Objective evaluation of tongue diagnosis ability using a tongue diagnosis e-learning/e-assessment system based on a standardized tongue image database.

Background: In Kampo medicine, tongue examination is used to diagnose the pathological condition "Sho," but an objective evaluation method for its diagnostic ability has not been established. We constructed a tongue diagnosis electronic learning and evaluation system based on a standardized tongue image database. Purpose: This study aims to verify the practicality of this assessment system by evaluating the tongue diagnosis ability of Kampo specialists (KSs), medical professionals, and students. Methods: In the first study, we analyzed the answer data of 15 KSs in an 80-question tongue diagnosis test that assesses eight aspects of tongue findings and evaluated the (i) test score, (ii) test difficulty and discrimination index, (iii) diagnostic consistency, and (iv) diagnostic match rate between KSs. In the second study, we administered a 20-question common Kampo test and analyzed the answer data of 107 medical professionals and 56 students that assessed the tongue color discrimination ability and evaluated the (v) correct answer rate, (vi) test difficulty, and (vii) factors related to the correct answer rate. Result: In the first study, the average test score was 62.2 ± 10.7 points. Twenty-eight questions were difficult (correct answer rate, <50%), 34 were moderate (50%-85%), and 18 were easy (≥85%). Regarding intrarater reliability, the average diagnostic match rate of five KSs involved in database construction was 0.66 ± 0.08, and as for interrater reliability, the diagnostic match rate between the 15 KSs was 0.52 (95% confidence interval, 0.38-0.65) for Gwet's agreement coefficient 1, and the degree of the match rate was moderate. In the second study, the difficulty level of questions was moderate, with a correct rate of 81.3% for medical professionals and 82.1% for students. The discrimination index was good for medical professionals (0.35) and poor for students (0.06). Among medical professionals, the correct answer group of this question had a significantly higher total score on the Kampo common test than the incorrect answer group (85.3 ± 8.4 points vs. 75.8 ± 11.8 points, p < 0.01). Conclusion: This system can objectively evaluate tongue diagnosis ability and has high practicality. Utilizing this system can be expected to contribute to improving learners' tongue diagnosis ability and standardization of tongue diagnosis.

Application of objective structured clinical examination (OSCE) for the evaluation of Kampo medicine training.

BACKGROUND: The purpose of this study was to develop an objective, content-valid, and reliable assessment method for Kampo medicine using an objective structured clinical examination (OSCE) for the assessment of clinical competence in Kampo medicine. METHODS: We developed a blueprint followed by a list of 47 assessment items and three task scenarios related to clinical competence in Kampo medicine. An eight-member test committee checked the relevance of the assessment items on a Likert scale. We calculated a content validity index and content validity ratio, and used the Angoff method to set the passing threshold. We trained a total of nine simulated patients with three assigned to each scenario. We conducted an OSCE for 11 candidates with varying medical abilities, and conducted three stations per person, which were evaluated by one evaluator in one room by direct observation. We used video recordings to test the inter-rater reliability of the three raters. We used the test results to verify the reliability of the assessment chart. RESULTS: The inter-rater reliability (intraclass correlation coefficient [2,1]) was 0.973. The reliability of the assessment chart for each scenario (Cronbach's α) was 0.86, 0.89, and 0.85 for Scenarios 1, 2, and 3, respectively. The reliability of the assessment chart for the whole OSCE (Cronbach's α) was 0.90. CONCLUSIONS: We developed a content-valid new OSCE assessment method for Kampo medicine and obtained high inter-rater and test reliabilities. Our findings suggest that this is one of the most reliable evaluation methods for assessing clinical competence in Kampo medicine.

Kampo Formulae for the Treatment of Neuropathic Pain ∼ Especially the Mechanism of Action of Yokukansan ∼.

