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Biomedical subjects

G P Lewis

Publications and source records attributed to G P Lewis.

At least 19 recordsLinked to original sources
PubMed1995

Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study.

A 16-week, double-blind, placebo controlled, dose titration study was done on 100 normotensive patients age 45 years or older to determine the efficacy and safety of doxazosin, a selective alpha 1-adrenoceptor antagonist, in the treatment of benign prostatic hyperplasia (BPH). Of the 41 efficacy evaluable patients 88% underwent dose titration to a maximum of 8 mg. doxazosin once daily. Maximum and average urinary flow rates increased significantly above baseline with doxazosin (2.9 ml. per second and 1.4 ml. per second, respectively) compared with placebo (0.7 ml. per second and 0.3 ml. per second, respectively). A significant effect on maximum flow rate was noted as early as week 2 of double-blind treatment at the initial efficacy evaluation. Doxazosin was superior to placebo in patient and investigator assessments of total, obstructive and irritative BPH symptoms. The onset of efficacy for total patient-assessed symptoms was significant for doxazosin compared to placebo 4 weeks after the start of the treatment regimen. Statistically significant decreases in mean blood pressure of 4 to 6 mm. Hg were noted with doxazosin compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 44% of patients given doxazosin and 30% of those given placebo. Our results strongly demonstrate that doxazosin is significantly superior to placebo in the treatment of BPH in normotensive patients, with the patient experiencing significant relief early after initiation of therapy.

Aged↗
PubMed1995

Changes in the organization and expression of cytoskeletal proteins during retinal degeneration induced by retinal detachment.

PURPOSE: The goal of this study was to determine the changes in the organization of the retinal cytoskeleton after experimental retinal detachment. METHODS: Cat retinas were detached from the retinal pigment epithelium and then processed for Western blot analysis and fluorescence microscopy. Proteins examined included glial fibrillary acidic protein (GFAP), vimentin, tubulin, and actin. Sections were viewed using a laser scanning confocal microscope. RESULTS: GFAP and vimentin: At 1 day after detachment, there was an aggregation of intermediate filaments in the endfoot of Müller cells. At 3 days, intermediate filament containing Müller cell processes could be detected within the subretinal space, and, at 28 days, these processes formed large glial scars in the subretinal space. beta-tubulin: At 3 days after detachment, an increase in immunolabeling could be detected within the Müller cell endfoot and in Müller cell processes within the subretinal space. Actin: At 3 days after detachment, rhodamine-phalloidin staining decreased in the inner segments, the photoreceptor synaptic terminals, and the outer limiting membrane. CONCLUSIONS: The decrease in labeling of the photoreceptor inner segment and synaptic terminal cytoskeleton may be a key indicator of early changes in photoreceptors after detachment. The increase in cytoskeletal proteins GFAP, vimentin, and tubulin within the retinal Müller cells after detachment may help to stabilize this cell type as it hypertrophies during glial scar formation. Inhibition of this response may aid in the treatment of diseases in which Müller cell hypertrophy plays a role.

Animals↗
PubMed1995

Apoptotic photoreceptor degeneration in experimental retinal detachment.

PURPOSE: To investigate the possibility that cell death in retinal detachment may occur by reactivation of apoptotic programmed cell death mechanisms. METHODS: Unilateral retinal detachments were created in adult cats using 0.25% sodium hyaluronate; detached and control retinas were studied at different intervals. Internucleosomal DNA fragmentation (one of the landmarks of apoptosis) was investigated in tissue sections with the TUNEL technique, which uses terminal transferase to label with biotinylated nucleotides the 3' ends of DNA fragments. Sections also were labeled with propidium iodide, which intensely stains pyknotic nuclei. In addition, one time point was selected for analysis with electron microscopy. RESULTS: TUNEL-positive (T+) and propidium iodide-positive (PI+) cells almost never were observed in retinas from control eyes, but they were abundant at defined time points after retinal detachment, appearing almost exclusively in the photoreceptor layer. Their frequency was particularly high 1 to 3 days after detachment but declined rapidly over the next several weeks. T+ cells were still present 28 days after retinal detachment. Electron microscopy also revealed evidence of apoptotic cells after retinal detachment. CONCLUSIONS: Results are consistent with the hypothesis that photoreceptor degeneration after retinal detachment occurs through apoptosis, usually associated with intrinsic, programmed cell death mechanisms. The detection of a rapid wave of photoreceptor degeneration seems to suggest that early therapeutic interventions might be recommended; agents capable of interfering with the apoptotic mechanism could have a role in the prevention of cell losses that represent a critical complication of retinal detachment.

