Functional effects of eotaxin are selectively upregulated on IL-5 transgenic mouse eosinophils

Synergistic interactions between cytokines, chemokines and adhesion molecules may facilitate the selective recruitment of eosinophils into sites of allergic inflammation. Ovalbumin-sensitized IL5TG mice responded to antigen challenge with robust airway eosinophilia 24 and 72 hr post-exposure. Adhesion molecule expression and functional responsiveness of immune cells derived from IL5TG mice to various inflammatory mediators were evaluated. IL5TG-derived eosinophils, but not neutrophils, expressed higher levels of CD49d and CD11b relative to WT. Functional responsiveness to eotaxin was increased in IL5TG eosinophils as demonstrated by a 10× increase in its potency in producing actin polymerization and 3× increase in CD11b upregulation relative to WT. These data are consistent with increased CCR3 expression on IL5TG eosinophils. Responsiveness of eosinophils to LTB4 or MIP-1 was similar between WT and IL-5TG mice. These data provide evidence of synergy between eosinophil-specific cytokines and chemokines that may promote accumulation of this cell type under conditions of allergic inflammation in vivo.     

Detrusor Contractility and Compliance Characteristics in Adult Male Patients With Obstructive and Nonobstructive Voiding Dysfunction

Purpose

To understand better the contractility and compliance characteristics of the detrusor in patients with varying degrees of outlet obstruction, we analyzed urodynamic studies in elderly men with obstructive and nonobstructive voiding dysfunction.

Materials and Methods

All patients were evaluated with video urodynamics, including cystometry, isometric tests, voiding profilometry and post-void residual measurement. Bladder compliance, detrusor contractility, detrusor reserve, detrusor instability and the severity of outlet obstruction were determined in each patient. Patients were stratified into 4 groups: urodynamically normal, detrusor instability, outlet obstruction and outlet obstruction with detrusor instability.

Results

A significant correlation was found between the maximum isometric contraction pressure and the severity of obstruction in 168 patients. Maximum isometric contraction pressure was significantly greater in patients with than without obstruction, independent of detrusor instability. Although compliance was not significantly different among the groups, the proportion of patients with poor compliance (less than 30 ml./cm. water) was lowest in the normal group. The detrusor reserve was significantly less in patients with chronic retention (post-void residual more than 200 ml.) than in those with lower post-void residuals.

Conclusions

The increase in detrusor contractility with increasing outlet obstruction suggests a compensatory response to obstruction. Furthermore, a decrease in bladder compliance does not appear to be a consistent finding in patients with outlet obstruction,although the proportion of patients with poor compliance is higher in the group with obstruction and/or detrusor instability than in those with normal urodynamic findings. The decrease in detrusor reserve in patients with high post-void residual volumes suggests that the detrusor reserve reflects the degree of detrusor decompensation.     

Bladder tissue regeneration using acellular bi-layer silk scaffolds in a large animal model of augmentation cystoplasty

Acellular scaffolds derived from Bombyx mori silk fibroin were investigated for their ability to support functional tissue regeneration in a porcine model of augmentation cystoplasty. Two bi-layer matrix configurations were fabricated by solvent-casting/salt leaching either alone (Group 1) or in combination with silk film casting (Group 2) to yield porous foams buttressed by heterogeneous surface pore occlusions or homogenous silk films, respectively. Bladder augmentation was performed with each scaffold group (6 × 6 cm²) in juvenile Yorkshire swine for 3 m of implantation. Augmented animals exhibited high rates of survival (Group 1: 5/6, 83%; Group 2: 4/4, 100%) and voluntary voiding over the course of the study period. Urodynamic evaluations demonstrated mean increases in bladder capacity over pre-operative levels (Group 1: 277%; Group 2: 153%) which exceeded nonsurgical control gains (144%) encountered due to animal growth. Similarly, elevations in bladder compliance were substantially higher in augmented animals from baseline (Group 1: 357%; Group 2: 147%) in comparison to controls (41%). Gross tissue evaluations revealed that both matrix configurations supported extensive de novo tissue formation throughout the entire original implantation site which exhibited ultimate tensile strength similar to nonsurgical counterparts. Histological and immunohistochemical analyses showed that both implant groups promoted comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent cytokeratin, uroplakin, and p63 protein expression in both matrix groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by synaptophysin-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. Ex vivo organ bath studies demonstrated that regenerated tissues supported by both silk matrices displayed contractile responses to carbachol, α,β-methylene-ATP, KCl, and electrical field stimulation similar to controls. Our data detail the ability of acellular silk scaffolds to support regeneration of innervated, vascularized smooth muscle and urothelial tissues within 3 m with structural, mechanical, and functional properties comparable to native tissue in a porcine model of bladder repair.     

