Search

Recently, π-π stacked antiaromatic π-systems have received considerable attention because they can exhibit stacked-ring aromaticity due to substantial intermolecular orbital interactions. Here, we report three antiaromatic norcorrole dimers that self-assemble to form supramolecular architectures through chiral self-sorting. A 2,2'-linked norcorrole dimer with 3,5-di-tert-butylphenyl groups forms a π-stacked dimer both in solid and solution states via homochiral self-sorting. Its association constant in solution is (3.6±1.7)×10 5  M -1 at 20 °C. In the solid state, 3,3'-linked norcorrole dimers with 3,5-di-tert-butylphenyl and phenyl groups afford macrocyclic and helical supramolecular assemblies via heterochiral and homochiral self-sorting, respectively. Notably, the subtle modification in the substituent resulted in a complete change in the structure of the aggregates and the chiral self-sorting mode. The present findings demonstrate that structural manipulation in antiaromatic monomer units leads to the formation of various supramolecular assemblies on the basis of the attractive interactions between antiaromatic π-systems., (© 2024 Wiley-VCH GmbH.)

Objectives: The effectiveness and safety of propofol-based sedation and midazolam sedation in pediatric bidirectional endoscopy were compared., Methods: We retrospectively analyzed the cases of pediatric patients (≤15 years old) who had undergone bidirectional endoscopy, esophagogastroduodenoscopy, and colonoscopy by pediatric gastroenterologists. Demographic data, indications, sedatives/dosages, clinical outcomes, endoscopic findings, adverse events, and total patient time requirements (total time in which patients stay in our hospital) were compared in the two sedation groups., Results: Ninety-one children (51 boys, 40 girls, mean age 13 years, range 9-15) treated at our hospital were enrolled. Propofol alone or in combination with midazolam and/or pentazocine was administered to 51 patients (propofol-based sedation group). Midazolam alone or in combination with pentazocine was administered to the other 40 patients (midazolam sedation group). In the propofol group, the following mean doses were used: propofol, 96 mg (range 40-145 mg); midazolam, 4.9 mg (range 3-5 mg); and pentazocine, 7.5 mg. In the midazolam group, the mean doses of midazolam and pentazocine were 6.2 mg (range 4-10 mg) and 15 mg, respectively. All procedures were successfully completed by pediatric gastroenterologists. The total procedure times and endoscopic findings were similar in the two groups, but the median patient time requirement in the propofol group was significantly shorter versus the midazolam group (7.3 h vs. 8.4 h, p < 0.001). No adverse events occurred in either group., Conclusions: Propofol-based sedation in pediatric bidirectional endoscopy was safely and effectively performed by pediatric gastroenterologists, and its patient time requirement was shorter than that for midazolam sedation., Competing Interests: None., (© 2024 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Nuclear magnetic resonance (NMR) shielding constants have been calculated for Ni(II) bis(pentafluorophenyl)norcorrole and its face-to-face stacked dimer at the Hartree-Fock (HF), second-order Møller-Plesset perturbation theory (MP2), complete-active-space self-consistent-field (CASSCF) levels as well as at density functional theory (DFT) levels using several functionals. The calculated 1 H NMR shielding constants agree rather well with the experimental ones. The shielding constants of N and Ni calculated at DFT, HF, and MP2 levels differ from those obtained in the CASSCF calculations due to near-degeneracy effects at the Ni atom. The calculated magnetically induced current densities show that the monomer is antiaromatic, sustaining a strong global paratropic ring current, and the dimer is aromatic, sustaining a strong diatropic ring current. Qualitatively the same current density is obtained at the employed levels of theory. The most accurate ring-current strengths are probably obtained at the MP2 level. The aromatic dimer has a short intermolecular distance of less than 3 Å. The intermolecular interaction changes the nature of the frontier orbitals leading to a formal double bond between the norcorrole macrocycles.

A π-conjugated molecule with one electronic spin often forms a π-stacked dimer through molecular orbital interactions between two unpaired electrons. The bonding is recognized as a multicentered two-electron interaction between the two π-conjugated molecules. Here, we disclose a multicentered bonding interaction between two antiaromatic molecules involving four electrons. We have synthesized an antiaromatic porphyrin analogue, Ni(II) bis(pentafluorophenyl)norcorrole. Its dimer adopts a face-to-face stacked structure with an extremely short stacking distance of 2.97 Å. The close stacking originates from a multicenter four-electron bonding interaction between the two molecules. The bonding electrons were experimentally observed via synchrotron X-ray diffraction analysis and corroborated by theoretical calculations. The intermolecular interaction of the molecular orbitals imparts the stacked dimer with aromatic character that is distinctly different from that of its monomer.

Brain functional connectivity in the resting-state represents intrinsic functional states and correlates with cognitive performance. In patients with schizophrenia, reports on the relationships between forms of functional disconnectivity in local areas and cognitive disability have used resting-state functional magnetic resonance imaging data. Meanwhile, cognitive deficits in relation to inter-network forms of functional connectivity on a large scale are not well understood. This study examines cognitive functions in relation to the number of resting-state inter-network forms of functional connectivity focusing on task-positive networks (fronto-parietal network [FPN] and cingulo-opercular network [CON]) and task-negative network (default mode network [DMN]). We compare patients with schizophrenia (SCH group) and healthy controls (HC group). We conducted a functional network analysis by applying graph theory and evaluated cognitive functions using the Brief Assessment of Cognition in Schizophrenia . The number of forms of functional connectivity between FPN and DMN and between CON and DMN were significantly higher in SCH group than in HC group, and those in SCH group were also weakly correlated with their attention scores. It is suggested that fewer than typical functional segregations between task-positive and task-negative networks in SCH group relate to inefficient distribution of cognitive resources and low attentional abilities.

