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Background The prognostic factors for azacitidine in untreated acute myeloid leukemia (AML) patients ineligible for intensive therapy remain unknown. Objective To identify prognostic factors for azacitidine monotherapy and assist clinicians in deciding whether to use azacitidine monotherapy or other therapies. Methods We retrospectively analyzed 27 patients with AML who were newly treated with azacitidine between 2013 and 2021 at our hospital. We evaluated potential predictors based on the overall survival (OS). Results A univariate analysis found that an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 and platelet count (Plt)27,000/μL had a significant negative influence on the OS. A multivariate analysis confirmed that both factors had significant independent adverse effects on the OS. An ECOG PS ≥2 and Plt27,000/μL were thus assigned 1 point each, and a clinical scoring system was created. Log-rank testing showed that the 0-point group (n=12) had a median OS of 680 days (95% confidence interval [CI] 220-898 days) and a 1-year OS rate of 80.8% (95% CI 42.3%-94.9%), the 1-point group (n=11) had a median OS of 90 days (95% CI 62-345 days) and a 1-year OS rate of 18.2% (95% CI 2.9%-44.2%), and the 2-point group (n=4) had a median OS of 82 days (95% CI 19-not applicable [NA] days) and a 1-year OS rate of 0% (95% CI NA-NA). The p-value of 0.00008 indicated that this scoring was useful. Conclusion The ECOG PS and Plt can be used to predict the OS with azacitidine monotherapy in untreated AML patients ineligible for intensive therapy.

The aim of this study was to investigate the association between lithium levels in drinking water and prevalence of Alzheimer's dementia (AD).Lithium levels in the drinking water of 808 cities and wards (i.e., 785 Japanese cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to the prevalence of AD during the 5 years from 2010 to 2014, which was calculated on the basis of the national data base of Ministry of Health, Labor, and Welfare of Japan. Multiple regression analyses were used to investigate the association of lithium levels with the prevalence of AD with adjustment for relevant factors (proportions of one-person households as a family factor and people in primary industry employment as a job factor, annual total sunshine hours as a meteorological factor, and total number of beds of psychiatric hospitals as a medical factor) in total, male, and female elderly populations.The adjusted model showed a significant inverse association of lithium levels with female, but not with male, or total prevalence of AD.These findings suggest that higher lithium levels in drinking water may be associated with lower prevalence of AD in female, but not male, populations.

Introduction Bright light therapy (BLT) has been used for treating seasonal affective disorder, depression and bipolar depression. However, it's precise mechanism remains unclear. Bright light exposure (BL) induces neurogenesis in the adult rat hippocampal dentate gyrus (DG). We hypothesized that BL may induce neurogenesis in the human DG as well. Method A 4-week randomized controlled trial study was conducted, where healthy participants were randomly assigned to a BL group (10,000 lux) or dim light exposure group (DL group; 50 lux). Magnetic resonance imaging was performed at baseline and after 4 weeks. Longitudinal hippocampal subfield segmentation was generated via the FreeSurfer 7.1.1 hippocampal subfields module to evaluate volume of bilateral granule cell and molecular layer of the DG-head and -body. Results Our final sample size was 20, which consisted of BL group (n = 10) and DL group (n = 10). After age and sex adjustment, significant effects of time and group were detected in the left DG-head volume (p = 0.04). In the BL group, the left DG-head volume significantly increased (p = 0.004), whereas no significant volumetric change was observed in the DL group. Conclusions This study revealed that 4-week BL significantly increased left DG-head volume in healthy participants. Thus, neurogenesis might be induced by BL in the human DG, which is a completely new mechanism of BLT.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p

