Development of a Reverse-Yield Factor Database Disaggregating Japanese Composite Foods into Raw Primary Commodity Ingredients Based on the Standard Tables of Food Composition in Japan.

The reverse-yield factor (RF) database was developed for qualitatively and quantitatively disaggregating Japanese composite foods into raw primary commodity (RPC) ingredients. Representative equations for four types (dried, salted, fermented and mixed foods) were developed to calculate RFs using the food content and composition data for composite foods listed in the Standard Tables of Food Composition in Japan-2020-(STFCJ), published by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Out of 1150 composite foods identified in the STFCJ, RFs for 54 dried, 41 salted, 40 fermented and 818 mixed foods were obtained. RFs for 197 mixed foods could not be calculated because these foods were produced from ingredients with no specified information and/or through complex processing. The content and composition of Japanese composite foods would be interpreted representatively by RFs in the developed database.

How can we promote vaccination of the mass population?-Lessons from the COVID-19 vaccination defaults.

While vaccines are pivotal in combating COVID-19, concerns about side effects and complex procedures have hindered complete vaccination. Prior studies suggest that individuals defaulted to opt-out exhibit higher COVID-19 vaccination rates compared to those in opt-in systems. However, these studies were conducted in countries with a tolerant attitude towards vaccination and default changes, targeting specific age groups, and did not address potential deterrents like the increase in cancellation rates on the day, discomfort towards changing defaults, or the possibility of the opt-out effect being a one-time occurrence. Under the hypothesis that the default nature of the COVID-19 vaccination system influences attitudes towards vaccination even in countries conservative about vaccination and default changes like in Japan, we aimed to examine the differences in the first and second dose vaccination rates, cancellation rates, and the number of complaints between the opt-in and opt-out systems for COVID-19 vaccination. An email survey was conducted in 10 cities in A Prefecture, Japan. The results showed not only higher COVID-19 vaccination rates across all comparable age groups in the opt-out group but also a notably smaller decrease in the second-dose vaccination rate compared to the opt-in group, all achieved without any complaints about the system's introduction. Consequently, it can be inferred that the potential inhibiting factors were largely overcome. Despite some limitations, such as regional specificity, the study suggests that opt-out systems might increase COVID-19 vaccination coverage without leading to significant cancellations or complaints, presenting a promising strategy to facilitate vaccination efforts.

The vision for public health dietitians' skill improvement over the next 10 years in Japan: A qualitative study.

Objectives: To obtain the basis for developing a new human resource development program. We examined the association between their position type and their vision for skill improvement in the profession in the next 10 years. Study design: This was a qualitative study. Methods: In 2021, we conducted an exhaustive survey of Japanese public health dietitians working in Japanese local governments. Using qualitative content analysis, we analyzed the participants' descriptions of how the profession could improve their skills over the next 10 years. Results: Regardless of the participants' organization of employment or their target position type, seven common categories were extracted; [goals], [health promotion activities], [organizational activities], [evaluation from others], [cooperation], [skills to be acquired], and [means for improving skills]. Depending on the organization type, 35-40 subcategories were extracted from those who wanted to be staff, 35-38 subcategories from those who wanted to be supervisors, and 20-37 subcategories from those who wanted to be managers. Different subcategories were extracted to describe the difference between specialists and generalists in [goals]. Participants described challenges with [evaluation from others] and [collaboration], regardless of the target position type or [goals]. Conclusion: The vision for Japanese public health dietitians' skill improvement to achieve in the next 10 years describes challenges with business evaluation and collaborative work. However, participants differed across what skills they wanted to improve based on the direction of their careers. To offer public health dietitians learning content that connects with their desired direction, a new human resource development program needs to be considered.

Individual Learning Needs of Japanese Public Health Dietitians by Years of Experience in Health Promotion.

