HK1133461B

HK1133461B - Biological load indicator and method of measuring biological load

Info

Publication number: HK1133461B
Application number: HK09111442.2A
Authority: HK
Inventors: 关山敦生
Original assignee: 关山敦生
Priority date: 2006-02-17
Filing date: 2007-02-16
Publication date: 2014-08-01

Description

Bioburden indicator and bioburden measuring method

Technical Field

The present invention relates to a bioburden indicator and a method of measuring bioburden. Specifically, the present invention relates to the technical field of objectively evaluating bioburden such as stress and fatigue by a method of molecular biology.

Background

Mental and/or physical stress affects host defense mechanisms including nervous, endocrine, and immune systems (see non-patent documents 1 and 2). Various cytokines (e.g., IL-1. beta., IL-6, TNF-. alpha., etc.) are up-regulated by stress (see non-patent documents 1 and 3). This suggests that cytokines may be involved in interfering with host defense (see non-patent document 4). However, the molecular mechanisms by which stress induces cytokines that can reduce host defense are not well understood.

Interleukin-18 (IL-18) is a cytokine that is found as an interferon- γ (IFN- γ) inducing factor (see non-patent document 5 and patent document 1). IL-18 has various biological activities, such as induction of Fas ligand, improvement of cytolytic activity of T cells (see non-patent document 6), and production of IL-4 and IL-13 (see non-patent document 7). IL-18 activates Toll-like receptor 2 (see non-patent document 9) and myelodifferentiation protein (Myd) -88 (see non-patent document 10). This activation is required for the induction of IL-6 (see non-patent document 11). Therefore, IL-18 is involved in the production of 2 cytokines Th1 and Th2 (see non-patent document 12).

IL-18 was produced as a 24kD precursor protein, and then processed to an 18kD mature active form by IL-1. beta. converting enzyme (ICE, also referred to as caspase-1) (see non-patent document 13). Caspase-1 is induced as an inactive precursor protein, procaspase-1, and then activated by caspase-11 (see non-patent document 14). It has been reported that trans-activation of NF-KB is required for expression of caspase-11 mRNA (see non-patent document 15), and that the activation is mediated by P38MAP kinase (see non-patent document 16). It has also been reported that induction of caspase-11 mRNA by LPS (lipopolysaccharide) and activation of caspase-1 after induction are inhibited by SB203580, which is a P38MAP kinase inhibitor, in glioma cell line C6 (see non-patent document 17).

In recent studies, it has been reported that IL-18mRNA is expressed in adrenal gland in response to adrenocorticotropic hormone (ACTH) and cold stress (cold stress) (see non-patent document 18). It has also been reported that different promoters are used for the expression of IL-18mRNA in adrenal gland and immune cells (see non-patent document 19). However, none of the 2 studies reported induction of mature IL-18. On the other hand, it has been reported that IL-18 in plasma is elevated in patients in psychiatric medicine (see non-patent document 20).

In modern society, people work and live under various stress conditions. Generally, there is an individual difference in the perception of stress, and there is no clear indication of the presence or absence or strength of stress. The present inventors have found that a stress increases cytokines such as IL-18 through current studies, and have revealed that IL-18 serves as a signal transduction pathway at the tip of a stress cascade (stress cascade) to enable objective evaluation of stress (see patent document 2 and non-patent documents 21 to 23).

Patent document 1: japanese laid-open patent publication No. 8-193098

Patent document 2: international publication No. 2006/003927 pamphlet

Non-patent document 1: dugue, B, et al Scand.J.Clin.invest.53, 555-561 (1993)

Non-patent document 2: Kiecolt-Glaser, J.K. et al Proc.Natl.Acad.Sci.USA93, 3043-3047 (1996)

Non-patent document 3: endocrinology133, 2523 to 2530(1993)

Non-patent document 4: schubert, C. et al Psychosom. Med.61, 876-882 (1999)

Non-patent document 5: zhou, D.et al Nature378, 88-91 (1995)

Non-patent document 6: nakanishi, K. et al, Annu.Rev.Immunol.19423-474 (2001)

Non-patent document 7: hoshino, T.et al J.Immunol.162, 5070-5077 (1999)

Non-patent document 8: dinarello, C.A. et al J.Leukoc.biol.63, 658-664 (1998)

Non-patent document 9: blase, K. et al. Inflamm. Res.50, 552-560 (2001)

Non-patent document 10: adachi, O. et al Immunity9, 143-150 (1998)

Non-patent document 11: takeuchi, O. et al J.Immunol.165, 5392-5396 (2000)

Non-patent document 12: J.Immunol.166, 7014-7018 (2001)

Non-patent document 13: gu, Y, et al Science275, 206-209 (1997)

Non-patent document 14: wang, S. et al, Cell92, 501-509 (1998)

Non-patent document 15: schauvliege, R, et al, J.biol.chem.277, 41624-41630 (2002)

Non-patent document 16: vanden Berghe, W, et al J.biol.chem.273, 3285-3290 (1998)

Non-patent document 17: hur, J, et al FEBS Lett.507, 157-162 (2001)

Non-patent document 18: conti, B, et al J.biol.chem.272, 2035-2037 (1997)

Non-patent document 19: J.Immunol.165, 6287-6292 (2000)

Non-patent document 20: kokai, M. et al, J.Immunother.25, 68-71 (2002)

Non-patent document 21: sekiyama, A. et al Immunity22(6), 669-677 (2005)

Non-patent document 22: sekiyama, A. et al J Neurommunol.171 (1-2), 38-44 (2006)

Non-patent document 23: sekiyama, A. et al J Med invest.52, 236-239 (2005)

Disclosure of Invention

Problems to be solved by the invention

Organisms have mechanisms for maintaining certain biological functions in response to load and stimuli, and such mechanisms are known as homeostatic or host defense mechanisms. Mental, physical, chemical stress and/or fatigue are known to be a burden on homeostasis or host defense mechanisms, and various diseases are generated due to the disruption of homeostasis or host defense mechanisms.

Homeostasis such as stress, fatigue and depression or stress states of host defense mechanisms can cause mental disorders, physical disorders and even suicide, and are a major health-threatening problem. However, since these symptoms are basically subjective symptoms, evaluation can be performed only by self-assessment. Moreover, it is very difficult to detect an abnormality by known biochemical or psychological tests, and thus it is impossible to make an objective evaluation, grasp the degree, or make a countermeasure. At present, although various biochemical or physiological indexes are proposed, hormones or amines are unstable and difficult to quantify, and although changes in their levels are associated with stress, they are not suitable as indexes.

The purpose of the present invention is to provide means capable of objectively and specifically evaluating various loads on an organism, such as fatigue, which can be evaluated only by subjective symptoms. Further, since the living body senses a load on homeostasis or a host defense mechanism accompanied by a sense of discomfort, the object of the present invention inevitably includes providing a means capable of objectively and specifically evaluating the sense of discomfort and the sense of comfort of the living body.

Means for solving the problems

As a result of intensive studies in view of the above-mentioned problems, the present inventors have found that various bioburdens including stress and fatigue can be objectively grasped by thoroughly investigating changes in expression of cytokines, chemokines, and the like constituting an in vivo cascade mainly involving IL-18, and have completed the present invention.

That is, the present invention is as follows.

An indicator of stress comprising at least 2 factors selected from the group consisting of: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin (Eotaxin), basic fibroblast growth factor (FGF basic), G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5 (neurotropin 5), MCP-3, beta-2-microglobulin (beta-2-microglobulin), angiotensin II (angieinsin II), CSF-3, CXC chemokine ligand 1(CXC chemokine ligand1), CXC chemokine ligand 5 and HGF. [2] A test agent for stress comprising at least 2 molecules selected from the group consisting of molecules that can specifically recognize, respectively, factors comprising: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF.

An indicator of fatigue comprising at least 2 factors selected from the group consisting of: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF.

A detection agent for fatigue, comprising at least 2 molecules selected from the group consisting of molecules that can specifically recognize, respectively, factors including: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF.

The detecting agent of the above [2] or [4], wherein the above molecule is an antibody.

A method for measuring stress, which comprises the step of measuring the amount of a factor in a biological sample using the aforementioned detecting agent of [2] or [5 ].

A method for measuring fatigue, which comprises the step of measuring the amount of a factor in a biological sample using the aforementioned detecting agent of [4] or [5 ].