To elucidate dynamic changes in native BCR‐ABL and alternatively spliced tyrosine kinase inhibitor (TKI)‐resistant but function‐dead BCR‐ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR‐ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR‐ABLIns35bp, accounting for 0.8% of the total IS BCR‐ABL, corresponding to actual BCR‐ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR‐ABL but not BCR‐ABLIns35bp, leading to the initial increase in the proportion of BCR‐ABLIns35bp. Thereafter, both native BCR‐ABL and BCR‐ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI‐resistant BCR‐ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR‐ABL + clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function‐dead BCR‐ABLIns35bp, suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis‐splicing BCR‐ABLIns35bp, occurring at the particular pseudo‐splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR‐ABL extracting BCR‐ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention., Dynamic changes were observed in BCR‐ABL and BCR‐ABLIns35bp after TKI discontinuation. BCR‐ABL+ cells responsible for early relapse after cessation of TKI treatment might derive from the residual native BCR‐ABL addicted clones. In contrast, some patients whose MRD mainly consisted of BCR‐ABLIns35bp transiently lost DMR during a relatively late phase after TKI discontinuation and thereafter regained DMR spontaneously without TKI resumption.

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.

Aim We aimed to investigate the hypotheses that hyperthymic temperament may be positively associated with self-directedness and self-transcendence with adjustment for relevant factors. Methods Using the database of our previous studies, the data from 111 healthy subjects with scores for both the Temperament and Character Inventory and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire were secondarily used for the present study. Results Hyperthymic Temperament scores were significantly and positively associated with Self-Transcendence scores, but not with Self-Directedness scores, following adjustment for relevant factors. Despite the lack of association between self-transcendence and self-directedness, cooperativeness was significantly and positively associated with self-transcendence and self-directedness, but not with hyperthymic temperament. Moreover, despite the lack of association between hyperthymic temperament and self-directedness, harm avoidance was significantly and negatively associated with hyperthymic temperament and self-directedness, but not with self-transcendence. Conclusion The present findings suggest that hyperthymic temperament may be positively associated with self-transcendence, but not with self-directedness. Moreover, hyperthymic temperament may be, a selfish and reckless trait, self-transcendence may be altruistic and not reckless, and self-directedness may be altruistic but reckless.

Objectives The aims of the present study thus were (a) to further investigate the association between lithium levels in drinking water and suicide rates by adjusting relevant factors using the so far largest available dataset in Japan, (b) to confirm sex differences, (c) to estimate the effects of long-term exposure to trace lithium, (d) to investigate the effects of drinking bottled instead of tap water, and (e) to exploratorily investigate which lithium levels may be associated with lower suicide rates. Methods Mean lithium levels in drinking water of all 808 cities and wards (ie, 785 cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to mean suicide standardized mortality ratios (SMRs) during the 7 years from 2010 to 2016. Multiple regression analyses adjusted for the size of each population were used to investigate the association of lithium levels with suicide SMRs with adjustments for relevant factors. Results The adjusted model showed significant inverse associations of lithium levels with total and male SMRs, but not with female SMRs. Neither the proportion of residents who continued to live in the same city nor the consumption of bottled water changed the association between lithium levels and suicide SMRs. Finally, it was 30 μg/L or more that was associated with lower suicide SMRs. Conclusions The present findings reconfirm the inverse association between lithium levels in drinking water and suicide rates particularly in the male population.

Aim In order to resolve the equivocal relationship between anxious temperament rated by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A) and harm avoidance rated by the Temperament and Character Inventory (TCI), the present study aimed to investigate whether the anxious temperament scale and the harm avoidance scale are significantly associated with adjustment of relevant factors. Our hypothesis was that anxious temperament might be associated with harm avoidance. Methods From the database of our previous studies, the data of 111 healthy subjects who had both TCI and TEMPS-A scores were extracted for the present study. Two multiple regression analyses were performed: one to predict variance in anxious temperament scores without and with harm avoidance scores, and relevant factors; and another to predict variance in harm avoidance scores without and with anxious temperament scores, and relevant factors. Results Anxious temperament was significantly and positively associated with depressive temperament, irritable temperament, and Hamilton Rating Scale for Depression whereas harm avoidance was significantly and negatively associated with hyperthymic temperament, novelty seeking, persistence, and self-directedness, although both were significantly and positively associated with each other. Conclusion These findings support our hypothesis and suggest that anxious temperament may have 'depressive proneness' whereas harm avoidance may have 'passive proneness.'