Lifelong education for dietitians in Japan is based mainly on competencies according to years of experience. Because learning content differs depending on the desired position and specialty, training programs that reflect the individual learning needs of public health dietitians are needed. This study aimed to assess the individual learning needs of public health dietitians via years of experience in health promotion. In 2021, an online survey of public health dietitians involved in health promotion in prefectures, designated cities, and other municipalities throughout Japan was conducted. Years of experience in health promotion were categorized as early (<10 years), mid-career (10-19 years), and leadership (≥20 years) periods. To ascertain individual learning needs, the survey asked about respondents' desired final position, career path, and skills they felt they needed to improve in the future. Of the 1649 public health dietitians analyzed, all administrative categories preferred to work as public health generalists in mid-career or leadership periods rather than in the early period. In municipalities, more public health dietitians across all experience categories selected "professional competence", such as knowledge in specialized areas and nutritional guidance techniques. It was suggested that public health dietitians in the mid-career and leadership periods have individual learning needs, in both nutrition specialists and public health generalists.

Online training of Covid-19 infection prevention and control for healthcare workers in psychiatric institutes.

BACKGROUND: This study aimed to develop a unique online infection prevention and control (IPC) training on Covid-19 for healthcare workers in psychiatric institutes in Japan and to examine its efficacy based on its impact on the knowledge, attitude, and confidence about IPC for Covid-19 among the healthcare workers. METHOD: This quasi-experimental study was conducted using online training on Covid-19 IPC for healthcare workers in various psychiatric institutes from April 2021 to March 2022. An online training video on Covid-19 IPC was developed. Voluntary healthcare workers in psychiatric institutes located in five prefectures in Japan were recruited to participate in this training. The participants then completed 30 min of online training and surveys about knowledge, attitude, and confidence were conducted pre, post, and three months after the training. The video training and surveys were contextually validated by the experts, but not by any previous study. RESULTS: A total of 224 participants were included, of which 108 (54.0%) were men. The mean (standard deviation (SD)) age and the mean occupational experience were 47.4 (9.5) and 18.0 (12.6) years, respectively. Among the participants, 190 (84.8%) completed the post-training, and 131 (58.5%) completed the three-month-later training surveys. The total score on the quizzes in the post-training (+ 31.1%, SD 15.7, p-value < 0.01) and three-month-later training (+ 14.9%, SD 16.8, p-value < 0.01) surveys had significantly increased from that in the pre-training survey. In contrast, the total score in the three-month-later training had significantly decreased from that in the post-training survey (-16.1%, SD 16.7, p-value < 0.01). CONCLUSION: Thirty minutes of online training about IPC for Covid-19 had improved knowledge, confidence, and attitude among psychiatric healthcare workers. Regular online training would help in preventing the transmission or formation of clusters of Covid-19 in psychiatric healthcare institutes.

The Impact of KRAS Status on the Required Surgical Margin Width for Colorectal Liver Metastasis Resection.

Local recurrence after colorectal liver metastasis (CRLM) resection severely affects survival; however, the required surgical margin width remains controversial. This study investigated the impact of KRAS status on surgical margin width and local recurrence rate (LRR) post-CRLM resection. Overall, 146 resected CRLMs with KRAS status (wild-type KRAS (wtKRAS): 98, KRAS mutant (mKRAS): 48) were included. The LRR for each group, R1 (margin positive) and R0 (margin negative), was analyzed by KRAS status. R0 was further stratified into Ra (margin ≥ 5 mm) and Rb (margin < 5 mm). Patients with local recurrence had significantly worse 5-year overall survival than those without local recurrence (p = 0.0036). The mKRAS LRR was significantly higher than wtKRAS LRR (p = 0.0145). R1 resection resulted in significantly higher LRRs than R0 resection for both wtKRAS and mKRAS (p = 0.0068 and p = 0.0204, respectively), and while no significant difference was observed in the Ra and Rb LRR with wtKRAS, the Rb LRR with mKRAS (33.3%) was significantly higher than Ra LRR (5.9%) (p = 0.0289). Thus, R0 resection is sufficient for CRLM with wtKRAS; however, CRLM with mKRAS requires resection with a margin of at least 5 mm to prevent local recurrence.

