Prostate tissue stiffness as measured with a resonance sensor system: a study on silicone and human prostate tissue in vitro.
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Aged↗
Biomedical subjects
Simon Phipps
Publications and source records attributed to Simon Phipps.
Limbal relaxing incisions versus on-axis incisions to reduce corneal astigmatism at the time of cataract surgery.
PURPOSE: To compare limbal relaxing incisions (LRIs) with placement of the corneal cataract incision on the steepest keratometric axis for the reduction of preexisting corneal astigmatism at the time of cataract surgery. SETTING: The Queen Elizabeth Hospital, Adelaide, South Australia, Australia. METHODS: In a prospective single center study, patients having 1.5 diopters (D) or more of keratometric astigmatism were randomly assigned to 2 surgical techniques: on-axis incisions (OAIs) consisting of a single clear corneal cataract incision centered on the steepest corneal meridian or LRIs consisting of 2 arcuate incisions straddling the steepest corneal meridian and a temporal clear corneal incision. Vector analysis of the target axis flattening effect was used to assess the efficacy of treatment. RESULTS: Seventy-one eyes of 71 patients were evaluated, 33 in the OAI group and 38 in the LRI group. Six weeks postoperatively, the flattening effect was 0.41 D (median and interquartile range 0.15 to 0.78 D) in the OAI group and 1.21 D (range 0.43 to 2.25 D) in the LRI group (P = .002). After 6 months, the flattening effect was 0.35 D (range 0.00 to 0.96 D) and 1.10 D (range 0.25 to 1.79 D), respectively (P = .004). CONCLUSION: The amount of astigmatism reduction achieved at the intended meridian was significantly more favorable with the LRI technique, which remained consistent throughout the follow-up period.
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Acute allergen-induced airway remodeling in atopic asthma.
Studies in animals and in human atopic skin suggest that allergen challenge may activate acute tissue remodeling changes via transforming growth factor-beta pathways. We determined whether inhalational allergen challenge in subjects with mild asthma induces similar acute changes to the airway epithelial mesenchymal trophic unit (EMTU). Endobronchial mucosal biopsies obtained before and 24 h after challenge were examined by confocal microscopy for extracellular matrix deposition in the reticular basement membrane (RBM). Cells actively involved in extracellular matrix synthesis were identified as immunoreactive to heat shock protein 47, a chaperone of collagen synthesis. Interleukin-4/13 and transforming growth factor-beta-activated cells were identified by specific antibodies to phosphorylated (phospho-) signal transducer and activator of transcription 6 and phospho-Smad2, respectively. After allergen challenge, there was a significant increase in the number of heat shock protein 47-positive airway fibroblasts (P = 0.003) and in the thickness of tenascin in the RBM (P = 0.031). There were also increases in the number of phospho-Smad2+ epithelial cells (P = 0.04) and nuclear phospho-Smad2+ fibroblasts (P = 0.03), as well as phospho-signal transducer and activator of transcription 6+ epithelial cells (P = 0.03), after allergen challenge. Thus, allergen challenge in patients with mild asthma induces activation of epithelial cells and fibroblasts in the EMTU as well as increased tenascin deposition within the RBM. Airway remodeling in asthma may, in part, result from repeated acute activation of the EMTU by allergen exposure.
Allergens↗
A role for eosinophils in airway remodelling in asthma.
Over the years, the role of the eosinophil in asthma and allergic processes has been disputed. Recent human experiments using a humanised monoclonal antibody to interleukin-5 (IL-5), and animal studies involving specific IL-5 gene deletion, indicates that eosinophils might control downstream repair and remodelling processes. Eosinophils are a rich source of fibrogenic factors, particularly transforming growth factor-beta (TGF-beta), the latent form of which is activated by epithelial-cell expression of the intergin alpha(v)beta(6). The emerging role for the eosinophil in airway remodelling might be important in future anti-asthma strategies. However, more effective eosinophil-depleting agents than anti-IL-5 are required before the definitive role of this cell type in asthma airway pathophysiology can be established.
Animals↗
Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin.
Anti-IL-5 monoclonal antibody (mepolizumab) reduces baseline bronchial mucosal eosinophils and deposition of extracellular matrix proteins in the reticular basement membrane in mild asthma. Here we report the effect of anti-IL-5, in the same patients, on allergen-induced eosinophil accumulation, tenascin deposition (as a marker of repair and remodelling) and the magnitude of the late-phase allergic cutaneous reaction. Skin biopsies were performed in 24 atopic subjects at allergen- and diluent-injected sites before 6 and 48 h after, three infusions of a humanized, monoclonal antibody against IL-5 (mepolizumab) using a randomized double-blind, placebo-controlled design. Anti-IL-5 significantly inhibited eosinophil infiltration in 6 h and 48 h skin biopsies as well as the numbers of tenascin immunoreactive cells at 48 h. In contrast, anti-IL-5 had no significant effect on the size of the 6 or 48 h late-phase cutaneous allergic reaction. This study (a) suggests that eosinophils are unlikely to cause the redness, swelling, and induration characteristic of the peak (6 h) late-phase cutaneous allergic reaction and (b) shows that decreases in tenascin positive cells at 48 h correlates with reduction of eosinophils, so providing further evidence of involvement in remodelling processes associated with allergic inflammation.
Adolescent↗
Quantitative morphometric analysis of individual resected prostatic tissue specimens, using immunohistochemical staining and colour-image analysis.
