Coordination-Mediated Synthesis of Purification-Free Bivalent 99mTc-Labeled Probes for in Vivo Imaging of Saturable System.

In the synthesis of technetium-99m (99mTc) labeled target-specific ligands, the presence of a large excess of unlabeled ligands over 99mTc in the injectate hinders target accumulation of 99mTc-labeled ligands by competing for target molecules. To circumvent the problem, we recently developed a concept of the metal coordination-mediated multivalency, and proved the concept with a 99mTc-labeled trivalent compound [99mTc(CO)3(CN-RGD)3]+. In this study, D-penicillamine (Pen) was selected as a chelating molecule and a cyclic RGDfK peptide was conjugated to Pen via a hexanoic linkage (Pen-Ahx-c(RGDfK)). 99mTc complexation reaction, and the stability, integrin αvß3 binding affinity, and biodistribution of the 99mTc-labeled probe were investigated to evaluate the applicability of the concept to bivalent probes. 99mTc-[Pen-Ahx-c(RGDfK)]2 was obtained over 95% radiochemical yields under low Pen-Ahx-c(RGDfK) concentration (50 µM). 99mTc-[Pen-Ahx-c(RGDfK)]2 showed approximately 10-times higher integrin αvß3 binding affinity than the monovalent compounds, Pen-Ahx-c(RGDfK) and c(RGDyV). In biodistribution studies, the tumor accumulation of 99mTc-[Pen-Ahx-c(RGDfK)]2 was decreased to 77% and 43% of HPLC-purified (Pen-Ahx-c(RGDfK)-free) 99mTc-[Pen-Ahx-c(RGDfK)]2 by the presence of 5 nmol of unlabeled Pen-Ahx-c(RGDfK) and Re-[Pen-Ahx-c(RGDfK)]2, respectively. 99mTc-[Pen-Ahx-c(RGDfK)]2 provided tumor image without removing unlabeled ligand, while a 99mTc-labeled monovalent probe prepared from a monovalent ligand could not. These findings indicate the availability of the design concept to prepare 99mTc-labeled bivalent probes with a variety of 99mTc core and other metallic radionuclides of clinical relevance.

Psychosocial correlates of cortisol levels in fingernails among middle-aged workers.

It was recently suggested that cortisol levels in fingernails reflect cumulative hormone exposure over a relatively long period. This exploratory study cross-sectionally investigated the relationships between fingernail cortisol level and psychosocial stress in a sample of middle-aged workers (94 men and 29 women). The participants were asked to grow their fingernails for ∼2 weeks and then provide fingernail samples from every digit by using nail clippers. Further, they completed questionnaires for assessment of exposure to psychosocial stress in the past (stressful life events in the workplace in the previous year; e.g. change to a different line of work) and in the present (job stress and perceived stress). Results of a regression analysis adjusting for the effects of demographic variables showed that experience of stressful life events, but not job stress and perceived stress, was associated with elevated fingernail cortisol level. These findings indicate the potential of fingernail samples to retrospectively reflect individual differences in cortisol levels related to past psychosocial stress.

The Mechanism of False in Vitro Elevation of Uric Acid Level in Mouse Blood.

Thirty minutes incubation at room temperature elevates the uric acid (UA) level of mouse blood in a test tube, and has previously been reported as "false in vitro elevation of the uric acid level." However the UA level of human blood does not elevate using the same incubation. We clarified the mechanism of the false in vitro UA elevation using mice with highly active hypoxanthine phosphoribosyl transferase (Hprt) of B6-ChrXC(MSM), a consomic mouse strain with the chromosome portion of Mus musculus morocinus in the Hprt gene site, or mice with a targeted deletion of the urate oxidase gene (Uox) (Uox-knockout (KO)). The plasma levels of UA, hypoxanthine, and xanthine, determined by HPLC, were compared with those of C57BL/6J laboratory mice used as controls. The uric acid level of Uox-KO mice was approximately 10 times higher than that of control, did not elevated after incubation in the test tube. With allopurinol, the hypoxanthine levels of B6-ChrXC(MSM) and Uox-KO were significantly lower than that of controls. Without allopurinol, the UA and xanthine levels of B6-ChrXC(MSM) were significantly lower than those of C57BL/6J controls. Even with allopurinol, the UA and xanthine levels were still significantly lower than that of controls. In conclusion, "false in vitro elevation of uric acid level" seems to be caused by low levels of erythrocyte HPRT activity and the low plasma uric acid level of laboratory mice.

