 3-4 Hz (MI FRs/3- 4   Hz ) from the amygdala, hippocampus, and lateral temporal lobe (LTL) pre-SelAH and the LTL post-SelAH, and subsequently categorized the patients into good and poor seizure outcome groups. We compared the occurrence rates and MIs over each region of interest between both groups. Receiver operating characteristic analysis was used to identify the most optimal indicator to predict poor surgical outcomes., Results: In the poor seizure outcome group, an increase in the occurrence rate of ripples was seen in the hippocampus and LTL pre-SelAH and the LTL post-SelAH. The MI Ripples/3- 4   Hz from the LTL pre-SelAH was the most indicative factor of poor outcome., Conclusions: High occurrence rate of ripples and MI Ripples/3- 4   Hz from the LTL showed wide epileptogenicity in TLE patients with poor seizure outcomes after SelAH. Our data suggest that the analysis of the occurrence rate of HFOs and MI HFOs/3- 4   Hz from ioECoG, especially from the LTL, can indicate the distribution of epileptogenicity in TLE with HS., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Lymph node metastasis (LNM) is one of the most adverse prognostic factors in extrahepatic cholangiocarcinoma (EHCC) cases. As next-generation sequencing technology has become more widely available, the genomic profile of biliary tract carcinoma has been clarified. However, whether LNMs have additional genomic alterations in patients with EHCC has not been investigated. Here, we aimed to compare the genomic alterations between primary tumors and matched LNMs in patients with EHCC., Methods: Sixteen patients with node-positive EHCCs were included. Genomic DNA was extracted from tissue samples of primary tumors and matched LNMs. Targeted amplicon sequencing of 160 cancer-related genes was performed., Results: Among the 32 tumor samples from 16 patients, 91 genomic mutations were identified. Genomic mutations were noted in 31 genes, including TP53, MAP3K1, SMAD4, APC, and ARID1A. TP53 mutations were most frequently observed (12/32; 37.5%). Genomic mutation profiles were highly concordant between primary tumors and matched LNMs (13/16; 81.3%), and an additional genomic mutation of CDK12 was observed in only one patient., Conclusion: Genomic mutations were highly concordant between primary tumors and matched LNMs, suggesting that genotyping of archived primary tumor samples may help predict genomic mutations of metastatic tumors in patients with EHCC., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: The removal of the bottom of sulcus dysplasia (BOSD) often includes the gyral crown; however, this method has been controversial. We hypothesized that the epileptogenic zone of the BOSD does not include the gyral crown. To reveal the depth and extent of the epileptogenic zone of the BOSD, we applied the two electrophysiological modalities: (1) the occurrence rate (OR) of high-frequency oscillations (HFOs) and (2) modulation index (MI), reflecting the strength of phase-amplitude coupling between HFOs and slow oscillations., Methods: We investigated the ripples [80-200 Hz] and fast ripples [200-300 Hz]) in HFOs and MI (HFOs [80-300 Hz] and slow oscillations [3-4 Hz]). We opened the sulcus at the BOSD and implanted the subdural electrodes directly over the MRI visible lesion. All patients (n = 3) underwent lesionectomy and the gyral crown was preserved., Results: Pathological findings demonstrated focal cortical dysplasia type IIb and seizure freedom was achieved. The OR of the HFOs was not significantly different between the BOSD and the gyral crown. In contrast, the MI between HFOs and slow oscillations in the BOSD was significantly higher than that in the gyral crown., Conclusion: High MI values distinguished the epileptogenic BOSD from the non-epileptogenic gyral crowns. MI could be a more informative biomarker of epileptogenicity than the OR of HFOs in a subset of patients with the BOSD., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

