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Aim This study sought to characterize the plasma metabolite profiling of patients with major depressive disorder (MDD). Methods Psychiatric assessments were made with the Structured Clinical Interview for DSM-IV Axis I Disorders. In the exploratory cohort, plasma metabolite profiles of 34 MDD patients and 31 mentally healthy controls were compared using capillary electrophoresis-mass spectrometry. Among the candidate metabolites, we focused on a metabolite showing the largest difference. The absolute concentrations were measured in two cohorts from a psychiatric primary care clinic to characterize the accuracy of the metabolite biomarker. Results Among 23 metabolites significantly lower in the MDD group than in healthy controls, we focused on phosphoethanolamine (PEA) as a candidate. The reduction of PEA levels in MDD was checked in independent clinical sample sets. An ion-chromatography-fluorescence detection method was developed to measure plasma PEA levels. In the preliminary cohort, we examined 34 MDD and 43 non-MDD subjects. The area under the receiver-operator curve (AUC) was 0.92, with sensitivity/specificity greater than 88%, at a cut-off of 1.46 μM. In the checking cohort, with 10 MDD and 13 non-MDD subjects, AUC was 0.89, with sensitivity/specificity of 86% and 100%, respectively, at a cut-off of 1.48 μM. Plasma PEA inversely correlated with MDD severity, depressed mood, loss of interest, and psychomotor retardation. Conclusion These results suggest that plasma PEA level could be a candidate biomarker of MDD in the clinical setting. Further studies comparing MDD and mentally healthy controls are needed to confirm the utility of PEA as a biomarker for depression.

Plasma phosphoethanolamine (PEA) levels are significantly decreased in major depressive disorder (MDD) patients compared to healthy controls: Also, in chronic ACTH treatment mouse model of MDD, plasma and frontal cortex PEA were significantly decreased compared to vehicle treated controls: PEA has thus been proposed as a potential diagnostic biomarker for MDD. However, the neuroendocrine mechanism by which PEA changes in vivo, and its role in the pathobiology of MDD is not yet known. Previous in vitro studies reported that the endogenous LXR agonist 25-hydroxycholesterol, the intermediate precursor for the conversion of cholesterol to steroid hormones in the adrenal gland, caused increased PEA levels in cells. To understand PEA function in the neuroendocrine circuitry of MDD, in vivo effects of 25-hydroxylcholesterol on PEA levels in blood plasma, adrenal gland, and brain nuclei implicated in MDD were studied in mice. Both targeted and untargeted metabolomics analysis using capillary electrophoresis-mass spectrometry were applied to measure PEA and various metabolite levels in the respective tissues. Here we report that while acute LXR agonism with 25-hydroxycholesterol decreased plasma PEA levels, chronic LXR agonism significantly increased plasma PEA levels in both male and female mice. Moreover, in the adrenal gland where LXR agonism mediates the synthesis of glucocorticoids from cholesterol, 25-hydroxycholesterol significantly increased adrenal PEA levels in female mice; with no change in PEA in male mice compared to vehicle treated controls. Furthermore, in the hypothalamus compared to vehicle controls, LXR agonism caused significant PEA level decrease in female mice by 20%; and by 80% increase in male mice. Additionally, metabolomics results showed significant changes in levels of several metabolites in key brain and peripheral tissues of 25-hydroxycholesterol treated mice. These results are suggestive of a neuroendocrine role for PEA in the pathobiology of MDD; and that by way of LXR signaling PEA may impact the hypothalamic-pituitary-adrenal axis in the control of stress response. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Major depression is a chronic illness and a major component of disease burden, with high prevalence in women than in men. Plasma phosphoethanolamine (PEA) levels are significantly decreased in major depressive disorder (MDD) patients compared to healthy controls. Additionally, in the chronic ACTH treatment MDD mouse model, plasma and frontal cortex PEA were significantly decreased compared to vehicle treated controls. However, the reasons behind MDD prevalence in females, the neuroendocrine mechanisms by which PEA changes in vivo, and its role in the pathobiology of MDD is not yet understood. In cells, LXR agonist 25-hydroxycholesterol increased PEA levels: To understand the sexually dimorphic PEA function in the neuroendocrine circuitry of MDD, basal in vivo central and peripheral PEA levels, as well as post 25-hydroxylcholesterol treatment PEA levels in blood plasma, adrenal gland, and brain nuclei implicated in MDD were studied in mice. Both targeted and untargeted metabolomics analysis using capillary electrophoresis-mass spectrometry were applied to measure PEA and various metabolite levels in the respective tissues. Here we report that compared to vehicle control females, vehicle treated male mice had about 50% higher basal plasma PEA levels than females. In the brain areas implicated in MDD, male mice displayed significantly increased basal PEA levels compared to female basal levels by about 3 fold. Specifically, basal PEA levels in males were higher than females in the frontal cortex, striatum, hippocampus, hypothalamus, and the amygdala. Moreover, while acute LXR agonist, 25-hydroxycholesterol decreased plasma PEA levels, chronic LXR agonism significantly increased plasma PEA levels in both male and female mice. Hypothalamic PEA decreased by 20% in females and 80% in males after LXR agonist treatment. Moreover, basal adrenal PEA was 45% significantly higher in females than in males; and 25-hydroxycholesterol significantly increased female adrenal PEA by 35% over basal levels, with no change in males. Metabolomics analysis further revealed significant changes in levels of several metabolites in the plasma, brains, and adrenals of 25-hydroxycholesterol treated mice in a sexually dimorphic manner. These findings underscore the importance of the PEA-LXR system in explaining the sexual dimorphic differential coping strategy of the two sexes to stressful stimuli; and may serve as a novel potential diagnostic and therapeutic target for major depressive disorder. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Aims Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. Methods and results The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000–04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50–79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality. The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73–1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55–0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64–0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01–4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07–11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03–1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40–0.99), respectively. Conclusion An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