Kampo medicine has been practiced as traditional medicine (TM) in Japan. Kampo medicine uses Kampo formulae that are composed of multiple crude drugs to make Kampo formulae. In Japan, Kampo formulae are commonly used instead of or combined with Western medicines. If drug therapy that follows the guidelines for neuropathic pain does not work or cannot be taken due to side effects, various Kampo formulae are considered as the next line of treatment. Since Kampo formulae are composed of two or more kinds of natural crude drugs, and their extracts contain many ingredients with pharmacological effects, one Kampo formula usually has multiple effects. Therefore, when selecting a formula, we consider symptoms other than pain. This review outlines the Kampo formulae that are frequently used for pain treatment and their crude drugs and the basic usage of each component. In recent years, Yokukansan (YKS) has become one of the most used Kampo formulae for pain treatment with an increasing body of baseline research available. We outline the known and possible mechanisms by which YKS exerts its pharmacologic benefits as an example of Kampo formulae's potency and holistic healing properties.

Kampo (Traditional Japanese Herbal) Formulae for Treatment of Stomatitis and Oral Mucositis.

Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional Japanese herbal medicines termed Kampo formulae (i.e., Hangeshashinto, Orengedokuto, Inchinkoto, Orento, Byakkokaninjinto, Juzentaihoto, Hochuekkito, and Shosaikoto) are used for treating various types of stomatitis and mucositis. Its use has been based on the Kampo medical theories-empirical rules established over thousands of years. However, recently, clinical and basic research studies investigating these formulae have been conducted to obtain scientific evidence. Clinical studies investigating efficacies of Shosaikoto and Orento for the treatment of cryptogenic stomatitis and acute aphthous stomatitis and those investigating the effects of Hangeshashinto, Orengedokuto, and Juzentaihoto on chemotherapy- or radiotherapy-induced mucositis have been conducted. The Kampo formulae comprise several crude drugs, whose mechanisms of action are gradually being clarified. Most of these drugs that are used for the treatment of stomatitis possess anti-inflammatory, analgesic, and antioxidative properties. In this review, we introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of stomatitis and oral mucositis.

Sonographic Evaluation of Bone Formation After Sagittal Split Ramus Osteotomy.

OBJECTIVES: The aim of this study was to assess the applicability of sonography for evaluation of mandible bone healing after orthognathic surgery. METHODS: The study included 10 patients who underwent orthognathic surgery. To assess new bone formation after sagittal split ramus osteotomy, the echo intensities of ultrasound (US) reflections of the proximal segment, distal segment, and bone gap were measured with a real-time US scanner at 1 day, 1, 2, 3, and 4 weeks, and 2 and 4 months postoperatively. RESULTS: The mean echo intensity of US reflections of the bone gap gradually increased and became equivalent to that of bone surfaces by 4 weeks postoperatively. X-ray tomograms confirmed bone formation at the bone gap at the same time. CONCLUSIONS: This study indicates that sonography may be useful for evaluating osseous healing after orthognathic surgery.

Traditional Japanese herbal medicines for treatment of odontopathy.

This article highlights several refractory oral diseases, such as stomatitis, burning mouth syndrome (BMS), glossalgia, atypical facial pain (AFP), oral cancer, dry mouth, and Sjögren's syndrome (SJS), in which use of Japanese herbal medicines, Kampo medicines (KM), on the basis of Kampo theory could exert the maximum effects on human body. (1) In acute stomatitis, heat because of agitated vital energy may affect the head, chest, and middle abdominal region. Stomatitis is also related to the generation of reactive oxygen species (ROS). There are many antioxidants in the crude extracts of KM. Thus, we can control environmental factors (cold, heat, dampness, dryness) and vital energy, blood, and fluid of the organ systemically using KM to treat stomatitis and eliminate local ROS accumulation. (2) BMS, glossalgia, and AFP are multifactorial syndromes involving the interaction of biological and psychological factors. Local temperature decrease and edema often occur in chronic pain. These are local circulatory disturbances that can be resolved by improving the flow of blood and fluid. Several KM, such as Tokishakuyakusan and Kamishoyosan (KSS), are effective for enhancing peripheral circulation. Those such as Saikokaryukotuboreito, Yokukansan, KSS, and Saibokutou can reduce stress and associated pain by altering glutamatergic and monoaminergic transmission in the brain. The clinical efficacy of KM for BMS and AFP may depend on the regulation of the mesolimbic dopaminergic and descending glutamatergic pain modulation systems. (3) Regarding oral cancer treatment, I introduce four possible applications of KM, inhibition of the proliferation of cancer cells, complementation of the main cancer therapy, reduction of side effect caused by the main anti-cancer therapy and improvement of quality of life such as the overall status and/or oral discomfort. This review explains in more details Hozai such as Hochuekkito (HET), Juzendaihoto, and Ninjinyoeito (NYT) that are frequently used to improve both immunosuppression and deficiencies of Ki, Ketsu, and Sui in oral cancer patients. (4) Heat- and cold-dryness stages exist in dry mouth and SJS. Byakkokaninjinto is useful for heat-dryness, while NYT, Bakumondoto, and HET have moisturizing effects in the cold-dryness stage. Thus, Kampo therapy is useful for many oral diseases that cannot be cured by western medicine.

