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Background: Pulmonary hypertension (PH) has recently been described as a complex clinical syndrome affecting multiple organ systems, including the heart, lungs, and skeletal muscle, each of which plays an important role in exercise capacity. However, the relationship between exercise capacity and skeletal muscle abnormalities in patients with PH has not been fully elucidated., Methods: We retrospectively analysed the exercise capacity and measures of skeletal muscle of 107 patients with PH without left heart disease (mean age 63 ± 15 years, 32.7% males, n = 30/6/66/5 in the clinical classification Group 1/3/4/5)., Results: Sarcopenia, low appendicular skeletal muscle mass index, low grip strength, and slow gait speed, determined by international criteria, were found in 15 (14.0%), 16 (15.0%), 62 (57.9%), and 41 (38.3%) patients, respectively. The mean 6-min walk distance of all patients was 436 ± 134 m and was independently associated with sarcopenia (standardised β = -0.292, p < 0.001). All patients with sarcopenia showed reduced exercise capacity defined as 6-min walk distance < 440 m. Multivariable logistic regression analysis showed that each of the components of sarcopenia was associated with reduced exercise capacity (adjusted odds ratio and 95% confidence interval of appendicular skeletal muscle mass index: 0.39 [0.24-0.63] per 1 kg/m 2 , p = 0.006, grip strength: 0.83 [0.74-0.94] per 1 kg, p = 0.003, and gait speed: 0.31 [0.18-0.51] per 0.1 m/s, p < 0.001)., Conclusions: Sarcopenia and its components are associated with reduced exercise capacity in patients with PH. A multifaceted evaluation may be important in the management of reduced exercise capacity in patients with PH., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest involved in this research., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The Seto Inland Sea, the largest inland sea in Japan, is a rich fishery with high biodiversity and productivity. Monogeneans have been studied for more than 120 years, and 58 nominal species have been recorded in the Seto inland Sea. This study provided DNA information on five species of Benedenia sensu lato (Capsalidae) from marine fishes from the sea, and one of them, Benedenia kobudai n. sp., is described from Semicossyphus reticulatus (Perciformes: Labridae). This new species differs from the other congeners by the hooded appearance between the anterior attachment organs, the morphology of the penis, the absence of the lobe near the vaginal pore and the common genital pore, the position of the vaginal pore, the germarium lying near the slightly hexagonal testes, the morphology of the haptor, and the shape and position of the hamuli. Phylogenetic analysis showed B. kobudai n. sp. in a separate clade from the other Benedenia species, B. epinepheli, B. hoshinai, B. sekii, and B. seriolae collected from the sea. Each of the newly provided DNA sequences (28S rDNA, ITS1-5.8S-ITS2, cox1) of the above four species are based on specimens obtained from the type hosts and/or type localities and are considered important for future taxonomic re-examination and confirmation of the reliability of the registered sequences. Furthermore, these four species are important causes of fish diseases in aquaculture, and it is expected that information on the distribution, host range, and occurrence of fish diseases for each capsalid secured by molecular identification will be accumulated. The Life Science Identifier (LSID): urn:lsid:zoobank.org:pub:26C15D17-CFD1-450D-9FCE-EFFF692D2133., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Antiseizure drug (ASD)-induced skin rash remains the main side effect of seizure management in patients with glioma. New generations of ASDs, such as levetiracetam (LEV) and lacosamide (LCM) are associated with less frequent skin rashes than conventional ASDs. However, there are few reports regarding the incidence of skin rashes by LEV and LCM in patients with glioma. Therefore, the aim of this study was to investigate the incidence and risk factors of LEV- and LCM-associated skin rashes in patients with glioma., Methods: We compared the incidence of ASD-associated skin rash between 353 patients with glioma and 125 patients with meningioma, who received LEV or LCM and underwent surgery between 2017 and 2019 at our institution. Furthermore, to evaluate the association between potential risk factors and ASD-associated skin rashes, univariate and multivariate analyses were performed., Results: The incidence of ASD-associated skin rash in patients with glioma was higher (11 %) than in those with meningiomas (1.6 %). The multivariate regression analysis showed that adjuvant treatment with radiotherapy (p = 0.023) and a history of drug allergy (p = 0.023) were significant risk factors for ASD-associated skin rash. The rate of ASD-related skin rashes in patients with glioma was also higher than the previously reported rates of 1-3 % in patients with epilepsy., Conclusion: Our results indicate that adjuvant treatment with radiotherapy and a history of drug allergy correlated with a high incidence of ASD-related skin rashes in patients with glioma who receive LEV and LCM. Patients with these two factors should be carefully checked for skin rashes., Competing Interests: Declarations of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Resection of the dominant side of gliomas extending to the frontal operculum has high risk of severe language dysfunction. Here, we report recording cortico-cortical evoked potentials (CCEP) using only two 6-strand strip electrodes to monitor language-related fibers intraoperatively. We examined whether this simple procedure is useful for removing gliomas extending to the dominant side of frontal operculum., Methods: This study included 7 cases of glioma extending to the left frontal operculum. The frontal language area (FLA) was first identified by functional mapping during awake craniotomy. Next, a 6-strand strip electrode was placed on the FLA, while on the temporal side, an electrode was placed so as to slide parallel to the sylvian fissure toward the posterior language area. Electrical stimulation was performed using the electrode on the frontal side, and CCEPs were measured from the electrode on the temporal side., Results: CCEPs were detected in all cases. Immediately after surgery, all patients demonstrated language dysfunction to varying degree. CCEP decreased to 10% in 1 patient, who recovered language function after 24 months. CCEP decreased slightly 80% in 1, and, in the 5 other cases, CCEPs did not change. These 5 patients soon recovered language function within 2 weeks to 1 month., Conclusions: This study confirmed the utility of CCEP monitoring using only two 6-strand strip electrodes during one-step surgery. We believe this simple method helped in monitoring intraoperative language function and predicting its postoperative recovery in patients with gliomas extending to the dominant side of frontal operculum., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Molecular studies of the Capsalidae suggested that the genus Benedenia is polyphyletic, but a taxonomic organization of the genus that reflects molecular data has not yet been proposed. As a result of molecular analysis (28S rDNA, ITS1-5.8S-ITS2, and cox1 data) including specimens of Benedeniinae newly obtained from Okinawa-jima Island in Japan, two new genera and the revival of Tareenia independent to the genus Benedenia are proposed. Gracilobenedenia n. gen. is distinguished from the other genera of Benedeniinae based on morphological characteristics. This new genus comprises 6 species: G. lutjani n. comb. (type species), G. anticavaginata n. comb., G. rohdei n. comb., G. beverleyburtonae n. comb., G. kuremibai n. gen., n. sp., and G. hichi n. gen., n. sp. Armatobenedenia n. gen. is a monotypic genus for A. armata n. comb. The present molecular phylogenetic analysis showed the independence of Tareenia, and it can be morphologically separated from the other benedeniines. Four species including two new species obtained from Okinawa-jima Island are reported: G. kuremibai n. sp., G. hichi n. sp., G. lutjani n. comb., and Metabenedeniella parva. Furthermore, in the species identification and phylogenetic analysis of capsalids, the usefulness of not only the 28S rDNA but also ITS and the cox1 regions was suggested. These genes were evaluated the efficacy of those regions in DNA barcoding, and the ITS and cox1 regions shown to be useful for DNA barcoding in capsalids compared to the 28S rDNA sequence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: In the treatment of adult congenital heart disease (ACHD), the transfer of patients from pediatric cardiologists to ACHD cardiologists is of relevance. However, little is known about the clinical courses of ACHD patients that have been referred by non-CHD-specialized doctors (n-CSDs)., Methods: This retrospective cohort study included 230 patients (average age: 37 ± 15.2 years, male: 97) who were referred to a single specialized ACHD center between April 2016 and July 2019. We compared the characteristics and clinical courses between patients referred by n-CSDs and those referred by CHD-specialized-doctors (CSDs)., Results: Overall, 121 (53%) patients were referred by n-CSDs. Among them, 91 (75%) patients were referred by adult cardiologists. Univariate analysis showed that the patients referred by n-CSDs were older than those referred by CSDs (41.6 ± 16.3 vs. 32.0 ± 12.0 years, p <  0.01), were more likely to have simple CHD, and less likely to have severe CHD (27.0% vs. 12.8% and 16.5% vs. 40.4%, respectively, p <  0.01). Patients referred by n-CSDs were also more likely to have a history of loss of follow-up (16.5% vs. 3.7%, p <  0.01) and to require invasive treatments after referral, including cardiac surgeries and transcatheter interventions (47.9% vs. 26.6 %, p <  0.01). Notably, unintended invasive treatments that were not designated by the referring doctors were more frequently required in patients with moderate complexity referred by n-CSDs (50.0% vs. 23.3%, p =  0.02)., Conclusions: Patients with moderate CHD complexity referred by n-CSDs are more likely to require unintended invasive treatments. Referrals to specialized ACHD centers may be most beneficial for these patients., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: A better understanding of the epidemiology of pediatric out-of-hospital cardiac arrest (OHCA) occurring in nursery schools and kindergartens is indispensable to establish an evidence-based strategy for prevention and improved outcomes. This study aimed to describe the incidence, characteristics, and outcomes of pediatric OHCAs that occurred in certified nursery schools and kindergartens., Methods: Stop and Prevent cardIac aRrest, Injury, and Trauma in Schools (SPIRITS) is a study to construct and analyze a nationwide registry of pediatric OHCAs occurring in school settings in Japan. Using data from the SPIRITS registry, we assessed the incidence, characteristics, and outcomes of pediatric OHCAs that occurred in certified nursery schools/kindergartens between April 2008 and December 2016., Results: During the study period, 37 OHCA patients (31 in certified nursery schools and 6 in kindergartens) were confirmed. The overall incidence rate was 0.13 per 100,000 children per year. Among 37 patients, 57% (21/37) had an OHCA while napping and 35% (13/37) experienced OHCA that was witnessed by bystanders. Although public-access automated external defibrillator pads were applied by bystanders in 24% (9/37) of cases, only 1 patient actually received defibrillation. Overall, the proportion of 1-month survival with favorable neurological outcomes after OHCA was 19% (7/37). Among those with OHCA of non-medical origins, 60% (3/5) of patients experienced arrest caused by suffocation, 60% (3/5) by drowning, and 100% (1/1) by head injury. In contrast, no patient had 1-month favorable neurological outcomes among those with OHCA of medical origins such as presumed cardiac origin (0/17), sudden infant death syndrome (0/6), acute viral myocarditis (0/1), respiratory disease (0/1), and ventricular fibrillation (0/1)., Conclusions: In this population, the majority of pediatric OHCAs occurring in certified nursery schools/kindergartens had non-ventricular fibrillation rhythm, and their outcomes after OHCA of medical origin were poor., (Copyright © 2020. Published by Elsevier Ltd.)

