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Background\\nUltrasonic gray-scale median (GSM) of the carotid wall reflects its composition and low-GSM carotid plaque is considered to be vulnerable. This study aimed to evaluate the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes mellitus (T2DM).\\n\\nMethods\\nThis is a post hoc sub-analysis using data obtained from the SPIKE trial, a randomized controlled trial that demonstrated the beneficial effect of sitagliptin on the progression of carotid intima-media thickness in patients with T2DM. A total of 274 T2DM patients with no past history of apparent cardiovascular disease (137 in the sitagliptin treatment group and 137 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA during the 104-week treatment period.\\n\\nResults\\nThe mean GSM-CCA significantly increased in the sitagliptin treatment group (adjusted ΔGSM = 2.40 ± 1.19 [mean ± SE], p = 0.044) but not in the conventional treatment group (adjusted ΔGSM = 1.32 ± 1.19, p = 0.27). However, there was no significant difference in changes in mean GSM-CCA between the treatment groups.\\n\\nConclusions\\nA post hoc sub-analysis suggests that the tissue characteristics of the carotid arterial wall were improved in the sitagliptin treatment group during the 104-week treatment period, but not in the conventional treatment group. However, there was no between-group difference in the changes of GSM values between the two treatment groups. Prespecified studies with large sample sizes would be necessary to confirm our findings.

Although many studies have shown that carotid intima-media thickness (IMT) is associated with coronary artery disease (CAD), it remains inconclusive whether assessment of carotid IMT is useful as a screening test for asymptomatic but severe CAD in diabetic patients. A total of 333 asymptomatic type 2 diabetic patients without history of CAD underwent exercise electrocardiogram or myocardial perfusion scintigraphy for detection of silent myocardial ischemia, and those whose test results were positive were subjected to coronary computed tomography angiography or coronary angiography. The ability of carotid IMT to identify severe CAD corresponding to treatment with revascularization was examined by receiver-operating characteristic (ROC) curve analyses. Among the 333 subjects, 17 were treated with revascularization. A multiple logistic regression analysis showed that maximum IMT was an independent predictor of severe CAD even after adjustment for conventional risk factors. ROC curve analyses revealed that the addition of maximum IMT to conventional risk factors significantly improved the prediction ability for severe CAD (from area under the curve, 0.67 to 0.79; P = 0.039). The greatest sensitivity and specificity were obtained when the cut-off value of maximum IMT was set at 2.45 mm (pretest probability, 5%; posttest probability, 11%; sensitivity, 71%). When we applied age-specific cut-off values, the sensitivity of screening further increased in both the nonelderly (pretest probability, 6%; posttest probability, 10%; sensitivity, 100%) and the elderly subjects (pretest probability, 5%; posttest probability, 15%; sensitivity, 100%). Our study suggests that carotid maximum IMT is useful for screening asymptomatic type 2 diabetic patients with severe CAD equivalent to revascularization.

Introduction\\nUltrasonic tissue characterization of the carotid wall using gray-scale median (GSM) reflects its composition and low-GSM plaque is considered to be unstable. The present study evaluated the effect of alogliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes (T2DM).\\n\\nMethods\\nThis is a post hoc subanalysis using data obtained from the SPEAD-A trial, a randomized controlled trial that demonstrated the beneficial effect of alogliptin treatment on the progression of carotid intima-media thickness in patients with T2DM with no past history of apparent cardiovascular disease. A total of 322 subjects (161 in the alogliptin treatment group and 161 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA (common carotid artery) during the 104-week observation period.\\n\\nResults\\nBoth alogliptin treatment and conventional treatment significantly increased the mean GSM-CCA (from 60.7 ± 12.3 to 65.9 ± 10.1, p < 0.001 and 58.8 ± 14.4–65.2 ± 12.2, p < 0.001, respectively) and there was no significant difference in changes in mean GSM-CCA between the treatment groups (p = 0.95). Additionally, there were no differences in the changes in the left and right GSM-CCA between the groups.\\n\\nConclusions\\nA post hoc subanalysis revealed an improvement of tissue characteristics in the carotid arterial wall in both the alogliptin treatment group and the conventional treatment group during the 104-week treatment period and that there was no significant difference between the treatment groups.

Little is known about the related factors of plaque echogenicity in diabetic subjects. This was a single-center, retrospective, study investigating a subgroup of patients of a previously published trial. We enrolled 179 middle-aged and older Japanese type 2 diabetic patients with carotid plaque, and examined the parameters related with echogenicity of carotid plaque evaluated by gray-scale median (GSM). Proportion of males and body mass index (BMI) were significantly higher and HDL-cholesterol was significantly lower in the patients with low GSM (<48) plaques (n=89) as compared to those without it (n=90). A multiple logistic regression analysis with gender, BMI, and HDL-cholesterol as independent variables and the presence of low GSM plaques as an objective variable showed that male (odds ratio (OR) 2.36, 95%CI 1.05–5.31, p=0.037) and BMI (OR 1.12 [1.01–1.24], p=0.029) were independently associated with low GSM plaques. Another multiple logistic regression analysis with gender, BMI, and low-HDL–cholesterolemia (HDL-C <40mg/dl) as independent variables showed that low-HDL–cholesterolemia (OR 2.30 [1.03–5.13], p=0.042) and BMI (OR 1.11 [1.00–1.22], p=0.046) were independently associated with low GSM plaques. Our study suggests that gender, BMI and low-HDL-cholesterol are important determinants of the content of the vascular wall in diabetic subjects.