Cyclothymic temperament possesses a central dimension that includes rapid fluctuations in mood and emotional instability, and it is regarded as a prodromal state of bipolar disorder. The aim of the present study is to explore the neural correlates of cyclothymic temperament. We used the data of 55 healthy participants in our previous study and analyzed the association between cyclothymic temperament scores rated by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A) and the uptake of [18F]-FDG measured by positron emission tomography (PET). A whole brain analysis revealed a cluster of [18F]-FDG uptake significantly and positively associated with cyclothymic temperament scores, located in the right superior parietal lobule (SPL). Even after adjustment for relevant factors, there remained a significant cluster of [18F]-FDG uptake with cyclothymic temperament scores in the right SPL. In ROI analyses, there were similar significant peaks in the right SPL in association with cyclothymic temperament scores. These findings suggest that the right superior parietal lobule may be one of the neural correlates of cyclothymic temperament.

Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting. Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH. Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF. Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. Figure 1 Figure 1. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

The Specific Levels of Functioning Scale (SLOF) has been reported to provide a measure of social function in patients with schizophrenia. The aim of this multi-center study was to determine convergent validity of the Japanese version of SLOF, and if cognitive insight would be associated with social function. Fifty-eight patients with schizophrenia participated in the study. Social function, neurocognition, and daily activity skills were evaluated by the Social Functioning Scale (SFS), Brief Assessment of Cognition in Schizophrenia (BACS) and UCSD Performance-based Skills Assessment-Brief (UPSA-B), respectively. We also assessed cognitive insight with the Beck Cognitive Insight Scale (BCIS). Significant relationships were noted between scores on the SLOF vs. those of the SFS, BACS, UPSA-B, and BCIS. Specifically, the correlation between performance on the UPSA-B and SLOF scores was significantly more robust compared to the correlation between performance on the UPSA-B and scores on the SFS. Similarly, the correlation between scores on the BACS and SLOF tended to be more robust than that between the BACS and SFS. Importantly, while the correlation between scores on the BCIS and SLOF reached significance, it was not so between scores on the BCIS and SFS. The SLOF Japanese version was found to provide a measure of social consequences in patients with schizophrenia. Importantly, this study is the first to indicate the relationship between cognitive insight and social function evaluated by the SLOF. This finding is consistent with the observation that SLOF scores were considerably associated with performances on objective functional measures.

Objectives: Mindfulness is a method of training the regulation of attention with non-judgmental acceptance that is linked to beneficial effects on health. The existential approach supports the uniqueness of each individual and helps to provide meaning to their lives. In this randomized controlled trial, we examined whether mindfulness-based intervention (MBI) and the existential approach could be combined sequentially and whether they operated antagonistically or cooperatively. Methods: One hundred thirty-seven participants aged 20 years or older without any severe mental disorders were randomly assigned (1:1), via an envelope method, to receive either 8-week MBI (N = 68) or 4-week MBI followed by 4-week existential approach (EXMIND) (N = 69). Participants were first allocated to a waiting-list group and subsequently randomized to the MBI group or EXMIND group. The primary outcome was self-compassion scale (SCS) total scores at 0, 4, and 8 weeks during intervention or waiting. The analyses were performed by linear mixed models for both primary and secondary outcomes following the intention-to-treat principle. Results: Both MBI and EXMIND groups had significantly increased SCS total scores compared to those of the waiting group, with mean SCS total scores of 2.3 (SD 3.0) in the MBI group and 2.1 (2.9) in the EXMIND group versus 0.3 (2.2) in the waiting group. Conclusions: Our findings suggest that MBI followed by existential approach are not antagonistic and may have cooperative effects, suggesting that EXMIND may be a useful treatment.