OBJECTIVE: To develop a method for obtaining morphometric measurements representative of individual chips from transurethral resection of the prostate (TURP). MATERIALS AND METHODS: In all, 232 sections were cut in pairs from 25 TURP chips, collected from four patients undergoing TURP for benign prostatic hyperplasia. Individual tissue chips were processed, embedded in paraffin wax and pairs of neighbouring sections cut from the specimens at intervals of 300 microm throughout the thickness of the specimen. Of each pair, the epithelial tissue (ET) of one and the smooth muscle (SM) of the other section were stained immunohistochemically with anti-prostate-specific antigen and anti-SM myosin, respectively. Proportions of ET and SM within the sections were measured with colour-image analysis and calculated within the TURP chips using all pairs of sections cut from the specimen, and the first pair of sections only. The differences between the sets of results were analysed using descriptive statistics. RESULTS: From each TURP chip, 3-7 pairs of sections were cut; for both ET and SM within each chip the differences between the results calculated using data from all pairs of sections and the first pair alone were small, as were the distributions of these differences within each prostate. CONCLUSIONS: Morphometric measurements from one section from a processed TURP chip, as opposed to serial sections, can be used to reliably assess the morphology of tissue within that specimen. This permits a considerable saving of resources when undertaking morphometric image analysis of resected prostatic tissue specimens.
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Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor alpha-chain expression by cytokines: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor alpha expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor alpha expression.
Our recent data suggested that tissue eosinophils may be relatively insensitive to anti-IL-5 treatment. We examined cross-regulation and functional consequences of modulation of eosinophil cytokine receptor expression by IL-3, IL-5 GM-CSF, and eotaxin. Incubation of eosinophils with IL-3, IL-5, or GM-CSF led to reduced expression of IL-5R alpha, which was sustained for up to 5 days. Eosinophils incubated with IL-5 or IL-3 showed diminished respiratory burst and mitogen-activated protein kinase kinase phosphorylation in response to further IL-5 stimulation. In contrast to these findings, eosinophil expression of IL-3R alpha was increased by IL-3, IL-5, and GM-CSF, whereas GM-CSF receptor alpha was down-regulated by GM-CSF, but was not affected by IL-3 or IL-5. CCR3 expression was down-regulated by IL-3 and was transiently reduced by IL-5 and GM-CSF, but rapidly returned toward baseline. Eotaxin had no effect on receptor expression for IL-3, IL-5, or GM-CSF. Up-regulation of IL-3R alpha by cytokines was prevented by a phosphoinositol 3-kinase inhibitor, whereas this and other signaling inhibitors had no effect on IL-5R alpha down-regulation. These data suggest dynamic and differential regulation of eosinophil receptors for IL-3, IL-5, and GM-CSF by the cytokine ligands. Since these cytokines are thought to be involved in eosinophil development and mobilization from the bone marrow and are present at sites of allergic inflammation, tissue eosinophils may have reduced IL-5R expression and responsiveness, and this may explain the disappointing effect of anti-IL-5 therapy in reducing airway eosinophilia in asthma.
Cell Differentiation↗
Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics.
Eosinophil-derived TGF-beta has been implicated in remodeling events in asthma. We hypothesized that reduction of bronchial mucosal eosinophils with anti-IL-5 would reduce markers of airway remodeling. Bronchial biopsies were obtained before and after three infusions of a humanized, anti-IL-5 monoclonal antibody (mepolizumab) in 24 atopic asthmatics in a randomized, double-blind, placebo-controlled study. The thickness and density of tenascin, lumican, and procollagen III in the reticular basement membrane (RBM) were quantified immunohistochemically by confocal microscopy. Expression of TGF-beta1 mRNA by airway eosinophils was assessed by in situ hybridization, and TGF-beta1 protein was measured in bronchoalveolar lavage (BAL) fluid by ELISA. At baseline, airway eosinophil infiltration and ECM protein deposition was increased in the RBM of asthmatics compared with nonasthmatic controls. Treating asthmatics with anti-IL-5 antibody, which specifically decreased airway eosinophil numbers, significantly reduced the expression of tenascin, lumican, and procollagen III in the bronchial mucosal RBM when compared with placebo. In addition, anti-IL-5 treatment was associated with a significant reduction in the numbers and percentage of airway eosinophils expressing mRNA for TGF-beta1 and the concentration of TGF-beta1 in BAL fluid. Therefore eosinophils may contribute to tissue remodeling processes in asthma by regulating the deposition of ECM proteins.
Antibodies, Monoclonal↗
The relationship between allergen-induced tissue eosinophilia and markers of repair and remodeling in human atopic skin.
Several in vitro studies suggest that eosinophils may play a role in fibrosis, remodeling, and repair processes associated with IgE-mediated hypersensitivity. However, the relationship in vivo, between allergen-induced tissue eosinophilia and markers of repair has yet to be established in human atopic subjects. Using the allergen-induced cutaneous late-phase reaction as a model of allergic inflammation, we have tested the hypothesis that eosinophil-derived TGF-beta1 and IL-13 are temporarily associated with myofibroblast formation and deposition of tenascin and procollagen I. Biopsies were taken from atopic volunteers at 1, 3, 6, 24, 48, and 72 h after intradermal allergen challenge and were examined by immunohistochemistry. Following the peak of the late-phase reaction (6 h) there were persisting TGF-beta1(+) eosinophils, alpha-smooth muscle actin(+) myofibroblasts, tenascin immunoreactivity, and procollagen-I(+) cells 24-48 h postchallenge. Direct evidence of generation of repair markers was obtained by coculture of eosinophils and fibroblasts. This resulted in alpha-smooth muscle actin immunoreactivity that was inhibitable by neutralizing Abs to TGF-beta as well as production of tenascin transcripts and protein product. TGF-beta1 and IL-13 also induced tenascin expression. We conclude that TGF-beta1 and IL-13, provided partially by eosinophils, contribute to repair and remodeling events in allergic inflammation in human atopic skin.
Actins↗