Refractory Depression With Persistent Sore Throat and Hypochondriacal Delusion of SARS-CoV-2 Infection: A Case Study.

ABSTRACT: Herein, we present a case of a female patient with a persistent sore throat, which preceded a hypochondriacal delusion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Both the sore throat and hypochondriacal delusion persisted together, despite the repeatedly negative results of reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 and a moderate improvement in her depression. Four possibilities for the patient's sore throat were discussed: pain symptoms of somatic symptom disorder, pain symptoms of depression, delusion of pain in her throat, and somatic hallucination as a sore throat. Consequently, somatic hallucinations were considered the most likely. In any case, the present findings suggest that sore throat can precede hypochondriacal delusion of SARS-CoV-2 infection in some noninfected patients. When patients continue to complain of a sore throat despite the negative results of SARS-CoV-2 by the RT-PCR test, we should consider that it might be a somatic hallucination and soon hypochondriacal delusions may occur, leading to the manifestation of other symptoms of psychiatric disorders, such as depression, which may be refractory and/or suicidal.

Lithium in drinking water and Alzheimer's dementia: Epidemiological Findings from National Data Base of Japan.

OBJECTIVES: The aim of this study was to investigate the association between lithium levels in drinking water and prevalence of Alzheimer's dementia (AD). METHODS: 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. RESULTS: The adjusted model showed a significant inverse association of lithium levels with female, but not with male, or total prevalence of AD. CONCLUSIONS: These findings suggest that higher lithium levels in drinking water may be associated with lower prevalence of AD in female, but not male, populations.

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

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.

Lithium in drinking water and suicide prevention: The largest nationwide epidemiological study from Japan.

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.

Addition of plerixafor for mobilization of stem cells with bortezomib is feasible in dialysis-dependent multiple myeloma.

Plerixafor and bortezomib have recently been used in autologous stem cell collection to increase the amount of stem cells collected. However, no reports have described the combined use of plerixafor and bortezomib in cases of dialysis-dependent multiple myeloma. The dialysis-dependent multiple myeloma patient in the present study had a small amount of CD34-positive cells with plerixafor and filgrastim, and also with bortezomib and cyclophosphamide. However, by adding plerixafor to bortezomib and cyclophosphamide, collected CD34-positive cells were increased six-fold compared to the previous day. These findings suggest that the combination of plerixafor and bortezomib may be effective in those patients.

Tyrosine kinase inhibitors induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase II on genomic BCR-ABL.

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.

Safety and Seropositivity after Live Attenuated Vaccine in Adult Patients Receiving Hematopoietic Stem Cell Transplantation.

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.

Relationship between hyperthymic temperament, self-directedness, and self-transcendence in medical students and staff members.

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.

Relationship between ambient light and glucose metabolism in healthy subjects.

BACKGROUND: Given the reported inverse association between light and depressive mood, ambient light may also be associated with some of the brain regions in healthy subjects. The present study aims to investigate the effects of ambient light on glucose metabolism in the brain. We used the data of 28 healthy participants of the no intervention group from our previous randomized controlled trial and analyzed the association between ambient light and [18F]-FDG uptake in the brain. RESULTS: A whole brain analysis revealed a cluster of [18F]-FDG uptake that was significantly and inversely associated with log-transformed ambient light in the left culmen of the left cerebellum vermis. After adjustment for age, gender and serum melatonin levels, there remained a significant cluster of [18F]-FDG uptake with log-transformed ambient light in the left cerebellar vermis. CONCLUSIONS: The present findings suggest that the uptake of [18F]-FDG is significantly and inversely associated with ambient light in the left cerebellar vermis in healthy subjects. The cerebellar vermis may be involved in mood suppression which may be alleviated by light exposure where glucose uptake and metabolism in this area are decreased. Trial Registration This study is a secondary analysis of the previous randomized study which was registered as UMIN000007537. Retrospectively registered (March 20th, 2012).

Relationship between anxious temperament and harm avoidance in medical students and staff.

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.'

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8(+) T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8(+) T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8(+) T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8(+) T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226(high)CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226(+)CD8(+) T cells produced higher amount of various cytokines than CD226(-) ones, and CD226(high)CD8(+) T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8(+) T cells against HUVECs. Finally, the neutralization of CD226 in CD8(+) T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8(+) T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.

CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor.

