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We report a possible charge ordering model of triangular mixed valence material YbFe2O4. It was found that a crystal synthesized with high stoichiometry on iron vacancy shows new and simple extinction rule in the superlattice reflections. The Laue class of the diffraction signal is expressed as 2/m. With the consideration of the charge neutrality and the superlattice signal of (1/3 1/3 0), we derived 5 possible charge ordering models of this material. [ABSTRACT FROM AUTHOR]

Purpose: The relationship between the pharmacokinetics and effects of gefitinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is unknown. In this study, we examined the correlation between gefitinib plasma concentration and progression-free survival (PFS) in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R.Methods: The retrospective analysis examined 40 patients who were administered 250 mg of gefitinib daily. All patients were diagnosed with and treated for advanced non-small cell lung carcinoma with sensitive EGFR mutations between January 2011 and November 2013 at Akita University Hospital, Akita, Japan. The 40 patients were divided into four groups by trough plasma concentration (high or low) and mutation type (exon 19 deletions or exon 21 L858R point mutations). PFS, response rate, and toxic effects were analyzed in all four groups.Results: After excluding 5 patients, the remaining 35 were successfully analyzed. For the patients with exon 19 deletions, there was no significant difference in PFS between the high and low plasma concentration groups (median survival: 12.0 vs. 17.0 months, P = 0.9548). In contrast, the PFS was significantly shorter for patients with exon 21 point mutations and low vs. high concentrations of gefitinib (median survival: 8.0 vs. 16.0 months, P < 0.05).Conclusions: The results suggest that low gefitinib plasma concentrations in patients with exon 21 L858R point mutations may be associated with shorter PFS in NSCLC patients. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) to define metabolically active hypoxic volume, and investigate its clinical significance in relation to progression free survival (PFS) and overall survival (OS) in glioblastoma patients. Experimental Design: Glioblastoma patients ( n = 32) underwent FMISO PET, FDG PET, and magnetic resonance imaging (MRI) before surgical intervention. FDG and FMISO PET images were coregistered with gadolinium-enhanced T1-weighted MR images. Volume of interest (VOI) of gross tumor volume (GTV) was manually created to enclose the entire gadolinium-positive areas. The FMISO tumor-to-normal region ratio (TNR) and FDG TNR were calculated in a voxel-by-voxel manner. For calculating TNR, standardized uptake value (SUV) was divided by averaged SUV of normal references. Contralateral frontal and parietal cortices were used as the reference region for FDG, whereas the cerebellar cortex was used as the reference region for FMISO. FDG-positive was defined as the FDG TNR ≥1.0, and FMISO-positive was defined as FMISO TNR ≥1.3. Hypoxia volume (HV) was defined as the volume of FMISO-positive and metabolic tumor volume in hypoxia (hMTV) was the volume of FMISO/FDG double-positive. The total lesion glycolysis in hypoxia (hTLG) was hMTV × FDG SUVmean. The extent of resection (EOR) involving cytoreduction surgery was volumetric change based on planimetry methods using MRI. These factors were tested for correlation with patient prognosis. Results: All tumor lesions were FMISO-positive and FDG-positive. Univariate analysis indicated that hMTV, hTLG, and EOR were significantly correlated with PFS ( p = 0.007, p = 0.04, and p = 0.01, respectively) and that hMTV, hTLG, and EOR were also significantly correlated with OS ( p = 0.0028, p = 0.037, and p = 0.014, respectively). In contrast, none of FDG TNR, FMISO TNR, GTV, HV, patients' age, or Karnofsky performance scale (KPS) was significantly correlated with PSF or OS. The hMTV and hTLG were found to be independent factors affecting PFS and OS on multivariate analysis. Conclusions: We introduced hMTV and hTLG using FDG and FMISO PET to define metabolically active hypoxic volume. Univariate and multivariate analyses demonstrated that both hMTV and hTLG are significant predictors for PFS and OS in glioblastoma patients. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptors ( GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR-mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two-hybrid ( MYTH) approach and identified interacting partners for 48 selected full-length human ligand-unoccupied GPCRs in their native membrane environment. The resulting GPCR interactome connects 686 proteins by 987 unique interactions, including 299 membrane proteins involved in a diverse range of cellular functions. To demonstrate the biological relevance of the GPCR interactome, we validated novel interactions of the GPR37, serotonin 5- HT4d, and adenosine ADORA2A receptors. Our data represent the first large-scale interactome mapping for human GPCRs and provide a valuable resource for the analysis of signaling pathways involving this druggable family of integral membrane proteins. [ABSTRACT FROM AUTHOR]

Background: Bevacizumab (BEV), a humanized monoclonal antibody, become a currently important chemotherapeutic option for the patients with recurrent glioma. The aim of this retrospective study is to investigate whether 18F-Fluoromisonidazole (FMISO) PET have the potential to detect BEV-resistant gliomas in the early-stage. Methods: We reviewed the FMISO PET and MRI appearances before and 3 to 4 courses after BEV treatment on 18 recurrent glioma patients. FMISO accumulation was assessed by visual inspection and semi-quantitative values which were tumor-to-normal (T/N) ratio and hypoxic volume. MRI responses were evaluated based on RANO (Response Assessment in Neuro-Oncology) criteria. The prognostic analysis was performed in relation to the response assessment by FMISO PET and MRI using overall survival (OS) after BEV application. Results: After BEV application, MRI revealed partial response in 14 of 18 patients (78%), of which 9 patients also demonstrated decreased FMISO accumulation. These 9 patients (50%) were classified as “MRI-FMISO double responder”. As for the other 5 patients (28%), FMISO accumulation volumes increased or remained stable after BEV treatment although partial responses were achieved on MRI. Therefore, these cases were classified as “MRI-only responder”. The remaining 4 patients (22%) did not show treatment response on FMISO PET or MRI (“non-responder”). MRI-FMISO double responders showed significantly longer OS than that in other groups (median 12.4 vs 5.7 months; P < 0.001), whereas there were no overall survival difference between MRI-only responders and non-responders (median OS, 5.7 and 4.8 months; P = 0.58). Among the pre-treatment clinical factors, high FMISO T/N ratio was a significant prognostic factor of overall survival in these patients under the assessment of Cox proportional hazard model. Conclusions: Recurrent gliomas with decreasing FMISO accumulation after short-term BEV application could derive a survival benefit from BEV treatment. Change in FMISO PET appearance can identify BEV-resistant gliomas in early-stage regardless of MRI findings in a comprehensible way. [ABSTRACT FROM AUTHOR]