As an idea to ensure the success of OMICS research, there is Virchow's pathological ideas of physical disease. This idea is that one cell, a group of cells, a substance, and a group of substances are specific for each disease. Based on this idea, it can be inferred that the unity and purity of the sample and the disease used are extremely important factors. In this study, the aim is to show how the difference in trivial centrifugal conditions of whole blood affected the plasma concentration of Phosphoethanolamine (PEA), a biomarker of depression shown in our previous study, It turned out that the value of PEA increases when the rotor is a swing type, or when the temperature at the time of centrifugation is set at 4°C. This increase might be due to platelet contamination in isolated plasma. Therefore, especially when the researchers are looking to discover an unknown marker, special attention should be paid to sample.

Background : Non-participants to psychosocial studies have been shown to have higher mortality, and mortality differs between partial and complete responders to psychosocial questionnaires. Yet, there is very little information available directly linking survey response status with completing suicide. Methods : The study population consisted of the participants of the Japanese Public Health Center-based prospective study. Ninety-nine thousand four hundred thirty-nine subjects who returned the 10-year follow-up questionnaire and 31 754 individuals who did not return the questionnaire were included in our analyses. The risk of dying by suicide according to response status was estimated by Cox regression models. Results : There were 358 suicides during 1 128 831 person-years of follow-up (mean follow-up time: 8.6 years). Of those who returned the questionnaire, 53.9% were full responders, 42.8% were partial non-responders, and 3.3% were complete non-responders. The risk of suicide was increased for both complete non-responders [hazard ratio (HR) = 1.84, 95% confidence interval (CI), 0.51, 6.64] and partial non-responders (HR = 1.36, 95% CI, 0.999, 1.84) to the questionnaire as a whole. The adjusting variables explained around 40% of the risk for complete non-responders whereas they did not explain the increased risk of suicide for partial non-responders. The risk of dying by suicide was significantly increased for partial non-responders to the subscale on coping (HR = 1.36, 95% CI, 1.01, 1.85) and for complete non-responders to questions on sleep (HR = 2.07, 95% CI, 1.03, 4.16). Conclusions : Partial and complete non-responders have increased suicide risk compared with complete non-responders. More than one non-responder category should therefore be considered when interpreting data pertaining to psychosocial questionnaires in longitudinal studies.

Purpose Cross-sectional studies have shown an association between different coping styles and suicidal behavior. It is unknown whether there is any prospective association between coping behaviors and suicide in the general population. Methods The study population consisted of participants of the Japanese Public Health Center-based Prospective Study. In the 10-year follow-up questionnaire, subjects aged 50–79 years were asked how they handle daily problems. Coping behaviors were used to determine two coping strategies (approach coping and avoidance coping). Of 99,439 subjects that returned the 10-year follow-up questionnaire, 70,213 subjects provided complete answers on coping and were included in our analyses. Cox regression models, adjusted for confounders, were used to determine the risk of committing suicide according to coping style. Mean follow-up time was 8.8 years. Results Two coping behaviors were significantly associated with suicide over time: planning (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41–0.98) and self-blame (HR, 2.20; 95% CI, 1.29–3.76). Of the coping strategies, only the avoidance coping strategy was significantly associated with suicide (HR, 2.45; 95% CI, 1.24–4.85). Conclusions For the first time, two coping behaviors and one coping strategy have been shown to have a significant prospective association with suicide in a general population.

This chapter outlines several illustrative cases for proposed future rural planning based on the landscape labor accounts. At first, the three case-studies for Asami, Nyu, and Kayumi in Part 3 (see Chaps. 13– 15) are compared, and characteristics or issues of labor accounts in agricultural areas are described. Second, the general characteristics of community management based on the other cases will be shown; finally, appropriate policies, social systems, and initiatives for sustainable management of agriculture and rural areas are discussed.

This study sought to characterize the plasma metabolite profiling of patients with major depressive disorder (MDD).Psychiatric assessments were made with the Structured Clinical Interview for DSM-IV Axis I Disorders. In the exploratory cohort, plasma metabolite profiles of 34 MDD patients and 31 mentally healthy controls were compared using capillary electrophoresis-mass spectrometry. Among the candidate metabolites, we focused on a metabolite showing the largest difference. The absolute concentrations were measured in two cohorts from a psychiatric primary care clinic to characterize the accuracy of the metabolite biomarker.Among 23 metabolites significantly lower in the MDD group than in healthy controls, we focused on phosphoethanolamine (PEA) as a candidate. The reduction of PEA levels in MDD was checked in independent clinical sample sets. An ion-chromatography-fluorescence detection method was developed to measure plasma PEA levels. In the preliminary cohort, we examined 34 MDD and 43 non-MDD subjects. The area under the receiver-operator curve (AUC) was 0.92, with sensitivity/specificity greater than 88%, at a cut-off of 1.46 μM. In the checking cohort, with 10 MDD and 13 non-MDD subjects, AUC was 0.89, with sensitivity/specificity of 86% and 100%, respectively, at a cut-off of 1.48 μM. Plasma PEA inversely correlated with MDD severity, depressed mood, loss of interest, and psychomotor retardation.These results suggest that plasma PEA level could be a candidate biomarker of MDD in the clinical setting. Further studies comparing MDD and mentally healthy controls are needed to confirm the utility of PEA as a biomarker for depression.

