JP5553525B2 - Bio-load indicator and bio-load measurement method - Google Patents

Description

  The present invention relates to a bioburden indicator and a bioload measurement method. Specifically, the present invention relates to a technical field in which biological loads such as stress and fatigue are objectively evaluated by a molecular biological approach.

  Mental and / or physical stress affects host defense, including nerve, endocrine and immune systems (see Non-Patent Documents 1 and 2). Physiologically active factors involved in host defense, specifically hormones such as glucocorticoids, neurotransmitters such as catecholamines, and some cytokines increase due to stress (see Non-Patent Documents 1 and 3). However, the molecular mechanism by which stress alters the pharmacokinetics of these molecular groups is not well understood.

  Under stress, in addition to increases in blood glucocorticoids and catecholamines (see Non-Patent Document 4), salivary amylase (see Non-Patent Document 5) and blood cytokines (Non-Patent Documents 1 and 3) Reference) was reported. Living organisms have long been considered to exhibit similar responses to any load, regardless of the type of mental stress, physical stress, physical stress, or chemical stress (see Non-Patent Document 6). Therefore, stress response was defined as pan-adaptive syndrome (see Non-Patent Document 6). Therefore, it has been considered impossible to discriminate applied stress from the physical changes after stress and evaluate the strength.

  It was believed that hormones, neurotransmitters, and cytokines fluctuate according to certain pharmacokinetics as a whole, depending on infection, inflammation, nutritional status, exercise, etc., and maintain a specific body level pattern (Non-Patent Documents) 1 and 6). However, the inventor's study revealed a secretory pathway of interleukin (IL) -18 that is activated only when stress, particularly mental stress, is applied. That is, IL-18 secreted from macrophages depending on inflammation or infection (see Non-Patent Document 8) is adrenal cortex secreted from the pituitary gland during non-inflammatory and non-infectious stress, particularly mental stress. It was shown to be expressed in the adrenal gland by stimulating hormone (ACTH) (see Non-Patent Document 7) and secreted into the blood (see Non-Patent Document 9-11).

  IL-18 is a cytokine secreted during inflammation and infection, and has been shown to suppress the induction and secretion of IL-6 (see Non-Patent Document 12 and Patent Document 1). IL-6 is induced only when the blood level rises due to IL-18, and the blood level is raised (see Non-Patent Document 9-11). This means that IL-18 and IL-6 have specific reactions to mental stress, and their activation causes distortion in the concentration relationship between the two.

  In addition to IL-18 and IL-6, many of the immunoregulatory molecules of hormones, neurotransmitters, and cytokines are usually in addition to mental stress and stress due to exercise, inflammation, infection, age, sex, obesity It varies depending on the degree. Therefore, each body level is under the strong influence of external and internal environment (refer nonpatent literature 1). Therefore, even if these constitutively secreted molecules are measured and a strain is found in the concentration relationship, whether it is due to a specific stress or due to inflammation, infection, age, sex, obesity, etc. Evaluation could not be performed (conference presentation as shown in Non-Patent Document 13).

  In modern society, clear indicators of stress have not yet been developed. For this reason, humans are exposed to various stresses, and are exposed not only to reduced labor efficiency, loss of vitality, and reduced quality of life, but also to high risk of mental illness, reduced immunity, or autoimmune diseases. In order to determine and evaluate stress and biological load, the present inventor first needs to find a molecule that shows a specific response to stress and discover a combination of molecules that occurs only under stress. In addition, it was concluded that it is important to discover strains that occur only under stress in their molecular level correlation (see Patent Documents 2 and 3).

JP-A-8-193098 International Publication No. 2006/003927 Pamphlet International Publication No. 2007/094742 Pamphlet

Plotnikoff, P.N. et al., Cytokines, Stress and Immunity, second edition. CRC Press. 1-16 (2007) Kiecolt-Glaser, J. K. et al. Proc. Natl. Acad. Sci. USA 93, 3043-3047 (1996) Dugue, B. et al. Scand. J. Clin. Invest. 53, 555-561 (1993) Davis EP, Granger DA. Psychoneuroendocrinology. (2009) Su, H. et al. Free Radic Biol Med. 46. 914-21 (2009) Motzer SA, Hertig V. Nurs Clin North Am. 39. 1-17 (2004) Conti, B. et al. J. Biol. Chem. 272, 2035-2037 (1997) Okamura, H. et al. Nature 378, 88-91 (1995) Sekiyama, A. et al. Immunity 22 (6), 669-677 (2005) Sekiyama, A. et al. J Neuroimmunol. 171 (1-2), 38-44 (2006) Sekiyama, A. et al. J Med Invest. 52, 236-239 (2005) Sakao, Y. et al., Int Immunol. 11. 471-480 (1999) Sekiyama, A. et al. Biol Psych. 63. 12S-13S (2008)

The living body has a function to keep the function of the living body constant in response to a load and a stimulus, and this function is called homeostasis and a biological defense mechanism. It has been known that mental, physical, physical, and chemical stress and fatigue are burdened on homeostasis and biological defense mechanisms, and various diseases are caused by the breakdown of homeostasis and biological defense mechanisms.
Homeostasis such as stress, fatigue, and depression, and the state of loading of the body's defense mechanisms can cause psychiatric disorders, physical disabilities and even suicide, and are serious health threats. However, since these symptoms were fundamentally subjective symptoms, they could only be evaluated by self-reports. Furthermore, it is extremely difficult to detect abnormalities by known biochemical tests and psychological tests, and it is impossible to objectively evaluate, grasp the degree, and take measures. Various biochemical or physiological indicators have been proposed so far, but hormones and amines have low stability and lack quantitativeness, and the level changes in conjunction with stress, but the indicators are I couldn't. In addition, many of the molecules related to host defense are affected by various factors such as age, sex, and body weight, and since they are normally secreted, it was impossible to know what changed them.
An object of the present invention is to provide means capable of objectively and specifically evaluating loads on various living bodies including fatigue, which only had an evaluation method that relied on subjective symptoms. In addition, since the burden on the living body homeostasis and the living body defense mechanism is perceived with discomfort for the living body, the object of the present invention is a means that can objectively and specifically evaluate the discomfort and comfort for the living body. Inevitably also includes providing.

As a result of intensive studies in view of the above problems, the present inventor comprehensively examined changes in expression of intracellular trophic factors, cytokines that have been thought not to be secreted, midkine, lymphokine, etc., during stress response. I found what was secreted. Based on these findings, we have newly identified a group of factors that constitute the in vivo cascade that activates only under stress, and also clarified strains at the body molecular level that are characteristically caused by various types of stress. Based on these findings, it was found that various biological loads such as stress and fatigue can be objectively grasped, and the present invention has been completed.
That is, the present invention is as follows.