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.

Objective Bright light therapy is widely used as the treatment of choice for seasonal affective disorder. Nonetheless, our understanding of the mechanisms of bright light is limited and it is important to investigate the mechanisms. The purpose of this study is to examine the hypothesis that bright light exposure may increase [18F]-fluorodeoxyglucose (FDG) uptake in olfactory bulb and/or hippocampus which may be associated neurogenesis in the human brain. Method A randomized controlled trial comparing 5-day bright light exposure + environmental light (bright light exposure group) with environmental light alone (no intervention group) was performed for 55 participants in a university hospital. The uptake of [18F]FDG in olfactory bulb and hippocampus using FDG positron emission tomography was compared between two groups. Results There was a significant increase of uptake in both right and left olfactory bulb for bright light exposure group vs. no intervention group. After adjustment of log-transformed illuminance, there remained a significant increase of uptake in the right olfactory bulb. Conclusion The present findings suggest a possibility that 5-day bright light exposure may increase [18F]FDG in the right olfactory bulb of the human brain, suggesting a possibility of neurogenesis. Further studies are warranted to directly confirm this possibility.

Background Human leukocyte antigen (HLA) genotypes in lamotrigine -induced (LTG-induced) cutaneous adverse drug reactions (cADRs) have been described in several reports but controversy remains even for a given ethnic group. We attempted to clarify a possible association between LTG-induced cADRs and HLA alleles in Japanese patients. Method Sixteen subjects, including eight patients with LTG-induced cADRs and eight LTG-tolerant controls were included in this study. All eight patients with LTG-induced cADRs gave positive results in a drug-induced lymphocyte stimulation test (DLST) with LTG. We performed HLA-typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1, using PCR with sequence-specific oligonucleotide probes and multiple analyte profiling (xMAP) technology (Luminex System; Luminex Corporation, Austin, TX). We examined differences between allele frequencies in our two groups of subjects and the allele frequencies in the general Japanese population. Results The frequencies of HLA-DRB1*0405, and HLA-DQB1*0401 alleles were higher in our LTG-cADRs patients than the reference frequencies in the general Japanese population. We also detected HLA-DQA1*0303 frequently in our LTG-cADRs patients, but data for this allele in the Japanese population was not available. Our observation was presumably due to the linkage disequilibrium among the three alleles. The haplotype frequency of HLA-DRB1*0405, DQB1*0401 and DQA1*0303 in our LTG-cADRs subjects was also different from the corresponding haplotype frequency in the database for the Japanese population and the difference was statistically significant. One patient with the HLA-DRB1*0405, -DQB1*0401 and DQA1*0303 haplotype was safely re-treated with LTG after results of a DLST with LTG ceased to be positive about 4 months after discontinuation of LTG. Limitations Our analysis included only 16 patients. Associations between LTG-induced cADRs and specific HLA loci will have to be confirmed in larger studies. Conclusions LTG-induced cADRs are associated with HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303.

Previous studies have predicted that reciprocal activation of GATA-1 and PU.1 regulates myelo-erythroid versus myelo-lymphoid lineage commitment in early hematopoiesis. Such PU.1-activating myelo-lymphoid progenitors exist within the lymphoid-primed multipotent progenitor (LMPP) population at the primitive Lineage−Sca-1+c-Kit+ (LSK) stage. We here show that the counterpart of GATA-1-activating myelo-erythroid progenitor resides also at the LSK stage, expressing CD41 at a high level. Purified CD41hi LSK cells showed exceedingly strong and prolonged myelo-erythroid-restricted reconstitution, and primed myelo-erythroid gene expression with a more primitive molecular signature as compared to the original common myeloid progenitor (CMP). The CD41hi LSK cells more strongly contributed to emergent and malignant myelopoiesis than LMPPs, and produced the original CMP by downregulating Sca-1 and CD41, suggesting that they are the earliest CMPs. Thus, the hematopoietic developmental map should be revised by integrating the primary branchpoint comprised of the new, isolatable CD41hi CMP and the LMPP populations. Stem Cells 2015;33:976–987