Stress has been shown to affect brain activity and exert potent and complex modulatory effects on pain. Several behavioral tests have shown that acute stress produces hyperalgesia, depending on the stress conditions. In the present study, we investigated the effects of single restraint stress on the tactile threshold and anxiety sensitivity in mice. Mice were evaluated for the tactile threshold using von Frey filaments and for anxiety sensitivity using the elevated plus maze (EPM) test. Tactile thresholds were lowered by both 2 and 4 hour of restraint stress, but anxiety-like behaviors were observed only after 4 hour of restraint stress in the EPM test. In addition, we found that alfaxalone, which is a positive allosteric modulator of the γ-aminobutyric acid (GABA) A receptor, prevented restraint stress-induced hyperalgesia-like and anxiety-like behaviors. These results indicate that GABAergic function appears to be critical in the regulation of physical stress-induced hyperalgesia and anxiety., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

The utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum-based chemotherapy has been established for cancers from different histologies. However, the therapeutic relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum-based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum-based chemotherapy, the SLFN11-positive group (n = 25) showed significantly better overall survival than the SLFN11-negative group (n = 25, P = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11-0.91; P = .033). Conversely, in the cohort of 70 BC cases not receiving platinum-based chemotherapy, the SLFN11-positive group (n = 29) showed significantly worse overall survival than the SLFN11-negative group (n = 41, P = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5-azacytidine and entinostat restored SLFN11 expression and resensitized cells to cisplatin and carboplatin in SLFN11-negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum-based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

For the creation of next-generation organic electronic materials, the integration of π-systems has recently become a central theme. Such functional materials can be assembled by supramolecular polymerization when aromatic π-systems are used as monomers, and the properties of the resulting supramolecular polymer strongly depend on the electronic structure of the monomers. Here, we demonstrate the construction of a supramolecular polymer consisting of an antiaromatic π-system as the monomer. An amide-functionalized Ni II norcorrole derivative formed a one-dimensional supramolecular polymer through π-π stacking and hydrogen-bonding interactions, ensuring the persistency of the conducting pathway against thermal perturbation, which results in higher charge mobility along the tightly bound linear aggregates than that of the aromatic analogue composed of Zn II porphyrins., (© 2021 Wiley-VCH GmbH.)

Background: The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish., Methods: In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments., Results: We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth., Conclusions: Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Three-dimensional aromaticity arising from the close stacking of two antiaromatic π-conjugated macrocycles has recently received considerable attention. Here, a cyclophane consisting of two antiaromatic Ni(II) norcorrole units tethered with two flexible alkyl chains was synthesized. The norcorrole cyclophane showed crystal polymorphism providing three different solid-state structures. Surprisingly, one of them adopted an aligned face-to-face stacking arrangement with negligible displacement along the slipping axis. Although the exchange repulsion between two π-clouds should be maximized in this orientation, the π-π distance is remarkably close (3.258 Å). Three-dimensional aromaticity in this conformation has been supported experimentally and theoretically as evidenced by small bond length alternations as well as the presence of a diatropic ring current. An analogous cyclophane with two aromatic Ni(II) porphyrin units was prepared for comparison. The porphyrin cyclophane exhibited a slipped-stacking conformation with a larger displacement (2.9 Å) and a larger interplanar distance (3.402 Å) without noticeable change of the aromaticity of each porphyrin unit. In solution, the norcorrole cyclophane forms a twist stacking arrangement with effective interplanar orbital overlap and exists in an equilibrium between stacked and nonstacked structures. Thermodynamic parameters of the stacking process were estimated, revealing an inherently large attractive interaction operating between two norcorrole units, which has been further supported by energy decomposition analysis.

Background: Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC., Methods: We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids., Results: GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs., Conclusions: This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.

DNA-damaging agents include first-line drugs such as platinum (cisplatin, carboplatin), topoisomerase inhibitors (etoposide, doxorubicin), and replication inhibitors (cytarabine, gemcitabine). Despite their wide and long usage, there is no clinically available biomarker to predict responses to these drugs. Schlafen 11 (SLFN11), a putative DNA/RNA helicase, recently emerged as a dominant determinant of sensitivity to these drugs by enforcing the replication block in response to DNA damage. Since the clinical importance of SLFN11 is implicated, a comprehensive analysis of SLFN11 expression across human organs will provide a practical resource to develop the utility of SLFN11 in the clinic. In this study, we established a scoring system of SLFN11 expression by immunohistochemistry (IHC) and assessed SLFN11 expression in ~ 700 malignant as well as the adjacent non-tumor tissues across 16 major human adult organs. We found that the SLFN11 expression is tissue specific and varies during tumorigenesis. Although The Cancer Genome Atlas (TCGA) is a prevailing tool to assess gene expression in various malignant and normal tissues, our IHC data exhibited obvious discrepancy from the TCGA data in several organs. Importantly, SLFN11-negative tumors, potentially non-responders to DNA-damaging agents, were largely overrated in TCGA because TCGA samples are a mixture of infiltrating immune cells, including T cells, B cells, and macrophages, which have strong SLFN11 expression. Thus, our study reveals the significance of immunohistochemical procedures for evaluating expression of SLFN11 in patient samples and provides a robust resource of SLFN11 expression across adult human organs.

Extracellular high-mobility group box 1 (HMGB1) is known to mediate the inflammatory response through pattern recognition receptors, including the receptor for advanced glycation end products (RAGE) or the toll-like receptors (TLRs). The aim of the present study was to investigate whether papaverine, a novel RAGE inhibitor, could suppress inflammatory pain in mice after several time points, which was induced by the injection of complete Freund's adjuvant (CFA). We also investigated the influence of redox modulation during a state of chronic inflammatory pain. Although papaverine did not suppress CFA-induced mechanical allodynia on Day 7, papaverine significantly suppressed CFA-induced mechanical allodynia on Days 14 and 28. In contrast, the radical scavenger N-tert-Butyl-α-phenylnitrone (PBN) suppressed mechanical allodynia in mice on Days 7 and 14, but not on Day 28. We demonstrated that the RAGE inhibitor improves mechanical allodynia in chronic inflammatory conditions. Moreover, we also found that high levels of reactive oxygen species (ROS) contributed to the early phase of CFA-induced mechanical allodynia. Precisely, lower ROS levels contributed to the inflammatory pain response via the all-thiol HMGB1/RAGE signaling pathway during the chronic state. These findings led us to propose that ROS levels modulate RAGE and/or TLR4-mediated inflammatory allodynia by regulating the concentrations of disulfide HMGB1 or all-thiol HMGB1., (© 2020 Wiley Periodicals LLC.)