Background: There is a need to determine why prior concussion has been associated with adverse outcomes in some retired and active athletes. We examined whether serum inflammatory markers moderate the associations of prior concussion with hippocampal volumes and neurobehavioral functioning in active high school and collegiate athletes., Methods: Athletes (N = 201) completed pre-season clinical testing and serum collection (C-reactive protein [CRP]; Interleukin-6 [IL]-6; IL-1 receptor antagonist [RA]) and in-season neuroimaging. Linear mixed-effects models examined associations of prior concussion with inflammatory markers, self-reported symptoms, neurocognitive function, and hippocampal volumes. Models examined whether inflammatory markers moderated associations of concussion history and hippocampal volume and/or clinical measures., Results: Concussion history was significantly associated with higher symptom severity, p = 0.012, but not hippocampal volume or inflammatory markers (ps > 0.05). A significant interaction of prior concussion and CRP was observed for hippocampal volume, p = 0.006. Follow-up analyses showed that at high levels of CRP, athletes with two or more prior concussions had smaller hippocampal volume compared to athletes without prior concussion, p = 0.008. There was a significant interaction between prior concussion and levels of IL-1RA on memory scores, p = 0.044, i.e., at low levels of IL-1RA, athletes with two or more concussions had worse memory performance than those without prior concussion (p = 0.014)., Conclusion: Findings suggest that certain markers of systemic inflammation moderate the association between prior concussion and hippocampal volume and episodic memory performance. Current findings highlight potential markers for predicting at-risk individuals and identify therapeutic targets for mitigating the long-term adverse consequences of cumulative concussion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pleomorphic xanthoastrocytoma (PXA) is categorized as grade II, other astrocytic tumors per the 2016 World Health Organization classification. Despite being a relatively benign type of tumor, PXA often has an aggressive clinical course. The more malignant form of PXA is now known as anaplastic pleomorphic xanthoastrocytoma (A-PXA) and is categorized as a grade III tumor. Clinical and genetic factors associated with malignant transformation remain unclear. In particular, typical genetic expression patterns in PXA and A-PXA remain unidentified., Case Description: We present a case of recurrent PXA in which malignant transformation followed a promoter mutation in TERT. In this case, genetic chronologic changes accompanying malignant transformation of PXA were thoroughly examined. The promoter mutation was detected in the second operative specimen after stereotactic radiosurgery (SRS) at the first tumor recurrence. Subsequently, a malignant transformation to the A-PXA occurred at the time of the second recurrence, and the tumor repeatedly recurred afterward., Conclusions: TERT promotor mutations may contribute to the malignant transformation of PXA; the mechanism of this mutation is unknown, but it may have been caused by SRS. Therefore, improvident use of radiation should be avoided to prevent the malignant transformation of PXA., (Copyright © 2018. Published by Elsevier Inc.)