[1] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF -An indicator of stress comprising at least two factors selected from the group consisting of β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1.
[2] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and a test agent for stress comprising at least two molecules selected from the group consisting of molecules specifically recognizing VCAM-1 .
[3] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF -An indicator of fatigue comprising at least two factors selected from the group consisting of β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1.
[4] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF Fatigue testing agent comprising at least two molecules selected from the group consisting of molecules specifically recognizing -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1 .
[5] The test agent according to [2] or [4], wherein the molecule is an antibody.
[6] A method for measuring stress, comprising a step of measuring the amount of a factor in a biological sample using the test agent according to [2] or [5].
[7] A method for measuring fatigue comprising a step of measuring the amount of a factor in a biological sample using the test agent according to [4] or [5].
[8] The measurement method according to [6] or [7], wherein the biological sample is plasma, serum, saliva or urine.
[9] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF An indicator agent weighted and distributed to at least two factors selected from the group consisting of -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1, Similar to fatigue, stress, depressed mood, comfortable mood, unpleasant mood, mood modulation, compulsive, panic, anxiety, phobia, social phobia, social phobia, tension, work intensity, learning intensity, depression, schizophrenia, depression An indicator for evaluating a mental state selected from the group consisting of a mental state, a mental state similar to schizophrenia, and the risk of suicide.
[10] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF -an indicator agent weighted and distributed to at least two factors selected from the group consisting of -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1, comprising mental fatigue, stress, Depression, depression, mood disorders, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, maladjustment to work or learning, thoughtful death, personality disorder, alcoholic An indicator for evaluating the intensity of a mental disorder selected from the group consisting of psychosis, insomnia, circadian rhythm disorders, psychoneuropathy, dementia, central nervous degenerative diseases, and suicide attempts.
[11] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF mental fatigue comprising at least two molecules selected from the group consisting of molecules specifically recognizing -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1, Physical fatigue, stress, depressed mood, comfort mood, unpleasant mood, mood modulation, obsessive-compulsive, panic, anxiety, phobia, social phobia, social phobia, tension, work intensity, learning intensity, depression, schizophrenia, depression A test agent for a mental condition selected from the group consisting of a similar mental condition, a mental condition similar to schizophrenia, and the risk of suicide.
[12] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF mental fatigue comprising at least two molecules selected from the group consisting of molecules specifically recognizing -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1, Stress, depression, depression, mood disorder, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, maladjustment to work or learning, suicidal ideation, personality disorder, A test agent for the severity of mental disorders selected from the group consisting of alcoholic psychosis, insomnia, diurnal rhythm disorders, neuropsychiatric disorders, dementia, central nervous degenerative diseases, and suicide attempts.
[13] The test agent according to [11] or [12], wherein the molecule is an antibody.
[14] A step of measuring the amount of a factor in a biological sample using the test agent according to [11] or [13] and a weighted distribution of the amount obtained in the measurement step to [9] Mental fatigue, physical fatigue, stress, depressed mood, comfortable mood, unpleasant mood, mood modulation, obsessive compulsive, panic, anxiety, phobia, social phobia, social phobia, tension, including steps to compare with the indicated indicators A method of measuring mental status selected from the group consisting of: labor intensity, learning intensity, depression, schizophrenia, mental status similar to depression, mental status similar to schizophrenia, and suicide risk.
[15] A step of measuring the amount of a factor in a biological sample using the test agent according to [12] or [13] and a weighted distribution of the amount obtained in the measurement step to [10] Mental fatigue, stress, depression, depression, mood disorders, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, including steps to compare with the indicated indicators Psychiatric disorders selected from the group consisting of maladjustment to work or learning, suicidal ideation, personality disorder, alcoholic psychosis, insomnia, diurnal rhythm disorders, neuropsychiatric disorders, dementia, central nervous degenerative diseases and suicide attempts Strength measurement method.
[16] The measurement method according to [14] or [15], wherein the biological sample is plasma, serum, saliva or urine.
[17] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF A test in which at least two molecules selected from the group consisting of molecules specifically recognizing -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1 are stored in separate compartments. Kit, mental fatigue, physical fatigue, stress, depressed mood, comfort mood, unpleasant mood, mood modulation, obsessive-compulsive, panic, anxiety, phobia, social fear, social fear, tension, labor intensity, learning intensity A test kit for mental status selected from the group consisting of depression, schizophrenia, mental status similar to depression, mental status similar to schizophrenia, and risk of suicide.
[18] IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF A test in which at least two molecules selected from the group consisting of molecules specifically recognizing -β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1 are stored in separate compartments. Kits with mental fatigue, stress, depression, depression, mood disorders, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, labor or learning Mental disorder selected from the group consisting of indications, thoughts of death, personality disorder, alcoholic psychosis, insomnia, circadian rhythm disorders, neuropsychiatric disorders, dementia, central nervous degenerative diseases and suicide attempts Strength testing kit.
[19] The test kit according to [17] or [18], wherein the molecule is an antibody.

  According to the stress or fatigue index agent of the present invention, since it contains factors that specifically express and form cascades according to each of various loads applied to the living body, The degree of fatigue can be evaluated objectively and molecularly. According to the test agent for stress or fatigue of the present invention, since it contains a molecule that recognizes a factor that specifically expresses and forms a cascade according to various loads applied to a living body, The degree of stress or fatigue can be examined objectively and quantitatively. According to the method for measuring stress or fatigue of the present invention, since the concentration of factors in a biological sample is measured using the test agent of the present invention, the degree of stress or fatigue of mammals including humans is objectively determined. And can be measured quantitatively. According to the indicator agent obtained by weighted distribution of the above factors of the present invention, it is possible to objectively, comprehensively and molecularly evaluate the intensity of various mental states or mental disorders in mammals including humans. . According to the test agent for the strength of mental state or psychiatric disorder of the present invention, it contains molecules recognizing factors such as midkine and nutritional factors that have various actions in the living body, and the molecules are weighted and distributed. It is possible to objectively and quantitatively examine the intensity of various mental states or psychiatric disorders in mammals including According to the method for measuring the intensity of mental state or mental disorder according to the present invention, the test agent for mental state or mental disorder of the present invention is used as an indicator of the indicator for mental state or mental disorder of the present invention. It is possible to objectively and quantitatively evaluate the intensity of various mental states or psychiatric disorders in mammals including According to the test kit for mental state or psychiatric disorder according to the present invention, since the test drug of the present invention is stored in separate compartments, the intensity of the mental state or psychiatric disorder is provided for the convenience of independent or comprehensive testing. be able to.

  Various mental and fatigue assessments and assessments of mental and fatigue disorders have required time-consuming examinations by trained specialists, who can collect blood, spinal fluid, or urine. Since it can be carried out only with this, it can be easily incorporated into daily health examinations.