Validation of the most cost-effective nudge to promote workers' regular self-weighing: a cluster randomized controlled trial.

Regular self-weighing is useful in obesity prevention. The impact of nudge-based occupational self-weighing programs in the cluster randomized controlled trial was examined. The primary outcome was regular self-weighing after 6 months, which we used to compute cost-effectiveness. Participants were Japanese local government employees who underwent 1 h workshops after being assigned to one of the three nudge groups. Each group was designed according to the nudges' Easy, Attractive, Social, Timely framework: quiz group (n = 26, attractive-type nudges), implementation intentions group (n = 25, social-type nudges), and growth mindset group (n = 25, timely type nudges). A reference group (n = 36, no nudges) was also formed. After 6 months, all three interventions were effective for regular self-weighing, with the growth mindset intervention (60.0%) being significantly more effective. The cost-effectiveness of the growth mindset group was 1.7 times and 1.3 times higher than that of the quiz group and the implementation intentions group, respectively. Findings from our study are expected to facilitate the use of nudges for health practitioners and employers, which in turn may promote obesity prevention.

A Food Consumption-Based Diet Quality Score and Its Correlation With Nutrient Intake Adequacy Among Japanese Children.

OBJECTIVE: Diet quality indices reflect overall dietary patterns better than single nutrients or food groups. Focusing on the needs of children, this study developed a measure of adherence to the Japanese Food Guide Spinning Top (JFGST), which was developed by the Ministry of Health, Labour and Welfare and Ministry of Agriculture, Forestry and Fisheries, Japan, and determined the correlation between index scores and nutrient intake. RESEARCH METHODS AND PROCEDURES: This cross-sectional study was conducted among 48 children between six and nine years of age from a coastal town in the Kinki region of Japan. Data were collected between August 2012 and March 2013, including the 12-day diet records (three days over four seasons) of each participant. For children, adherence to the JFGST entails the consumption of five core food groups, including grain, fish and meat, vegetables, milk, and fruits (total possible score of 50). Spearman's correlation coefficients were calculated to identify any correlations between JFGST scores and nutrient intake. RESULTS: The mean participant JFGST score was 25 ± 10. Higher JFGST scores were correlated with higher intake of monounsaturated fatty acids, n-6 polyunsaturated fatty acids, dietary fiber, potassium, calcium, magnesium, phosphorus, zinc, copper, vitamin A, vitamin D, riboflavin, pantothenate, and vitamin C. JFGST scores were also positively correlated with nutrient adequacy for calcium, magnesium, iron, zinc, copper, vitamin A, thiamine, riboflavin, vitamin B6, vitamin B12, folate, and vitamin C. CONCLUSION: The index employed in this study may adequately express diet quality among Japanese children.

Association between Parent and Child Dietary Sodium and Potassium Intakes: Aomori Prefectural Health and Nutrition Survey, 2016.

This study investigated the association between parent and child sodium and potassium intakes using data from the 2016 Aomori Prefectural Health and Nutrition Survey. We analyzed one day dietary record data of 103 mothers, 94 fathers, 51 children aged 1-3 years, 39 children aged 4-6 years, 91 children aged 7-14 years, and 56 children aged 15-19 years. We also examined the association of sodium and potassium intake between co-habiting grandparents and their grandchildren. After adjusting for covariates, the total daily sodium intake in mothers was positively associated with that in children for every age group. Potassium intakes by the mothers during breakfast and dinner were positively associated with those in children aged 1-3, 4-6, and 7-14 years. The associations in sodium and potassium intakes between fathers and children were weaker. In addition, these associations were similar to those between the sodium intakes of grandchildren and their grandparents. The association between mother and child sodium and potassium intakes at breakfast and dinner was related to the consumption of similar foods, which suggests the importance of home environment in influencing total dietary sodium and potassium intake in Japanese people.

Familial pulmonary thromboembolism with a prothrombin mutation and antithrombin resistance.