Background: The prognosis for World Health Organization (WHO) grade II/III meningiomas is worse than for WHO grade I meningiomas. Histopathologic grade should ideally be identified during tumor resection, but current methods are time-consuming and have doubtful reliance. The aim of this study was to evaluate intraoperative flow cytometry (iFC) as a method for providing ultrarapid evaluation of meningioma malignancy., Methods: A total of 117 meningiomas were analyzed with iFC during surgery. For each, the malignancy index (MI) was calculated as the number of cells with a greater than normal DNA content as a proportion of the total number of cells. Each specimen was investigated histopathologically and was diagnostically graded according to the 2016 WHO grading system. MI results were compared with WHO grades of the meningiomas., Results: The automatic measurement of iFC took approximately 9 minutes on average. The difference in MI between grade I and grade II/III meningiomas was statistically significant (P < 0.001). Receiver operating characteristic analysis provided an optimal cutoff MI value of 8.0% for discrimination between grade I and grade II/III groups, with 64.7% sensitivity and 85.0% specificity for grade II/III meningiomas., Conclusions: Our method of calculating MI with iFC appears to be technically feasible and reliable for ultrarapid evaluation of meningioma malignancy. MI with iFC could potentially enable determination of an optimal treatment strategy during surgery, such as extent of resection of the tumor and management of invaded normal brain or nerves., (Copyright © 2018. Published by Elsevier Inc.)