5-Fluorouracil (5-FU) is one of the most frequently used pharmacological agents in the treatment of colorectal cancer (CRC). Resistance to chemotherapy is a major cause of treatment failure of CRC, and it is a well known fact that cancer stem cells play a significant role in the acquisition of drug resistance. In this study, we focused on the KHDRBS3 gene that encodes KH RNA Binding Domain Containing, Signal Transduction Associated 3. We first clarified the relationship between KHDRBS3 and 5-FU resistance. We then observed higher expression levels of KHDRBS3 in KRAS-mutant organoids and cell lines in comparison with KRAS wild-type organoids and cell lines. Immunohistochemical analysis using CRC cases revealed that the prognosis of KHDRBS3-positive patients was significantly worse compared with that of KHDRBS3-negative patients. Univariate and multivariate Cox proportional hazards analyses showed that KHDRBS3 was an independent prognostic factor in patients with CRC. We determined that KHDRBS3 might play a crucial role in the acquisition of stem cell properties, such as drug resistance and spheroid/organoid formation, by regulating CD44 variant expression and the Wnt signaling pathway. In an immunodeficient mouse model, KHDRBS3-positive cells showed efficient tumor formation and formed metastatic lesions in the lungs. These results indicated that KHDRBS3 plays a crucial role in drug resistance and anchorage-independent growth by maintaining stem cell-like features in CRC cells. KHDRBS3 could be a promising candidate marker for predicting chemotherapeutic effect and prognosis in CRC patients., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Tacrolimus (TAC) is essential for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HSCT). We have sometimes observed large fluctuations in TAC concentration. However, links between the variability in the concentration or the concentration/dose (C/D) ratio of TAC and clinical complications remain ambiguous. To clarify relationships between various parameters of TAC and early complications such as pre-engraftment immune reactions/engraftment syndrome, aGVHD, and transplant-associated thrombotic microangiopathy (TA-TMA), a total of 146 patients who underwent allo-HSCT were included. Intrapatient variabilities in the concentration and C/D ratio of TAC were estimated by intrapatient mean absolute deviation (iMAD). The mean concentration and C/D ratio of TAC were not significantly different between with and without complications. A strong association was observed between greater iMAD for TAC C/D ratio from days 15 to 21 and the development of TA-TMA. iMAD values for TAC C/D ratio of 11.4 or greater was a risk factor for TA-TMA and the cumulative incidence of nonrelapse mortality (NRM) was significantly higher in patients with iMAD values for TAC C/D ratio of 11.4 or greater. Intrapatient variability in the C/D ratio of TAC was associated with the incidence of TA-TMA and NRM and might be useful for predicting TA-TMA.

Acute myeloid leukemia (AML) associated with double-minute chromosomes (dmin) is a rare condition and has a poor prognosis. A 68-year-old man with leukocytosis and thrombocytopenia was admitted to our hospital. Bone marrow aspiration showed that 79.5% of myeloblasts were positive for myeloperoxidase. The patient was diagnosed with acute myeloid leukemia (French-American-British classification: M2, World Health Organization classification: AML, not otherwise specified, AML with maturation). Chromosomal analysis revealed the presence of dmin: 45, X, -Y, 5-33 dmin. Fluorescence in situ hybridization revealed multiple MYC signals, and spectral karyotyping showed that dmin was derived from chromosome 8. These findings indicated resistance to chemotherapy alone. After the standard induction therapy with daunorubicin and cytarabine, the number of myeloblasts in the bone marrow decreased, and the amplified MYC signals disappeared. Then, the patient achieved complete remission. Reportedly, most patients with AML correlated with dmin have a complex karyotype, except for this case. Owing to the absence of a complex karyotype, the patient had good sensitivity to chemotherapy. Further studies with a larger population of patients with AML associated with dmin, but without complex karyotypes, should be conducted to accurately predict prognosis in such cases.

5-FU is one of the key drugs in the treatment of gastric cancer (GC). Much evidence has shown that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance. The organoid is a novel 3D cell culture system technology that sustains stem-cell-driven formation of near-physiological, self-renewing tissues using specific niche factors in a dish. In this study, we established GC organoids (GCOs) and gradually treated them with higher concentrations of 5-FU. We successfully harvested four 5-FU-resistant GCOs, which were supported by significant changes in the expression of molecules related to 5-FU metabolism. We then performed microarray analysis using three normal gastric organoids and three pairs of 5-FU-resistant and parental GCOs. Through the comparison of expression profiles and further validation, we chose KHDRBS3 as a target gene. We found KHDRBS3 to be an independent prognostic factor in GC patients, especially in GC patients treated with 5-FU chemotherapy. We also determined that KHDRBS3 might play an important role in the acquisition of stem cell-like features, such as multi-drug resistance and organoid formation, by regulating CD44 variant expression. We found KHDRBS3, which is thought to play an important role in the acquisition of characteristics of CSCs in GC, to be a promising candidate marker for predicting therapeutic effect and prognosis in GC patients.

One major cause of treatment-related death is transplant-associated thrombotic microangiopathy (TA-TMA). Because of difficulties with diagnosis, many criteria for TA-TMA have been defined. Some patients clinically suspected as TA-TMA have been treated as TA-TMA regardless of TA-TMA criteria fulfillment (clinical-TMA). To examine sensitivities of TA-TMA criteria for clinical-TMA, we retrospectively evaluated 160 patients undergoing allogeneic hematopoietic stem cell transplantation by five major TA-TMA criteria and compared them with clinical-TMA. Cumulative incidences of TA-TMA and non-relapse mortality (NRM) were widely diverse between criteria. Thirty-eight patients fulfilled one or more TA-TMA criteria (total-TMA), and 12 of them fulfilled only one criterion. In patients with total-TMA, thrombocythemia, serum creatinine > 1.5 × baseline, and proteinuria were especially repeatedly observed among TA-TMA criteria. Ninety-two percent of clinical-TMA patients were classified as patients with total-TMA, and high NRM incidences were exhibited in patients with total-TMA even without clinical-TMA. Hematopoietic cell transplant-comorbidity index ≥ 3, nutritional risk index < 83.5, and grade II-IV acute graft-versus-host disease were extracted as independent risk factors for total-TMA. TA-TMA summation criteria that can cover most of clinical-TMA patients and high-risk patients of NRM were useful in clinical settings, and items of TA-TMA criteria previously described might be triggers for applying TA-TMA criteria.

meso-Dimethylnorcorrole NiII complex exhibited enough stability under ambient conditions despite the distinct antiaromaticity. The small methyl substituents realized a dense and long-range π-stacking in its solid state, which resulted in the superior electron-transporting ability to previously reported NiII norcorroles.