We describe the case of a 45-year-old man with congenital thrombophilia induced by antithrombin resistance. He had recurrent venous thrombosis without traditional risk factors or abnormal coagulation function and had a family history of venous thrombosis which included his mother, brother, and nephew. We suspected the association of hereditary antithrombin resistance, which has been reported in some cases of familial venous thromboses due to prothrombin mutations. Although prothrombin abnormality typically shows a bleeding tendency, variations of arginine at position 596 in the gene encoding prothrombin have been reported to conversely cause thrombosis. Therefore, we tested and detected antithrombin resistance in the patient's plasma. We also performed genetic analysis for his second filial generation, and found a missense mutation (c.1787G>A), resulting in a substitution of arginine for glutamine at position 596 (p.Arg596Gln) in the gene encoding prothrombin (called prothrombin Belgrade). The Gln596 substitution caused the susceptibility to thrombosis. This variation is the same as one previously reported in Serbia and India, and it is the third report in Japan. .

Overall nutrient and total fat intake among Japanese people: The INTERLIPID Study Japan.

BACKGROUND AND OBJECTIVES: Total fat intake is linked to the intake of other nutrients. Little data are available on the extent to which total fat affects diet quality in Japanese people. We investigated the relationship between total fat intake and other nutrient intake using INTERLIPID/ INTERMAP data on Japanese people living in Japan. METHODS AND STUDY DESIGN: The participants included 371 men and 401 women with a healthy body mass index and between the ages of 40 and 59 from 4 population samples in Japan. Nutrient intake data were based on four in-depth 24-hour dietary recalls per person. RESULTS: Analysis of covariance adjusted for age revealed that total fat intake was positively related to intakes of calcium, thiamine, riboflavin, meat, eggs, and milks and dairy products for both sexes. Total fat intake was inversely associated with carbohydrate and cereals intake for both sexes. On average, men with total fat intake between 25.0 and 27.4% of total energy had saturated fatty acids above 7%, which is the upper limit recommended for preventing lifestyle-related diseases. Men with total fat intake less than 20% of total energy had a higher risk of not meeting the Dietary Reference Intakes for Japanese (2015) for some nutrients. CONCLUSIONS: Total fat intake was positively associated with calcium, thiamine, and riboflavin intakes and inversely associated with carbohydrate intake. Our results suggest that in 40-59-year-old men with a healthy body mass index, total fat intake between 20 and 27% of total energy may best support adequate intake of other nutrients.

Relationship of Consumption of Meals Including Grain, Fish and Meat, and Vegetable Dishes to the Prevention of Nutrient Deficiency: The INTERMAP Toyama Study.

A Japanese-style diet consists of meals that include grain (shushoku), fish and meat (shusai), and vegetable dishes (fukusai). Little is known about the association of such meals (designated well-balanced meals hereafter) with nutrient intake. We therefore examined the frequency of well-balanced meals required to prevent nutrient deficiency. Participants were Japanese people, ages 40 to 59 y, from Toyama, recruited for INTERMAP, in an international population-based study. Each person provided 4 in-depth 24-h dietary recalls (149 men, 150 women). The prevalence of risk ratios of not meeting the Dietary Reference Intakes for Japanese (2015) was calculated. Well-balanced diets were assessed by the Japanese Food Guide Spinning Top. We counted the frequencies of meals in which participants consumed 1.0 or more servings of all 3 dishes categories. We divided the frequency of consumption of well-balanced meals into the following 4 groups: <1.00 time/d, 1.00-1.49 times/d, 1.50-1.74 times/d, and ≥1.75 times/d. Compared with participants in the highest frequency group for well-balanced meals, those who consumed well-balanced meals less than once a day had a higher risk of not meeting the adequate intake for potassium and the recommended dietary allowance for vitamin A. Those who consumed well-balanced meals on average less than 1.50 times per day had a higher risk of not meeting the recommended dietary allowance for calcium and vitamin C. Our results suggest that individuals should on average consume well-balanced meals more than 1.5 times per day to prevent calcium and vitamin C deficiencies.

