Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity

It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression

Estrogen/Estrogen Receptor Alpha Signaling in Mouse Posterofrontal Cranial Suture Fusion

BACKGROUND: While premature suture fusion, or craniosynostosis, is a relatively common condition, the cause is often unknown. Estrogens are associated with growth plate fusion of endochondral bones. In the following study, we explore the previously unknown significance of estrogen/estrogen receptor signaling in cranial suture biology. METHODOLOGY/PRINCIPAL FINDINGS: Firstly, estrogen receptor (ER) expression was examined in physiologically fusing (posterofrontal) and patent (sagittal) mouse cranial sutures by quantitative RT-PCR. Next, the cranial suture phenotype of ER alpha and ER beta knockout (alphaERKO, betaERKO) mice was studied. Subsequently, mouse suture-derived mesenchymal cells (SMCs) were isolated; the effects of 17-beta estradiol or the estrogen antagonist Fulvestrant on gene expression, osteogenic and chondrogenic differentiation were examined in vitro. Finally, in vivo experiments were performed in which Fulvestrant was administered subcutaneously to the mouse calvaria. Results showed that increased ERalpha but not ERbeta transcript abundance temporally coincided with posterofrontal suture fusion. The alphaERKO but not betaERKO mouse exhibited delayed posterofrontal suture fusion. In vitro, addition of 17-beta estradiol enhanced both osteogenic and chondrogenic differentiation in suture-derived mesenchymal cells, effects reversible by Fulvestrant. Finally, in vivo application of Fulvestrant significantly diminished calvarial osteogenesis, inhibiting suture fusion. CONCLUSIONS/SIGNIFICANCE: Estrogen signaling through ERalpha but not ERbeta is associated with and necessary for normal mouse posterofrontal suture fusion. In vitro studies suggest that estrogens may play a role in osteoblast and/or chondrocyte differentiation within the cranial suture complex

An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic 2 reprogramming and mammary tumourigenesis

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis

Designing Telerobotic Systems as Distributed CORBA-based Applications

Virtual laboratories and on-line robots are examples of distributed telerobotic systems based on emerging Internet technologies

Influence of predicting the diagnosis from history on the accuracy of physical examination

Kiyoshi Shikino, Masatomi Ikusaka, Yoshiyuki Ohira, Masahito Miyahara, Shingo Suzuki, Misa Hirukawa, Kazutaka Noda, Tomoko Tsukamoto, Takanori Uehara Department of General Medicine, Chiba University Hospital, Chiba, Chiba Prefecture, Japan Background: This study aimed to clarify the influence of predicting a correct diagnosis from the history on physical examination by comparing the diagnostic accuracy of auscultation with and without clinical information. Methods: The participants were 102 medical students from the 2013 clinical clerkship course. Auscultation was performed with a cardiology patient simulator. Participants were randomly assigned to two groups. Each group listened to a different simulated heart murmur and then made a diagnosis without clinical information. Next, a history suggesting a different murmur was provided to each group and they predicted the diagnosis. Finally, the students listened to a murmur corresponding to the history provided and again made a diagnosis. Correct and incorrect diagnosis rates of auscultation were compared between students with and without clinical information, between students predicting a correct or incorrect diagnosis from the history (correct and incorrect prediction groups, respectively), and between students without clinical information and those making an incorrect prediction. Results: For auscultation with or without clinical information, the correct diagnosis rate was 62.7% (128/204 participants) versus 54.4% (111/204 participants), showing no significant difference (P=0.09). After receiving clinical information, a correct diagnosis was made by 102/117 students (87.2%) in the correct prediction group versus 26/87 students (29.9%) in the incorrect prediction group, showing a significant difference (P=0.006). The correct diagnosis rate was also significantly lower in the incorrect prediction group than when the students performed auscultation without clinical information (54.4% versus 29.9%, P<0.001). Conclusion: Obtaining a history alone does not improve the diagnostic accuracy of physical examination. However, accurately predicting the diagnosis from the history is associated with higher diagnostic accuracy of physical examination, while incorrect prediction is associated with lower diagnostic accuracy of examination. Keywords: cardiac examination, clinical history, clinical reasoning, diagnostic accuracy, general medicin