BackgroundAlthough there is speculation that individuals living in the vicinity of nuclear disasters have persistent mental health deterioration due to psychological stress, few attempts have been made to examine this issue.AimsTo determine whether having been in the vicinity of the Nagasaki atomic bomb explosion in the absence of substantial exposure to radiation affected the mental health of local inhabitants more than half a century later.MethodParticipants were randomly recruited from individuals who lived in the vicinity of the atomic bomb explosion in uncontaminated suburbs of Nagasaki. This sample (n = 347) was stratified by gender, age, perception of the explosion and current district of residence. Controls (n = 288) were recruited from among individuals who had moved into the area from outside Nagasaki 5–15 years after the bombing, matched for gender, age and district of residence. The primary outcome measure was the proportion of those at high risk of mental disorder based on the 28-item version of the General Health Questionnaire, with a cut-off point of 5/6. Other parameters related to individual perception of the explosion, health status, life events and habits were also assessed.ResultsHaving been in the vicinity of the explosion was the most significant factor (OR = 5.26, 95% CI 2.56–11.11) contributing to poorer mental health; erroneous knowledge of radiological hazard showed a mild association. In the sample group, anxiety after learning of the potential radiological hazard was significantly correlated with poor mental health (PConclusionsHaving been in the vicinity of the atomic bomb explosion without radiological exposure continued to be associated with poorer mental health more than half a century after the event. Fear on learning about the potential radiological hazard and lack of knowledge about radiological risk are responsible for this association.

Background Psychological stress is a modifiable risk factor for health outcomes and can be managed through coping mechanisms. Biological and behavioral hypotheses have been proposed to explain the association between stress coping strategies and cancer outcomes. Methods The Japan Public Health Center-based study asked questions on coping behaviors in its 10-year follow-up survey. 55,130 subjects aged 50–79 without a history of cancer diagnosis and who provided complete answers on coping were included in analyses on cancer incidence and mortality. Hazard Ratios (HR) according to coping style were determined using Cox regression models adjusted for known confounders for cancer. Results Mean follow-up time was 9.5 years for cancer incidence and 9.8 years for cancer mortality. The utilization of the approach-oriented coping strategy (HR = 0.85, 95% CI: 0.72–0.99) and a behavior of positive reappraisal (HR = 0.84, 95% CI: 0.72–0.97) was associated with a reduced risk of cancer mortality. The approach-oriented coping strategy was further associated with localized cancer incidence (HR = 1.13, 95% CI: 1.01–1.27) and screening-detected cancers (HR = 1.35, 95% CI: 1.15–1.58). The avoidance oriented coping strategy was inversely associated with cancer incidence (HR = 0.69, 95% CI: 0.50–0.94) only after excluding events occurring in the first three years of follow-up. Conclusion The results of this study may favor the behavioral hypothesis to explain associations between premorbid coping styles and cancer outcomes.

The aim of this article is to introduce the proteomic analysis of psychiatric disorders and psychological stress and the ongoing study on Tsunami victims in Srilanka.

Recurrent disasters such as the tsunami in South East Asia and floods in New Orleans have focused attention on the need for disaster management based on objective data. The goals of this study were to estimate the prevalence of posttraumatic stress disorder following a major disaster and to determine the relationship between exposure to traumatic events and the resulting psychological dysfunctions, namely PTSD and depression. The Harvard Trauma Questionnaire (HTQ) and The Hopkins Symptom Checklist-25 (HSCL-25) were administered to 106 participants (mean age 38.98 years; 42 males and 64 females) that included a group affected by the tsunami, consisting of 90 participants (mean age 40.27; 36 males and 54 female) and a control group consisting of 18 participants (mean age 31.22; 9 males and 8 females). Results indicated that 42% of participants who had experienced the tsunami were suffering from PTSD. Moreover, 45.8% of participants were suffering from depression. A logistic regression analysis indicated that experiencing the destruction of a house and property beyond repair, as well as witnessing the death of a child, an elderly relative, neighbour or friend, significantly predicted a diagnosis of PTSD. Being without food and water, the destruction of a house or property beyond repair, separation from family, being injured and being close to death were powerful determinants of PTSD and depression. These findings indicate that disaster management efforts in the future should focus on providing immediate medical treatment and supplies of food and water to disaster victims. Promptly reuniting family members, rebuilding houses and properties, as well as providing psychotherapy, particularly to bereaving victims, to those who had near death experiences and to those who were severely injured, should also be the priority in disaster management.

We attempted to measure symptomatic characteristics of PTSD in the victims of Tsunami disaster at Sri Lanka. At first, we develop the Harvard Traumatic Questionnaire (HTQ), Impact of the Event Scale Revised (IES-R), Hopkins Symptom Checklist (HCL) in Sri Lankan version for assessment. An expert in English and Sri Lankan translated these scales from English to Sri Lankan. Then, back-translation was done by a psychologist to check the difference between both versions. We administered these scales of the Sri Lankan version to 127 people who have been met with the Tsunami disaster [mean age = 39.0 (S.D. = 13.9)]. Psychometric properties of these scales were examined. Internal consistency as Cronbach's alpha of IES-R was 0.95. We determined if an individual met symptom criteria for the occurrence of PTSD according to a scoring algorithm proposed by the Harvard Refugee Trauma Group on the basis of DSM-4 diagnosis criteria derived from HTQ. We compared IES-R score of individual who has PTSD by HTQ with the score of non-PTSD. The difference was statistically significant by two-tailed t test ( t = − 6.44, df = 1/84, p