  From these things, this invention can be used for the presence or absence of general stress, the presence or absence of fatigue, and strength determination irrespective of whether it is a healthy person. Based on this, reconstruction of the foundations of preventive medicine and public health administration; evaluation and management of life intensity and mental health of patients undergoing illness treatment; evaluation and management of life intensity and mental health of patients in the disease recovery stage; Industrial or occupational health or occupational injury scope assessment; work environment assessment; labor intensity assessment; residence or labor environment assessment; school hygiene or learning environment or strength assessment; environmental assessment; disease or disorder characterized by stress or fatigue Assessment of the state of the condition (Psychosomatic, Depression, Psychiatric Neuropathy, Chronic Fatigue Syndrome, Personality Disorder, Personality Disorder, Maladjustment Syndrome, Hikikomori, Moetsuki Syndrome, Apathy, Psychogenic Response, PTSD, and most other diseases) It can be used to unify stress assessment standards in Japan; and to formulate international standards for each of the above assessments.

FIG. 1 shows the results of logistic regression analysis used in the determination of depression in Example 10. FIG. 2 shows the results of logistic regression analysis used in the determination of schizophrenia in Example 11.

  The evaluation object in the present invention is divided into a load state and a disease state in a living body. In the present invention, the evaluation discriminating dimension is the state and its manifestation in the case of the state, and the type and degree of the manifested disease state in the case of the disease state. Furthermore, the present invention provides a criterion for evaluating a disease state by an approach from grasping a potential state, that is, a variation in lymphokine and midkine in a living body, against a disease state that has no objective evaluation criterion even in a manifested state. Also aiming.

  IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG , Β-NGF, SCF, SCGF-β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and at least two factors selected from the group consisting of VCAM-1.

  In the present invention, the “index agent” refers to an in vivo marker that serves as an index for objectively grasping various mental states for which only an evaluation method based on self-report has been established. Alternatively, the “index agent” may be an in vivo marker that serves as an index for objectively grasping the intensity of mental disorder.

  In the present invention, “biological load” means a chemical, physical, mental, verbal or labor load on the spirit and body of the living body. Further, the “biological load” is meant to include a constant load from the inside of the living body caused by a disease state or the like. For example, the biological homeostasis failure state, the biological homeostasis failure load state, the biological homeostasis failure precursor state, the biological defense mechanism failure state, the biological defense mechanism failure load, the biological defense mechanism failure precursor state, and the like are also included in the “biological load” in the present invention. .

  In the present invention, the term “stress” means various responses of the living body due to an extra chemical, physical, mental, verbal, or labor-related extraordinary load on the spirit and body of the living body. Further, “stress” also means various responses of the living body due to a constant load applied from inside the living body.

  In the present invention, “fatigue” means all kinds of fatigue including physical fatigue and mental fatigue.

  The factor contained in the indicator agent of the present invention is at least two selected from the above group. In order to become a more specific index of fatigue, there are 3 to 21 types, preferably 3 to 15 types, more preferably 5 to 13 types, and even more preferably 8 to 12 types.

  In the present invention, “IL-1α” is published as a human amino acid sequence and a base sequence in Genbank accession number: NM_000575, etc., and can be isolated or produced by a method known per se. “IL-1α” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “IL-2ra” is published as a human amino acid sequence and a base sequence in Genbank accession numbers: NM — 000417, AY563103, etc., and can be isolated or produced by a method known per se. In addition, “IL-2ra” includes homologues thereof (homologues and splice variants), mutants, derivatives, matured bodies, amino acid modifications, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “IL-16” is published as a human amino acid sequence and nucleotide sequence in Genbank accession numbers: NM — 172217, NM — 004513, BC040272, etc., and can be isolated or produced by a method known per se. “IL-16” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “CTACK” is published as a human amino acid sequence and nucleotide sequence under Genbank accession number: NM — 006664 and the like, and can be isolated or produced by a method known per se. “CTACK” includes its homologues (homologs and splice variants), mutants, derivatives, matures, amino acid modifications and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “GRO-α” is published as a human amino acid sequence and base sequence in Genbank accession numbers: NM — 001511, BC011976, etc., and can be isolated or produced by a method known per se. “GRO-α” includes homologues thereof (homologues and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “ICAM-1” is published as a human amino acid sequence and base sequence under Genbank accession number: NM — 002001, etc., and can be isolated or produced by a method known per se. “ICAM-1” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “IFN-α2” is published as Genamino Accession Number: NM — 000605 as a human amino acid sequence and base sequence, and can be isolated or produced by a method known per se. “IFN-α2” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “LIF” is published as a human amino acid sequence and nucleotide sequence under Genbank accession number: NM — 002309 and can be isolated or produced by a method known per se. “LIF” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “MCP-3” is published as a human amino acid sequence and a base sequence under Genbank accession numbers: X72309, X72308, etc., and can be isolated or produced by a method known per se. “MCP-3” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “M-CSF” is published as a human amino acid sequence and a base sequence in Genbank accession number: NM — 000757, etc., and can be isolated or produced by a method known per se. “M-CSF” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “MIF” is published as a human amino acid sequence and base sequence under Genbank accession number: NM — 002415, etc., and can be isolated or produced by a method known per se. “MIF” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “MIG” is published as a human amino acid sequence and a base sequence in Genbank accession number: NM — 002416, etc., and can be isolated or produced by a method known per se. “MIG” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “β-NGF” is published as a human amino acid sequence and nucleotide sequence under Genbank accession number: NM — 002506, etc., and can be isolated or produced by a method known per se. “Β-NGF” includes its homologues (homologs and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “SCF” is published as a human amino acid sequence and nucleotide sequence under Genbank accession number: M59964, and can be isolated or produced by a method known per se. “SCF” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “SCGF-β” is published as a human amino acid sequence and base sequence in Genbank accession number: D86586, etc., and can be isolated or produced by a method known per se. “SCGF-β” includes homologues thereof (homologues and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “SDF1a” is published as a human amino acid sequence and base sequence in Genbank accession numbers: AY874118, L36034, etc., and can be isolated or produced by a method known per se. “SDF1a” includes homologues thereof (homologues and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “TNF-β” is published as a human amino acid sequence and a base sequence in Genbank accession numbers: X02911, X01393, NM_009588, NM_002341, BC069330, D12614, D00102, L11015, etc., and a method known per se. It can be isolated or produced by “TNF-β” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured forms, amino acid modified forms, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “S100” is a calcium-binding protein having a loop-helix-loop structure called EF-hand, similar to Troponin C and the like. Isolated from bovine brain in 1965. Low molecular acid protein of about 8-14kD. It takes a dimeric structure consisting of two subunits α (Gene: 1q21) and β (Gene: 21q22), and S100A (also αα also exists) consisting of α chain β chain and S100B consisting of β chain β chain Point to. Currently 16 subtypes have been identified. S100A is registered with NCBI as Gene ID: 6271, published as a human amino acid sequence and a base sequence under Genbank accession number: NM_006271, and can be isolated or produced by a method known per se. S100B is registered with NCBI as Gene ID: 6285, published as a human amino acid sequence and a base sequence under Genbank accession number: NM_006272, etc., and can be isolated or produced by a method known per se. “S100” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “RAGE (Receptor for Advanced glycation end products)” is published as a human amino acid sequence and a base sequence in Genbank accession numbers: NM — 00136, NM — 172197, etc., and is isolated or produced by a method known per se. be able to. “RAGE” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “IL-18BP” is disclosed as a human amino acid sequence and a base sequence in Genbank accession numbers: AF215907, NM025217, NM001039659, NM1733042, NM001039660, NM001145055, NM001145057, and the like. Can be separated or manufactured. “IL-18BP” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  In the present invention, “VCAM-1” is published as a human amino acid sequence and a base sequence under Genbank accession numbers: NM — 080682, NM — 001078, X53051, etc., and can be isolated or produced by a method known per se. “VCAM-1” includes homologues thereof (homologs and splice variants), mutants, derivatives, matured products, amino acid modified products, and the like. Here, examples of homologs include proteins of other species such as mice and rats corresponding to human proteins, and these were identified by HomoloGene (http://www.ncbi.nlm.nih.gov/HomoloGene/) It can be identified a priori from the base sequence of the gene. Variants also include naturally occurring allelic variants, non-naturally occurring variants, and variants having amino acid sequences modified by artificial deletions, substitutions, additions or insertions. . Examples of the mutant include those that are at least 70%, preferably 80%, more preferably 95%, and still more preferably 97% homologous to a protein or (poly) peptide without mutation. The amino acid modifications include naturally occurring amino acid modifications and non-naturally occurring amino acid modifications, and specific examples include phosphorylated amino acids.