Background: Previously, we compared the hyperthymic scores of residents in Sapporo, Koshigaya, and Oita (which are located at latitudes of 43 degrees N, 36 degrees N, and 33 degrees N in Japan, respectively) using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A). We found that residents who lived at lower latitudes had higher hyperthymic temperament scores; however, the mechanism of the effect of latitude on hyperthymic temperament remained unclear. The current study examined the mediators of the latitude effect in additional regions with different annual temperatures and amounts of ambient sunshine. Methods: The Japanese archipelago stretches over 4000 km from north to south and has four large islands: Hokkaido, Honshu, Shikoku, and Kyushu. In addition to the TEMPS-A previously reported data collected at Sapporo (latitude 43 degrees N), Koshigaya (36 degrees N), and Oita (33 degrees N), we collected the TEMPS-A data of 189 and 106 residents from Takaoka (36 degrees N) and Obihiro (42 degrees N), respectively. Taken together, these five regions have different patterns (i.e., highs and lows) of annual ambient total sunshine (hours) and mean temperature (degrees C). The effect of latitude, sunshine, and temperature on affective temperaments was analyzed for five Japanese regions. Results: Multiple regression analyses revealed that latitude predicted significant variance in hyperthymic temperament. Ambient temperature, but not sunshine, significantly affected hyperthymic temperament. Limitations: The light exposure that residents actually received was not measured. The number of regions studied was limited. The findings might not generalize to residents across Japan or other countries. Conclusions: The present findings suggest that latitude affects hyperthymic temperament, and ambient temperature might mediate this effect. (C) 2014 Elsevier B.V. All rights reserved

Objective The aim of this study was to assess the safety and efficacy of lenalidomide (Len), with the dose adjusted according to the renal function, plus low-dose dexamethasone (Dex) in older patients with bortezomib (Bor)-resistant multiple myeloma (MM). Methods The study included 68 consecutive patients 70 years of age or older diagnosed with MM at our institute and ineligible for high-dose melphalan therapy plus autologous stem cell transplantation. Fifteen older patients with relapsed or refractory MM (RRMM) previously treated with Bor-containing regimens were treated with the combination of Len plus low-dose Dex. Results The median treatment duration was 12 months (range, 9 to 43 months), with all patients responding to Len plus low-dose Dex. All patients showed significant renal dysfunction between the beginning and end of treatment; however, the renal function improved in all cases. Conclusion Treatment with dose-adjusted Len combined with low-dose Dex is an effective and safe therapy for older RRMM patients exhibiting renal impairment after receiving Bor-based therapies.

In order to resolve the equivocal relationship between anxious temperament rated by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A) and harm avoidance rated by the Temperament and Character Inventory (TCI), the present study aimed to investigate whether the anxious temperament scale and the harm avoidance scale are significantly associated with adjustment of relevant factors. Our hypothesis was that anxious temperament might be associated with harm avoidance.From the database of our previous studies, the data of 111 healthy subjects who had both TCI and TEMPS-A scores were extracted for the present study. Two multiple regression analyses were performed: one to predict variance in anxious temperament scores without and with harm avoidance scores, and relevant factors; and another to predict variance in harm avoidance scores without and with anxious temperament scores, and relevant factors.Anxious temperament was significantly and positively associated with depressive temperament, irritable temperament, and Hamilton Rating Scale for Depression whereas harm avoidance was significantly and negatively associated with hyperthymic temperament, novelty seeking, persistence, and self-directedness, although both were significantly and positively associated with each other.These findings support our hypothesis and suggest that anxious temperament may have 'depressive proneness' whereas harm avoidance may have 'passive proneness.'