Although international business travel is increasing, there is a lack of research on its repercussions for mental health. This study analysed the long-term influence of international business travel on the mental health status by comparing depression, anxiety and job stress between workers with and without international assignment experience. The subjects were divided into an ëexperienced groupí composed of 70 male workers who had experienced an overseas assignment of at least six months, and a ënon-experienced groupí consisting of 2,163 male workers who had not. To assess the mental health status, Zungís Self-Rating Depression Scale (SDS) and Sheehanís Patient Rated Anxiety Scale (Sheehan) were employed. The Job Content Questionnaire (JCQ) was used to examine job stress. In addition, information about the characteristics of the overseas assignments was collected. The experienced group had significantly higher scores for job control, supervisor support and coworker support in the JCQ, while no differences were observed for the SDS and Sheehan. Whether or not the subjects travelled abroad with their families, whether or not they went against their will, and whether or not they enjoyed their stay had no effects on their mental health. Job demand had a significantly positive correlation with the duration of the assignment.

Social support is supposed to have a positive health effect via alteration of immunity. In this study, associations between perceived social support and immune systems were examined. Immunological assessments, e.g. T cell count, Natural Killer cell count, Interferon-gamma, Interleukin-4, and psychological assessments, e.g. Generic Job Stress Questionnaire were conducted on male employees. Two-way (social support x job stressor) analyses of covariance controlling for age, smoking, alcohol consumption, and exercise revealed that there were main effects of perceived social support on NK cell counts, IL-4, and Th1/Th2 balance. On the other hand, interaction effects were observed on T cell counts and INF-gamma production in vitro. Social support affects immune function in a way that is consistent with both the direct and buffering hypotheses depending on the sources of support and the immune parameter.

An Erratum has been published for this article in Stress and Health 20(5) 2004, 309. The relationship between past traumatic experience and stress tolerance is poorly understood. To investigate the relationship among past exposure to trauma, stress tolerance and other mental health indexes, experience of traumatic events, depression, anxiety, and job strain were assessed in 2959 male and 279 female workers. Job strain was used as an indicator of stress tolerance in this study. Past traumatic experience was shown to increase later anxiety for both sexes, and increase depression and job strain in male subjects. For the first time, people with past traumatic experiences were found to feel a stressor's influence more strongly. Further, those influences differed according to the type of past trauma. The existence of interactions among the experience of traumatic events, depression/anxiety, and strain indicated that stress tolerance seemed to be an important element in the trauma response mechanism. Copyright © 2004 John Wiley & Sons, Ltd.

Background: Specific coping styles have been shown to modulate stress-induced immune alterations and influence actual health outcomes. This study examined the effects of stressors and coping styles on human T-cell subpopulations and in vitro cytokine production using a cross-sectional design. Methods: Seventy-one men (18–60 years old) were asked to complete a self-administered questionnaire that evaluates quantitative workload, mental demand and coping styles. The numbers of T-cell subpopulations and concentrations of interferon-γ (IFN-γ) and interleukin-4 (IL-4) after stimulation with phytohemaglutinin were measured. Results: Positive and negative coping were negatively related to IL-4 and the number of CD4+ cells, respectively. Interactions between positive coping and mental demand significantly affected the number of CD8+ cells, IFN-γ, IL-4 and the IFN-γ/IL-4 ratio. Among men reporting high mental demand, positive coping was related to increased IFN-γ and IFN-γ/IL-4. Among men reporting low mental demand, positive coping was related to a decreased number of CD8+ cells and lower concentrations of IFN-γ and IL-4. Analyses adjusting for the numbers of CD3+ and CD8+ cells revealed that the interactive effects of positive coping and mental demand on cytokine levels were attributable to the changes in T-cell function rather than the number of T cells. No modulating effect of anxiety on the associations of stressors and coping with immune function was observed. Depressive symptoms slightly, though not significantly, modulated the association of negative coping and the number of CD4+ cells. Conclusions: From the perspective of immunology, optimal stress characteristics were determined by an individual’s coping styles, with positive coping being associated with stress-induced changes in the number of CD8+ cells and in vitro cytokine production from T cells. Our findings suggest that it is important to consider the interactive effects of the complexity of work and the individual coping style in stress management.

Prior studies have revealed that the sympathetic nervous system regulates the clinical and pathological manifestations of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model mediated by Th1 T cells. Although the regulatory role of catecholamines has been indicated in the previous works, it remained possible that other sympathetic neurotransmitters like neuropeptide Y (NPY) may also be involved in the regulation of EAE. Here we examined the effect of NPY and NPY receptor subtype-specific compounds on EAE, actively induced with myelin oligodendrocyte glycoprotein 35–55 in C57BL/6 mice. Our results revealed that exogenous NPY as well as NPY Y1 receptor agonists significantly inhibited the induction of EAE, whereas a Y5 receptor agonist or a combined treatment of NPY with a Y1 receptor antagonist did not inhibit signs of EAE. These results indicate that the suppression of EAE by NPY is mediated via Y1 receptors. Furthermore, treatment with the Y1 receptor antagonist induced a significantly earlier onset of EAE, indicating a protective role of endogenous NPY in the induction phase of EAE. We also revealed a significant inhibition of myelin oligodendrocyte glycoprotein 35–55-specific Th1 response as well as a Th2 bias of the autoimmune T cells in mice treated with the Y1 receptor agonist. Ex vivo analysis further demonstrated that autoimmune T cells are directly affected by NPY via Y1 receptors. Taken together, we conclude that NPY is a potent immunomodulator involved in the regulation of the Th1-mediated autoimmune disease EAE.

