Caveolin-1 Phosphorylation Is Essential for Axonal Growth of Human Neurons Derived From iPSCs.

Proper axonal growth and guidance is essential for neuron differentiation and development. Abnormal neuronal development due to genetic or epigenetic influences can contribute to neurological and mental disorders such as Down syndrome, Rett syndrome, and autism. Identification of the molecular targets that promote proper neuronal growth and differentiation may restore structural and functional neuroplasticity, thus improving functional performance in neurodevelopmental disorders. Using differentiated human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs), the present study demonstrates that during early stage differentiation of human NPCs, neuron-targeted overexpression constitutively active Rac1 (Rac1CA) and constitutively active Cdc42 (Cdc42CA) enhance expression of P-Cav-1, T-Cav-1, and P-cofilin and increases axonal growth. Similarly, neuron-targeted over-expression of Cav-1 (termed SynCav1) increases axonal development by increasing both axon length and volume. Moreover, inhibition of Cav-1(Y14A) phosphorylation blunts Rac1/Cdc42-mediated both axonal growth and differentiation of human NPCs and SynCav1(Y14A)-treated NPCs exhibited blunted axonal growth. These results suggest that: (1) SynCav1-mediated dendritic and axonal growth in human NPCs is dependent upon P-Cav-1, (2) P-Cav-1 is necessary for proper axonal growth during early stages of neuronal differentiation, and (3) Rac1/Cdc42CA-mediated neuronal growth is in part dependent upon P-Cav-1. In conclusion, Cav-1 phosphorylation is essential for human neuronal axonal growth during early stages of neuronal differentiation

Expansion Thoracoplasty Affects Lung Growth and Morphology in a Rabbit Model: A Pilot Study

Background: Thoracic insufficiency syndrome represents a novel form of postnatal restrictive respiratory disease occurring in children with early-onset scoliosis and chest wall anomalies. Expansion thoracoplasty improves lung volumes in children with thoracic insufficiency syndrome; however, how it affects lung development is unknown. Questions/purposes: Using a rabbit model of thoracic insufficiency syndrome, we evaluated the effect of expansion thoracoplasty on the response of biologic mechanisms in the alveolar microstructure. Methods: Using archived material from a previous experiment, 10 4-week-old New Zealand rabbits were divided into three groups: normal (n = 3), disease (n = 3), and treated (n = 4). Left ribs four to eight were tethered in seven rabbits at age 5 weeks to induce hypoplasia of the left hemithorax (disease). At age 10 weeks, four of these rabbits were treated by expansion thoracoplasty (treated). At age 24 weeks, lungs were excised and processed. Alveolar density and parenchymal airspace were measured on histologic sections. Immunohistochemistry was performed for vascular endothelial growth factor receptor 2 (angiogenesis), KI-67 (cell proliferation), and RAM-11 (macrophages). Results: Alveolar walls were poorly perfused and airspace fraction was larger (emphysematous) in disease rabbits than normal or treated rabbits. Immunohistochemistry provided inconclusive evidence to support the concept that pulmonary hypoplasia is induced by thoracic insufficiency syndrome and controlled by expansion thoracoplasty. Conclusions: Treatment of thoracic insufficiency syndrome by expansion thoracoplasty may prevent emphysematous changes in the alveolar microstructure, thereby enhancing gas exchange

TCT-669 Very Low Intravenous Contrast Dose (20 cc) Computed Tomographic Angiography Protocol for Pre-Procedural Assessment of the Aortic Annulus Prior to Transcatheter Aortic Valve Replacement: Validation by 3-Dimensional Transesophageal Echocardiography

Von Dr. Fr. Dietric

Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution.

Thy-1-negative lung fibroblasts are resistant to apoptosis. The mechanisms governing this process and its relevance to fibrotic remodeling remain poorly understood. By using either sorted or transfected lung fibroblasts, we found that Thy-1 expression is associated with downregulation of anti-apoptotic molecules Bcl-2 and Bcl-xL, as well as increased levels of cleaved caspase-9. Addition of rhFasL and staurosporine, well-known apoptosis inducers, caused significantly increased cleaved caspase-3, -8, and PARP in Thy-1-transfected cells. Furthermore, rhFasL induced Fas translocation into lipid rafts and its colocalization with Thy-1. These in vitro results indicate that Thy-1, in a manner dependent upon its glycophosphatidylinositol anchor and lipid raft localization, regulates apoptosis in lung fibroblasts via Fas-, Bcl-, and caspase-dependent pathways. In vivo, Thy-1 deficient (Thy1-/-) mice displayed persistence of myofibroblasts in the resolution phase of bleomycin-induced fibrosis, associated with accumulation of collagen and failure of lung fibrosis resolution. Apoptosis of myofibroblasts is decreased in Thy1-/- mice in the resolution phase. Collectively, these findings provide new evidence regarding the role and mechanisms of Thy-1 in initiating myofibroblast apoptosis that heralds the termination of the reparative response to bleomycin-induced lung injury. Understanding the mechanisms regulating fibroblast survival/apoptosis should lead to novel therapeutic interventions for lung fibrosis

Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock

<p>Abstract</p> <p>Background</p> <p>Lactate clearance, a surrogate for the magnitude and duration of global tissue hypoxia, is used diagnostically, therapeutically and prognostically. This study examined the association of early lactate clearance with selected inflammatory, coagulation, apoptosis response biomarkers and organ dysfunction scores in severe sepsis and septic shock.</p> <p>Methods</p> <p>Measurements of serum arterial lactate, biomarkers (interleukin-1 receptor antagonist, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1, high mobility group box-1, D-Dimer and caspase-3), and organ dysfunction scores (Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Multiple Organ Dysfunction Score, and Sequential Organ Failure Assessment) were obtained in conjunction with a prospective, randomized study examining early goal-directed therapy in severe sepsis and septic shock patients presenting to the emergency department (ED). Lactate clearance was defined as the percent change in lactate levels after six hours from a baseline measurement in the ED.</p> <p>Results</p> <p>Two-hundred and twenty patients, age 65.0 +/- 17.1 years, were examined, with an overall lactate clearance of 35.5 +/- 43.1% and in-hospital mortality rate of 35.0%. Patients were divided into four quartiles of lactate clearance, -24.3 +/- 42.3, 30.1 +/- 7.5, 53.4 +/- 6.6, and 75.1 +/- 7.1%, respectively (<it>p </it>< 0.01). The mean levels of all biomarkers and organ dysfunction scores over 72 hours were significantly lower with higher lactate clearance quartiles (<it>p </it>< 0.01). There was a significant decreased in-hospital, 28-day, and 60-day mortality in the higher lactate clearance quartiles (<it>p </it>< 0.01).</p> <p>Conclusions</p> <p>Early lactate clearance as a surrogate for the resolution of global tissue hypoxia is significantly associated with decreased levels of biomarkers, improvement in organ dysfunction and outcome in severe sepsis and septic shock.</p

Does race impact functional outcomes in patients undergoing robotic partial nephrectomy?

Background: The role of race on functional outcomes after robotic partial nephrectomy (RPN) is still a matter of debate. We aimed to evaluate the clinical and pathologic characteristics of African American (AA) and Caucasian patients who underwent RPN and analyzed the association between race and functional outcomes. Methods: Data was obtained from a multi-institutional database of patients who underwent RPN in 6 institutions in the USA. We identified 999 patients with complete clinical data. Sixty-three patients (6.3%) were AA, and each patient was matched (1:3) to Caucasian patients by age at surgery, gender, Charlson Comorbidity Index (CCI) and renal score. Bivariate and multivariate logistic regression analyses were used to evaluate predictors of acute kidney injury (AKI). Kaplan-Meier method and multivariable semiparametric Cox regression analyses were performed to assess prevalence and predictors of significant eGFR reduction during follow-up. Results: Overall, 252 patients were included. AA were more likely to have hypertension (58.7% Conclusions: Although African American patients were more likely to have hypertension, renal function outcomes of robotic partial nephrectomies were not significantly different when stratified by race. However, future studies with larger cohorts are necessary to validate these findings

Diversity and relationships of eggplants from three geographically distant secondary centers of diversity

Eggplant (Solanum melongena L.) was domesticated in the Indo-Birmanian region, which is also the primary center of diversity for this crop. From there eggplant spread to other regions, and diversity accumulated in several secondary centers of diversity. We have assessed the diversity and relationships of 52 accessions of eggplant from three geographically distant secondary centers of diversity (China, Spain, and Sri Lanka) using 28 morphological descriptors and 12 highly polymorphic genomic SSRs. A wide variation was found for most morphological traits, and significant differences among the three centers of diversity were detected for 22 of these traits. The PCA analysis showed that eggplants from the three origins were morphologically differentiated, and accessions from each of the three secondary centers of diversity presented a typical combination of morphological characteristics. In this respect, discriminant analysis showed that accessions could be correctly classified to their origin using only six traits. The SSR characterization identified 110 alleles and allowed obtaining a unique genetic fingerprint for each accession. Many alleles were found to be private to each origin, but no universal alleles were found for any of the origins. The PCA analysis showed that the genetic differentiation among origins was less clear than for morphological traits, although the analysis of the population structure shows that accessions mostly group according to the origin, but also provides evidence of migration among the three secondary centers of diversity. The genetic diversity (HT) within each origin was high, ranging between H-T = 0.5400 (Sri Lanka) and H-T = 0.4943 (China), while the standardized genetic differentiation (G'(ST)) among origins was moderate (G'(ST) = 0.2657). The correlation between morphological and SSR distances was non-significant (r = 0.044), indicating that both data are complementary for the conservation of germplasm and breeding of eggplant. These results are relevant for the management of genetic resources, breeding programmes, and evolutionary studies of eggplant.This work was financed by the Ministerio de Ciencia e innovacion (grants AGL2009-07257 and RF-2008-00008-00-00) (http://www.micinn.es). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Hurtado Ricart, M.; Vilanova Navarro, S.; Plazas Ávila, MDLO.; Gramazio, P.; Fonseka, HH.; Fonseka, R.; Prohens Tomás, J. (2012). Diversity and relationships of eggplants from three geographically distant secondary centers of diversity. PLoS ONE. 7:41748-41748. https://doi.org/10.1371/journal.pone.0041748S4174841748