Increased Waist Circumference after One-Year Is Associated with Poor Chewing Status.

BACKGROUND: This study aimed to investigate the relationship between an increase in waist circumference (WC) after 1 year and self-reported chewing status in 10,870 Japanese adults who had received health checkups. Subsequently, 8068 participants were included in the final analysis. METHODS: We defined an increase in WC ≥ 5 cm after 1 year as an unhealthy increase; in total, 613 (7.5%) respondents met this criterion. Chewing status was evaluated using a self-reported questionnaire at baseline; 1080 (13%) respondents were diagnosed with poor chewing status. RESULTS: After adjusting for age, gender, WC, body mass index (BMI), and chewing status, an increase in WC ≥ 5 cm was found to be positively associated with gender (females: odds ratios [ORs]: 1.206; 95% confidence intervals [CIs]: 1.008-1.443), WC (ORs: 0.967; 95% CIs: 0.954-0.981), BMI (≥25 kg/m2; ORs: 2.194; 95% CIs: 1.715-2.808), and chewing status (poor; ORs: 1.356; 95% CIs: 1.084-1.697). CONCLUSIONS: These findings suggest that increased WC after 1 year was associated with self-reported poor chewing status in Japanese adults.

Association between failed eradication of 7-day triple therapy for Helicobacter pylori and untreated dental caries in Japanese adults.

Helicobacter pylori (H. pylori) infection is a cause of gastric disorders and is treated mainly by pharmacotherapy with antimicrobial agents. An association has been reported between dental caries and H. pylori infection. As antimicrobial agents are less effective inside dental caries because of impaired blood circulation, the presence of untreated dental caries (decayed teeth) may influence the success of H. pylori eradication treatment. In this cross-sectional study, we examined whether failed eradication of H. pylori was associated with decayed teeth in Japanese adults. Enrolled were 226 participants who received dental checkups among those treated for eradication of H. pylori at Asahi University Hospital between April 2019 and March 2021. Treatment efficacy was assessed by urea breath test. Eradication failed in 38 participants (17%), decayed teeth in 32 participants (14%), and number of 0.34 teeth per participants. Multivariate logistic regression analyses showed that failed eradication of H. pylori was associated with decayed teeth (presence: odds ratio, 2.672; 95% confidence interval, 1.093-6.531) after adjusting for gender, age, and brushing frequency. These results indicate that failed eradication of H. pylori was associated with decayed teeth and suggest that untreated dental caries may impact treatment for eradication of H. pylori.

Association between dental caries and Helicobacter pylori infection in Japanese adults: A cross-sectional study.

Helicobacter pylori (H. pylori) is widely known as a cause of gastric disorders. Presence of H. pylori in dental pulp has been reported. Dental caries may influence the presence or absence of systemic H. pylori infection by serving as a source of H. pylori. In this cross-sectional study, we examined whether H. pylori infection in blood were associated with dental caries in Japanese adults. The participants were 752 individuals (513 males and 239 females, mean age 53.8 years) who underwent both H. pylori testing (H. pylori antibody test and pepsinogen test) and dental checkups at the Asahi University Hospital Human Health Center between April 2018 and March 2019. Those diagnosed as positive for H. pylori antibody test or positive for serum pepsinogen test as H. pylori test in the human health checkup were judged as those with H. pylori infection in the blood. In our study, 83 participants (11%) were determined to be infected with H. pylori in the blood. The proportion of those with decayed teeth was higher in participants with H. pylori infection in blood than in those without H. pylori infection in blood (p< 0.001). The logistic analysis showed that presence of H. pylori infection in blood was positively associated with those with decayed teeth (OR, 5.656; 95% CI, 3.374 to 9.479) after adjusting for age, gender, gastric disease, regular dental checkups, antibiotic medication history, and decayed teeth. Furthermore, the proportion of H. pylori infection in blood increased according to number of decayed teeth (p< 0.001). The results indicate that H. pylori infection in blood were associated with decayed teeth. Untreated dental caries may have an impact on systemic H. pylori infection.

Relationship between Chewing Status and Fatty Liver Diagnosed by Liver/Spleen Attenuation Ratio: A Cross-Sectional Study.