Animals↗
PubMed1995

Use of the MIB-1 antibody for detecting proliferating cells in the retina.

PURPOSE: To study intraretinal proliferation as a response to experimental retinal detachment using an antibody that recognizes the nuclear specific antigen Ki-67 in proliferating cells. METHODS: Experimental retinal detachments were produced in cats (1, 3, 7, and 28 days) and rabbits (1, 3, and 7 days). The animals were killed and the eyes were fixed and embedded in paraffin. Histologic sections were processed for immunohistochemistry using the MIB-1 antibody to detect the Ki-67 protein. Labeled cells were identified, and the proliferative response was quantified. RESULTS: In normal cat retina, approximately 0.05 cells per millimeter of retina are labeled. In cat retina detached for 1, 3, 7, or 28 days, the number of cells labeled by MIB-1 is 0.06, 5.03, 1.38, and 0.23 cells per millimeter of retina, respectively. MIB-1 labeling yields an approximate fivefold increase over the number of proliferating cells detected in retinal sections using 3H-thymidine autoradiography. Detachment of the rabbit retina elicits a similar response as measured by MIB-1 immunohistochemistry. CONCLUSIONS: In contrast to 3H-thymidine, which labels cells in S-phase only, the MIB-1 antibody labels proliferating cells regardless of their location within the cell cycle. MIB-1 labeling, therefore, is a more accurate means of evaluating cellular proliferation in the retina and elsewhere in the central nervous system, and it is a relatively simple way of evaluating the effects of agents that may affect this response.

Animals↗
PubMed1994

Rapid changes in the expression of glial cell proteins caused by experimental retinal detachment.

We examined the expression of several proteins normally present in Müller's glia after the production of experimental retinal detachment in adult cats. Retinas were detached for one-half to seven days, after which the tissue was processed for correlative immunocytochemistry and biochemistry. Previous studies demonstrated that the intermediate filament proteins glial fibrillary acidic protein and vimentin, increase after long-term retinal detachment (30 to 60 days), whereas glutamine synthetase, carbonic anhydrase C, and cellular retinaldehyde-binding protein all decrease to barely detectable levels. Alterations in Müller cell protein expression are rapid and specific events that can be detected as early as two days after retinal detachment. By seven days, levels of protein expression are similar to those in the long-term retinal detachments. Within the first week after injury the Müller cell processes hypertrophy and begin forming glial scars, which indicates that early intervention may be required to halt or reverse the effects of detachment.

Animals↗
PubMed1992

Basic fibroblast growth factor: a potential regulator of proliferation and intermediate filament expression in the retina.

Proliferation of astrocytes, and a concomitant increase of intermediate filaments in astrocytes are two fundamental responses of the CNS to injury. We have previously identified these two events in the retina's response to detachment of the neural retina from the adjoining monolayer of retinal pigmented epithelium. In order to analyze the potential role of basic fibroblast growth factor (bFGF) in these responses, we studied cellular proliferation and intermediate filament protein expression in the retinas of cats and rabbits 4 d and 4 weeks after a single intravitreal injection of 1 microgram of bFGF. Our results show that bFGF stimulates both of these processes in an otherwise normal eye. The eyes that received bFGF had significantly elevated numbers of 3H-thymidine-labeled Müller cells, astrocytes, vascular cells, retinal pigmented epithelial cells, microglia, and macrophages by comparison to control eyes. This proliferation was apparent at 4 d after the injection of bFGF but not after 4 weeks. In control eyes, antibodies to glial fibrillary acidic protein and vimentin labeled intermediate filaments only in the inner (vitread) portion of the Müller cells, the specialized radial astrocytes that span the width of the retina. In eyes that had been injected with bFGF, almost the entire Müller cell cytoplasm was labeled at 4 d after injection; after 4 weeks, the cytoplasmic labeling intensity had increased significantly. Release or activation of endogenous stores of bFGF after injury or disease may be involved in the control of cellular proliferation and intermediate filament expression in the retina and elsewhere in the CNS.

