Specific consistency score for rational selection of epilepsy resection surgery candidates.

OBJECTIVE: Degree of indication for epilepsy surgery is determined by taking multiple factors into account. This study aimed to investigate the usefulness of the Specific Consistency Score (SCS), a proposed score for focal epilepsy to rate the indication for epilepsy focal resection. METHODS: This retrospective cohort study included patients considered for resective epilepsy surgery in Kyoto University Hospital from 2011 to 2022. Plausible epileptic focus was tentatively defined. Cardinal findings were scored based on specificity and consistency with the estimated laterality and lobe. The total points represented SCS. The association between SCS and the following clinical parameters was assessed by univariate and multivariate analysis: (1) probability of undergoing resective epilepsy surgery, (2) good postoperative seizure outcome (Engel I and II or Engel I only), and (3) lobar concordance between the noninvasively estimated focus and intracranial electroencephalographic (EEG) recordings. RESULTS: A total of 131 patients were evaluated. Univariate analysis revealed higher SCS in the (1) epilepsy surgery group (8.4 [95% confidence interval (CI) = 7.8-8.9] vs. 4.9 [95% CI = 4.3-5.5] points; p < .001), (2) good postoperative seizure outcome group (Engel I and II; 8.7 [95% CI = 8.2-9.3] vs. 6.4 [95% CI = 4.5-8.3] points; p = .008), and (3) patients whose focus defined by intracranial EEG matched the noninvasively estimated focus (8.3 [95% CI = 7.3-9.2] vs. 5.4 [95% CI = 3.5-7.3] points; p = .004). Multivariate analysis revealed areas under the curve of .843, .825, and .881 for Parameters 1, 2, and 3, respectively. SIGNIFICANCE: SCS provides a reliable index of good indication for resective epilepsy surgery and can be easily available in many institutions not necessarily specializing in epilepsy.

Allyl isothiocyanate, an activator of TRPA1, increases gastric mucosal blood flow through calcitonin gene-related peptide and adrenomedullin in anesthetized rats.

Allyl isothiocyanate (AITC) activates transient receptor potential ankyrin 1 (TRPA1) channel, which is involved in the control of intestinal mucosal blood flow. However, the mechanism underlying the increased gastric mucosal blood flow (GMBF) in response to AITC remains unknown. We examined the effect of AITC on GMBF in the ex vivo stomachs of normal and sensory deafferented rats using a laser Doppler flowmeter. Mucosal application of AITC increased GMBF in a concentration-dependent manner. Repeated AITC exposure resulted in a marked desensitization. The increased GMBF response induced by AITC was entirely blocked by co-application of TRPA1 channel blockers HC-030031 or AP-18. Increased GMBF in response to AITC was significantly attenuated by chemical deafferentation following systemic capsaicin injections (total dose: 100 mg/kg). In contrast, increased GMBF responses to capsaicin, a transient receptor potential vanilloid 1 (TRPV1) activator, were completely abolished by chemical deafferentation. The increased GMBF response to AITC was markedly inhibited by BIBN 4096, a calcitonin gene-related peptide receptor (CGRP) antagonist, or AGP-8412, an adrenomedullin receptor antagonist. These results suggest that AITC-stimulated TRPA1 activation results in the increased GMBF through the release of CGRP and adrenomedullin.

Contribution of traditional Japanese Kampo medicines, kakkonto with shosaikotokakikyosekko, in treating patients with mild-to-moderate coronavirus disease 2019: Further analysis of a multicenter, randomized controlled trial.