Background The Japanese archipelago stretches over 4000 km from north to south and has four large islands: Hokkaido, Honshu, Shikoku, and Kyushu. Previously, using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A), we compared the hyperthymic scores of residents in Sapporo, Obihiro, Takaoka, Koshigaya, and Oita cities (which are located at latitudes of 43°N, 42°N, 36°N, 36°N and 33°N with various combinations of ambient temperament and sunshine in Japan, respectively). We found that latitude predicted significant variance in hyperthymic temperament, and that ambient temperature, but not sunshine, significantly affected hyperthymic temperament scores. However, the analysis failed to consider the effects of naturally occurring low-dose lithium on temperament. Methods In addition to the TEMPS-A data previously collected, we measured lithium levels of the five cities. The effect of temperature, sunshine, and lithium levels on hyperthymic temperament was analyzed for the five cities. Results A stepwise multiple regression analysis revealed that lithium levels as well as latitude, but not temperature or sunshine, predicted significant variance in hyperthymic temperament scores. Hyperthymic temperament scores were significantly and positively associated with lithium levels whereas they were significantly and negatively associated with latitude. Limitations The light, temperature, lithium exposure that residents actually received was not measured. The number of regions studied was limited. The findings might not be generalized to residents across Japan or other countries. Conclusions The present findings suggest that lithium in drinking water may positively maintain hyperthymic temperament, and that latitude may negatively maintain it.

Introduction: Lamotrigine is widely used for mood disorders including bipolar disorder and major depression, but its therapeutic levels have yet to be determined. This study was conducted to investigate the hypothesis that lamotrigine may have a therapeutic window for mood disorders. Methods: 25 patients with mood disorders received lamotrigine for more than one year during which time plasma lamotrigine levels were measured at least once. Their mental state was retrospectively and regularly but blindly assessed using the Clinical Global Impression–Severity (CGI-S) scale. In order to investigate our hypothesis, we depicted the relationship between the last lamotrigine levels and the last CGI scores in 25 patients. If any, the potential therapeutic window was further investigated. Results: The relationship between the last lamotrigine levels and the last CGI scores in the 25 patients indicated the presence of a therapeutic window of lamotrigine from 5 to 11 μg/mL. The repeated measures of ANOVA reached a significant tendency of the effects of lamotrigine levels within 5–11 μg/mL on better CGI-S scores, and the CGI-S scores at the last observation of the 15 patients whose lamotrigine levels were within 5–11 μg/mL were significantly better than those of 10 patients whose lamotrigine levels were not within 5–11 μg/mL. Conclusion: These findings suggest that lamotrigine may have a therapeutic window for patients with mood disorder from 5 to 11 μg/mL.

Background It is well-known that Type A behavior pattern is characterized by hard-driving, competitive behavior and time urgency. Also, people with hyperthymic temperament are known to have high energy levels and are full of plans. It is therefore hypothesized that hyperthymic temperament is associated with rapid processing and fast reaction time in making decisions. Methods Using data from our previous experimental studies ( N =58) examining brightness judgment and brightness preference, reaction time (RT) was investigated in relation to hyperthymic temperament scores and fMRI signal changes of the left inferior orbitofrontal cortex during brightness judgment. Results RT for brightness judgment was significantly shorter than RT for brightness preference. Significant associations were found between RT for brightness preference and hyperthymic temperament scores, and RT for brightness preference and fMRI signal changes of the left inferior orbitofrontal cortex whilst performing brightness preference task. Multiple regression analysis revealed that RT for brightness preference task was significantly and negatively associated with hyperthymic temperament scores, and significantly and positively associated with fMRI signal changes of the left inferior orbitofrontal cortex. Limitations It is uncertain whether the findings of RT (around 1 s) can be extrapolated to routine life (around 24 h) and whether RT for brightness preference can be generalized to a variety of daily activities. Conclusions The present findings suggest that hyperthymic temperament is associated with rapid processing. Further studies are required to overcome the above limitations.