miR-203 Inhibits Frizzled-2 Expression via CD82/KAI1 Expression in Human Lung Carcinoma Cells.

CD82/KAI1, a member of the tetraspanin superfamily, is a suppressor of metastasis and CD82 inhibits canonical Wnt signaling via downregulation of several Frizzled (FZD) isoforms, resulting in accumulation of ß-catenin at the cell membrane. In this study, we investigated the mechanism through which CD82 inhibited FZD expression by examining the effects of microRNAs (miRNAs). The miRanda algorithm predicted 11 miRNAs from FZD sequences. Among these miRNAs, CD82 caused upregulation of miR-203 (by 2.095-fold) and downregulation of miR-338-3p (by 0.354-fold) as compared with control cells. Transfection with miR-203 and miR338-3p mimics or inhibitors revealed that miR-203 downregulated FZD2 mRNA (by 0.268-fold) and protein expression (by 0.701-fold). Moreover, transfection with the miR-203 mimic also inhibited cell migration. Therefore, these findings suggested that CD82 enhanced the expression of miR-203 and directly downregulate FZD2 expression, suppressing cancer metastasis by inhibition of the Wnt signaling pathway.

Prostaglandin E(2) receptor EP(4)-selective agonist (ONO-4819) increases bone formation by modulating mesenchymal cell differentiation.

Prostaglandin E(2) (PGE(2)) positively regulates bone resorption and formation mainly mediated through the EP(4) receptor, a subtype of PGE(2) receptors. ONO-4819, an EP(4) receptor-selective agonist, has been shown to increase bone volume, density, and strength; however, the mechanism of these effects has yet to be fully elucidated. To explore this matter, ONO-4819 (10µg/kg) was injected into intact rats twice a day for 5weeks, and their bones were then analyzed by morphological techniques. The effects of ONO-4819 on the differentiation of bone cells were also examined in vitro. Bone morphometric analysis showed that osteoblast number, bone volume, mineral apposition rate, and bone formation rate were significantly increased by ONO-4819, whereas osteoclast number was not affected. Immunohistochemical examination demonstrated that ONO-4819 increased the number of Runx2- and Osterix-positive osteoblasts in rats. In vitro studies using the multipotent mesenchymal cell line C3H10T1/2 showed that ONO-4819 induced alkaline phosphatase (ALPase) activity and up-regulated the mRNA expression of ALPase and Osterix. In contrast, ONO-4819 reduced the mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited adipocyte differentiation of C3H10T1/2 cells, which findings are consistent with the observation that the age-dependent increase in adipocyte number in the bone marrow was significantly suppressed in the ONO-4819-treated animals. ONO-4819 also dose-dependently increased osteoclast-like cell formation in vitro, but the required concentrations were much higher than those to induce osteoblast differentiation. These results collectively suggest that ONO-4819 increased bone formation by stimulating osteoblast differentiation and function, possibly through modulating mesenchymal cell differentiation in the bone.

Multi-shelled q-ball imaging: moment-based orientation distribution function.

