Biomedical subjects
I Grierson
Publications and source records attributed to I Grierson.
Reversal of topical antiglaucoma medication effects on the conjunctiva.
OBJECTIVE: To determine whether the adverse effects of antiglaucoma medications could be reversed before filtration surgery, potentially reducing the risk of subsequent failure. METHODS: One month before surgery, 30 patients who were receiving multiple antiglaucoma medications underwent an inferior bulbar conjunctival biopsy, ceased using sympathomimetic drops, and began treatment with topical corticosteroid, (1% fluorometholone four times daily). At the time of surgery two conjunctival biopsy specimens were obtained, one from the operation site (superior bulbar region), and one from the inferior bulbar region. The biopsy specimens were quantitatively analyzed by light microscopy. In addition, the outcome of first trabeculectomy for 16 of these patients was compared with that of 16 matched patients who had not undergone an altered preoperative regimen of topical therapy. RESULTS: During a 1-month period a notable decrease occurred in the number of fibroblasts and inflammatory cells throughout the conjunctiva. Inferior bulbar conjunctiva was found to be representative of superior bulbar conjunctiva with respect to these changes. Furthermore, evidence comparing the matched patients suggested that the altered preoperative regimen may have improved the success rate of trabeculectomy. CONCLUSIONS: The preoperative regimen used reversed the adverse conjunctival effect of topical medication. The regimen may be of clinical benefit in improving the success rate of trabeculectomy.
Ischemia-reperfusion-induced muscle damage. Protective effect of corticosteroids and antioxidants in rabbits.
We examined the potential protective effect of pretreatment with corticosteroids or antioxidants (ascorbic acid or allopurinol) in rabbits with reperfusion-induced damage to skeletal muscle after ischemia. 4 hours of limb ischemia induced by a pneumatic tourniquet, followed by reperfusion for 1 hour, caused a considerable amount of ultrastructural damage to the anterior tibialis muscles accompanied by a rise in circulating creatine kinase activity. Pretreatment of animals with depomedrone by a single 8 mg bolus injection led to a preservation of the anterior tibialis structure on both light and electron microscopy. High-dose continuous intravenous infusion with ascorbic acid (80 mg/hr) throughout the period of ischemia and reperfusion also preserved skeletal muscle structure, although allopurinol in various doses had no protective effect. These data are fully compatible with a mechanism of ischemia/reperfusion-induced injury to skeletal muscle, involving generation of oxygen radicals and neutrophil sequestration and activation. They also indicate that damage to human skeletal muscle caused by prolonged use of a tourniquet is likely to be reduced by simple pharmacological interventions.
Transscleral flow of aqueous humor: an in vitro experiment.
BACKGROUND AND OBJECTIVE: The minimal scleral flap thickness to ensure transscleral flow following a trabeculectomy has never been determined. The present study was designed to determine, in vitro, the critical scleral flap thickness that allows transscleral flow. MATERIALS AND METHODS: The apparatus consisted of two horizontal glass chambers (A and B) connected to each other by a customized scleral disc holder. High-pressure chamber A (at 25 mm Hg) was filled with sodium pertechnetate (99mTc) labeled normal saline and low-pressure chamber B (at 5 mm Hg) with normal saline. Transscleral flow of labeled normal saline from high-pressure chamber A via varying thickness scleral discs to low-pressure chamber B was observed over 16 hours using a gamma camera. Computer analysis was performed on the obtained images. RESULTS: Transscleral flow of labeled saline was observed only with scleral discs 0.5 mm thick or less. CONCLUSIONS: If the findings hold true for the in vivo situation, aqueous humor may reach the subconjunctival space following trabeculectomy via the transscleral route, provided scleral flap thickness is less than 0.5 mm. In addition, normal uveoscleral aqueous outflow may occur across sclera less than 0.5 mm thick, e.g., posterior to extraocular muscle insertions.
Damage to skeletal muscle induced by prolonged ischemia and reperfusion.
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Migration of cultured bovine trabecular meshwork cells to aqueous humor and constituents.