  It is preferable that the molecular groups constituting the indicator agent of the present invention are stored in separate containers. Moreover, the indicator agent of this invention may contain the other component, as long as it has the said molecular group as a main component. Examples of other components include, but are not limited to, solvents such as buffer solutions and physiological saline, stabilizers, bacteriostatic agents, preservatives, and the like.

  The indicator agent of the present invention serves as an indicator that the animal's physiological condition is in fatigue due to stress or fatigue, preferably psychological stress. In particular, the degree of fatigue can be easily and quantitatively determined by using the concentration ratio of the factor in an animal biological sample, preferably plasma, serum, saliva or urine as an index. An increase in the amount of the above various factors in the living body is also an indicator of fatigue. Specifically, it is possible to prepare a concentration correlation table of at least two factors contained in the indicator agent of the present invention from a normal value to a case of weak fatigue or strong fatigue so that it can be compared with a specimen. preferable.

  The test agent for stress or fatigue of the present invention is IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG , Β-NGF, SCF, SCGF-β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and at least two molecules selected from the group consisting of molecules that specifically recognize VCAM-1 It is characterized by doing.

  Examples of the molecule include antibodies, peptides (excluding antibodies), nucleic acids, low molecular compounds, and the like. Antibodies that are relatively readily available or manufacturable are preferred.

The “antibody” includes an antigen binding property such as a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a single chain antibody, or an F (ab ′) ₂ or Fab ′ fragment or a fragment generated by a Fab expression library. A portion of the antibody having is included.

  The “peptide (excluding antibody)” refers to a protein component that specifically binds to the above factor (specific protein), specifically, a cytokine-binding protein, a cytokine receptor, a cytokine-solubilized receptor, or Their binding sites are exemplified.

  The “nucleic acid” refers to a nucleic acid having a specific base sequence capable of binding to the above factor (specific protein), and specifically includes DNA, RNA, or a nucleic acid analog.

  The “low molecular weight compound” refers to an organic or inorganic low molecular weight compound designed based on the three-dimensional structure and electrostatic properties of the peptide.

The antibody can be produced according to a conventional method (Current Protocol in Molecular Biology, Chapter 11.12 to 11.13 (2000)). Specifically, when the antibody is a polyclonal antibody, an oligopeptide having a partial amino acid sequence of these factors is synthesized using any of the factors expressed and purified in Escherichia coli according to a conventional method or according to a conventional method. Thus, it is possible to immunize a non-human animal such as a rabbit and obtain it from the serum of the immunized animal according to a conventional method. On the other hand, in the case of a monoclonal antibody, it was obtained by immunizing a non-human animal such as a mouse with any of the factors expressed and purified in Escherichia coli or the like according to a conventional method, or an oligopeptide having a partial amino acid sequence of these proteins. It can be obtained by culturing hybridoma cells prepared by cell fusion of spleen cells and myeloma cells (Current protocols in Molecular Biology edit. Ausubel et al. (1987) Publish. John Wiley and Sons. Section 11.4-11.11. ). Chimeric antibodies can be produced with reference to, for example, “Experimental Medicine (Special Issue), Vol. 6, No. 10, 1988”, Japanese Examined Patent Publication No. 3-73280, and the like. F (ab ′) ₂ or Fab ′ can be produced by treating immunoglobulin with the proteases pepsin or papain, respectively.

  Such an antibody is contained in the test agent in a free state, a labeled state, or a solid phase. The test agent of the present invention may contain a carrier generally contained in a diagnostic agent. Such carriers include, but are not limited to, preservatives, stabilizers, buffers, water, saline, and other solvents.

  The present invention provides a method for measuring stress or fatigue, comprising the step of measuring the amount of a factor in a biological sample using the test agent.

  The method of measuring stress or fatigue can be performed by qualitatively or quantifying the amount of a factor in a biological sample, preferably plasma, serum, saliva or urine, by a known method using a molecule contained in the test agent, preferably an antibody. It can be measured quantitatively. A protein array system in a liquid phase that performs a binding reaction in a suspension of microbeads using a microbead with a protein recognition sensor attached as a system that can easily and simultaneously measure such a large number of proteins. (Example: Bio-Plex (trade name) suspension array system (manufactured by Bio-Rad Laboratories)) is preferred. When such an array system is used, a wide measurement range from several pg / ml to several tens of ng / ml can be measured.

  By comparing the amount of each factor thus obtained in the biological sample with the stress or fatigue indicator, it is possible to objectively and qualitatively or quantitatively evaluate the degree of stress or fatigue of the animal.

  The animals are preferably vertebrates such as humans, and particularly domestic animals such as cows, horses, pigs, sheep, goats, chickens, dogs and cats, or pets. By applying the method for measuring stress or fatigue of the present invention to livestock or pet animals, the stress or fatigue state of animals in the field of animal husbandry or pet industry where artificial breeding is likely to lead to stress. Can be objectively monitored, and it is convenient for grasping the health status of animals and managing them well.

  In the test agent of the present invention, the molecules, preferably antibodies, are preferably stored in separate containers. By storing the molecules in separate containers, it can be used as a test kit for the strength of mental condition or mental disorder described later. Examples of other reagents included in the test kit include buffers for diluting the reagents and biological samples, fluorescent dyes, reaction containers, positive controls, negative controls, instructions describing the test protocol, and the like. By using the kit of the present invention, it is possible to easily measure the intensity of a mental condition or a mental disorder.

