Role of endothelin in the exercise intolerance of chronic heart failure

In conclusion, plasma levels of the endothelialderived vasoconstrictor endothelin-1 (but not those of other neurohormonal vasoconstrictor factors), measured during exercise correlated closely with objective variables of exercise capacity in patients with heart failure. These findings suggest that endothelin-1 may contribute to exercise intolerance in patients with heart failure, perhaps by limiting the ability of the peripheral vasculature to dilate during exercise.     

Relative motion of lung and chest wall promotes uniform pleural space thickness

The pleural space is modeled in two dimensions as a thin layer of fluid separating a deformable membrane and a rigid surface containing a bump. We computed the steady-state membrane configuration and fluid pressure distribution during relative sliding of the two surfaces. For physiologically relevant values of membrane tension, shear flow-induced pressures near the bump and far-field pressure gradients are similar to those measured in vivo within the pleural space (e.g. Lai-Fook et al.) [J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 56 (1984) 1633-1639]. Deformation of the membrane over the bump suggests that the pressure field generated by the sliding motion promotes an even layer of fluid in the pleural space, preventing asperities from touching. Results also suggest a possible mechanism for pleural fluid redistribution during breathing, whereby irreversible fluid motion is associated with the deformability of the membrane.     

An Automated Self‐Similarity Analysis of the Pulmonary Tree of the Sprague–Dawley Rat

We present the results of an automated analysis of the morphometry of the pulmonary airway trees of the Sprague–Dawley rat. Our work is motivated by a need to inform lower‐dimensional mathematical models to prescribe realistic boundary conditions for multiscale hybrid models of rat lung mechanics. Silicone casts were made from three age‐matched, male Sprague–Dawley rats, immersed in a gel containing a contrast agent and subsequently imaged with magnetic resonance (MR). From a segmentation of this data, we extracted a connected graph, representing the airway centerline. Segment statistics (lengths and diameters) were derived from this graph. To validate this MR imaging/digital analysis method, airway segment measurements were compared with nearly 1,000 measurements collected by hand using an optical microscope from one of the rat lung casts. To evaluate the reproducibility of the MR imaging/digital analysis method, two lung casts were each imaged three times with randomized orientations in the MR bore. Diameters and lengths of randomly selected airways were compared among each of the repeated imaging datasets to estimate the variability. Finally, we analyzed the morphometry of the airway tree by assembling individual airway segments into structures that span multiple generations, which we call branches. We show that branches not segments are the fundamental repeating unit in the rat lung and develop simple mathematical relationships describing these structures for the entire lung. Our analysis shows that airway diameters and lengths have both a deterministic and stochastic character. Anat Rec, 2008. © 2008 Wiley‐Liss, Inc.     

Role of predicted transmembrane domains for type III translocation, pore formation, and signaling by the Yersinia pseudotuberculosis YopB protein

YopB is a 401-amino-acid protein that is secreted by a plasmid-encoded type III secretion system in pathogenic Yersinia species. YopB is required for Yersinia spp. to translocate across the host plasma membrane a set of secreted effector proteins that function to counteract immune signaling responses and to induce apoptosis. YopB contains two predicted transmembrane helices (residues 166 to 188 and 228 to 250) that are thought to insert into the host plasma membrane during translocation. YopB is also required for pore formation and host-cell-signaling responses to the type III machinery, and these functions of YopB may also require membrane insertion. To elucidate the importance of membrane insertion for YopB function, YopB proteins containing helix-disrupting double consecutive proline substitutions in the center of each transmembrane domain were constructed. Yersinia pseudotuberculosis strains expressing the mutant YopB proteins were used to infect macrophages or epithelial cells. Effector translocation, pore formation, and host-cell-signaling responses were studied. Introduction of helix-disrupting substitutions into the second transmembrane domain of YopB resulted in a nonfunctional protein that was not secreted by the type III machinery. Introduction of helix-disrupting substitutions into the first transmembrane domain of YopB resulted in a protein that was fully functional for secretion and for interaction with YopD, another component of the translocation machinery. However, the YopB protein with helix-disrupting substitutions in the first transmembrane domain was partially defective for translocation, pore formation, and signaling, suggesting that all three functions of YopB involve insertion into host membrane.     

The additive benefit of hypnosis and cognitive-behavioral therapy in treating acute stress disorder

This research represents the first controlled treatment study of hypnosis and cognitive- behavioral therapy (CBT) of acute stress disorder (ASD). Civilian trauma survivors (N=87) who met criteria for ASD were randomly allocated to 6 sessions of CBT, CBT combined with hypnosis (CBT-hypnosis), or supportive counseling (SC). CBT comprised exposure, cognitive restructuring, and anxiety management. CBT-hypnosis comprised the CBT components with each imaginal exposure preceded by a hypnotic induction and suggestions to engage fully in the exposure. In terms of treatment completers (n=69), fewer participants in the CBT and CBT-hypnosis groups met criteria for posttraumatic stress disorder at posttreatment and 6-month follow-up than those in the SC group. CBT-hypnosis resulted in greater reduction in reexperiencing symptoms at posttreatment than CBT. These findings suggest that hypnosis may have use in facilitating the treatment effects of CBT for posttraumatic stress.     

Improving delivery of hydrophobic drugs from hydrogels through cyclodextrins

A simple and effective technique of improving delivery of hydrophobic drugs from swellable systems is presented. Conventional methods of drug loading in hydrogel systems are limited by the characteristics of the pharmacological agent. The approach we present uses complexants to modulate drug release. Crosslinked poly(ethylene glycol) (PEG) hydrogels were synthesized, characterized, and used for vascular applications. The release of cyclosporine (CyA) from PEG hydrogels is significantly altered by the sterilization techniques. It was hypothesized that the release of CyA from PEG hydrogels can be modulated by using complexants. A cyclodextrin-CyA complex solution was prepared and used for drug loading. The sterilized PEG hydrogels that were loaded using the cyclodextrin-CyA complex solution had favorable release characteristics compared with the release from PEG hydrogels that were loaded using the conventional technique. Hence, drug release from swellable systems can be tailored by the application of this strategy.     

GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice

GM-CSF promotes homeostasis of myeloid cells. We report that GM-CSF upregulates mRNA and protein production of the soluble form of membrane bound VEGF receptor-1 (sVEGFR-1) in human monocytes. This sVEGFR-1 was biologically active, as cell-free supernatants from GM-CSF-stimulated monocytes blocked detection of endogenously expressed VEGF and inhibited endothelial cell migration and tube formation, even in the presence of exogenous rhVEGF. VEGF activity was recovered by neutralizing sVEGFR-1. To determine whether these events were important in vivo, Matrigel plugs were incubated with rhVEGF, rhGM-CSF, or rhGM-CSF/rhVEGF and injected into mice. Plugs containing GM-CSF or GM-CSF/VEGF had less endothelial cell invasion than plugs containing rhVEGF and were similar to plugs incubated with PBS alone. Neutralizing antibodies specific for sVEGFR-1 injected in these plugs reversed the effects of GM-CSF or GM-CSF/VEGF, while an isogenic antibody did not. Thus, GM-CSF and monocytes play a vital role in angiogenesis through the regulation of VEGF and sVEGFR-1.