Introduction: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information., Methods: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis., Results: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever., Conclusions: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: To visualize and validate the dynamics of interhemispheric neural propagations induced by single-pulse electrical stimulation (SPES)., Methods: This methodological study included three patients with drug-resistant focal epilepsy who underwent measurement of cortico-cortical spectral responses (CCSRs) during bilateral stereo-electroencephalography recording. We delivered SPES to 83 electrode pairs and analyzed CCSRs recorded at 268 nonepileptic electrode sites. Diffusion-weighted imaging (DWI) tractography localized the interhemispheric white matter pathways as streamlines directly connecting two electrode sites. We localized and visualized the putative SPES-related fiber activation, at each 1-ms time window, based on the propagation velocity defined as the DWI-based streamline length divided by the early CCSR peak latency., Results: The resulting movie, herein referred to as four-dimensional tractography, delineated the spatiotemporal dynamics of fiber activation via the corpus callosum and anterior commissure. Longer streamline length was associated with delayed peak latency and smaller amplitude of CCSRs. The cortical regions adjacent to each fiber activation site indeed exhibited CCSRs at the same time window., Conclusions: Our four-dimensional tractography successfully animated neural propagations via distinct interhemispheric pathways., Significance: Our novel animation method has the potential to help investigators in addressing the mechanistic significance of the interhemispheric network dynamics supporting physiological function., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine the optimal depth electrode montages for the assessment of effective connectivity based on single-pulse electrical stimulation (SPES). To determine the effect of SPES locations on the extent of resulting neuronal propagations., Methods: We studied 14 epilepsy patients who underwent invasive monitoring with depth electrodes and measurement of cortico-cortical evoked potentials (CCEPs) and cortico-cortical spectral responses (CCSRs). We determined the effects of electrode montage and stimulus sites on the CCEP/CCSR amplitudes., Results: Bipolar and Laplacian montages effectively reduced the degree of SPES-related signal deflections at extra-cortical levels, including outside the brain, while maintaining those at the cortical level. SPES of structures more proximal to the deep white matter, compared to the cortical surface, elicited greater CCEPs and CCSRs., Conclusions: On depth electrode recording, bipolar and Laplacian montages are suitable for measurement of near-field CCEPs and CCSRs. SPES of the white matter axons may induce neuronal propagations to extensive regions of the cerebral cortex., Significance: This study helps to establish the practical guidelines on the diagnostic use of CCEPs/CCSRs., 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 © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Signaling adaptor protein Crk has been shown to play an important role in various human cancers. Crk links tyrosine kinases and guanine nucleotide exchange factors (GEFs) such as C3G and Dock180 to activate small G-proteins Rap and Rac, respectively. In pancreatic cancer, various molecular targeted therapies have provided no significant therapeutic benefit for the patients so far due to constitutive activation of KRAS by frequent KRAS mutation. Therefore, the establishment of novel molecular targeted therapy in KRAS-independent manner is required. Here, we investigated a potential of Crk as a therapeutic target in pancreatic cancer. Immunohistochemistry on human pancreatic cancer specimens revealed that the patients with high expression of Crk had a worse prognosis than those with low expression. We established Crk-knockdown pancreatic cancer cells by siRNA using PANC-1, AsPC-1, and MIA PaCa-2 cells, which showed decreased cell proliferation, invasion, and adhesion. In Crk-knockdown pancreatic cancer cells, the decrease of c-Met phosphorylation was observed. In the orthotopic xenograft model, Crk depletion prolonged survival of mice significantly. Thus, signaling adaptor protein Crk is involved in malignant potential of pancreatic cancer associated with decrease of c-Met phosphorylation, and Crk can be considered to be a potential therapeutic molecular target., 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 © 2020 Elsevier Inc. All rights reserved.)

