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Objective:To investigate the effects of Guiling Gao on body temperature, gastrointestinal motility, gastrointestinal hormones, Th1/Th2 cytokines and water metabolism in rats with damp-heat syndrome.Methods:Totally 60 SD rats were randomly divided into control group, model group, mosapride group, Guiling Gao low dose group (3.4 g/kg), medium dose group (6.8 g/kg) and high dose group (13.6 g/kg) according to random number table method, with 10 rats in each group. Except for the blank group, the other groups adopted the method of "environmental factors + fat and sweet diet + biological factors" to prepare the rat model of damp heat syndrome of febrile diseases. After modeling, they were administered by gavage for 7 days. During the experiment, the general state, body weight and body temperature were observed, the gastric residue rate of rats was calculated by weighing method, the intestinal propulsion rate of rats was calculated by charcoal propulsion method, and the levels of serum motilin (MTL), gastrin (GAS), somatostatin (SS), substance P (SP),IL-4 and interferon-γ (IFN-γ) were detected by ELISA, and the changes of aquaporin 3 (AQP3) mRNA transcription level were detected by real-time PCR.Results:Compared with the model group, the weight of rats in Guiling Gao high dose group increased after experiment of 22 days ( P<0.05), and body temperature of rats in Guiling Gao medium and high dose group decreased in 19-20 day ( P<0.01); and the gastric emptying rate and the small intestine propulsion rate of small intestine in Guiling Gao medium and high dose group increased significantly ( P<0.01 or P<0.05); the serum MTL, GAS and SP levels increased ( P<0.01 or P<0.05), and SS decreased ( P<0.01 or P<0.05) in the Guiling Gao medium and high dose groups; The levels of IL-4, IFN-γ and IFN-γ/IL-4 ratio decreased ( P<0.01); The expression of AQP3 mRNA (1.16 ± 0.25 vs. 0.23 ± 0.01) in the Guiling Gao high dose group was up-regulated ( P<0.01). Conclusions:Guiling Gao can effectively improve the activity state of damp-heat syndrome model rats caused by complex factors. This mechanism may be related to enhancing gastrointestinal movement, increasing gastrointestinal hormone secretion, restoring the dynamic balance of immune system Th1/Th2 and promoting the transport of water from intestinal cavity.
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ObjectiveTo investigate the role of cyclic adenosine monophosphate （cAMP）/protein kinase A （PKA）/cAMP-response element binding protein （CREB） signaling pathway in water metabolism and intestinal epithelial permeability in ulcerative colitis （UC） and the intervention mechanism of Shaoyaotang based on the theory of large intestine governing fluids. MethodSixty male SD rats were divided into blank group， model group， mesalazine group （0.42 g·kg-1）， Shaoyaotang low-dose group （11.1 g·kg-1）， Shaoyaotang medium-dose group （22.2 g·kg-1） and Shaoyaotang high-dose group （44.4 g·kg-1）， with 10 in each group. The UC rat model of internal retention of dampness-heat was established by compound factors. The blank group and the model group were given normal saline （ig）. The mesalazine group was given mesalazine （ig）， and Shaoyaotang low-， medium- and high-dose groups were administrated with corresponding doses of Shaoyaotang （ig）. The treatment lasted for 14 days. The diarrhea score and fecal moisture content of rats in each group were observed. The contents of diamine oxidase （DAO） and D-lactic acid in plasma were detected by enzyme-linked immunosorbent assay （ELISA）. The protein expressions of aquaporin （AQP）8， AQP4， ZO-1 and Occludin in colon tissues were detected by immunohistochemistry， while those of cAMP， PKA and CREB in colon tissues were determined by Western blot. ResultCompared with the normal group， the model group had elevated diarrhea score and fecal moisten content （P<0.01）， increased contents of DAO and D-lactic acid in plasma （P<0.01） and decreased protein expressions of ZO-1， Occludin， AQP8， AQP4， cAMP， PKA and CREB in colon （P<0.01）. Compared with the conditions in the model group， the contents of DAO and D-lactic acid in plasma in each administration groups were lower （P<0.01）， while the protein expressions of ZO-1， Occludin， AQP8， AQP4， cAMP， PKA and CREB in colon were higher （P<0.01）. ConclusionShaoyaotang alleviates the diarrhea in UC， probably through activating cAMP/PKA/CREB signaling pathway， up-regulating expressions of AQPs， enhancing tight junctions in intestinal epithelium and thus improving the water metabolism in colon and the intestinal mucosal permeability.