Background Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Since recent several studies indicate an association between illuminance and hyperthymic temperament, it can be hypothesized that more hyperthymic temperament subjects have a different threshold of brightness or darkness perception in comparison with less hyperthymic temperament subjects. Methods We compared the threshold of brightness and darkness judgment between more and less hyperthymic subjects, and by simultaneously using fMRI we compared activations of whole brain between these subjects by two sample t -test. Furthermore, the association between the activations and hyperthymic temperament scores was analyzed. Results Although there was no significant difference in the threshold of brightness or darkness judgment between more and less hyperthymic subjects, there was a significant difference in activations of the regions including left superior temporal gyrus, left inferior orbitofrontal cortex, left triangular inferior frontal gyrus and left insula between these subjects. Moreover, there was a significantly positive association between a cluster containing left inferior orbitofrontal cortex and hyperthymic temperament scores. The common activated region of these two analyses (categorical and continuous ones) was determined as left inferior orbitofrontal cortex. Limitations Limitation of the present study is a lack of brightness and darkness preference experiment between more and less hyperthymic subjects. Conclusions The present findings suggest that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder.

Background Type A behavior pattern (TABP) has been regarded as a putative risk factor for coronary heart disease and recent studies from our group suggest that TABP individuals, identified via the Bortner scale whose validity had been confirmed by structured interviews, may have a greater tendency towards hyperthymic temperament, shorter sleep time and shorter snooze time. Since the Bortner scale was developed in USA and may reflect western culture, it is necessary to reconfirm our findings using a Japanese questionnaire such as Coronary-prone Type Scale for Japanese (CTS) and Kwansei Gakuin's daily life questionnaire (KG questionnaire). Methods Fifty healthy subjects were assessed for TABP using the Bortner scale, as well as the CTS and KG questionnaires. Hyperthymic temperament was assessed via the Japanese standardized version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire (TEMPS-A), while sleep time and snooze time were measured by actigraphy. Results Both CTS and KG questionnaire scores were significantly and positively associated with the Bortner scale scores. Although CTS and KG scores were significantly and positively associated with hyperthymic temperament scores, none were associated with sleep time or snooze time. Limitations The number of subjects was relatively small. Conclusions The findings suggest that Japanese questionnaires such as CTS and KG questionnaires are valid as measures of TABP. Moreover, the association between TABP and hyperthymic temperament was reconfirmed by both CTS and KG questionnaires, whereas the association between TABP and sleep pattern was not. As such, the present findings provide supportive evidence about the usefulness of CTS and KG questionnaires.

Background: ABO-incompatible human leukocyte antigen (HLA)-matched platelets are used to manage thrombocytopenic patients with anti-HLA-A and/or anti-HLA-B (HLA-A/B) antibodies when ABO-identical donors are not available. This study assessed the effectiveness of ABO-incompatible HLA-matched platelets in an unselected group of patients with acute myeloid leukaemia (AML) undergoing cytotoxic chemotherapy. Material and Methods: The study cohort consisted of 12 AML patients undergoing cytotoxic chemotherapy and administered HLA-matched single donor platelet transfusions. Patients positive for anti-HLA-A/B antibodies were defined as candidates for HLA-matched platelet transfusion. The effectiveness of platelet transfusions was determined by measuring corrected count increments (CCIs). Results: The 12 patients received a total of 128 HLA-matched platelet transfusions. The median CCIs 1 hour after ABO-minor and -major incompatible HLA-matched transfusions were 11.4 (range: 3.2-24.9) and 12.4 (range: 3-37), respectively. There were no significant differences in 1- and 24-hour CCIs among ABO-identical and ABOminor and major incompatible transfusions. Discussion: ABO-incompatible HLA-matched platelets are effective in supporting thrombocytopenic AML patient’s positive for anti-HLA-A/B antibodies and undergoing cytotoxic chemotherapy.