We previously reported the finding of symptom relief in a randomized controlled trial with the combined use of kakkonto and shosaikotokakikyosekko added to conventional treatment in patients with coronavirus disease 2019 (COVID-19). For further evaluation, we performed post hoc analysis focused on symptom disappearance without recurrence, to determine a clearer effect of Kampo medicine. Patients with mild and moderate COVID-19 were randomly allocated to a control group receiving symptomatic therapy or a Kampo group receiving kakkonto (2.5 g) with shosaikotokakikyosekko (2.5 g) three times daily in addition to symptomatic therapy. The data of 161 patients (Kampo group, n = 81; control group, n = 80) were analyzed post hoc for the time to symptom disappearance. Kaplan-Meier and Cox proportional hazard estimates of disappearance of symptoms showed that all and each symptom targeted in this study disappeared faster in the Kampo group than in the control group, although not statistically significant (all symptomatic cases; hazard ratio [HR] 3.73, 95% confidence interval [CI] 0.46-29.98, log-rank p = 0.1763). In a supplemental assessment using covariate adjustment and competing risk analysis, fever disappeared faster in the Kampo group than in the control group (all symptomatic cases, HR 1.62, 95% CI 0.99-2.64, p = 0.0557; unvaccinated cases, HR 1.68, 95% CI 1.00-2.83, p = 0.0498) and shortness of breath disappeared significantly faster in Kampo group than in control group (all symptomatic cases, HR 1.92, 95% CI 1.07-3.42, p = 0.0278; unvaccinated cases, HR 2.15, 95% CI 1.17-3.96, p = 0.0141). These results demonstrate the advantages of Kampo treatment for acute COVID-19.

The beneficial effect of traditional Japanese herbal (Kampo) medicine, Hochu-ekki-to (Bu-Zhong-Yi-Qi-Tang), for patients with chronic wounds refractory to conventional therapies: A prospective, randomized trial.

Hochu-ekki-to (HET) is a traditional Japanese herbal (Kampo) medicine for the treatment of severe weakness, loss of appetite, and indigestion in elderly patients and for the prevention of opportunistic infections. The impact of HET on patients with chronic wounds refractory to conventional therapies was investigated in a prospective, randomized trial, including 18 patients divided into medication (7.5 g oral HET per day, n = 9) and control (n = 9) groups. Wound healing during the 12-week study period was scored based on depth, exudate, size, inflammation/infection, granulation tissue, necrotic tissue, and pocket size. At 12 weeks, wound healing progressed in all nine patients in the medication group, whereas wound healing progressed in only three patients in the control group (significant difference, p < 0.01; relative risk: 3.00). In the medication group, the total score decreased significantly at 8 weeks and later. To the best of our knowledge, this study was the first to show that HET promoted the healing of chronic wounds resistant to conventional treatments. HET may be a choice as an adjunctive therapy for chronic wounds, particularly for patients with malnutrition. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031620).

Bathing Frequency and Onset of Functional Disability Among Japanese Older Adults: A Prospective 3-Year Cohort Study From the JAGES.

BACKGROUND: While bathing styles vary among countries, most Japanese people prefer tub bathing to showers and saunas. However, few studies have examined the relationship between tub bathing and health outcomes. Accordingly, in this prospective cohort study, we investigated the association between tub bathing frequency and the onset of functional disability among older people in Japan. METHODS: We used data from the Japan Gerontological Evaluation Study (JAGES). The baseline survey was conducted from August 2010 through January 2012 and enrolled 13,786 community-dwelling older people (6,482 men and 7,304 women) independent in activities of daily living. During a 3-year observation period, the onset of functional disability, identified by new certification for need of Long-Term Care Insurance, was recorded. Tub bathing frequencies in summer and winter at baseline were divided into three groups: low frequency (0-2 times/week), moderate frequency (3-6 times/week), and high frequency (≥7 times/week). We estimated the risks of functional disability in each group using a multivariate Cox proportional hazards model. RESULTS: Functional disability was observed in a total of 1,203 cases (8.7%). Compared with the low-frequency group and after adjustment for 14 potential confounders, the hazard ratios of the moderate- and high-frequency groups were 0.91 (95% confidence interval [CI], 0.75-1.10) and 0.72 (95% CI, 0.60-0.85) for summer and 0.90 (95% CI, 0.76-1.07) and 0.71 (95% CI, 0.60-0.84) for winter. CONCLUSION: High tub bathing frequency is associated with lower onset of functional disability. Therefore, tub bathing might be beneficial for older people's health.

Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study.

Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18ß-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM-1.8 µM) and 18ß-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM-4.2 µM). 3-Monoglucuronyl 18ß-glycyrrhetinic acid, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways.