Background: The internal carotid artery is normally positioned posterolateral to the external carotid artery at the carotid bifurcation. An anatomic variation with the internal carotid artery positioned medial to the external carotid artery, the so-called twisted carotid bifurcation (TCB), is sometimes encountered in patients undergoing carotid endarterectomy (CEA). Little is known about the TCB or the implications for CEA., Objective: The present study investigated the demographics and surgical results of our patients with TCB who underwent CEA, and demonstrates the surgery in a video clip., Methods: Eleven of our series of 73 consecutive CEA patients (15.1%) had a TCB (TCB group). The basic surgical method was the same for both the TCB and non-TCB groups., Results: The patient demographics were almost identical between the 2 groups. No significant difference was observed in the degree of stenosis, the duration of operation, or the surgery-related complications between the 2 groups. However, 9 of 11 cases were right-sided in the TCB group; the only significant difference between the groups., Conclusions: CEA for TCB can be safely performed by extension of the normal procedure, but with more meticulous preoperative assessment and gentle maneuvers. The reason for the right-side dominance is still unknown. Further investigation is needed of this anatomic entity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background & Aims: Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape., Methods: We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features., Results: We identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients., Conclusions: BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information., Lay Summary: We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Whether to classify "advanced (subserosal layer or greater invasion)" biliary carcinoma centered in the cystic duct (BCCD) as gallbladder carcinoma (GBC) or perihilar cholangiocarcinoma (PHCC) remains unclear., Methods: The clinicopathological features and overall survival (OS) of patients with advanced BCCD were examined through a comparison with those of patients with advanced PHCC and with GBC., Results: 290 patients were classified as 199 PHCC, 44 GBC, and 47 BCCD. Patients with BCCD (median, 23 months) had significantly worse OS than those with PHCC (44 months, p = 0.030). OS of patients with BCCD, all of whom were classified as pT3 or pT4 by the American Joint Committee on Cancer (AJCC) classification of GBC, was similar to 27 patients with pT3 or pT4 GBC (23 months, p = 0.840). When the patients with BCCD were classified by the AJCC classification of PHCC, 36 were classified as pT2. OS among the patients with BCCD classified as pT2 by the PHCC classification (29 months) was significantly worse than that among patients classified as pT2 PHCC (48 months, p = 0.040)., Conclusion: These findings suggest that advanced BCCD is appropriately classified as a subtype of GBC because it can grow through the serosa., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Epilepsy requires the long-term administration of antiepileptic drugs (AEDs), and thus, we must consider the effects of prenatal AED exposure on fetus when treating female patients of child bearing age. Large prospective clinical researches in humans have demonstrated the following: (1) prenatal exposure to valproic acid (VPA), carbamazepine, and phenobarbital increases the risk of congenital malformations in a dose-dependent manner and (2) prenatal exposure to VPA increases the risk of higher brain function impairments including intellectual disabilities and autistic spectrum disorders in the offspring. Furthermore, basic researches in animals have shown that prenatal exposure to specific AEDs causes microscopic structural abnormalities in the fetal brain. Specifically, prenatal exposure to VPA has been reported to inhibit the differentiation of neural progenitor cells during the early to middle phases of neuronogenesis, leading to increased number of projection neurons in the superficial layers of postnatal neocortices in mice. It is indispensable to prescribe AEDs that are associated with lower risk of congenital malformations and impairment of higher brain functions as well as to administer them at requisite minimum doses., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Myelodysplastic syndromes (MDS) are a group of clonal neoplasms characterized by ineffective hematopoiesis. Hypomethylating agent (HMA) therapy is one of the mainstays of MDS therapy. Failure of HMA therapy is related to poor outcome; hence, new therapeutic approaches are warranted in these patients. In MDS, the immune system has a pivotal role in modulation of hematopoiesis and clonal expansion. In neoplastic conditions, immune checkpoint (PD-1 and CTLA4 molecules) hide tumor cells from immune surveillance. Identification of the pattern of expression of these molecules in MDS provides