This cross-sectional study investigated the relationship between chewing status and fatty liver among Japanese adults. Between April 2018 and March 2021, 450 individuals (352 males, 98 females; mean age 54.7 years) were recruited at the Asahi University Hospital Human Health Center. Chewing status was evaluated using a self-reported questionnaire. Liver/spleen (L/S) attenuation ratio < 0.9 on computed tomography was considered to indicate fatty liver, which was present in 69 participants (15%). Compared with participants without fatty liver, those with fatty liver had higher proportion of 25.0 (kg/m2) ≤ body mass index (BMI) (p < 0.001), higher serum hemoglobin A1c (HbA1c) (p < 0.001), higher systolic blood pressure (p < 0.001), higher diastolic blood pressure (p < 0.001), and lower serum high-density lipoprotein cholesterol (HDL cholesterol) (p = 0.011). Significant differences were also found in chewing status (p < 0.001) and eating speed (p = 0.011). Presence of fatty liver was positively associated with BMI (25.0 ≤; odds ratio [OR], 5.048; 95% confidence interval [CI], 2.550−9.992), serum HbA1c (OR, 1.937; 95% CI, 1.280−2.930), and chewing status (poor; OR, 8.912; 95% CI, 4.421−17.966) after adjusting for sex, age, BMI, serum HbA1c, systolic blood pressure, diastolic blood pressure, serum HDL cholesterol, chewing status, and eating speed. Poor chewing status was positively associated with L/S attenuation ratio. These results indicate a positive relationship between poor chewing status and fatty liver diagnosed by L/S attenuation ratio in Japanese adults.

Association between Self-Reported Chewing Status and Glycemic Control in Japanese Adults.

This cross-sectional study investigated the relationship between self-reported chewing status and glycemic control in 30,938 Japanese adults who participated in health checkups. Chewing status was evaluated using a self-reported questionnaire. We defined high hemoglobin A1c (HbA1c) levels as a HbA1c level ≥6.5%; 692 (2.2%) respondents met this criterion. After adjusting for gender, age, smoking status, exercise habits, body mass index and eating speed, high HbA1c levels was found to be associated with male gender (odds ratio (OR), 1.568; 95% confidence interval (CI), 1.310 to 1.878; p < 0.001), older age (OR, 1.077; 95% CI, 1.068 to 1.087; p < 0.001), higher body mass index (OR, 1.246; 95% CI, 1.225 to 1.268; p < 0.001), current smoker status (OR, 1.566; 95% CI, 1.303 to 1.882; p < 0.001) and chewing difficulty (OR, 1.302; 95% CI, 1.065 to 1.591; p < 0.05). In conclusion, self-reported chewing difficulty was associated with high HbA1c levels in Japanese adults.

[Imaging Parameter Optimization of 3D Radial Stack-of-stars MRA with FID Sampling after Treatment of Cerebral Aneurysms with Metallic Devices].

Magnetic resonance angiography (MRA) using ultra-short TE (uTE) is known to be used for the evaluation of cerebral aneurysm after treatment such as clipping and coiling. However, conventional uTE sequences are not appropriate as an additional imaging sequence for 3D time-of-flight (TOF)-MRA because it is not possible to shorten scan time and acquire selective-volume imaging. To solve the problem, we focused on the combination of uTE sampling and 3D radial scan sequences. In this study, we examined the optimal imaging parameters of the proposed uTE-MRA. A simulated blood flow phantom with stents (Enterprise) and titanium clips (YASARGIL) was used for optimizing the TR, flip angle (FA), and radial percentage. The signal intensity in the simulated vessel was measured in each imaging condition, and the ratio of the presence or absence of a stent was evaluated as a relative in-stent signal (RIS). In addition, the diameter of the signal loss of the simulated artery was measured for each imaging condition, and signal loss length (SLL) of a clip was calculated from the average value. The RIS improved with increasing the FA and shortening the TR, but it did not change by changing the radial percentage. The SLL became smaller at the coil as the FA increased, but there was no significant difference between the intersection and the blade. There was also no significant difference between TR and radial percentage. The effective imaging conditions for uTE-MRA to improve the vascular description of the evaluation after treatment of cerebral aneurysms with metallic devices were those with large FA and short TR.

Periodontal Condition Is Correlated with Deep and Subcortical White Matter Hyperintensity Lesions in Japanese Adults.