Gyrodactylus medaka n. sp. (Monogenea: Gyrodactylidae) is described from the skin, fins, and gills of medaka Oryzias latipes (Beloniformes: Adrianichthyidae) from Japan. This new species was collected from wild medaka in Hiroshima, Aichi, Saga, and Kumamoto prefectures, and laboratory-reared medaka in Chiba and Aichi prefectures. The small marginal hook sickle (≤4 μm) and the length of the marginal hook of the new species are the diagnostic morphological characters differentiated from other gyrodactylids reported from Asia. The pairwise sequence divergences for the interspecific variation in ITS regions and the phylogenetic analysis suggest that the populations of G. medaka n. sp. may have a similar genetic variation as the medaka populations in Japan. Gyrodactylus medaka n. sp. and Dactylogyrus oryziasi (Monogenea: Dactylogyridae) can maintain their populations in laboratory aquaria using medaka as their hosts, and these monogeneans and medaka have the potential as experimental model animals for clarifying various aspects of their host-parasite relationships. In addition, we report the composition of modified ammonium picrate-glycerin (APG) and show it is advantageous for monogenean taxonomy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Transient focal magnetic resonance imaging (MRI) abnormalities after status epilepticus (SE) are rarely seen in patients with benign brain tumors, and the underlying mechanism is still unknown. We report a rare case of cerebral cavernous malformation with transient focal MRI abnormalities around the tumor and accumulation of 11C-methionine on positron emission tomography (PET) after SE. These findings mimicked those of a glioma because the MRI and methionine PET findings were similar. We also speculate about the cause of this phenomenon in relation to pathologic findings of this case., Case Description: A 51-year-old man suffered from SE. MRI demonstrated a focal T2/fluid-attenuated inversion recovery hyperintense area. 11C-methionine PET showed high accumulation of methionine in the same lesion. The initial diagnosis was low-grade glioma. However, these MRI abnormalities were transient and completely resolved. The patient underwent surgical removal of the tumor, and the histologic diagnosis was typical cavernous malformation. Pathologic findings of the gyrus around the tumor revealed mild gliosis with proliferating astrocytes but no evidence of glioma., Conclusions: This case suggests that transient focal MRI abnormalities after SE may indicate reversible cortical brain edema. Accumulation of 11C-methionine on PET could occur in the corresponding lesion even if no malignant tumor is present. Because distinguishing transient MRI abnormalities after SE from a glioma is difficult, repeated imaging studies should be performed in patients with brain tumor-related seizures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the efficacy of stereotactic radiotherapy combined with bevacizumab (SRT-Bv) compared with Bv treatment for recurrent high-grade gliomas (HGGs)., Methods: Data for patients with recurrent HGGs who received SRT and Bv (n = 29) or Bv (n = 29) between June 2014 and September 2016 were retrospectively analyzed. All patients received conventional radiotherapy (total, 60 Gy) before this study. SRT was administered at a median dose of 42 Gy in 3-7 fractions. The recurrence pattern was classified into 3 groups: in-field, marginal, and out-field., Results: The median overall survival in the SRT-Bv group was significantly longer than that in the Bv group (10.4 vs. 5.6 months; P = 0.02). In patients with isocitrate dehydrogenase wild-type tumors, the SRT-Bv treatment significantly prolonged survival more than the Bv treatment (10.9 vs. 8.2 months; P = 0.01). The World Health Organization grade and presence or absence of SRT were significant prognostic factors in the univariate analysis. Besides brain edema in 2 cases and asymptomatic subdural hematoma in 1 case, no other severe adverse effect due to SRT-Bv treatment was recorded. The pattern of recurrence was as follows: in-field, 2 cases (7%); marginal, 8 cases (28%); out-field, 11 cases (38%); no recurrence on radiologic findings, 6 cases (21%); and uncertain, 2 cases (7%)., Conclusions: SRT-Bv treatment significantly prolonged survival duration more than Bv treatment and provides good local control in patients with recurrent HGGs, especially those with isocitrate dehydrogenase wild-type tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The objective of the present study was evaluation of the prognostic significance of DNA ploidy assessed with intraoperative flow cytometry (iFC) during resection of low-grade gliomas (LGG)., Patients and Methods: Retrospective analysis of 102 consecutive cases of newly diagnosed WHO grade II supratentorial gliomas, surgical removal of which was accompanied by iFC, was done. There were 46 diffuse astrocytomas (DA) and 56 oligodendrogliomas (OD). According to iFC, 68 tumors (67%) were considered non-aneuploid and 34 (33%) aneuploid. Median extent of resection (EOR) was 95% (mean, 89.0 ± 14.5%). Postoperative FRT with or without adjuvant chemotherapy was administered in 24 cases (24%)., Results: With median follow-up of 29.9 months (range, 9.4-66.9 months), neither median overall survival (OS) nor median progression-free survival (PFS) were reached. The 3-year actuarial OS and PFS rates were 95.8% and 86.3%, respectively. Non-aneuploid DNA histogram type of the tumor was associated with significantly longer OS both in univariate (P = 0.0094) and multivariate (P = 0.0232) analyses, and with longer PFS in univariate analysis (P = 0.0184). Aneuploidy was encountered more frequently in DA, than in OD (43% vs. 25% of cases; P = 0.0488). Tumor progression was noted in 15 DA and 4 patients succumbed to the disease; in this subgroup the main unfavorable prognostic factors for OS and PFS were presence of aneuploidy (P = 0.0510) and MIB-1 index ≧3.9% (P = 0.0141), respectively. Aneuploid DA more frequently progressed to glioblastoma than to anaplastic astrocytoma, but this difference did not reach statistical significance (P = 0.1362). In contrast, only one OD progressed (non-aneuploid neoplasm), and no one patient with such tumor died of the disease., Conclusions: DNA ploidy assessed with iFC may be effectively used as prognostic indicator in cases of LGG, especially of DA. Aneuploid tumors demonstrate more aggressive clinical course translated into shorter OS of patients. Thus, their detection during surgery may be helpful for decision on the optimal EOR, and for choice of the most appropriate postoperative adjuvant therapy., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Accurate preoperative and intraoperative differentiation between primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM) is sometimes difficult. Distinguishing between these tumors during surgery is important because surgical treatment is different between the 2 tumors. In this study, we established a new method of intraoperative differentiation between PCNSL and GBM using intraoperative flow cytometry (iFC), and we retrospectively tested whether iFC was useful for the intraoperative diagnosis of PCNSL and GBM., Methods: We analyzed the iFC data of 250 patients (28 with PCNSL and 222 with GBM) and then evaluated aneuploidy and S-phase population., Results: Aneuploidy was detected in 54.5% of GBM cases but in only 7.14% of PCNSL cases. Aneuploidy indicated GBM, but it was difficult to distinguish PCNSL from GBM when a tumor had a diploid pattern. Thus, for tumors without aneuploidy, we evaluated the S-phase population: S2, the ratio of the average height of the S-phase to the height of the diploid peak. S2 was significantly higher in PCNSL than in GBM. Based on these results, we established an algorithm for differentiating between PCNSL and GBM using DNA aneuploidy and S2. Comparing this new iFC algorithm and the permanent pathologic diagnosis, the sensitivity was 89.3%, the specificity was 93.7%, and the accuracy was 93.2%., Conclusions: iFC is useful for the intraoperative differentiation between PCNSL and GBM and it aids in intraoperative decision making within a short time. The accuracy of intraoperative diagnosis of these tumors seems to be higher with the combination of iFC and intraoperative rapid pathologic diagnosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Health Directors of the US Affiliated Pacific Islands (USAPI) declared a State of Emergency due to epidemic proportions of lifestyle diseases: cancer, obesity and other non-communicable diseases (NCDs) in 2010. This paper describes the development, implementation, and evaluation of a USAPI policy, system and environment (PSE) approach to address lifestyle behaviors associated with cancer and other NCDs., Methods: Each of USAPI jurisdictions applied the PSE approach to tobacco and nutrition interventions in a local institution, faith based, or community setting. A participatory community engagement process was utilized to: identify relevant deleterious health behaviors in the population, develop PSE interventions to modify the context in which the behavior occurs in a particular setting, implement the PSE intervention through five specified activities, and evaluate the activities and behavior change associated with the intervention., Results: PSE interventions have been implemented in all USAPI jurisdictions. Current human and financial resources have been adequate to support the interventions. Process and behavior change evaluations have not been completed and is ongoing. Personnel turnover and maintaining the intervention strategy in response due to shifting community demands has been the biggest challenge in one site., Conclusion: From 2014 through 2016 the PSE approach has been used to implement PSE interventions in all USAPI jurisdictions. The intervention evaluations have not been completed. The PSE intervention is novel and has the potential to be a scalable methodology to prevent cancer and modify NCD risk in the USAPI and small states., (Published by Elsevier Ltd.)