an interesting alternative within clinical trials., Materials and Methods: We describe the clinicopathologic correlations by morphology, immunohistochemistry (PD-L1) and flow cytometry immunophenotypic analysis in an MDS patient treated with immune checkpoint PD-1 inhibitor., Results: Bone marrow (BM) morphology, differential counts and aberrant flow markers were assessed before and after anti PD-1 inhibitor therapy. At baseline, BM showed severe trilineage dysplasia with decreased granulopoiesis; after therapy, BM showed normal trilineage hematopoiesis. A decrease in PD-L1 expression, by manual and automatic analysis, was also noted from 15% to 5% after 26 months of treatment. The findings correlated with the recovery of peripheral blood counts and transfusion independency., Conclusion: BM morphology and PD-L1 expression by immunohistochemistry can be used to assess treatment response in immune checkpoints therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Aims: Coronary computed tomography (CT) angiography allows non-invasive classification of non-calcified coronary plaques (NCCPs) based on Hounsfield unit (HU) values. This methodology, however, is somewhat limited for reliable classification of NCCPs. Therefore, we evaluated the effective atomic number (EAN) for classifying NCCPs by single-source dual-energy CT with fast tube voltage switching (SSDECT)., Methods: We prospectively enrolled 18 patients undergoing both SSDECT and intravascular ultrasonography (IVUS). Monochromatic images at 70 keV and EAN images were reconstructed from SSDECT data sets. Regions of interest (ROIs) within NCCPs were placed on IVUS-matched SSDECT images, and mean HU values and EANs for soft and fibrous plaques, classified using IVUS, were compared with an unpaired t-test., Results: We placed 96 ROIs in 29 soft plaques and 37 ROIs in 15 fibrous plaques in 12 coronary arteries of 11 patients. The mean HU value in soft plaques (58.2 ± 32.8 HU) was significantly lower than that in fibrous plaques (103.9 ± 48.3 HU) (p < 0.001). The mean EAN in soft plaques (8.7 ± 0.5) was also significantly lower than that in fibrous plaques (9.6 ± 0.5) (p < 0.0001). Area under the curve for EAN (0.91) was significantly higher than that for HU value (0.79) in receiver operating characteristic curve analysis (p = 0.046). With a cutoff EAN of 9.3, sensitivity was 90% and specificity, 87%; whereas with a cutoff HU value of 55.0 HU, sensitivity was 62% and specificity, 93%., Conclusions: EAN measurement by SSDECT can be clinically useful for accurately classifying soft and fibrous coronary plaques., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To provide an organizational schema for systematic error and random error in estimating causal measures, aimed at clarifying the concept of errors from the perspective of causal inference., Methods: We propose to divide systematic error into structural error and analytic error. With regard to random error, our schema shows its four major sources: nondeterministic counterfactuals, sampling variability, a mechanism that generates exposure events and measurement variability., Results: Structural error is defined from the perspective of counterfactual reasoning and divided into nonexchangeability bias (which comprises confounding bias and selection bias) and measurement bias. Directed acyclic graphs are useful to illustrate this kind of error. Nonexchangeability bias implies a lack of "exchangeability" between the selected exposed and unexposed groups. A lack of exchangeability is not a primary concern of measurement bias, justifying its separation from confounding bias and selection bias. Many forms of analytic errors result from the small-sample properties of the estimator used and vanish asymptotically. Analytic error also results from wrong (misspecified) statistical models and inappropriate statistical methods., Conclusions: Our organizational schema is helpful for understanding the relationship between systematic error and random error from a previously less investigated aspect, enabling us to better understand the relationship between accuracy, validity, and precision., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: An early IV beta blocker during primary percutaneous coronary intervention (PCI) has been shown to reduce infarct size in ST-segment elevation acute myocardial infarction (STEMI), although the underlying mechanism is unknown. The aim of this study was to investigate the efficacy of early infusion of landiolol, the short-acting beta-1 adrenergic receptor blocker, on the reperfusion status in a STEMI., Methods: We conducted a prospective, single-group trial of landiolol during the primary PCI for a STEMI. Landiolol was started intravenously just before reperfusion. The reperfusion status and outcomes in 55 treated patients were compared with those in 60 historical controls treated without landiolol. The optimal reperfusion was assessed by an ST-segment resolution (STR), coronary flow, and myocardial brush grade (MBG) after reperfusion., Results: Patients in the landiolol group achieved a higher rate of an STR (64% vs. 42%, p=0.023) and MBG 2/3 (64% vs. 45%, p=0.045), whereas coronary flow was comparable between the two groups. A multivariate analysis showed that landiolol use was an independent predictor of an STR (odds ratio 2.99, 95% confidence interval 1.25-7.16, p=0.014). The incidence of non-sustained ventricular tachycardia (27% vs. 50%, p=0.014), hypotension (15% vs. 32%, p=0.046), and progression to Killip class grade III or IV (0% vs. 10%, p=0.028) were lower in the landiolol group., Conclusion: Early infusion of landiolol during the primary PCI was associated with optimal reperfusion and a lower incidence of adverse events in comparison with the control group., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Compared to transpulmonary pressure gradient (TPPG), diastolic pulmonary vascular pressure gradient (DPG) may be a more sensitive and specific indicator for pulmonary hypertension (PH) due to left heart disease (LHD) with significant pulmonary vascular disease (PVD). The aim of this study was to investigate the incidence and clinical features of PH-LHD with PVD classified by DPG and TPPG., Methods: We analyzed 410 patients admitted for symptomatic heart failure (HF) (New York Heart Association ≥2) and who underwent right heart catheterization (RHC) at compensated stage between 2007 and 2012. Patients with PH-LHD were divided into 3 groups according to the value of DPG and TPPG (Non-PVD group: DPG <7mmHg and TPPG ≤12mmHg; TPPG-PVD group: DPG <7mmHg and TPPG >12mmHg; DPG-PVD group: DPG ≥7mmHg). Multivariate Cox regression analysis was applied to investigate whether each PH-LHD category predicts death or HF readmission after adjusting for other variables., Results: PH-LHD was observed in 164 patients (40%) with symptomatic HF. Thirteen patients (3%) were allocated into DPG-PVD group, while 24 patients were allocated into TPPG-PVD group (6%). DPG-PVD group was significantly associated with death or HF readmission compared to non-PVD group (hazard ratio: 3.57; 95% CI: 1.33 to 9.55, p=0.01), while the association between TPPG-PVD group and non-PVD group did not reach statistical significance (hazard ratio: 1.89; 95% CI: 0.77 to 4.64, p=0.17)., Conclusions: PH-LHD with PVD classified by DPG was significantly associated with poor long-term clinical outcomes, whereas the association between PH-LHD with PVD classified by TPPG and clinical outcomes did not reach statistical significance. However, further studies are needed, because there was no substantial difference in clinical outcomes between PH-LHD with PVD classified by DPG and PH-LHD with PVD classified by TPPG., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The optimal preoperative therapeutic strategy for patients with coronary artery disease (CAD) is an important concern in the era of drug-eluting stents and antiplatelet therapy. However, there are few studies about the impact of prior percutaneous coronary intervention (PCI) on perioperative major adverse cardiac events (MACEs) and bleeding events associated with oral antiplatelet therapy. The aim of this study was to examine the risks and benefits of performing PCI before non-cardiac surgery (NCS) in patients with CAD., Methods: We investigated 130 patients who had angiographically significant and stable CAD and underwent NCS after index coronary angiography. We divided the patients into two groups: patients undergoing PCI with coronary stenting (PCI group), and those not undergoing PCI before NCS (no-PCI group), and compared the MACEs and bleeding events within 30 days from NCS between the groups., Results: There were 53 and 77 patients in the PCI and no-PCI groups, respectively. MACEs were observed in 2 patients (3.8%) in the PCI group and 3 patients (3.9%) in the no-PCI group (p=0.97), whereas bleeding events were observed in 10 (18.9%) and 8 patients (10.4%) in the PCI and no-PCI groups, respectively (p=0.17). There were no significant differences between the two groups in terms of MACEs and bleeding events., Conclusions: The rate of MACEs following NCS was not significantly different between the PCI and no-PCI groups, while the rate of bleeding events was higher in the PCI group without reaching statistical significance. This study suggests that patients with stable CAD may be able to safely undergo NCS without revascularization even in the presence of significant coronary artery stenosis., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The perioperative risk of non-cardiac surgery (NCS) in the patients on antiplatelet therapy after percutaneous coronary intervention (PCI) remains unclear., Methods: This study was a retrospective and single center study. Between January 2008 and December 2011, 198 patients who had already received PCI underwent NCS in our hospital. Among them, 63 patients underwent surgery on dual antiplatelet