CN116990498A - Application of plasma tryptophan metabolite in diagnosis of migraine in children - Google Patents
Application of plasma tryptophan metabolite in diagnosis of migraine in children Download PDFInfo
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- 208000019695 Migraine disease Diseases 0.000 title claims abstract description 100
- 206010027599 migraine Diseases 0.000 title claims abstract description 100
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical class C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 title claims abstract description 27
- 238000003745 diagnosis Methods 0.000 title abstract description 22
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 100
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 claims abstract description 50
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims abstract description 47
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229940116269 uric acid Drugs 0.000 claims abstract description 47
- 241000282465 Canis Species 0.000 claims abstract description 46
- 239000000090 biomarker Substances 0.000 claims description 26
- 210000002966 serum Anatomy 0.000 claims description 14
- 238000008157 ELISA kit Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical class OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 2
- 208000035475 disorder Diseases 0.000 abstract description 2
- 210000002381 plasma Anatomy 0.000 description 24
- 206010015037 epilepsy Diseases 0.000 description 21
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 20
- 206010003791 Aura Diseases 0.000 description 20
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 11
- 230000035945 sensitivity Effects 0.000 description 8
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- 206010052787 migraine without aura Diseases 0.000 description 3
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- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The application belongs to the technical field of disease diagnosis, and particularly relates to application of plasma tryptophan metabolites in migraine diagnosis of children. The application discloses that kynurenine metabolite disorder exists in migraine children, in particular to kynurenine and quinolinic acid, which are suggested to play an important role in the occurrence and development of migraine in children. The application proves that quinolinic acid, canine uric acid and 5-hydroxytryptamine have important values for diagnosing migraine in children. Furthermore, the application establishes the normal reference range of the quinolinic acid, the canine uric acid and the 5-hydroxytryptamine of children, thereby helping to improve the diagnosis accuracy of migraine of children and reducing the missed diagnosis rate and the misdiagnosis rate, and having good practical application value.
Description
Technical Field
The application belongs to the technical field of disease diagnosis, and particularly relates to application of plasma tryptophan metabolites in migraine diagnosis of children.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the application and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Migraine is a multifactorial neurovascular disorder, one of the most common primary headaches, affecting up to 12% of the general population. The total prevalence of migraine in children is about 7.7%. Migraine can affect children's learning, daily activities, and physical and mental health.
At present, the diagnosis of migraine is mainly based on clinical symptoms of subjective description of patients and the lack of objective diagnosis indexes for eliminating headache caused by other causes. Especially young children have difficulty in accurately describing their symptoms, resulting in complicated diagnosis of migraine, assessment of severity, and identification of concomitant symptoms. Thus, there is an urgent need for an objective and quantified marker to aid in diagnosing and assessing migraine in children.
Disclosure of Invention
In order to overcome the defects in the prior art, the inventor provides application of plasma tryptophan metabolites in migraine diagnosis of children through long-term technical and practical exploration. The application has good diagnostic value through screening plasma tryptophan metabolites including tryptophan, kynurenine, canine uric acid, quinolinic acid and 5-hydroxytryptamine. Based on the above results, the present application has been completed.
In order to achieve the technical purpose, the application adopts the following technical scheme:
in a first aspect of the application, there is provided a biomarker for diagnosing migraine in children, said biomarker being selected from any one or more of the following tryptophan metabolites: canine uric acid, quinolinic acid, and 5-hydroxytryptamine.
Further, the biomarker is a group consisting of quinolinic acid, canine uric acid, and 5-hydroxytryptamine. Experiments prove that when the quinolinic acid, the canine uric acid and the 5-hydroxytryptamine are used for jointly diagnosing migraine of children, the AUC, the sensitivity and the specificity are respectively 0.893, 94.0% and 78.0%, and the diagnostic value is obviously improved compared with that of single indexes.
In a second aspect of the application, there is provided the use of an agent for detecting a marker as described above in the manufacture of a product for diagnosing migraine in children.
Compared with the prior art, the one or more technical schemes have the following beneficial effects:
the technical scheme discloses that kynurenine metabolite disorder exists in migraine children, particularly kynurenine acid and quinolinic acid, which is suggested to play an important role in the occurrence and development of migraine in children. The technical scheme proves that quinolinic acid, canine uric acid and 5-hydroxytryptamine have important values for diagnosing migraine of children.