PURPOSE: q-ball imaging (QBI) reconstructs the orientation distribution function (ODF) that describes the probability for a spin to diffuse in a given direction, and it is capable of identifying intravoxel multiple fiber orientations. The local maxima of ODF are assumed to indicate fiber orientations, but there is a mismatch between the orientation of a fiber crossing and the local maxima. We propose a novel method, multi-shelled QBI (MS-QBI), that gives a new ODF based on the moment of the probability density function of diffusion displacement. We test the accuracy of the fiber orientation indicated by the new ODF and test fiber tracking using the new ODF. METHODS: We performed tests using numerical simulation. To test the accuracy of fiber orientation, we assumed that 2 fibers cross and evaluated the deviation of the measured crossing angle from the actual angle. To test the fiber tracking, we used a numerical phantom of the cerebral hemisphere containing the corpus callosum, projection fibers, and superior longitudinal fasciculus. In the tests, we compared the results between MS-QBI and conventional QBI under the condition of approximately equal total numbers of diffusion signal samplings between the 2 methods and chose the interpolation parameter such that the stabilities of the results of the angular deviation for the 2 methods were the same. RESULTS: The absolute value of the mean angular deviation was smaller in MS-QBI than in conventional QBI. Using the moment-based ODF improved the accuracy of fiber pathways in fiber tracking but maintained the stability of the results. CONCLUSION: MS-QBI can more accurately identify intravoxel multiple fiber orientations than can QBI, without increasing sampling number. The high accuracy of MS-QBI will contribute to the improved tractography.

q-Space imaging using small magnetic field gradient.

q-Space diffusion analysis is a method to obtain the probability density function of the translational displacement of diffusing water molecules. Several quantities can be extracted from the function that indicate a characteristic of the water diffusion in tissue, e.g., the mean displacement of the diffusion, probability for zero displacement, and kurtosis of the function. These quantities are expected to give information about the microstructure of tissues in addition to that obtained from the apparent diffusion coefficient (ADC); however, this method requires high q (i.e., high b) values, which are undesirable in practical applications of the method using clinical magnetic resonance (MR) imaging equipment. We propose a method to obtain certain quantities that indicate a characteristic of the diffusion and that uses low q-value measurements. The quantities we can obtain are the moments of translational displacement, R; the n-th order moment is defined as the average of Rn (n: integer). Kurtosis can also be calculated from the second and fourth moments. We tried to map the moments and kurtosis using clinical MR imaging equipment. We also estimated the inherent errors of the moments obtained. Our method requires precision in measuring spin echo signals and setting q values rather than using high q-value measurements. Although our results show that further error reductions are desired, our method is workable using ordinary clinical MR imaging equipment.

Pathophysiological studies of trinitrobenzene sulfonic acid-induced colitis in Syrian hamsters (Mesocricetus auratus).

We developed a colitis model in Syrian hamsters (Mesocricetus auratus) to investigate the relationship between colitis and neutrophil elastase (NE). Colitis was induced by a single intracolonic dose of trinitrobenzene sulfonic acid (TNBS; 90 mg/ml) dissolved in 15% (vol/vol) ethanol. The ulcer area, tissue myeloperoxidase (MPO) activity, and luminal NE activity all were increased on Days 1 and 5, corresponding with the acute inflammatory histopathological changes. These acute inflammatory parameters subsequently decreased by Day 14, and chronic inflammatory histopathological changes became evident. Recurrence of inflammation was not observed during the period up to Day 28. To evaluate our colitis model, the effects of prednisolone were examined. Prednisolone was administered orally once on the day before induction of colitis, and animals were treated twice daily thereafter. Although prednisolone had little effect on the tissue MPO activity, prednisolone inhibited the ulcer area and NE activity. In addition, the effects of an NE-specific inhibitor (ONO-6818) on our TNBS-induced colitis model were examined. In the subcutaneous treatment study, ONO-6818 was administered once before the induction of colitis. Although ONO-6818 had little effect on the tissue MPO activity, the ulcer area and NE activity were decreased in the ONO-6818-treated group. The inhibitory effects on the ulcer area and NE activity were confirmed after oral treatment with ONO-6818 after induction of colitis. We conclude that our colitis model is useful for investigating the relationship between colitis and NE, and inhibition of NE activity can prevent the progression of ulceration.

