I wish to describe the outline of my life work of establishing the concept and practice of the Japanese psychosomatic medicine based upon the Oriental mind-body non-dualism. Soon after the introduction of biopsychosocial medical model (Engel) I proposed to add an ecological (bioethical) factor to this model. For the similar reason I developed the concept of alexisomia and alexicosmia in addition to that of alexithymia (Sifneos). Secondarily, I advocated that the Oriental preventive and therapeutic approaches which activate self-healing vital energy (Qi) must be re-evaluated as the core of Western psychosomatic medicine which combines somatic treatment and psychotherapy. Thus truly holistic understanding and treatment of the patient in Japanese psychosomatic medicine can not only be a core of modern medicine but also a root for overcoming the world crisis at present. I have found the essential role of Oriental somatopsychic selfcontrol such as Zazen. Yoga, Qi-gong etc. lies in the disolution of alexithymia, alexisomia and alexicosmia and activation of the potentials for homeostasis and selfrealization. Thus the concomittant use of these somatopsychic selfcontrols with various psychotherapies usually deepen the patient's experiential level and heightens the effect of psychotherapies. Our study on the cases of spontaneous regression of cancer, where the awakening to existential aspects of human beings induced by the sentence of incurable terminal cancer seems to stimulate psychoneuroimmunological activity to the maximal degree, may provide the concept of Oriental psychosomatic medicine based on existential philosophy with a scientific proof. The concept of QOL which was originated from the bioethical concept at terminal care is recently widely spreading all over the medical practice, especially for the purpose of holistic evaluation of the effect of various drugs, surgical operations, care for the aged and terminal cases etc. This tendency will contribute to the penetration of biopsychosocioethical concept to all fields of medicine and heighten the concern of social public to biopsychosocioethical medicine. However, too simple methods for the evaluation of QOL, which are inclined to miss the complex psychophysical mechanisms explored by the orthodox psychosomatic medicine must be re-evaluated by the orthodox psychological texts and biopsychosocioethical interviews. Thus, we are planning to support the sound development of QOL as a part of biopsychosocioethical medicine.

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The population of the aged over 65 years is rapidly increasing in Japan. We are having more and more aged people who are suffering from frail body and mind. So physicians who are engaged in psychosomatic medicine should be the primary physicians for them. I consider that the prevalence of neurosis among the elderly people is quite high. The level of blood pressure of the aged is very unstable and the author demonstrated a case which revealed elevation of his blood pressure during watching the television of his favourite sumo wrestler. Encouragement of the aged is to let them live in more pleasant life and let them understand the following remarks : "Now that we've added years to people's lives, it is also our responsibility to add life to their years"(Dr. Howard A. Rusk). It is our job to let the dying patients close their eyes in gentle way with the mind of aequanimitas. I consider that the psychosomatic medicine should also be supported by primary care medicine and holistic medicine.

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The neuronal and immune systems are ontogenically independent organs with an independent function which preserves the homeostasis of the body. The recent evidence provided information that immune system could be activated by non-antigenic stimulus e.g.stress. The information on bidirectional communication between the neuronal and immune systems has been growing, while increasing evidence suggests that neuromodulators released from the neuronal systems influence the immune cells. In addition, the activated immune cells release an array of immunomodulators that influence the physiologinc function of the nervous system. An attempt was made to recover the altered immune function following the exposure to stress by the treatment of the olfactory system with various fragrances. Through the deta with the experimentally designed models it was also defined that the individual sensitivity to the fragrances was found to be modulated by the genetic background of the individual.

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Substance P (SP), a potent neuropeptide, which localezed to sensory nerves and released by many physiological stimuli included in stress, has been implicated in airway neurologenic inflammation. We have studied the effects of capsaicin (CAP)-induced tachykinin release and exogenously applied SP on eosinophil (EOS) recruitment into the airway in guinea pigs in vivo. We aerosolized several concentrations of CAP or SP and its C-terminal octapeptide SO_<4-11> and N-terminal fragment SP_<1-9> to male guinea pigs. Respiratory resistance (Rrs) of guinea pigs was measured by an oscillation technique and histological studies of the bronchi were also made. Inhaled exposure of CAP and SP resulted in both significant inceases in Rrs with PC_<2000> CAP and SP of 0.97±0.25(×10_<-6>M) and 0.95±0.11(×10_<-6>M)(n=5), respectively. Both stimulations also provoked striking eosinophilia in the bronchi in time- and dose-dependent manners. SP_<4-11> was found to be similar potent as in SP_<1-1>1-evoked EOS migration, while SP_<1-9> was inactive up to concentrations of 10_<-4>M, indicating that the C-terminal fragment appered to be essential. A neutral endopeptidase inhibitor, phosphoramidon potentiated both CAP- and SP-induced EOS infiltration. By contrast, pretreatment with [D-Pro^<2>, D-Trp^<7,9>]-SP, an analogue of SP and its receptor antagonist, diminished the response. We conclude that SP is capable of causing a striking eosinophilia in the lung in vivo, and may contribute to the airway inflammation in patients with asthma. This would provide further support for a link between SP and EOS in asthma.