Association of subjective and objective socioeconomic status with subjective mental health and mental disorders among Japanese men and women.

BACKGROUND: An inverse association between socioeconomic status (SES) and mental health has been previously well reported, but the evidence is limited in Asian populations. PURPOSE: We therefore investigated the association of SES and subjective mental health and prevalence of any mental disorders in the general population of Japan. METHOD: We used data from the World Mental Health Japan Survey of 1,496 randomly selected people aged 20 years and older in Japan. Information on education level and household income were used as objective SES indicators, and subjective social status (SSS) was measured by responses to a question regarding social position. We calculated odds ratios of SES indicators for poor subjective mental health and 12-month prevalence of any mental disorders. RESULTS: The adjusted odds ratio (OR) (95 % confidence interval (CI)) of respondents who rated themselves as lower than middle status in the country (low SSS group) for poor subjective mental health was 2.24 (95 % CI: 1.41, 3.57) with reference to those who rated themselves as higher than middle status (high SSS group). Similarly, inverse associations of education level and household income with poor subjective mental health were identified. A J-shaped association was confirmed between SSS and 12-month prevalence of any mental disorders. The adjusted OR (95 % CI) of SSS for any mental diseases was 0.53 (95 % CI: 0.32, 0.86) for the middle SSS group and 1.61 (95 % CI: 0.96, 2.72) for the low SSS group, compared with the high SSS group. Those associations were not attenuated when objective SES indicators were adjusted. CONCLUSION: We found inversely linear associations between subjective and objective SES and poor subjective mental health among Japanese men and women. SSS was not significantly associated with 12-month prevalence of any mental disorders. Substantial social inequalities in mental health were identified in Japan, which has been considered an egalitarian society with relatively few inequalities in health.

Macrophage migration inhibitory factor is a possible candidate for the induction of microalbuminuria in diabetic db/db mice.

Preventing the onset of microalbuminuria in diabetic nephropathy is a problem that needs urgent rectification. The use of a mouse model for diabetes is vital in this regard. For example, db/db mice exhibit defects in the leptin receptor Ob-Rb sub-type, while the ob/ob strain exhibits defects in the leptin ligand. These mouse strains demonstrate type 2 diabetes, either with or without microalbuminuria, respectively. The purpose of the present study was to use DNA microarray technology to screen for the gene responsible for the onset of diabetic microalbuminuria. Using Affymetrix Mouse Gene ST 1.0 arrays, microarray analysis was performed using total RNA from the kidneys of ob control, ob/ob, db/m, and db/db mice. Microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that transcription of the macrophage migration inhibitory factor (MIF) gene was significantly enhanced in the kidneys of db/db mice. Western blotting showed that levels of MIF protein was enhanced in the kidneys of both diabetic db/db and ob/ob mice. On the other hand, elevation of urinary MIF excretion detected by enzyme-linked immunosorbent assay (ELISA) was only in db/db mice and preceded the onset of microalbuminuria. Immunofluorescence studies revealed that MIF was expressed in mouse kidney glomeruli. While MIF expression was enhanced in the diabetic kidneys of both mouse strains, the elevated secretion from db/db mouse kidneys may be responsible for initiating the onset of microalbuminuria in diabetic nephropathy.

Social capital and stigma toward people with mental illness in Tokyo, Japan.

Living in a community with high social capital might lead to lower stigma towards people with mental illness. We examined the association between social capital and stigma toward people with mental illness in the community of Tokyo, Japan. A random sample of 2,000 community residents was selected and surveyed. Data from 516 respondents were analyzed. In this study, two individual-based social capital variables were significantly and negatively associated with the stigma score, while area-based social capital was not significantly associated with the stigma score. Social capital, particularly reciprocity/norm of cooperation and trust in the community, may be associated with lower stigma.