  The present invention relates to the factor groups (IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β- NGF, SCF, SCGF-β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1). Stress, Depressive mood, Comfortable mood, Discomfort, Mood modulation, Obsessive compulsiveness, Panic, Anxiety, Fear, Social phobia, Social phobia, Tension, Labor intensity, Learning intensity, Depression, Schizophrenia, Depression-like spirit It can be provided as an indicator for evaluating a mental state selected from the group consisting of a state, a mental state similar to schizophrenia, and the risk of suicide.

  Here, “a mental state similar to depression and a mental state similar to schizophrenia” is a mental state that appears to be depression or schizophrenia but does not actually suffer or develop these mental disorders. State, mood disorder, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, social tension, over tension, maladjustment to work or learning, suicidal ideation, personality disorder, alcoholic psychosis, insomnia, day It also includes mental states similar to mental disorders, including perirhythmic disorders, psychoneuropathy, and suicide attempts.

  The present invention relates to the factor groups (IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β- NGF, SCF, SCGF-β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1) are used as indicators that are weighted and distributed to mental fatigue, stress, and depression. , Depression, mood disorder, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, maladjustment to work or learning, thoughtful death, personality disorder, alcoholic psychosis , Insomnia, circadian rhythm disorder, psychoneuropathy, dementia (Alzheimer-type senile dementia, Alzheimer's disease, Pick's disease), central nervous degenerative disease (OPCA (olive nuclear cerebellar degeneration) Can be provided as the indicator for evaluating the intensity of Parkinson's disease, psychiatric disorders selected from the group consisting of diffuse Lewy body disease) and suicide attempt.

  None of the above indicator agents is not only a state, disorder or disease onset state, but also a pre-disease state (that is, it is not recognized as a disease that is obvious by physical examination, but the sprouting of the disease state and disease state exists, It is also possible to evaluate the situation in which the risk is significantly predicted.

  In the present invention, the term “stress” means various responses of the living body due to chemical, physical, mental, verbal, or labor-related extraordinary loads applied to the spirit and body of the living body. The weight distribution method can provide an indication of a specific stress due to a specific load. Specifically, by multiplying each factor by a coefficient obtained by weighted distribution, an index of stress as a mental state or stress as a mental disorder can be provided.

  In the present invention, “fatigue” includes physical fatigue and mental fatigue, and provides an index focusing on physical fatigue and an index focusing on mental fatigue depending on the manner of weighted allocation of the factors. be able to. Specifically, by multiplying each factor by a coefficient obtained by weighted distribution, it is possible to provide an index of mental disorder based on mental state or mental fatigue including physical fatigue and mental fatigue.

  In the present invention, “depressed mood” refers to the contents defined in DSM-IV.

  In the present invention, “depression” refers to the contents defined in DSM-IV and a group of diseases that have been called “major depression” in psychiatry.

  In the present invention, “mood modulation” refers to ups and downs of mood.

  In the present invention, “mood disorder” means the contents defined in DSM-IV.

  In the present invention, “schizophrenia” refers to the contents defined in DSM-IV.

  In the present invention, “compulsive” refers to the contents defined in DSM-IV.

  In the present invention, “obsessive compulsive disorder” refers to the contents defined in DSM-IV.

  In the present invention, “panic” means the contents defined in DSM-IV.

  In the present invention, “panic disorder” refers to the contents defined in DSM-IV.

  In the present invention, “anxiety” refers to the contents defined in DSM-IV.

  In the present invention, “anxiety disorder” refers to the contents defined in DSM-IV.

  In the present invention, “phobia” refers to the contents defined in DSM-IV.

  In the present invention, “personal fear” refers to the contents defined in DSM-IV.

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

  In the present invention, “tension” refers to a response to a chemical, physical, mental, verbal or exertional load, which is mainly characterized by mental tension and enhancement (response) of the sympathetic nervous system.

  In the present invention, “excess tension” refers to the contents defined in DSM-IV.

  In the present invention, “labor strength” refers to the degree of fatigue that can be known after work through a Kraepelin test, a fatigue level survey, or the like.

  In the present invention, “non-adaptation to labor” refers to the contents defined in DSM-IV.

  In the present invention, the “learning intensity” refers to the degree of fatigue that can be known after learning by a Kraepelin test, a fatigue level survey, or the like.

  In the present invention, “maladjustment to learning” refers to the contents defined in DSM-IV.

  In the present invention, the “degree of suicide risk” refers to the contents defined in DSM-IV.

  In the present invention, “thought for death” refers to the contents defined in DSM-IV.

  In the present invention, “suicide attempt” refers to the contents defined in DSM-IV.

  In the present invention, “personality disorder” refers to the contents defined in DSM-IV.

  In the present invention, “alcoholic psychosis” refers to the contents defined in DSM-IV.

  In the present invention, “insomnia” refers to the contents defined in DSM-IV.

  In the present invention, “diurnal rhythm disorder” refers to the contents defined in DSM-IV.

  In the present invention, “psychotic neurosis” refers to the contents defined in DSM-IV.

  In the present invention, “comfort feeling” refers to the contents defined in DSM-IV.

  In the present invention, “discomfort” refers to the contents defined in DSM-IV.

  In the present invention, the “depressed state” refers to the contents defined in DSM-IV.

  In the present invention, “dementia” refers to the contents defined in DSM-IV.

  In the present invention, “Alzheimer type senile dementia” refers to the contents defined in DSM-IV.

  In the present invention, “Alzheimer's disease” refers to the contents defined in DSM-IV.

  In the present invention, “Pick disease” refers to the contents defined in DSM-IV.

  In the present invention, “central nervous degenerative disease” refers to the contents defined in DSM-IV.

  In the present invention, “OPCA (olive nuclear bridge cerebellar degeneration)” refers to the contents defined in DSM-IV.

  In the present invention, “Parkinson's disease” refers to the contents defined in DSM-IV.

  In the present invention, “diffuse Lewy body disease” refers to the contents defined in DSM-IV.

  Unless otherwise specified, mental disorders defined in DSM-IV are incorporated into the present invention within the scope of the defined contents. If DSM-IV is revised, the revised version can be applied.

  The weighted and distributed factors included in the indicator for the intensity of mental state or mental disorder of the present invention are at least two types selected from the above group. In order to be a more specific index of the intensity of each mental state or mental disorder, there are 3 to 21 types, preferably 3 to 15 types, more preferably 5 to 13 types, and even more preferably 8 to There are 12 types.

  It is preferable that the molecule group constituting the indicator for the intensity of mental state or mental disorder of the present invention is stored in a separate container. Further, the mental state indicator of the present invention may contain other components as long as the molecular group is a main component. Examples of other components include, but are not limited to, solvents such as buffer solutions and physiological saline, stabilizers, bacteriostatic agents, preservatives, and the like.

  The indicator for the intensity of mental state or psychiatric disorder of the present invention is an objective indicator in the field of animal mental health. In particular, various mental states can be easily and quantitatively known by using as an index the weighted and distributed factors in animal biological samples, preferably plasma, serum, saliva or urine.