BACKGROUND: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma. METHODS: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53. RESULTS: Metformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells. CONCLUSION: These data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.

The association between objective tongue color and endoscopic findings: results from the Kyushu and Okinawa population study (KOPS).

BACKGROUND: The relation between tongue color and gastroesophageal disease is unclear. This study was done to investigate the associations between tongue color (TC), endoscopic findings, Helicobacter.pylori infection status, and serological atrophic gastritis (SAG). METHODS: The participants were 896 residents of Ishigaki Island, Okinawa, aged 28-86 years. The tongue was photographed, esophagogastroduodenoscopy was done, and serum antibody to H.pylori was measured. SAG was defined as a serum Pepsinogen (PG)Ilevel ≤70 ng/ml and a PGI/IIratio ≤3.0. TC was measured by the device-independent international commission on Illumination 1976 L*a*b* color space standards at four points: (1) edge, (2) posterior, (3) middle, and (4) apex. We also calculated the ratio of the tongue edge to the three other measured points to examine the association between the coating of the tongue and the endoscopic and laboratory findings. RESULTS: Participants were excluded who had two or more endoscopic findings (n = 315) or who had SAG without seropositivity to H.pylori (n = 33). The remaining 548 participants were divided into three groups: SAG and seropositive to H.pylori (n = 67), seropositive to H.pylori alone (n = 56), and without SAG and seronegative for H.pylori (n = 425). We divided 425 residents into a single endoscopic finding positive group (n = 207) and a negative group, which served as a control (n = 218). The most frequent single endoscopic finding was esophageal hernia (n = 110), followed by erosive esophagitis (n = 35) and erosive gastritis (EG) (n = 45). EH was significantly associated with TC (2b*/1b*) (P < 0.05). EG was significantly associated with TC (3a*, 3b*) (P < 0.05). Seropositivity to H.pylori was significantly associated with TC (3 L*, 3 L*/1 L*) (P < 0.05, <0.01), and seropositivity to both H.pylori and SAG was significantly associated with TC (3 L*/1 L*) (P < 0.05). Multivariate analysis extracted TC (3a*, 3b*) as an independent factor associated with a differential diagnosis of EG (Odds ratio (OR) 2.66 P = 0.008, OR 2.17 P = 0.045). CONCLUSIONS: The tongue body color of the middle area reflects acute change of gastric mucosa, such as erosive gastritis. Tongue diagnosis would be a useful, non-invasive screening tool for EG.

Effects of Sitting and Supine Positions on Tongue Color as Measured by Tongue Image Analyzing System and Its Relation to Biometric Information.

Tongue diagnosis is one of the important diagnostic methods in Kampo (traditional Japanese) medicine, in which the color and shape of the tongue are used to determine the patient's constitution and systemic symptoms. Tongue diagnosis is performed with the patient in the sitting or supine positions; however, the differences in tongue color in these two different positions have not been analyzed. We developed tongue image analyzing system (TIAS), which can quantify tongue color by capturing tongue images in the sitting and supine positions. We analyzed the effects on tongue color in two different body positions. Tongue color was quantified as L∗a∗b∗ from tongue images of 18 patients in two different body positions by taking images with TIAS. The CIEDE 2000 color difference equation (ΔE00) was used to assess the difference in tongue color in two different body positions. Correlations were also determined between ΔE00, physical characteristics, and laboratory test values. The mean and median ΔE00 for 18 patients were 2.85 and 2.34, respectively. Of these patients, 77.8% had a ΔE00 < 4.1. A weak positive correlation was obtained between ΔE00 and systolic blood pressure and fasting plasma glucose. Approximately 80% of patients' tongue color did not change between the sitting and supine positions. This indicates that the diagnostic results of tongue color are trustworthy even if medical professionals perform tongue diagnosis in two different body positions.

Neuronal nitric oxide synthase-derived nitric oxide is involved in gastric mucosal hyperemic response to capsaicin in rats.

