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Biomedical subjects

Paul Reynolds

Publications and source records attributed to Paul Reynolds.

9 recordsLinked to original sources
PubMed2006

Gene expression profiling of target genes in ventilator-induced lung injury.

In the lungs, high-pressure mechanical ventilation induces an inflammatory response similar to that observed in acute respiratory distress syndrome. To further characterize these responses and to compare them with classical inflammatory pathways, we performed gene expression profiling analysis of 20,000 mouse genes in isolated blood-free (to exclude genes from sequestered leukocytes) perfused mouse lungs exposed to low-pressure ventilation (10 cmH2O), high-pressure ventilation (25 cmH2O, overventilation), and LPS treatment. A large number of inflammatory and apoptotic genes were increased by both overventilation and LPS. However, certain growth factor-related genes, as well as genes related to development, cellular communication, and the cytoskeleton, were only regulated by overventilation. We validated and confirmed increased mRNA expression pattern of five genes (amphiregulin, gravin, Nur77, Cyr61, interleukin-11) by real-time PCR; furthermore, we confirmed increased protein expression of amphiregulin by immunohistochemistry and immunoblotting assays. These genes represent novel candidate genes in ventilator-induced lung injury.

A Kinase Anchor Proteins↗
PubMed2006

An assessment of interrater reliability of the ASA physical status classification in pediatric surgical patients.

BACKGROUND: The American Society of Anesthesiologists physical status classification (ASA-PS) is used worldwide by anesthesia providers as an assessment of the preoperative physical status of patients. This assessment score has been inconsistently assigned by anesthesia providers among adult surgical patients. This study tested the reliability of assignment of ASA-PS classification among pediatric anesthesia providers. METHODS: A postal questionnaire was sent to a randomly selected sample of full members of the Society of Pediatric Anesthesiologists. Participants were asked to assign ASA-PS for 10 clinical case scenarios chosen from regular pediatric surgical cases at the investigators' institution. RESULTS: The response rate to our mailing was 54%. There was a moderate overall agreement among pediatric anesthesia providers in assigning ASA-PS for pediatric surgical patients (exact agreement 40.5-78.6%; kappa = 0.479). Exact agreement improved for combined ASA classifications of I and II (83%), and III and IV (95%). CONCLUSION: These findings suggest a moderate agreement among pediatric anesthesia providers in assigning ASA-PS classification to selected pediatric case scenarios. Most disagreement, however, represented a tendency of outside care providers to assign a higher ASA physical status for cases. Furthermore, agreement was excellent for low risk (i.e. ASA I and II) as well as high risk (ASA III and IV) cases.

Adolescent↗
PubMed2004

Finite-element analysis of material and parameter effects in laser-based thermoelastic ultrasound generation.

Laser-based, thermoelastic transduction methods have potential in very high frequency (>50 MHz), high-density two-dimensional (2-D) arrays for a variety of very high-resolution superficial imaging applications, including in vivo tissue sectioning. Previous studies of these transducers generally have been based on experimental measurements or theoretical analyses using various simplifying assumptions. These theoretical models are mostly 1-D and best matched to simple geometries with a minimum number of component materials. In this work, we use a new thermoelastic solver in a commercially available finite-element analysis (FEA) software package to analyze multidimensional effects in laser-based devices of arbitrary geometry with the potential for use with arbitrary material properties. The FEA approach was verified first against experimental data. Thereafter, we explored the impact of various design variables, including laser spot size and laser penetration depth.

Anatomy, Cross-Sectional↗
PubMed2004

Precompensated excitation waveforms to suppress harmonic generation in MEMS electrostatic transducers.

Microelectromechanical systems (MEMS) electrostatic-based transducers inherently produce harmonics as the electrostatic force generated in the transmit mode is approximately proportional to the square of the applied voltage signal. This characteristic precludes them from being effectively used for harmonic imaging (either with or without the addition of microbubble-based contrast agents). The harmonic signal that is nonlinearly generated by tissue (or contrast agent) cannot be distinguished from the inherent transmitted harmonic signal. We investigated two precompensation methods to cancel this inherent harmonic generation in electrostatic transducers. A combination of finite element analysis (FEA) and experimental results are presented. The first approach relies on a calculation, or measurement, of the transducer's linear transfer function, which is valid for small signal levels. Using this transfer function and a measurement of the undesired harmonic signal, a predistorted transmit signal was calculated to cancel the harmonic inherently generated by the transducer. Due to the lack of perfect linearity, the approach does hot work completely in a single iteration. However, with subsequent iterations, the problem becomes more linear and converges toward a very satisfactory result (a 18.6 dB harmonic reduction was achieved in FEA simulations and a 20.7 dB reduction was measured in a prototype experiment). The second approach tested involves defining a desired function [including a direct current (DC) offset], then taking the square root of this function to determine the shape of the required input function. A 5.5 dB reduction of transmitted harmonic was obtained in both FEA simulation and experimental prototypes test.