Background: The aim of the study is to elucidate whether parathyroid hormone (PTH) levels after parathyroidectomy affect the prognosis of patients with secondary hyperparathyroidism. Subjects and methods: Two hundred and ninety-five patients, who underwent PTx without autotransplantation from July 1998 to December 2011, were divided into the low ( n = 148) and high ( n = 147) PTH groups, using the median value of each mean value of intact PTH after surgery (16.6 pg/mL). After observation for 5.00 years, we evaluated demographic factors, influences of postoperative mineral metabolism, magnitude of uremia, and vitamin D receptor activators on their prognosis, with the multivariate Cox proportional hazard model. Results: While overall survival rates in the high and low PTH groups were 54.9 and 74.2 %, respectively ( P = 0.1500), cardiovascular survival rates were 71.6 and 94.4 %, respectively ( P = 0.0256). The hazard ratio for cardiovascular mortality in the high PTH group (≥16.6 pg/mL) was 3.132 ( P = 0.0470), and those in groups with the median age more than 59 years and with cardiovascular disease were 2.654 ( P = 0.0589) and 3.377 ( P = 0.0317), respectively. The intact PTH level 6 days after surgery and the mean postoperative intact PTH value showed a strong correlation (Spearman ρ = 0.9007, P < 0.0001, y = 0.4725 x + 30.395, R = 0.51798). Conclusion: The present study suggests that maintaining low PTH levels after parathyroidectomy reduces cardiovascular mortality and improves the prognosis. Total parathyroidectomy (more than 4 glands) without autotransplantation seems to be one of the treatment options for managing severe secondary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Background To evaluate the accuracy of tumor size by maximum diameter, ABC/2 formula, and planimetry method using thick-slice and thin-slice magnetic resonance imaging (MRI). Methods Maximum diameter and tumor volume calculated using ABC/2 formula (V1) and planimetry method with thick-slice MRI (V2) and thin-slice MRI (V3) were examined in 83 meningiomas. Form factor (FF) analysis was performed to assess irregularity of the tumor. V3 values were considered as real tumor volumes. The accuracy of V1 and V2 was evaluated using ratio and difference from V3. Meningiomas were categorized by tumor locations: skull base (anterior, middle, and posterior) and non–skull base (calvaria and other sites). Results Correlation between maximum diameter and V3 was statistically significant ( r = 0.91), but the error was significant in tumors with longer maximum diameters. Correlation between V1 and V3 was significant ( r = 0.97). However, V1 tended to be larger in middle skull base meningiomas or in tumors with low FF values ( R 2 = 0.21). V2 represented relatively accurate volumes in both groups except in the case of small meningiomas. When tumors were demonstrated within 3 fractions on thick-slice MRI, the ratio of V2 to V3 showed significant variability. Conclusions Using the ABC/2 formula, the volume of meningiomas in the middle skull base or meningiomas with low FF value might be calculated larger than the real tumor volume. The planimetry method with thick-slice MRI demonstrated relatively accurate volumes if the tumor was fractionated in >4 slices. [ABSTRACT FROM AUTHOR]

Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), the postoperative course is varied. We retrospectively analyzed the resolution pattern of the spasm and specified predictors for delayed cure after MVD. This study included 114 consecutive patients with typical HFS. All of them were followed up for at least 1 year after operation. Patients were divided into three groups depending on the postoperative course: immediate cure, delayed cure, and failure. To identify the predictive factors for delayed cure after MVD, logistic regression analyses were applied using candidate clinical factors, such as duration of symptom, the tendency of the spasm, preoperative medical treatment, and offending vessels. Among the 114 patients, 107 patients were cured. For those cured, 65 patients were classified as immediate cure and 42 patients were classified as delayed cure. Cumulative spasm-free rates after 1 week, 1 month, and 3 months after MVD were 70, 88, and 97 %, respectively. No predictive factors between the cured and failure groups were observed. According to multivariate analysis, preoperative anticonvulsant therapy was found to be the sole significant predictive factor for delayed cure after MVD ( p = 0.025). A significant correlation between delayed cure and preoperative anticonvulsant therapy was found in our study, which suggests that hyperexcitation of the facial nucleus plays an important role in pathogenesis of delayed cure. Therefore, if a patient demonstrating a positive response to preoperative anticonvulsant therapy showed a persistent spasm after MVD, reoperation should be delayed for at least 3 months after the initial operation. [ABSTRACT FROM AUTHOR]

Purpose: Tumor necrosis is one of the indicators of tumor aggressiveness. F-fluoromisonidazole (FMISO) is the most widely used positron emission tomography (PET) tracer to evaluate severe hypoxia in vivo. Because severe hypoxia causes necrosis, we hypothesized that intratumoral necrosis can be detected by FMISO PET in brain tumors regardless of their histopathology. We applied FMISO PET to various types of brain tumors before tumor resection and evaluated the correlation between histopathological necrosis and FMISO uptake. Methods: This study included 59 brain tumor patients who underwent FMISO PET/computed tomography before any treatments. According to the pathological diagnosis, the brain tumors were divided into three groups: astrocytomas (group 1), neuroepithelial tumors except for astrocytomas (group 2), and others (group 3). Two experienced neuropathologists evaluated the presence of necrosis in consensus. FMISO uptake in the tumor was evaluated visually and semi-quantitatively using the tumor-to-normal cerebellum ratio (TNR). Results: In visual analyses, 26/27 cases in the FMISO-positive group presented with necrosis, whereas 28/32 cases in the FMISO-negative group did not show necrosis. Mean TNRs with and without necrosis were 3.49 ± 0.97 and 1.43 ± 0.42 ( p < 0.00001) in group 1, 2.91 ± 0.83 and 1.44 ± 0.20 ( p < 0.005) in group 2, and 2.63 ± 1.16 and 1.35 ± 0.23 ( p < 0.05) in group 3, respectively. Using a cut-off value of TNR = 1.67, which was calculated by normal reference regions of interest, we could predict necrosis with sensitivity, specificity, and accuracy of 96.7, 93.1, and 94.9 %, respectively. Conclusions: FMISO uptake within the lesion indicated the presence of histological micro-necrosis. When we used a TNR of 1.67 as the cut-off value, intratumoral micro-necrosis was sufficiently predictable. Because the presence of necrosis implies a poor prognosis, our results suggest that FMISO PET could provide important information for treatment decisions or surgical strategies of any type of brain tumor. [ABSTRACT FROM AUTHOR]

Background/Aims: Serrated lesions (SLs) of the large bowel occasionally manifest as inverted growths with endophytic expansion within the muscularis mucosa. The aims of this investigation were to investigate the incidence of inverted SLs (ISLs) among SLs and to describe the clinicopathologic features. Methods: We reviewed the colonoscopy records from 2006 to 2014 at our institution and identified cases of endoscopically or surgically resected SLs, including hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/ Ps) and traditional serrated adenomas (TSAs). The incidence of ISLs among the SLs and their colonoscopic findings were investigated retrospectively. Results: There were 35 HPs in 30 patients, 80 SSA/Ps in 65 patients and 70 TSAs in 65 patients. The incidence of ISLs was significantly higher among SSA/Ps (8.8%) and HPs (5.7%) than among TSAs (0%; p = 0.04). A predominant right-sided location, a flat-elevated configuration with a central depression and round-open pit pattern or expanded crypt openings were characteristic of ISLs of the SSA/P type. Conclusions: Right-sided flat lesions with a central depression and round or expanded crypts are indicative of ISLs of the SSA/P type. [ABSTRACT FROM AUTHOR]

A novel class of Na V 1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse Na V 1.7 inhibitory activities with fair subtype selectivity over Na V 1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin. [ABSTRACT FROM AUTHOR]

Background: Patients with hypoalbuminemia often fail to respond to increased doses of loop diuretics. We therefore performed a post hoc analysis to investigate the pharmacological action of tolvaptan and whether it is dependent on the serum albumin level.Methods: This analysis was based on four previous clinical trials of tolvaptan in patients with liver cirrhosis who exhibited insufficient response to conventional diuretics. We analyzed the correlation between the change in the initial 24-h cumulative urine volume from baseline and the serum albumin level at baseline, and assessed potential predictive factors of response to tolvaptan.Results: The correlation coefficient was 0.029 in the placebo group and -0.112 in the 7.5 mg tolvaptan group of patients with liver cirrhosis. Administration of tolvaptan provoked a stable response regardless of the serum albumin level. Tolvaptan use was identified as a significant predictor of pharmacological action, and was shown to change the initial urine volume by 885 mL (P < 0.0001) in liver cirrhosis patients.Conclusions: In this post hoc analysis, tolvaptan increased the initial urine volume from baseline regardless of serum albumin levels. Use of tolvaptan as an add-on therapy to loop diuretics can be considered an optimal therapeutic option in patients with insufficient response to loop diuretics. [ABSTRACT FROM AUTHOR]