BACKGROUND AND AIMS: Activation of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin leads to gastric hyperemic response through capsaicin-sensitive sensory nerves and nitric oxide (NO). The aim of the present study is to examine which isoform of nitric oxide synthase (NOS)/NO is involved in the hyperemic response to capsaicin in the rat stomach. METHODS: Gastric mucosal blood flow (GMBF) was measured by laser Doppler flowmetry in rats. The localizations of TRPV1 and neuronal NOS (nNOS) in the rat gastric mucosa were detected by immunohistochemical staining. RESULTS: The nNOS inhibitor N(5)-[imino(propylamino)methyl]-L-ornithine substantially reduced GMBF during capsaicin application, whereas the endothelial NOS (eNOS) inhibitor N(5)-(1-iminomethyl)-L-ornithine did not affect the effect of capsaicin during the application. The nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester apparently inhibited the capsaicin-induced GMBF, while the inducible NOS inhibitor 1400W did not affect GMBF response to capsaicin. The immunohistochemical studies revealed nerve fibers coexpressing TRPV1 and nNOS around blood vessels in the gastric submucosa. CONCLUSION: We demonstrated for the first time that nNOS/NO is involved in gastric hyperemic responses to capsaicin.

Reliability of non-contact tongue diagnosis for Sjögren's syndrome using machine learning method.

Sjögren's syndrome (SS) is an autoimmune disease characterized by dry mouth. The cause of SS is unknown, and its diverse symptoms make diagnosis difficult. The Saxon test, an intraoral examination, is used as the primary diagnostic method for SS, however, the risk of salivary infection is problematic. Therefore, we investigate the possibility of diagnosing SS by non-contact and imaging observation of the tongue surface. In this study, we obtained tongue photographs of 60 patients at the Tsurumi University School of Dentistry outpatient clinic to clarify the relationship between the features of the tongue and SS. We divided the tongue into four regions, and the color of each region was transformed into CIE1976L*a*b* space and statistically analyzed. To clarify experimentally the possibility of SS diagnosis using tongue color, we employed three machine-learning models: logistic regression, support vector machine, and random forest. In addition, we constructed diagnostic prediction models based on the Bagging and Stacking methods combined with three machine-learning models for comparative evaluation. This analysis used dimensionality compression by principal component analysis to eliminate redundancy in tongue color information. We found a significant difference between the a* value of the rear part of the tongue and the b* value of the middle part of the tongue in SS and non-SS patients. In addition to the principal component scores of tongue color, the support vector machine was trained using age, and achieved high accuracy (71.3%) and specificity (78.1%). The results indicate that the prediction of SS diagnosis by tongue color reaches a level comparable to machine learning models trained using the Saxon test. This is the first study using machine learning to predict SS diagnosis by non-contact tongue observation. Our proposed method can potentially support early SS detection simply and conveniently, eliminating the risk of infection at diagnosis, and it should be validated and optimized in clinical practice.

Conventional and Kampo Medicine Treatment for Mild-to-moderate COVID-19: A Multicenter, Retrospective, Observational Study by the Integrative Management in Japan for Epidemic Disease (IMJEDI Study-observation).

Objective Patients in whom coronavirus disease 2019 (COVID-19) was suspected or confirmed between January 1, 2020, and October 31, 2021, were enrolled from Japanese hospitals in this multicenter, retrospective, observational study. Methods Data on the treatment administered (including conventional and Kampo medicine) and changes in common cold-like symptoms (such as fever, cough, sputum, dyspnea, fatigue, and diarrhea) were collected from their medical records. The primary outcome was the number of days without a fever (with a body temperature <37°C). The secondary outcomes were symptomatic relief and the worsening of illness, defined as the presence of a condition requiring oxygen inhalation. The outcomes of patients treated with and without Kampo medicine were compared. Patients We enrolled 962 patients, among whom 528 received conventional and Kampo treatment (Kampo group) and 434 received conventional treatment (non-Kampo group). Results Overall, after adjusting for the staging of COVID-19 and risk factors, there were no significant between-group differences in the symptoms or number of days being afebrile. After performing propensity score matching and restricting the included cases to those with confirmed COVID-19 who did not receive steroid administration and initiated treatment within 4 days from the onset, the risk of illness worsening was significantly lower in the Kampo group than in the non-Kampo group (odds ratio=0.113, 95% confidence interval: 0.014-0.928, p=0.0424). Conclusion Early Kampo treatment may suppress illness worsening risk in COVID-19 cases without steroid use. Further randomized controlled studies are needed to confirm the clinical benefit of Kampo medicine for COVID-19.