Effects of the neutrophil elastase inhibitor (ONO-6818) on acetic acid induced colitis in Syrian hamsters.

Neutrophil elastase (NE) released from neutrophils during inflammation is related to tissue disturbance and organ failure. We investigated the effects of an orally active NE inhibitor, ONO-6818, on acetic acid induced colitis in Syrian hamsters. The ulcer area, hemoglobin level in the colonic lumen, NE activity, and tissue myeloperoxidase (MPO) activity in the colitis control animals were significantly increased compared to the normal control ones. Either oral or subcutaneous treatment with ONO-6818 had significant inhibitory effects on the ulcer area, hemoglobin level and NE activity in the colonic lumen, but ONO-6818 did not have a significant inhibitory effect on tissue MPO activity. We conclude that NE is closely related to the development of inflammation in acetic acid-induced colitis in Syrian hamsters and that the condition is improved by the inhibition of NE.

Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats.

Prostaglandin E(2) (PGE(2)) is essential for fracture healing. Systemic administration of EP4 ligands such as PGE(2) and other synthetic EP4 agonists appears to transduce anabolic signals by binding to receptor EP4. Therefore, the present study was designed to test whether administration of EP4 agonist accelerates the healing of drill-hole injury in the femoral diaphysis. After surgery, a total of 128 Wistar rats, at the age of 12 weeks, were assigned to basal control (n = 8), and three groups with respective doses of 0 (vehicle control), 10 (low-dose), and 30 (high-dose) microg/kg body weight of the agent were subcutaneously injected twice a day. Femoral specimens were obtained at 0, 5, 7, 14, 21, and 28 days. In EP4 agonist-treated groups, the total bone volume of the regenerating bone in the defect did not significantly differ, but the regenerated cortical bone volume measured by histomorphometry and cortical bone mineral content (Ct. BMC) by pQCT dose-dependently increased at 14 and 21 days compared to the control. In the high-dose group, the value of osteoclast surface significantly increased compared with that in the control at 14 days. Expression levels of osteocalcin and TRAP mRNAs in the injured tissue increased at 14 days. Expression levels of EP4, BMP-2, and RANKL mRNAs increased at 7 days in the high-dose group. The bone mineral values of the lumbar bone at 28 days, measured by DXA, did not differ in the three groups. These data indicated that systemic administration of EP4 agonist ONO-4819.CD accelerated cortical bone healing after drill-hole injury by upregulating the local turnover of the regenerating bone.

Colonic ulceration and increase of neutrophil elastase activity in the acetic acid-induced colitis model in Syrian hamsters.

A novel colitis model using Syrian hamsters was developed. Colitis was induced by intracolonic administration of 1% acetic acid, and the ulcer area, tissue myeloperoxidase (MPO) activity, and luminal neutrophil elastase (NE) activity of the colon were determined at 1, 3, 8, 24 and 48 hr after colitis induction. The histopathological changes of the colon were also examined in this model. An increase of tissue MPO activity and NE activity was evident at 3 hr after induction of colitis, peaked at 24 hr, and decreased subsequently. The increase of luminal NE activity was well correlated with the colonic ulcer area. In histopathological examination, ulceration, erosion, crypt abscesses, neutrophil infiltration, hemorrhage, and edema were seen. The effects of prednisolone were examined to evaluate the adequacy of our colitis model. Syrian hamsters were treated orally with prednisolone at 18 and 1 hr before and at 6 hr after induction of colitis, and the ulcer area, tissue MPO activity, and luminal NE activity were evaluated at 24 hr after colitis induction. Prednisolone therapy had little effect on the tissue MPO activity. However, the NE activity of the prednisolone-treated group was significantly decreased. In addition, although prednisolone did not significantly decrease the ulcer area, a tendency toward decrease was noted. We conclude that this new model of experimental colitis in Syrian hamsters is useful for investigating the pathophysiology of colitis, especially useful for studying the relationship between colitis and NE activity.

Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E2 promotes both bone resorption and bone formation. By infusing PGE2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE2 induced expression of core-binding factor alpha1 (Runx2/Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis.