Nitric oxide-dependent cytoskeletal changes and inhibition of endothelial cell migration contribute to the suppression of angiogenesis by RAD50 gene transfer

AbstractPrevious reports showed that human RAD50 (hRAD50) gene delivery induced regression of an experimental rat tumor and porcine neointimal hyperplasia. In this study, we examined the effects of hRAD50 on the morphological changes and migration of endothelial cells (EC) as possible mechanisms by which hRAD50 might block angiogenesis. Quantitative image analysis revealed significant inhibition of the number and total area of blood vessels in rat tumor tissues following hRAD50 gene delivery. hRAD50 distorted actin and tubulin arrangements, and significantly reduced the F/G-actin ratio and increased the nitric oxide (NO) production in the primary cultured human EC. These effects were blocked by pretreatment with L-NAME (NG-nitro-L-arginine-methyl ester), a NO synthase inhibitor. FACScan analysis showed that NO was involved in the necrosis and apoptosis of EC by hRAD50. hRAD50 also inhibited EC migration in an in vitro wound-healing model. These results indicate that NO-dependent cytoskeletal changes and inhibition of EC migration contribute to the suppression of angiogenesis by hRAD50 delivery in vivo

Effects of a radiation dose reduction strategy for computed tomography in severely injured trauma patients in the emergency department: an observational study

<p>Abstract</p> <p>Background</p> <p>Severely injured trauma patients are exposed to clinically significant radiation doses from computed tomography (CT) imaging in the emergency department. Moreover, this radiation exposure is associated with an increased risk of cancer. The purpose of this study was to determine some effects of a radiation dose reduction strategy for CT in severely injured trauma patients in the emergency department.</p> <p>Methods</p> <p>We implemented the radiation dose reduction strategy in May 2009. A prospective observational study design was used to collect data from patients who met the inclusion criteria during this one year study (intervention group) from May 2009 to April 2010. The prospective data were compared with data collected retrospectively for one year prior to the implementation of the radiation dose reduction strategy (control group). By comparison of the cumulative effective dose and the number of CT examinations in the two groups, we evaluated effects of a radiation dose reduction strategy. All the patients met the institutional adult trauma team activation criteria. The radiation doses calculated by the CT scanner were converted to effective doses by multiplication by a conversion coefficient.</p> <p>Results</p> <p>A total of 118 patients were included in this study. Among them, 33 were admitted before May 2009 (control group), and 85 were admitted after May 2009 (intervention group). There were no significant differences between the two groups regarding baseline characteristics, such as injury severity and mortality. Additionally, there was no difference between the two groups in the mean number of total CT examinations per patient (4.8 vs. 4.5, respectively; p = 0.227). However, the mean effective dose of the total CT examinations per patient significantly decreased from 78.71 mSv to 29.50 mSv (p < 0.001).</p> <p>Conclusions</p> <p>The radiation dose reduction strategy for CT in severely injured trauma patients effectively decreased the cumulative effective dose of the total CT examinations in the emergency department. But not effectively decreased the number of CT examinations.</p

Ubiquitin Ligases of the N-End Rule Pathway: Assessment of Mutations in UBR1 That Cause the Johanson-Blizzard Syndrome

Background: Johanson-Blizzard syndrome (JBS; OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, facial dysmorphism with the characteristic nasal wing hypoplasia, multiple malformations, and frequent mental retardation. Our previous work has shown that JBS is caused by mutations in human UBR1, which encodes one of the E3 ubiquitin ligases of the N-end rule pathway. The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. One class of degradation signals (degrons) recognized by UBR1 are destabilizing N-terminal residues of protein substrates. Methodology/Principal Findings: Most JBS-causing alterations of UBR1 are nonsense, frameshift or splice-site mutations that abolish UBR1 activity. We report here missense mutations of human UBR1 in patients with milder variants of JBS. These single-residue changes, including a previously reported missense mutation, involve positions in the RING-H2 and UBR domains of UBR1 that are conserved among eukaryotes. Taking advantage of this conservation, we constructed alleles of the yeast Saccharomyces cerevisiae UBR1 that were counterparts of missense JBS-UBR1 alleles. Among these yeast Ubr1 mutants, one of them (H160R) was inactive in yeast-based activity assays, the other one (Q1224E) had a detectable but weak activity, and the third one (V146L) exhibited a decreased but significant activity, in agreement with manifestations of JBS in the corresponding JBS patients. Conclusions/Significance: These results, made possible by modeling defects of a human ubiquitin ligase in its yeast counterpart, verified and confirmed the relevance of specific missense UBR1 alleles to JBS, and suggested that a residual activity of a missense allele is causally associated with milder variants of JBS