Background: Extent of resection (EOR) remains controversial in therapy for glioblastoma (GBM). However, an increasing number of studies favor maximum EOR as being associated with longer patient survival. Residual tumor volume (RTV) has also recently emerged as a prognostic factor. Low-field intraoperative magnetic resonance imaging (iMRI) has contributed to improve the EOR of GBM. The purpose of this study was to analyze the relationships between EOR/RTV and overall survival (OS)/progression-free survival (PFS) in patients with newly diagnosed GBM using low-field iMRI., Methods: Adult patients who underwent surgery for newly diagnosed supratentorial GBM between 2000 and 2012 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate analysis was used to evaluate the relationships between EOR/RTV and OS/PFS., Results: Of 168 patients, 126 (75%) died and 154 (91%) showed tumor recurrence. Median OS and PFS for patients with iMRI were 19.3 months (95% confidence interval, 15.4-23.7 months) and 9.5 months (95% confidence interval, 7.8-10.8 months). Median preoperative tumor volume was 37.0 cm 3 (interquartile range [IQR], 19.9-59.8 cm 3 ). Median RTV was 0 cm 3 (IQR, 0-1.6 cm 3 ). Median EOR was 100% (IQR, 96.2%-100%). In multivariate analysis, after controlling for age and Karnofsky Performance Status, EOR and RTV remained significantly associated with survival (hazard ratio, 1.56; P = 0.018) and recurrence (hazard ratio, 1.53; P = 0.013). Maximum RTV for survival was 3 cm 3 ., Conclusions: This volumetric analysis for low-field iMRI showed that both EOR and RTV were significantly associated with survival and recurrence. We determined a threshold RTV of 3 cm 3 as the maximum RTV associated with survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A new dactylogyrid monogenean Dactylogyrus bicorniculus sp. nov. is described from the gills of the kazetoge bitterling, Rhodeus atremius atremius (Jordan and Thompson, 1914), an endemic species in Japan, from Saga Prefecture, northern Kyūshū. D. bicorniculus sp. nov. resembles Dactylogyrus bicornis Malevitskaja, 1941 and Dactylogyrus lophogonus Zhang and Ji, 1980 because they have two common features, a large V-shaped ventral bar and well-developed second marginal hooks. However, the new species is distinguished from these congeners by a shorter penis and an accessory piece. A phylogenetic analysis of 28S rDNA shows that D. bicorniculus sp. nov. is a basal species with the T-shaped ventral bar in the genus. The new species has strict host-specificity to R. a. atremius, one of the endangered freshwater fishes in Japan, and may face the danger of co-extinction with its host., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In animal models of acute myocardial infarction, n-3 polyunsaturated fatty acids (PUFAs) administered before coronary occlusion have been suggested to prevent induction of ventricular arrhythmia and limit infarct size. However, the relation between the serum levels of n-3 PUFAs and ischemia/reperfusion (I/R) injury remains unclear., Methods: 211 patients with ST-segment elevation acute myocardial infarction received emergency percutaneous coronary intervention (PCI) within 6h from the onset. The patients were divided into two groups according to the sum of serum eicosapentaenoic acid (EPA) levels and docosahexaenoic acid (DHA) levels before PCI: group L (n=106), EPA+DHA <155μg/ml and group H (n=105), EPA+DHA ≥155μg/ml. The Selvester QRS-scoring system was used to estimate the serial change in infarct size., Results: Time to reperfusion was similar between the 2 groups. The QRS score before PCI was higher in group L than in group H (2.42±2.00 vs 1.85±2.01, p=0.015). The proportion of patients with I/R injury immediately after reperfusion, defined as reperfusion ventricular arrhythmias (25% vs 11%, p=0.006) and ST-segment re-elevation (44% vs 22%, p<0.001), was also higher in group L than in group H, followed by a greater increment in the QRS score during PCI (3.51±2.51 vs 2.54±1.91, p=0.006) and higher peak levels of creatinine phosphokinase (3552±241U/L vs 2660±242U/L, p<0.01). On multivariate analysis, serum level of EPA+DHA was an independent predictor of reperfusion injury (odds ratio 0.985, p=0.032)., Conclusion: Serum level of n-3 PUFAs before PCI may be a predictor of I/R injury and the resultant extent of myocardial damage. These findings suggest a protective effect of serum n-3 PUFAs on ischemic myocardium., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Bacteria adapt to environmental changes by altering gene expression patterns with the aid of signal transduction machinery called the two-component regulatory system (TCS), which consists of two protein components, a sensor kinase and response regulator. We examined the role of the TCS in bacterial adaptation to host environments using genetically tractable organisms, Escherichia coli as a pathogen and Drosophila melanogaster as a host. To determine the strength of the transcription promoters of TCS-encoding genes in Drosophila, adult flies were infected with a series of E. coli strains that expressed GFP driven by the promoters of genes coding for 27 sensor kinases and 32 response regulators of E. coli TCS followed by the measurement of fluorescence intensities. We further analyzed EnvZ-OmpR among the TCS encoded by genes having stronger promoters. A mutant E. coli strain lacking EnvZ-OmpR had a higher pathogenic effect on fly survival than that of the parental strain, and the forced expression of envZ and ompR in the mutant strain lowered its pathogenicity. The lack of EnvZ-OmpR did not affect the growth of E. coli in a culture medium as well as the level of colony-formable E. coli in flies. An increase in E. coli virulence with the loss of EnvZ-OmpR was observed in flies defective in an Imd-mediated humoral response, and both the mutant and parental strains were equally engulfed by hemocytes in vitro. These results suggest that EnvZ-OmpR mitigated the virulence of E. coli in Drosophila by a mechanism not accompanied by a change of bacterial burden. This behavior of E. coli is most likely a bacterial strategy to achieve persistent infection., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Japan approved clozapine for treatment-resistant schizophrenia in June 2009. The aim of this study was to evaluate clozapine's efficacy and tolerability in Japanese patients. A twelve-week, single-arm clinical trial of clozapine in treatment-resistant schizophrenia inpatients, was conducted under real-world conditions using raters masked for type of antipsychotic. Thirty-eight patients were recruited, with 33 (86.8%) completing the trial. At week 12, clozapine was associated with significant improvement in the Positive and Negative Syndrome Scale (PANSS) total (p < 0.0001), PANSS positive (p < 0.0001), negative (p = 0.0055) and general subscale scores (p < 0.0001). Significant improvements occurred in all PANSS scores by week 4, the first post-baseline psychopathology rating. Altogether, 50.0% of patients showed ≥20% reduction in PANSS total score, 20.6% had ≥30% reduction and 14.7% had >40% reduction. Eighteen patients (47.4%) were discharged before week 12. However, all patients experienced ≥1 adverse event. Two of 38 patients (5.2%) dropped out due to moderate leucopenia and one of them developed agranulocytosis after stopping clozapine. However, both patients recovered. Eight adverse events (hypersalivation, fatigue, sedation, constipation, insomnia, nausea/vomiting, chest pain and leucopenia) were observed in 34-79% of patients. These findings suggest that clozapine is beneficial in Japanese treatment-resistant schizophrenia patients. However, attention should be paid to patients' adverse events., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We previously characterized the l-Ser analog #290, H(tBut)-l-Ser-O-Methyl·HCl, as a novel inhibitor of osteoclastogenesis which functions in both mouse and human cells. Here, we assessed the activity of #290 in animal models of osteoporosis and rheumatoid arthritis. Treatment of animals with #290 both prevented bone loss and led to the recovery of lost bone in osteoporotic mice. When inflammatory arthritis was induced in SKG mice, #290 treatment suppressed arthritis scores and significantly prevented the destruction of calcaneous bones. Additionally, #290 reciprocally modulated the mammalian target of rapamycin (mTOR) pathway in osteoclasts and osteoblasts in vitro, suggesting a dual effect on bone homeostasis. Our results demonstrate that #290 is a potential novel therapeutic tool for the treatment and/or study of diseases associated with bone destruction., (2011 Elsevier Ltd. All rights reserved.)