Animals↗
PubMed1991

Sequestration of basic fibroblast growth factor in the primate retinal interphotoreceptor matrix.

The interphotoreceptor matrix (IPM) occupies the extracellular space between the photoreceptors of the retina and the apical surface of the retinal pigmented epithelium. A large proportion of the IPM is composed of aqueous-insoluble glycoconjugates, including chondroitin sulfate-containing proteoglycans, the distribution of which exhibits both apical-basal and photoreceptor cell type-specific heterogeneities. The precise function of most insoluble IPM constituents is unknown, although the available evidence suggests some may contribute to retinal adhesion or photoreceptor survival. We have now identified basic fibroblast growth factor (bFGF), or an immunologically related protein from the FGF family, within the IPM. The IPM is labeled on sections of primate retinas by a battery of polyclonal antibodies (Abs) directed against various peptide sequences of bFGF and by an Ab to bovine brain bFGF. bFGF Abs also bind to purified preparations of aqueous-insoluble IPM. All bFGF Abs utilized cross-react with equivalent low molecular mass components of 16.5-17.5 kDa on Western blots of insoluble IPM proteins, purified bFGF, and recombinant bFGF. The Abs do not bind any aqueous-soluble IPM components, suggesting that the bFGF is normally bound to an insoluble IPM constituent(s) in situ. The fact that bFGF is sequestered in the IPM and is located in such close proximity to the photoreceptors, the retinal pigmented epithelium, and Mueller's glia raises the strong possibility that it is synthesized by and regulates the activities of one or more of these three cell types in vivo.

Animals↗
PubMed1991

Opsin distribution and protein incorporation in photoreceptors after experimental retinal detachment.

The distribution of opsin was examined immunocytochemically after experimental retinal detachment in adult cats. Retinal detachments were produced by injecting fluid between the retinal pigment epithelium and neural retina. One to 60 days later the animals were killed. Tissue areas from detached and attached retinal regions from the eye with the detached retina, as well as normal (control) retinas, were processed for post-embedding light and electron microscopic immunocytochemistry. In normal and attached retinal regions, anti-opsin labeled the outer segments and Golgi apparatus most heavily, although the entire photoreceptor plasma membrane was labeled at a low level. Beginning at 2 days after retinal detachment, immunolabeling increased in the photoreceptor inner segment, cell body and synaptic terminal plasma membranes. This pattern of anti-opsin labeling continued at all intervals up through the 60-day detachment time-point. Injection of radiolabeled amino acid in detachments from 1 to 30 days show that radiolabeled protein is still transported to the truncated outer segments of the photoreceptor cells. In addition, these outer segment disks label with anti-opsin. These data imply that opsin continues to be transported and incorporated into the outer segments of photoreceptors showing severe degeneration as a result of long-term detachment from the RPE.

Animals↗
PubMed1991

Intraretinal proliferation induced by retinal detachment.

Cellular proliferation after retinal detachment was studied by 3H-thymidine light microscopic autoradiography in cats that had experimental detachments of 0.5-180 days duration. The animals underwent labeling 2 hr before death with an intraocular injection of 200 microCi of 3H-thymidine. The number of labeled nuclei were counted in 1-micron thick tissue sections in regions of detachment, in regions of the experimental eyes that remained attached, and in control eyes that had no detachments. In the normal eye, in one that had only the lens and vitreous removed, and in the eyes with 0.5- and 1-day detachments, the number of labeled nuclei ranged from 0/mm (0.5-day detachment) to 0.38/mm (lens and vitreous removed only). By 2 days postdetachment, the number of labeled nuclei increased to 2.09/mm. The highest levels of labeling occurred in two animals with detachments of 3 (7.86/mm) and 4 (7.09/mm) days. Thereafter, the numbers declined steadily until near-baseline counts were obtained at 14 days. The number of labeled nuclei was slightly elevated in the attached regions of two animals with 3-day detachments. Labeled cell types included: Müller cells, astrocytes, pericytes, and endothelial cells of the retinal vasculature, and both resident (microglial cells) and invading macrophages. In an earlier study RPE cells were also shown to proliferate in response to detachment. Thus, these data show that proliferation is a rapid response to detachment, reaching a maximum within 4 days, and that virtually every nonneuronal cell type in the retina can participate in this response. The data suggest that events leading to such clinical manifestations as proliferative vitreoretinopathy and subretinal fibrosis may have their beginnings in this very early proliferative response.