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ObjectiveTo explore the effect of oleanolic acid （OA） on water metabolism in mice with water-dampness retention caused by spleen deficiency and the mechanism. MethodThe 60 SPF Kunming （KM） mice were randomized into blank group （n=10） and modeling group （n=50）. Through long-term living in damp place and irregular diet， water-dampness retention caused by spleen deficiency was induced in modeling mice. Then the model mice were randomly classified into model group， natural recovery group， and low-dose， medium-dose， and high-dose OA groups. The mice in the blank group， model group， and natural recovery group were given （ig） 10 mL·kg-1·d-1 normal saline， and mice in the low-dose， medium-dose， and high-dose OA groups received 50， 100， 200 mg·kg-1·d-1 OA， respectively. The intervention lasted 7 days. Before and after modeling and administration， the general conditions of the mice were observed and body weight of mice was measured. The water content in feces and tissues was detected with the oven-drying method， and water load index and organ coefficient were measured with the weighing method. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the urinary D-xylose excretion， serum gastrin （GAS）， total protein （TP）， albumin （ALB）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， interleukin-6 （IL-6）， antidiuretic hormone （AVP）， aquaporin 1 （AQP1） in renal medulla， and liver Na+-K+-ATPase. At the same time， OA was docked with ALB， IL-6， AQP1， and Na+-K+-ATPase. ResultCompared with the blank group， the model group showed withered hair， emaciation， laziness， bradykinesia， slow weight growth， infrequent spontaneous activities， high water content in feces and tissues， low weight loss after water loading， high coefficient of each organ （P<0.05， P<0.01）. Moreover， the model group had less urinary D-xylose excretion， lower serum levels of GAS， TP， ALB， and HDL-C， higher levels of TC， LDL-C， AVP， and IL-6， lower expression of Na+-K+-ATPase in the liver， and higher expression of AQP1 in renal medulla than the blank group （P<0.05， P<0.01）. The three OA groups demonstrated better general conditions， faster weight gain， more frequent spontaneous activities， lower water content in feces and tissues， larger weight loss after water loading， and lower coefficient of each organ than the model group （P<0.05， P<0.01）. Moreover， compared with the model group， the three OA groups had high D-xylose excretion， high serum levels of GAS， TP， ALB， and HDL-C， low serum levels of TC， LDL-C， AVP， and IL-6， high expression of Na+-K+-ATPase in liver， and low expression of AQP1 in renal medulla （P<0.05， P<0.01）. The recovery in each OA group was better than that in natural recovery group. Molecular docking results also confirmed that OA had high binding affinity with ALB， IL-6， AQP1， and Na+-K+-ATPase. ConclusionOA can alleviate the abnormal water metabolism in mice with water-dampness retention caused by spleen deficiency， which lays a basis for its potential clinical application.
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OBJECTIVE@#To observe the effect of acupuncture and moxibustion on the water content of stratum corneum (WCSC), expression of serum inflammatory factors and aquaporin 3 (AQP3) in skin, lung and rectum in guinea pigs with eczema of skin damp-heat accumulation, and to explore the possible mechanism of acupuncture and moxibustion for regulating skin barrier function.@*METHODS@#A total of 24 male albino guinea pigs were randomly divided into a blank group (n=6) and a modeling group (n=18). The guinea pigs in the modeling group were induced by 2,4-dinitrochlorobenzene (DNCB) to establish the eczema model of skin damp-heat accumulation. The guinea pigs with successful modeling were further randomly divided into a model group, a medication group and an acupuncture-moxibustion group, 6 guinea pigs in each group. The guinea pigs in the medication group were treated with loratadine tablets (0.8 mg/kg) by gavage, once a day for 7 days; the guinea pigs in the acupuncture-moxibustion group were treated with acupuncture at "Feishu" (BL 13), "Pishu" (BL 20), "Quchi" (LI 11), "Zusanli" (ST 36) and "Xuehai" (SP 10); at the same time, moxibustion was applied at "Feishu" (BL 13) and "Zusanli" (ST 36), moxibustion intervention for 10 min and needle retaining for 15 min at each acupoint, once a day for 7 days. The eczema area and severity index (EASI) score was evaluated before and After intervention, and WCSC and trans-epidermal water loss (TEWL) were measured by skin tester. After intervention, The HE staining was used to observe the changes of skin histomorphology in each group; ELISA was used to measure the contents of serum immunoglobulin E (IgE), interleukin (IL)-4 and IL-17; Western blot was used to measure the protein expression of AQP3 in skin, lung and rectum.