PURPOSE: To investigate the migration of cultured bovine trabecular meshwork cells to aqueous humor and some of its constituents, and to compare the migration of normally proliferating and growth-arrested cells. METHODS: Cellular migration was evaluated in 48-well microchemoattraction chambers, and the chemoattractants used were bovine aqueous humor, glycoproteins, and growth factors. RESULTS: The meshwork cells responded well to bovine aqueous humor, and antibody neutralization experiments showed that fibronectin accounted for approximately 40% of aqueous chemoattraction. The glycoproteins laminin, thrombospondin, and transferrin elicited only modest migratory activity. Platelet-derived growth factor was the most powerful chemoattractant of the growth factors tested, and the others produced moderate migratory effects. Basic fibroblast growth factor was not chemoattractive on its own but stimulated migration when combined with heparin. Growth-arrested cells showed less migration to a standardized chemoattractive stimulus than did proliferating meshwork cells. CONCLUSIONS: For the first time, aqueous humor was shown to act as a migratory stimulus for meshwork cells in vitro. The major attractant is fibronectin; the remaining active constituents must still be identified.
Adverse effects of topical antiglaucoma medication. I. The conjunctival cell profile.
OBJECTIVE: To determine the effect of various long-term topical antiglaucoma regimens on the cell population profile of the conjunctiva. METHODS: Conjunctival biopsy specimens from 124 patients undergoing filtration surgery were assessed quantitatively by light microscopy. Preoperatively, the patients had used a drug for only a brief period (group A; n = 28), a beta-blocker alone (group B; n = 31), a beta-blocker in combination with a miotic (group C; n = 33), or a combination of beta-blocker, miotic, and sympathomimetic (group D; n = 32). RESULTS: The conjunctiva in groups A and B was similar. Group C conjunctiva differed, but the changes were most marked in biopsy specimens from patients in group D, where there was a significant decrease in goblet cells (P < .05); increase in pale cells, macrophages, and lymphocytes within the epithelium (P < .001); and increase in fibroblasts (P < .001), macrophages (P < .001), mast cells (P < .05), and lymphocytes (P = .01) in the substantia propria. In addition, the effect of duration of therapy was assessed. Administration of topical medication for more than 3 years was found to increase the numbers of pale cells within the epithelium (P < .05); fibroblasts (P < .05), macrophages (P < .001), lymphocytes (P < .01), and mast cells (P = .001) within the superficial substantia propria; and the numbers of fibroblasts (P = .01) and macrophages (P < .05) within the deep substantia propria. CONCLUSIONS: The compared treatment regimens affected the conjunctiva to different degrees, with multiple-drug topical therapy exerting the greatest effect on the degree of subclinical inflammation within the conjunctiva. The results also indicated that administration of topical medication, irrespective of type, for 3 years or more induced a significant degree of subclinical inflammation.
Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery.
OBJECTIVE: To determine the effect of long-term topical antiglaucoma therapy on the results of glaucoma filtration surgery and to relate any differences to the cell population profile of the conjunctiva. METHODS: Filtration surgery was performed in 124 patients (trabeculectomy in 112 and triple procedures [trabeculectomy, cataract extraction, and intraocular lens implantation] in 12), and the outcome of these procedures was assessed after a minimum follow-up of 6 months. A conjunctival biopsy specimen was obtained at the time of surgery. The patients were divided into four groups according to the type of topical therapy administered. The duration of therapy tended to be greater for the patients treated with a greater number of medication types. The outcome of trabeculectomy was assessed in 106 of the patients. RESULTS: In comparison with the briefly treated-primary surgery group, the success rate of trabeculectomy (90% [n = 28]) was similar to that in the group treated with beta-blockers (93% [n = 29]). The trabeculectomy success rate for patients treated with beta-blockers and miotics was significantly lower (72%, P < .01 [n = 29]), and that for the group treated with beta-blockers, miotics, and sympathomimetics was even lower (45%, P < .001, [n = 20]). CONCLUSIONS: Various treatment regimens were associated with differential effects on the success rate of trabeculectomy. Long-term topical combination therapy was identified as a significant risk factor for failure of trabeculectomy. Preoperative conjunctival cell counts from patients whose trabeculectomies were successful were compared with those whose trabeculectomies failed. Failure was associated with significantly more pale cells (P < .01), macrophages (P < .05), and lymphocytes (P < .05) in the epithelium; fibroblasts (P < .05) and macrophages (P < .05) in the superficial substantia propria; and both macrophages and lymphocytes in the deep substantia propria (P < .01). Thus, preoperative subclinical conjunctival inflammation induced by previous topical medication was identified as a risk factor for failure of trabeculectomy.
Activation and suppression of fibroblast function.