Impact of alcohol intake on the relationships of uric acid with blood pressure and cardiac hypertrophy in essential hypertension.

BACKGROUND: Hyperuricemia, which is frequently associated with hypertension, can be caused by alcohol intake. To date, limited data have shown the link between alcohol intake and hyperuricemic hypertension. METHODS: We retrospectively examined the influence of alcohol intake on the relationship between the uric acid level and blood pressure or cardio-metabolic parameters in 171 untreated non-failing hypertensive patients (mean 59.3±10.7 years). Cross-sectional analysis was separately performed in regular alcohol drinkers (more than 25g/day ethanol, n=74, 82.4% men) and non-drinkers (n=97, 33.0% men). RESULTS: Diastolic blood pressure was significantly higher in drinkers than in non-drinkers (101.6±11.5mmHg vs. 96.8±8.2mmHg, p<0.01). Estimated glomerular filtration rate (80.4±14.7mL/min/1.73m2 vs. 80.0±17.8mL/min/1.73m2) and body mass index (BMI, 24.7±4.4kg/m2 vs. 24.8±4.2kg/m2) were similar in the two groups. In the drinker group, the uric acid level (mean 6.3±1.7mg/dL) was positively correlated with both systolic and diastolic blood pressures (r=0.270/p=0.020 and r=0.354/p=0.0020, respectively), and with the markers of cardiac hypertrophy, including electrocardiographic voltage (V1S+V5R, r=0.244/p=0.042) and echocardiographic left ventricular mass index (r=0.270/p=0.026). These correlations were also observed in the male drinker sub-group. In the non-drinkers, the uric acid level (mean 5.0±1.4mg/dL) was positively correlated with BMI (r=0.369/p=0.0002) but not with blood pressure or the markers of cardiac hypertrophy. CONCLUSIONS: The results suggest that the role of uric acid in blood pressure might differ between hypertensive drinkers and non-drinkers. In regular alcohol drinkers, there was a positive association of uric acid level with blood pressure and the severity of cardiac hypertrophy. In non-regular drinkers, an increased uric acid level is likely to be closely associated with increased BMI.

EphrinA/EphA signal facilitates insulin-like growth factor-I-induced myogenic differentiation through suppression of the Ras/extracellular signal-regulated kinase 1/2 cascade in myoblast cell lines.

Insulin-like growth factor-I (IGF-I) activates not only the phosphatidylinositol 3-kinase (PI3K)-AKT cascade that is essential for myogenic differentiation but also the extracellular signal-regulated kinase (ERK) 1/2 cascade that inhibits myogenesis. We hypothesized that there must be a signal that inhibits ERK1/2 upon cell-cell contact required for skeletal myogenesis. Cell-cell contact-induced engagement of ephrin ligands and Eph receptors leads to downregulation of the Ras-ERK1/2 pathway through p120 Ras GTPase-activating protein (p120RasGAP). We therefore investigated the significance of the ephrin/Eph signal in IGF-I-induced myogenesis. EphrinA1-Fc suppressed IGF-I-induced activation of Ras and ERK1/2, but not that of AKT, in C2C12 myoblasts, whereas ephrinB1-Fc affected neither ERK1/2 nor AKT activated by IGF-I. IGF-I-dependent myogenic differentiation of C2C12 myoblasts was potentiated by ephrinA1-Fc. In p120RasGAP-depleted cells, ephrinA1-Fc failed to suppress the Ras-ERK1/2 cascade by IGF-I and to promote IGF-I-mediated myogenesis. EphrinA1-Fc did not promote IGF-I-dependent myogenesis when the ERK1/2 was constitutively activated. Furthermore, a dominant-negative EphA receptor blunted IGF-I-induced myogenesis in C2C12 and L6 myoblasts. However, the inhibition of IGF-I-mediated myogenesis by down-regulation of ephrinA/EphA signal was canceled by inactivation of the ERK1/2 pathway. Collectively, these findings demonstrate that the ephrinA/EphA signal facilitates IGF-I-induced myogenesis by suppressing the Ras-ERK1/2 cascade through p120RasGAP in myoblast cell lines.