The appropriateness of single page of activation of the cardiac catheterization laboratory by emergency physician for patients with suspected ST-segment elevation myocardial infarction: a cohort study

<p>Abstract</p> <p>Background</p> <p>The early use of reperfusion therapy has a significant effect on the prognosis of patients with ST-segment elevation myocardial infarction (STEMI), and it is recommended that emergency department (ED) physicians activate the cardiac catheterization laboratory (CCL) as soon as possible to treat these patients. The aim of this study was to examine the appropriateness of emergency physician activation of the CCL for patients with suspected STEMI. Inappropriate activations (i.e., false positive activations) were identified according to a variety of criteria.</p> <p>Methods</p> <p>All patients with emergency physician CCL activations between August 2009 and April 2011 were included in the study. False positive cases were defined according to ECG criteria and cardiologists' reviews of patients' initial clinical information.</p> <p>Results</p> <p>ED physicians used a STEMI page to activate the CCL 117 times. According to reviews by cardiologists, this activation was appropriate 89.8% of the time (in 105/117 cases). Truly unnecessary activation (i.e., cases in which STEMI was not identified by the cardiologists, no clear culprit coronary artery was present, no significant coronary artery disease and cardiac biomarkers were negative) occurred 5.1% of the time (in 6/117 cases).</p> <p>Conclusions</p> <p>CCL activation was appropriate for most patients and was unnecessary in a relatively small percentage of cases. This result supports the current recommendation for CCL activation by emergency physicians. Such early activation is a key strategy in the reduction of door-to-balloon time.</p

Small and Medium Amplitude Oscillatory Shear Rheology of Model Branched Polystyrene (PS) Melts

Linear and nonlinear rheological properties of model comb polystyrenes (PS) with loosely to densely grafted architectures were measured under small and medium amplitude oscillatory shear (SAOS and MAOS) flow. This comb PS set had the same length of backbone and branches but varied in the number of branches from 3 to 120 branches. Linear viscoelastic properties of the comb PS were compared with the hierarchical model predictions. The model underpredicted zero-shear viscosity and backbone plateau modulus of densely branched comb with 60 or 120 branches because the model does not include the effect of side chain crowding. First- and third-harmonic nonlinearities reflected the hierarchy in the relaxation motion of comb structures. Notably, the low-frequency plateau values of first-harmonic MAOS moduli scaled with M$^{-2}$$_{w}$ (total molecular weight), reflecting dynamic tube dilution (DTD) by relaxed branches. Relative intrinsic nonlinearity Q$_{0}$ exhibited the difference between comb and bottlebrush via no low-frequency Q$_{0}$ peak of bottlebrush corresponding to backbone relaxation, which is probably related to the stretched backbone conformation in bottlebrush

Gastric Yolk Sac Tumor: A Case Report and Review of the Literature

Gastric yolk sac tumors are extremely rare and their prognosis is poor; most patients have widespread metastases at the time of diagnosis. The treatment of gastric yolk sac tumors consists of aggressive chemotherapy combined with radiotherapy and surgery. Here, we first report a case of gastric yolk sac tumor presenting as an early gastric cancer that was cured after a gastrectomy with lymphadenectomy

Versatile double hydrophilic block copolymer: dual role as synthetic nanoreactor and ionic and electronic conduction layer for ruthenium oxide nanoparticle supercapacitors