Deep and subcortical white matter hyperintensity (DSWMH) lesions are a small-vessel disease of the brain. The aim of this cross-sectional study was to investigate the relationship between DSWMH lesions and periodontal status in Japanese adults who participated in a health check. We enrolled 444 consecutive participants (mean age, 54.5 years) who received both brain and oral health evaluation services at the Asahi University Hospital. Magnetic resonance imaging was used to detect DSWMH lesions. Periodontal status was assessed using the community periodontal index. Of the study participants, 215 (48.4%) had DSWMH lesions. Multivariate logistic regression showed that the presence of DSWMH lesions was significantly related to age ≥ 65 years (vs. < 65 years, odds ratio [OR] = 2.984, 95% confidence interval [CI] = 1.696-5.232), systolic blood pressure ≥ 140 mmHg (vs. < 140 mmHg, OR = 2.579, 95% CI = 1.252-5.314), the presence of ≥ 28 teeth (vs. < 28 teeth, OR = 0.635, 95% CI = 0.420-0.961), and probing pocket depth (PPD) ≥ 6 mm (vs. PPD < 6 mm, OR = 1.948, 95% CI = 1.132-3.354) after adjustment for confounding factors. Having PPD ≥ 6 mm may be a risk factor for DSWMH lesions in Japanese adults.

Evaluation of scattered radiation from fluoroscopy using small OSL dosimeters.

Recently, there has been a significant amount of interest in studying the importance of radiation doses to the eye lens during endoscopic retrograde cholangiopancreatography (ERCP). A study that focused on measuring the scattered radiation using an ionization chamber survey meter reported that a lead curtain was useful in reducing the scattered radiation. The over-couch X-ray tube system tends to deliver higher doses to the head and neck of the staff involved in the procedure than the under-couch X-ray tube position. In this study, a small optically stimulated luminescence (OSL) dosimeter called the nanoDot was used to evaluate and measure the amount of radiation; this dosimeter was developed by Landauer Ltd. and was specifically designed for point measurements. There are numerous studies that have reported the usefulness of personal OSL dosimeters other than the nanoDot to measure scattered radiation. Here, we evaluated the amount of scattered radiation, along with the degree of reduction achieved with the use of a protective curtain, while employing a personal OSL dosimeter and nanoDot. When the scattered radiation dose was measured using the nanoDot, the maximum recorded value without a protective curtain was 0.363 mGy and that with a protective curtain was 0.026 mGy, both at the height of 100 cm. The maximum reduction rate of scattered radiation while using a protective curtain was approximately 93% and 97% at 100 cm and 150 cm, respectively. The measured values recorded using both personal OSL dosimeters and nanoDot machine were strongly correlated.

Associations between caries experience, dietary habits, and metabolic syndrome in Japanese adults.

Dental caries could be a risk factor for metabolic syndrome (MetS); however, there is limited evidence of such a relationship in the literature. This cross-sectional study investigated the relationships among dental caries experience, dietary habits, and MetS in Japanese adults. A total of 937 participants aged 40-74 years underwent a health check, including dental examination. Decayed, missing, and filled teeth (DMFT) were used as an index of caries experience. The mean DMFT score was 14, and 12% of the participants had MetS in this study. Multivariate logistic regression analyses showed that the prevalence of MetS was significantly related to DMFT (first vs. fourth quartile, odds ratio [OR] = 1.80; P < 0.05). In addition, the OR of DMFT for MetS was found to be greater in each successively higher DMFT quartile. The prevalence of MetS was significantly related to daily coffee consumption (OR = 0.51, P < 0.01), and the relationship between DMFT and MetS was noted after adjusting for daily coffee consumption. There appears to be a positive association between caries experience and MetS in Japanese adults. This relationship increased with the increase in DMFT regardless of dietary habits.

Investigating the minimum distance between the finger flexor tendons and distal radius during wrist and finger positions in healthy people.

PURPOSE: Rupture of the flexor pollicis longus (FPL) and index flexor digitorum profundus (FDP2) tendons often occurs after locking plate fixation for distal radius fracture. This study aimed to determine the shortest tendon-radius distances of different hand positions. METHODS: Fifty-nine hands of 30 healthy volunteers were studied. Distances between the FPL or FDP2 and distal radius were calculated in six wrist positions: 30° palmar flexion, neutral, 30° dorsiflexion, 60° dorsiflexion, maximum dorsiflexion, and 40° ulnar deviation with three finger positions (full extension and flexion of fingers, full flexion of the thumb or index finger, and full extension of the other four fingers). The shortest distance between the FPL or FDP2 and distal radius was noted. RESULTS: The shortest distance between the FPL and distal radius was during maximum wrist dorsiflexion with isolated thumb flexion. The distance between the FDP2 and distal radius was shortest with all-finger flexion in 30° wrist dorsiflexion. CONCLUSIONS: It is necessary to measure the distance between the FPL and distal radius in maximal wrist dorsiflexion with full flexion of the isolated thumb, as the shortest distance was observed with flexion of the isolated thumb. On the contrary, we recommend measuring the distance between the FDP2 and distal radius in 30° wrist dorsiflexion with flexion of all fingers.