Background: The transcribed ultraconserved regions (T-UCRs) are a novel class of long non-coding RNAs and are involved in the development of several types of cancer. Although several different papers have described the oncogenic role of Uc.63+, there are no reports mentioning its importance in gastric cancer (GC) biology., Methods: In this study, we evaluated Uc.63+ expression using clinical samples of GC by qRT-PCR, and also assessed the correlation between Uc.63+ expression and clinico-pathological factors., Results: The upregulation of Uc.63+ was significantly correlated with advanced clinico-pathological features. Knockdown of Uc.63+ significantly repressed GC cell growth and migration, whereas overexpression of Uc.63+ conversely promoted those of GC cells. In situ hybridization of Uc.63+ revealed its preferential expression in poorly differentiated adenocarcinoma. We further conducted a microarray analysis using MKN-1 cells overexpressing Uc.63- and found that NF-κB signaling was significantly upregulated in accordance with Uc.63+ expression., Conclusion: Our results suggest that Uc.63+ could be involved in GC progression by regulating GC cell growth and migration via NF-κB signaling.

Objectives: Subjective tinnitus loudness has been measured using loudness matches, which compare tinnitus loudness with pure tones from an audiometer. When patients compare the sound pressure of certain noises with the tinnitus loudness, however, there may be remarkable differences from the measurements according to loudness matches. Subjective loudness (SubL) is an estimation of the sound pressure of tinnitus loudness by comparison of noises considered to be most similar to tinnitus loudness of patient. We examine whether SubL is inferior to loudness matches in measurement of subjective tinnitus loudness., Design: Single-group cross-sectional study., Patients: Included in this study were a clinical group of 111 patients with the chief complaint of subjective tinnitus. Seven of the 111 patients were excluded due to missing audiometry or questionnaire data., Methods: Patients assessed the tinnitus loudness and related distress using visual analogue scales (VAS-L and VAS-S) and answered the Tinnitus Handicap Inventory (THI). Hearing acuity, tinnitus pitch, and loudness were then measured using an audiometer., Results: VAS-L, VAS-S, and THI scores significantly correlated with loudness match using Goodwin's method (SL2) and SubL. Subgroup analysis based on patient ages indicated that all correlations of SL2 with VAS-L, VAS-S, and THI scores were no longer seen in patients more than 60 years of age. Meanwhile, SubL correlated with VAS-L, VAS-S, and THI scores in all subgroups., Conclusions: SubL was a good reflection of self-reported loudness and distress of tinnitus. It may therefore be a simple and easy means of assessing tinnitus loudness and associated distress during pre-examination without an audiometer.

Background/aim: This study aimed to determine the anxiolytic effect of a putative glyoxalase 1 inhibitor, piceatannol, as well as its antitumor activities on the stress-induced tumor growth of Lewis lung carcinoma., Materials and Methods: The anxiolytic activities of piceatannol (1-30 mg/kg) were assessed using the elevated plus maze (EPM) test. We also evaluated the pharmacological modulation of stress-induced tumor growth; the mice were treated with piceatannol (3 and 30 mg/kg) from the 10 th day till the 19 th day after administration of the LLC cells., Results: At the low dose (3 mg/kg), piceatannol significantly increased the time spent in the open arms of the EPM test when compared with the vehicle. At higher doses (30 mg/kg), it significantly suppressed the stress-induced enhancement of tumor growth., Conclusion: A low dose of piceatannol exerts an anxiolytic effect, and high doses have an antitumor effect., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Permanent impairment (PI) of vital organs is one of the transplantation-related health problems affecting the quality of life and morbidity even in patients who do not develop graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT), but no data are available on PI of multiple organs. This retrospective study aimed to estimate a novel composite endpoint of PI-free, relapse-free survival (PIRFS) in 164 allo-HCT recipients. We defined PI as >26% to 30% impairment of the whole person in 6 vital organs using the whole person impairment rating. Conventional GVHD-free/relapse-free survival (GRFS) and PIRFS at 5 years were 33.8% (95% confidence interval [CI], 26.5% to 41.3%) and 40.6% (95% CI, 32.6% to 48.4%), respectively. In the whole cohort, PIRFS was higher than GRFS at any time after allo-HCT. However, PIRFS was lower than GRFS after day 397 post-transplantation in patients who underwent umbilical cord blood transplantation (UCBT). In UCBT recipients, 5-year GRFS and PIRFS were 47.6% (95% CI, 34.3% to 59.7%) and 39.2% (95% CI, 26.6% to 51.5%), respectively. The cumulative incidence of PI after 5 years was 20.9% (95% CI, 13.7% to 29.0%) in patients surviving for ≥6 months without relapse. The multivariate analysis revealed that high disease risk (hazard ratio [HR], 1.91; 95% CI, 1.26 to 2.88; P < .01) and Karnofsky Performance Status score ≤90% at transplantation (HR, 1.73; 95% CI, 1.14 to 2.63; P = .01) were correlated with the lower PIRFS, whereas UCBT (HR, 2.35; 95% CI, 1.11 to 4.99; P = .03), grade III-IV acute GVHD by day 180 (HR, 3.59; 95% CI, 1.04 to 12.4; P = .04), and thrombotic microangiopathy by day 180 (HR, 2.74; 95% CI, 1.10 to 6.87; P = .03) were significantly correlated with a higher incidence of PI. More than 20% of long-term survivors had PI. Our data suggest that PIRFS is a useful endpoint for assessing long-term transplantation success from a different perspective than has been established previously., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest Shinichi Yamada, Shun Takahashi, Yuji Ohoshi, Takuya Ishida, Tomikimi Tsuji, Kazuhiro Shinosaki, Masaki Terada, Satoshi Ukai declare that there are no conflicts of interest related to the study.

Aim: This is a cross-sectional study of relation between metabolic syndrome and cognitive function in community-dwelling non-demented older adults in Japan. We examine the effect of metabolic syndrome and its components on global cognitive function. We also aim to clarify differences of specific cognitive domains between the subjects with and without metabolic syndrome., Methods: We studied 2150 subjects aged between 60 and 90 years whose scores on mini mental state examination (MMSE) were over 23 points. We analyzed difference in MMSE scores between the subjects with and without metabolic syndrome. Logistic regression analysis was performed with MMSE score as the dependent variable and metabolic syndrome components as the independent variable adjusted with age. We also examined differences in attention, logical memory, and verbal and category fluency between the subjects with and without metabolic syndrome., Results: MMSE scores were not significantly different between subjects with and without metabolic syndrome. In logistic regression analysis, the score of MMSE was significantly negatively associated with triglycerides in males and significantly negatively associated with abdominal circumference in females. Subjects with metabolic syndrome showed significantly lower performance of attention tasks compared to subjects without metabolic syndrome., Conclusions: Our results suggest that in community-dwelling non-demented Japanese older adults, attention but not global cognitive function may be impaired by metabolic syndrome. Inverted association between some components of metabolic syndrome and global cognitive function indicate necessity of further studies on the relation between undernutrition and cognitive function., Competing Interests: The authors declare no conflicts of interest.