[Epidemiology of psychiatric disorders among medically ill patients].

This article reviews recent epidemiological findings on the relationship between physical and psychiatric conditions. First, physical disorders may be a risk factor of mental disorders. The WHO World Mental Health (WMH) Surveys indicated that the prevalence of most mental disorders were high among persons with a variety of physical disorders. Second, mental disorders may affect the course and prognosis of physical disorders. Several studies reported increased mortality when depression was comorbid with cancer, stroke, heart disease and diabetes. Third, social functioning was more deteriorated among those with comorbid physical and mental disorders than those with either of them. The comorbidity with mental disorders and its impact on the longevity and social life are observed for most physical disorders.

Study profile: protocol outline and study perspectives of the cohort by the National Institute of Occupational Safety and Health, Japan (JNIOSH cohort).

How work burden affects physical and mental health has already been studied extensively; however, many issues have remained unexamined. In 2017, we commenced a prospective cohort study of workers at companies in Japan, with a follow-up period of 5-10 years, in order to investigate the current situation of overwork-related health outcomes. From 2017 to 2020, a target population of 150,000 workers across 8 companies was identified. Of these, almost 40,000 workers agreed to participate in the baseline survey. Data on working hours, medical check-up measurements, occupational stress levels, and lifestyle habits were collected. The average age of the participants at baseline was 39.2 ± 11.7 years; 73.1% were men, and 87.7% were regular employees. The most common working hours by self-reported was 41-50 hours per week during normal season, and it increased to more than 50 hours during busy season. Furthermore, more than half of the participants reportedly experienced a form of sleep problem, and the percentage of those who experienced nonrestorative sleep was particularly high.

Benefits of group compassion-focused therapy for treatment-resistant depression: A pilot randomized controlled trial.

Major depression is one of the most common mental health problems worldwide. More than one-third of patients suffer from treatment-resistant depression (TRD). In this study, we explored the feasibility of group compassion-focused therapy (CFT) for TRD using a randomized controlled trial with two parallel groups. Eighteen participants were randomly allocated to the intervention group (CFT and usual care) and control group (usual care alone) and a participant in each group withdrew. Participants in the intervention group received a 1.5-h session every week for 12 weeks. The effects of the intervention on the participants' scores were calculated using a linear mixed model. There was a larger reduction in their depressive symptoms and fears of compassion for self and a greater increase in their compassion for self compared to the control group participants. The reliable clinical indices showed that in the CFT (intervention) group, three of nine participants recovered (33%), two improved (22%), two recovered but non-reliably (22%), and the condition of two remained unchanged (22%). These findings indicate adequate feasibility of group CFT for TRD in Japanese clinical settings. Clinical trial registration: [https://clinicaltrials.gov/], identifier [UMIN 000028698].

Cost of depression among adults in Japan in 2005.

AIM: Major depression is expected to become the leading contributor to disease burden worldwide by 2020. Previous studies have shown that the societal cost of depression is not less than that of other major illnesses, such as cardiovascular diseases or AIDS. Nevertheless, the cost of depression in Japan has never been examined. The goal of the present study was to estimate the total cost of depression in Japan and to clarify the characteristics of this burden. METHODS: A prevalence-based approach was adopted to measure the total cost of depression. The total cost of depression was regarded as being comprised of the direct cost, morbidity cost and mortality cost. Diagnoses included in this study were depressive episodes and recurrent depressive disorder according to the ICD-10 or major depressive disorder according to the DSM-IV. Data were collected from publicly available statistics and the World Mental Health Japan Survey database. RESULTS: The total cost of depression among adults in Japan in 2005 was estimated to be ¥2.0 trillion. The direct cost was ¥0.18 trillion. The morbidity cost was ¥0.92 trillion, while the mortality cost was ¥0.88 trillion. CONCLUSION: The societal costs caused by depression in Japan are enormous, as in other developed countries. Low morbidity costs and extremely high mortality costs are characteristic in Japan. Effective interventions for preventing suicide could reduce the societal costs of depression.