Both cellular and humoral functions of the immune system are modulated by the sympathetic nervous system (SNS). This interaction is mainly mediated by the release of catecholamines (CA) and their receptor-specific action on immune cells. However, neuropeptide Y (NPY), also present in sympathetic nerve terminals, is released upon SNS-stimulation. NPY modulates potent immunological effects in vitro and in vivo, such as differentiation of T helper cells, monocyte mediator release, NK cell activation, and immune cell redistribution. In addition to this direct action within the neuroimmune crosstalk, NPY is also able to modulate the immunomodulatory effects of other neurotransmitters, thereby acting as a neuroimmune co-transmitter. This review will discuss key findings from recent studies, provide implications for the clinical situation, and integrate the pleiotropic functions of NPY in the context of neuroimmune interactions.

Although a previous meta analysis showed some substantial relationships between social support and immune function, there is still no knowledge about the effects of social support on natural killer (NK) cell number. In this study we examined the direct relationships between peripheral lymphocyte subpopulations and several aspects of social support. We administered the Japanese version of the Stress and Coping Inventory (SCI) by Rahe (1994) to 98 male workers with a written informed consent. Blood samples were collected at 10.00 hours. Lymphocytes subsets were measured by flowcytometry using CD3, CD16, and CD56 antibodies. Partial correlation coefficient controlled by age and smoking between social support and immune cells revealed that there were weak but significant correlations between perceived social support and the numbers of CD3-/CD16+and CD3-/CD56+ NK cells (r = 0.25, 0.26). There was no correlation between social support and percentage of NK cells. Positive correlation of perceived social support with NK cell numbers suggested that perceived social support has a direct effect on NK cells and that increased social support might be accompanied by high natural immunity. Further investigation should be undertaken to elucidate why only perceived social support was correlated to NK cells. Copyright © 2003 John Wiley & Sons, Ltd.

Aims: To evaluate effects of exposure to bisphenol A diglycidyl ether (BADGE) on urinary excretion of bisphenol A, and plasma gonadotrophic hormones and testosterone in male epoxy resin sprayers. Methods: Cross sectional study of 42 workers whose job was to spray epoxy resin hardening agents including BADGE and mixed organic solvents, and 42 matched control workers without BADGE use in the same machine plants. Results: Concentrations of urinary bisphenol A were higher in the epoxy resin sprayers (median 1.06 µmol/mol creatinine) compared with the controls (median 0.52 µmol/mol creatinine). Urinary metabolite concentrations of organic solvents used were all higher in the epoxy resin workers compared with the controls. Endocrinological examination showed different concentrations of follicle stimulating hormone (FSH) between the epoxy sprayers (median 5.3 mIU/ml) and the controls (median 7.6 mIU/ml). FSH showed a mild correlation with urinary bisphenol A, but not with the metabolites of organic solvents. Luteinising hormone and free testosterone concentrations did not differ between the two groups. Conclusion: BADGE may generate bisphenol A endogenously. Results suggest that bisphenol A may disrupt secretion of gonadotrophic hormones in men. The clinical significance of endocrine disrupting effects by bisphenol A should be further investigated in male workers exposed to bisphenol A.

The authors developed the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J) and investigated its reliability and validity in four different groups: workers with lifetime mixed traumatic events, survivors of an arsenic poisoning case, survivors of the Hanshin-Awaji earthquake, and survivors of the Tokyo Metro sarin attack. Evidence includes retest reliability and internal consistency of the IES-R-J. Posttraumatic stress disorder (PTSD) and partial PTSD cases indicated significantly higher scores than non-PTSD cases. The IES-R-J can be a useful self-rating diagnostic instrument particularly for survivors with PTSD symptoms as a clinical concern (PTSD + partial PTSD) by using a 24/25 cutoff in total score. In analysis of scale structure, the majority of intrusion and hyperarousal items were subsumed under the same cluster, whereas avoidance items made up a separate cluster. Female patients indicated higher scores than male patients. A negative weak correlation between age and the score was found only among female earthquake survivors. The IES-R-J can be used as a validated instrument in future international comparative research.

The paper shows the challenge of tackling “On-site Research Training (ORT)” for establishment of “basic and clinical environmental studies.” Concepts of synthesis and generalization are important for understanding environmental issues in the real world. Essential approaches are communication with real society and environment, and collaboration of researchers and students in various academic disciplines. These bring us new ideas, understanding of complex structures, and solutions to real problems. The concept of “Mandala” describing comprehensive composition on environmental issues should be produced as well as organization of methodologies supporting a clinical approach.

Objective: The lateral hypothalamic area (LHa) is involved in various functions such as feeding, drinking, sexual and reward behavior, among others. Recently, we demonstrated that the LHa can regulate cellular immunity in the spleen. In experiments involving the LHa, it was noticed that the spleen shrinks noticeably after LHa destruction. To explore this phenomenon further, the effect of LHa lesioning on splenocyte apoptosis was investigated. Methods: Male Wistar-King-Aptekman rats underwent bilateral lesioning of their LHa and consequent spleen weights, splenocyte numbers and apoptosis were measured. For the detection of splenocyte apoptosis, both ELISA, which measures DNA fragmentation within the splenocytes, and flow cytometry, which measures the percentage of apoptotic lymphocytes in the spleen, were used. Results: In the LHa-lesioned rats, spleen weights and the number of splenocytes decreased significantly within 24 h. Additionally, in the spleen, lymphocyte apoptosis significantly increased compared to the control after 6 h. Conclusion: These results suggest that the LHa may play a role in immunoregulation by affecting lymphocytes in the spleen through apoptosis and may be relevant to the pathway of stress-induced apoptosis.