Nutritional status is an important component of cancer care, and malnutrition itself can cause death in 10% to 20% of cancer patients. A nutritional risk index (NRI) is a useful tool for nutritional assessment of cancer patients. This study aimed to evaluate the impact of pretransplant NRI values on outcomes of allogeneic hematopoietic cell transplantation (allo-HSCT). One hundred sixty patients who underwent allo-HSCT between January 2008 and July 2017 at Konan Kosei Hospital were included in this single-center, retrospective analysis. NRI was calculated at the beginning of the conditioning regimen. The patients were divided into high NRI (NRI ≥ 97.5) and low NRI (NRI < 97.5) groups, and overall survival (OS), nonrelapse mortality (NRM), and cumulative incidences of acute and chronic graft-versus-host disease (GVHD) were evaluated. Two-year OS rates were 76% (95% confidence interval [CI], 63% to 83%) and 50.4% (95% CI, 38% to 62%) in the high NRI and low NRI groups, respectively (P < .001). One-year cumulative incidences of NRM were 7.9% (95% CI, 3.5% to 15%) and 23% (95% CI, 14% to 33%; P = .014) and 2-year cumulative relapse rates were 17% (95% CI, 10% to 26%) and 32% (95% CI, 21% to 43%; P = .10) in the high NRI and low NRI groups, respectively. The multivariate analysis indicated low NRI was a significant risk factor for OS and NRM. Conversely, high NRI was associated with increased incidences of grades II to IV acute GVHD and chronic GVHD. Additionally, the subgroup analysis according to stem cell source revealed a significant benefit of higher NRI on survival only in umbilical cord blood recipients. Overall, these results suggest that pretransplant NRI might predict OS and NRM after allo-HSCT., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

As one candidate alloy for future Generation IV and fusion reactors, a dual-phase 12Cr oxide-dispersion-strengthened (ODS) alloy was developed for high temperature strength and creep resistance and has shown good void swelling resistance under high damage self-ion irradiation at high temperature. However, the effect of helium and its combination with radiation damage on oxide dispersoid stability needs to be investigated. In this study, 120 keV energy helium was preloaded into specimens at doses of 1 × 10 15 and 1 × 10 16 ions/cm 2 at room temperature, and 3.5 MeV Fe self-ions were sequentially implanted to reach 100 peak displacement-per-atom at 475 °C. He implantation alone in the control sample did not affect the dispersoid morphology. After Fe ion irradiation, a dramatic increase in density of coherent oxide dispersoids was observed at low He dose, but no such increase was observed at high He dose. The study suggests that helium bubbles act as sinks for nucleation of coherent oxide dispersoids, but dispersoid growth may become difficult if too many sinks are introduced, suggesting that a critical mass of trapping is required for stable dispersoid growth.

Objective: Controlling hyperactive and mixed delirium is extremely important for the continuation of cancer treatment in palliative care. In general, oral antipsychotics are the first-line drug therapy for delirium; however, oral administration is problematic in patients presenting dysphagia. In this case report, we describe an end-stage cancer patient with aphagia who developed delirium and responded to sublingual antipsychotic asenapine for treating delirium. We also discuss the effectiveness of asenapine in hyperactive delirium as well as its usefulness for treating delirium in palliative care., Method: A cancer patient with delirium was treated with several oral antipsychotics commonly used to treat delirium but did not respond to any of them. The patient subsequently developed aphagia with progression of the disease. Sublingual asenapine was therefore given to treat delirium., Result: Asenapine was effective in treating delirium without causing any obvious side effects., Significance of Results: In the present case, asenapine was effective in treating hyperactive delirium that did not respond to commonly used antipsychotics. Because asenapine is a sublingual tablet, it can be used in patients with dysphagia and aphagia. In addition, this drug is anticipated to diminish the burden of end-stage patients from taking oral medications. Furthermore, its management is easier compared with injections, and can therefore also be easily used in homecare patients. Based on these perspectives, asenapine may become an important option for treating delirium in palliative care.

Introduction: The corpus callosum serves the essential role of relaying cognitive information between the homologous regions in the left and the right hemispheres of the brain. Cognitive impairment is a core dysfunction of schizophrenia, but much of its pathophysiology is unknown. The aim of this study was to elucidate the association between microstructural abnormalities of the corpus callosum and cognitive dysfunction in schizophrenia., Methods: We examined stepwise multiple regression analysis to investigate the relationship of the fractional anisotropy (FA) of callosal fibers in each segment with z-scores of each brief assessment of cognition in schizophrenia subtest and cognitive composite score in all subjects (19 patients with schizophrenia [SZ group] and 19 healthy controls [HC group]). Callosal fibers were separated into seven segments based on their cortical projection using tract-specific analysis of diffusion tensor imaging., Results: The FA of callosal fibers in the temporal segment was significantly associated with z-scores of token motor test, Tower of London test, and the composite score. In the SZ group, the FA of callosal fibers in the temporal segment was significantly associated with the z-score of the Tower of London test. In addition, the FA of callosal fibers in temporal segment showed significant negative association with the positive and negative syndrome scale negative score in the SZ group. Compared to the HC group, the FA in temporal segment was significantly decreased in the SZ group., Conclusion: Our results suggest that microstructural abnormalities in the callosal white matter fibers connecting bilateral temporal lobe cortices contribute to poor executive function and severe negative symptom in patients with schizophrenia., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Cryptogenic organizing pneumonia (COP) after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by frequent recurrence. Few studies have examined onset and recurrence patterns of COP after HSCT. We investigated the clinical features of COP after HSCT in a single-center retrospective study including 165 consecutive patients who underwent allogeneic HSCT. Eighteen patients (11%) developed COP after HSCT. Hypoxemia and pleural effusion at the onset of COP were significantly associated with umbilical cord blood transplantation (P = 0.002 and P = 0.002, respectively). Recurrence of COP was observed in six patients and significantly associated with the presence of chronic graft-versus-host disease (cGVHD; P = 0.013) and stem cell sources other than umbilical cord blood (P = 0.038). Four patients with COP died of pulmonary failure after recurrence of COP. No patients who underwent umbilical cord blood transplantation experienced recurrence of COP. These findings suggest that the clinical features at the onset of COP may depend on stem cell sources. Moreover, both stem cell source and the absence or presence of cGVHD may affect COP recurrence, indicating the need to develop treatment strategies against COP according to stem cell source and risk of cGVHD.