The method of [6] or [7] above, wherein the biological sample is plasma, serum, saliva or urine.

An indicator for assessing mental state, the indicator being formed by weighted proportioning (proportional weighting) of at least 2 factors selected from the group consisting of: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF, the mental state is selected from the group consisting of mental fatigue, physical fatigue, stress, mood depression, mood elevation, mood depression, dysthymia, obsessive-compulsive, panic, anxiety, phobias, crowd phobia, social phobia, stress, intensity of labor, learning intensity, depression, schizophrenia, mental states resembling depression, mental states resembling schizophrenia, and suicide risk.

An indicator for assessing the intensity of a psychotic disorder, the indicator being formed by weighting at least 2 factors selected from the group consisting of: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF, the psychiatric disorder is selected from the group consisting of mental fatigue, stress, depression, depressive states, mood disorders, schizophrenia, obsessive compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobias, excessive stress, maladaptation to work or learning, suicidal moods, personality disorders, alcoholism psychosis, insomnia, disorders of circadian rhythms, psychoneurosis, dementia, central neurodegenerative disorders, and suicide attempts.

A detection agent for mental states, comprising at least 2 molecules selected from the group consisting of molecules that can specifically recognize, respectively, factors comprising: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF, the mental state is selected from the group consisting of mental fatigue, physical fatigue, stress, mood depression, mood elevation, mood depression, dysthymia, obsessive-compulsive, panic, anxiety, phobias, crowd phobia, social phobia, stress, intensity of labor, learning intensity, depression, schizophrenia, mental states resembling depression, mental states resembling schizophrenia, and suicide risk.

A test agent for the intensity of a psychotic disorder, which test agent comprises at least 2 molecules selected from the group consisting of molecules that specifically recognize, respectively, factors comprising: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF, the psychiatric disorder is selected from the group consisting of mental fatigue, stress, depression, depressive states, mood disorders, schizophrenia, obsessive compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobias, excessive stress, maladaptation to work or learning, suicidal moods, personality disorders, alcoholism psychosis, insomnia, disorders of circadian rhythms, psychoneurosis, dementia, central neurodegenerative disorders, and suicide attempts.

The detecting agent of the above [11] or [12], wherein the above molecule is an antibody.

A method of determining mental state, the method comprising: a step of measuring the amount of the factor in the biological sample using the detection drug according to the above [11] or [13], and a step of comparing the amount obtained in the above measurement step with the indicator according to the above [9] after weighting and matching, wherein the mental state is selected from the group consisting of mental fatigue, physical fatigue, stress, emotional depression, emotional elevation, depressed mood, dysthymia, obsessive-compulsive, panic, anxiety, phobia, crowd phobia, social phobia, stress, labor intensity, learning intensity, depression, schizophrenia, mental states similar to depression, mental states similar to schizophrenia, and suicide risk.

A method of determining the intensity of a psychotic disorder, which method comprises: a step of measuring the amount of the factor in a biological sample using the detection drug according to the above [12] or [13], and a step of comparing the amount obtained in the above measurement step with the indicator according to the above [10], wherein the mental disorder is selected from mental fatigue, stress, depression, depressive state, mood disorder, schizophrenia, obsessive compulsive disorder, panic disorder, anxiety disorder, phobias, crowd phobia, social phobia, excessive stress, poor adaptation to work or learning, suicide mood, personality disorder, alcoholism psychosis, insomnia, circadian rhythm disorder, psychoneurosis, dementia, central neurodegenerative disease, and suicide attempt.

The method of the above [14] or [15], wherein the above biological sample is plasma, serum, saliva or urine.

A kit for the detection of mental states, said kit comprising in different compartments (components) at least 2 molecules selected from the group of molecules that can specifically recognize respectively the following factors, said factors comprising: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF, the mental state is selected from the group consisting of mental fatigue, physical fatigue, stress, mood depression, mood elevation, mood depression, dysthymia, obsessive-compulsive, panic, anxiety, phobias, crowd phobia, social phobia, stress, intensity of labor, learning intensity, depression, schizophrenia, mental states resembling depression, mental states resembling schizophrenia, and suicide risk.

A kit for detecting the intensity of a psychotic disorder, said kit comprising in distinct compartments at least 2 molecules selected from the group of molecules that can each specifically recognize a factor comprising: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF, the psychiatric disorder is selected from the group consisting of mental fatigue, stress, depression, depressive states, mood disorders, schizophrenia, obsessive compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobias, excessive stress, maladaptation to work or learning, suicidal moods, personality disorders, alcoholism psychosis, insomnia, disorders of circadian rhythms, psychoneurosis, dementia, central neurodegenerative disorders, and suicide attempts.

The detection kit according to the above [17] or [18], wherein the above molecule is an antibody.

Effects of the invention

According to the indicator of stress or fatigue of the present invention, since it contains a factor group such as cytokines having various actions in a living body, the degree of stress or fatigue of a mammal typified by an artificial human can be objectively and molecularly evaluated. The agent for detecting stress or fatigue of the present invention contains molecules that recognize factors such as cytokines having various actions in vivo, and therefore can objectively and quantitatively detect the level of stress or fatigue in mammals typified by humans. According to the method for measuring stress or fatigue of the present invention, since the concentration of the factor in the biological sample is measured using the detection drug of the present invention, the degree of stress or fatigue of a mammal typified by humans can be objectively and quantitatively measured. The indicator obtained by weighting and proportioning the factors can objectively and thoroughly evaluate the intensity of various mental states or mental disorders of mammals represented by human beings on the molecular biological level. The agent for detecting the intensity of mental state or mental disorder according to the present invention contains molecules capable of recognizing factors such as cytokines having various actions in vivo, and the molecules are mixed in a weight ratio, so that the intensity of mental state or mental disorder in mammals represented by humans can be objectively and quantitatively detected. According to the method for measuring the intensity of mental state or mental disorder of the present invention, the agent for detecting mental state or mental disorder of the present invention is used, and the indicator of mental state or mental disorder of the present invention is used as an indicator, so that the intensity of various mental states or mental disorders of mammals including humans can be objectively and quantitatively evaluated. The test kit for the intensity of a mental state or mental disorder according to the present invention can suitably provide an individual or complete test for the intensity of a mental state or mental disorder, since it comprises the test agent of the present invention in different compartments.

Therefore, the present invention can be used for the reconstruction of the basis of preventive medicine and public health administration (public health administration); the intensity of life (lifestyle level) of a patient in rehabilitation for a disease, the evaluation and management of mental health, the intensity of life of a patient in recovery from a disease, the evaluation and management of mental health; public or occupational health and worker disaster scope identification; evaluating a working environment; evaluating the labor intensity; residential or work environment evaluation; evaluation of school hygiene and learning environment or learning intensity; evaluating the environment; evaluation of the state of diseases or disorders characterized mainly by stress or fatigue (psychosomatic diseases, depression, psychoneurosis, chronic fatigue syndrome, personality disorders, adaptation disorder syndrome (maladjustment syndrome), social withdrawal (social withdrawal), psychosomatic depletion syndrome (bumout syndrome), apathy, psychogenic reactions (psychogenic reactions), PTSD and almost all other diseases); the international integration of stress evaluation criteria; and the establishment of international standards for the above-mentioned various evaluations.

Brief Description of Drawings

FIG. 1a is a graph showing correlation patterns (correlation patterns) of cytokine or chemokine amounts in plasma of 402 healthy subjects in total (correlation coefficients 0.50 to 0.6499 are light gray, 0.65 to 0.7999 are dark gray, 0.8 to 0.9999 are black; at a correlation coefficient of 0.50, the relative risk of correlation is p < 0.001. in the table, darker shading indicates higher correlation, as well as in the following correlation table).

FIG. 1b is a graph showing the correlation pattern of the cytokine or chemokine amounts in plasma of 142 healthy subjects on frequent night shifts before the shift.

FIG. 1c is a graph showing the correlation pattern of the cytokine or chemokine amounts in plasma of the above subjects after a night shift.

FIG. 1d is a chart of the classification of 90 subjects randomly sampled from the above subjects into pre-and post-shift categories by logistic regression analysis (logistic regression analysis) using the present invention. The positive diagnosis rate using the invention is 88%.