Interaction of scaffolding adaptor protein Gab1 with tyrosine phosphatase SHP2 negatively regulates IGF-I-dependent myogenic differentiation via the ERK1/2 signaling pathway.

Grb2-associated binder 1 (Gab1) coordinates various receptor tyrosine kinase signaling pathways. Although skeletal muscle differentiation is regulated by some growth factors, it remains elusive whether Gab1 coordinates myogenic signals. Here, we examined the molecular mechanism of insulin-like growth factor-I (IGF-I)-mediated myogenic differentiation, focusing on Gab1 and its downstream signaling. Gab1 underwent tyrosine phosphorylation and subsequent complex formation with protein-tyrosine phosphatase SHP2 upon IGF-I stimulation in C2C12 myoblasts. On the other hand, Gab1 constitutively associated with phosphatidylinositol 3-kinase regulatory subunit p85. To delineate the role of Gab1 in IGF-I-dependent signaling, we examined the effect of adenovirus-mediated forced expression of wild-type Gab1 (Gab1(WT)), mutated Gab1 that is unable to bind SHP2 (Gab1(DeltaSHP2)), or mutated Gab1 that is unable to bind p85 (Gab1(Deltap85)), on the differentiation of C2C12 myoblasts. IGF-I-induced myogenic differentiation was enhanced in myoblasts overexpressing Gab1(DeltaSHP2), but inhibited in those overexpressing either Gab1(WT) or Gab1(Deltap85). Conversely, IGF-I-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation was significantly repressed in myoblasts overexpressing Gab1(DeltaSHP2) but enhanced in those overexpressing either Gab1(WT) or Gab1(Deltap85). Furthermore, small interference RNA-mediated Gab1 knockdown enhanced myogenic differentiation. Overexpression of catalytic-inactive SHP2 modulated IGF-I-induced myogenic differentiation and ERK1/2 activation similarly to that of Gab1(DeltaSHP2), suggesting that Gab1-SHP2 complex inhibits IGF-I-dependent myogenesis through ERK1/2. Consistently, the blockade of ERK1/2 pathway reversed the inhibitory effect of Gab1(WT) overexpression on myogenic differentiation, and constitutive activation of the ERK1/2 pathway suppressed the enhanced myogenic differentiation by overexpression of Gab1(DeltaSHP2). Collectively, these data suggest that the Gab1-SHP2-ERK1/2 signaling pathway comprises an inhibitory axis for IGF-I-dependent myogenic differentiation.

Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling.

Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1beta (NRG-1beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1beta/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1beta induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1beta upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1beta/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.

Effect of probe arrangement on reproducibility of images by near-infrared topography evaluated by a virtual head phantom.

The effect of the probe arrangement on the reproducibility of topographic images of the concentration changes in oxygenated hemoglobin and deoxygenated hemoglobin is evaluated by a virtual head phantom. A virtual head phantom consists of five types of tissue the 3D structure of which is based on a magnetic resonance imaging scan of an adult head. Localized and broadened brain activation is assumed in a virtual head phantom. The topographic images are obtained from the reflectance detected by the standard probe arrangement and the double-density probe arrangement. The uneven thickness of the superficial layer, which cannot be evaluated by the previous slab model, affects the distribution of measured activation in the topographic image, and this reduces the position reproducibility of near-infrared (NIR) topography with the standard probe arrangement. The overlapping measurements by the double-density probe arrangement can improve the reproducibility of the image obtained by NIR topography.

MDR1 T-129C polymorphism can be predictive of differentiation, and thereby prognosis of colorectal adenocarcinomas in Japanese.