Association between eating behavior and poor glycemic control in Japanese adults.

This study investigated the relationship between eating behavior and poor glycemic control in 5,479 Japanese adults with hemoglobin A1c (HbA1c) <6.5% who participated in health checks. Respondents to a 2013 baseline survey of eating behavior, including skipping breakfast and how quickly they consumed food were followed up until 2017. We defined poor glycemic control after follow-up as HbA1c ≥6.5%, or increases in HbA1c of ≥0.5% and/or being under medication to control diabetes. We identified 109 (2.0%) respondents who met these criteria for poor glycemic control. After adjusting for sex, age, smoking status, body mass index (BMI), and eating behavior, the risk of poor glycemic control was increased in males (odds ratio [OR], 2.38; 95% confidence interval [CI] 1.37-4.12; p < 0.01), and associated with being older (OR, 1.07; 95% CI, 1.04-1.11; p < 0.001), having a higher BMI (OR, 1.29; 95% CI 1.23-1.35; p < 0.001), skipping breakfast ≥3 times/week (OR, 2.44; 95% CI, 1.35-4.41; p < 0.01), and changing from eating slowly or at medium speed to eating quickly (OR, 2.11; 95% CI, 1.04-4.26; p < 0.05). In conclusion, Japanese adults who were male, older, had a high BMI, skipped breakfast ≥3 times/week and ate quickly were at increased risk for poor glycemic control.

Self-reported behavior of eating quickly is correlated with visceral fat area in Japanese non-obese adults.

BACKGROUND AND OBJECTIVES: This cross-sectional study investigated the relationship between eating speed and fat accumulation in Japanese non-obese adults. METHODS AND STUDY DESIGN: In total, 381 non-obese participants aged 35-74 years underwent a health checkup including fat distribution. All participants underwent magnetic resonance imaging to quantify visceral fat area (VFA) and subcutaneous fat area (SFA). Information on eating speed was obtained using a self-administrated questionnaire. RESULTS: The numbers of participants with self-reported behavior of eating slowly, medium, or quickly were 24 (6.3%), 180 (47.2%), and 177 (46.5%), respectively. The prevalence of VFA ≥100 cm2 was higher in the eating quickly group than in the eating slowly (p<0.05) or medium groups (p<0.05). On the other hand, no significant differences in SFA ≥100 cm2 were observed between groups. In addition, multiple stepwise regression analysis showed that eating quickly was positively correlated with VFA (standard ß=0.068, p<0.05), but not with SFA. CONCLUSIONS: Although eating quickly was positively correlated with bigger VFA in Japanese non-obese adults, no associations were found between eating speed and SFA.

Association between Chewing Problems and Sleep among Japanese Adults.

An association between physical illness and sleep has been suggested. Disordered chewing might be a physical factor that is associated with sleep issues. This cross-sectional study aimed to determine whether chewing problems are associated with sleep in Japanese adults. Sleep and chewing issues were evaluated in 6,025 community residents using a self-reported questionnaire. The prevalence of poor sleep quality and sleeping for <6 h/day (short duration) were 15.6% and 29.4%, respectively. Multivariate logistic regression analyses showed that prevalence of poor sleep quality was significantly associated with self-reported medical history (odds ratio (OR), 1.30; p < 0.001), self-reported symptoms (OR, 4.59; p < 0.001), chewing problems (OR, 1.65; p < 0.001), and poor glycemic control (OR, 1.43; p=0.035). The prevalence of short sleep duration was also significantly associated with female sex (OR, 1.23; p=0.001), self-reported symptoms (OR, 1.60; p < 0.001), chewing problems (OR, 1.30; p=0.001), and being overweight (OR, 1.41; p < 0.001). In conclusion, chewing problems were associated with poor sleep quality and short sleep duration among Japanese adults.

Dorsal-approach open reduction for irreducible dislocation of the hallux interphalangeal joint: A case series.