FIG. 2a is a graph showing the pattern of correlation of cytokine or chemokine amounts in plasma after 1 hour of Kreppellin loading (correlation coefficients 0.50-0.6499 are light grey, 0.65-0.7999 are dark grey, 0.8-0.9999 are black; at correlation coefficient 0.50, the relative risk of correlation is p < 0.001. in the table, darker shades indicate higher correlation, as well as in the following correlation table).

FIG. 2b is a graph showing the correlation pattern of cytokine or chemokine amounts in plasma after 3 hours of Kreppeline loading.

Figure 2c is a graph showing the correlation pattern of cytokine or chemokine amounts in plasma after 3 hours of exposure to a kreppellin load and 3 hours of rest.

FIG. 2d is a table of classifications made by logistic regression analysis of the data for 1 hour and 3 hours of Kreppellin loading.

FIG. 2e is a table of classifications from logistic regression analysis of the data after 3 hours of Kreppeline loading and 3 hours of recovery.

FIG. 2f is a graph of the correlation pattern of cytokine or chemokine amounts in plasma 1 hour after performing a plate exercise assay (treadmill exercise).

FIG. 2g is a graph of the correlation pattern of cytokine or chemokine amounts in plasma 3 hours after performing a plate movement assay.

Figure 2h is a graph of the correlation pattern of cytokine or chemokine amounts in plasma after 3 hours of plate movement assay and 3 hours of rest.

FIG. 2i is a classification chart obtained by logistic regression analysis of the data before and after the plate movement test for 1 hour.

FIG. 2j is a table of classifications made by logistic regression analysis of data after the end of the plate motion test and on day 2 after the test.

FIG. 2k is a table of classifications from logistic regression analysis of data between groups subjected to a 1 hour Kreppeline load and a 1 hour plate movement test, respectively.

FIG. 21 is a table of classifications made by logistic regression analysis of data between groups subjected to a Kreppeline load for 3 hours and a plate motion test for 3 hours, respectively.

FIG. 2m is a classification chart obtained by logistic regression analysis of data between groups subjected to a Kreppeline load for 3 hours and subjected to a 3-hour recovery and a plate motion test for 3 hours and subjected to a 3-hour recovery, respectively.

FIG. 2n is a table of classifications made by logistic regression analysis of data between groups at day 2 after the Kreppellin load and day 2 after the plate movement test, respectively.

FIG. 3a is a graph showing the correlation pattern of cytokine or chemokine amounts in the plasma of depression patients (correlation coefficient 0.50-0.6499 light grey, 0.65-0.7999 dark grey, 0.8-0.9999 black. at correlation coefficient 0.50, the relative risk of correlation is p < 0.001. in the table, darker shading indicates higher correlation).

FIG. 3b is a classification chart obtained by determining whether a subject can be classified into a healthy person and a depressed person according to the present invention by logistic regression analysis.

FIG. 4a is a graph showing the correlation pattern of the amount of cytokines or chemokines in the plasma of schizophrenic patients (correlation coefficient 0.50-0.6499 light grey, 0.65-0.7999 dark grey, 0.8-0.9999 black; at correlation coefficient 0.50, the relative risk of correlation is p < 0.001. in the table, darker shades indicate higher correlation).

FIG. 4b is a classification chart obtained by determining whether the subjects can be classified into healthy persons and schizophrenic patients according to the present invention by logistic regression analysis.

FIG. 4c is a classification chart obtained by determining whether a subject can be classified into a depressive patient and a schizophrenia patient according to the present invention.

Best Mode for Carrying Out The Invention

The evaluation object of the present invention can be classified into a load state and a pathological state of an organism. In the case of a loaded state, the point of evaluation and discrimination in the present invention is the state and the degree of its manifestation; on the other hand, in the case of pathological conditions, the focus is on the kind and degree of pathological conditions that are manifested. Further, regarding pathological conditions in which no objective evaluation criteria are provided for the apparent state, the present invention is also directed to providing an evaluation criterion for pathological conditions by grasping potential states, i.e., by grasping changes in cytokines or chemokines within an organism.

The stress or fatigue indicator of the present invention comprises at least 2 factors selected from the group consisting of: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF.

In the present invention, the "indicator" means any living body marker for objectively grasping various indicators of mental states that can be confirmed only by self-assessment. Alternatively, the "indicator" may also be a living marker for objectively grasping the intensity of mental disorder.

In the present invention, "bioburden" refers to a chemical, physical, mental, linguistic, or work load on a mental state or physical condition (physical condition) of a living body. The definition of "bioburden" also includes a constant burden from the inside of a living body due to a pathological state or the like. For example, the "bioburden" in the present invention includes a state of disruption of homeostasis in an organism, a state of disruption load of homeostasis in an organism, a state of prodromal disruption of homeostasis in an organism, a state of disruption of host defense mechanism, a load of disruption of host defense mechanism, a state of prodromal disruption of host defense mechanism, and the like.

In the present invention, "stress" refers to various responses of an organism caused by the application of a chemical, physical, mental, verbal or operational temporary load to the mental state or physical condition of the organism. Further, "stress" refers to various responses of an organism caused by a constant load applied to the inside of the organism.

In the present invention, "fatigue" refers to any type of fatigue, including physical fatigue and mental fatigue.

The factors contained in the indicator of the present invention are at least 2 selected from the above-mentioned factor groups. In order to indicate fatigue more specifically, the factors are selected from the group consisting of 3 to 41, preferably 3 to 28, more preferably 5 to 20, and further preferably 8 to 12 of the above factors.

In the present invention, "IL-1. beta. is a polypeptide having a human amino acid sequence and a base sequence represented by the following gene library Accession No.: NM-000576, etc., can be isolated or manufactured by known methods. Furthermore, "IL-1. beta" also includes congeners (e.g., homologues) thereofSubstances (homologues) and splice variants), variants, derivatives, mature forms and amino acid modified analogues (analogues with amino acid modifications) and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-1 ra" is a nucleotide sequence expressed by the gene bank accession number: the disclosed substances, such as NM _173841, NM _173842, NM _173843, and NM _000577, can be isolated or manufactured by known methods. Furthermore, "IL-1 ra" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphorylates of amino acids。

In the present invention, "IL-2" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: NM-000586, and the like, can be isolated or manufactured by known methods. Moreover, "IL-2" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-4" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: NM-000589, NM-172348, and the like can be isolated or manufactured by a known method. Moreover, "IL-4" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www. ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. Furthermore, the variants include those having at least 70% homology with the non-mutated protein or (poly) peptide,preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-5" is a nucleotide sequence expressed by the accession number of the gene bank as a human amino acid sequence and a base sequence: NM-000879, and the like, can be isolated or manufactured by known methods. Moreover, "IL-5" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-6" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: NM-000600, and the like, can be isolated or manufactured by known methods. Moreover, "IL-6" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm. nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having a sequence which is deleted, substituted, or mutated by man,A variant in which a modified amino acid sequence is added or inserted. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-7" is a nucleotide sequence expressed by the accession number of the gene bank as a human amino acid sequence and a base sequence: NM-000880 et al, which can be isolated or manufactured by known methods. Moreover, "IL-7" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-8" is a nucleotide sequence expressed by the accession number of the gene bank as a human amino acid sequence and a base sequence: NM-000584, etc., can be isolated or manufactured by known methods. Moreover, "IL-8" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih. gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-9" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: NM-000590, and the like, can be isolated or manufactured by known methods. Moreover, "IL-9" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-10" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: NM-000572, and the like, can be isolated or manufactured by known methods. Moreover, "IL-10" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like.Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih. gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-12" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the GenBank: NM-002187, NM-000882, and the like can be isolated or manufactured by a known method. Moreover, "IL-12" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-13" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of GenBank: NM-002188, and the like, can be isolated or manufactured by known methods. Moreover, "IL-13" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-15" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: the substances disclosed in NM-000585, NM-172174, NM-172175, etc. can be isolated or manufactured by known methods. Moreover, "IL-15" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, may be listedPhosphoric acid salts of amino acids are exemplified.

In the present invention, "IL-17" is a nucleotide sequence expressed by the accession number of the gene bank as a human amino acid sequence and a base sequence: NM-002190 and the like can be isolated or produced by a known method. Moreover, "IL-17" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm. nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-18" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the gene bank: NM-001562, and the like, can be isolated or manufactured by known methods. Moreover, "IL-18" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified. In the present invention, it is preferred that IL-18 be in a mature form.