Work e-mail after hours and off-job duration and their association with psychological detachment, actigraphic sleep, and saliva cortisol: A 1-month observational study for information technology employees.

OBJECTIVE: A sufficient duration of time off after work is necessary to ensure workers' health. Better quality of off-job time can also facilitate recovery from fatigue, but its quantitative influence is largely unknown. We aimed to examine how off-job time quality (as measured by the frequency of emailing after work), and off-job duration is associated with psychological detachment, actigraphic sleep, and saliva cortisol using a 1-month observational study. METHODS: The participants were 58 daytime employees working at an information technology company. Sleep actigraphy and saliva cortisol as well as self-reported outcomes were repeatedly measured for 1 month. Two-way (work e-mail frequency × off-job time) multilevel mixed-effects linear regression analyses were performed in both continuous and categorical variables. RESULTS: The frequency of work e-mailing after hours was significantly associated with self-reported outcomes and actigraphic sleep quality, while a significant association was not found in cortisol awakening responses and actigraphic sleep duration. A significantly larger cortisol response after awakening was found in shorter, rather than longer, durations of off-job time. Self-reported detachment, rumination and carry-over fatigue showed significant interactions between work e-mail and off-job time, suggesting that worse outcomes were found in a higher frequency of work e-mail even when employees had longer amounts of off-job time. CONCLUSION: Our findings suggest that ensuring the quality and duration of off-job time is beneficial for recovery from work with sufficient sleep. Specifically, the frequency of e-mailing after work should be minimized to make recovery complete.

Lifetime prevalence, psychiatric comorbidity and demographic correlates of "hikikomori" in a community population in Japan.

The epidemiology of "hikikomori" (acute social withdrawal) in a community population is not clear, although it has been noted for the past decade in Japan. The objective of this study is to clarify the prevalence of "hikikomori" and to examine the relation between "hikikomori" and psychiatric disorders. A face-to-face household survey was conducted of community residents (n=4134). We defined "hikikomori" as a psychopathological phenomenon in which people become completely withdrawn from society for 6 months or longer. We asked all respondents whether they had any children currently experiencing "hikikomori". For respondents aged 20-49 years old (n=1660), we asked whether they had ever experienced "hikikomori". A total of 1.2% had experienced "hikikomori" in their lifetime. Among them, 54.5% had also experienced a psychiatric (mood, anxiety, impulse control, or substance-related) disorder in their lifetime. Respondents who experienced "hikikomori" had a 6.1 times higher risk of mood disorder. Among respondents, 0.5% currently had at least one child who had experienced "hikikomori". The study suggests that "hikikomori" is common in the community population in Japan. While psychiatric disorders were often comorbid with "hikikomori", half of the cases seem to be "primary hikikomori" without a comorbid psychiatric disorder.

Organizational justice, psychological distress, and work engagement in Japanese workers.

PURPOSE: To investigate the cross-sectional association between organizational justice (i.e., procedural justice and interactional justice) and psychological distress or work engagement, as well as the mediating roles of other job stressors (i.e., job demands and job control, or their combination, effort-reward imbalance [ERI], and worksite support). METHODS: A total of 243 workers (185 males and 58 females) from a manufacturing factory in Japan were surveyed using a self-administered questionnaire including the Organizational Justice Questionnaire, Job Content Questionnaire, Effort-Reward Imbalance Questionnaire, K6 scale, Utrecht Work Engagement Scale, and other covariates. Multiple mediation analyses with the bootstrap technique were conducted. RESULTS: In the bivariate analysis, procedural justice and interactional justice were significantly and negatively associated with psychological distress; they were significantly and positively associated with work engagement. In the mediation analysis, reward at work (or ERI) significantly mediated between procedural justice or interactional justice and psychological distress; worksite support significantly mediated between procedural justice or interactional justice and work engagement. CONCLUSION: The effects of organizational justice on psychological distress seem to be mediated by reward at work (or ERI) while those regarding work engagement may be mediated by worksite support to a large extent, at least in Japanese workers.