@*RESULTS@#Before the intervention, compared with the blank group, the EASI scores and TEWL were increased in the remaining groups (P<0.01), and the WCSC was decreased (P<0.01). After the intervention, compared with the model group, the EASI scores and TEWL were decreased (P<0.05, P<0.01), and WCSC was increased (P<0.01) in the medication group and the acupuncture-moxibustion group. The epidermal structure in the blank group was complete and the fibers in the dermis were arranged orderly; in the model group, epidermal hyperkeratosis, proliferation of granular layer, spinous cell layer and basal layer, and disordered arrangement of dermal fibers and infiltration of inflammatory cells were observed. The morphological performance in the medication group and the acupuncture-moxibustion group was better than that in the model group. Compared with the blank group, the contents of serum IgE and IL-17 were increased (P<0.01), and the content of serum IL-4 and the protein expression of AQP3 in skin, lung and rectum were decreased in the model group (P<0.01, P<0.05). Compared with the model group, the contents of serum IgE and IL-17 were decreased and the contents of serum IL-4 were increased in the medication group and the acupuncture-moxibustion group (P<0.01), and the protein expression of AQP3 in skin, lung and rectum in the acupuncture- moxibustion group were increased (P<0.05). Compared with the medication group, the contents of serum IgE and IL-17 were increased (P<0.01), and the content of serum IL-4 was decreased (P<0.01) in the acupuncture-moxibustion group.@*CONCLUSION@#Acupuncture and moxibustion could improve the epidermal water metabolism and skin tissue morphology in guinea pigs with eczema of skin damp-heat accumulation. Its mechanism may be related to regulating inflammatory factors, up-regulating the expression of AQP3, and then repairing the skin barrier function.
Subject(s)
Humans , Male , Acupuncture Therapy , Eczema/therapy , Hot Temperature , Immunoglobulin E , Interleukin-17 , Interleukin-4 , Moxibustion , WaterABSTRACT
Orthostatic dysregulation is also a social problem as a disease of puberty today, and its treatment has attracted attention. Ten cases suspected to be orthostatic dysregulation based on diagnostic criteria of Society of Pediatric Psychology were diagnosed and treated with Kampo medicine, and all improvements were made. After analyzing 10 cases, Symptomcomplex resulting from blood stagnation (血証), Disorders of the body's water metabolism (水毒), Psychosomatic factors (心身症的要因) were found as a background to cause orthostatic dysregulation. In these backgrounds, kamishoyosan, unkeito, and tokishakuyakusan were prescribed for symptom-complex resulting from blood stagnation. Goreisangokumibinroto and ryokeijutsukanto were prescribed for disorders of the body's water metabolism. Saikokeishito and saibokuto were prescribed for the psychosomatic factors. Therapeutic effect of modern medical treatment is insufficient. It is considered that medical diagnosis and treatment with Kampo medicine is very effective.
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Objective: In this study, the transcriptome profile of the stems from Pinellia ternata treated by 30% polyethylene glycol simulated drought stress was analyzed, the key enzyme genes responded to the drought stress were explored, so as to explore the molecular mechanism of P. ternata sprout tumble responded to the drought stress. Methods: The stem segments of P. ternata under drought stress were used as research materials. The Illumina Hiseq 2500 platform was applied for transcriptome sequencing, and bioinformatics analysis was performed on the transcriptome data. Results: A total of 23.00 Gb clean data was obtained, 37 467 952 and 39 903 362 clean reads were gained from the control groups and the drought stress treatment, respectively, and 100 274 uingenes were assembled by Trinity software. A total of 41 132 unigenes were finally obtained with functional annotations against the Nr, eggNOG, Pfam, Swiss-Prot, KOG, GO, KEGG, and COG databases. Furthermore, 4 052 differentially expressed genes (DEGs) were obtained, in details, 2 080 DEGs were up-regulated while 1 972 DEGs were with down-regulated expression. KEGG Pathway enrichment analysis showed that DEGs were mostly involved in ribosome, carbon metabolism, starch and sucrose metabolism, plant hormone signal transduction and biosynthesis of amino acids process. The expression levels of the genes encoded plant hormone metabolism and signal transduction, redox-related enzymes, heat shock proteins and vacuolar processing enzymes were significantly promoted after drought stress treatment, while most of the DEGs encoded aquaporins were down-regulated. Conclusion: By analyzing the transcriptome profiles of P. ternata under drought stress simulated by PEG, the candidate genes associated with water metabolism, plant hormone and signal transduction, as well as the related responsive proteins were obtained, which could provide abundant genetic resources and theoretical basis for understanding the mechanism of P. ternata sprout tumble caused by drought stress.