Purpose: We investigated whether impaired patterns of myocardial fatty acid imaging were associated with cardiac death in dialysis patients without coronary lesions. Methods: We prospectively enrolled 155 hemodialysis patients without obstructive coronary artery disease, who had been examined by single-photon emission computed tomography (SPECT) using the iodinated fatty acid analogue BMIPP. Uptake of BMIPP on SPECT was graded in 17 segments on a five-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores. Of the enrolled 155 participants, we analyzed 95 who had BMIPP summed scores ≥ 6 (52 men and 43 women, 65 ± 11 years). BMIPP scores ≥ 2 in ≥ 2 consecutive segments in SPECT were defined as focal, and the others as non-focal pattern. Results: Of 95 participants analyzed, 42 (44.2 %) showed focal and 53 (55.8 %) non-focal type. During follow-up for 5.1 ± 2.0 years, 42 died of cardiac events. The occurrence of cardiac death was higher in the focal than in the non-focal group (30/42 [71.4 %] versus 12/53 [22.6 %], p = 0.001). In stepwise Cox hazard analysis, focal pattern was associated with cardiac death (hazard ratio 2.266), independent of impairment of BMIPP SPECT (BMIPP summed scores ≥ 12). The predictive potential of BMIPP SPECT for cardiac death was higher ( p < 0.001) in the left anterior descending artery area compared with other coronary territories. Conclusions: Focal impairment in myocardial fatty acid imaging in the left anterior descending area may strongly predict cardiac death in this population. [ABSTRACT FROM AUTHOR]

Because it is highly infiltrative, malignant glioma is a cancer with a poor prognosis despite multidisciplinary treatment strategies, such as aggressive surgery and chemoradiotherapy, necessitating new therapeutic approaches to control migration of tumor cells. In our study, we investigated the efficacy of sonodynamic therapy of glioma cells in vitro using porphyrin derivatives, including 5-aminolevulinic acid, protoporphyrin IX and talaporfin sodium, as sonosensitizers. These substances have been known to accumulate in glioma cells and are expected to have cytotoxic effects on sonication. Our study found that the cytotoxicity of sonication of glioma cells is enhanced by each sonosensitizer and that the efficacy of sonodynamic therapy may depend on the degree of intracellular accumulation of sonosensitizer. Also, the study suggests that induction of apoptosis is a major mechanism underlying cell death. Though further investigations are necessary, our preliminary result indicates a potential for sonodynamic therapy with sonosensitizers in glioma treatment. [ABSTRACT FROM AUTHOR]

Error in Affiliation In the original publication, there were some errors in the affiliation(s) for Masayuki Tanaka, Sanae Isaki, Keiko Yokoyama and Akira Miyajima. Reference 1 Komiyama T., Kim H., Tanaka M., Isaki S., Yokoyama K., Miyajima A., Kobayashi H. RNA-seq and Mitochondrial DNA Analysis of Adrenal Gland Metastatic Tissue in a Patient with Renal Cell Carcinoma. RNA-seq and Mitochondrial DNA Analysis of Adrenal Gland Metastatic Tissue in a Patient with Renal Cell Carcinoma. [Extracted from the article]

Voluntary exercise can ameliorate insulin resistance. The underlying mechanism, however, remains to be elucidated. We previously demonstrated that inducible nitric oxide synthase (iNOS) in the liver plays an important role in hepatic insulin resistance in the setting of obesity. In this study, we tried to verify our hypothesis that voluntary exercise improves insulin resistance by reducing the expression of iNOS and subsequent S-nitrosylation of key molecules of glucose metabolism in the liver. Twenty-one Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats were randomly assigned to a sedentary group or exercise group subjected to voluntary wheel running for 20 weeks. The voluntary exercise significantly reduced the fasting blood glucose and HOMA-IR in the OLETF rats. In addition, the exercise decreased the amount of iNOS mRNA in the liver in the OLETF rats. Moreover, exercise reduced the levels of S-nitrosylated Akt in the liver, which were increased in the OLETF rats, to those observed in the LETO rats. These findings support our hypothesis that voluntary exercise improves insulin resistance, at least partly, by suppressing the iNOS expression and subsequent S-nitrosylation of Akt, a key molecule of the signal transduction pathways in glucose metabolism in the liver. [ABSTRACT FROM AUTHOR]

Purpose: C-methionine (MET) PET is an established diagnostic tool for glioma. Studies have suggested that MET uptake intensity in the tumor is a useful index for predicting patient outcome. Because MET uptake is known to reflect tumor expansion more accurately than MRI, we aimed to elucidate the association between volume-based tumor measurements and patient prognosis. Methods: The study population comprised 52 patients with newly diagnosed glioma who underwent PET scanning 20 min after injection of 370 MBq MET. The tumor was contoured using a threshold of 1.3 times the activity of the contralateral normal cortex. Metabolic tumor volume (MTV) was defined as the total volume within the boundary. Total lesion methionine uptake (TLMU) was defined as MTV times the mean standardized uptake value (SUVmean) within the boundary. The tumor-to-normal ratio (TNR), calculated as the maximum standardized uptake value (SUVmax) divided by the contralateral reference value, was also recorded. All patients underwent surgery (biopsy or tumor resection) targeting the tissue with high MET uptake. The Kaplan-Meier method was used to estimate the predictive value of each measurement. Results: Grade II tumor was diagnosed in 12 patients (3 diffuse astrocytoma, 2 oligodendroglioma, and 7 oligoastrocytoma), grade III in 18 patients (8 anaplastic astrocytoma, 6 anaplastic oligodendroglioma, and 4 anaplastic oligoastrocytoma), and grade IV in 22 patients (all glioblastoma). TNR, MTV and TLMU were 3.1 ± 1.2, 51.6 ± 49.9 ml and 147.7 ± 153.3 ml, respectively. None of the three measurements was able to categorize the glioma patients in terms of survival when all patients were analyzed. However, when only patients with astrocytic tumor ( N = 33) were analyzed (i.e., when those with oligodendroglial components were excluded), MTV and TLMU successfully predicted patient outcome with higher values associated with a poorer prognosis ( P < 0.05 and P < 0.01, respectively), while the predictive ability of TNR did not reach statistical significance ( P = NS). Conclusion: MTV and TLMU may be useful for predicting outcome in patients with astrocytic tumor. [ABSTRACT FROM AUTHOR]