In the present invention, "eotaxin" is a protein expressed as a human amino acid sequence and a base sequence by the accession number of the gene bank: the substance disclosed in D49372 and the like can be isolated or produced by a known method. Furthermore, "eotaxin" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs thereof, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, the "basic fibroblast growth factor" is a polypeptide having a sequence represented by the following amino acid sequence and base sequence in the form of a human amino acid sequence represented by the following gene library accession No.: NM-002006, and the like, can be isolated or manufactured by known methods. Furthermore, "basic fibroblast growth factor" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like thereof. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified. "basic fibroblast growth factor" is also referred to as "FGF-2".

In the present invention, "G-CSF" is a substance disclosed by a gene library or the like as a human amino acid sequence and a base sequence, and can be isolated or produced by a known method. Furthermore, "G-CSF" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "GM-CSF" is a nucleotide sequence obtained by the following gene library accession number: the substances disclosed in X03021, M10633 and the like can be isolated or produced by a known method. Furthermore, "GM-CSF" also includes analogs (e.g., homologs and splice variants), variants, derivatives, and synthetases thereofMature forms and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IFN-. gamma.is expressed as a human amino acid sequence and a base sequence by the accession number of the GenBank: NM-000619, and the like, can be isolated or manufactured by known methods. Furthermore, "IFN- γ" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like thereof. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IP-10" is a gene library or the like which is a human amino acid sequence or a base sequenceThe cloth material can be isolated or produced by a known method. Moreover, "IP-10" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "MCP-1" is a substance that is published as a human amino acid sequence and a base sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "MCP-1" includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "MIP-1. alpha" is a substance disclosed as a human amino acid sequence or a base sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "MIP-1 α" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "MIP-1. beta. is a substance disclosed as a human amino acid sequence or a base sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "MIP-1 β" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The above-mentioned variants include those having at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, still more preferably 9%7 percent. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "PDGF-BB" is a substance published as a human amino acid sequence or a human nucleotide sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "PDGF-BB" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "RANTES" is a substance disclosed as a human amino acid sequence and a base sequence by a gene library or the like, and can be isolated or produced by a known method. Moreover, "RANTES" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs thereof, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/ HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. And do, doThe above-mentioned variants include those having at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "TNF-. alpha.is a substance disclosed as a human amino acid sequence or a nucleotide sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "TNF- α" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "VEGF" is a substance that has been published as a human amino acid sequence and a human nucleotide sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "VEGF" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants,Non-naturally occurring variants and variants having an amino acid sequence modified by artificial deletion, substitution, addition or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-3" is a substance disclosed by Hs.694 and the like registered in NCBI as a human amino acid sequence and a nucleotide sequence, and can be isolated or produced by a known method. Moreover, "IL-3" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/ HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IL-11" is a polypeptide represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of the GenBank: NM-000641, and the like, can be isolated or manufactured by known methods. Moreover, "IL-11" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "IFN-. alpha.is a substance disclosed as a human amino acid sequence or a nucleotide sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "IFN- α" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like thereof. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "CSF-2" is a substance disclosed as a human amino acid sequence or a nucleotide sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "CSF-2" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, andamino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "TGF-. beta.is a substance disclosed by Hs.645227 and the like registered in NCBI as a human amino acid sequence and a nucleotide sequence, and can be isolated or produced by a known method. Moreover, "TGF-. beta.s" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs thereof, and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "neurotrophin 5" is a protein obtained by registering a human amino acid sequence and a human base sequence at NCBIHs.266902 and the like can be isolated or produced by a known method. Furthermore, "neurotrophin 5" also encompasses its congeners (e.g., homologues and splice variants), variants, derivatives, mature forms, amino acid modified analogues, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "MCP-3" is a polypeptide having a sequence represented by the following amino acid sequence and base sequence as a human amino acid sequence by the accession number of a gene bank: the substance disclosed in X72309 or the like can be isolated or produced by a known method. Moreover, "MCP-3" also includes its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih. gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications, non-naturally occurring amino acid modificationsSpecifically, the ornaments may be phosphoric acid esters of amino acids.

In the present invention, "β -2-microglobulin" is a substance disclosed by hs.534255 registered in NCBI as a human amino acid sequence and a nucleotide sequence, and can be isolated or produced by a known method. Moreover, "beta-2-microglobulin" also encompasses its congeners (e.g., homologues and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, the human amino acid sequence and base sequence of "angiotensin II" are known and can be isolated or produced by a known method. Moreover, "angiotensin II" also encompasses its congeners (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The above-mentioned variant may be at least 70% of the non-mutated protein or (poly) peptideThe homology variant of (3) is preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "CSF-3" is a substance disclosed by Hs.2233 registered in NCBI as a human amino acid sequence and a nucleotide sequence, and can be isolated or produced by a known method. Also, the term "CSF-3" includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www.ncbi.nlm. nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "CXC chemokine ligand 1" is a substance published as a human amino acid sequence and a base sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "CXC chemokine ligand 1" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs thereof, and the like. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "CXC chemokine ligand 5" is a substance published as a human amino acid sequence and a base sequence by a gene library or the like, and can be isolated or produced by a known method. Furthermore, "CXC chemokine ligand 5" also includes analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, and amino acid modified analogs thereof, and the like. Among them, examples of the homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be obtained from the same species as those obtained by the Homologene (R) ((R))http://www. ncbi.nlm.nih.gov/HomoloGene/) And deducing and identifying the base sequence of the identified gene. Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

In the present invention, "HGF" is a substance disclosed by hs.396530 registered in NCBI as a human amino acid sequence and a base sequence, and can be isolated or produced by a known method. Moreover, "HGF" also encompasses analogs (e.g., homologs and splice variants), variants, derivatives, mature forms, amino acid modified analogs, and the like thereof. Among them, examples of homologues include proteins of other species such as mouse and rat corresponding to human proteins, and these proteins can be deduced and identified from the nucleotide sequence of a gene identified by homologGene (http:// www.ncbi.nlm.nih.gov/homologGene /). Variants include naturally occurring allelic variants, non-naturally occurring variants, and variants having an amino acid sequence modified by artificial deletion, substitution, addition, or insertion. The variant may have at least 70% homology with the non-mutated protein or (poly) peptide, preferably 80%, more preferably 95%, and still more preferably 97%. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specifically, phosphate of amino acid can be exemplified.

The cytokines and chemokines described above constituting the indicator of the present invention are preferably placed in different containers. The indicator of the present invention may contain other components as long as the factors such as the above-mentioned cytokine and chemokine are used as main components. Examples of the other components include solvents (e.g., buffers, physiological saline, etc.), stabilizers, bacteriostats, preservatives, and the like, but are not limited thereto.

The indicator of the present invention may indicate a physiological state of an animal that is trapped in stress or fatigue, preferably a physiological state of fatigue due to psychological stress. In particular, the degree of fatigue can be easily and quantitatively understood by using the above-described factors as an index in a biological sample of an animal, preferably plasma, serum, saliva or urine. For example, in the case of mice, the amount of IL-18 in serum is 100pg/ml or less before the psychological stress load, 120 to 200pg/ml 5 hours after the stress load for 1 hour, and more than 1000pg/ml after the stress load for 6 hours, and the amount of IL-18 increases with the increase in stress load. On the other hand, since the half-life of IL-18 is about 10 hours, an indicator containing IL-18 is suitable as an indicator of fatigue. In addition to IL-18, an increase in the amount of each of the above factors in the living body can be used as an indicator of fatigue. In particular, the indicator of the invention preferably comprises an amount of at least 2 factors, prepared in advance, from the normal value to the case of weak or even strong fatigue, in order to be able to be compared with the sample.

The stress or fatigue detecting agent of the present invention is characterized by comprising at least 2 molecules selected from molecules that can specifically recognize each of the following factors: IL-1 beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF.

The molecule may include an antibody, a peptide (antibody-removed), a nucleic acid, a low molecular compound, and the like. Antibodies that are relatively easily available or manufactured are preferred.

The "antibody" includes polyclonal antibodies, monoclonal antibodies, chimeric antibodies, single-chain antibodies, and antibodies in which a part of the antibody has an antigen-binding property (for example, F (ab')₂Fragments or Fab' fragments and fragments generated by Fab expression libraries, etc.).