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Objective:To investigate the effect of Saposhnikoviae Radix on Tongxie Yaofang in regulating water metabolism and 5-serotonin（5-HT） signal system in diarrhea type irritable bowel syndrome（IBS-D）rats. Method:The 40 IBS-D SD rats were randomly divided into model group, Tongxie Yaofang wituout Saposhnikoviae Radix group (26 g·kg-1), Tongxie Yaofang decoction group (30 g·kg-1), Tongxie Yaofang with double Saposhnikoviae Radix group (34 g·kg-1),another 10 normal SD rats were selected as the normal group.Except for normal group, the rats in other groups were separated from their mothers and induced by acetic acid to establish D-IBS model. These rats in the each group were administered with corresponding drugs for 14 days. The diarrhea indexs and the water contents of the feces were observed and calculated. The Na+-K+-ATPase activities in the intestinal mucosa were detected by micro method. The contents of 5-HT were detected by enzyme linked immunosorbent assay (ELISA). The activities of monoamine oxidase A (MAO-A) were detected by chemiluminescence method. The expressions of aquaporin 4 (AQP4) in colon were detected by immunohistochemistry. Protein expression levels of HT receptor 3 (5-HT3R), HT receptor 4 (5-HT4R) and serotonin transporter (SERT) in hypothalamus and colon were detected by Western blot. Result:Compared with normal group, the fecal water contents, contents of 5-HT in hypothalamus and colon, activities of MAO-A, expressions of 5-HT3R were significantly increased in model group (P<0.01), and the activities of Na+-K+-ATPase, expressions of AQP4, 5-HT4R and SERT were reduced significantly (P<0.01). Compared with model group, the diarrhea indexs and fecal water contents, contents of 5-HT in hypothalamus and colon, activities of MAO-A, expressions of 5-HT3R were significantly decreased in each experimental group, and the activities of Na+-K+-ATPase, expressions of AQP4,5-HT4R and SERT were significantly increased(P<0.05，P<0.01),however, there was no significant difference in the expression of 5-HT3R protein in Tongxie Yaofang wituout Saposhnikoviae Radix group.Compared with Tongxie Yaofang wituout Saposhnikoviae Radix group,the diarrhea index, fecal water content, 5-HT content, MAO-A enzyme activity, and protein expression of 5-HT3R were significantly decreased in Tongxie Yaofang group and Tongxie Yaofang with double Saposhnikoviae Radix group(P<0.05，P<0.01), and the activity of Na+-K+-ATPase and protein expression of SERT were significantly increased(P<0.05，P<0.01). Conclusion:Saposhnikoviae Radix can enhance the effects of Tongxie Yaofang on improving the water metabolism of rats with IBS-D and regulating the multi-target of 5-HT signaling system, further confirming the synergistic effect of Saposhnikoviae Radix.