Purpose: Previous radiological investigations have generally shown the superiority of metabolic imaging in distinguishing high-grade from low-grade glioma, but the presence of an oligodendroglial component may affect the diagnostic accuracy. We investigated the diagnostic accuracy of PET imaging using C-methionine (MET) and F-fluorodeoxyglucose (FDG) in distinguishing high-grade from low-grade glioma, in correlation with the oligodendroglial component. Methods: The study population comprised adult patients who underwent preoperative PET imaging using both MET and FDG within 1 week and successful excision of the tumour tissue, which confirmed WHO grade II-IV glioma. We examined the tumour metabolic activity in terms of lesion-to-normal uptake ratios (L/N ratio) in both MET PET and FDG PET images. We assessed the correlation between the imaging results and the histological findings to determine the diagnostic accuracy of receiver operating characteristics (ROC) analysis in detecting high-grade tumours. Results: We studied 46 patients with glioma (13 low-grade and 33 high-grade), including 26 with an oligodendroglial components. The L/N ratios of the PET images showed significantly higher metabolic activities in high-grade gliomas than in low-grade gliomas for both MET (4.29 ± 1.22 and 2.36 ± 0.72, respectively; p < 0.0001) and FDG (1.72 ± 0.91 and 0.77 ± 0.26, respectively; p = 0.0007) images, although significant overlaps in L/N ratio were observed between high-grade and low-grade gliomas. Excluding the 26 patents with an oligodendroglial component improved the separation for both MET (4.62 ± 1.14 vs. 2.16 ± 0.63; p < 0.001) and FDG (1.76 ± 0.87 vs. 0.71 ± 0.14; p < 0.05) images. The ROC analyses demonstrated the clinical utility of the metabolic radiotracers in distinguishing high-grade from low-grade gliomas, showing similar AUC values for MET (0.91) and FDG (0.92). Excluding the 26 patents with an oligodendroglial component also further improved the diagnostic accuracy for both MET (AUC 0.98), and FDG (AUC 1.00) images. The metabolic radiotracers were significantly correlated with the MIB-1 labelling index ( R = 0.52, p < 0.05 for MET; R = 0.52, p < 0.05, for FDG) only in gliomas without an oligodendroglial component. Conclusion: For better characterization of gliomas and for risk assessment, the results of metabolic PET imaging should be revised after obtaining the pathological report, because oligodendroglial differentiation may positively influence the substrate metabolism and thus complicated the preoperative evaluation. [ABSTRACT FROM AUTHOR]

The objective of this study was to clarify the effects of disease on neurally mediated syncope (NMS) during an acute stress reaction. We analyzed the mechanism of the molecular interaction and the polymorphisms of the alpha-2 adrenoreceptor (α2B-AR) gene as the potential psychiatric cause of incentive stress. We focused on the following three genotypes of the repeat polymorphism site at Glu 301–303 in the α2B-AR gene: Glu12/12, Glu12/9, and Glu9/9. On the basis of our clinical research, NMS is likely to occur in people with the Glu12/9 heterotype. To verify this, we assessed this relationship with the interaction of Gi protein and adenylate cyclase by in silico analysis of the Glu12/9 heterotype. By measuring the difference in the dissociation time of the Gi-α subunit twice, we found that the Glu12/9 heterotype suppressed the action of adenylate cyclase longer than the Glu homotypes. As this difference in the Glu repeat number effect is thought to be one of the causes of NMS, we investigated the evolutionary significance of the Glu repeat number. Glu8 was originally repeated in simians, while the Glu12 repeats occurred over time during the evolution of bipedalism in humans. Taken with the Glu12 numbers, NMS would likely become a defensive measure to prevent significant blood flow to the human brain. [ABSTRACT FROM AUTHOR]

Background: Although histological diagnosis is indispensable in treating primary central nervous system lymphoma (PCNSL), we sometimes face an intractable situation in which tissue can be obtained only from a deep-seated brain lesion. In place of a histological diagnosis, the diagnostic adequacy of the combined use of 18 F-FDG PET and corticosteroid administration for PCNSL located in a deep-seated brain structure is reported. Methods: Patients with a deep-seated tumor were treated as having PCNSL without histological confirmation, based on the following criteria: (1) there was no evidence of systemic malignancy; (2) the tumor showed an extremely high FDG uptake relative to normal gray matter on pretreatment 18 F-FDG PET; (3) the tumor decreased in size 1 week after diagnostic therapy by corticosteroid administration on contrast-enhanced T1-weighted magnetic resonance imaging (MRI). FDG uptake of the lesion was evaluated by the maximum of standardized uptake values (SUVmax) and tumor-to-normal ratio of the SUV (T/N ratio). The extent of the tumor reduction was calculated by volumetric analysis for the treatment response to corticosteroid administration. Results: Ten patients (4 males and 6 females) matched these criteria. On pretreatment 18 F-FDG PET, mean SUVmax in the tumor was 24.8 (8.75-60.75), and mean T/N ratio was 3.24 (2.17-5.12). The extent of tumor volume reduction was shown to be 21 to 68 % 1 week after diagnostic therapy by corticosteroids. Mean total dose and duration of corticosteroids were 719 mg as prednisolone and 6.5 days, respectively. Nine patients achieved complete response and one patient achieved partial response on MRI after standard treatment for PCNSL with high-dose methotrexate and/or whole-brain irradiation. Conclusion: Although the value of biopsy is universal, combining 18 F-FDG PET and corticosteroid administration is an important alternative method that may lead to the diagnosis of deep-seated PCNSLs in cases with intractable histopathological confirmations. [ABSTRACT FROM AUTHOR]

An alkali-metal containing (AC) layer, specifically sodium (Na), is necessary for improving Cu(In x Ga 1- x )Se 2 (CIGS) solar cell performance on an alkali-free flexible substrate. However, we found that Na from the AC precursor layer diffused not only into the CIGS absorber layer but also into our flexible metal foil substrate, the surface of which was covered with an Al 2 O 3 layer, and thus creating Na depletion in the CIGS layer. In this work, newly developed alkali-metal block (AB) layers are introduced between the AC layers and the metal foil substrates in order to suppress Na diffusion into the substrates and enhance Na diffusion into the CIGS layers. Using different AB layer materials—Ti, TiO 2 , and TiN—and AC layers with systematically-varied thickness, Na concentrations in the CIGS layers and the solar cell efficiencies are investigated. Ti and TiN AB layers efficiently enhance the Na diffusion into the CIGS absorber layers. As a result, a high efficiency of 17.6% is obtained on the metal foil substrate using optimally prepared AC and AB layer of TiN. The AB layer controls the Na diffusion from the AC layer in one direction, and thus contributes to the precise control of Na concentrations in the CIGS layer. Hence, high efficiency solar cells on a variety of flexible substrates will be achieved comparable to those on soda-lime glass substrates. [ABSTRACT FROM AUTHOR]

Purpose: The N- and C-terminal regions of dynorphin (Dyn) A (1-17) activate opioid and N-methyl-D-aspartate receptors, respectively. Earlier studies demonstrated that Dyn-converting enzyme cleaved Dyn A (1-17) mainly at the Arg-Arg bond, resulting in the production of N- and C-terminal region peptide fragments, and that this enzyme was not inhibited by a mixture of the three peptidase inhibitors (PIs) amastatin (A), captopril (C), and phosphoramidon (P). The purpose of the present study was to evaluate antinociceptive potential and toxicity with intracerebroventricular administration of Dyn A (1-17) or (1-13) under pretreatment with a mixture of A, C, and P and/or Dyn-converting enzyme inhibitor ( p-hydroxymercuribenzoate). Methods: Peptide fragments from Dyn A (1-17) following incubation with membrane preparation under pretreatment with a mixture of the three PIs was identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS). Infusion of drugs and peptides into the third ventricle in rats was performed via indwelling cannulae. Induction of antinociception and toxicity by Dyn A (1-17), Dyn A (1-13), Dyn A (1-6), or Dyn A (7-17) were determined by the tail-flick test and induction of barrel rotation, respectively. The effects of the PIs on antinociception and toxicity were evaluated by a dose−response study and a comparison of differences among various combinations of Dyn A (1-17) or Dyn A (1-13) and the three PIs and p-hydroxymercuribenzoate. Results: MALDI-TOF-MS analysis identified Dyn A (1-6) and Dyn A (1-10) fragments as products following incubation of Dyn A (1-17) with membrane preparation of rat midbrain under pretreatment with a mixture of the three PIs. Pretreatment with a mixture of the three PIs produced an approximately 30-fold augmentation in antinociception induced by low-dose intracerebroventricular administration of Dyn A (1-17) or (1-13) in a μ-, δ- and κ-opioid receptor antagonist-reversible manner, but without signs of toxicity such as barrel rotation in the rat. Dyn A (1-17)-induced antinociception and toxicity was greater than that of Dyn A (1-6), Dyn A (1-13), or Dyn A (7-17) at the same dose. Dyn A (1-17)-induced antinociception and toxicity under pretreatment with various combinations of the three PIs and p-hydroxymercuribenzoate was greater than that with a mixture of the three PIs alone. Conclusion: These findings suggest that administration of a mixture of the three PIs increases Dyn A (1-17)- or (1-13)-induced antinociception under physiological conditions without toxicity. [ABSTRACT FROM AUTHOR]