The aim of this study is to evaluate whether noninvasive ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future cardiovascular events (CVE) in asymptomatic type 2 diabetic patients. We prospectively evaluated the association between Calibrated-IBS value, an ultrasonic marker for tissue characteristics of carotid plaque, and CVE in 85 asymptomatic type 2 diabetic patients with carotid plaque. The median follow-up period was 7.9 years, and there were 20 new CVE. The risk of CVE was significantly higher in the subjects with low Calibrated-IBS values (<-17.1 dB; n = 42) as compared with those with high values (≥-17.1 dB; n = 43) (P = 0.004, log-rank test). Cox proportional hazards regression analysis revealed that both Calibrated-IBS value (hazard ratio [HR] 0.802 [95% CI 0.710-0.906]; P < 0.0001) and plaque thickness (1.938 [1.170-3.213]; P = 0.010) were independently associated with CVE, even after adjustment for the 10-year risk for a general cardiovascular disease estimated by Framingham risk scoring (FRS). Time-dependent receiver operating characteristic curve analysis for CVE at 10 years after the baseline examinations revealed that area under the curve for Calibrated-IBS was 0.76 (0.60-0.90) and substantially higher than those for plaque thickness (0.60 [0.45-0.79]) and FRS (0.60 [0.40-0.78]). These analyses also revealed that the addition of both plaque thickness and Calibrated-IBS value to conventional risk factors significantly improved the event prediction. Calibrated-IBS value could improve the risk prediction of CVE in asymptomatic type 2 diabetic patients with carotid plaque.

Though models with the radiative neutrino mass generation are phenomenologically attractive, the complicated relationship between the flavour structure of additional Yukawa matrices and the neutrino mass matrix sometimes is a barrier to explore the models. We introduce a simple prescription to analyze the relation in a class of models with the asymmetric Yukawa structure. We then apply the treatment to the Zee-Babu model as a concrete example of the class and discuss the phenomenological consequences of the model. The combined studies among the neutrino physics, the lepton flavour violation, and the search for the new particles at the collider experiments provide the anatomy of the Zee-Babu model.

CD8 is a cell surface glycoprotein that is expressed on the majority of thymocytes and approximately 30% of peripheral T cells, most commonly as a heterodimer of an α and a β chain. CD8 is referred to as a coreceptor for the T cell receptor (TCR) complex and plays an important role in the differentiation and peripheral function of CD8+ T cells. While the CD8α chain alone is sufficient to mediate interactions with the TCR/MHC complex and enhance antigen responsiveness in some systems, increasing evidence suggests that the CD8β chain contributes unique functions. CD8β chain may influence the avidity and/or specificity of the interaction of CD8 with the MHC molecule. Furthermore, a significant decrease in the number of mature CD8+ T cells was observed in mice with a homozygous, disruption of the CD8β gene. To assess signaling events mediated by the CD8αβ heterodimer, T cell hybridomas expressing CD8αβ or CD8αα were generated. In the CD8αβ+ hybridomas several observations suggested that CD8β enhances CD8α-associated Lck kinase activity: (1) in in vitro kinase assays, antibody-mediated cross-linking of CD8 resulted in 10-fold greater activation of Lck kinase activity compared to cells expressing CD8αα alone; (2) in vivo, enhanced tyrosine phosphorylation of several intracellular proteins was observed upon TCR/CD8 cross-linking of CD8αβ-expressing hybridomas, compared to cells expressing CD8αα alone; and (3) Lck association with CD8α was stabilized by the co-expression of CD8β. Thus, CD8β regulates the activity of Lck kinase activity associated with CD8α. Although the cytoplasmic domain of CD8β is only 19 amino acids long and does not contain any known protein-binding motifs, it is critical for the enhancement in CD8α-associated Lck kinase activity; co-expression of a cytoplasmic tail-deleted CD8β in T cell hybridomas failed to enhance CD8α-associated Lck activity and cellular tyrosine phosphorylation. Mice with various CD8β mutations have been generated by several groups. CD8β-deficient mice exhibited a dramatic impairment in the transition from double positive to CD8 single positive thymocytes. In transgenic mice expressing a cytoplasmic domain-deleted CD8β, a reduction in the number of CD8 cells was also observed. In comparison to wild type mice, CD8α-associated Lck kinase activity was decreased two- to six-fold in thymocytes and peripheral T cells of CD8β mutant mice. Furthermore, the degree of reduction in CD8-associated Lck kinase activity correlated with the severity of impairment of CD8+ T cell development. Thus, the activation of CD8-associated Lck kinase activity contributed by CD8β may play a critical role in the selection and differentiation of mature CD8+ T cells. As we hypothesized that the critical function of CD8β in thymic maturation is mediated by its ability to enhance CD8-associated Lck kinase activity, the developmental requirement for CD8β might be bypassed by enabling efficient CD8β-independent activation of CD8-associated Lck kinase. To test this hypothesis, a chimeric molecule consisting of the extracellular and transmembrane domains of CD8α directly ligated to Lck (CD8α-Lck) was constructed; the construct was prepared as a transgene and will be assessed with respect to its ability to reconstitute CD8 T cell development in CD8β mutant mice. This thesis provides evidence for the ability of CD8β to enhance Lck kinase activity associated with CD8α. Analysis of CD8β mutant mice suggest that this regulation of Lck activity is critical for the differentiation of mature CD8+ T cells.