  The indicator of fatigue or the indicator of the intensity of mental state or mental disorder of the present invention may be a combination of numerical values weighted and distributed to factors included in the indicator, that is, a database. By creating a database of index agents, various mental states can be easily and quantitatively known for each item from the measurement values obtained using the test agent of the present invention.

  The test agent for the intensity of mental state or psychiatric disorder according to the present invention includes the above-described factors (IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF, SCF, SCGF-β, SDF1a, TNF-β, S100, RAGE, IL-18BP, and VCAM-1) each selected from the group consisting of molecules It contains at least two kinds of molecules.

  The molecules and other components contained in the test agent for mental condition or mental disorder of the present invention are the same as those contained in the test agent for stress or fatigue.

The present invention includes a step of measuring the amount of a factor in a biological sample using the test agent for the intensity of the mental state or mental disorder, and the mental state or mental disorder by weighted distribution of the amount obtained in the measurement step A method for measuring the intensity of a mental condition or mental disorder, comprising the step of comparing with an indicator of the intensity of

  A method for measuring the strength of a mental condition or a mental disorder is a biological sample, preferably plasma, serum, by a known method using a molecule, preferably an antibody, contained in the test agent for the mental condition or the strength of a mental disorder. The concentration of factors in saliva or urine can be measured. For example, a Bio-Plex suspension array system (manufactured by Bio-Rad Laboratories) is preferable as a system that can easily and simultaneously measure such a large number of proteins.

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

  The animals are preferably vertebrates such as humans, and particularly domestic animals such as cows, horses, pigs, sheep, goats, chickens, dogs and cats, or pets. By applying the method for measuring the intensity of mental state or mental disorder of the present invention to livestock or pet animals, in the field of animal husbandry or pet industry where artificial breeding is likely to lead to stress, It is possible to objectively monitor the intensity of mental state or mental disorder, which is convenient for understanding the mental health of animals.

  The test kit for the intensity of mental state or psychiatric disorder according to the present invention is characterized in that at least two kinds of the molecules, preferably antibodies, are stored in separate compartments. Examples of other reagents included in the test kit include buffers for diluting the reagents and biological samples, fluorescent dyes, reaction containers, positive controls, negative controls, instructions describing the test protocol, and the like. By using the test kit of the present invention, the mental state can be easily measured.

According to the present invention, it is possible to analyze the level of the factor in various mental states or mental disorders with high throughput. Individual differences can also be easily found based on the findings found by the present invention. From these facts, it is possible to discover a new gene from a difference due to individual differences in the response of molecular groups to stress, specifically, midkine, lymphokine and the like found in the present invention, and to apply to screening for stress tolerance. . The present invention can also be used to determine the effect of a drug having an anti-stress effect. The advantages of the present invention are described below.
1: Measure with a set originally developed for stress indicators.
2: When using plasma or serum, all factors can be measured in a 50 μL sample.
3: The entire process can be completed in about 6 hours.
4: All the obtained data can be made into a database and statistically processed easily.

  By utilizing the above-mentioned advantages for stress and other measurements, it is possible to integrate and evaluate the data collected using conventional questionnaires and interviews of doctors and psychologists over many days (for that purpose, for each facility) It is possible to grasp stress and other mental states quickly and at a much lower cost compared to the above).

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention in detail, this invention is not restrict | limited at all by these Examples. In the following examples, volunteer subjects were preliminarily approved by the ethics committee of the institution, and then informed consent was obtained, various tests were performed, and blood was collected.

Example 1: Discrimination between mental load and physical load A healthy volunteer was subjected to the Kraepelin test (calculation: mental load), and physical stress was applied to the same 120 volunteers four weeks later. 1 ml of blood was collected in a blood collection spitz containing an anticoagulant, and plasma was separated under cooling at 4 ° C. Plasma is stored frozen or on ice, dispensed into 50 μl, and then 21 types of cytokines were removed using a microbead protein array system (Bio-Plex Suspension Array System (originally modified from Bio-Rad Laboratories)). Simultaneously measured. Furthermore, cytokines were also measured by a conventional ELISA method, and the blood concentration of each cytokine was determined. Logistic regression analysis and non-linear discriminant analysis were performed to discriminate between mental load and physical load, using the obtained blood LIF concentration and MIG concentration as independent variables. The results (discrimination table) are shown in Table 1.

  As shown in Table 1, discrimination was successful with a sensitivity of 97% and a specificity of 95%. Volunteers participating in this experiment have not adjusted their age, height, or weight. As a result of examining by logistic regression analysis whether the subject was misjudged or not by age, gender, height, weight and BMI, there was no bias in discrimination by age, gender, height, weight and BMI. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors.

Example 2: Determination of the degree of mental load A healthy volunteer was subjected to the Kraepelin test (calculation: mental load). Blood was analyzed by the method described in Example 1 before and 2 hours after the operation, and the blood GRO-α concentration and IL-16 concentration obtained as a result of the analysis were used as independent variables. ) Logistic regression analysis and nonlinear discriminant analysis were performed to discriminate after 2 hours. The results (discrimination table) are shown in Table 2.

  As shown in Table 2, the sensitivity and specificity were both 100% and the discrimination was successful.

Example 3 Discrimination of Recovery from Mental Load A healthy volunteer (120 volunteers) was subjected to the Kraepelin test (calculation: mental load) for 4 hours. Blood was analyzed by the method described in Example 1 immediately after 4 hours and 3 hours after the end of the test (load), and the blood SCF concentration, IL-2ra concentration, and VCAM-1 concentration obtained as a result were analyzed. As independent variables, logistic regression analysis and nonlinear discriminant analysis were performed to discriminate between immediately after execution and 3 hours after the end of loading. The results (discrimination table) are shown in Table 3.

  As shown in Table 3, the sensitivity was 89% and the specificity was 91%. If a larger number was used, it could be discriminated at a high rate. Volunteers participating in this experiment have not adjusted their age, height, or weight. As a result of examining by logistic regression analysis whether the subject was misjudged or not by age, gender, height, weight and BMI, there was no bias in discrimination by age, gender, height, weight and BMI. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No marker and determination method based on blood having such performance have been reported so far, and it is the first method for determining the degree of recovery from mental stress (fatigue). By the change of the numerical value, the anti-fatigue effect of the food or pharmaceutical composition can be verified.

Example 4: Determination of degree of physical load Physical load was applied to 120 healthy volunteers. The blood was analyzed by the method described in Example 1 before and 2 hours after the operation, and the blood CTACK concentration, β-NGF concentration, and TNF-β concentration obtained as a result were set as independent variables. Logistic regression analysis and nonlinear discriminant analysis were performed to discriminate 2 hours after the execution (load). The results (discrimination table) are shown in Table 4.

  As shown in Table 4, the sensitivity was 90% and the specificity was 93%. If a larger number of factors were used, discrimination was possible at a high rate. Volunteers participating in this experiment have not adjusted their age, height, or weight. As a result of examining by logistic regression analysis whether the subject was misjudged or not by age, gender, height, weight and BMI, there was no bias in discrimination by age, gender, height, weight and BMI. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No blood-based marker and determination method based on blood having such performance have been reported so far, and this is the first method for determining the strength of physical load (fatigue). By the change of this numerical value, it is possible to verify the anti-fatigue effect of foods and pharmaceutical compositions.