Animals↗
PubMed1990

Role of tumor necrosis factor in flavone acetic acid-induced tumor vasculature shutdown.

Flavone acetic acid (FAA), a novel investigational antitumor agent, has been shown to cause early vascular shutdown in several experimental murine tumors, and this phenomenon is believed to be crucial to FAA's antitumor effects. However, the basis of this FAA-induced tumor vascular shutdown is unknown. In this study a radioactive tracer-clearance technique has been used as an objective indication of tumor blood flow to show that i.p. administered FAA induces a progressive and sustained reduction in blood flow in a colon 26 tumor growing s.c. in syngeneic mice. As early as 1 h after administration, there was a significant increase in the t1/2 clearance value for intratumorally injected 133Xe, reaching a peak at 3 h (117.3 +/- 36.4 versus 7.8 +/- 0.85 min for controls). Significant inhibition of blood flow was still apparent 48 h after a single injection of drug. This FAA-induced vascular shutdown was virtually abolished in tumor-bearing mice pretreated with an antiserum against tumor necrosis factor, while no such effect was observed in controls pretreated with nonimmune serum (t1/2 of 10.8 +/- 1.2 versus 65.6 +/- 8.0 min for controls). Furthermore, in vitro FAA was seen to induce tumor necrosis factor secretion from murine peritoneal cells and splenocytes. These studies suggest that FAA-induced tumor vascular shutdown in the colon 26 tumor is mediated by tumor necrosis factor.

Animals↗
PubMed1990

Inhibition of prostacyclin formation by cyclosporin is not due to reduced availability of arachidonic acid in membrane phospholipids of cultured human endothelial cells.

Our studies have shown that CS inhibits PGI2 production in HUVEC, that this inhibition is not overcome when exogenous AA is supplied, that the inhibitory action of CS is proximal to PGI2 synthetase and finally that there is abundant free AA available in membrane phospholipids of CS treated HUVEC [4,5]. In conclusion, CS does not appear to inhibit PGI2 synthesis by reducing the availability of free AA in the endothelial cell membrane. Although CS appears to inhibit cyclo-oxygenase, we can not exclude an additional effect on acyltransferase.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Diurnal blood pressure in patients with mild-to-moderate hypertension treated with once-daily benazepril hydrochloride.

This study evaluated the blood pressure effects of administration of once daily oral benazepril hydrochloride, a new angiotensin-converting enzyme (ACE) inhibitor, for mild-to-moderate hypertension. After a 2 to 4 week placebo baseline period, patients with diastolic blood pressure between 95 and 114 mm Hg, were randomized to receive either placebo or benazepril hydrochloride, 5, 10, 20, or 40 mg, once daily in double-blind fashion for 28 days. Blood pressure was measured predose and at 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after the dose during inpatient observation days at the end of the placebo baseline period, and on the first and last day of the double-blind treatment period; and 24 hours after the dose at weekly outpatient visits. All doses of benazepril hydrochloride resulted in clinically important reductions in diastolic and systolic blood pressures that lasted between 12 and 24 hours after both the first dose, and following the last dose after 4 weeks of treatment. The findings indicate that benazepril hydrochloride may be clinically useful as once-daily monotherapy in many patients with hypertension.

Administration, Oral↗
PubMed1989

Inhibitory effects of diclofenac and indomethacin on interleukin-1-induced changes in PGE2 release. A novel effect on free arachidonic acid levels in human synovial cells.

The inhibitory effects of two non-steroidal anti-inflammatory drugs (NSAIDS), diclofenac and indomethacin, on interleukin-1 (IL-1)-induced changes in arachidonic acid (AA) release and prostaglandin E2(PGE2) production by human synovial cells was investigated. Both diclofenac and indomethacin potently inhibited IL-1 alpha-induced PGE2 release, with IC50 values of 1.6 +/- 0.02 nM and 5.5 +/- 0.1 nM, respectively. A novel effect on IL-1 alpha-mediated changes in AA levels was observed using cells labelled with radioactive AA. Both drugs at micromolar concentrations (10-30 microM) showed an apparent inhibition of IL-1 alpha-induced increases in radioactivity associated with free AA. Concomitant with this inhibition, there was an increase in radioactivity associated with phosphatidylethanolamine (PE) and triglyceride (TG). As the drugs had no effect on IL-1 alpha-induced decreases in radioactivity associated with phosphatidylcholine (PC), this result was interpreted as being due to an enhanced acylation of AA into PE and TG. These results suggest that whilst at nanomolar concentrations, diclofenac and indomethacin can inhibit IL-1 alpha-induced PGE2 output, at micromolar concentrations an effect on free AA levels is also evident. This may have consequences for the release of other mediators such as leukotrienes, whose synthesis also involves the level of free AA.