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Objective:To discuss the effect of Arisaema Rhizoma and Pinelliae Pedatisectae Rhizoma on water metabolism and hemorheolog in rats. Method:A total of 50 healthy SD rats were randomly divided into 5 groups, namely normal group, high-dose Arisaema Rhizoma group (1.2 g·kg·d-1), low-dose Arisaema Rhizoma group (1.2 g·kg·d-1), high-dose Pinelliae Pedatisectae Rhizoma group (1.2 g·kg·d-1) and low dose Pinelliae Pedatisectae Rhizoma group (0.3 g·kg·d-1), with 10 rats in each group. The effects of Arisaema Rhizoma and Pinelliae Pedatisectae Rhizoma on water metabolism and hemorheology were compared, with the micturition index, fecal volume, fecal water content, pathological morphology of submandibular gland, aquaporin (AQP2) content in kidney, adenosine cyclic 3′,5′-(hydrogen phosphate)/current good manufacture practices (cAMP/cGMP) and Na+-K+-ATP enzyme content in serum as the evaluation indexes of water metabolism, and the whole blood viscosity (WBV) and erythrocyte aggregation index (RE) as the evaluation indexes of hemorheolog. Result:Compared with normal group, the fecal volume, fecal water content and AQP2 expression decreased significantly， acinus of submandibular gland were atrophied， micturition index, cAMP/cGMP and Na+-K+-ATP enzyme content in serum were increased significantly， WBV and RE were increased significantly in high-dose Arisaema Rhizoma and Pinelliae Pedatisectae Rhizoma groups（P<0.05）, but with no significant difference between them. Conclusion:High-dose Arisaema Rhizoma and Pinelliae Pedatisectae Rhizoma groups had significant effects on water metabolism and hemorheology in rats, suggesting that attention shall be given to the safety of Arisaema Rhizoma and Pinelliae Pedatisectae Rhizoma. And this study provides a theoretical basis for the rational use of the two traditional Chinese medicines in clinic.
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Aquaporins,known as a family of water channel proteins,are crucial factors involved in colonic transmembrane water transport and play important roles in maintaining the homeostasis of internal and external environment of intestinal cells and modulating enteric nerve functions. Diarrhea-predominant irritable bowel syndrome( IBS-D)is a commonly seen gastrointestinal functional disorder in clinical practice. Recently,there are more and more researches focusing on the roles of aquaporins in IBS-D,however,mechanisms of its protective or damaging effects on IBS-D are still not clear. In this review article,the progress of research on the modulatory effect of aquaporins in IBS-D was summarized.
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Background Age-related cataract is a common cause of blindness.However,its cause and pathogenic mechanism have not been fully understood.Recent studies revealed that aquaporin 1 (AQP1) and AQP0 are closely related to the pathogenesis of cataract.Objective This study was to investigate the differential distribution and expression of AQP0 and AQP1 in lenses with age-related cataract and explore its effect on pathogenesis of age-related cataract.Methods Seventeen anterior capsular membrane samples and nucleus samples of lenses were collected from age-related cataract patients during the small incision nonphacoemulsification cataract extraction,and 6 normal lens samples were obtained from health donors in the First Affiliated Hospital of Fujian Medical University.The expression and distribution of AQP1 and AQP0 in the lenses were detected by immunohistochemistry,and the relative expression levels of AQP1 and AQP0 proteins in the lenses were assayed by using Western blot assay.This study protocol was approved by Ethic Committee of this hospital,and written informed consent was obtained from each patient.Results Immunohistochemistry showed that in the normal lenses,AQP1 expressed mainly in LECs;while AQP0 primarily expressed in fiber cells of the lens cortex and nucleus.The relative expression levels of AQP1 and AQP0 in the lenses with age-related cataract (absorbance) were 0.223±0.008 and 0.118±0.015,which were significantly lower than 0.246±0.007 and 0.149±0.007 in the normal lenses (t =-4.508,-3.291,both at P＜0.01).Western blot revealed that the relative expression levels of AQP1 and AQP0 in the lenses with age-related cataract (absorbance) were 0.663 ± 0.012 and 0.599 ± 0.015,which were significantly reduced in comparison with 0.844±0.041 and 0.955 ±0.064 in the normal lenses (t =-7.492,P＜0.05;t =-9.570,P＜0.01).Conclusions AQP1 and AQP0 distribute in different sites of lenses.The expressions of AQP1 and AQP0 are obviously down-regulated in lenses with age-related cataract,suggesting that AQP1 and AQP0 probably play different roles in the pathogenesis of age-related cataract.