Furthermore, the technical scheme establishes the normal reference range of the quinolinic acid, the canine uric acid and the 5-hydroxytryptamine of children, thereby helping to improve the diagnosis accuracy of migraine of children and reducing the missed diagnosis rate and the misdiagnosis rate, and having good practical application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application.
FIG. 1 is a graph showing the comparison of 5-hydroxytryptamine concentration in blood plasma of infants suffering from migraine and healthy children in accordance with an embodiment of the present application, wherein a is the infant group suffering from migraine and b is the healthy child group in the abscissa.
Fig. 2 is a graph showing the comparison of kynurenine concentration in blood plasma of infants suffering from migraine and healthy children in accordance with an embodiment of the present application, wherein a is the group of infants suffering from migraine and b is the group of healthy children in the abscissa.
FIG. 3 is a graph showing the comparison of quinolinic acid concentrations in blood plasma of infants suffering from migraine and healthy children in accordance with an embodiment of the present application, wherein a is the infant group suffering from migraine and b is the healthy child group in the abscissa.
FIG. 4 is a graph showing comparison of 5-hydroxytryptamine concentrations in plasma for migraine, migraine without aura, and healthy group in accordance with an embodiment of the present application, wherein a is the group of migraine infants with aura, b is the group of migraine infants without aura, and c is the group of healthy children in the abscissa.
Fig. 5 is a graph showing comparison of canine uric acid concentration in plasma for migraine, migraine without aura, and healthy group in accordance with an embodiment of the present application, wherein a is the group of migraine infants with aura, b is the group of migraine infants without aura, and c is the group of healthy children in abscissa.
FIG. 6 is a graph showing comparison of quinolinic acid concentrations in plasma for migraine, migraine without aura, and healthy group in accordance with an embodiment of the present application, wherein a is the group of migraine infants with aura, b is the group of migraine infants without aura, and c is the group of healthy children in the abscissa.
Fig. 7 is a graph showing comparison of plasma concentrations of 5-hydroxytryptamine between migraine, migraine at intervals, and healthy subjects in the examples of the present application, wherein a is the group of infants suffering from migraine at intervals, b is the group of infants suffering from migraine at intervals, and c is the group of healthy subjects in the abscissa.
Fig. 8 is a graph showing a comparison of plasma uric acid concentrations among migraine, migraine at an inter-episode and a healthy group in accordance with an embodiment of the present application, wherein a is a group of infants suffering from migraine at an inter-episode, b is a group of infants suffering from migraine at an inter-episode, and c is a group of healthy children.
Fig. 9 is a graph showing comparison of the concentration of quinolinic acid in plasma among migraine, migraine at intervals, and healthy groups in the examples of the present application, wherein a is the group of infants suffering from migraine at intervals, b is the group of infants suffering from migraine at intervals, and c is the group of healthy children in the abscissa.
FIG. 10 is a graph of the diagnostic value of 5-hydroxytryptamine (5-HT) versus migraine in children in an example of the present application.
FIG. 11 is a graph showing the diagnostic value of canine uric acid (KYNA) in relation to migraine in children in an embodiment of the present application.
FIG. 12 is a graph of the diagnostic value of quinolinic acid (QUIN) versus migraine in children in an embodiment of the present application.
FIG. 13 is a graph showing the diagnostic value of a combination of 5-hydroxytryptamine, canine uric acid, and quinolinic acid for migraine in children in accordance with an embodiment of the present application.
FIG. 14 is a graph showing the diagnostic value of the combination of 5-hydroxytryptamine, canine uric acid, and quinolinic acid in an external validation queue for migraine in children in accordance with an embodiment of the present application.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof. In addition, biological methods not described in detail in the examples are all conventional in the art, and specific operations may be referred to in biological guidelines or product specifications. In the present application, the diagnosis may be an auxiliary diagnosis.
In an exemplary embodiment of the application, a biomarker for diagnosing migraine in children is provided, said biomarker being selected from any one or more of the following tryptophan metabolites: canine uric acid, quinolinic acid, and 5-hydroxytryptamine.