The fibroblast is the central player in the wound repair and scarring processes that occur in the anterior segment of the eye. Glaucoma filtration surgery is the ultimate example of the importance of the wound healing process, as this process is the major determinant of the success of this procedure. We highlight the role of the fibroblast, and discuss some of the growth factors stimulating fibroblast proliferation, migration and extracellular matrix production in the wound environment. We also review current methods of suppressing fibroblast proliferation, the new concepts that have arisen from laboratory studies, and future directions of investigation and treatment.
Development, repair and regeneration of the retinal pigment epithelium.
An overview is presented of the retinal pigment epithelium (RPE) cell in repair and regeneration. Changes in the RPE associated with repair activities have been described as metaplasia. However, evidence is presented to show that RPE cells do not become either fibroblasts or macrophages but merely adopt the appearance of these cell types in pathological conditions. The phenotypic alterations seem to be substrate-related. The fibroblast form predominates on two-dimensional substrates rich in fibronectin and in three-dimensional collagen matrices. The macrophage form seems to be associated with insubstantial or inadequate substrates such as the vitreous, photoreceptor debris and some cell surfaces. In altered circumstances the dedifferentiated RPE can rapidly revert to an epithelioid form. However, the regeneration of an effective RPE mosaic is more difficult and dependent on many factors including the size of the initial lesion, the condition of the basement area, the status of the neuroretina and the existing pathology in the eye. The importance for the regeneration of a normal functioning RPE of the cells being out of the cell cycle, establishing effective junctioning, reorganising their cytoskeleton and having the required adhesive balance with the basement membrane is emphasised.
Cytokeratin-containing cells in proliferative diabetic retinopathy membranes.
Immunohistochemical techniques were used to investigate the relation between retinal pigment epithelial cells (RPE), traction retinal detachment (TRD) membranes, and combined traction rhegmatogenous retinal detachment (CTR) membranes in proliferative diabetic retinopathy. Seven CTR and five TRD membranes were obtained during closed microsurgery. Six of the seven CTR membranes and one of the five TRD membranes contained RPE. Eleven of the 12 diabetic membranes incorporated glial cells. The findings emphasise that the intravitreal membranes of proliferative diabetic retinopathy contain a diversity of cell types and indicate that RPE tend to contribute to CTR, rather than TRD, membranes. The histopathological appearance of CTR membranes is that of a hybrid between TRD and proliferative vitreo-retinopathy membranes.
Racial differences in the results of glaucoma filtration surgery: are racial differences in the conjunctival cell profile important?
Conjunctival biopsies were obtained at the time of filtration surgery from 90 patients with glaucoma; 45 of these patients were black and 45 white. Forty nine of the patients (25 black, 24 white) had undergone a primary trabeculectomy. Comparisons between black and white patients were made with respect to the results of surgery and differences in conjunctival cell profile. In agreement with many authors, trabeculectomy was found to be less successful in black patients (67% compared with 80%), although this finding was not statistically significant by survival analysis. In addition, conjunctiva from black patients was found to contain a greater number of macrophages and a smaller number of both mast cells and goblet cells in comparison with white patients. There was a tendency for conjunctiva from black patients to contain more fibroblasts. Conjunctiva obtained from the patients whose filtration surgery subsequently failed was found to contain more fibroblasts, macrophages, and basal epithelial pale cells. A greater number of conjunctival macrophages and possibly fibroblasts in black patients may partially explain the tendency for a lower success rate of filtration surgery in this group of patients.
Prolonged localized tissue effects from 5-minute exposures to fluorouracil and mitomycin C.
Rabbits undergoing full-thickness glaucoma filtering surgery were exposed for 5 minutes to one of three intraoperative treatments: (1) distilled water; (2) fluorouracil, 50 mg/mL; or (3) mitomycin C, 0.4 mg/mL. Tissue samples were taken from the subconjunctival and scleral tissues at the treated area and 90 degrees and 180 degrees from the center of the treated area and the adjacent cornea 2 mm from the limbus, 1 hour, 5 days, and 30 days postoperatively. The biopsy specimens were then placed in tissue culture media and the fibroblast outgrowths measured. Five-minute intraoperative treatments with fluorouracil resulted in a reversible delay of fibroblast outgrowths from treated subconjunctival and scleral tissues of just over 1 week in this model, whereas treatment with mitomycin C, 0.4 mg/mL, resulted in prolonged inhibition of at least 30 days. These effects were localized to the area treated. The many clinical implications of these findings are discussed.
Ultrastructure of the trabecular meshwork in untreated cases of primary open-angle glaucoma (POAG).
