VEGF promotes assembly of the p130Cas interactome to drive endothelial chemotactic signalling and angiogenesis

p130Cas is a polyvalent adapter protein essential for cardiovascular development, and with a key role in cell movement. In order to identify the pathways by which p130Cas exerts its biological functions in endothelial cells we mapped the p130Cas interactome and its dynamic changes in response to VEGF using high-resolution mass spectrometry and reconstruction of protein interaction (PPI) networks with the aid of multiple PPI databases. VEGF enriched the p130Cas interactome in proteins involved in actin cytoskeletal dynamics and cell movement, including actin-binding proteins, small GTPases and regulators or binders of GTPases. Detailed studies showed that p130Cas association of the GTPase-binding scaffold protein, IQGAP1, plays a key role in VEGF chemotactic signalling, endothelial polarisation, VEGF-induced cell migration, and endothelial tube formation. These findings indicate a cardinal role for assembly of the p130Cas interactome in mediating the cell migratory response to VEGF in angiogenesis, and provide a basis for further studies of p130Cas in cell movement

Predictors of failed attendances in a multi-specialty outpatient centre using electronic databases.

BACKGROUND: Failure to keep outpatient medical appointments results in inefficiencies and costs. The objective of this study is to show the factors in an existing electronic database that affect failed appointments and to develop a predictive probability model to increase the effectiveness of interventions. METHODS: A retrospective study was conducted on outpatient clinic attendances at Tan Tock Seng Hospital, Singapore from 2000 to 2004. 22864 patients were randomly sampled for analysis. The outcome measure was failed outpatient appointments according to each patient's latest appointment. RESULTS: Failures comprised of 21% of all appointments and 39% when using the patients' latest appointment. Using odds ratios from the mutliple logistic regression analysis, age group (0.75 to 0.84 for groups above 40 years compared to below 20 years), race (1.48 for Malays, 1.61 for Indians compared to Chinese), days from scheduling to appointment (2.38 for more than 21 days compared to less than 7 days), previous failed appointments (1.79 for more than 60% failures and 4.38 for no previous appointments, compared with less than 20% failures), provision of cell phone number (0.10 for providing numbers compared to otherwise) and distance from hospital (1.14 for more than 14 km compared to less than 6 km) were significantly associated with failed appointments. The predicted probability model's diagnostic accuracy to predict failures is more than 80%. CONCLUSION: A few key variables have shown to adequately account for and predict failed appointments using existing electronic databases. These can be used to develop integrative technological solutions in the outpatient clinic

Engaging communication experts in a Delphi process to identify patient behaviors that could enhance communication in medical encounters

<p>Abstract</p> <p>Background</p> <p>The communication literature currently focuses primarily on improving physicians' verbal and non-verbal behaviors during the medical interview. The Four Habits Model is a teaching and research framework for physician communication that is based on evidence linking specific communication behaviors with processes and outcomes of care. The Model conceptualizes basic communication tasks as "Habits" and describes the sequence of physician communication behaviors during the clinical encounter associated with improved outcomes. Using the Four Habits Model as a starting point, we asked communication experts to identify the verbal communication behaviors of patients that are important in outpatient encounters.</p> <p>Methods</p> <p>We conducted a 4-round Delphi process with 17 international experts in communication research, medical education, and health care delivery. All rounds were conducted via the internet. In round 1, experts reviewed a list of proposed patient verbal communication behaviors within the Four Habits Model framework. The proposed patient verbal communication behaviors were identified based on a review of the communication literature. The experts could: approve the proposed list; add new behaviors; or modify behaviors. In rounds 2, 3, and 4, they rated each behavior for its fit (agree or disagree) with a particular habit. After each round, we calculated the percent agreement for each behavior and provided these data in the next round. Behaviors receiving more than 70% of experts' votes (either agree or disagree) were considered as achieving consensus.</p> <p>Results</p> <p>Of the 14 originally-proposed patient verbal communication behaviors, the experts modified all but 2, and they added 20 behaviors to the Model in round 1. In round 2, they were presented with 59 behaviors and 14 options to remove specific behaviors for rating. After 3 rounds of rating, the experts retained 22 behaviors. This set included behaviors such as asking questions, expressing preferences, and summarizing information.</p> <p>Conclusion</p> <p>The process identified communication tasks and verbal communication behaviors for patients similar to those outlined for physicians in the Four Habits Model. This represents an important step in building a single model that can be applied to teaching patients and physicians the communication skills associated with improved satisfaction and positive outcomes of care.</p

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma

Evidence suggests that multiple tumors, including pancreatic adenocarcinoma, display heterogeneity in parameters that are critical for tumor formation, progression and metastasis. Understanding heterogeneity in solid tumors is increasingly providing a plethora of new diagnostic and therapeutic approaches. In this study, a particular focus was put on identifying a subpopulation of stem cell-like, slow cycling tumor cells in a pancreas adenocarcinoma cell lines. Using a label retention technique a subpopulation of slow cycling cells (DiI+/SCC) was identified and further evaluated in the BxPC-3 and Panc03.27 cell lines. These slowly cycling cells managed to retain the lipophilic labeling dye DiI, while the bulk of the cells (>94%) did not. The DiI+/SCC population, showed only a partial overlap with the CSC markers CD24+/CD44+, CD133+ and ALDH but they survived chemotherapeutic treatment, and were able to recreate the initial heterogeneous tumor cell population. DiI+/SCCs exhibited an increased invasive potential as compared with their non-label retaining, faster cycling cells (DiI−/FCC). They also had increased tumorigenic potential and morphological changes resembling cells that have undergone an epithelial to mesenchymal transition (EMT). Analysis of DiI+/SCC cells by real time PCR revealed a selective up-regulation of tell tale components of the Hedgehog/TGFβ pathways, as well as a down-regulation of EGFR, combined with a shift in crucial components implied in EMT. The presented findings offer an expanded mechanistic understanding that associates tumor initiating potential with cycling speed and EMT in pancreatic cancer cell lines