In yet another embodiment of the present application, the biomarker is a group consisting of quinolinic acid, canine uric acid, and 5-hydroxytryptamine. Experiments prove that when the quinolinic acid, the canine uric acid and the 5-hydroxytryptamine are used for jointly diagnosing migraine of children, the AUC, the sensitivity and the specificity are respectively 0.893, 94.0% and 78.0%, and the diagnostic value is obviously improved compared with that of single indexes.
The biomarker is derived from a subject plasma sample, further the biomarker is derived from a subject serum sample.
In yet another embodiment of the application, there is provided the use of an agent for detecting a biomarker as described above in the manufacture of a product for diagnosing migraine in children.
The reagent for detecting the biomarker may specifically include, but is not limited to, a reagent required for detecting the biomarker based on an enzyme-linked immunosorbent assay, which is not specifically limited herein.
The product can be a detection kit, such as an enzyme-linked immunosorbent assay kit.
And setting a normal reference value of the biomarker in the application process, and judging that the subject is or is candidate as a child migraine infant when the expression level of the biomarker of the subject is not in the normal reference value range.
Specifically, the biomarker is one or more of serum quinolinic acid, serum canine uric acid and serum 5-hydroxytryptamine.
The normal reference values of the serum quinolinic acid, the serum canine uric acid and the serum 5-hydroxytryptamine are respectively 248.30-260.48 pmol/ml, 598.75-636.50 mu mol/l and 325.42-362.33 ng/ml.
The application is further illustrated by the following examples, which are given for the purpose of illustration only and are not intended to be limiting. If experimental details are not specified in the examples, it is usually the case that the conditions are conventional or recommended by the sales company; the present application is not particularly limited and can be commercially available.
Examples
Materials and methods:
study participants:
50 migraine children and 120 healthy children matched with age and sex in the Qilu hospital of Shandong university are used as exploration queues for screening diagnosis markers of migraine tryptophan metabolites of children, and 50 migraine children and 50 healthy children matched with age and sex are used as verification queues for verifying the diagnosis capability, sensitivity and specificity of the diagnosis markers. Age 4 to 18 years, according to the definition of the third edition of the international headache disorder classification, migraine with or without aura is diagnosed, and two or more neurologists are required for diagnosis, which is an inclusion criterion for migraine patients. In our study, migraine patients, secondary headaches, mental diseases, congenital diseases, and other serious organ diseases, who use medications for more than two months, were prohibited from being included in the study.
Standard protocol approval and patient consent:
the study was approved by the ethical review Committee of Qilu hospital institution at Shandong university (KYLL-202111-186-1). We have obtained written permissions for the participant guardian or the patient himself.
Test procedure:
first, the participant is asked to fill out a questionnaire. The questionnaire consists of the participant's basic information and medical history. The control questionnaire does not include a medical history section. All participants were asked to maintain a fasted state and to rest in a sitting position for 10 minutes before blood was obtained. Blood was withdrawn from their left or right antecubital vein. The collected blood was centrifuged at 3000r for 30 minutes at 4 ℃. The supernatant was stored at-80℃until assayed. The contents of tryptophan, kynurenine, canine uric acid, quinolinic acid and 5-hydroxytryptamine in the samples were determined using an enzyme-linked immunosorbent assay kit (Jiangsu enzyme-free Co., jiangsu, china). Optical density was measured immediately at 450nm using an enzyme-labeled instrument.
Statistical analysis:
data are expressed as mean ± standard deviation, and statistical analysis was performed using SPSS for Windows (version 27.0, SPSS Inc., chicago, il. The Shapiro-Wilk test and the Kolmogorov-Smirnov test were used to evaluate the normal differences between groups or between groups, and the independent sample t-test, analysis of variance, spierman correlation was used. ROC analysis was performed and the area under the curve (AUC) was calculated to assess the diagnostic value of tryptophan metabolites in children's migraine. p <0.05 is considered statistically significant.
Results:
1. basic characteristics of study population
We collected plasma samples of 50 migraine children (31 boys, average age 10.35±2.19 years) and 120 healthy children (68 boys, average age 9.10±5.87 years) from the shandong university zilu hospital as an exploration cohort. The average age of migraine group and control group was not different (p=0.510), and the average of course of disease (6.00±23.00 months), time of onset (3.00±4.00 hours), VAS score (6.00±2.00 minutes) and frequency (16.50±14.00 times/month) are shown in table 1. 33 migraine sufferers are in the attack stage when blood is taken, and 11 migraine sufferers have aura when suffering from headache. 8 and 4 migraine patients had visual and sensory auras, respectively. Migraine in children often occurred in the forehead and bilateral temporo-regions (table 1).