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 CD41(hi) 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 CD41(hi) 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 CD41(hi) CMP and the LMPP populations.

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.

[A case report of malignant lymphoma receiving infliximab therapy with Behçet's disease].

BACKGROUND: To report a case of malignant lymphoma occurring in Behçet's disease (BD) with infliximab therapy. CASE: A 62-year-old man was diagnosed with BD in 1997. Despite treatment with colchicine, cyclosporine and prednisolone, he had frequent bilateral posterior ocular attacks. He was started on infliximab in August 2007 and for 6 months had no ocular attacks. Cyclosporine was therefore reduced. After 4 years of infliximab administration, he had neither ocular attacks nor general symptoms. However, he had general malaise and weight loss from the end of March 2012. Peripheral blood examination showed abnormal cells, so we terminated the infliximab. Bone marrow aspiration showed diffuse proliferation of medium to large lymphoid cells, and the histological diagnosis was diffuse large B-cell lymphoma. He was treated with 8 cycles of chemotherapy and 4 times intrathecal chemotherapy, and is now in remission. After termination of infliximab, he had no further ocular attacks. CONCLUSION: Although malignant lymphoma associated with BD is rare, attending ophthalmologists need to keep it in mind.

Association between irritable temperament and glucose metabolism in the left insula and the right cerebellum.

INTRODUCTION: Affective temperaments are assumed to have biological and neural bases. In the present study, we analyzed 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images of healthy participants to explore the neural basis of affective temperaments. METHOD: We utilized data of affective temperament measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire and 18F-FDG PET images of healthy participants from two of our previous studies. A multiple regression analysis was performed to assess the association between 18F-FDG uptake and temperament scores using Statistical Parametric Mapping 12. RESULTS: The final sample included 62 healthy participants. Whole-brain analysis revealed a cluster of 18F-FDG uptake that was significantly and positively associated with irritable temperament scores in the right cerebellum (Crus II, VIII, and IX). After further adjustment for the other four temperament scores, whole-brain analysis revealed a cluster of 18F-FDG uptake significantly and positively associated with irritable temperament scores in the left insula and right cerebellum (Crus II, VIII, and IX). However, no significant association was found between 18F-FDG uptake and the other four temperaments (depressive, cyclothymic, hyperthymic, and anxious). CONCLUSIONS: The left insula and right cerebellum of the cerebrocerebellar circuit may be one of the neural bases of irritable temperament.

Predictors of the Overall Survival with Azacitidine Monotherapy in Untreated Acute Myeloid Leukemia Patients Ineligible for Intensive Therapy.

Objective The prognostic factors for azacitidine in untreated acute myeloid leukemia (AML) patients ineligible for intensive therapy remain unknown. 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 Plt <27,000/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.

Increased volume of the left hippocampal dentate gyrus after 4 weeks of bright light exposure in patients with mood disorders: a randomized controlled study.

Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had previously conducted a randomized controlled trial (RCT) in which a 4-week period of BL in healthy participants resulted in increased volume of the left DG-head. This study aimed to investigate the effects of BL on the DG in patients with mood disorders. A 4-week RCT was conducted in which patients with mood disorders were randomly assigned to either a BL group (10,000 lx) or dim light exposure group (DL group; 50 lx). All patients underwent clinical assessment and magnetic resonance imaging at baseline and after the intervention. The study registration number is UMIN000019220. Our final sample included 24 patients (BL group, n = 12; DL group, n = 12). A significant effect of time and group was detected in the volumes of the left DG-head (F (1, 22) = 11.6, partial η2 = 0.35, p = 0.003) and left DG-total (left DG-total = left DG-head + left DG-body; [F (1, 22) = 6.5, partial η2 = 0.23, p = 0.02]). Additionally, the BL group demonstrated a significant increase in the volume of the left DG-head (95% CI: -5.4 to -1.6, d = 1.2, p = 0.002) and left DG-total (95% CI: -6.3 to -1.5, d = 1.06, p = 0.005) as well as a positive correlation between the percentage change in the volume of the left DG-total and the percentage change in the scores of the mood visual analog scale (r = 0.58, p = 0.04). In conclusion, our study results suggest that compared to DL, BL leads to a significantly greater increase in the left DG volume in patients with mood disorders. This increase in the left DG volume may be associated with mood improvement in the patients.