Thirty-one trabeculectomy specimens of patients suffering from primary open-angle glaucoma (POAG) who had received no, or only minor, medication prior to surgery were ultrastructurally and quantitatively analysed. Most of the specimens revealed thickened trabeculae, increased amounts of plaque-material deposited within the cribriform layer and an abundance of long spacing (lattice) collagen. The uveal meshwork was partly deprived of cells whereas the cribriform layer often contained numerous enlarged, light cells with many small mitochondria and lysosomes but no prominent endoplasmic reticulum or Golgi complexes. The quantitation of sheath-deprived plaque material (SD plaques) in a defined area of inner and outer wall of Schlemm's canal showed no significant difference between the untreated cases studied here and the treated ones studied previously. However, both groups had significantly higher amounts of SD plaque material in the inner wall than normal controls of a similar age range.
Inflammatory cells in proliferative vitreoretinopathy subretinal membranes.
BACKGROUND: The inflammatory cell content of subretinal membranes occurring in proliferative vitreoretinopathy (PVR) has not yet been well characterized. This study was undertaken to investigate the inflammatory cells present in PVR subretinal membranes. METHODS: Eight subretinal membranes obtained surgically from eyes with PVR complicating rhegmatogenous retinal detachment were studied immunohistochemically using the avidin-biotin complex technique and a panel of monoclonal and polyclonal antibodies. RESULTS: T lymphocytes were found in five of the eight subretinal membranes. CD4+ T cells were demonstrated in four and CD8+ T cells in one of the membranes. T cells bearing the interleukin 2 receptor were found in two of four membranes studied. Macrophages were found in four membranes. No B lymphocytes or neutrophils were demonstrated, and there were no significant deposits of complement or immunoglobulins. Expression of the MHC class II antigen HLA DR was consistently found in frozen specimens. Glial cells and retinal pigment epithelial cells also were present in the membranes, often adjacent to T cells, although overall no obvious relationship was found between glial or retinal epithelial cells and T cells. CONCLUSION: The findings indicate that T lymphocytes are present in PVR subretinal membranes and have the potential to interact with other cell types in the pathogenesis of this condition.
The importance of cellular changes in the conjunctiva of patients with uveitic glaucoma undergoing trabeculectomy.
The results of trabeculectomy in patients with glaucoma secondary to uveitis are poor, but the exact cause of this remains unknown. Therefore, a study was undertaken to determine differences between conjunctiva from patients with glaucoma secondary to uveitis and that from patients with primary open angle glaucoma. Conjunctival biopsies from three patient groups were quantitatively analysed by light microscopy. Group A consisted of 10 patients with glaucoma secondary to uveitis who, prior to surgery, had been treated with topical steroids and topical beta-blocker drugs. Control groups (groups B and C) each consisted of 10 patients with primary open angle glaucoma for whom primary trabeculectomy (group B) or trabeculectomy following failure of topical beta-blockers alone (group C) was planned. Treatment with topical beta-blocker drugs was found to redistribute mast cells within the conjunctiva but to have no significant effect on cell numbers. In comparison with either control group, uveitic conjunctiva was found to contain significantly more fibroblasts, lymphocytes and macrophages. It is possible that these differences are responsible for an enhanced risk of excessive external bleb fibrosis, failure of filtration surgery and poor results with adjunctive 5-fluorouracil.
The extracellular matrix of reparative tissue in the vitreous: fibronectin production in proliferative diabetic retinopathy membranes.
In a preliminary investigation into the origins of the extracellular matrix glycoprotein fibronectin in proliferative diabetic retinopathy (PDR) membranes, four globes containing PDR membranes were subjected to in situ hybridisation and immunohistochemical studies. Fibronectin mRNA was found in PDR membrane cells in two of the four globes. The fibronectin-producing cells exhibited fibroblast-like or macrophage-like morphology. Occasional intraretinal macrophage-like cells which contained fibronectin mRNA were also observed in three of the eyes. Variable fibronectin immunoreactivity was observed in all the PDR membranes, while the fibronectin staining pattern in the underlying retina was similar to that reported for albumin in eyes with breakdown of the blood-retina barrier. The findings suggest that fibronectin in PDR membranes originates from both plasma-derived fibronectin and the membrane cells, and support the concept that extracellular matrix components play an important role in PDR membrane progression.
Adverse effects of topical antiglaucomatous medications on the conjunctiva.
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