therapy (DAPT group) and 88 patients on single antiplatelet therapy (SAPT group). We compared bleeding events and cardiovascular events during perioperative period between the two groups., Results: There was no stent thrombosis in either group. The bleeding events in the DAPT group were significantly higher than that in the SAPT group (9.5% vs 2.3%, p=0.049). There was no difference in events between with or without heparin-bridge in the SAPT group., Conclusions: The frequency of bleeding events was higher in the DAPT group. Both bleeding and cardiovascular events with aspirin alone were low in our study. It may be safe to undergo NCS with SAPT after PCI., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The objective of this study was to develop equations to predict carcass tissue weights and percentages and boneless carcass non-trimmed cut weights by using the cold carcass weight (CCW) and three other traits at the 6-7th rib section, which are routinely collected in carcass markets in Japan. Carcasses from 94 Japanese Black steers were used for the multiple regression analysis with a stepwise procedure and a novel Least Absolute Shrinkage and Selection Operator (LASSO). The accuracies of prediction (R(2)) and RMSEs for the carcass tissue and cut weights were similar between the two procedures. In contrast, LASSO appeared to be the better procedure for predicting carcass tissue percentages. The longissimus muscle area and subcutaneous fat thickness were the important predictors for the lean percentage in the stepwise procedure, and CCW was additionally selected when the LASSO procedure was used., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Diffuse pulmonary arteriovenous malformations (AVMs) are associated with a poor prognosis and the therapeutic strategy remains controversial. We describe a pediatric patient with diffuse pulmonary AVMs associated with hereditary hemorrhagic telangiectasia (HHT), who presented with two cerebral AVMs in the parietal and occipital lobes as well. Of note, successful bilateral lung transplantation not only improved the hypoxemia but also resulted in size reduction of the cerebral AVMs. Although it is essential to consider involvements other than pulmonary AVMs, especially brain AVMs, to decide the indication, lung transplantation can be a viable therapeutic option for patients with diffuse pulmonary AVMs and HHT., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We developed a simple and rapid method for the simultaneous determination of phosphorus-containing amino acid herbicides (glyphosate, glufosinate, bialaphos) and their major metabolites, aminomethylphosphonic acid (AMPA) and 3-methylphosphinicopropionic acid (MPPA), in human serum. Serum samples were filtrated through an ultrafiltration membrane to remove proteins. The filtrate was then washed with chloroform, and injected into a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Chromatographic separation was achieved on a hydrophilic interaction chromatography (HILIC) column. Determination of the target herbicides and metabolites was successfully carried out without derivatization or solid phase extraction (SPE) cartridge clean-up. The recoveries of these compounds, added to human serum at 0.2μg/mL, ranged from 94% to 108%, and the relative standard deviations (RSDs) were within 5.9%. The limits of detection (LODs) were 0.01μg/mL for MPPA, 0.02μg/mL for AMPA, 0.03μg/mL for both glyphosate and glufosinate, and 0.07μg/mL for bialaphos, respectively., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: We sought to assess whether hyperinsulinemia is associated with percentage lipid and coronary plaque burden in nondiabetic patients with acute coronary syndromes (ACS)., Background: Hyperinsulinemia carries an increased risk of cardiovascular disease even in pre-diabetic patients, but the precise mechanisms of its effects remain unclear., Methods: Nonculprit coronary lesions associated with mild-to-moderate stenosis in 82 nondiabetic patients with ACS were examined by integrated backscatter intravascular ultrasound (IB-IVUS), using a 40-MHz intravascular catheter. Conventional IVUS and IB-IVUS measurements from the worst 10-mm segment (1-mm intervals) were calculated. All patients underwent a 75-g oral glucose tolerance test (OGTT) to calculate the area under the insulin concentration-time curve (AUC insulin) from 0 to 120 min., Results: Patients in the high tertile of AUC insulin had a significantly greater percentage lipid area and absolute lipid volume than did patients in the intermediate and low tertiles (tertile 3 vs. tertile 2 vs. tertile 1; 37.6 ± 16.6% vs. 25.8 ± 11.9% vs. 27.5 ± 14.7%, p < 0.01 by analysis of variance [ANOVA], and 29.9 ± 22.6 mm(3) vs. 15.3 ± 12.6 mm(3) vs. 17.7 ± 12.7 mm(3), p < 0.01 by ANOVA, respectively) and a smaller percentage fibrosis area (55.0 ± 11.5% vs. 61.7 ± 9.4% vs. 60.7 ± 9.4%, p = 0.03 by ANOVA). Multiple regression analysis showed that the high