In rats splenic natural killer (NK) cell activity was found to be significantly higher following chronic uncontrollable electrical stimulation of the lateral hypothalamus in fully conscious rats, compared to sham-operated rats. In a pre-test study, all rats had demonstrated that the electrode site had self-stimulating properties, which supports the possibility that the experience of reward may be implicated in NK cell activity augmentation.

Electrical stimulation of the lateral hypothalamus (LH) in rats increased splenic natural killer (NK) cell activity, whereas electrical ablation of the LH decreased it. However, the percentage of NK cells, as detected by the anti-NKR-P1 monoclonal antibody, in the spleen did not change significantly. These results suggest that the LH does not modulate the splenic NK cell activity by increasing the NK cell number but by increasing the intrinsic NK cell activity itself.

This study examined the relationship of sleep characteristics including insomnia with scores on alexithymia in a sample of 171 Japanese working men. Levels of nonrestorative sleep and daytime sleepiness reported on a sleep questionnaire were significantly associated with scores on Depression and Confusion on the Profile of Mood States for Japanese men who had a high mean score on the Toronto Alexithymia Scale.

We examined the influences of perceived parental bonding on scores on alexithymia in a sample of 232 college students. Ratings on mothers' care, a scale of the Parental Bonding Inventory were significantly and negatively correlated with scores on the Toronto Alexithymia Scale, and also with ratings on Difficulty Describing Feelings but not Difficulty Identifying Feelings and Externally Oriented Thinking. These results were replicated in another sample of 156 college students. Although our findings were based on simple correlations, they suggest that perceived mothers' low care is related to adults' scores on alexithymia, in particular, the construct, Difficulty Describing Feelings.

Natural killer cell (NK) activity in WKA and SD rats was found to be significantly higher following electrical stimulation of the lateral hypothalamus (LH) compared to sham operated. There was no such difference between sham operated rats and those receiving electrical stimulation in the frontal cortex as a control. Operations were performed under sodium pentobarbital anesthetic, and NK activity against YAC-1 target cells was measured 20 h later using 51Cr release assay. The LH area stimulated is a potent reward center and that stimulation of this point increased NK activity opens the possibility that pleasure might play a role in cellular immunity.

High rates of medical morbidity have been reported in subjects with posttraumatic stress disorder (PTSD). The authors examined immune function in subjects in remission from past PTSD.The initial study group was composed of 1,550 Japanese male workers. Japanese versions of the Events Check List, the Impact of Event Scale-Revised, and the Diagnostic Interview Schedule for DSM-IV were used to identify subjects who had a past history of PTSD. Twelve of the workers were identified as having such a history. These men were matched in age and smoking habits, which affect immunity, to 48 comparison subjects who had similar stressful life experiences but no current or past history of PTSD. Natural killer (NK) cell activity, lymphocyte subset counts, and production of interferon gamma (IFN-gamma) and interleukin-4 (IL-4) were measured in the 60 men by means of phytohemagglutinin stimulation.The number of lymphocytes, number of T cells, NK cell activity, and total amounts of IFN-gamma and IL-4 were significantly lower in the 12 men with a past history of PTSD.PTSD leaves a long-lasting immunosuppression and has long-term implications for health.

Publisher Summary This chapter summarizes the effect of the LH and reward behavior on the augmentation of cellular immunity. In addition to NK cell population and function, T-cell populations and Th1 functions are modulated centrally by the LH and by reward stimulation. LH does not modulate splenic NK cell activity by increasing NK cell numbers, but rather by increasing NK cell activity. Chronic stimulation of the LH caused significant augmentation of NK cell activity. Rats responding to LH stimulation with feeding showed a slightly greater effect than those responding with a locomotor reaction. The observed effects were anatomically specific. The involvement of the LH in reward phenomena was shown to be associated with NK cell augmentation as well. T-cell and Th1 cell functions are sensitive to stress. However, there are no data that illustrate the correlation of reward center with T cells and with their function. Results strongly suggest that excitation of the LH is linked with reward behavior and that pleasure increases type 1 T-cell functions. Ablation of the LH decreased Th1 activity and augmented Th2 activity. The direction of the effects of LH treatment on T-cell function coincides nicely with the effects on NK cells. It might now be safely said that reward links with increased Th1 activity and that, together with NK cell activity, reward or pleasure plays an important role in anticancer, antiviral, and cellular immunity via T-cell cytokine production.

Background: Past traumatic experiences have been reported to lower stress tolerance, thereby increasing job strain. However, the relationship between past traumatic experiences and employee sickness absence is poorly understood. Aims: This study explores the relationship between sickness absence and past traumatic experience with regard to the amount of time lapsed after the experience, job strain and other mental health states such as depression and anxiety. Methods: A total of 3238 workers were assessed for levels of traumatic stress, depressive status, anxiety and job stress. Results: Odds ratios of the presence of traumatic experiences to sickness absence, adjusted for sex, age and depressive and anxiety states, were presented according to the length of time that had passed since the traumatic events. The odds ratio in the 0—1 Years Group was 1.75 ( p < 0.05), and the odds ratio for the 19+ Years Group was 1.46 ( p < 0.1). Conclusions: Past traumatic events are related to sickness absence. Sickness absence resulting from a past traumatic experience is important with respect to industrial health.