A new diradical having two 4,8,10-trioxotriangulene (TOT) neutral radical units linked through an m-phenylene moiety was synthesized and characterized by ESR measurements. An electrochemical study showed that the diradical undergoes two one-electron reductions to generate corresponding dianion species, suggesting the electronic interaction between two TOT units through the π-conjugated spacer. A strong intramolecular interaction between the two TOT units gives rise to the spin-projected small hyperfine couplings in comparison with those of the monomer. Furthermore, the temperature dependent ESR measurement revealed that the dimer behaves as an S=1 species in the ground state with a ferromagnetic interaction of 2 J/k B =+7±3 K., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A sodium salt of a polycyclic trioxotriangulene (TOT) anion with six triethylene glycol chains exhibiting the formation of a colored ionic liquid at room temperature was synthesized. The ionic liquid is air- and water-stable, reflecting thermodynamic stabilization of a charge-delocalized TOT anion. Upon protonation of the TOT anion, the salt shows halochromic behaviors in solution and even in the neat liquid state with HCl vapor. The ionic liquid shows no morphological change with the chromism, presumably as a result of poor intermolecular interactions between π skeletons.

The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. In the present study, we investigated the impact of MTX dosage on clinical outcomes following UCBT in a single-center retrospective study. Of 70 UCBT recipients included in this study, 37 received MTX at doses of 10 mg/m 2 on day 1, and 7 mg/m 2 on days 3 and 6 (low-dose MTX: LD-MTX), and 33 received MTX at doses of 15 mg/m 2 on day 1, and 10 mg/m 2 on days 3 and 6 (standard-dose MTX: SD-MTX), in addition to tacrolimus (TAC). Grade 3-4 acute GVHD and/or transplant-related complications with endothelial cell damage were considered severe transplant-related complications. Univariate analysis findings revealed that the risk of grade 3-4 acute GVHD was significantly lower in the SD-MTX group than in the LD-MTX group (P = 0.013). Multivariate analysis findings revealed that SD-MTX was significantly associated with a lower incidence of severe transplant-related complications (HR = 0.25; 95% CI, 0.07-0.87; P = 0.029). We conclude that SD-MTX in combination with tacrolimus is optimal for GVHD prophylaxis in UCBT.

Reduced pulmonary function is commonly observed after allogeneic hematopoietic stem cell transplantation (HSCT); however, its relationship with the development of noninfectious pulmonary complications (NIPCs) is unclear, and the impact of changes in pulmonary function test (PFT) values on HSCT outcome remains controversial. We conducted a retrospective study including 150 patients to investigate changes in PFTs and impact on clinical outcome. PFT data at around 1 year after HSCT were available in 84 patients, and showed a significant time-dependent decline in percentage predicted forced expiratory volume in 1 s and other parameters. We focused on %FEV1, calculated decline of %FEV1 from pretransplant to around 1 year after HSCT (Δ%FEV1), and divided patients into good-Δ%FEV1 or poor-Δ%FEV1 groups, using a cut-off point of 20% decline of Δ%FEV1. In the poor-Δ%FEV1 group, half of the patients developed NIPCs. In the good-Δ%FEV1 group, PFT values were maintained, whereas those of the poor-Δ%FEV1 group declined significantly. Multivariate analysis showed that busulfan use was a risk factor for %FEV1 decline, and poor-Δ%FEV1 was a risk factor for overall survival. These data indicate that decline of %FEV1 may be a useful indicator of pulmonary damage after HSCT, and is strongly associated with busulfan use.

Objectives: Eating disorders result in poor nutrition, poor physical conditions and even suicidality and mortality. Although polyunsaturated fatty acids (PUFAs) have attracted attention in the emerging field of nutritional psychiatry, their role in eating disorders remains unknown. This meta-analysis investigates the differences of PUFA levels between patients with eating disorders and healthy controls, and the potentially beneficial effects of PUFAs in such patients., Methods: We conducted a systematic literature search and meta-analysis under the random effects model., Result: Eleven studies were included in the current meta-analysis. Compared with controls, 379 patients with eating disorders had significantly higher plasma levels of alpha-linolenic acid, eicosapentaenoic acid, stearidonic acid, osbond acid, palmitoleic acid, oleic acid, and total omega-3 fatty acids; and lower levels of total omega-6 fatty acids and omega-6/omega-3 ratio. Eating disorders were associated with significantly higher red blood cell membrane levels of palmitoleic acid and oleic acid and lower levels of adrenic acid, arachidonic acid, and total omega-6 fatty acids. In addition, PUFA supplements were associated with a benefit to body weight outcomes but not disease severity and mood symptoms in interventional trials., Discussion: This meta-analysis indicates abnormal levels of PUFAs in peripheral blood tissues in patients with eating disorders. The relationship between PUFAs and eating disorders should be interpreted cautiously considering the specific lipid metabolism under starvation state. To investigate the role of PUFAs on psychopathological and therapeutic effects in eating disorders, further larger clinical studies are warranted., (Copyright © 2019. Published by Elsevier Ltd.)