We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors.

Objective: Normal sleep-wake regulation is dependent upon an oscillatory circadian rhythm promoting alertness and sleep at appropriate times of day. Circadian rhythms have been noted to be disturbed as a consequence of both normal aging and age-associated pathologies like Alzheimer disease (AD). However, the relationship between the consequences of normal versus pathological aging upon circadian regulation remains unclear. The authors evaluated the similarities and differences between the consequences of aging and AD on endogenous circadian rhythm., Methods: Authors measured locomotor activity and, with a constant routine protocol, core body temperature, examining differences and similarities in circadian disturbances in groups of normal elderly and patients with probable AD (pAD), as compared with a comparison group of young, normal volunteers, measuring endogenous circadian amplitude (ECA) and endogenous circadian phase (ECP) of core body temperature, and made parametric and nonparametric assessments of locomotor activity rhythms., Results: The ECP of core body temperature was delayed in patients with pAD versus both normal young and normal elderly subjects, whereas the ECA was reduced both in normal elderly and pAD subjects compared with a comparison group of young subjects. There was also disassociation of the activity and core body temperature rhythms in both age groups versus the young subjects., Conclusions: Authors observed changes in endogenous circadian rhythm in pAD that were consonant with those seen in normal aging (amplitude reduction; loss of phase coordination) and also observed changes that were apparently discrete from those seen in normal aging (phase delay).

One Japanese pedigree of familial essential thrombocythemia (FET) inherited in an autosomal-dominant manner is presented. A unique point mutation, serine 505 to asparagine 505 (Ser505Asn), was identified in the transmembrane domain of the c-MPL gene in all of the 8 members with thrombocythemia, but in none of the other 8 unaffected members in this FET family. The Ba/F3 cells expressing the mutant Asn505 acquired interleukin 3 (IL-3)-independent survival capacity, whereas those expressing wild-type Ser505 did not. The autonomous phosphorylation of Mek1/2 and Stat5b was observed in the mutant Ba/F3 cells in the absence of IL-3. The former was also found in platelets derived from the affected individual in the absence of thrombopoietin. These results show that the Asn505 is an activating mutation with respect to the intracellular signaling and survival of the cells. This is the first report of FET deriving from a dominant-positive activating mutation of the c-MPL gene.