Example 5: Determination of recovery from physical load Physical load was applied to 120 healthy volunteers. Blood was analyzed by the method described in Example 1 immediately after 4 hours and 3 hours after completion, and the blood MIF concentration, SDF1a concentration, and VCAM-1 concentration obtained as a result were used as independent variables. Logistic regression analysis and nonlinear discriminant analysis were performed to discriminate 3 hours after completion. The results (discrimination table) are shown in Table 5.

  As shown in Table 5, the sensitivity is 81% and the specificity is 88%. If a larger number of factors were used, discrimination was possible at a high rate. Volunteers participating in this experiment have not adjusted their age, height, or weight. As a result of examining by logistic regression analysis whether the subject was misjudged or not by age, gender, height, weight and BMI, there was no bias in discrimination by age, gender, height, weight and BMI. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No blood-based marker and determination method based on blood having such performance have been reported so far, and this is the first method for determining the strength of physical load (fatigue). By the change of the numerical value, it is possible to verify the anti-fatigue effect and the recovery assisting effect of the food or pharmaceutical composition.

Example 6: Discrimination of mental illness (depression) The blood of 100 depression patients who obtained cooperation consent and 200 healthy persons who similarly obtained consent were analyzed by the method described in Example 1, Logistic regression analysis and nonlinear discriminant analysis were performed to classify depression and healthy individuals, using the resulting MCP-3 and ICAM-1 concentrations in the blood as independent variables. The results (discrimination table) are shown in Table 6.

  As shown in Table 6, discrimination is possible with a correct diagnosis rate of 98%. Volunteers participating in this experiment have not adjusted their age, height, or weight. As a result of examining by logistic regression analysis whether the subject was misjudged or not by age, gender, height, weight and BMI, there was no bias in discrimination by age, gender, height, weight and BMI. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No blood-based marker and determination method with such performance has been reported so far. The determination method with such accuracy is unparalleled.

Example 7: Discrimination of mental illness (schizophrenia) New subjects were recruited for this experiment. The blood of 100 patients with schizophrenia who obtained consent for cooperation and 200 healthy persons who similarly obtained consent were analyzed by the method described in Example 1, and the blood IL-16 concentration obtained as a result was analyzed. Logistic regression analysis and non-linear discriminant analysis were performed to classify schizophrenia and healthy subjects using GRO-α concentration and LIF concentration as independent variables. The results (discrimination table) are shown in Table 7.

  As shown in Table 7, discrimination was possible with a correct diagnosis rate of 92%. Volunteers participating in this experiment have not adjusted their age, height, or weight. As a result of examining by logistic regression analysis whether the subject was misjudged or not by age, gender, height, weight and BMI, there was no bias in discrimination by age, gender, height, weight and BMI. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No marker and determination method based on blood having such performance has been reported so far, and a determination method having such accuracy is unlike any other.

Example 8: Discrimination between psychiatric disorders (schizophrenia and depression) Even if discrimination can be made between healthy subjects and patients, it is not sufficient if it is not possible to discriminate differences in blood cytokine responses to diseases with different pathologies I tried to distinguish between mental disorders. New subjects were recruited for this experiment. The blood of 100 patients with depression and 100 patients with schizophrenia who agreed to cooperate was analyzed by the method described in Example 1, and the resulting blood LIF concentration and SCGF-β concentration were independently determined. As variables, logistic regression analysis and nonlinear discriminant analysis were performed to classify depression patients and schizophrenia. The results (discrimination table) are shown in Table 8.

  As shown in Table 8, discrimination is possible with a correct diagnosis rate of 100%. Volunteers participating in this experiment have not adjusted their age, height, or weight. No marker and determination method based on blood having such performance have been reported so far, and such determination method and accuracy are unlike any other.

Example 9: Determination of whether or not a night shift was performed The method described in Example 1 was performed by collecting blood at the same time on the morning and holiday of a night shift for 120 ordinary workers who had agreed to cooperate. Analyzed with Logistic regression analysis and non-linear discriminant analysis were performed to classify whether night shifts were performed or not, using all 21 factor concentrations obtained as a result as independent variables. The results (discrimination table) are shown in Table 9.

  As shown in Table 9, it can be determined with a correct diagnosis rate of 100%. Volunteers who participated in this experiment, regardless of the presence or absence of the underlying disease, have not adjusted their age, height, and weight. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No marker and determination method based on blood having such performance has been reported so far, and a determination method having such accuracy is unlike any other.

Example 10: Discrimination of mental illness (depression) The blood of 200 depressed patients who obtained cooperation consent and 400 healthy persons who similarly obtained consent were analyzed by the method described in Example 1. Specifically, by measuring the blood levels of all 21 factors, the logistic regression analysis shows that the concentration correlation of each factor in the depression group is different from that in the healthy group. confirmed. Set the coefficient for each molecule with the concentration of all factors as an independent variable, and create a formula that calculates 1 from each molecular blood concentration of a depression patient and 0 from each molecular blood concentration of a healthy person A mathematical model for was built. The result of the calculation using the mathematical formula is shown in FIG. In the figure, the horizontal axis represents the score of the mathematical formula based on the blood molecule concentration, and the vertical axis represents the number of cases distributed in the score area. That is, the farther both groups are, the more effectively the mathematical model separates them. Although the implementation method of Example 10 is not different from Example 1-9 in the implementation principle, a diagram is shown in order to visually show the accuracy and robustness of discrimination according to the present invention.

  As shown in FIG. 1, there is no overlap between the two groups, and discrimination is possible with a correct diagnosis rate of 100%. Volunteers participating in this experiment have not adjusted their age, height, or weight. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No marker and determination method based on blood having such performance has been reported so far.

Example 11: Discrimination of mental illness (schizophrenia) The blood of 200 schizophrenia patients who obtained consent for cooperation and 400 healthy persons who similarly obtained consent was analyzed by the method described in Example 1. . Specifically, the blood levels of all 21 factors were measured, and the logistic regression analysis showed that the concentration correlation of each factor in the schizophrenia group was different from that in the healthy group Confirmed with. Using the concentration of all factors as an independent variable, setting a coefficient for each molecule, creating a formula that calculates 1 from each molecular blood concentration of patients with schizophrenia and 0 from each molecular blood concentration of healthy subjects, A mathematical model for discrimination was built. FIG. 2 shows the result of calculation using mathematical formulas. In the figure, the horizontal axis represents the score of the mathematical formula based on the blood molecule concentration, and the vertical axis represents the number of cases distributed in the score area. That is, the farther both groups are, the more effectively the mathematical model separates them. Although the implementation method of Example 11 is not different from Example 1-9 in the implementation principle, a diagram is shown in order to visually show the accuracy and robustness of discrimination according to the present invention.