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired immune-mediated disorder that leads to autonomic failure. It is sometimes complicated by mental and behavioral symptoms. We report a case of 72-year-old male with AAG who was admitted to the psychiatric department for prolonged severe delirium. Repeated loss of consciousness attributed to severe orthostatic hypotension disturbed recovery from delirium. In addition, intracerebral hemorrhage occurred during hospitalization, and this cerebrovascular event may have been substantially affected by unstable blood pressure due to AAG. This case suggests importance of differential diagnosis of AAG in patients with mental and behavioral symptoms accompanying severe autonomic failure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic stem cell transplantation (HSCT). However, the usefulness of the HCT-CI in single-unit umbilical cord blood transplantation (UCBT) remains unclear. We investigated the impact of the HCT-CI on the clinical outcomes of allogeneic HSCT in a single-center retrospective study including 53 recipients of UCBT (UCBT group) and 90 recipients of other HSCT (non-UCBT group). In the non-UCBT group 2-year OS rates for HCT-CI score < 3 and ≥3 were 67% (n = 74; 95% confidence interval [CI], 54% to 78%) and 26% (n = 16; 95% CI, 7% to 51%), respectively (P = .001). In the UCBT group these rates were 66% (n = 39; 95% CI, 48% to 79%) and 69% (n = 14; 95% CI, 36% to 87%), respectively (P = .73). In the non-UCBT group 1-year NRM rates for HCT-CI score < 3 and ≥3 were 14% (95% CI, 6.4% to 22%) and 37% (95% CI, 14% to 61%), respectively (P = .02). In the UCBT group these rates were 6.1% (95% CI, 3.4% to 24%) and 7.7% (95% CI, .4% to 29%), respectively (P = .78). Using multivariate analysis we showed that HCT-CI score ≥ 3 was significantly associated with lower OS (hazard ratio, 3.06; 95% CI, 1.47 to 6.38; P = .003) and higher NRM (hazard ratio, 2.87; 95% CI, 1.18 to 6.96; P = .02) for the non-UCBT group. UCBT showed good OS with low incidence of NRM, even in patients with high HCT-CI scores. Altogether, we propose single-unit UCB to be a promising stem cell source for improving survival in patients with multiple comorbidities., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Elucidation of abnormal connections throughout the whole brain is necessary to understand temporal lobe epilepsy (TLE). We examined abnormalities in whole-brain white matter integrity and their relationship with duration of illness in patients with TLE., Methods: The subjects were 15 patients with TLE and 17 healthy controls. Mean duration of illness in the TLE group was 21.6 years. Tract-based spatial statistics (TBSS) were used for diffusion tensor imaging (DTI) analysis. Four diffusion tensor metrics, that is, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and then examined for differences between the TLE and healthy control groups. We also examined for correlations between DTI parameters and duration of illness in the TLE group., Results: In the TLE group, compared with the healthy control group, FA was reduced, and MD and RD were increased, not only in the limbic and temporal lobe regions and their directly connecting regions in both hemispheres, but also in remote white matter regions. Duration of illness showed a significant negative correlation with mean whole-brain FA and a significant positive correlation with both mean whole-brain MD and RD. Brain regions showing correlation between disease duration and DTI metrics also extended to the limbic area and its connecting regions, and to remote white matter regions., Significance: The results of this study suggest that widespread abnormalities in white matter integrity in patients with TLE are associated with long-term disease.

Background: Little is known regarding interhemispheric functional connectivity (FC) abnormalities via the corpus callosum in subjects with bipolar disorder (BD), which might be a key pathophysiological basis of emotional processing alterations in BD., Methods: We performed tract-based spatial statistics (TBSS) using diffusion tensor imaging (DTI) in 24 healthy control (HC) and 22 BD subjects. Next, we analyzed the neural networks with independent component analysis (ICA) in 32HC and 25 BD subjects using resting-state functional magnetic resonance imaging., Results: In TBSS analysis, we found reduced fractional anisotropy (FA) in the corpus callosum of BD subjects. In ICA, functional within-connectivity was reduced in two clusters in the sensorimotor network (SMN) (right and left primary somatosensory areas) of BD subjects compared with HCs. FC between the two clusters and FA values in the corpus callosum of BD subjects was significantly correlated. Further, the functional within-connectivity was related to Young Mania Rating Scale (YMRS) total scores in the right premotor area in the SMN of BD subjects., Limitations: Almost all of our BD subjects were taking several medications which could be a confounding factor., Conclusions: Our findings suggest that interhemispheric FC dysfunction in the SMN is associated with the impaired nerve fibers in the corpus callosum, which could be one of pathophysiological bases of emotion processing dysregulation in BD patients.

Although diffusion tensor imaging (DTI) have revealed brain abnormalities in bipolar disorder (BD) subjects, DTI methods might not detect disease-related abnormalities in the white matter (WM) where nerve fibers are crossing. We investigated BD myelin-related abnormal brain regions in both gray matter and WM for 29 BD and 33 healthy control (HC) participants using T1-weighted (T1w)/T2-weighted (T2w) ratio images that increase myelin-related contrast irrespective of nerve fiber orientation. To check effect of the brain volume, the results were compared with those of voxel-based morphometry (VBM). We found significantly lower T1w/T2w signal intensity in broad WM regions in BD subjects, including the corpus callosum, corona radiata, internal capsule, middle cerebellar peduncle and cerebellum. Regional volume reduction was found in the WM bilateral posterior thalami and retrolenticular part of the internal capsules of BD subjects. We also performed tract-based spatial statistics (TBSS) in 25 BD and 24 HC participants and compared those for the T1w/T2w ratio images. Both methods detected the BD corpus callosum abnormality. Further, the ratio images detected the corona radiata and the cerebellar abnormality in BD. These results suggest that T1w/T2w ratio image analysis could take a complementary role with the DTI method in elucidating myelin-related abnormalities in BD., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Cognitive impairment is strongly associated with functional outcome in patients with schizophrenia but its pathophysiology remains largely unclear. Involvement of omega-3 fatty acids in the cognitive function of healthy individuals and patients with neuropsychiatric disease has received increasing attention. The aim of this study was to examine the relationship between omega-3 fatty acids with cognitive function, social function, and psychiatric symptoms in patients with schizophrenia. The subjects included 30 patients with schizophrenia or schizoaffective disorder. Psychiatric symptoms, cognitive function, and social function were assessed using the Positive and Negative Syndrome Scale, the Brief Assessment of Cognition in Schizophrenia (BACS), and the Social Functioning Scale (SFS), respectively. Blood serum omega-3 fatty acids were assessed using gas chromatography. The BACS composite score was significantly correlated with blood eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. In addition, a daily dose of antipsychotic medication was negatively and significantly correlated with the blood DHA level and with the BACS composite score. Step-wise multiple regression analyses demonstrated that the SFS score was significantly associated with the BACS composite score. Our results indicate that reduced blood omega-3 fatty acids are associated with cognitive impairment, which then impacts social functioning outcomes in schizophrenia.