Sonic hedgehog (Shh) is a secreted morphogen crucial for appropriate cellular proliferation during mammalian development. The activated Shh signaling is known to predispose to human tumors such as medulloblastoma and basal cell carcinoma, while a role of Shh signaling in the other common tumors is still controversial. Here we showed the overexpression of Shh in five cell lines among 14 human oral squamous cell carcinoma (OSCC) cell lines. One of the Shh-expressing OSCC cell lines HSQ-89 showed the inhibition of G1/S transition and apoptotic cell death by treatment with Cyclopamine, a steroidal alkaloid that blocks the intracellular Shh signaling. Furthermore, we found that treatment with Y-27632, a specific inhibitor of Rho-associated kinase, mimicked the effect of Cyclopamine on the cell cycle progression of HSQ-89. Our study revealed the involvement of activated Shh signaling in the cellular proliferation of OSCC cells, indicating Shh signaling might be a good therapeutic target for OSCC.

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. We have analyzed frequencies of mutant alleles and PMs based on the published data in previous study (Shimizu, T. et al.: Bioinformatics research on inter-racial difference in drug metabolism, I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.). The study shows that there were racial differences in the frequencies of each mutant allele and PMs. In the present study, the correlation between genotypes and drug-metabolizing enzyme activities was investigated. The result showed that enzyme activities varied according to the genotypes of subjects even in the same race. On the other hand, if subjects had the same genotypes, almost no racial differences were observed in drug-metabolizing enzyme activities. From these results, it was supposed that the racial differences in activities of these enzymes could be explained by the differences in distribution of genotypes. It would be possible to explain the racial differences in drug-metabolizing enzyme activities based on the differences on individual pharmacogenetic background information, not merely by comparison of frameworks such as races and nations.

Previously, we reported a new category of photosensitive disorder named ultraviolet-sensitive syndrome (UVs S) [T. Itoh, T. Fujiwara, T. Ono, M. Yamaizumi, UVs syndrome, a new general category of photosensitive disorder with defective DNA repair, is distinct from xeroderma pigmentosum variant and rodent complementation group 1, Am. J. Hum. Genet. 56 (1995) 1267-1276.]. Cells derived from these patients show impaired recovery of RNA synthesis (RRS) after UV-irradiation irrespective of having a normal level of unscheduled DNA synthesis (UDS). These characteristics are reminiscent of Cockayne syndrome (CS) cells. By comparing sensitivity of the UV-induced p53 response in cells with different types of defects in nucleotide excision repair, we hypothesized that the UV-induced p53 response is triggered by inhibition of RNA synthesis [M. Yamaizumi, T. Sugano, UV-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle, Oncogene 9 (1994) 2775-2784.]. To test this hypothesis, we determined sensitivity of the p53 response in UVs S cells by immunostaining, Western blotting, and FACScan analysis. Maximal nuclear accumulation of p53 in the UVs S cells was observed with a one-third UV dose required for that in normal cells, while almost identical p53 responses were observed in UVs S and normal cells following treatment with heat or alpha-amanitin. Recovery of RNA synthesis after a low dose of UV-irradiation was impaired in UVs S cells to the same extent as seen in CS cells. These results provide further evidence to support our previous hypothesis regarding the mechanism of the p53 response induced by DNA damage.

Fifty-nine patients with acute leukemia were studied by flow cytometry using monoclonal antibody against DNA polymerase alpha. Since fresh and frozen cells showed identical flow cytometric histograms, 86 cryopreserved samples (39 from peripheral blood and 47 from bone marrow) were used in this study. The DNA polymerase alpha-positive population ranged from 16.3 to 84.7% in peripheral blood, and from 6.5 to 92.1% in bone marrow. A positive correlation (r = 0.80; p < 0.01) was found between DNA polymerase alpha-positive populations in peripheral blood and bone marrow from the same patient. This suggests that the DNA polymerase alpha-positive population in the bone marrow can be estimated from that in peripheral blood. A negative correlation was observed between the positive population in bone marrow samples and the time to reach a nadir (r = -0.58: p < 0.01), while a positive correlation was found between the tumor cell count in bone marrow and the DNA polymerase alpha-positive population (r = 0.64; p < 0.01) in patients who responded to chemotherapy.

The 11q13 breakpoint region of t(11;14) (q13;q32), translocated to the Ig heavy chain locus at 14q32, has been designated as BCL-1 for B-cell leukemia/lymphoma-1, but the nature of the transcriptional unit has long remained unclear. Recently, the PRAD1 gene encoding cyclin D1, isolated from the 11q13 region, was proposed as a candidate BCL-1 gene on the basis of chromosome walking and concordant overexpression of PRAD1 mRNA in cell lines with t(11;14)(q13;q32). We report here molecular analysis of a variant translocation at the BCL-1 locus, t(11;22)(q13;q11), showing juxtaposition of the Ig light chain gene, Ig lambda, to the PRAD1 gene at its 3' end, resulting in overexpression of PRAD1 mRNA. Because only the PRAD1 gene is present between the Ig heavy chain and light chain gene breakpoints, an identity between BCL-1 and the PRAD1/cyclin D1 gene is strongly indicated.

Left ventricular systolic and diastolic performance was examined using Doppler and M-mode echocardiography in 42 patients with chronic renal failure before and after hemodialysis. Twenty patients with left ventricular hypertrophy, 22 without hypertrophy and 30 normal subjects were studied. Chronic renal failure patients showed significantly larger chamber diameters of the left ventricle, left atrium and right ventricle than did normal subjects. This group also exhibited greater fractional shortening, stroke volume and cardiac output. Before hemodialysis, patients with left ventricular hypertrophy had a significantly higher cardiac output and the greater ratio of late to early diastolic peak flow velocities (A/R) than did patients without hypertrophy. After hemodialysis, there were significant reductions in blood pressure, ventricular and atrial dimensions, stroke volume and cardiac output. The velocities of early and late diastolic left ventricular filling and the deceleration rate were also significantly reduced. The heart rate, A/R, deceleration half time, and the ratio of deceleration half time to acceleration half time (DHT/AHT) were significantly increased. The greater the amount of fluid removed, the greater the changes in the above values. Patients with left ventricular hypertrophy exhibited significant reductions in fractional shortening, ejection fraction, stroke volume and cardiac output, compared to those without hypertrophy. However, patients without hypertrophy showed more significant decrease in the acceleration half time and increase in DHT/AHT than did patients with hypertrophy. These findings demonstrated normal systolic function and impaired diastolic properties in patients with chronic renal failure, who had left ventricular hypertrophy unaccompanied by dilatation.

