Analysis of Regional Mechanics in Canine Lung Injury Using Forced Oscillations and 3D Image Registration

Acute lung injury is characterized by heterogeneity of regional mechanical properties, which is thought to be correlated with disease severity. The feasibility of using respiratory input impedance ($Z_{rs}$) and computed tomographic (CT) image registration for assessing parenchymal mechanical heterogeneity was evaluated. In six dogs, measurements of ($Z_{rs}$) before and after oleic acid injury at various distending pressures were obtained, followed by whole lung CT scans. Each ($Z_{rs}$) spectrum was fit with a model incorporating variable distributions of regional compliances. CT image pairs at different inflation pressures were matched using an image registration algorithm, from which distributions of regional compliances from the resulting anatomic deformation fields were computed. Under baseline conditions, average model compliance decreased with increasing inflation pressure, reflecting parenchymal stiffening. After lung injury, these average compliances decreased at each pressure, indicating derecruitment, alveolar flooding, or alterations in intrinsic tissue elastance. However, average compliance did not change as inflation pressure increased, consistent with simultaneous recruitment and strain stiffening. Image registration revealed peaked distributions of regional compliances, and that small portions of the lung might undergo relative compression during inflation. The authors conclude that assessments of lung function using ($Z_{rs}$) combined with the structural alterations inferred from image registration provide unique but complementary information on the mechanical derangements associated with lung injury

Comparison of Image Registration Based Measures of Regional Lung Ventilation from Dynamic Spiral CT with Xe-CT

Purpose: Regional lung volume change as a function of lung inflation serves as an index of parenchymal and airway status as well as an index of regional ventilation and can be used to detect pathologic changes over time. In this article, we propose a new regional measure of lung mechanics --- the specific air volume change by corrected Jacobian. Methods: 4DCT and Xe-CT data sets from four adult sheep are used in this study. Nonlinear, 3D image registration is applied to register an image acquired near end inspiration to an image acquired near end expiration. Approximately 200 annotated anatomical points are used as landmarks to evaluate registration accuracy. Three different registration-based measures of regional lung mechanics are derived and compared: the specific air volume change calculated from the Jacobian (SAJ); the specific air volume change calculated by the corrected Jacobian (SACJ); and the specific air volume change by intensity change (SAI). Results: After registration, the mean registration error is on the order of 1 mm. For cubical ROIs in cubes with size 20 mm $\times$ 20 mm $\times$ 20 mm, the SAJ and SACJ measures show significantly higher correlation (linear regression, average $r^2=0.75$ and $r^2=0.82$) with the Xe-CT based measure of specific ventilation (sV) than the SAI measure. For ROIs in slabs along the ventral-dorsal vertical direction with size of 150 mm $\times$ 8 mm $\times$ 40 mm, the SAJ, SACJ, and SAI all show high correlation (linear regression, average $r^2=0.88$, $r^2=0.92$ and $r^2=0.87$) with the Xe-CT based sV without significant differences when comparing between the three methods. Conclusion: Given a deformation field by an image registration algorithm, significant differences between the SAJ, SACJ, and SAI measures were found at a regional level compared to the Xe-CT sV in four sheep that were studied

Exploring the metabolic network of the epidemic pathogen Burkholderia cenocepacia J2315 via genome-scale reconstruction

<p>Abstract</p> <p>Background</p> <p><it>Burkholderia cenocepacia </it>is a threatening nosocomial epidemic pathogen in patients with cystic fibrosis (CF) or a compromised immune system. Its high level of antibiotic resistance is an increasing concern in treatments against its infection. Strain <it>B. cenocepacia </it>J2315 is the most infectious isolate from CF patients. There is a strong demand to reconstruct a genome-scale metabolic network of <it>B. cenocepacia </it>J2315 to systematically analyze its metabolic capabilities and its virulence traits, and to search for potential clinical therapy targets.</p> <p>Results</p> <p>We reconstructed the genome-scale metabolic network of <it>B. cenocepacia </it>J2315. An iterative reconstruction process led to the establishment of a robust model, <it>i</it>KF1028, which accounts for 1,028 genes, 859 internal reactions, and 834 metabolites. The model <it>i</it>KF1028 captures important metabolic capabilities of <it>B. cenocepacia </it>J2315 with a particular focus on the biosyntheses of key metabolic virulence factors to assist in understanding the mechanism of disease infection and identifying potential drug targets. The model was tested through BIOLOG assays. Based on the model, the genome annotation of <it>B. cenocepacia </it>J2315 was refined and 24 genes were properly re-annotated. Gene and enzyme essentiality were analyzed to provide further insights into the genome function and architecture. A total of 45 essential enzymes were identified as potential therapeutic targets.</p> <p>Conclusions</p> <p>As the first genome-scale metabolic network of <it>B. cenocepacia </it>J2315, <it>i</it>KF1028 allows a systematic study of the metabolic properties of <it>B. cenocepacia </it>and its key metabolic virulence factors affecting the CF community. The model can be used as a discovery tool to design novel drugs against diseases caused by this notorious pathogen.</p