We have investigated the IR photoluminescence (PL) behavior of Cu-doped β-FeSi2 nanocrystals (β-NCs) embedded in Si layers. The diffusion rate of Cu atom was controlled by annealing. The most appropriate condition brought the largest intensities of both the intrinsic A band emission at 0.803 eV by 214% and the acceptor related C band emission at ∼0.75 eV by 582% in comparison with those of non-doped β-NCs. Rutherford backscattering spectrometry (RBS) revealed increase of Cu atoms in the Si layer with β-NCs with increasing the anneal duration. The C band enhancement surely is originated from increase of a density of state at acceptor levels relating to increase of Cu in β-lattice. Photocarrier injection PL measurements (PCI-PL) reveal that the enhancement of the A band emission may be attributed to a controlled migration process of holes with a repeated trap process due to Cu-doping into the Si phase. This dynamic condition leads to an increase of valence band offset at the β-NCs/Si heterointerfaces where the migration of holes from the β-NCs to Si is prevented, so that a radiative recombination rate can be enhanced. (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Purpose: Previous in vitro studies have shown that degradation of opioid peptides during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), namely, amastatin, captopril, and phosphoramidon. In the present in vivo study, we evaluate the effects of intrathecal administration of these PIs on antinociception by [Met]enkephalin (ME) or PIs themselves. Methods: Drugs were administered into the thoracolumbar level of the spinal cord in the intrathecal space in rat. Induction of antinociception was measured by the tail immersion assay, with 55 °C as the nociceptive stimulus. Effects of PIs on antinociception were evaluated by dose-response study (ME, 1-20 nmol; PIs, 1-20 nmol each), by comparison of differences among two combinations of PIs (amastatin and captopril; captopril and phosphoramidon; amastatin and phosphoramidon) and three PIs (amastatin, captopril, and phosphoramidon), and by using opioid receptor selective antagonists. Results: Intrathecal administration of ME with these three PIs or PIs alone significantly and dose dependently increased antinociception in a μ- and δ-opioid receptor antagonist-reversible manner; moreover, the degree of antinociception with a combination of any two of these was less than that with all three, indicating that any residual single peptidase could inactivate significant amounts of ME. Conclusion: The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in inactivation of opioid peptides at the spinal level. [ABSTRACT FROM AUTHOR]

Cancer stem cells are thought to be closely related to tumor progression and recurrence, making them attractive therapeutic targets. Stem cells of various tissues exist within niches maintaining their stemness. Glioblastoma stem cells ( GSCs) are located at tumor capillaries and the perivascular niche, which are considered to have an important role in maintaining GSCs. There were some extracellular matrices ( ECM) on the perivascular connective tissue, including type 1 collagen. We here evaluated whether type 1 collagen has a potential niche for GSCs. Imunohistochemical staining of type 1 collagen and CD133, one of the GSCs markers, on glioblastoma ( GBM) tissues showed CD133-positive cells were located in immediate proximity to type 1 collagen around tumor vessels. We cultured human GBM cell lines, U87MG and GBM cells obtained from fresh surgical tissues, T472 and T555, with serum-containing medium ( SCM) or serum-free medium with some growth factors ( SFM) and in non-coated (Non-coat) or type 1 collagen-coated plates ( Col). The RNA expression levels of CD133 and Nestin as stem cell markers in each condition were examined. The Col condition not only with SFM but SCM made GBM cells more enhanced in RNA expression of CD133, compared to Non-coat/ SCM. Semi-quantitative measurement of CD133-positive cells by immunocytochemistry showed a statistically significant increase of CD133-positive cells in Col/ SFM. In addition, T472 cell line cultured in the Col/ SFM had capabilities of sphere formation and tumorigenesis. Type 1 collagen was found in the perivascular area and showed a possibility to maintain GSCs. These findings suggest that type 1 collagen could be one important niche component for CD133-positive GSCs and maintain GSCs in adherent culture. [ABSTRACT FROM AUTHOR]

Human skeletal muscle fiber is heterogenous due to its diversity of slow- and fast-twitch fibers. In human, slow-twitched fiber gene expression is correlated to MOTS-c, a mitochondria-derived peptide that has been characterized as an exercise mimetic. Within the MOTS-c open reading frame, there is an East Asian-specific m.1382A>C polymorphism (rs111033358) that changes the 14th amino acid of MOTS-c (i.e., K14Q), a variant of MOTS-c that has less biological activity. Here, we examined the influence of the m.1382A>C polymorphism causing MOTS-c K14Q on skeletal muscle fiber composition and physical performance. The myosin heavy chain (MHC) isoforms (MHC-I, MHC-IIa, and MHC-IIx) as an indicator of muscle fiber composition were assessed in 211 Japanese healthy individuals (102 men and 109 women). Muscular strength was measured in 86 physically active young Japanese men by using an isokinetic dynamometer. The allele frequency of the m.1382A>C polymorphism was assessed in 721 Japanese athletes and 873 ethnicity-matched controls. The m.1382A>C polymorphism genotype was analyzed by TaqMan SNP Genotyping Assay. Individuals with the C allele of the m.1382A>C exhibited a higher proportion of MHC-IIx, an index of fast-twitched fiber, than the A allele carriers. Men with the C allele of m.1382A>C exhibited significantly higher peak torques of leg flexion and extension. Furthermore, the C allele frequency was higher in the order of sprint/power athletes (6.5%), controls (5.1%), and endurance athletes (2.9%). Additionally, young male mice were injected with the MOTS-c neutralizing antibody once a week for four weeks to mimic the C allele of the m.1382A>C and assessed for protein expression levels of MHC-fast and MHC-slow. Mice injected with MOTS-c neutralizing antibody showed a higher expression of MHC-fast than the control mice. These results suggest that the C allele of the East Asian-specific m.1382A>C polymorphism leads to the MOTS-c K14Q contributes to the sprint/power performance through regulating skeletal muscle fiber composition. • There is an East Asian-specific m.1382A>C polymorphism in the mtDNA that changes the 14th amino acid of MOTS-c (i.e., K14Q). • C allele of the MOTS-c m.1382A>C showed a higher percentage of MHC-IIx and muscular strength than the A allele. • C allele frequency of the MOTS-c m.1382A>C polymorphism overrepresented in the sprint/power athletes. • MOTS-c neutralizing, mimicking C allele, showed lower and higher expression of MHC-slow and -fast than controls. [ABSTRACT FROM AUTHOR]