  As shown in FIG. 2, there is no overlap between the two groups, and discrimination is possible with a correct diagnosis rate of 100%. Volunteers participating in this experiment have not adjusted their age, height, or weight. That is, it was shown that the above sensitivity and specificity can be obtained regardless of these factors. No marker and determination method based on blood having such performance has been reported so far.

  According to the present invention, in a transient biological reaction state, it is possible to evaluate the strength of a load received from the outside world or to predict the effect of the load. Specifically, it is possible to evaluate each person's ease of fatigue and resilience from the evaluation of fatigue and recovery due to external loads. In addition, it is possible to evaluate the degree of influence that a certain factor has on fatigue and resilience for each individual. For this reason, if the present invention is utilized in the field of occupational health, it will lead to prevention of occupational accidents. Furthermore, it can contribute to the development of pharmaceuticals, foods, lifestyle-related products, designs, images, sound, architecture, living environment, etc. that can reduce stress.

  According to the present invention, in the normal pathological condition of a living body, it is possible to evaluate a disease state, grasp a latent pathological condition, and discover a disease before manifesting as a subjective symptom. , Evaluation of therapeutic effects, determination of the effectiveness or ineffectiveness of treatments, numerous pathological conditions (specifically, for example, skin damage due to ultraviolet rays, atopic dermatitis, psoriasis, common wounds, pemphigus, ichthyosis, light Hypersensitivity, burns involving inflammatory changes in the skin, radiation skin disorders; Alzheimer's disease, Alzheimer-type senile dementia, diffuse Lewy body disease, Pick's disease, Vinswanger's disease, Parkinson's disease, Parkinson's syndrome, cerebral ischemia, Cerebral ischemia / reperfusion disorder, carbon monoxide poisoning, thinner poisoning, neonatal hemorrhagic encephalopathy, hypoxic encephalopathy, hypertensive encephalopathy, epilepsy, multiple sclerosis, HIV brain , Cerebral circulatory disorder, cerebrovascular disorder, diurnal rhythm abnormality, appetite abnormality, pituitary dysfunction such as Addison disease, acromegaly and gonadal development disorder, thyroid dysfunction, obesity, glycemic control abnormality, primary aldosteronism Adrenal dysfunctions such as Cushing's disease, bone formation abnormalities; inflammatory diseases, autoimmune diseases, dysregulation of the host defense system; diseases that have joint inflammation such as rheumatoid arthritis, gout and arthritis as the core of the pathology; Renal failure, fluid regulation, disruption of potassium / sodium / chloride balance, edema, impaired glucose tolerance such as diabetes, ulcer, convulsions, heart failure, pulmonary edema, hypoproteinemia, bleeding tendency, renal tubular epithelium It is possible to centrally grasp and manage diseases such as cell loss and inflammation that are the core of the disease state; menstrual abnormalities, endometriosis, diseases caused by pituitary dysfunction such as decreased libido, etc. Not, it is possible to contribute to the efficiency of preventive medicine. Furthermore, according to the present invention, it is easy to select a trial group in drug or food development.

Claims (10)

Mental fatigue, depression, depression, mood disorders, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, comprising two molecules that specifically recognize IL-2ra and IL-16, respectively Phobia, social phobia, social phobia, overtension, maladjustment to work or learning, suicidal ideation, personality disorder, alcoholic psychosis, insomnia, circadian rhythm disorder, psychoneuropathy, dementia, central nervous degenerative disease and Intensity of mental disorder selected from the group consisting of suicide attempts, or mental fatigue, physical fatigue, depression, comfort, discomfort, mood modulation, obsessive-compulsive, panic, anxiety, phobia, social phobia, social phobia, A test agent for mental status selected from the group consisting of tension, labor intensity, learning intensity, depression, schizophrenia, mental status similar to depression, mental status similar to schizophrenia, and the risk of suicide.   The test agent according to claim 1, wherein the molecule is an antibody. A step of measuring the amount of a factor in a biological sample using the test agent according to claim 1 or 2, and a step of weighting and distributing the amount obtained in the measurement step and comparing with the following indicator agent, The indicator agent is an indicator agent formed by weighted distribution of two types of factors, IL-2ra and IL-16,
Mental fatigue, depression, depression, mood disorder, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, maladjustment for work or learning, thoughtful death, personality Intensity of mental disorder selected from the group consisting of disorder, alcoholic psychosis, insomnia, circadian rhythm disorder, neuropsychiatric disorder, dementia, central nervous degenerative disease and suicide attempt, or
Mental fatigue, physical fatigue, depressed mood, comfort mood, unpleasant mood, mood modulation, obsessive compulsiveness, panic, anxiety, phobia, social phobia, social fear, tension, work intensity, learning intensity, depression, schizophrenia, It is an indicator for evaluating a mental state similar to depression, a mental state similar to schizophrenia, and a mental state selected from the group consisting of the risk of suicide.
Including mental fatigue, depression, depression, mood disorders, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, maladjustment to work or learning, rare death Intensity of mental disorder selected from the group consisting of thought, personality disorder, alcoholic psychosis, insomnia, diurnal rhythm disorder, psychoneurosis, dementia, central nervous degenerative disease and suicide attempt, or
Mental fatigue, physical fatigue, depressed mood, comfort mood, unpleasant mood, mood modulation, obsessive compulsiveness, panic, anxiety, phobia, social phobia, social fear, tension, work intensity, learning intensity, depression, schizophrenia, A method for measuring a mental state selected from the group consisting of a mental state similar to depression, a mental state similar to schizophrenia, and the risk of suicide.   The measurement method according to claim 3, wherein the biological sample is plasma, serum, saliva or urine. A test kit in which molecules that specifically recognize IL-2ra and IL-16 are stored in separate compartments,
Mental fatigue, depression, depression, mood disorder, schizophrenia, obsessive-compulsive disorder, panic disorder, anxiety disorder, phobia, social phobia, social phobia, overtension, maladjustment for work or learning, thoughtful death, personality Intensity of mental disorder selected from the group consisting of disorder, alcoholic psychosis, insomnia, circadian rhythm disorder, neuropsychiatric disorder, dementia, central nervous degenerative disease and suicide attempt, or
Mental fatigue, physical fatigue, depressed mood, comfort mood, unpleasant mood, mood modulation, obsessive compulsiveness, panic, anxiety, phobia, social phobia, social fear, tension, work intensity, learning intensity, depression, schizophrenia, A test kit for a mental condition selected from the group consisting of a mental condition similar to depression, a mental condition similar to schizophrenia, and the risk of suicide.   The test kit according to claim 5, wherein the molecule is an antibody.   A test agent for fatigue comprising two molecules that specifically recognize IL-2ra and IL-16, respectively.   The test drug according to claim 7, wherein the molecule is an antibody.   The fatigue measuring method including the process of measuring the quantity of the factor in a biological sample using the test | inspection agent of Claim 8. The measurement method according to claim 9, wherein the biological sample is plasma, serum, saliva or urine .

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