The "peptide (antibody-removed)" refers to a protein component that specifically binds to the factor (specific protein), and specifically includes a cytokine-binding protein, a cytokine receptor, a cytokine soluble receptor (cytokine soluble receptor), or a binding site thereof.

The "nucleic acid" refers to a nucleic acid having a specific nucleotide sequence capable of binding to the factor (specific protein), and specifically, it includes DNA, RNA, and nucleic acid analogs.

The "low molecular compound" refers to an organic or inorganic low molecular compound designed according to the steric structure and electrostatic properties of the peptide.

The antibody can be produced by a conventional method (Current protocols in Molecular Bio)log), section: 11.12 to 11.13 (2000)). Specifically, when the antibody is a polyclonal antibody, any of the above-mentioned factors purified by expression in E.coli or the like by a conventional method or an oligopeptide having a partial amino acid sequence of the factor synthesized by a conventional method is used to immunize a non-human animal such as a rabbit, and the polyclonal antibody is obtained from the serum of the immunized animal by a conventional method. On the other hand, in the case where the antibody is a monoclonal antibody, a non-human animal such as a mouse can be immunized with any of the above-mentioned factors purified by expression in Escherichia coli or the like by a conventional method or an oligopeptide having a partial amino acid sequence of these proteins, and the resulting spleen cell and myeloma cell are subjected to cell fusion to prepare a hybridoma cell, and the monoclonal antibody can be obtained from the cultured hybridoma cell (molecular biology laboratory Manual, edited: Ausubel et al (1987) published: John Wiley and sons, section: 11.4 to 11.11). The chimeric antibody can be produced, for example, by referring to "Experimental medicine, provisional publication No. Vol.6, No.10, 1988" or Japanese examined patent publication No. 03-73280 ". F (ab')₂Or Fab' can be separately produced by treating immunoglobulin with pepsin or papain as a protease.

The above-mentioned detection reagent contains an antibody in a free state, a labeled state or an immobilized state. The detection drug of the present invention may comprise a carrier which is usually contained in a diagnostic reagent. Examples of the carrier include, but are not limited to, preservatives, stabilizers, buffers, solvents (e.g., water, physiological saline, etc.), and the like.

The present invention provides a method for measuring stress or fatigue, which comprises the step of measuring the amount of a factor in a biological sample using the aforementioned detection agent.

The method for measuring stress or fatigue can be qualitatively or quantitatively measured by a known method using the molecule (preferably antibody) contained in the above-mentioned detection drug, for example, the amount of the factor in a biological sample (preferably plasma, serum, saliva or urine). As a system capable of simultaneously and easily measuring many of the above proteins, a liquid-phase protein array system (for example, Bio-Plex (trade name) Suspension array system (Bio-Rad Laboratories) in which binding reaction is carried out in a microbead Suspension using microbeads having protein recognition sensors attached thereto is preferable. In the case of using the array system, measurement can be performed over a wide measurement range of several pg/ml to several tens of pg/ml.

By comparing the amounts of the respective factors obtained in the biological sample with the above-mentioned stress or fatigue indicator, the degree of stress or fatigue of the animal can be objectively and qualitatively or quantitatively evaluated.

The animal is preferably a vertebrate such as a human being, and particularly preferably a domestic or pet animal such as a cow, horse, pig, sheep, goat, chicken, dog, or cat. The method for measuring stress or fatigue of the present invention is applicable to livestock and pet animals, and can objectively monitor the stress or fatigue state of an animal in the field of livestock and pet industry where artificial breeding is likely to cause stress, so that the health state of an animal can be easily grasped and good management can be performed.

In the detection reagent of the present invention, the above-mentioned molecules are preferably placed in different containers, and the molecules are preferably antibodies. Since the above molecules are placed in different compartments, they can be used as a test kit for the intensity of mental states or disorders as described below. Examples of other reagents and articles contained in the detection kit include a buffer (for diluting a reagent or a biological sample), a fluorescent dye, a reaction vessel, a positive control, a negative control, and an instruction for a detection protocol. By using the kit of the present invention, the intensity of mental state or mental disorder can be easily measured.

The present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of the above-mentioned factors (IL-1. beta., IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-. gamma., IFN-. alpha., IP-10, MCP-1, MIP-1. alpha., MIP-1. beta., PDGF-BB, RANTES, TNF-. alpha., VEGF, CSF-2, TGF-. beta., neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, alpha., PDGF-4, IL-6, IL-7, IL-8, IL-9, IL-10, CXC chemokine ligand1, CXC chemokine ligand 5 and HGF) as an indicator for the evaluation of a mental state selected from the group consisting of mental fatigue, physical fatigue, stress, mood depression, mood elevation, mood depression, dysthymia, obsessive-compulsive, panic, anxiety, phobia, crowd phobia, social phobia, stress, intensity of labor, intensity of learning, depression, schizophrenia, depressive-like mental states, schizophrenia-like mental states and suicidal risks.

Wherein, "a depressive-like mental state, a schizophrenia-like mental state" means a mental state in which the mental disorder is not actually suffered from or suffered from although it appears as depression or schizophrenia, and includes mental states similar to mental disorders including mood disorders, obsessive-compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobias, excessive stress, poor adaptation to work or learning, suicidal moods, personality disorders, alcoholism psychosis, insomnia, circadian rhythm disorders, psychoneurosis, suicide attempts, and the like.

The present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of the above-mentioned factors (IL-1. beta., IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-. gamma., IFN-. alpha., IP-10, MCP-1, MIP-1. alpha., MIP-1. beta., PDGF-BB, RANTES, TNF-. alpha., VEGF, CSF-2, TGF-. beta., neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, alpha., PDGF-4, IL-6, IL-7, IL-8, IL-9, IL-10, CXC chemokine ligand1, CXC chemokine ligand 5 and HGF) as an indicator for assessing the intensity of a psychiatric disorder selected from the group consisting of mental fatigue, stress, depression, depressive state, mood disorders, schizophrenia, obsessive-compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobias, excessive stress, poor adaptation to work or learning, suicidal mood, personality disorders, alcoholism psychosis, insomnia, circadian rhythm disorders, psychoneurosis, dementia (senile dementia of the alzheimer's type, alzheimer's disease, pick's disease), central neurodegenerative disorders (OPCA (olivopontocerebellar atrophy), parkinson's disease, diffuse Lewy small body disease) and suicide attempts.

All of the above indicators can evaluate not only the state of onset of a condition, disorder or disease, but also the state before onset of a disease (i.e., a state in which the presence of a pathological state or a signal from a pathological state, although a disease cannot be identified clearly by physical examination, can significantly predict the risk of onset).

In the present invention, "stress" refers to various responses of an organism caused by applying a temporary load of chemical, physical, mental, linguistic or work to the spirit or body of the organism, and provides an index of a specific stress caused by a specific load by a method of weighting the above factors. Specifically, by multiplying the coefficients obtained by the weight ratios by the respective factors, it is possible to provide an index of stress as mental state or stress as mental disorder.

In the present invention, "fatigue" includes physical fatigue and mental fatigue, and any one of the indexes with physical fatigue as a major point and the indexes with mental fatigue as a major point can be provided by the method of the weighted ratio of the above factors. Specifically, by multiplying the coefficients obtained by the weighting ratios by the respective factors, it is possible to provide an index of mental state represented by physical fatigue and mental fatigue or an index of mental disorder due to mental fatigue.

In the present invention, "emotional depression" means the content defined in DSM-IV.

In the present invention, "depression" refers to the group of diseases defined in DSM-IV and referred to as "major depression" in psychomedicine.

In the present invention, "dysthymia" refers to the fluctuation of mood.

In the present invention, "mood disorder" means the content defined in DSM-IV.

In the present invention, "schizophrenia" means the content defined in DSM-IV.

In the present invention, "compulsive" refers to the content defined in DSM-IV.

In the present invention, "obsessive compulsive disorder" refers to the definition in DSM-IV.

In the present invention, "panic" refers to what is defined in DSM-IV.

In the present invention, "panic disorder" refers to the content defined in DSM-IV.

In the present invention, "anxiety" refers to the definition in DSM-IV.

In the present invention, "anxiety disorder" means the content defined in DSM-IV.

In the present invention, "phobia" refers to the definition in DSM-IV.

In the present invention, "crowd phobia" refers to the definition in DSM-IV.