The chicken domestication process represents a typical model of artificial selection, and gives significant insight into the general understanding of the influence of artificial selection on recognizable phenotypes. Two Japanese domesticated chicken varieties, the fighting cock (Shamo) and the long-crowing chicken (Naganakidori), have been selectively bred for dramatically different phenotypes. The former has been selected exclusively for aggressiveness and the latter for long crowing with an obedient sitting posture. To understand the particular mechanism behind these genetic changes during domestication, we investigated the degree of genetic differentiation in the aforementioned chickens, focusing on dopamine receptor D2, D3, and D4 genes. We studied other ornamental chickens such as Chabo chickens as a reference for comparison. When genetic differentiation was measured by an index of nucleotide differentiation (NST) newly devised in this study, we found that the NST value of DRD4 for Shamo (0.072) was distinctively larger than those of the other genes among the three populations, suggesting that aggressiveness has been selected for in Shamo by collecting a variety of single nucleotide polymorphisms. In addition, we found that in DRD4 in Naganakidori, there is a deletion variant of one proline at the 24th residue in the repeat of nine prolines of exon 1. We thus conclude that artificial selection has operated on these different kinds of genetic variation in the DRD4 genes of Shamo and Naganakidori so strongly that the two domesticated varieties have differentiated to obtain their present opposite features in a relatively short period of time. [ABSTRACT FROM AUTHOR]

Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999–2001 at the age of 33–35 years. A follow-up was conducted 9 years later during 2008–2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions. [ABSTRACT FROM AUTHOR]

Temozolomide ( TMZ) is an oral alkylating agent which is widely used in the treatment of glioblastoma ( GBM) and is composed of astrocytic and/or oligodendroglial tumors, and the evaluation of O6-methylguanine DNA methyltransferase ( MGMT) expression is important to predict the response to TMZ therapy. In this study, we conducted immunohistochemical analysis of 117 cases of Japanese GBM including 19 cases of GBM with oligodendroglioma component ( GBMO), using a scoring system for quantitative evaluation of staining intensity and proportion of MGMT, and performed survival analysis of these patients. Immunohistochemically, 55 cases (47%) were positive for MGMT with various intensities and proportions (total score ( TS) ≥ 2), while 62 cases (53%) were negative ( TS = 0). The distribution of MGMT expression pattern was not affected by any clinicopathological parameters such as the histological subtype ( GBM vs. GBMO), age and gender. The survival analysis of these patients revealed that the minimal expression of MGMT ( TS ≥ 2) was a significant unfavorable prognostic factor ( P < 0.001) as well as resectability ( P = 0.004). Moreover, multivariate analysis showed that minimal MGMT expression in GBM was the most potent independent predictor for progression free survival ( P < 0.001) and also overall patient survival ( P < 0.001). This is the first report employing the scoring system for both staining intensity and proportion to evaluate immunohistochemical MGMT expression in GBM. In addition, our results emphases the clinicopathological values of the immunohistochemical approach for MGMT expression in glioma patients as a routine laboratory examination. [ABSTRACT FROM AUTHOR]

Objective: Pineal parenchymal tumors of intermediate differentiation (PPTID) are extremely rare tumor entities, and only limited data are available regarding their pathologic features and biologic behaviors. Because grading criteria of pineal parenchymal tumors (PPTs) have yet to be established, the treatment strategy and prognosis of PPTIDs remain controversial. We describe the clinicopathologic study of six patients with PPTID and compare responses for the treatment and prognosis with cases of pineocytoma (PC) and pineoblastoma (PB). From this analysis, we attempt to clarify the treatment strategy for PPTIDs. Methods: This study included 15 patients with PPTs, consisting of 6 PCs, 6 PPTIDs, and 3 PBs. We focused on the 6 patients with PPTIDs. All PPTID cases were treated surgically, and radiotherapy and chemotherapy were administered as adjuvant therapies in some cases. We have earlier reported the histopathologic study (Neuropathology 32:647-653, 2012). Briefly, we examined mitotic figures and necrosis by hematoxylin-eosin staining and immunohistochemical markers such as neuronal markers (synaptophysin, neurofilament (NF), and neuronal nuclear antigen), and an MIB-1 labeling index was determined. Results: In the PPTID cases, the extent of resection was variable and the recurrence rates among patients varied according to stage and treatment. All PC patients underwent total resection with no recurrence. All PB patients underwent resection and adjuvant therapy with radiotherapy and chemotherapy. There were no recurrences in patients with PC or PB. The results of histopathologic findings have been already reported as mentioned above. Briefly, the results indicated no mitotic figure or necrosis in any of the six cases of PPTID, but those features were observed in PB cases. All cases even including PC and PB were immunopositive for neuronal markers. The MIB-1 labeling index of PPTID was 3.5%, whereas it was 0% in PC and 10.5% in PB. Conclusions: Good radiosensitivity of PPTIDs was observed in our series. Because there are cases with discrepancies between images and pathologic findings, it is very difficult to determine the proper treatment strategy for PPTIDs. Proliferative potential was correlated with World Health Organization grade, although the immunoreactivity of neuronal markers did not correlate with the histologic grade. [Copyright &y& Elsevier]

Background/Aims: The assessment of myocardial fatty acid metabolism impairment by single-photon emission computed tomography (SPECT) using 123I-β-methyliodophenyl-pentadecanoic acid (BMIPP) might predict the risk of cardiac death in hemodialysis patients. We investigated the potential of oral nicorandil to improve myocardial fatty acid metabolism after percutaneous coronary intervention (PCI) in this population. Methods: We evaluated 128 hemodialysis patients who had obtained coronary revascularization by PCI (90 men and 38 women, 66 ± 9 years). Participants for the analysis were randomly assigned to either the nicorandil (n = 63) or control group (n = 65). BMIPP SPECT was performed every year after coronary revascularization by PCI. Uptake on SPECT was graded in 17 segments on a 5-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores (SS). Results: The incidence of cardiac death was lower (p = 0.004) in the nicorandil group (7/63, 11.1%) than in the control group (21/65, 32.3%) during a mean follow-up of 2.7 ± 1.4 years. BMIPP SS reduction rates improved in the nicorandil group compared with the control group from 3 years of administration. In Kaplan-Meier analyses, free survival rate of cardiac death was higher in patients with a ≥20% BMIPP SS reduction rate as compared with those with a <20% BMIPP SS reduction rate (p = 0.0001). In multiple logistic analysis, oral administration of nicorandil was associated with ≥20% reduction rates of BMIPP SS (odds ratio 2.823, p = 0.011). Conclusion: Long-term oral administration of nicorandil may improve impaired myocardial fatty acid metabolism after coronary revascularization by PCI in hemodialysis patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Protein ingestion after resistance exercise increases muscle protein synthesis (MPS) in a dose-dependent manner. However, the molecular mechanism(s) for the dose-dependency of MPS remains unclear. This study aimed to determine the dose response of mammalian target of rapamycin (mTOR) signaling in muscle with ingestion of protein after resistance exercise. Methods: Fifteen male subjects performed four sets of six unilateral isokinetic concentric knee extensions. Immediately after exercise, eight subjects consumed water only. The other seven subjects, in a randomized-order crossover design, took either a 10 [3.6 g essential amino acids (EAA)] or 20 g (7.1 g EAA) solution of whey protein. Muscle biopsies from the vastus lateralis muscle were taken 30 min before and 1 h after resistance exercise. Phosphorylation of Akt (Ser473), mTOR (Ser2448), 4E-BP1 (Thr37/46), and S6K1 (Thr389) was measured by western blotting. Results: Concentric knee extension exercise alone did not increase phosphorylation of Akt and mTOR 1 h after exercise, but ingesting protein after exercise significantly increased the phosphorylation of Akt and mTOR in a dose-dependent manner ( P < 0.05). 4E-BP1 phosphorylation significantly decreased after resistance exercise ( P < 0.05), but subjects who took 10 or 20 g of protein after exercise showed increased 4E-BP1 from post-exercise dephosphorylation ( P < 0.05). S6K1 phosphorylation significantly increased after resistance exercise ( P < 0.05), and 20 g of protein further increased S6K1 phosphorylation compared with ingestion of 10 g ( P < 0.05). Conclusions: These findings suggest that whey protein intake after resistance exercise activates mTOR signaling in a dose-dependent manner in untrained men. [ABSTRACT FROM AUTHOR]