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We have previously reported that increase of bronchial responsivenes in the restriction stress guinea pig group as compared to that in controls was observed. Moreover, radical oxygen products from bronchoalveolar lavage fluid (BALF) cells obtained from the stress group were also increased, suggensting these phenomena might accelerate the phenomena of inflammatory reactions. On the other hand, adhesion molecules, especially intercellular adhesion molecule-1(ICAM-1), are considered to play an important role in inflammatory processes in allergic and immune reactions such as bronchial asthma. Therefore, in this study, our investigation was designed to clarify whether stress is involved in adhesion molecules expression on inflammatory cells and endothelial cells (EC). Results were as follows ; 1) IL-1,which is considered to play an important role in psychoneuroimmunological phenomena, induced ICAM-1 expression on human EC. 2) Moreover, PAF and PF4,which may be stricking chemotactic agents and activating agents for eosinophils, also induced ICAM-1 expression on human EC. 3) The leukocyte adherence to plasma coated glass in the electric shock stress guinea pig model was augmented as compared to that of controls. 4) Eosinophil counts as well as eosinophil percentages in adherent leukocytes in the electric shock stress group were greater than those of controls. 5) Moreover, leukocyte adherence to autologous bronchial ciliary cells was also augmented in the stress group as compared to that of controls. In conclusion taken together, stress might be involved in adhesion molecules expression resulting in acceleration of allerginc inflammatory reactions such as bronchial asthma.

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Depression is a biological entity consisting of psychiatric and somatic symptoms. Such symptoms are based on homeostatic dysregulation. Recently, imuune function in depression has been noted with the advance of psychoneuroimmunology. Several reports indicated depression to be accompanied by reduced immune function including reduced natural killer cell activity and lymphocyte proliferation to mitogens. On the other hand, antidepressants have been shown to suppress immune function. More attention to immunomodulation is thus needed in therapy for depression with antidepressants. Immunosuppressinve effects of antidepressants were evaluated only in vivo. Such a direct action may represent nonspedific toxic effets because of non-physiological high concentration used in the experiments. Indirect effects of antidepressants on immunity through neuroendocrine modulation should be assesed in the future to study immunomodulation by antidepressants treatment. We confirmed our previous finding indicating olfactory bulbectomy to suppress plaque forming cell (PFC) preduction to sheep red blood cells. In our recent study, immunomodulatory effects of imipramine (IMP) were evaluated by IMP administration at 5mg/kg/day for 3 or 10 days in sham-operated or olfactory bulbectomized mice. Five mg/kg/day is the physiological dose. IMP administration for 3 days caused significant suppression of PFC production in sham-operated mice and to olfactory bulbectomized mice failed to have any effect. By IMP administration for 10 days, PFC production was significantly inhibited in sham-operated mice, while restored in olfactory bulbectomized mice. Present results indicate antidepressants to exert divergent effects on immune function, depending possibly on neural functioning. Antidepressants possess modulating properties for various neurotransmission mechanisms in the brain such as beta-adrenrgic receptor downregulation. In contrast to the possibility of increased function in central beta-receptors, the function of lymphocyte beta-receptor has been shown to possibly decrease in depression and upregulate by the repeated administration of antidepressants. These differences between central and lymphyocyte beta-receptor function may be significanlt. The peripheral noradrenergic function may be under tonic inhibitory influence of the central noradrenergic system, and thus dysregulated central noradrenergic activity may induce sympathetic hyperactivity associated with immunosuppressive effects in depression. The restoration of immune function in depression by antidepressants may be related to peripheral beta-action adjustment.

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It is well known that immunological functions are influenced by psychological stresses. Psychological stresses influence also usual behaviors such as eating and sleep. Therefore, it is important to investigate the effect of diet or sleep on the immunological functions. In this paper, we analysed the effects of starvation or sleep deprivation on immunological functions using animal models. 1) The body weight and the weights of thymus, spleen or liver were significantly losed, when DBA/2 mice were starved. The degree of weight loss was correlated with the duration of starvation. However, the weight of adrenal gland was not changed by starvation within 4 days. 2) The proportion of B lymphocyte in the spleen was decreased by starvation. On the contrary, the proportion of T lymphocyte was increased. 3) In vitro IL-2 production, mixed lymphocyte reaction and the response to PHA were rather enhanced by 2 or 3 days of starvation. 4) Natural killer cell activity was suppressed by more than 1 day of starvation. 5) In Fisher rats which were REM-sleep deprived for 3 days, organ weights of spleen, liver and thymus were smaller, and that of adrenal was larger than in control group. 6) There were no differences in responses to Con A and NK activity between the REM-de-prived group and the control group. However, the REM-deprived group showed lower response to PHA and phagocytic activity of granulocyte than the control group. These results indicated that immune function was influenced by starvation or sleep deprivation. It depends on the period , degree and method of stressors. Several T cell functions were enhanced by short-period of starvation. Sleep deprivation for 3 days suppressed several immune functions.

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