INTRODUCTION: The common treatment for hallux interphalangeal joint dislocation is closed reduction, but some cannot be reduced by interposition of the sesamoid or the plantar plate in the interphalangeal joint, and such cases need open reduction. PRESENTATION OF CASE: In case 1, the patient was a 17-year-old boy who was injured when a motorcycle fell on his right hallux. X-ray revealed Miki type 2 IP joint dislocation. Because closed reduction failed, open reduction via the dorsal approach to the hallux IP joint was performed. In case 2, the patient was a 17-year-old boy who was hit by a car whilst walking. X-ray revealed Miki type 2 dorsal dislocation of the hallux IP joint. After closed reduction, X-ray and CT revealed that the IP joint dislocation changed from Miki type 2 to type 1. Open reduction was performed through the dorsal approach. DISCUSSION: Fifteen cases of Miki type 2 changed to type 1 after closed reduction, and type 1 dislocation is often overlooked, leading to some chronic cases. X-rays should be performed after repositioning, specifically in lateral and oblique views. CONCLUSION: We experienced two cases of irreducible dislocation of the hallux IP joint. One of our cases was reclassified from Miki type 2 to type 1, but we did not overlook the failed closed reduction, as we performed CT. Hence, we recommend additional lateral-view X-rays and/or CT imaging.

Correlation between ultrasound-diagnosed non-alcoholic fatty liver and periodontal condition in a cross-sectional study in Japan.

This cross-sectional study investigated the relationship between periodontal condition and ultrasound-diagnosed non-alcoholic fatty liver disease (NAFLD) in a Japanese oral health check population. A total of 1226 consecutive participant were enrolled in the study. Abdominal ultrasonography was applied to diagnose NAFLD. Of the study participants, 339 (27.7%) had ultrasonography-diagnosed NAFLD. The participants with NAFLD had a significantly higher prevalence of probing pocket depth (PPD) ≥ 4 mm (86.7%) than those without NAFLD (72.9%) (p < 0.05). After adjusting for gender, age, Brinkman index, regular exercise habits, body mass index, number of teeth present, presence of periodontitis, blood pressure, and serum parameters, there was a statistically significant difference in the adjusted odds ratios of having PPD ≥ 4 mm for NAFLD (Odds ratio = 1.881, 95% confidence interval 1.184-2.987, p < 0.01). Having PPD ≥ 4 mm may be a risk factor for ultrasound-diagnosed NAFLD in this cross-sectional study of a Japanese oral health check population.

How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.

A case report of an isolated fracture through the radial bicipital tuberosity.

INTRODUCTION: Generally, anatomical reduction of shaft fractures through operative treatment is necessary to restore the anatomical relationship of the forearm bones. However, a number of nerves and vessels are located in the proximal radius, which complicates surgery. In this study, we aimed to reduce postoperative complications by using a posterior approach. PRESENTATION OF CASE: We describe an isolated fracture through the radial bicipital tuberosity in a 69-year-old man caused by direct blunt force and our management of the fracture. The patient underwent an operation for the fracture under brachial plexus block. The injury was explored using the posterior approach, and plate fixation was performed after confirming the absence of obstacles to rotation on pronation and supination. One year later, the patient did not have any difficulties in activities of daily living. DISCUSSION: Since an isolated fracture through the radial bicipital tuberosity is more distal than the radial head and neck and more proximal than a common radius diaphysis fracture, we had to consider a different operative approach. The nerve and blood vessels of the forearm, such as the radial nerve and artery, run in a complicated fashion around the proximal radius; thus, we chose the posterior approach because of its simpler surgical technique and lower complication risk, compared with the anterior approach. CONCLUSION: Surgeons can obtain a favorable treatment result using the posterior approach to the fracture and reduce complications by ensuring with rigid fixation using a locking plate.

Edaravone and its clinical development for amyotrophic lateral sclerosis.

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

Structural and mechanistic studies of the base-induced Sommelet-Hauser rearrangement of N-α-branched benzylic azetidine-2-carboxylic acid-derived ammonium salts.

The base-induced Sommelet-Hauser rearrangement of N-α-branched benzylic azetidine-2-carboxylic acid ester-derived ammonium salts to obtain α-arylazetidine-2-carboxylic acid esters was investigated. The substrates, two diastereomeric salts (1S,2S,1'S)- and (1R,2R,1'S)-2, showed different reactivities. The rearrangement of (1S,2S,1'S)-2a proceeded with a perfect N-to-C chirality transfer to provide (R)-3a in 74% yield with 99% ee. However, the rearrangement of (1R,2R,1'S)-2a under the same conditions afforded (S)-3a in only 15% yield with a lower 66% ee, along with the competitive [1,2] Stevens rearrangement product 4a. Structural and mechanistic studies of this rearrangement were carried out to clarify the exact reason. Our results define the scope and limitations of the Sommelet-Hauser rearrangement and provide unique synthetic access to α-aryl amino acid derivatives.

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3ß inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.