Well-preserved natural killer (NK) cell cytotoxicity (NKCC) is associated with healthy aging. The objective of the survey was to investigate psychological factors related to NKCC and NK cell populations in elderly women. A cross-sectional study involving 181 participants was conducted using the Japanese version of the 28-item General Health Questionnaire (GHQ) and additional questions assessing psychological status and lifestyle. Spearman's rank test revealed a significant negative correlation between NKCC and the GHQ depression subscale (GHQ-D) scores. Significantly reduced NKCC was found in participants presenting high GHQ-D scores (12or = GHQ-D, n = 58) compared with those showing middle (8or = GHQ-Dor = 11, n = 55) or low (GHQ-D = 7, n = 68) scores. Adjusting for covariates regarding lifestyle, multiple logistic regression analysis was applied; consequently, significant associations were found between reduced NKCC and high depressive symptoms and between increased NK cell numbers and life satisfaction. These results indicated a clue to longitudinal studies in the future.

Energy expenditure abnormalities have been observed in anorexia nervosa (AN). The uncoupling proteins (UCPs) have been implicated as having a role in energy metabolism and thermogenesis, and an association between a marker flanking the UCP-2/UCP-3 gene cluster and AN has been reported. Also known are insertion/deletion and -866G/A polymorphisms in the UCP-2 gene, and the -55C/T polymorphism in the UCP-3 gene. Differences in these alleles are reportedly related to changes in energy expenditure, body mass index, fat tissue accumulation and obesity. Therefore, this case-control association analysis was done to determine whether any of these UCP-2/3 gene polymorphisms are related to a predisposition to AN. In analysis of a cohort of 106 female Japanese AN sufferers and 126 normal female controls, we found no between-group differences in the polymorphism frequencies of these groups. The hypothesis that differences in the UCP-2/3 gene influence the susceptibility to AN was not supported.

Repeated use of methamphetamine (MAP) is known to cause neurotoxicity in the dopaminergic neurons of the striatum. Recently, we reported that FK506, a calcineurin inhibitor and immunosuppressive agent, could attenuate acute behavioral changes and the development of sensitization after administration of MAP. In this study, we investigated the effects of FK506 on the neurotoxicity in the dopaminergic neurons induced by repeated administration of MAP. BALB/c mice were injected subcutaneously (s.c.) with vehicle (10 ml/kg) or MAP (4 mg/kg) four times every 2 h. Vehicle (10 ml/kg) or FK506 (0.1, 0.3, 1 or 3 mg/kg i.p.) was administered 15 min before the first MAP administration. Three days later, we assessed the contents of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mouse striatum using high-performance liquid chromatography (HPLC). We also examined the immunohistochemistry of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse brain. Repeated administration of MAP decreased significantly the contents of DA and DOPAC in the mouse striatum, and pretreatment with FK506 inhibited significantly the reduction of DA and DOPAC in the mouse brain by repeated administration of MAP. Furthermore, repeated administration of MAP decreased significantly the immunoreactivity of DAT and TH in the striatum as compared to controls. Pretreatment with FK506 (3 mg/kg) attenuated significantly the reduction of DAT and TH immunoreactivity after repeated administration of MAP. These results suggest that FK506 shows protective effects on the MAP-induced neurotoxicity in the dopaminergic neurons of the mouse striatum.

To examine the relationship between altered cellular immune status and clustered features of the metabolic syndrome, we measured body mass index (BMI), serum concentrations of high-density lipoprotein-cholesterol, triglycerides, fasting plasma glucose, and blood pressure levels as well as differential leukocyte counts and lymphocyte sub-populations among 439 apparently healthy Japanese men aged 35-60 years. The components of the metabolic syndrome were defined based on the following criteria: BMI/=25.0 kg/m(2), fasting plasma glucose/=6.11 mmol/l, systolic blood pressure/=130 mmHg and/or diastolic blood pressure/=85 mmHg, high-density lipoprotein (HDL)-cholesterol1.03 mmol/l, and fasting triglyceride/=1.69 mmol/l. Counts of total leukocyte, total lymphocyte, CD3 + T cell, CD4 + T cell, and CD4 + CD45RO + T cell significantly correlated with the number of components of the metabolic syndrome (0, 1, 2, and 3+) after adjustment for age and smoking status. These findings were more evident among smokers than among non-smokers. The counts of total leukocytes, total lymphocytes and more specifically memory (CD4 + CD45RO + T) cells were elevated with clustered features of the metabolic syndrome in middle-aged men, which suggest the involvement of altered cellular immune status in the pathogenesis of atherosclerosis.

Objectives: Insomnia is associated with physical and mental disorders. We examined the effect of insomnia on immune functions, focusing on the T helper 1 (Th1)/ T helper 2 (Th2) balance, by a cross-sectional design. Methods: We provided a self-administered questionnaire to evaluate sleep habits, smoking and medical disorders to 578 men without any toxic exposure (20–64 years old), and measured natural killer (NK) cell activity in 324 men and production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) after stimulation with phytohemagglutinin in 254 men. According to the criteria of DSM-IV, in which insomnia is classified into primary and secondary insomnia, we assessed the effect of insomnia on immune functions, controlling for age and smoking in groups with and without medical disorders. Results: The prevalence of insomnia in the present study was 9.2%. In the absence of medical disorders, insomniac men had a significantly lower IFN-γ and ratio of IFN-γ to IL-4 than noninsomniac men. Men with insufficient sleep or difficulty initiating sleep (DIS) had a significantly lower IFN-γ to IL-4 ratio than those not suffering from insufficient sleep or DIS. In the presence of medical disorders, insomniac men had significantly higher IL-4 than noninsomniac men. Men with difficulty maintaining sleep (DMS) had a significantly lower IFN-γ to IL-4 ratio than men without DMS. NK cell activity was independent of insomnia. Conclusions: The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.