Dietary agonists of TRPV1 inhibit gastric acid secretion in mice.

Capsaicin and 6-gingerol, pungent components of chilli pepper and ginger, are known as dietary agonists of transient receptor potential vanilloid-1. Transient receptor potential vanilloid-1 nerve fibers are recognized to play a role in gastric mucosal integrity in rats. In the present studies, we examined the acute effects of peroral administration of capsaicin and 6-gingerol on gastric acid secretion in conscious mice. These agents were given p. o. 30 min before the pylorus was ligated. Oral administration of capsaicin (1.0-100 mg/kg) or 6-gingerol (1.5-50 mg/kg) significantly and dose-dependently inhibited basal acid secretion. Pretreatment with BCTC, a transient receptor potential vanilloid-1 antagonist, significantly reversed the reduced basal acid secretion by capsaicin or 6-gingerol. The combination of the lowest doses of capsaicin and 6-gingerol markedly inhibited basal acid secretion in conscious mice and this was also significantly reversed by BCTC. Moreover, the combination of the maximal dose of capsaicin and 6-gingerol inhibited basal acid secretion only to the level of a single administration of the maximal dose of capsaicin. These results suggest that the combination of capsaicin and 6-gingerol has an additive effect on the inhibition of gastric acid secretion through activation of transient receptor potential vanilloid-1. In separate experiments, intraduodenal administration of either capsaicin (30 mg/kg) or 6-gingerol (15 mg/kg), whose doses were observed to have a significant inhibitory effect by oral administration, tended to inhibit basal acid secretion compared with the vehicle. These results suggest that the combination of capsaicin and 6-gingerol has an additive effect on inhibition of gastric acid secretion through activation of transient receptor potential vanilloid-1, and oral administration of transient receptor potential vanilloid-1 agonists directly stimulates transient receptor potential vanilloid-1 in the gastric lumen, resulting in a potent reduction of gastric acid secretion.

Association of Rsa polymorphism of the estrogen receptor-ß gene with rheumatoid arthritis.

To investigate the possible influence of the single nucleotide polymorphism (SNP) of the estrogen receptor-ß gene, rs1256049 (Rsa) in exon 5, on the frequency of rheumatoid arthritis (RA), 263 RA patients and 174 control subjects with osteoarthritis (OA) were recruited. Rsa polymorphism was detected using a PCR-RFLP, Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method. The occurrence of both mutant allele (G) and genotype (GG) were significantly higher in RA than in OA patients (allele P = 0.008, OR: 1.501, 95%CI: 1.12-2.02). In RA patients, GG genotype frequency was higher in severe RA patients than mild RA patients. Moreover, there was significant difference between severe RA patients and OA patients (P = 0.009), also the allele distribution was significant different between severe RA, mild RA, and OA patients (P = 0.025, 95%CI = 0.61-0.93). With respect to gender, GG genotype was statistically more frequent in female RA patients than that of OA, while such an association was not observed in men. Above all, the presence of the GG genotype could be a risk factor for RA and such trend might be different in gender, although additional larger scale study is needed.

Extraction efficiency of shosaikoto (xiaochaihu tang) and investigation of the major constituents in the residual crude drugs.

Shosaikoto (Xiaochaihu Tang) is one of the frequently used traditional herbal medicines (Kampo medicines, Japan). To realize the effective use of precious crude drugs, we investigated the major constituents in the residual crude drugs after decoction and aimed for extraction efficiency of shosaikoto with regard to the extract, tannin content, and major constituents. We found that the residual crude drugs had large amounts of compounds, especially saikosaponin b(2), which had a 78.3% yield compared to that in the first decoction. The extraction efficiency increased when decoction time and volume of water increased. Both increases had an additive effect on the yield of the extract and saikosaponin b(2) in particular. We also found that the size of crude drug pieces that are available in Japanese markets is suitable for decoction because of quick permeation of water. From our study, the second decoction may be a valuable contribution to medical treatment and of effective use of crude drugs. Moreover, time and volume of water should be increased when patients have trouble in preparing a decoction. Our study revealing the factors that influence the extraction efficiency of shosaikoto will be the basis for empirical evidence about decocting Kampo medicine.

Current status of Kampo medicine curricula in all Japanese medical schools.

BACKGROUND: There have been a few but not precise surveys of the current status of traditional Japanese Kampo education at medical schools in Japan. Our aim was to identify problems and suggest solutions for a standardized Kampo educational model for all medical schools throughout Japan. METHODS: We surveyed all 80 medical schools in Japan regarding eight items related to teaching or studying Kampo medicine: (1) the number of class meetings, target school year(s), and type of classes; (2) presence or absence of full-time instructors; (3) curricula contents; (4) textbooks in use; (5) desire for standardized textbooks; (6) faculty development programmes; (7) course contents; and (8) problems to be solved to promote Kampo education. We conducted descriptive analyses without statistics. RESULTS: Eighty questionnaires were collected (100%). (1) There were 0 to 25 Kampo class meetings during the 6 years of medical school. At least one Kampo class was conducted at 98% of the schools, ≥4 at 84%, ≥8 at 44%, and ≥16 at 5%. Distribution of classes was 19% and 57% for third- and fourth-year students, respectively. (2) Only 29% of schools employed full-time Kampo medicine instructors. (3) Medicine was taught on the basis of traditional Japanese Kampo medicine by 81% of the schools, Chinese medicine by 19%, and Western medicine by 20%. (4) Textbooks were used by 24%. (5) Seventy-four percent considered using standardized textbooks. (6) Thirty-three percent provided faculty development programmes. (7) Regarding course contents, "characteristics" was selected by 94%, "basic concepts" by 84%, and evidence-based medicine by 64%. (8) Among the problems to be solved promptly, curriculum standardization was selected by 63%, preparation of simple textbooks by 51%, and fostering instructors responsible for Kampo education by 65%. CONCLUSIONS: Japanese medical schools only offer students a short time to study Kampo medicine, and the impetus to include Kampo medicine in their curricula varies among schools. Future Kampo education at medical schools requires solving several problems, including curriculum standardization.

Cheminformatics modeling of the correlation between Bupleurum Root-formula medicines and Excess and Deficiency pattern in the diagnostic criteria of Sho in Kampo (traditional Japanese medicine) by non-targeted direct infusion mass spectrometry with machine learning.

Kampo is a form of traditional Japanese medicine, and its therapeutic strategy has been validated empirically over millennia, mainly in Asia. Kampo therapy aims to holistically prevent and treat disease based on the specific diagnosis Sho (in Japanese), in contrast with modern medical treatment which focuses on a patient's affected parts and local conditions. The medicines formulated using crude drugs derived from natural sources (Kampo formulas) are prescribed for patients according to their specific Sho, and thus the Kampo medication system is very complex. However, our previous study strongly suggested that Kampo medication theory could be explained by chemometrics and informatic approaches [Okada et al. in J Nat Med 70:107-114, 2016]. Here, we studied a group of seven formulas with Bupleurum Root and Scutellaria Root as the principal crude drugs. First, decoctions of the formulas were prepared and their supernatants were analyzed by non-targeted direct infusion mass spectrometry (MS) and principal component analysis, which is a type of unsupervised machine learning. Next, supervised machine learning was used to perform partial least squares modeling of the MS data matrix trained on the patients' constitution of Excess, Deficiency, or Medium between these two states (EDM) in Sho. The results showed that the correlation between the chemical fingerprints obtained by MS analysis and EDM could be modeled well using this approach. This cheminformatics modeling approach successfully interpreted part of the complex Kampo medication system studied using the fingerprints of formulas obtained by MS analysis and was consistent with the predicted Sho.