Purpose: In a previous study using the tail-flick test, we found that intracerebroventricular administration of d-serine, an endogenous co-agonist at the glycine sites of N-methyl- d-aspartate (NMDA) receptors, elicited an antinociceptive effect on thermal nociception. The purpose of the present study was to evaluate the effect of intracerebroventricular administration of d-serine on nociception induced by tissue damage or inflammation using the formalin test. Methods: Infusion of drugs into the third ventricle in rat was performed via indwelling cannulae. Drugs were infused at a volume of 10 μl over 2 min, and the infusion cannula was left in place for 2 min before removal. The formalin test was performed 10 min after drug administration. Results: Intracerebroventricular administration of d-serine significantly and dose-dependently decreased the number of flinches in both the early and late phases in the formalin test. This antinociceptive effect was antagonized by intracerebroventricular administration of L-701,324, a selective antagonist at the glycine sites of NMDA receptors. Conclusion: The present data suggest that activation of NMDA receptors via glycine sites at the supraspinal level induces an antinociceptive effect on both acute and tonic pain. [ABSTRACT FROM AUTHOR]

To study the male and female lineages of East Asian and European humans, we have sequenced 25 short tandem repeat markers on 453 Y-chromosomes and collected sequences of 72 complete mitochondrial genomes to construct independent phylogenetic trees for male and female lineages. The results indicate that East Asian individuals fall into two clades, one that includes East Asian individuals only and a second that contains East Asian and European individuals. Surprisingly, the European individuals did not form an independent clade, but branched within in the East Asians. We then estimated the divergence time of the root of the European clade as ∼41,000 years ago. These data indicate that, contrary to traditional views, Europeans diverged from East Asians around that time. We also address the origin of the Ainu lineage in northern Japan. [ABSTRACT FROM AUTHOR]

Human muscle fiber composition is heterogeneous and mainly determined by genetic factors. A previous study reported that experimentally induced iron deficiency in rats increases the proportion of fast-twitch muscle fibers. Iron status has been reported to be affected by genetic factors. As the TMPRSS6 rs855791 T/C and HFE rs1799945 C/G polymorphisms are strongly associated with iron status in humans, we hypothesized that the genotype score (GS) based on these polymorphisms could be associated with the muscle fiber composition in humans. Herein, we examined 214 Japanese individuals, comprising of 107 men and 107 women, for possible associations of the GS for iron status with the proportion of myosin heavy chain (MHC) isoforms (I, IIa, and IIx) as markers of muscle fiber composition. No statistically significant correlations were found between the GS for iron status and the proportion of MHC isoforms in all participants. When the participants were stratified based on sex, women showed positive and negative correlations of the GS with MHC-IIa (age-adjusted p = 0.020) and MHC-IIx (age-adjusted p = 0.011), respectively. In contrast, no correlation was found in men. In women, a 1-point increase in the GS was associated with 2.42% higher MHC-IIa level and 2.72% lower MHC-IIx level. Our results suggest that the GS based on the TMPRSS6 rs855791 T/C and HFE rs1799945 C/G polymorphisms for iron status is associated with muscle fiber composition in women. [ABSTRACT FROM AUTHOR]

In the CNS, primary tumors with rhabdoid components are classified as atypical teratoid/rhabdoid tumor, rhabdoid meningioma or rhabdoid glioblastoma. The authors present a young adult patient with supratentorial rhabdoid tumor incidentally found after head trauma as a small pre-existing lesion in the parahippocampal gyrus. MRI demonstrated an area of hypointensity on T1-weighted images and hyperintensity on T2-weighted and fluid attenuated inversion recovery images. A serial MR scan revealed no change 3 months after the initial examination but drastic changes at 6 months. As the tumor and accompanying intratumoral hemorrhage enlarged rapidly, resection of the tumor was performed. Histopathology revealed that the main component of the tumor was typical rhabdoid cells with some necrotic areas. There were also pathological features consistent with oligoastrocytoma. The specimen had neither vascular proliferation usually seen in high-grade glioma nor the meningothelial pattern that suggests meningioma. Immunohistochemical findings revealed that cells were strongly positive for vimentin, epithelial membrane antigen and INI-1 antibody throughout the specimen. Further, monosomy 22 was detected by fluorescence in situ hybridization. The tumor was finally thought to be an unclassifiable primitive rhabdoid tumor with oligoastrocytoma that arose in the CNS. The patient died within 5 months of detection of the tumor, regardless of surgical resection, radiotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Osteoprotegerin (OPG), a regulator of bone resorption, is involved in the pathogenesis of rheumatoid arthritis (RA) and atherosclerosis. OPG is elevated in patients with coronary artery disease, and high OPG levels are associated with cardiac disease severity and mortality in the general population. The purpose of this study was to investigate the relationship of serum OPG levels, traditional coronary risk factors, and RA-related factors to carotid atherosclerosis in RA patients. Methods: Ninety-one RA patients were studied (85 % women, age 60 ± 10 years). Serum OPG levels were measured by an enzyme-linked immunosorbent assay. The prevalence of carotid plaque was assessed by ultrasonographic imaging in all patients. The relationship between various clinical characteristics, OPG, and carotid plaque was examined. Results: Serum OPG levels were significantly higher in patients with carotid plaque than in those without plaque (median level 1,397 vs. 887 pg/mL, respectively; P = 0.006). There were no significant differences between RA patients with and without carotid plaque with respect to sex, duration of RA, blood pressure, body mass index, smoking, low-density lipoprotein cholesterol, Disease Activity Score-28, van der Heijde-modified Sharp score, and prednisolone dose. After adjusting for age, sex, and C-reactive protein, elevated levels of OPG were still associated with a higher prevalence of carotid plaque in patients with RA ( P = 0.038). Conclusion: RA patients suffer from accelerated atherosclerosis and also have increased levels of OPG. The serum OPG level is independently associated with carotid plaque. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Dry axilla can sometimes be found among dehydrated older patients. In this study, we measured the axillary moisture and assessed it as possible marker for dehydration. Methods: Twenty-nine older patients admitted with acute medical conditions participated in this study. Dehydration was diagnosed by the calculated serum osmolality of greater than 295mOsm/L. The moisture of axilla was measured by a skin moisture impedance meter which was applied at the center of axilla of patients. Results: 11 patients (7 males and 4 females) were diagnosed as dehydrated and 18 patients (10 males and 8 females) were diagnosed as non-dehydrated. The mean axillary moisture (33%) in the dehydrated group was significantly lower than that (42%) in the non-dehydrated group (p<0.05). The axillary moisture≥50% showed the sensitivity of 88%. The axillary moisture<30% showed the specificity of 91%. Use of a single cutoff value of 40% moisture produced the sensitivity of 59% and the specificity of 9%. As for the physical signs, dry axilla had also moderate sensitivity and excellent specificity to detect dehydration. Conclusions: The measurement of the axillary moisture could help assess dehydration. Dehydration could be ruled out when the axillary moisture≥50%, while it could be ruled-in when the axillary moisture is <30%. [Copyright &y& Elsevier]