In the present invention, "social phobia" refers to the contents defined in DSM-IV.

In the present invention, "stress" refers to a response to a chemical, physical, mental, linguistic or work load, which is mainly characterized by mental stress, and hyperactivity (response) of the sympathetic nervous system.

In the present invention, "overstrained" refers to the content defined in DSM-IV.

In the present invention, the term "labor intensity" refers to the degree of fatigue that can be known by performing the Kraepelin test, fatigue detection, etc. after labor.

In the present invention, "poorly adapted to work" means as defined in DSM-IV.

In the present invention, the "learning strength" refers to the degree of fatigue that can be obtained by performing a kreppellin test, fatigue detection, or the like after learning.

In the present invention, "poor adaptation to learning" refers to the content defined in DSM-IV.

In the present invention, "suicide risk" refers to the content defined in DSM-IV.

In the present invention, "suicide mood" means the content defined in DSM-IV.

In the present invention, "suicide attempt" refers to the definition in DSM-IV.

In the present invention, "personality disorder" means the content defined in DSM-IV.

In the present invention, "alcoholism psychosis" means the one defined in DSM-IV.

In the present invention, "insomnia" means the content defined in DSM-IV.

In the present invention, "circadian rhythm disorder" means the one defined in DSM-IV.

In the present invention, "psychoneurosis" means the one defined in DSM-IV.

In the present invention, "mood elevation" means the content defined in DSM-IV.

In the present invention, "mood lowering" means the content defined in DSM-IV.

In the present invention, "depressive state" means the content defined in DSM-IV.

In the present invention, "dementia" means the one defined in DSM-IV.

In the present invention, "senile dementia of Alzheimer type" means the content defined in DSM-IV.

In the present invention, "Alzheimer's disease" means the definition in DSM-IV.

In the present invention, "pick's disease" refers to the definition in DSM-IV.

In the present invention, "central neurodegenerative disease" refers to the definition in DSM-IV.

In the present invention, "OPCA (Olive bridged cerebellar atrophy)" means the content defined in DSM-IV.

In the present invention, "Parkinson's disease" means the content defined in DSM-IV.

In the present invention, "diffuse Lewy body disease" refers to the content defined in DSM-IV.

The mental disorder defined by DSM-IV, although not specifically described above, is included in the present invention as long as it is within the defined range. If DSM-IV is revised, the mental disorder is subject to its revision.

The indicator of the intensity of mental state or mental disorder of the present invention contains at least 2 factors in the weight ratio selected from the above-mentioned factors. In order to indicate the intensity of each mental state or mental disorder more specifically, the factors are selected from 3 to 41, preferably 3 to 28, more preferably 5 to 20, and still more preferably 8 to 12 of the above-mentioned factors.

The above cytokines and chemokines, which constitute the indicator of the intensity of the mental state or disorder of the present invention, are preferably placed in different containers. The indicator of the present invention may contain other components as long as the factors such as the above-mentioned cytokine and chemokine are used as main components. Examples of the other components include solvents (e.g., buffers, physiological saline, etc.), stabilizers, bacteriostats, and preservatives, but are not limited thereto.

The indicator of the intensity of mental state or mental disorder of the present invention can be an objective index in the field of mental hygiene of animals. In particular, by using the factors in the above-described weight ratios in a biological sample of an animal, preferably plasma, serum, saliva or urine, as an index, it is possible to easily and quantitatively understand various mental states.

The indicator of fatigue or the indicator of the intensity of a mental state or disorder of the present invention may be a combination of factors contained in the indicator according to a weighted ratio value, i.e., a database. By making the indicator database, it is possible to easily and quantitatively recognize each item of mental various states from the measurement values obtained by using the detection drug of the present invention.

The agent for detecting the intensity of a mental state or mental disorder of the present invention is characterized by comprising a compound selected from the group consisting of those which specifically recognize the above-mentioned factors (IL-1. beta., IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IFN-gamma, IFN-alpha, IP-10, MCP-1, MIP-1. alpha., MIP-1. beta., PDGF-BB, RANTES, TNF-alpha, VEGF, CSF-2, TGF-beta, neurotrophin5, TNF-alpha, VEGF-1. alpha., MIP-1. alpha. and VEGF, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand1, CXC chemokine ligand 5, and HGF).

The molecules and other components contained in the drug for assaying mental state or mental disorder of the present invention are the same as those contained in the above-mentioned drug for assaying stress or fatigue.

The present invention provides a method for determining the intensity of a mental state or disorder, the method comprising: a step of measuring the amount of the factor in a biological sample using a detection drug for the intensity of the mental state or mental disorder; and comparing the amount obtained in the measuring step with an indicator of the intensity of the mental state or mental disorder.

The method for measuring the intensity of mental state or mental disorder can be carried out by measuring the concentration of a factor in a biological sample (preferably plasma, serum, saliva or urine) by a known method using a molecule (preferably an antibody) contained in the aforementioned drug for measuring the intensity of mental state or mental disorder. As a system capable of simultaneously and easily measuring many of the above proteins, for example, a Bio-Plex suspension array system (manufactured by Bio-Rad Laboratories) is preferable.

By comparing the value obtained by multiplying the amount of each factor in the obtained biological sample by the coefficient with the indicator of mental state, the mental state of the animal can be objectively and quantitatively evaluated.

The animal is preferably a vertebrate such as a human being, and particularly preferably a domestic or pet animal such as a cow, horse, pig, sheep, goat, chicken, dog, or cat. The method for measuring mental state or mental disorder intensity of the present invention can be applied to livestock and pet animals, and can objectively monitor the mental state or mental disorder intensity of an animal in the field of livestock and pet industry where stress is likely to occur in artificial breeding, so that the health state of an animal can be easily grasped.

The kit for detecting the intensity of a mental state or disorder according to the present invention is characterized in that the above-mentioned molecules, preferably antibodies, are preferably placed in separate compartments. Examples of other reagents and articles contained in the detection kit include a buffer (for diluting a reagent or a biological sample), a fluorescent dye, a reaction vessel, a positive control, a negative control, and an instruction for a detection protocol. By using the detection kit of the present invention, mental states can be easily measured.

The present invention allows high throughput analysis of the above factors in various mental states or disorders. The findings obtained according to the present invention enable individual differences to be easily found. Therefore, the present invention can be used to find a new gene or to screen (screening) stress resistance, since individual differences lead to differences in the response of the amount of cytokines to stress. Furthermore, the present invention can be used for determining the effect of a drug having an anti-stress effect. The invention has the following advantages:

1: the measurement was performed using an apparatus independently developed for indicating stress.

2: in the case of using plasma or serum, the whole factor measurement can be performed using 50. mu.L of the sample.

3: the whole process can be completed in about 6 hours.

4: all the obtained data can be databased, and the statistical treatment is simple and convenient.

Compared with the conventional method (therefore, the phenomenon that results are different between different institutions) of integrating collected interviews by doctors or psychologists and even data collected by questionnaires for several days and evaluating the data, the mental states of stress and the like can be grasped inexpensively and quickly by applying the advantages to the measurement of stress and the like.

Examples

The present invention will be described in more detail with reference to examples and the like, but the present invention is not limited to these examples and the like. In the following examples, volunteer subjects were subjected to various tests and blood collection after receiving approval from the ethical committee of the institution in advance and obtaining consent.

Example 1: mental state and fatigue state scale

402 volunteer subjects were subjected to questionnaire psychological tests, and were investigated using SDS, MAS, GHQ, STAI, CMI, subjective symptom surveys (produced by the institute of labor and health), social phobia scales, crowd phobia scales, and independently developed living condition questionnaires, to confirm that the subjects were healthy. After confirming the health of the subject, 1ml of blood was taken in a blood collection conical body (spitz) containing an anticoagulant at the same time point of the morning of the day of rest and the morning of the night shift ending, respectively, and plasma was separated under cooling at 4 ℃. The plasma was stored frozen or on ice, and the cytokines shown in each of the plasma were simultaneously measured by a protein array system of beads (Bio-Plex suspension array system manufactured by Bio-Rad Laboratory, which was independently modified by the present inventors). The cytokine types were also measured by a conventional ELISA method to determine the blood concentration of each cytokine type.