Objectives: Recent studies have shown that apoptosis is involved in stress responses. The present study examined if stressors increase in vitro apoptosis of peripheral blood T lymphocytes in a dose-dependent manner. Methods: Daily subjective stress was quantitatively analyzed in 40 nonsmoking men with a daily hassles questionnaire. Apoptosis of T lymphocytes was measured by flowcytometry using Annexin V/PI double staining method after 0, 12, and 24 h of culture in the presence or absence of dexamethasone (DEX). Using a cross-sectional design, the current study examined the relationship between stress and in vitro apoptosis of T cells. Results: Results showed that apoptosis of T lymphocytes in vitro has a significant correlation with stress and age. Stress was positively correlated with percentage of apoptosis in T cells after 12 h of culture, irrespective of DEX treatment. Age was positively correlated with the percentage of T cell apoptosis after 0 and 12 h of coculture with DEX. Conclusions: These results indicate that age-related apoptosis and stress-related apoptosis of T cells are modulated through different mechanisms. This is the first study to show that in vitro lymphocyte apoptosis is influenced by daily stress in a dose-dependent manner.

Elevated plasma tumor necrosis factor-alpha (TNFalpha) levels and enhanced spontaneous TNFalpha release from peripheral blood mononuclear cells in patients with anorexia nervosa (AN) have been reported. TNFalpha activates the hypothalamic-pituitary-adrenal axis and reduces food intake, which is characteristic of eating disorders. Recently, three novel polymorphisms in the 5'-flanking region of the TNFalpha gene were reported at positions -1031 (T --> C substitution), -863 (C --> A) and -857 (C --> T). Differences in these alleles are reportedly related to altered TNFalpha-transcriptional promoter activity. Therefore, we performed a case-control association analysis to determine whether any of those three polymorphisms in the TNFalpha promoter region were involved in a predisposition to AN. The results of our analysis of a cohort of 79 female Japanese AN sufferers and 127 normal female control subjects provide no support for the hypothesis that -1031T/C, -863 C/A and -857C/T polymorphisms in the TNFalpha gene promoter region influence the susceptibility to AN.

Genetic factors have been implicated in playing a significant role in susceptibility to anorexia nervosa (AN). Among many candidate genes for AN, an association with the A allele of the -1438G/A polymorphism in the promoter region of the 5-HT2A receptor has been reported. However, these findings are controversial and all patients studied to date have been Caucasian. This study was designed to determine whether this association is reproducible in Japanese subjects. This case-control study of a cohort of 75 female Japanese AN sufferers and 127 normal female control subjects revealed no significant association between the 5-HT2A promoter polymorphism and AN. Thus, at least for Japanese subjects, the A-allele of the -1438G/A polymorphism in the promoter region of the 5-HT2A receptor gene does not contribute to a predisposition to AN.

We have screened 200 Japanese workers and 105 Japanese patients with alcoholism for the mutation in the signal peptide of pre-pro-neuropeptide Y resulting in a substitution of proline for leucine at position 7. This polymorphism was reported in the Finnish and Dutch populations recently. None of our subjects displayed the mutation at this site. Therefore, this allele does not play any role in the development of alcoholism in the Japanese population.

Though immune outcome is known to be determined by which helper T cell response predominates, no local mechanism has yet been established which can explain how the neuronal system may control this. It is possible that the nervous system releases neuropeptides at specific local sites of infection or challenge, which triggers lymphocytes at those points to release specific cytokine profiles. These may then influence the direction of the Th1/Th2 response and therefore immune outcome. The aim of this study was to evaluate whether and if so how neuropeptides influence cytokine production by lymphocytes, especially T cells. We investigated the effects of neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP) on the production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) by stimulating nonadherent splenocytes and helper T cell clones with antigens in vitro in the presence or absence of these peptides. NPY greatly enhanced IL-4 production and inhibited IFN-gamma. CGRP inhibited IFN-gamma production markedly in a dose-dependent manner, but had no effects on IL-4 production. SP and VIP had no effects on IFN-gamma production, but SP enhanced and VIP suppressed IL-4 production slightly but consistently. Therefore neuropeptides can influence cytokine production. This opens the door to speculations that these specific cytokine profiles might play a part in influencing the direction of the consequent Th1/Th2 cascade and immune outcome and possibly the pathogenesis of immune-related diseases.

Alexithymia is a psychological trait characterized by a difficulty in verbalizing feelings, which has been associated with a number of illnesses, including bronchial asthma and cancer.In order to understand how psychological variables such as alexithymia affect physical health, we compared the lymphocyte subsets of men (n = 97, mean 30.6) rated as high and low alexithymic when measured by the Toronto Alexithymia Scale (TAS). We analyzed our data by considering alexithymia a categorical variable, using TAS scores of 62 and below, and 74 and above, and by considering alexithymia a continuous variable, using the mean TAS score (64.01) separating high from low alexithymia.When alexithymia was considered a categorical variable, highly alexithymic men had significantly lower numbers of the most cytotoxic natural killer (NK) subset, (CD57-CD16+ cells). When alexithymia was considered a continuous variable, in addition to the NK subset, killer effector T cell (CD8+CD11a+ cells) count was also significantly lower. These results were obtained after controlling for possible effects of smoking and alcohol intake.These results suggest that the negative modulation of cellular immunity, especially the cytotoxic lymphocytes, may be one mechanism which, combined with other factors that have a negative effect on the immune system such as stress, results in the association between alexithymia and ill health. It is suggested that future studies should, in addition to cell counts, attempt to identify the effects of psychological variables on the cytolytic activity of cytotoxic lymphocytes. Furthermore, follow-up studies should monitor the subjects over the years to demonstrate that alexithymia-mediated negative modulation of the immune system results in clinical pathologies.