One hundred seventy-one patients with aortic stenosis (AS) who had hemodynamic studies were evaluated by a scoring system of the seven following noninvasive variables which our laboratory had developed to estimate the severity of AS: left ventricular hypertrophy (LVH) by ECG; visible aortic valve calcification by chest x-ray examination; loudness of A2; Q to peak of systolic murmur; T-time of the carotid pulse; LV ejection time; and LVH by M-mode echocardiography. The range of the severity score is 0 to 16, and a score greater than or equal to 5 has been shown correctly to identify 93 percent of patients with severe AS (valve area less than or equal to 1.0 cm2). The present study has applied this method to the detection of progression of AS. Eleven patients (mean age, 60.4 years) were studied who had hemodynamic studies performed two to nine years apart (mean, three years). Progression of stenosis occurred in all, with an increase in mean aortic valve gradient from 23 +/- 4.7 mm Hg to 46 +/- 6.5 mm Hg (p less than 0.005). Aortic valve area decreased from 1.5 +/- 0.18 cm2 to 0.88 +/- 0.10 cm2 (p less than 0.005). Noninvasive scores increased in these patients from 0.7 +/- 0.5 to 7.1 +/- 2.3 (p less than 0.005). Thirty-five patients (mean age, 62.4 years) had repeat noninvasive studies one to six years apart (mean 3 years). Twenty-two (63 percent) had an increase in the noninvasive score of greater than or equal to 3 points, and 20 (57 percent) attained a score of greater than or equal to 5, indicating probable severe AS. The mean initial severity score was 2.2 +/- 0.3, and at the end of a mean follow-up of three years, the score was 8.3 +/- 0.6 (p less than 0.005). It is concluded that in the elderly male, progression of AS over a three-year period occurs in about 60 percent of patients, and progression can be detected by simple, noninvasive methods.

Peripheral blood specimens were obtained from 22 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) (16 in chronic phase, 2 in an accelerated phase, and 4 in blast crisis). Studies were performed to determine the frequency of the presence of the Ph1 chromosome in cells of lymphoid lineages. Rosetted (E+) lymphocytes (T lymphocytes) from nine patients in chronic phase and one patient in blast crisis were stimulated with T cell growth factor interleukin 2 (IL-2) and/or phytohemagglutinin (PHA). All ten patients had sufficient T lymphocyte metaphases for analysis and of a total of 461 metaphases examined, only one contained the Ph1 chromosome. Nucleated cells of density less than 1.077 g/mL were infected with Epstein-Barr virus (EBV). Following infection, cell lines were established from individual colonies attached to egg albumin-coated Lab-Tek slide chambers (clonal cell lines) or from suspension culture in 96-well tissue culture cluster dishes (nonclonal cell lines). Cell surface and intracellular marker analysis confirmed the B lymphocyte phenotype of all the cell lines examined. B lymphoblastoid cell lines were established from 16 of the 22 patients. All lines from 12 patients were Ph1-negative. From two chronic phase patients, both Ph1-positive and Ph1-negative lines were established. From one patient in an accelerated phase, only Ph1-positive lines were established. From another patient in blast crisis (of myeloblastic phenotype), only Ph1-positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient. Based on these results, it appears that most B cells and mature T cells in most CML patients are Ph1-negative, but that about 25% of patients have predominantly Ph1-positive B cells or a mixture of Ph1-positive and Ph1-negative B cells that are capable of growing as established cell lines after transformation with EBV.

A noninvasive point score system for the evaluation of severity of aortic stenosis (AS) was employed in a prospective study of 153 patients (mean age 64.8 +/- 0.8 years) referred from invasive studies or for the evaluation of a systolic murmur. Seven variables were recorded and scored as follows: LVH by ECG (0-2); aortic valve calcium by chest x-ray film (0-2); loudness of A2 (0-2); Q-peak of murmur (0-3); T-time of carotid pulse (0-3); ejection time (0-3); and LVH by echo (0-1). Range of the total score was 0-16. All patients had the aortic valve area (AVA) determined by cardiac catheterization. Data analysis revealed that the relation between the total score and the AVA was curvilinear with a score greater than or equal to 5 correctly identifying 100/107 (93 percent) of patients with a valve area of less than or equal to 1.0 cm2. If the patients with an AVA of less than or equal to 1.0 cm2 were considered severe and patients with a total score less than 5 were considered mild-moderate, the sensitivity, specificity, and predictive accuracy for a score greater than or equal to 5 were 93 percent, 96 percent, and 98 percent, respectively. The relation between the score and aortic valve gradient (AVG) was linear with a score of greater than or equal to 5 correctly identifying 84/88 (95 percent) with an AVG greater than or equal to 40 mm Hg. If the patients with a pressure gradient over 40 mm Hg were considered severe, the sensitivity, specificity, and predictive accuracy for a score greater than or equal to 5 were 95 percent, 72 percent, and 82 percent, respectively. It is concluded that a point score system employing seven noninvasive variables is simple and accurate in identifying patients with severe AS and would be a valuable addition to a Doppler determined gradient.