Construct validity and test-retest reliability of the World Mental Health Japan version of the World Health Organization Health and Work Performance Questionnaire Short Version: a preliminary study.

The aim of the study was to investigate test-retest reliability and construct validity of the World Mental Health Japan (WMHJ) version of World Health Organization Health and Performance Questionnaire (WHO-HPQ) short version according the COSMIN standard. We conducted two consecutive surveys of 102 full-time employees recruited through an Internet survey company in Japan, with a two-week interval in 2018. We calculated Pearson's correlation (r) of measures of the WHO-HPQ with other presenteeism scales (Stanford Presenteeism Scale, Work Functioning Impairment Scale, and perceived relative presenteeism), health and psychosocial job conditions. We tested the test-retest reliability (intraclass correlation, ICC) among those who reported no change of job performance during the follow-up. Among 92 (90%) respondents, the absolute presenteeism significantly correlated with WFun and perceived relative presenteeism (r=-0.341 and -0.343, respectively, p=0.001) and psychological distress (r=-0.247, p=0.018). The absolute/relative absenteeism did not significantly correlate with the other covariates. The test-retest reliability over a two-week period was high for the WHO-HPQ absolute presenteeism (ICC, 0.73), while those for absolute/relative absenteeism measures were moderate. The study found an adequate level of test-retest reliability, but limited support for the construct validity of the absolute presenteeism measure of the WMHJ version of the WHO-HPQ. Further research is needed to investigate the construct validity of the WHO-HPQ measures in a larger sample.

Objective and subjective working hours and their roles on workers' health among Japanese employees.

This study investigated the correlation between objective and subjective working hours (OWH and SWH, respectively) and their relation to the workers' health. The study included 6,806 workers of a Japanese company (response rate=86.6%). OWH were collected as the monthly data during fiscal year 2017 from the company record. SWH were self-reported as the weekly data during the past month in November 2017. Both OWH and SWH corresponded to the same period of one month (October 2017). Additionally, the data for the annual health checkup in fiscal year 2017 and self-reported mental health in November 2017 were collected. The results indicated that the longer OWH was related to more underestimation of SWH. The analyses of covariance adjusted for the selected variables showed that irrespective of OWH or SWH, significant relationships were found for stress responses but not for body mass index, aspartate and alanine aminotransferase, fasting blood glucose, hemoglobin A1c, high-density lipoprotein cholesterol, or triglyceride. However, significant relationships with only OWH were noted for systolic and diastolic blood pressure, low-density lipoprotein cholesterol, gamma-glutamyl transpeptidase, and positive work-related state of mind. The present findings show that SWH should be used carefully when assessing the health effects of long working hours.

[Effectiveness of Topical NSAIDs in a Gastric Cancer Patient with Bone Metastasis Pain during Therapy with Opioids and Oral NSAIDs].

Cancer patients often suffer from severe pain related to bone metastasis. We encountered a patient in whom the addition of topical non-steroidal anti-inflammatory drugs (NSAIDs) for persistent pain related to bone metastasis during therapy with opioids and oral NSAIDs reduced pain, improving activities of daily living (ADL). Fentanyl patches, celecoxib, denosumab, and topical NSAIDs (loxoprofen tape, felbinac) were administered to a 72-year-old patient with gastric cancer and pain related to bone metastasis. Pain control was favorable, with a numerical rating scale (NRS) score of 2 and Japanese version Support Team Assessment Schedule (STAS-J) score of 1. Intervention by pharmacists for the use of topical NSAIDs decreased both the NRS and STAS-J scores to zero, improving ADL. The results suggest that topical NSAIDs relieve bone-metastasis-related pain, improving ADL. When bone-metastasis-related pain is localized, the prescription of topical NSAIDs should be considered, and positive intervention by pharmacists regarding their usage should be promoted.