1 example of the results is shown in FIG. 1 a. After the blood concentration of each cytokine was measured, the correlation coefficient of the blood concentration of each cytokine was calculated and the correlation value with a high color marker was used as a result (the correlation coefficient was light gray from 0.50 to 0.6499, dark gray from 0.65 to 0.7999, and black from 0.8 to 0.9999. when the correlation coefficient was 0.50, the relative risk of correlation was p < 0.001). From the results, it was found that some cytokines had a high correlation in healthy subjects. Subsequently, a study was made of whether cytokine correlation in 142 healthy subjects who had frequent night shifts reflected the presence of the shift, and whether cytokine correlation could be used to distinguish between before and after the shift. It is clear from fig. 1b (before the night shift) and fig. 1c (after the night shift) that the correlation between the blood concentrations of the cytokines significantly changes. It is understood that there is a significant deviation from normal at the same point in time after the night shift. FIG. 1d shows by logistic regression analysis whether discrimination between pre-and post-night shifts by the present invention based on the cytokine correlation and targeting 90 subjects randomly sampled from the subjects. The positive diagnosis rate in the examples was 88%. Also, if the value of each cytokine is multiplied by the coefficient of items of depression, anxiety, phobia, and stress in a psychological test to generate a score, the tendency of depression, anxiety, or stress can be detected more sensitively than in a psychological test and is consistent with the result interviewed by a psychiatrist. This example shows that various mental states such as depression, excitement, tension, anxiety and the like can be grasped or evaluated by the measurement method of the present invention.

Example 2: the scale of mental or physical fatigue and the scale of stress

A Kreppelin test, which is a simple continuous calculation of mental fatigue load, or an aerobic plate exercise test, which is a physical fatigue load and has a pulse rate of 180 pulses per minute, was performed on 28 to 30 healthy subjects for 3 hours, and blood was collected before and after the test in the same manner as in example 1 to measure cytokines. Then, the same cytokine measurement was performed 24 hours after the start of the load (21 hours after the end of the load). The correlation coefficient of the blood concentration of each cytokine was calculated and the result was obtained as a correlation value with a high color marker.

From these results, it was found that the correlation between the whole cytokines before and after the above-mentioned each test and in the recovery period was changed. By comparing the calculation as mental load with the plate movement as body load, it was found that there was a combination of some cytokines having different strengths in the correlation, showing that the evaluation of fatigue and stress state could be grasped by the measuring method of the present invention.

Study and graphical representation by logistic regression analysis: whether or not a load has occurred in any of the krappelin task as a mental task and the plate exercise task as a physical task for all subjects based on the correlation between the cytokines can be determined. The results show that: the length of the load time of the Kreppeline test and the plate exercise test (positive diagnosis rate in the examples: the Kreppeline test 100% and the plate exercise test 81%) was determined, and the difference in recovery time between the subjects (positive diagnosis rate in the examples: the Kreppeline test 81% and the plate exercise test 100%) was determined, and whether the Kreppeline load or the plate exercise load was determined (positive diagnosis rate in the examples: 100%). The result means that not only the presence or absence of fatigue, but also the content or degree of fatigue can be classified, identified, and evaluated using the present invention. By utilizing the change in the positive diagnosis rate or the degree of recovery from the standard state shown in the classification table obtained by using the present invention by a drug, a food, a lifestyle habit or the like, it is meant that the effect or influence of the factors such as the drug, the food, or the lifestyle habit on the improvement of mental fatigue or physical fatigue can be clearly understood.

Example 3: diagnostic scale and evaluation scale for mental disorder

160 volunteer mental disorder patients diagnosed based on the international diagnostic standard DSM-IV were subjected to questionnaire psychological tests as much as possible, and investigated using SDS, MAS, GHQ, STAI, SCID, CMI, subjective symptom survey (produced by the institute of labor and health), social terrorism, crowd terrorism, and independently developed living condition questionnaires.

While the investigation was being carried out, 1ml of blood was taken into a blood collection conical body containing an anticoagulant, and plasma was separated under cooling at 4 ℃. The plasma was stored frozen or on ice, and the cytokines shown in each of the plasma were simultaneously measured by a protein array system of beads (Bio-Plex suspension array system manufactured by Bio-Rad Laboratory, which was independently modified by the present inventors). The cytokine types were also measured by a conventional ELISA method to determine the blood concentration of each cytokine type. On the other hand, a psycho-medical structured interview with all volunteers mastered their psychological inclination and status.

Multiplying the various cytokine values by the coefficients produces a score that can detect trends in depression, anxiety, or stress more sensitively than psychological tests, and consistent with the results interviewed by a psychiatrist. The score of the psychological test is personal information of the patient and is not disclosed, and the cytokine-related coefficient values of the depression patients are shown in fig. 3, and the cytokine-related coefficient values of the schizophrenia patients are shown in fig. 4. The correlation coefficient of the blood concentration of each cytokine was calculated and the result was obtained as a correlation value with a high color marker. It can be seen that the results are different from the correlation coefficient value table of the healthy subjects shown in fig. 1. Whether depression can be judged by using the present invention was investigated by logistic regression analysis, and the result was that the positive diagnosis rate was 91%.

Whether schizophrenia can be judged by using the present invention was investigated by logistic regression analysis, and the result was that the positive diagnosis rate was 96%.

The above results show that the state of various psychiatric disorders (e.g., depression, schizophrenia, excitation, stress, anxiety, etc.) can be grasped and evaluated using cytokine assays according to the methods of the present application. At the same time, it has been shown that the diagnosis and treatment effects of psychomedicine, which are very dependent on traditional experience and often inaccurate, can be determined unambiguously using cytokine assays. It is also shown that it can be used to determine the effect of a therapy. In addition, even mental symptoms of pathological states are often not displayed on the surface, and problems of the mental symptoms to the society are increasing. Based on the correlation found in the present invention, the present invention can sufficiently diagnose and evaluate the pathological condition of depression and schizophrenia, which are two major diseases in the field of psychomedicine.

If dementia (senile dementia of the alzheimer type, alzheimer's disease and pick's disease) and central neurodegenerative diseases (OPCA, parkinson's disease and diffuse Lewy small body disease) could be predicted, it would be a huge contribution to the QOL of the patients. According to the present invention, depression, mild dementia or central neurodegenerative disease can be distinguished at the stage of dementia or central neurodegenerative disease not becoming prominent, and it is expected to realize grouping (grouping) of mild dementia or mild degenerative disease advocated in the field of psychiatric medicine.

By using the correlation between the amount of the factor in blood, urine or saliva and the mental state, fatigue or stress level, which is found according to the present invention, the risk or degree of stress, fatigue or dysthymia (particularly depression) can be evaluated easily, inexpensively and objectively. The score distribution of each cytokine selected by changing can be used for evaluating stress, fatigue or dysthymia (particularly depression) separately in one assay in an optimal scale, and can be widely used.

Therefore, stress, fatigue, or dysthymia (depression) can be objectively evaluated and their degree grasped. Since cytokines are causative agents (positive agents) or exacerbating factors (exacerbating factors) of various diseases, care and preventive measures from the point of view of physical and mental unification can be provided.

Industrial applicability

According to the present invention, the intensity of a load from the outside can be evaluated or the effect of the load can be predicted in a state of a transient biological reaction. Specifically, by evaluating fatigue and recovery from an external load, the fatigue tendency (tendency to recovery) or the recovery ability of each person can be evaluated. Further, the degree of influence of a certain factor on fatigue tendency or recovery ability of each person can be evaluated. Therefore, the present invention can be applied to the field of labor hygiene, and can be used for prevention of a disaster of a worker. Moreover, it can contribute to the development of drugs, foods, daily necessities, designs, images, sounds, buildings, living environments, and the like, which can reduce stress.