The expression level of MDR1 mRNA was evaluated in colorectal adenocarcinomas and adjacent noncancerous colorectal tissues obtained from 21 Japanese patients. It was lower in the former than in the latter (p=0.012), suggesting its down-regulation as a consequence of malignant transformation of colorectal tissues, possibly with the suppression of differentiation. Relatively lower expression was suggested in moderately-differentiated colorectal adenocarcinomas than well-differentiated ones, but there was no statistical difference (p=0.111). MDR1 mRNA up-regulation was found in a colorectal adenocarcinoma cell line, HCT-15, after treatment with two typical differentiating agents, sodium butyrate and all-trans retinoic acid, suggesting its involvement in the cellular events, resulting in differentiation without malignant transformation. MDR1 T-129C, but not G2677A,T and C3435T, was associated with the lower expression of MDR1 mRNA both in colorectal adenocarcinomas (p=0.040) and adjacent noncancerous colorectal tissues (p=0.023), possibly being an useful invasive marker predicting poorly-differentiated colorectal adenocarcinomas and thereby the poor prognosis of the patients, especially when no extra biopsy samples will be obtained. Further investigations with relatively large number of patients should be undertaken to confirm these preliminary results.

MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer.

The genotype frequencies of MDR1 T-129C, C1236T, G2677A,T and C3435T SNPs were compared in 154 healthy Japanese and 100 healthy Caucasians to provide basic information on the inter-ethnic differences of pharmacotherapeutic outcome. The variants were found at allelic frequencies of 5.5%, 65.6%, 16.6%, 40.6% and 40.6%, for T-129C, C1236T, G2677A, G2677T and C3435T, respectively, in Japanese, and at 5.1%, 45.9%, 3.6%, 46.4% and 56.6%, respectively, in Caucasians, with a statistically significant difference for C1236T, G2677A,T and C3435T (p<0.001). G2677A was about 5-fold more frequent in Japanese than Caucasians. These genotype frequencies were also investigated in 95 Japanese patients with colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC), but no significant difference was detected, when compared with healthy Japanese subjects. The haplotype frequency reached a total of about 85% in Japanese with the following 4 major haplotypes; T(-129)-T1236-T2677-T3435 (36.1%), T(-129)-T1236-G2677-C3435 (22.5%), T(-129)-C1236-G2677-C3435 (14.2%) and T(-129)-C1236-A2677-C3435 (13.3%). The second and fourth haplotypes were hardly inferred in Caucasian, whereas T(-129)-C1236-G2677-T3435 (12.8%) was found to be Caucasian-specific. There was a tendency for higher frequencies of the T(-129)/C-(129)-C1236-A2677-C3435 haplotype in Japanese CRC patients and T(-129)-T1236-T2677-T3435 haplotype in Japanese ESCC patients, compared with that in healthy Japanese subjects.

Cardiac ischemia activates vascular endothelial cadherin promoter in both preexisting vascular cells and bone marrow cells involved in neovascularization.

Vascular endothelial cadherin (VE-cadherin) is expressed on vascular endothelial cells, which are involved in developmental vessel formation. However, it remains elusive how VE-cadherin-expressing cells function in postnatal neovascularization. To trace VE-cadherin-expressing cells, we developed mice expressing either green fluorescent protein or LacZ driven by VE-cadherin promoter using Cre-loxP system. Although VE-cadherin promoter is less active after birth than during embryogenesis in blood vessels, it is reactivated on cardiac ischemia. Both types of reporter-positive cells are found in the vasculature and in the infarcted myocardium. Those found in the vasculature were pre-existing endothelial cells and incorporated endothelial progenitor cells derived from extracardiac tissue. In addition to the vasculature, VE-cadherin promoter-activated cells were positive for CD45 in the bone marrow cells of the infarcted mice. VE-cadherin promoter-reactivated CD45-positive leukocytes were also found in the infarcted area. In addition, VE-cadherin promoter was activated in the bone marrow vessels of the infarcted mice. Collectively, our findings reveal a new ischemia-induced neovascularization mechanism involving VE-cadherin; the re-expressed VE-cadherin-mediated cell adhesion between cells may be involved not only in homing of bone marrow-derived cells to ischemic area but also mobilization from bone marrow.