The facile synthetic approach to ruthenium oxide nanoparticles using double hydrophilic block copolymers (DHBCs) and their application toward the supercapacitor are presented. Nanostructured hydrous ruthenium oxide (RuO2) nanoparticles are synthesized using a double hydrophilic block copolymer of poly(ethylene oxide)-block-poly(acrylic acid) (PEO-b-PAA) as a template, forming a micelle upon addition of the ruthenium precursor, which then transformed into RuO2 nanoparticles of controlled dimension with reducing agents. The synthesized hydrous RuO2 center dot xH(2)O nanoparticles are very stable for several months without any noticeable aggregates. Furthermore, we have demonstrated their utility in application as supercapacitors. Through annealing at 400 degrees C, we found that the crystallinity of RuO2 nanoparticles increases considerably with a simultaneous transformation of the surrounding double hydrophilic block copolymer into ionic and electronic conducting buffer layers atop RuO2 nanoparticles, which contribute to the significant enhancement of the overall specific capacitance from 106 to 962 F g(-1) at 10 mV s(-1). The RuO2 nanoparticles annealed at 400 degrees C also exhibit a superior retention of capacitance over 1000 cycles at very high charge-discharge rates at 20 A g(-1). We envision that the double hydrophilic block copolymer will provide a facile and general tool in creating functional nanostructures with controlled dimensions that are useful for various applications.close9

The validity of the canadian triage and acuity scale in predicting resource utilization and the need for immediate life-saving interventions in elderly emergency department patients

<p>Abstract</p> <p>Background</p> <p>We evaluated the validity of the Canadian Triage and Acuity Scale (CTAS) in elderly emergency department (ED) patients. In particular, we examined the sensitivity and specificity of the CTAS for identifying elderly patients who received an immediate life-saving intervention in the ED.</p> <p>Methods</p> <p>We reviewed the medical records of consecutive patients who were 65 years of age or older and presented to a single academic ED within a three-month period. The CTAS triage scores were compared to actual patient course, including disposition, discharge outcome and resource utilization. We calculated the sensitivity and specificity of the CTAS triage for identifying patients who received an immediate intervention.</p> <p>Results</p> <p>Of the 1903 consecutive patients who were ≥ 65 years of age, 113 (5.9%) had a CTAS level of 1, 174 (9.1%) had a CTAS level of 2, 1154 (60.6%) had a CTAS level of 3, 347 (18.2%) had a CTAS level of 4, and 115 (6.0%) had a CTAS level of 5. As a patient's triage score increased, the severity (such as mortality and intensive care unit admission) and resource utilization increased significantly. Ninety-four of the patients received a life-saving intervention within an hour following their arrival to the ED. The CTAS scores for these patients were 1, 2 and 3 for 46, 46 and 2 patients, respectively. The sensitivity and specificity of a CTAS score of ≤ 2 for identifying patients for receiving an immediate intervention were 97.9% and 89.2%, respectively.</p> <p>Conclusions</p> <p>The CTAS is a triage tool with high validity for elderly patients, and it is an especially useful tool for categorizing severity and for recognizing elderly patients who require immediate life-saving intervention.</p

Crystal Structure of the FERM Domain of Focal Adhesion Kinase

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. Through phosphorylation of proteins assembled at the cytoplasmic tails of integrins, FAK promotes signaling events that modulate cellular growth, survival, and migration. The amino-terminal region of FAK contains a region of sequence homology with band 4.1 and ezrin/radixin/moesin (ERM) proteins termed a FERM domain. FERM domains are found in a variety of signaling and cytoskeletal proteins and are thought to mediate intermolecular interactions with partner proteins and phospholipids at the plasma membrane and intramolecular regulatory interactions. Here we report two crystal structures of an NH2-terminal fragment of avian FAK containing the FERM domain and a portion of the regulatory linker that connects the FERM and kinase domains. The tertiary folds of the three subdomains (F1, F2, and F3) are similar to those of known FERM structures despite low sequence conservation. Differences in the sequence and relative orientation of the F3 subdomain alters the nature of the interdomain interface, and the phosphoinositide binding site found in ERM family FERM domains is not present in FAK. A putative protein interaction site on the F3 lobe is masked by the proximal region of the linker. Additionally, in one structure the adjacent Src SH3 and SH2 binding sites in the linker associate with the surfaces of the F3 and F1 lobes, respectively. These structural features suggest the possibility that protein interactions of the FAK FERM domain can be regulated by binding of Src kinases to the linker segment