tertile of AUC insulin was independently associated with an increased percentage lipid area (p < 0.05). On conventional IVUS analysis, external elastic membrane cross-sectional area was significantly increased with greater plaque volume in patients in the high tertile of AUC insulin (both p < 0.05 by ANOVA)., Conclusions: Hyperinsulinemia is associated with an increased lipid content and a greater plaque volume of nonculprit intermediate lesions in nondiabetic patients with ACS, suggesting that plaque vulnerability is increased in this subgroup of patients., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the precise mechanisms underlying the action of estrogenic endocrine disruptors, we evaluated the direct effects of synthetic estrogen diethylstilbestrol (DES) on steroidogenesis in Leydig cells, with particular emphasis on the expression of the cholesterol side-chain cleavage enzyme P450scc. Furthermore, the mechanism underlying the action of DES was compared with that of endogenous estrogen 17beta-estradiol (E2), which has a potency equivalent to that of DES., Main Methods: TTE1 Leydig cells were treated with 5 x 10(-)(8) microM to 5 microM DES or E2 for 24h, and P450scc gene expression and the histone modifications underlying their transcriptional activation were examined using reverse transcription-polymerase chain reaction (RT-PCR) and chromatin immunoprecipitation (ChIP), respectively., Key Findings: P450scc mRNA expression in the DES-treated and E2-treated cells reduced in inverse proportion to the dose of DES and E2, respectively; however, cAMP stimulation induced a recovery in the expression to a level approximately equal to those in the controls. In the DES-treated cells, ChIP assay revealed histone deacetylation in the P450scc promoter region. Interestingly, E2 did not cause histone deacetylation., Significance: In the early stages of steroidogenesis, DES and E2 directly induced a reduction in P450scc mRNA expression in inverse proportion to their doses, and treatment with cAMP restored the decreased P450scc mRNA expression. Furthermore, DES can induce alterations in the histone modification of the P450scc gene, and natural estrogen and synthetic estrogenic compounds such as DES may induce reproductive disorders through different molecular mechanisms., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess whether ultrasound attenuation and plaque rupture as detected by intravascular ultrasound (IVUS) are associated with the incidence of no-reflow phenomenon after percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI)., Background: No-reflow phenomenon is associated with worse long-term outcomes after STEMI. Therefore, reliable and feasible intravascular imaging techniques are needed to identify patient subgroups that would be at high risk for no-reflow phenomenon., Methods: One hundred seventy consecutive patients with STEMI who underwent PCI within 12 h after symptom onset were enrolled. The IVUS interrogation was performed before PCI., Results: No-reflow phenomenon occurred in 30 patients (18%), who had a higher incidence of no ST-segment resolution (50% vs. 9%; p < 0.001), a higher peak creatine kinase level (4,090 IU/l vs. 2,823 IU/l; p < 0.001), and a lower left ventricular ejection fraction in the chronic phase (51% vs. 59%; p < 0.01). Multivariate logistic regression analysis revealed that ultrasound attenuation with a longitudinal length of > or =5 mm, plaque rupture, and reperfusion time correlated with no-reflow phenomenon (all p < 0.05). In patients with both ultrasound attenuation > or =5 mm and plaque rupture, the incidence of no-reflow phenomenon was 88%, and the risk of decreased coronary reflow was higher than that predicted by either factor alone (p = 0.004 for interaction)., Conclusions: In patients with STEMI, a longer ultrasound attenuation and plaque rupture on IVUS are associated with an increased incidence of no-reflow phenomenon, suggesting that this subset of patients might be at high risk for distal embolism., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The chicken MHC-B locus affects the response to several strains of Rous sarcoma virus (RSV). We evaluated the association between haplotypes of the MHC-B locus and responses to the J strain of RSV by using an F(2) experimental resource family constructed with tumor-regressive (White Leghorn) and tumor-progressive (Rhode Island Red) chickens. The MHC-B haplotypes were determined by genotyping of the microsatellite marker LEI0258 and MHC-B locus class I alpha chain 2 (BF2). Two haplotypes in the resource family, one associated with tumor regression and one with progression, were defined by these 2 markers. To discriminate more precisely the regressive haplotype in this family, we further developed 35 SNP markers at the MHC-B locus. Information on the haplotypes revealed here should be useful for identifying chickens with regression and progression phenotypes of J-strain RSV-induced tumors.