Virtual Reality Exposure Therapy for Post-Traumatic Stress Disorder and Other Anxiety Disorders

Anxiety disorders, including phobias and post-traumatic stress disorder, are common and disabling disorders that often involve avoidance behavior. Cognitive-behavioral treatments, specifically imaginal and in vivo forms of exposure therapy, have been accepted and successful forms of treatment for these disorders. Virtual reality exposure therapy, an alternative to more traditional exposure-based therapies, involves immersion in a computer-generated virtual environment that minimizes avoidance and facilitates emotional processing. In this article, we review evidence on the application of virtual reality exposure therapy to the treatment of specific phobias and post-traumatic stress disorder and discuss its advantages and cautions.     

Theoretical analysis of the effects of viscous losses and abdominal straining on urinary outlet function

AIMS: The aim of this study was to theoretically explore the relationship between the tube law (TL) of the urethra and the pressure-flow (p-Q) relationship during micturition. The understanding of this relation is important for the evaluation of outlet obstruction by urodynamic interpretation of p-Q plots. METHODS: We simulated the outlet function by a lumped theoretical model, and suggested how the TL can be used to quantitatively predict the p-Q relationship of the system. Our analysis considered the relation between the TL and the steady state p-Q plot for various TLs including the hysteresis of the pressure-area relationship. RESULTS AND CONCLUSIONS: The inclusion of pressure losses distal to the flow controlling zone and experimentally measured p-A relations of the urethra in the model lead to the predictions that flow in the flow controlling zone is not always critical but is often in the sub-critical range, that an increase in abdominal pressure can increase the flow under certain conditions, and that hysteresis in the pressure-area relation is correlated to the hysteresis in the p-Q plot.     

The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common gamma chain, an integral component of cytokine receptors of the interleukin (IL)-2 family, including IL-4, -7, -9, -15, and -21. CP-690550 is a JAK3 inhibitor with immunosuppressive properties under development for transplantation. We evaluated alterations in circulating lymphocyte subsets in cynomolgus monkey blood following chronic (3-week), oral CP-690550 administration. Natural killer (NK) and CD8+ T cell numbers were reduced in a dose- and time-dependent manner; the latter was a primary effect on memory subsets. CD4+ T and B cell numbers were unaffected or slightly increased, respectively. NK cell numbers were reduced approximately 80% (vs. 35% in vehicle-treated animals) and returned to baseline levels within 3 weeks following treatment cessation. CD8+ T cells declined by a maximum 43% (vs. 25% for vehicle-treated animals) but rebounded significantly (300%) within 2 weeks after the last dose. Although CP-690550 did not result in reduction of CD4+ T cell number, these cells also increased (225%) within 2 weeks of treatment cessation. IL-15 is important for maintaining homeostasis of these cell types, and CP-690550 inhibited IL-15-induced CD69 expression in NK cells [inhibitory concentration 50% (IC50)=48.0+/-8.4 nM] and CD8+ T cells (IC50=16.2+/-1.5 nM).     

Predictors of virologic success in patients completing a structured antiretroviral adherence program.

This study describes the effects of a structured, educational/motivational antiretroviral adherence program on virologic and immunologic parameters in HIV-infected patients. Patients were referred because of either self- or provider-identified barriers to adherence. All patients completed 6 to 8 weekly sessions with a nurse or adherence counselor, followed by four quarterly sessions. Sessions included an adherence assessment, individualized patient education, review of adherence strategies, motivational messages, anticipatory planning, and adherence tools. The 58 patients had a mean enrollment CD4 (+) count of 223 cells/mm (3) and mean viral load of 196,454 copies/ml. At the last follow-up, the mean CD4 (+) count increased to 308 cells/mm (3) (p <.001), and mean viral load decreased to 43,309 (p <.001). Thirty (51.7%) patients achieved a viral load < 50 copies/ml at any point during follow-up. Factors associated with final viral load < 50 copies/ml included not being a cigarette smoker, receiving lamivudine in one's final regimen, and having an HIV risk behavior other than male-male sex.     

Hepatocellular carcinoma in a teenager with perinatally acquired HIV Infection without hepatitis B or C coinfection: a case report

A 19-year-old male with perinatally acquired HIV infection and AIDS (clinical stage 3) presented with a 9.1?×?5.0?cm hepatic mass. The resected mass was determined to be a hepatocellular carcinoma (HCC) without metastasis. The patient did not have active hepatitis B or C coinfection, as revealed by polymerase chain reaction (PCR), nor other risk factors for development of cirrhosis or HCC, and comprises only the second explicitly stated case of an HIV-positive individual developing HCC in the absence of concomitant hepatitis virus infection or other risk factors. This case illustrates the fact that as survival of perinatally infected individuals increases in the highly active antiretroviral therapy (HAART) era, new associations between HIV infection and other disease processes may be uncovered.