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone ( n = 55) or ACNU + PCZ ( n = 56) in the intention-to-treat population were 27.4 and 22.4 months ( p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone ( n = 40) or ACNU + PCZ ( n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Shakuyakukanzoto (SKT) composed of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix) has been traditionally used in Japan, Korea and China as an antispasmodic drug for the treatment of skeletal muscle cramps and intestinal cramps. Aim of this study: To evaluate the antispasmodic activity of SKT and its two components, as well as to identify the key constituents of the components which mediate this effect in skeletal muscles in vivo. Materials and methods: An experimental cramp model was constructed to evaluate the effects of peripherally-acting muscle relaxants on electrically-induced cramps under physiological conditions. This was accomplished by surgically isolating the motor supply to the gastrocnemius muscle in an anesthetized rat and delivering electrical stimuli to an isolated tibial nerve to induce tetanic contractions. We first tested dantrolene, a well-known peripherally-acting relaxant, to determine the sensitivity and reliability of our experimental model. We then evaluated the effects of SKT, P. radix, G. radix, and the eight active constituents of G. radix against tetanic contractions. Results: We found that dantrolene (10 and 30mg/kg, i.d.) rapidly and significantly inhibited tetanic contractions (P<0.01) irrespective of dose. SKT (0.5, 1.0, and 2.0g/kg, i.d.) and G. radix (0.5 and 1.0g/kg, i.d.) also significantly inhibited tetanic contractions (P<0.01) but in a dose-dependent manner owing to the actions of six of the eight active constituents in G. radix (liquiritin apioside, liquiritigenin, isoliquiritin apioside, isoliquiritigenin, glycycoumarin, and glycyrrhetinic acid, 20μmol/kg, i.v.). These constituents, which include flavonoids, a triterpenoid, and a courmarin derivative, demonstrated temporal variations in their inhibitory activity. In contrast, P. radix (0.5 and 1.0g/kg, i.d.) did not show a statistically significant antispasmodic effect in our study; however, we previously found that it had a significant antinociceptive effect. Conclusions: Our findings show that SKT inhibits tetanic contractions in vivo and that G. radix is the main antispasmodic component due to the actions of its active constituents, thus supporting the traditional use of SKT. We further propose that SKT containing the antispasmodic G. radix and antinociceptive P. radix is a pharmaceutically elegant option for muscle cramps as treatment requires a two-pronged approach, i.e., inhibition of hyperexcitable skeletal tissues and modulation of the pain accompanying cramps. [Copyright &y& Elsevier]

Perylenediimide (PDI) molecules are promising buildingblocks forphotophysical studies of electronic interactions within multichromophorearrays. Such PDI arrays are important materials for fabrication ofmolecular nanodevices such as organic light-emitting diodes, organicsemiconductors, and biosensors because of their high photostability,chemical and physical inertness, electron affinity, and high tinctorialstrength over the entire visible spectrum. In this work, PDIs havebeen organized into linear (L3) and trefoil (T3) trimer molecules and investigated by single-molecule fluorescencemicroscopy to probe the relationship between molecular structuresand interchromophoric electronic interactions. We found a broad distributionof coupling strengths in both L3and T3andhence strong/weak coupling between PDI units by monitoring spectralpeak shifts in single-molecule fluorescence spectra upon sequentialphotobleaching of each constituent chromophore. In addition, we useda wide-field defocused imaging technique to resolve heterogeneitiesin molecular structures of L3and T3embeddedin a PMMA polymer matrix. A systematic comparison between the twosets of experimental results allowed us to infer the correlation betweenintermolecular interactions and molecular structures. Our resultsshow control of the PDI intermolecular interactions using suitablemultichromophoric structures. [ABSTRACT FROM AUTHOR]

Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] were studied in in vivo and in vitro experiments. The exposure ratio of hydrolyzed metabolite (M2, primary metabolite in human plasma)/KW-7158 was higher than the ratio of thiophen-to-furan converted metabolite (M1)/KW-7158 in human subjects after oral administration, but the mouse, rat and dog studies gave opposite results. M2 was produced in the highest amount by the 9000g supernatant of small intestine, followed by that of liver and kidney in human subjects. After correction for protein contents, the results obtained suggested that the small intestine plays a major role in the metabolism to M2 for the first pass effect after oral administration of KW-7158. The formation of M2 was independent of the presence of NADPH and was inhibited by various esterase inhibitors. These observations suggested that the predominant enzymes or isozymes involved in the formation of M2 are esterases, which differ between humans and animals. Such differences may be one of the reasons for the species differences in the pharmacokinetics of KW-7158 between humans and animals. [ABSTRACT FROM AUTHOR]

The favorable prognosis of high-grade oligodendroglial tumor such as glioblastoma (GBM) with oligodendroglioma component (GBMO) has been suggested; however, the studies which examine the prognostic significance of oligodendroglial tumor were limited. In this study, we performed a histopathology-based reevaluation of 111 cases of high grade gliomas according to the latest World Health Organization (WHO), and compared the clinical outcomes between oligodendroglial tumors and pure astrocytic tumors. The survival analysis revealed that the patients with high grade oligodendroglial tumor including GBMO significantly indicated better prognosis compared to the patients with high grade pure astrocytic tumors (GBM and AA, anaplastic astrocytoma) as expected, and the obtained survival curves were almost identical to those from the patients with conventional Grade III or Grade IV tumors, respectively. Moreover, if the cases of oligodendroglial tumor were histopathologically excluded, the patients with AA exhibited extremely poor prognosis which was similar to that of GBM, suggesting that the histological identification of oligodendroglial tumor component, even partially, prescribe the prognosis of high grade glioma patients. This is the prominent report of retrospective clinicopathological analysis for high-grade gliomas throughout Grade III and IV, especially referring to the prognostic value of histological oligodendroglial tumor component; in addition, our results might offer an alternative aspect for the grading of high-grade astrocytic/oligodendroglial tumors. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas. Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that F fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO positron emission tomography (PET) for the differential diagnosis of GBM from lower grade gliomas. Methods: This prospective study included 23 patients with pathologically confirmed gliomas. All of the patients underwent FMISO PET and F-fluorodeoxyglucose (FDG) PET within a week. FMISO images were acquired 4 h after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion to normal tissue ratios and FMISO uptake volume were calculated. Results: Of the 23 glioma patients, 14 were diagnosed as having GBM (grade IV glioma in the 2007 WHO classification), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues ( p ≤ 0.001). One GBM patient was excluded from FDG PET study because of hyperglycemia. All GBM patients and three of the nine (33%) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 and 100% for FMISO, and 100 and 66% for FDG, respectively. The lesion to cerebellum ratio of FMISO uptake was higher in GBM patients (2.74 ± 0.60, range 1.71-3.81) than in non-GBM patients (1.22 ± 0.06, range 1.09-1.29, p ≤ 0.001) with no overlap between the groups. The lesion to gray matter ratio of FDG was also higher in GBM patients (1.46 ± 0.75, range 0.91-3.79) than in non-GBM patients (1.07 ± 0.62, range 0.66-2.95, p ≤ 0.05); however, overlap of the ranges did not allow clear differentiation between GBM and non-GBM. The uptake volume of FMISO was larger in GBM (27.18 ± 10.46%, range 14.02-46.67%) than in non-GBM (6.07 ± 2.50%, range 2.12-9.22%, p ≤ 0.001). Conclusion: These preliminary data suggest that FMISO PET may distinguish GBM from lower grade gliomas. [ABSTRACT FROM AUTHOR]