Recent studies suggest that the commensal microbiota affects not only host energy metabolism and development of immunity but also bone remodeling by positive regulation of osteoclast activity. However, the mechanism of regulation of bone cells by the commensal microbiota has not been elucidated. In this study, 8-week-old specific pathogen-free (SPF) and germ-free (GF) mice were compared in terms of alveolar bones and primary osteoblasts isolated from calvarias. Micro-CT analysis showed that SPF mice had larger body size associated with lower bone mineral density and bone volume fraction in alveolar bones compared with GF mice. Greater numbers of osteoclasts in alveolar bone and higher serum levels of tartrate-resistant acid phosphatase 5b were observed in SPF mice. Tissue extracts from SPF alveolar bone showed higher levels of cathepsin K, indicating higher osteoclast activity. SPF alveolar extracts also showed elevated levels of γ-carboxylated glutamic acid–osteocalcin as a marker of mature osteoblasts compared with GF mice. Polymerase chain reaction (PCR) array analysis of RNA directly isolated from alveolar bone showed that in SPF mice, expression of mRNA of osteocalcin, which also acts as an inhibitor of bone mineralization, was strongly enhanced compared with GF mice. Cultured calvarial osteoblasts from SPF mice showed reduced mineralization but significantly enhanced expression of mRNAs of osteocalcin, alkaline phosphatase, insulin-like growth factor-I/II, and decreased ratio of osteoprotegerin/receptor activator of nuclear factor-kappa B ligand compared with GF mice. Furthermore, PCR array analyses of transcription factors in cultured calvarial osteoblasts showed strongly upregulated expression of Forkhead box g1. In contrast, Gata-binding protein 3 was strongly downregulated in SPF osteoblasts. These results suggest that the commensal microbiota prevents excessive mineralization possibly by stimulating osteocalcin expression in osteoblasts, and enhances both osteoblast and osteoclast activity by regulating specific transcription factors.

The purpose of this study was to develop a model that can predict the postoperative visual acuity in eyes that had undergone vitrectomy for an epiretinal membrane (ERM). The Light Gradient Boosting Machine (LightGBM) was used to evaluate the accuracy of the prediction and the contribution of the explanatory variables. Two models were designed to predict the postoperative visual acuity in 67 ERM patients. Model 1 used the age, sex, affected eye, axial length, preoperative visual acuity, Govetto's classification stage, and OCT-derived vector information as features to predict the visual acuity at 1, 3, and 6 months postoperatively. Model 2 incorporated the early postoperative visual acuity as an additional variable to predict the visual acuity at 3, and 6 months postoperatively. LightGBM with 100 iterations of 5-fold cross-validation was used to tune the hyperparameters and train the model. This involved addressing multicollinearity and selecting the explanatory variables. The generalized performance of these models was evaluated using the root mean squared error (RMSE) in a 5-fold cross-validation, and the contributions of the explanatory variables were visualized using the average Shapley Additive exPlanations (SHAP) values. The RMSEs for the predicted visual acuity of Model 1 were 0.14 ± 0.02 logMAR units at 1 month, 0.12 ± 0.03 logMAR units at 3 months, and 0.13 ± 0.04 logMAR units at 6 months. High SHAP values were observed for the preoperative visual acuity and the ectopic inner foveal layer (EIFL) area with significant and positive correlations across all models. Model 2 that incorporated the postoperative visual acuity was used to predict the visual acuity at 3 and 6 months, and it had superior accuracy with RMSEs of 0.10 ± 0.02 logMAR units at 3 months and 0.10 ± 0.04 logMAR units at 6 months. High SHAP values were observed for the postoperative visual acuity in Model 2. Predicting the postoperative visual acuity in ERM patients is possible using the preoperative clinical data and OCT images with LightGBM. The contribution of the explanatory variables can be visualized using the SHAP values, and the accuracy of the prediction models improved when the postoperative visual acuity is included as an explanatory variable. Our data-driven machine learning models reveal that preoperative visual acuity and the size of the EIFL significantly influence postoperative visual acuity. Early intervention may be crucial for achieving favorable visual outcomes in eyes with an ERM.