Journal Article↗
PubMed2003

An empirical bayesian method for differential expression studies using one-channel microarray data.

Gene expression microarrays have become powerful tools in many areas of biological and biomedical research. These technologies allow researchers to measure the expression levels of thousands of genes in a tissue or cell sample simultaneously. One of the most common types of microarray experiments is simply an exploratory study to compare two samples (e.g. tumor and normal tissue) and look for a list of genes that might be differentially expressed between the two. Differential expression is typically measured by computing a t-statistic or similar statistic for each gene. The genes are then ranked according to the absolute value of the t-statistic, and the twenty or fifty best candidates might be studied in follow-up experiments. When sample sizes are small, the t-statistic can be problematic, because variances are estimated poorly and the "top 20" list is often dominated by the genes with the lowest variance estimates. Lönnstedt and Speed (2001) proposed an empirical Bayes method for avoiding this problem, and showed that their approach has lower false positive and false negative rates than t-statistic-based methods. However, their method was designed mainly for the two-channel microarray, which produces paired data. It is not suitable for technologies such as one-channel arrays that produce unpaired data. We propose a simplification for Lönnstedt and Speed's method, and then extend it to unpaired data with two or more independent treatments. We demonstrate our method on both simulated and real data. When the number of replicates is small, gene rankings based on our statistic appear to be much more reliable than rankings based on the t-statistic.

Journal Article↗
PubMed2003

DOCK4, a GTPase activator, is disrupted during tumorigenesis.

We used representational difference analysis to identify homozygous genomic deletions selected during tumor progression in the mouse NF2 and TP53 tumor model. We describe a deletion targeting DOCK4, a member of the CDM gene family encoding regulators of small GTPases. DOCK4 specifically activates Rap GTPase, enhancing the formation of adherens junctions. DOCK4 mutations are present in a subset of human cancer cell lines; a recurrent missense mutant identified in human prostate and ovarian cancers encodes a protein that is defective in Rap1 activation. The engulfment defect of C. elegans mutants lacking the CDM gene ced-5 is rescued by wild-type DOCK4, but not by the mutant allele. Expression of wild-type, but not mutant, DOCK4 in mouse osteosarcoma cells with a deletion of the endogenous gene suppresses growth in soft agar and tumor invasion in vivo. DOCK4 therefore encodes a CDM family member that regulates intercellular junctions and is disrupted during tumorigenesis.

Animals↗
PubMed2003

The parathyroid hormone-responsive B1 gene is interrupted by a t(1;7)(q42;p15) breakpoint associated with Wilms' tumour.

Wilms' tumour (WT) has a diverse and complex molecular aetiology, with several different loci identified by cytogenetic and molecular analyses. One such locus is on chromosome 7p, where cytogenetic abnormalities and loss of heterozygosity (LOH) indicate the presence of a Wilms' tumour suppressor gene. In order to isolate a candidate gene for this locus, we have characterized the breakpoint regions at a novel constitutional chromosome translocation (t(1;7)(q42;p15)), found in a child with WT and skeletal abnormalities. We identified two genes that were interrupted by the translocation: the parathyroid hormone-responsive B1 gene (PTH-B1) at 7p and obscurin at 1q. With no evidence for LOH at 1q42, we focused on the characterization of PTH-B1. We detected novel alternately spliced isoforms of PTH-B1, which were expressed in a wide range of adult and foetal tissues. Importantly, expression of two isoforms were disrupted in the WT of the t(1;7) patient. We also identified an additional splice isoform expressed only in 7p LOH tumours. The disruption of PTH-B1 by the t(1;7), together with aberrant splicing in sporadic WTs, suggests that PTH-B1 is a candidate for the 7p Wilms' tumour suppressor gene.

Alternative Splicing↗
PubMed2002

Secretin-mediated gene delivery, a specific targeting mechanism with potential for treatment of biliary and pancreatic disease in cystic fibrosis.

Gene therapy directed to the gastroenterological manifestations of cystic fibrosis (CF) would ideally be administered systemically. Such delivery would require efficient targeting at the cellular level to achieve a safe and effective therapy. Here we describe gene delivery using the secretin receptor (SR) as a basolateral target specific to the biliary and pancreatic epithelia affected in CF patients. We describe here targeting of a polycation-based nonviral gene delivery vector and retargeting of an adenoviral vector to cells expressing the SR in vitro. We were able to transfect cells expressing the SR up to 10-fold more efficiently than those not expressing the SR with a targeted polycation, SecGGC-lPEI. This targeting effect was secretin-specific and substantially reduced by competing secretin. SR-retargeted adenovirus transduced SR-expressing cells at more than sixfold higher levels than adenovirus alone. The SR may be an effective target for targeting systemically applied viral and nonviral gene delivery constructs to disease-affected tissues in CF patients.

Adenoviridae↗