Previous animal studies have suggested that hepatocyte growth factor (HGF) could be associated with depression- and anxiety-related behaviors. Our aim was to relate serum HGF levels with State-Trait Anxiety Inventory (STAI), Profile of Mood State (POMS), and Revised NEO Personality Inventory (NEO-PI-R) scores in patients with panic disorder (with or without agoraphobia) and healthy controls. We examined 67 patients with panic disorders and 97 controls. Patients were split into two groups according to whether they exhibited a 50% improvement in test scores (good/high response group: n = 26) or not (poor/low response group: n = 41). In both healthy control and panic disorder individuals, there were no significant associations between HGF serum levels and STAI or NEO-PI-R scores. However, there was a significant correlation between serum HGF levels and fatigue in healthy control subjects in as scored by POMS testing. HGF concentration in the good/high response group was significantly elevated compared to both the low/poor response group (p < 0.01) and the control group (p < 0.01). HGF levels in the poor response group did not differ from the control group (p = 0.48). These results indicate that increased serum HGF levels might be a requirement for antidepressant efficacy in patients with panic disorders.

Long-term analysis of infectious complication after high-dose immunosuppressive therapy with CD34-selected autologous hematopoietic stem cell transplantation for patients with severe autoimmune diseases (AD) was performed. Theoretically, CD34 selection can reduce the risk of reinfusion of autoreactive lymphocytes. However, it is also associated with a significant reduction in T cells, natural killer cells, and monocytes, which in turn may compromise immune reconstitution, thereby increasing the risk of infection. Moreover, AD compromises host immunity and causes organ damage resulting in dysfunction of the cutaneous or mucosal barrier. In this study, the incidence rate of infections is reported in 14 patients who underwent high-dose (200 mg/kg) cyclophosphamide therapy followed by reinfusion of CD34-selected autologous peripheral blood stem cells. Bacterial complication occurred in 3 of 14 (21%) patients. Cytomegalovirus reactivation and adenovirus hemorrhagic cystitis were observed in 9 (64%) and 2 (14%) patients, respectively. As for late infectious complications, 7 patients (50%) developed dermatomal varicella zoster virus infection. No infection-related mortality was seen in this case series. Because the risk for infections approaches that seen in allogeneic transplant recipients, infection surveillance, diagnostic workup, and prophylactic strategies similar to those applicable to allogeneic recipients are warranted.

To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872-11877) was composed of the interleukin 5 receptor alpha chain(+) (IL-5Ralpha(+)) and IL-5Ralpha(-) fractions, and the former was the hEoP. The IL-5Ralpha(+)CD34(+)CD38(+)IL-3Ralpha(+)CD45RA(-) hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Ralpha(-) hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an "IL-5Ralpha-negative" criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders.

Background Previously, we showed the inverse association between lithium in drinking water and male suicide in Kyushu Island. The narrow variation in meteorological factors of Kyushu Island and a considerable amount of evidence regarding the role of the factors on suicide provoked the necessities of adjusting the association by the wide variation in sunshine, temperature, rain fall, and snow fall. Methods To keep the wide variation in meteorological factors, we combined the data of Kyushu (the southernmost city is Itoman, 26°) and Hokkaido (the northernmost city is Wakkanai, 45°). Multiple regression analyses were used to predict suicide SMRs (total, male and female) by lithium levels in drinking water and meteorological factors. Results After adjustment of meteorological factors, lithium levels were significantly and inversely associated with male suicide SMRs, but not with total or female suicide SMRs, across the 153 cities of Hokkaido and Kyushu Islands. Moreover, annual total sunshine and annual mean temperature were significantly and inversely associated with male suicide SMRs whereas annual total rainfall was significantly and directly associated with male suicide SMRs. Limitations The limitations of the present study include the lack of data relevant to lithium levels in food and the proportion of the population who drank tap water and their consumption habits. Conclusions The present findings suggest that trace lithium is inversely associated with male but not female suicide after adjustment of meteorological factors.