Acute-Phase Reaction↗
PubMed1989

Prostanoid production by rat aortic endothelial cells by bradykinin and histamine.

The present studies demonstrate that rat aortic endothelial cells, when stimulated with either bradykinin or histamine, caused the release of both PGI2 and PGE2. The method has also been used to characterize the histamine receptor involved which is H1-subtype. The findings suggest that prostanoid production by bradykinin and histamine constitutes an alternative mechanism to endothelium-derived relaxing factor in mediating vasodilatation.

Animals↗
PubMed1989

Interleukin-1 potentiates bradykinin- and TNF alpha-induced PGE2 release.

The ability of interleukin-1 (IL-1 alpha), IL-1 beta, tumour necrosis factor alpha (TNF alpha) and bradykinin to cause prostaglandin E2 (PGE2) release from human synovial cells was examined. IL-1 alpha and IL-beta proved equipotent in their effect, and were up to four orders of magnitude more potent than TNF alpha after incubation for 24 h. Bradykinin proved the weakest of all the agonists examined. When the cells were pretreated with IL-1 alpha or IL-1 beta for 24 h, their ability to release PGE2 in response to a short incubation (1 h) with bradykinin, TNF alpha or a second dose of IL-1 was potentiated. In addition, TNF alpha and bradykinin were shown to increase the level of free arachidonic acid (AA) in the cells. Furthermore, a similar potentiation in the response of pretreated cells was observed with exogenous AA. It is already known that pretreatment with IL-1 for 24 h results in an induction of cyclo-oxygenase (CO). It seems likely, therefore, that activation of phospholipase A2 which occurs during a short incubation with IL-1, TNF alpha or bradykinin releases substrate, AA, which is more rapidly converted to PGE2 by cells in which CO has been induced. The result of these events might indicate a sustained release of PGE2 at sites of inflammation where such mediators are released.

Arachidonic Acid↗
PubMed1989

Factors influencing blood supply in wound granuloma quantitated by a new in vivo technique.

A new quantitative assay for measuring angiogenesis in a s.c. located sponge implant in rats is described. Using this model, which detects neovascularization by measuring alterations in 133Xe clearance, it has been shown that the known angiogenic factors, transforming growth factor alpha and tumor necrosis factor alpha, cause maximum vascularization of the sponge to occur by Day 11 postimplantation compared with Days 15 to 17 in control animals. The monokine interleukin 1 alpha is shown to be strongly angiogenic, suggesting that more than one macrophage-derived cytokine may be the active mediator in macrophage-induced angiogenesis. Extracellular matrix proteins appear to play a role in regulating the angiogenic response such that presoaking sponges in laminin (40 micrograms/ml) or fibrinogen (500 micrograms/ml) solutions induced a significant reduction in the time taken to achieve maximum 133Xe clearance values; no such enhancement of neovascularization was observed when sponges were presoaked in type IV collagen (100 micrograms/ml) solution. The assay described here, which is reproducible, objective, and quantitative, should be of considerable use in elucidating the molecular basis of angiogenesis regulation.

Animals↗
PubMed1989

PMN stimulation by factors from IL-1-treated human synovial cell cultures.

Following exposure of cultured human synovial cells to human recombinant interleukin 1 alpha (IL-1 alpha), we demonstrate the appearance of factors in the supernatant which stimulate human polymorphonuclear leukocyte (PMN) locomotion and elevate intracellular free calcium ([Ca++]i). The production of these factors can be abolished by actinomycin D or dexamethasone but not by cyclo-oxygenase or lipoxygenase inhibitors. In vivo, the supernatant induces a rapid accumulation of PMNs in rabbit skin following intradermal injection. These activities were not due to IL-1 itself, tumour necrosis factor (TNF alpha) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Such factors may play an important role in inflammatory responses involving IL-1.

Animals↗