A major question is whether exposure to mixtures of low-dose endocrine disruptors (EDs) having different action mechanisms affects neurodevelopment differently than exposure to EDs individually. We therefore investigated the effects of fetal and neonatal exposure to three typical EDs - bisphenol A (BPA), di-(2-ethylhexyl)-phthalate (DEHP), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - on the midbrain dopaminergic system associated with functions - including motor activity, emotion, and cognition - affected by neuropsychiatric diseases such as attention-deficit/hyperactivity disorder. ICR mouse dams and their pups were orally treated with BPA (5mg/(kg day)), DEHP (1mg/(kg day)), or TCDD (8ng/kg) individually, or with mixtures thereof, to compare the effects between sole and mixed administration. We analyzed tyrosine hydroxylase (TH)- and Fos-immunoreactive (ir) neurons as markers of dopamine and neuronal activation, respectively. The numbers of TH- and/or Fos-ir neurons and the intensity of TH-immunoreactivity within midbrain dopaminergic nuclei (A9, A10, and A8) of each sole administration group significantly differed from controls at 2, 4, and 6 weeks of age. In contrast, no significant differences were detected in the mixture groups, suggesting counteractions among those chemicals. These results indicate that ED mixtures as pollution have unique and elusive effects. Thyroid hormones and/or aryl hydrocarbon receptor-related mechanisms may be responsible for this counteraction.

Brain size variation among different mammals is tightly associated with different levels of cerebral function. Mechanisms that regulate the number of neurons and hence the size of the brain must be at least partially embedded within the very early phase of neocortical development, that is, embedded in proliferation/differentiation characteristics of the neural progenitor cells (NPCs) of the neocortex. Here we review a sequence of critical events through which the neocortex is formed in the embryonic forebrain, with particular emphasis on cell cycle kinetics of the NPCs that produce non-GABAergic projection neurons, the majority of neurons in the neocortex. In general, the critical parameters that determine the total number of cells produced by a given progenitor population through a sequence of cell cycles are (1) the number of cell cycles that constitute the production period and (2) the probability of cell cycle exit (Q fraction or Q) of progenitor cells for each of the cell cycles. We will also review molecular mechanisms that modulate the critical parameters above, with a special reference to the cell cycle regulatory protein p27(Kip1), inhibitor of G1 phase progression of the cell cycle. Finally the neocortical dysgenesis caused by genetic modification in mice where p27(Kip1) is either deleted or overexpressed is presented as examples of neuron number changes and resultant neocortical dysgenesis by Q fraction alteration.

A 23-year-old woman was admitted with progressive shortness of breath. Echocardiography showed a large volume of pericardial effusion, which indicated cardiac tamponade. Yellowish and puriform fluid with increased white blood cell count (neutrophil dominant) was aspirated, but antibiotics were ineffective. Further examination revealed the presence of positive anti ds-DNA antibody, anti SS-A antibody and anti Sm antibody, resulting in a diagnosis of systemic lupus erythematosus. Her condition was smoothly improved by predonisolone administration. Cardiac tamponade is a rare initial manifestation of systemic lupus erythematosus.

Objectives: To investigate the role of oxidative stress in left ventricular function after acute myocardial infarction., Methods: We studied 41 patients with acute myocardial infarction (30 men and 11 women, mean age 61.7 +/- 11.6 years) with Thrombolysis in Myocardial Infarction grade 3 recanalization of occluded coronary arteries within 12 hr after onset. Cardiac catheterization was performed at the time of admission and before discharge. Three markers for oxidative stress were measured: plasma lipid hydroperoxide, plasma creatol and whole arterial blood glutathione at the time of admission., Results: Mean time from onset to recanalization was 5.2 +/- 0.6 hr. The patients were divided into two groups according to the changes in left ventricular wall motion (LVWM); patients who showed improvement in LVWM and those without improvement. There were no significant differences in age, sex, coronary risk factors, severity of coronary artery disease, time from onset to recanalization or ejection fraction between two groups. Maximum creatine kinase and C-reactive protein levels in patients without LVWM improvement were significantly higher than in patients with improvement. Plasma levels of lipid hydroperoxide and creatol did not differ significantly between two groups. On the other hand, reduced glutathione/oxidized glutathione ratio in arterial blood in patients without LVWM improvement was significantly lower than in patients with LVWM improvement (69.8 +/- 3.4 vs 85.5 +/- 2.9, p < 0.05)., Conclusions: Our results suggest that whole arterial blood glutathione is more oxidized in acute myocardial infarction patients without LVWM improvement than in patients with improvement. Redox state of arterial blood can be a predicting factor for left ventricular function after acute myocardial infarction.