Role for Neuronal Nitric-Oxide Synthase in Cannabinoid-Induced Neurogenesis

ABSTRACT Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production. Accordingly, we measured neurogenesis in dentate gyrus (DG) and subventricular zone (SVZ) of CB1R-knockout (KO) and wild-type mice, some of whom were treated with the cannabi- or the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI). NOS activity was increased by ϳ25%, whereas bromodeoxyuridine (BrdU) labeling of newborn cells in DG and SVZ was reduced by ϳ50% in CB1R-KO compared with wild-type mice. 7-NI increased BrdU labeling in both DG and SVZ and to a greater extent in CB1R-KO than in wild-type mice. In addition, R(ϩ)-Win 55212-2 and 7-NI enhanced BrdU incorporation into neuron-enriched cerebral cortical cultures to a similar maximal extent and in nonadditive fashion, consistent with a shared mechanism of action. Double-label confocal microscopy showed coexpression of BrdU and the neuronal lineage marker doublecortin (Dcx) in DG and SVZ of untreated and 7-NI-treated CB1R-KO mice, and 7-NI increased the number of Dcx-and BrdU/Dcx-immunoreactive cells in SVZ and DG. Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO. Cannabinoids, which include naturally occurring plantderived compounds [e.g., ⌬ 9 -tetrahydrocannabinol (THC)], endogenous signaling molecules found in animal brains (e.g., anandamide and 2-arachidonoylglycerol), and synthetic drugs [e.g., R(ϩ)-Win 55212-2)], act on receptors in the brain to modify neuronal function. In addition to their effects on normal physiological functions such as blood pressure, immunity, pain perception, appetite, and cognition, cannabinoids can also regulate the severity of brain injury. We reported previously that administration of cannabinoids acting on the CB1 cannabinoid receptor (CB1R) reduces neuronal death from cerebral ischemi

Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice.

ABSTRACT Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain. To investigate this possibility, we measured neurogenesis by intraperitoneal injection of bromodeoxyuridine (BrdU), which labels newborn neurons, in wild-type and CB1R-knockout (CB1R-KO) mice. CB1R-KO mice showed reductions in the number of BrdU-labeled cells to ϳ50% of wild-type (WT) levels in dentate gyrus and subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. To test this further, WT mice were given the CB1R antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) before measuring neurogenesis with BrdU

Role for Neuronal Nitric Oxide Synthase in Cannabinoid-induced Neurogenesis

Abstract words: 240 Introduction words: 50

Systematic evaluation of genome-wide methylated DNA enrichment using a CpG island array

<p>Abstract</p> <p>Background</p> <p>Recent progress in high-throughput technologies has greatly contributed to the development of DNA methylation profiling. Although there are several reports that describe methylome detection of whole genome bisulfite sequencing, the high cost and heavy demand on bioinformatics analysis prevents its extensive application. Thus, current strategies for the study of mammalian DNA methylomes is still based primarily on genome-wide methylated DNA enrichment combined with DNA microarray detection or sequencing. Methylated DNA enrichment is a key step in a microarray based genome-wide methylation profiling study, and even for future high-throughput sequencing based methylome analysis.</p> <p>Results</p> <p>In order to evaluate the sensitivity and accuracy of methylated DNA enrichment, we investigated and optimized a number of important parameters to improve the performance of several enrichment assays, including differential methylation hybridization (DMH), microarray-based methylation assessment of single samples (MMASS), and methylated DNA immunoprecipitation (MeDIP). With advantages and disadvantages unique to each approach, we found that assays based on methylation-sensitive enzyme digestion and those based on immunoprecipitation detected different methylated DNA fragments, indicating that they are complementary in their relative ability to detect methylation differences.</p> <p>Conclusions</p> <p>Our study provides the first comprehensive evaluation for widely used methodologies for methylated DNA enrichment, and could be helpful for developing a cost effective approach for DNA methylation profiling.</p

Predictors of esophageal varices in patients with HBV-related cirrhosis: a retrospective study

<p>Abstract</p> <p>Background</p> <p>All patients with liver cirrhosis are recommended to undergo an evaluation of esophageal varices (EV) to assess their risk of bleeding. Predicting the presence of EV through non-invasive means may reduce a large number of unnecessary endoscopies. This study was designed to develop a predictive model for varices in patients with Hepatitis B virus-related cirrhosis.</p> <p>Methods</p> <p>The retrospective analysis was performed in 146 patients with Hepatitis B virus-related cirrhosis. The data were assessed by univariate analysis and a multivariate logistic regression analysis. In addition, the receiver operating characteristic curves were also applied to calculate and compare the accuracy of the model and other single parameters for the diagnosis of esophageal varices.</p> <p>Results</p> <p>We found the prevalence of EV in patients with Hepatitis B virus-related cirrhosis to be 74.7%. In addition, platelet count, spleen width, portal vein diameter and platelet count/spleen width ratio were significantly associated with the presence of esophageal varices on univariate analysis. A multivariate analysis revealed that only the spleen width and portal vein diameter were independent risk factors. The area under the receiver operating characteristic curve of regression function (RF) model, which was composed of the spleen width and portal vein diameter, was higher than that of the platelet count. With a cut-off value of 0.3631, the RF model had an excellent sensitivity of 87.2% and an acceptable specificity of 59.5% with an overall accuracy of 80.1%.</p> <p>Conclusion</p> <p>Our data suggest that portal vein diameter and spleen width rather than platelet count may predict the presence of varices in patients with Hepatitis B virus-related cirrhosis, and that the RF model may help physicians to identify patients who would most likely benefit from screenings for EV.</p