2. Kynurenine metabolic pathway metabolic disorder exists in children migraine
To see if migraine sufferers have a disturbed tryptophan metabolism, we studied the differences in concentration of tryptophan, 5-hydroxytryptamine, kynurenine, canine uric acid and quinolinic acid in blood plasma of migraine children and healthy children. We did not observe a significant difference in tryptophan and kynurenine concentrations in the two groups of children. But the concentration of 5-hydroxytryptamine in the plasma of children in the migraine group was on an ascending trend (5-hydroxytryptamine (migraine group) = 412.45ng/ml, 5-hydroxytryptamine (healthy group) = 359.77ng/ml, p= 0.0479). The concentration of canine uric acid in plasma of migraine patients was significantly reduced (canine uric acid (migraine group) = 546.81 μmol/l, canine uric acid (healthy group) = 617.63 μmol/l, p < 0.0001), and the concentration of quinolinic acid was significantly increased (quinolinic acid (migraine group) = 289.51 nmol/l, quinolinic acid (healthy group) = 254.39nmol/l, p < 0.0001) (fig. 1-3).
3. Premonitory and tryptophan metabolic disorders in children
To investigate whether tryptophan metabolites induced the onset of aura, we compared the concentrations of tryptophan, 5-hydroxytryptamine, kynurenine, canine uric acid and quinolinic acid in plasma in the group with aura migraine, in the group without aura and in the healthy group (table 2). However, there was no significant difference in tryptophan and kynurenine concentrations between the group with migraine, the group without migraine and the healthy group. The concentration of 5-hydroxytryptamine was significantly increased in the plasma of the group without aura compared to the group with aura migraine and the healthy group, and there was a downward trend in 5-hydroxytryptamine of the group with aura migraine (5-hydroxytryptamine (group without aura) = 421.44ng/ml, 5-hydroxytryptamine (group with aura) = 283.06ng/ml, 5-hydroxytryptamine (healthy group) = 359.77ng/ml, p=0.003). The plasma concentrations of canine uric acid in the group with and without aura were significantly reduced (canine uric acid (group with aura) = 535.81 μmol/l, canine uric acid (group without aura) = 538.36 μmol/l, canine uric acid (healthy group) = 620.59 μmol/l, p <0.001; quinolinic acid (group with aura) = 292.93 nmol/l, quinolinic acid (group without aura) = 288.06 nmol/l, quinolinic acid (healthy group) = 251.49nmol/l, p < 0.001). (FIGS. 4-6)
4. Migraine attacks and tryptophan metabolic disorders in children
To investigate the potential role of tryptophan metabolites in the induction of migraine attacks, we analyzed the concentrations of tryptophan, 5-hydroxytryptamine, kynurenine, canine uric acid and quinolinic acid in plasma in infants with migraine attacks during the attack period, during the attack period and in healthy children (table 3). We found no significant difference in tryptophan and kynurenine concentrations between the three groups. Whereas the concentration of 5-hydroxytryptamine during the onset of migraine patients is significantly higher than that of the inter-onset and healthy groups (5-hydroxytryptamine (onset) = 422.61 ng/ml, 5-hydroxytryptamine (inter-onset) = 277.63ng/ml, 5-hydroxytryptamine (healthy group) = 359.77ng/ml, p=0.001). The concentrations of canine uric acid in both the episodic and episodic groups were significantly reduced compared to the healthy group (canine uric acid (episodic) = 539.05 μmol/l, canine uric acid (episodic) = 536.28 μmol/l, canine uric acid (healthy group) = 620.59 μmol/l, p < 0.001). In contrast, the quinolinic acid concentration in both groups was significantly higher than in the healthy group (quinolinic acid (period of onset) = 289.04nmol/l, quinolinic acid (period of onset) = 288.20nmol/l, quinolinic acid (healthy group) = 251.49nmol/l, p < 0.001). (FIGS. 7-9)
5. Tryptophan metabolites have diagnostic value for migraine in children
The diagnostic value of tryptophan metabolites was evaluated by ROC analysis (table 4), of the five tryptophan metabolites, quinolinic acid was the best diagnostic for pediatric migraine, with AUC, sensitivity, specificity of 0.817, 82.4% and 75%, respectively. Second, canine uric acid also has a better ability to diagnose migraine in children with AUC, sensitivity, specificity of 0.736, 71.7% and 74.5%, respectively. AUC, sensitivity and specificity of 5-hydroxytryptamine were 0.596, 54.9%, 70.8%, respectively. In addition, we analyzed the diagnostic value of quinolinic acid, canine uric acid and 5-hydroxytryptamine in combination for the diagnosis of migraine in children, and the results showed that AUC, sensitivity and specificity were 0.897, 86.3% and 83.3%, respectively, and the diagnostic value was significantly higher than that of the individual indicators (fig. 10-13).