Objective and Subjective Working Hours and Their Roles on Workers' Health among Japanese Employees.

Table 3 of the above paper appeared incorrectly in print. Percentage figures on the table were inadvertently listed as negative values. These errors were corrected in online versions of this paper, as shown below.

The development of the Japanese version of the compassionate engagement and action scales.

The last few years have seen increasing research on self-report measures of compassion. The Compassionate Engagement and Action Scale (CEAS) is rooted in an evolutionary approach to compassion, which focuses on the competencies of compassion those are engagement with distress or suffering, and taking action to alleviate and prevent it. This study sought to validate the CEAS in a Japanese population using a cross-sectional design. A total of 279 students (82 males, 191 females, 6 unknown) answered self-report questionnaires, including the Japanese version of CEAS. We found single-factor structures for compassion for others scales, compassion from others scales, and compassion for self scales. All scales were found to have acceptable internal consistency, test-retest reliability, content validity, and construct validity. Even though some limitations, these results indicate that the Japanese version of CEAS is an adequately constructed and useful measure to assess compassionate engagement and action toward others, from others, and for the self with Japanese population.

Non-fearful vs. fearful panic attacks: a general population study from the National Comorbidity Survey.

BACKGROUND: Non-fearful panic attacks constitute a subgroup of panic attacks without the experience of subjective fear. However, previous studies were mostly carried out under medical settings and with small samples. The present study aims to clarify and expand the previous findings including the prevalence and characteristics of non-fearful panic attacks by using the National Comorbidity Survey (NCS) database. METHODS: From the 8098 original respondents in the NCS, subjects who met the DSM-III-R diagnostic criteria for a lifetime panic attack were selected. Of these, individuals with non-fearful panic attacks were identified and comparisons with subjects with fearful panic attacks were conducted. RESULTS: 30% of panic attacks occur without fears of dying or going crazy. Although these non-fearful panic attacks do not differ from their fearful counterparts in terms of age, age of onset or frequency of attacks, they are less often associated with some symptoms including shortness of breath, trembling, smothering and depersonalization, lead less often to anticipatory anxiety, and lead to less treatment with medication. Although they lead equally to panic disorder diagnosis and cause as much functional impairment, the non-fearful ones are less often associated with diagnoses of agoraphobia, as well as many other Axis I disorders such as major depressive disorder, simple phobia and substance-related disorders. LIMITATIONS: Recall bias and response bias may have distorted estimated relationships. CONCLUSIONS: Although milder in terms of symptomatology and some comorbidity, clinicians need to pay appropriate attention to non-fearful subtypes of panic attacks which appear to be equally dysfunctional.

Lifetime comorbidities between phobic disorders and major depression in Japan: results from the World Mental Health Japan 2002-2004 Survey.

BACKGROUND: Although often considered of minor significance in themselves, evidence exists that early-onset phobic disorders might be predictors of later more serious disorders, such as major depressive disorder (MDD). The purpose of this study is to investigate the association of phobic disorders with the onset of MDD in the community in Japan. METHODS: Data from the World Mental Health Japan 2002-2004 Survey were analyzed. A total of 2,436 community residents aged 20 and older were interviewed using the WHO Composite International Diagnostic Interview 3.0 (response rate, 58.4%). A Cox proportional hazard model was used to predict the onset of MDD as a function of prior history of DSM-IV specific phobia, agoraphobia, or social phobia, adjusting for gender, birth-cohort, other anxiety disorders, education, and marital status at survey. RESULTS: Social phobia was strongly associated with the subsequent onset of MDD (hazard ratio [HR]=4.1 [95% CI: 2.0-8.7]) after adjusting for sex, birth cohort, and the number of other anxiety disorders. The association between agoraphobia or specific phobia and MDD was not statistically significant after adjusting for these variables. CONCLUSIONS: Social phobia is a powerful predictor of the subsequent first onset of MDD in Japan. Although this finding argues against a simple neurobiological model and in favor of a model in which the cultural meanings of phobia play a part in promoting MDD, an elucidation of causal pathways will require more fine-grained comparative research.