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This study was aimed to investigate the effect of visceral pain and water metabolism on irritable bowel syndrome with diarrhea (IBS-D) model rats by moxibustion and its products. A total of 40 SD rats were randomly di-vided into the normal group, model group, moxibustion group, non-smoke moxibustion group, and moxa smoke group. IBS-D model was induced by colorectal distension with an inflatable balloon. The general condition of rats was ob-served. Visceral pain was assessed by abdominal withdrawal reflex (AWR) scores. The immunohistochemical method was used in the detection of claudin-1, AQP3, AQP8 and Na+/K+-ATPase protein expression. The results showed that compared with the normal group, the AWR scores, claudin-1, AQP3, AQP8 and Na+/K+-ATPase protein expres-sion in the colon were decreased in the model group (P < 0.01). The stool was loose, which was on hair around the anus. After moxibustion, non-smoke moxibustion and moxa smoke stimulation, the stool conditions of IBS-D model rats were improved. The AWR scores were decreased in different degrees (P < 0.05 or P < 0.01). Except Na+/K+-ATPase, expressions of claudin-1, AQP3 and AQP8 in colon were increased in different degrees (P < 0.05 or P <0.01). The comprehensive therapeutic effect showed that moxibustion was better than non-smoke moxibustion; and non-smoke moxibustion was better than moxa smoke stimulation. It was concluded that the combination of warm stimulation, optical radiation and moxa smoke induced best effect in improving visceral pain and water metabolism on IBS-D model rats. Among them, warm stimulation and optical radiation may play the main role.
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Objective To investigate the effect of compound catechu anti-diarrhea ointment on the expression of aquaporin3 (AQP3) in the colonic tissues of diarrhea rat model, and the mechanism thereof. Methods Forty SD rats were randomly divided into four groups:blank control group, model control group, positive control group and compound catechu anti-diarrhea ointment group. Rats were given 6 g blank matrix cream in model control group, 2 mL suspension of berberine in positive control group and compound catechu anti-diarrhea ointment in compound catechu anti-diarrhea ointment group, two times/d for 7 d. The rat model of diarrhea was established by using senna intragastric administration. The water content of feces was measured. The expression of AQP3 in colonic tissues was detected by immunohistochemistry assay. Results The water contents of feces were significantly higher in model control group (64.09±0.41)%than those of other three groups (F=53.879,P＜0.05). There was no significant difference in the water content of feces between compound catechu anti-diar-rhea ointment group (48.83 ± 1.08)%and positive control group (46.87 ± 2.19)%. The AQP3-positive cells were mainly ex-pressed in the intestinal mucosa. The dyeing index was significantly lower in model control group (0.85±0.18) than that of other three groups (F=14.971,P＜0.05). There was no significant difference in the dyeing index between compound catechu anti-diarrhea ointment group (1.30±0.18) and positive control group (1.37±0.14). Conclusion Compound catechu anti-di-arrhea ointment can significantly reduce the water contents of feces, which may be related to the increased AQP 3 expression in colonic tissues.
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The results of three cases involving administration of “Shien”, a Kampo formula containing Crotonis Semen, are reported here. The first case was a 48-year-old female, in whom orthopnea had appeared two years previously. She was diagnosed as having congestive heart failure. During the treatment period, the above symptom reappeared when she was fatigued. Based on a lessening of the symptoms after diarrhea, Shien was administered. After over ten abouts of diarrhea, the difficult breathing was eased and the cardiothoracic ratio decreased, as confirmed by chest x-ray.<br>The second case was a 64-year-old female. After the appearance of hyposarca and inappetence a year ago, she had been diagnosed as having amyloidosis brought on by nephrotic syndrome. The edema was reduced with combined administration of the Kampo formulas Hokikenchu-to and Bukuryoshigyaku-to. However, due to the persistence of poor appetite, and the marked presence of the (Oriental Medical) indicator of upper abdominal fullness, Shien was administered. After frequent bouts of diarrhea and vomiting, an improvement in the appetite and a decrease in abdominal fullness were seen.<br>The third case involved a 71-year-old female. After undergoing surgery for breast cancer eight years ago, edema appeared in her upper left arm. Due to the presence of the edema and constipation, both indicators for Shien, administration of this Kampo formula was commenced. Diarrhea occurred every day Shien was administered. A decrease in the upper arm diameter and weight was reported.<br>The results achieved in these three cases suggest that Shien is an effective treatment formula that can be used in cases of “Suidoku” (water metabolism disorders) when indicators such as upper abdominal fullness and constipation are present. Careful distinction between the “deficient” and “excessive” manifestation types (standard in Kampo theory) did not seem necessary.