6. Establishment of normal reference range of quinolinic acid, canine uric acid and 5-hydroxytryptamine in children plasma
The level of quinolinic acid, canine uric acid and 5-hydroxytryptamine of 120 healthy children is subjected to normal test, the skewness coefficients are-0.432, -0.012 and-0.220 respectively, the kurtosis coefficients are 0.346 and 0.755 and-0.668 respectively, and the three data of the Kolmogorov-Smirnov test and analysis are all in normal distribution, as shown in Table 5. 120 healthy children quinolinic acid, canine uric acid and 5-hydroxytryptamine have average numbers of 254.39nmol/l, 617.63 mu mol/l and 343.87ng/ml respectively, standard deviations of 34.03, 105.49 and 103.16, x+/-1.96 s are adopted on both sides of a 95% reference range, and normal reference ranges of children plasma quinolinic acid, canine uric acid and 5-hydroxytryptamine are 248.30-260.48 nmol, 598.75-636.50 mu mol/l and 325.42-362.33 ng/ml, which are shown in Table 6. The results of the tests of different individuals are shown in Table 7, and the comparison of the plasma levels of quinolinic acid, canine uric acid and 5-hydroxytryptamine in men and women has no statistical significance.
The external validation cohort for children's ability to diagnose migraine by plasma quinolinic acid, canine uric acid, 5-hydroxytryptamine in children included 50 migraine children (32 boys, mean age 9.10±4.32 years) and 50 healthy children (36 boys, mean age 8.90±5.57 years), with no statistical differences in gender and age. The ability of plasma quinolinic acid, canine uric acid, 5-hydroxytryptamine to diagnose pediatric migraine was evaluated using ROC analysis and the results are shown in table 8: the combined diagnosis of quinolinic acid, canine uric acid and 5-hydroxytryptamine was the best diagnostic for pediatric migraine (fig. 14), with AUC, sensitivity, specificity of 0.893, 94.0% and 78.0%, respectively.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A biomarker for diagnosing migraine in children, wherein the biomarker is selected from any one or more of the following tryptophan metabolites: canine uric acid, quinolinic acid, and 5-hydroxytryptamine.
2. The biomarker of claim 1, wherein the biomarker is a group consisting of quinolinic acid, canine uric acid, and 5-hydroxytryptamine.
3. The biomarker of claim 1 or 2, wherein the biomarker is derived from a subject plasma sample.
4. The biomarker of claim 3, wherein the biomarker is derived from a subject serum sample.
5. Use of an agent for detecting a biomarker according to any of claims 1 to 4, in the manufacture of a product for diagnosing migraine in children.
6. The use according to claim 5, wherein the product is an enzyme-linked immunosorbent assay kit.
7. The use of claim 5, wherein a normal reference value for the biomarker is set, and when the expression level of the biomarker in the subject is not within the normal reference value range, the subject is determined to be or is candidate for pediatric migraine infants; otherwise, the subject is not or is not candidate for child migraine sufferers; the biomarker is one or more of serum quinolinic acid, serum canine uric acid and serum 5-hydroxytryptamine.
8. The use according to claim 7, wherein said serum quinolinic acid has a normal reference value in the range of 248.30 to 260.48pmol/ml.
9. The use according to claim 7 wherein the normal reference value range for serum canine uric acid is 598.75 to 636.50 μmol/l.
10. The use according to claim 7, wherein the serum 5-hydroxytryptamine has a normal reference value in the range of 325.42 to 362.33ng/ml.
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