Cinobufagin inhibits proliferation of acute myeloid leukaemia cells by repressing c-Myc pathway-associated genes.

Cinobufagin is a cardiotoxic bufanolide steroid secreted by the Asiatic toad, Bufo gargarizans. Bufanolides inhibit Na+/K+ ATPase and have similar effects as cardiac glycosides, such as digitoxin or ouabain derived from toxic herbs. Recently, the anti-cancer effects of bufanolides have gained attention, however the underlying molecular mechanisms remain unclear. Selecting cinobufagin as a candidate anti-leukaemia agent, we here conducted transcriptomic analyses on the effect of cinobufagin on human acute myeloid leukaemia (AML) cell lines, HL60 and Kasumi-1. Flow cytometry analysis showed that cinobufagin induced apoptosis in both cell lines. RNA-sequencing (RNA-seq) of the two cell lines treated with cinobufagin revealed commonly downregulated genes with enrichment in the term "Myc active pathway" according to Gene Ontology (GO) analysis. Gene Set Enrichment Analysis (GSEA) of genes downregulated by cinobufagin also showed "MYC_TARGETS_V2" with the highest normalised enrichment score (NES) in both cell lines. In contrast, hallmarks such as "TNFA_SIGNALING_VIA_NFKB", "APOPTOSIS", and "TGF_BETA_SIGNALING" were significantly enriched as upregulated gene sets. Epigenetic analysis using chromatin immunoprecipitation and sequencing (ChIP-seq) confirmed that genes encoding cell death-related signalling molecules were upregulated by gain of H3K27ac, whereas downregulation of c-Myc-related genes was not accompanied by H3K27ac alteration. Cinobufagin is an anti-proliferative natural compound with c-Myc-inhibiting and epigenetic-modulating activity in acute myeloid leukaemia.

Japanese traditional Kampo medicine bofutsushosan improves body mass index in participants with obesity: A systematic review and meta-analysis.

BACKGROUND: The number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity. METHODS: We searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI. RESULTS: We included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: -0.52 kg/m2 [-0.86, -0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group. CONCLUSION: BTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity.

Evaluation of shoseiryuto for seasonal allergic rhinitis, using an environmental challenge chamber.

Background: Complementary and alternative medicine, including Japanese traditional medicine (JTM), has been used for various allergic diseases, but the evidence is limited. Shoseiryuto (Xiao-Qing-Long-Tang), one of the representative JTM drugs, is frequently used to treat allergic rhinitis (AR). However, its efficacy for seasonal AR has not been fully established. Using an Environmental challenge chamber (ECC), we evaluated the therapeutic effects of shoseiryuto on AR induced by Japanese cedar pollen (JCP). Methods: A placebo-controlled double-blind crossover study with shoseiryuto was conducted using the ECC. The shoseiryuto or placebo was orally administered from 2 weeks before the exposure test. The pollen exposure test was conducted for 3 h, and the pollen concentration was set at 8000 pollen/m3. The primary endpoint of the study was the total nasal symptom score (TNSS) during pollen exposure. A physician certified by the Japanese Society of Oriental Medicine as a specialist checked each participant's "pattern", a comprehensive expression of signs obtained from individual patients' subjective symptoms and other personal findings. Blood samples collected just before the first pollen exposure were stimulated with cedar antigens and used for immunological studies. Results: The results of the 46 participants were analyzed, and no significant side effects were detected. There was no significant difference in TNSS during pollen exposure for 3 h in the ECC between the shoseiryuto and placebo groups. However, some symptoms were improved in the shoseiryuto group after leaving the ECC. There was no significant correlation between the "fluid retention pattern" and TNSS. In immunological studies, shoseiryuto did not inhibit Th2-type cytokine production and mRNA expression. Conclusions: Oral administration of shoseiryuto from 2 weeks before pollen exposure did not prevent or inhibit immediate symptoms of AR induced by JCP in the ECC. Further study is needed to reevaluate the shoseiryuto specific "pattern" in JTM.