'To take care of the patients': Qualitative analysis of Veterans Health Administration personnel experiences with a clinical informatics system

<p>Abstract</p> <p>Background</p> <p>The Veterans Health Administration (VA) has invested significant resources in designing and implementing a comprehensive electronic health record (EHR) that supports clinical priorities. EHRs in general have been difficult to implement, with unclear cost-effectiveness. We describe VA clinical personnel interactions with and evaluations of the EHR.</p> <p>Methods</p> <p>As part of an evaluation of a quality improvement initiative, we interviewed 72 VA clinicians and managers using a semi-structured interview format. We conducted a qualitative analysis of interview transcripts, examining themes relating to participants' interactions with and evaluations of the VA EHR.</p> <p>Results</p> <p>Participants described their perceptions of the positive and negative effects of the EHR on their clinical workflow. Although they appreciated the speed and ease of documentation that the EHR afforded, they were concerned about the time cost of using the technology and the technology's potential for detracting from interpersonal interactions.</p> <p>Conclusions</p> <p>VA personnel value EHRs' contributions to supporting communication, education, and documentation. However, participants are concerned about EHRs' potential interference with other important aspects of healthcare, such as time for clinical care and interpersonal communication with patients and colleagues. We propose that initial implementation of an EHR is one step in an iterative process of ongoing quality improvement.</p

Motives for choosing growth-enhancing hormone treatment in adolescents with idiopathic short stature: a questionnaire and structured interview study

Background Growth-enhancing hormone treatment is considered a possible intervention in short but otherwise healthy adolescents. Although height gain is an obvious measure for evaluating hormone treatment, this may not be the ultimate goal for the person, but rather a means to reach other goals such as the amelioration of current height-related psychosocial problems or the enhancement of future prospects in life and society. The aim of our study was to clarify the motives of adolescents and their parents when choosing to participate in a growth-enhancing trial combining growth hormone and puberty-delaying hormone treatment. Methods Participants were early pubertal adolescents (25 girls, 13 boys) aged from 11 to 13 years (mean age 11.5 years) with a height standard deviation score (SDS) ranging from -1.03 to -3.43. All had been classified as idiopathic short stature or persistent short stature born small for the gestational age (intrauterine growth retardation) on the basis of a height SDS below -2, or had a height SDS between -1 and -2 and a predicted adult height SDS below -2. The adolescents and their parents completed questionnaires and a structured interview on the presence of height-related stressors, parental worries about their child's behavior and future prospects, problems in psychosocial functioning, and treatment expectations. Questionnaire scores were compared to norms of the general Dutch population. Results The adolescents reported normal psychosocial functioning and highly positive expectations of the treatment in terms of height gain, whereas the parents reported that their children encountered some behavioral problems (being anxious/depressed, and social and attention problems) and height-related stressors (being teased and juvenilized). About 40% of the parents were worried about their children's future prospects for finding a spouse or job. The motives of the adolescents and their parents exhibited rather different profiles. The most prevalent parental worries related to the current or future functioning of their children, while a few cases were characterized by no observed motives or by psychosocial problems only reported by the adolescents themselves. Conclusion The motives for participating in a growth-enhancing hormone trial are more obvious in the parents than in the adolescents themselves. Two out of three parents report worries about the future opportunities or observe modest current psychosocial problems in their children. The adolescents want to gain height, but the motivation underlying this remains unclear. Few of the adolescents experience psychosocial problems. Our analyses revealed differences among individuals in terms of motives, which implies that in an evaluation of hormone treatment, the importance of divergent outcome variables will also differ among individuals. Effectiveness evaluations of hormone treatment to increase height and the consequential fulfillment of other goals must be awaited

Histone Methylation by NUE, a Novel Nuclear Effector of the Intracellular Pathogen Chlamydia trachomatis

Sequence analysis of the genome of the strict intracellular pathogen Chlamydia trachomatis revealed the presence of a SET domain containing protein, proteins that primarily function as histone methyltransferases. In these studies, we demonstrated secretion of this protein via a type III secretion mechanism. During infection, the protein is translocated to the host cell nucleus and associates with chromatin. We therefore named the protein nuclear effector (NUE). Expression of NUE in mammalian cells by transfection reconstituted nuclear targeting and chromatin association. In vitro methylation assays confirmed NUE is a histone methyltransferase that targets histones H2B, H3 and H4 and itself (automethylation). Mutants deficient in automethylation demonstrated diminished activity towards histones suggesting automethylation functions to enhance enzymatic activity. Thus, NUE is secreted by Chlamydia, translocates to the host cell nucleus and has enzymatic activity towards eukaryotic substrates. This work is the first description of a bacterial effector that directly targets mammalian histones