Erythropoietin (EPO), a hematopoietic hormonal cytokine induced in response to hypoxia, has neuroprotective effects. EPO receptor (EPOR) is expressed in microglia, resident immune cells in the brain. However, the effect of EPO on microglial activation is not clear. In the present study, we demonstrated that the EPOR is highly expressed in microglia, rather than in neurons or astrocytes, in in vitro experiments. Therefore, we investigated whether EPO could attenuate lipopolysaccharide (LPS)-mediated activation of microglia in vitro. The BV-2 microglial cell line was treated with LPS in the absence or presence of EPO. In the presence of EPO, microglial expression of LPS-induced inflammatory cytokine genes was significantly decreased. In addition, EPO suppressed the LPS-induced phagocytic activity of BV-2 cells towards fluorescent beads, as well as induction of inducible nitric oxide synthase. In in vivo experiments, EPO significantly decreased the LPS-induced expression of inflammatory cytokine genes in mouse brains. Furthermore, morphological analysis of cortical microglia in the brains of mice stimulated with LPS revealed that combined treatment with EPO alleviated LPS-induced morphological changes in the microglia. These data indicate that EPO attenuates microglial activation, including morphological changes in vivo, phagocytosis in vitro, and the production of inflammatory cytokines in vivo and in vitro. Further investigation of EPO modulation of LPS-induced microglial activation may contribute to the development of novel neuroprotective therapies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The clinical introduction of rTMS for the treatment of depression is now progressing in Japan. On the basis of the successful results of a large-scale RCT, the US FDA approved an rTMS device in 2008, and four rTMS devices are now approved and used in several countries and the EC. The results of the meta-analysis of RCTs and the real-world naturalistic observa- tional studies show beneficial effects on treatment-resistant depression. The rTMS is generally well-tolerated and safe, but has a risk of seizure, with an estimated rate of approximately one in 1,000 patients. The rTMS is thought to be an effective treatment for those unable to benefit from initial antidepressant medication.

We report an 83-year-old woman with atypical senile dementia with Fahr-type calcification. Brain computed tomography demonstrated asymmetrical calcification predominant in the basal ganglia on the right side and pronounced diffuse cortical atrophy in the frontotemporal areas. The patient was clinically diagnosed with diffuse neurofibrillary tangles with calcification. Brain single photon emission computed tomography findings revealed that cerebral blood flow was reduced on the right side, as compared with the left side, in widespread areas. Hemispheric asymmetry in both calcification and cerebral blood flow suggests a relationship between calcification and vascular changes., (© 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.)

Introduction: One leading hypothesis suggests that schizophrenia (SZ) is a neurodevelopmental disorder caused by genetic defects in association with environmental risk factors that affect synapse and myelin formation. Recent magnetic resonance imaging (MRI) studies of SZ brain showed both gray matter (GM) reduction and white matter (WM) fractional anisotropy reduction. In this study, we used T1-weighted (T1w)/T2-weighted (T2w) MRI ratio images, which increase myelin-related signal contrast and reduce receiver-coil bias., Methods: We measured T1w/T2w ratio image signal intensity in 29 patients with SZ and 33 healthy controls (HCs), and then compared them against bias-corrected T1w images., Results: Mean T1w/T2w ratio signal intensity values across all SZ GM and WM voxels were significantly lower than those for the HC values (analysis of covariance with age, gender, handedness, and premorbid intelligence quotient as nuisance covariates). SZ mean WM T1w/T2w ratio values were related to Global Assessment of Functioning (GAF) scores and were inversely related to the positive psychotic symptoms of the Positive and Negative Syndrome Scale. Voxel-based analysis revealed significantly lower T1w/T2w ratio image signal intensity values in the right ventral putamen in SZ GM. T1w image intensities did not differ between the SZ and HC groups., Conclusions: T1-weighted/T2-weighted ratio imaging increased the detectability of SZ pathological changes. Reduced SZ brain signal intensity is likely due to diminished myelin content; therefore, mapping myelin-related SZ brain changes using T1w/T2w ratio images may be useful for studies of SZ brain abnormalities.

Tinnitus is the perception of phantom sound without an external auditory stimulus. Using neuroimaging techniques, such as positron emission tomography, electroencephalography, magnetoencephalography, and functional magnetic resonance imaging (fMRI), many studies have demonstrated that abnormal functions of the central nervous system are closely associated with tinnitus. In our previous research, we reported using resting-state fMRI that several brain regions, including the rectus gyrus, cingulate gyrus, thalamus, hippocampus, caudate, inferior temporal gyrus, cerebellar hemisphere, and medial superior frontal gyrus, were associated with tinnitus distress and loudness. To reconfirm these results and probe target regions for repetitive transcranial magnetic stimulation (rTMS), we investigated the regional cerebral blood flow (rCBF) between younger tinnitus patients (<60 years old) and the age-matched controls using single-photon emission computed tomography and easy Z-score imaging system. Compared with that of controls, the rCBF of tinnitus patients was significantly lower in the bilateral medial superior frontal gyri, left middle occipital gyrus and significantly higher in the bilateral cerebellar hemispheres and vermis, bilateral middle temporal gyri, right fusiform gyrus. No clear differences were observed between tinnitus patients with normal and impaired hearing. Regardless of the assessment modality, similar brain regions were identified as characteristic in tinnitus patients. These regions are potentially involved in the pathophysiology of chronic subjective tinnitus.

Background: The corpus callosum modulates interhemispheric communication and cognitive processes. It has been suggested that white matter abnormalities in the corpus callosum are related to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study was to examine microstructural abnormalities in callosal fibers separated by their connection to functional brain regions and determine the relationship of these abnormalities with cognitive function in MDD and BD., Methods: The subjects were 18 patients with MDD, 20 patients with BD, and 21 healthy controls. The callosal fibers were divided into 6 segments based on their cortical projection using tract-specific analysis of diffusion tensor imaging. We examined differences in the fractional anisotropy (FA) of callosal fibers in six segments among the three subject groups and examined the correlation between the FA in each segment and cognitive performance in the 3 groups., Results: The FA of anterior callosal fibers were reduced significantly in the MDD and BD groups compared to those in the HC group, and the FA of anterior callosal fibers correlated significantly with the raw scores of the digit sequencing task and symbol coding in the MDD group., Limitations: The patients were medicated at the time of scanning, and the MDD and BD groups were not matched for symptom severity., Conclusions: Our results suggest that MDD and BD have similar microstructural abnormalities in anterior callosal fibers connecting bilateral frontal cortices, and these abnormalities may be related to impairment of working memory and attention in MDD., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Low-frequency repetitive transcranial magnetic stimulation (rTMS) has received increasing attention for the treatment of tinnitus, but its therapeutic mechanisms are unclear. We performed low-frequency rTMS treatment for a patient with chronic tinnitus and examined changes of cortical excitability and cerebral blood flow using paired-pulse TMS and single-photon emission computed tomography. After the rTMS treatment, tinnitus loudness was decreased, cortical excitability was reduced, and blood flow in the thalamus was increased. Our results suggest that low-frequency rTMS treatment reduces tinnitus loudness by an inhibitory effect on the cortical excitability and a remote activation effect on the thalamus through the corticothalamic networks.