According to the present invention, it is possible to evaluate a pathological state and grasp a potential pathological state in a constant pathological state of an organism and even to find a disease before the development of subjective symptoms, and therefore, it is possible to early find and early treat the pathological state, evaluate a treatment effect, determine whether a treatment method is effective, uniformly grasp and manage a plurality of pathological states (specifically, for example, skin disorders (skin disorders) caused by ultraviolet rays or the like, atopic dermatitis, psoriasis, acne vulgaris, pemphigus vulgaris, ichthyosis, ocular allergy, burns containing inflammatory changes of the skin in the pathological state, radiodermopathy; alzheimer's disease, senile dementia of the alzheimer's type, diffuse Lewy body disease, pick's disease, bewang's disease, parkinson's syndrome, cerebral ischemia reperfusion injury, carbon monoxide poisoning, dilute poisoning (thinecoisoning), Hemorrhagic encephalopathy of newborn, hypoxic encephalopathy, hypertensive encephalopathy, epilepsy, multiple sclerosis, HIV encephalopathy, cerebral circulatory disorders, cerebrovascular accident, circadian rhythm disorder, appetite disorder, pituitary dysfunction such as Addison's disease, acromegaly and hypogonadism, thyroid dysfunction, obesity, abnormal control of blood glucose level, primary aldosteronism, adrenal dysfunction such as Cushing's disease, osteodystrophy; inflammatory diseases, autoimmune diseases, disorders of the host defense system; diseases with arthritis as the main pathological state, such as rheumatoid arthritis, gout, arthritis, and the like; renal failure, fluid disturbance, collapse of the balance of potassium ions, sodium ions and chloride ions, edema, impaired glucose tolerance such as diabetes, wasting, convulsions, heart failure, pulmonary edema, hypoproteinemia, bleeding tendency, renal urinary tubule epithelial cell shedding (defluorion of renal urinary epithelial cell), diseases with inflammation as the main pathological state; menstrual disorder, endometriosis, hyposexuality, and other diseases induced by pituitary dysfunction) and contributes to the efficiency of not only the treatment of pathological conditions but also the efficiency of preventive medicine. Furthermore, the selection of experimental groups in drug or food development can be facilitated according to the present invention.

The present application is based on Japanese application No. 2006-.

Claims

1. Use of at least 3 molecules selected from antibodies specifically recognizing the following factors, respectively, for the preparation of a detection drug for the detection of mental states by logistic regression analysis: eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, CSF-2, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, HGF, VEGF, TGF-beta, IL-3, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IFN-gamma, IFN-alpha, CXC chemokine ligand 5, IL-4, IL-8, IL-2, TNF-alpha, CXC chemokine ligand1, IL-1 beta and IL-1ra, said mental state being selected from mental fatigue, TNF-alpha, CXC chemokine ligand1, IL-1 beta and IL-1ra, Physical fatigue, stress, emotional depression, mood elevation, mood depression, dysthymia, obsessive-compulsive, panic, anxiety, phobias, crowd phobia, social phobia, tension, intensity of labour, intensity of learning, depression, schizophrenia, depressive-like mental states, schizophrenic-like mental states, and suicidal risks.

2. Use of at least 3 molecules selected from antibodies that specifically recognize the following factors, respectively, for the preparation of a detection drug for detecting the intensity of a psychotic disorder by logistic regression analysis: eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, CSF-2, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, HGF, VEGF, TGF-beta, IL-3, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IFN-gamma, IFN-alpha, CXC chemokine ligand 5, IL-4, IL-8, IL-2, TNF-alpha, CXC chemokine ligand1, IL-1 beta and IL-1ra, said mental disorder being selected from mental fatigue, mental stress, stress, depression, depressive states, mood disorders, schizophrenia, obsessive-compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobia, excessive stress, poor adaptation to work or learning, suicidal moods, personality disorders, alcoholism psychosis, insomnia, circadian rhythm disorders, psychoneurosis, dementia, central neurodegenerative diseases, and suicide attempts.

3. Use of a detector drug according to claim 1 in the manufacture of a medicament for the determination of mental state, said determination comprising: a step of measuring the amount of the factor in a biological sample by using the detecting agent according to claim 1, and a step of comparing the amount obtained in the measuring step after weighted proportioning with an indicator for evaluating the mental state selected from the group consisting of mental fatigue, physical fatigue, stress, emotional depression, emotional elevation, emotional depression, obsessive-compulsive disorder, social phobia, stress, intensity of labor, intensity of learning, depression, schizophrenia, mental states resembling depression, mental states resembling schizophrenia, and suicidal risk, and the indicator for evaluating the mental state selected from the group consisting of mental fatigue, physical fatigue, stress, emotional depression, emotional elevation, emotional depression, mental depression, obsessive-compulsive disorder, panic disorder, anxiety, phobia, human phobia, social phobia, stress, intensity of labor, intensity of learning, anxiety, phobia, a social phobia, a stress, a weighted ratio, and a step of comparing the amount obtained in the measuring step with, Depression, schizophrenia, a depressive-like psychotic state, a schizophrenia-like psychotic state, and a suicidal risk psychotic state, and comprising at least 3 factors selected from the group consisting of the following factors in a weighted ratio: eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1 α, MIP-1 β, PDGF-BB, RANTES, CSF-2, neurotrophin5, MCP-3, β -2-microglobulin, angiotensin II, CSF-3, HGF, VEGF, TGF- β, IL-3, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IFN- γ, IFN- α, CXC chemokine ligand 5, IL-4, IL-8, IL-2, TNF- α, CXC chemokine ligand1, IL-1 β, and IL-1 ra.

4. Use of the detector of claim 2 in the manufacture of a medicament for determining the intensity of a disorder, said determination comprising: a procedure for measuring the amount of the above-mentioned factor in a biological sample using the detecting agent according to claim 2, and a procedure for comparing the amount obtained in the above-mentioned measuring procedure after weighted proportioning with an indicator for evaluating the amount selected from the group consisting of mental fatigue, stress, depression, depressive state, mood disorder, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, crowd phobia, social phobia, excessive stress, poor adaptation to work or learning, suicidal mood, personality disorder, alcoholism, insomnia, circadian rhythm disorder, psychoneurosis, dementia, central neurodegenerative disease and suicide attempts, stress, depression, depressive state, mood disorder, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety, phobia, crowd phobia, social phobia, excessive stress, panic disorder, and suicide attempts, Intensity of maladaptive to work or learning, suicidal mood, personality disorder, alcoholism psychosis, insomnia, circadian rhythm disorder, psychoneurosis, dementia, central neurodegenerative disorder, and suicidal attempted psychotic disorder, and comprising at least 3 factors selected from the group consisting of the following factors in a weighted ratio: eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1 α, MIP-1 β, PDGF-BB, RANTES, CSF-2, neurotrophin5, MCP-3, β -2-microglobulin, angiotensin II, CSF-3, HGF, VEGF, TGF- β, IL-3, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IFN- γ, IFN- α, CXC chemokine ligand 5, IL-4, IL-8, IL-2, TNF- α, CXC chemokine ligand1, IL-1 β, and IL-1 ra.

5. Use according to claim 3 or 4, wherein said biological sample is plasma, serum, saliva or urine.

6. Use of at least 3 factors selected from the following factors in a weighted ratio for the preparation of an indicator for assessing a mental state: eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, CSF-2, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, HGF, VEGF, TGF-beta, IL-3, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IFN-gamma, IFN-alpha, CXC chemokine ligand 5, IL-4, IL-8, IL-2, TNF-alpha, CXC chemokine ligand1, IL-1 beta and IL-1ra, said mental state being selected from mental fatigue, TNF-alpha, CXC chemokine ligand1, IL-1 beta and IL-1ra, Physical fatigue, stress, emotional depression, mood elevation, mood depression, dysthymia, obsessive-compulsive, panic, anxiety, phobias, crowd phobia, social phobia, tension, intensity of labour, intensity of learning, depression, schizophrenia, depressive-like mental states, schizophrenic-like mental states, and suicidal risks.

7. Use of at least 3 factors selected from the following factors in a weighted ratio for the manufacture of an indicator for assessing the intensity of a psychotic disorder: eotaxin, basic fibroblast growth factor, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, PDGF-BB, RANTES, CSF-2, neurotrophin5, MCP-3, beta-2-microglobulin, angiotensin II, CSF-3, HGF, VEGF, TGF-beta, IL-3, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IFN-gamma, IFN-alpha, CXC chemokine ligand 5, IL-4, IL-8, IL-2, TNF-alpha, CXC chemokine ligand1, IL-1 beta and IL-1ra, said mental disorder being selected from mental fatigue, mental stress, stress, depression, depressive states, mood disorders, schizophrenia, obsessive-compulsive disorders, panic disorders, anxiety disorders, phobias, crowd phobias, social phobia, excessive stress, poor adaptation to work or learning, suicidal moods, personality disorders, alcoholism psychosis, insomnia, circadian rhythm disorders, psychoneurosis, dementia, central neurodegenerative diseases, and suicide attempts.