Transplantation of feline islets of Langerhans in the subretinal space of cat eyes.
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Animals↗
Biomedical subjects
C A Toth
Publications and source records attributed to C A Toth.
Matrix metalloproteinases and their inhibitors in human vitreous.
PURPOSE: To conduct zymographic analysis to study the matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in vitreous samples of patients undergoing pars plana vitrectomy as part of the treatment of vitreoretinal disease. METHODS: Forty-two vitreous samples were collected at the time of pars plana vitrectomy. Diagnoses included severe (exudative) age-related macular degeneration (AMD) (12), macular hole (10), presumed ocular histoplasmosis syndrome (6), proliferative diabetic retinopathy (PDR) (5), epiretinal membrane (4), vitreomacular traction syndrome (2), macroaneurysm with subretinal hemorrhage (1), central retinal vein occlusion with vitreous hemorrhage (1), and proliferative vitreoretinopathy (1). Gelatin zymography, reverse gelatin-zymography, carboxymethylated transferrin zymography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were performed on the liquid vitreous samples to assess for MMP and TIMP activity. RESULTS: Progelatinase A occurred in all vitrectomy samples. In addition, a band consistent with TIMP-2 occurred in all samples on reverse zymography. An inhibitor of MMP of a lower molecular weight than TIMP-1 was found in all the samples. A serine proteinase with a broad band around 180 kDa was found in 2 of the 11 AMD vitreous samples. A 75-kDa metalloproteinase was found in several AMD samples, but it was much more abundant in the PDR samples. CONCLUSIONS: Metalloproteinases and their endogenous inhibitors are present in human vitreous and may be involved in the pathogenesis of PDR and other vitreoretinal diseases.
Adult↗
A comparison of retinal morphology viewed by optical coherence tomography and by light microscopy.
OBJECTIVE: To compare the cross-sectional images of primate retinal morphology obtained by optical coherence tomography (OCT) with light microscopy to determine the retinal components represented in OCT images. METHODS: Laser pulses were delivered to the retina to create small marker lesions in a Macaca mulatta. These lesions were used to align in vivo OCT scans and ex vivum histologic cross sections for image comparison. RESULTS: The OCT images demonstrated reproducible patterns of retinal morphology that corresponded to the location of retinal layers seen on light microscopic overlays. Layers of relative high reflectivity corresponded to horizontally aligned retinal components such as the nerve fiber layer and plexiform layers, as well as to the retinal pigment epithelium and choroid. In contrast, the nuclear layers and the photoreceptor inner and outer segments demonstrated relative low reflectivity by OCT. CONCLUSIONS: Retinal morphology and macular OCT imaging correlate well, with alignment of areas of high and low reflectivity to specific retinal and choroidal elements. Resolution of retinal structures by OCT depends on the contrast in relative reflectivity of adjacent structures. Use of this tool will enable expanded study of retinal morphology, both normal and pathologic, as it evolves in vivo.
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Argon laser retinal lesions evaluated in vivo by optical coherence tomography.
PURPOSE: To assess the in vivo evolution of argon laser retinal lesions by correlating the cross-sectional structure from sequential optical coherence tomography with histopathologic sectioning. METHODS: Argon laser lesions were created in the retinas of Macaca mulatta and evaluated by cross-section optical coherence tomography, which was compared at selected time points with corresponding histopathology. RESULTS: Argon laser lesions induced an optical coherence tomography pattern of early outer retinal relative high reflectivity with subsequent surrounding relative low reflectivity that correlated well with histopathologic findings. The in vivo optical coherence tomography images of macular laser lesions clearly demonstrated differences in pathologic response by retinal layer over time. CONCLUSION: The novel sequential imaging of rapidly evolving macular lesions with optical coherence tomography provides new insight into the patterns of acute tissue response by cross-sectional layer. This sequential imaging technique will aid in our understanding of the rapid evolution of retinal pathology and response to treatment in the research and clinical setting.
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Recombinant hirudin prevents postoperative fibrin formation after experimental cataract surgery.
PURPOSE: The authors studied the effect of a direct acting antithrombin agent, desulfatohirudin variant 1 (Revasc, Ciba-Geigy, Ltd., Basel, Switzerland), on postoperative fibrin formation after cataract surgery in rabbits. METHODS: Phacoemulsification was performed in a masked fashion on 28 eyes of 28 New Zealand white rabbits. Ten control group eyes had lactated Ringer's solution in the infusion and an intracameral injection (approximately 1.5 ml) at the end of the case. Ten group 1 eyes received hirudin 100 micrograms/ml in the infusion and intracameral injection. Eight group 2 eyes had 100 micrograms/ml hirudin in the intracameral injection only. Using slit-lamp examination, all eyes were graded for the amount of fibrin and intraocular hemorrhage in a masked fashion on postoperative day 1. RESULTS: Comparison of the mean postoperative fibrin grade (0-4) in group 1 (mean = 0.3), group 2 (mean = 0.25) and the control group (mean = 3.4) revealed a statistically significant difference between hirudin-treated and control eyes (P = 0.0002 for group 1, P = 0.0005 for group 2). No intraocular hemorrhage was noted in any group. CONCLUSIONS: Recombinant hirudin significantly decreases postoperative fibrin formation in a rabbit cataract extraction model. Intracameral injection of hirudin alone appears to be at least as effective as infusion of hirudin throughout the case. With further study, this agent has potential for use in cataract surgery on patients known to be at high risk for postoperative fibrin formation.
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Diabetic retinopathy should not be a contraindication to thrombolytic therapy for acute myocardial infarction: review of ocular hemorrhage incidence and location in the GUSTO-I trial. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries.
OBJECTIVES: This study sought to evaluate the incidence of ocular hemorrhage in patients with and without diabetes after thrombolytic therapy for acute myocardial infarction. BACKGROUND: Ocular hemorrhage after thrombolysis has been reported rarely. However, there is concern that the risk is increased in patients with diabetes. In fact, diabetic hemorrhagic retinopathy has been identified as a contraindication to thrombolytic therapy without clear evidence that these patients have an increased risk for ocular hemorrhage. METHODS: We identified all suspected ocular hemorrhages from bleeding complications reported in patients enrolled in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I trial. Additional information was collected on a one-page data form. We compared the incidence and location of ocular hemorrhages in patients with and without diabetes. RESULTS: There were 40,899 patients (99.7%) with information about diabetic history and ocular bleeding. Twelve patients (0.03%) had an ocular hemorrhage. Intraocular hemorrhage was confirmed in only one patient. There were 6,011 patients (15%) with diabetes, of whom only 1 had an ocular hemorrhage (eyelid hematoma after a documented fall). The upper 95% confidence intervals for the incidence of intraocular hemorrhage in patients with and without diabetes were 0.05% and 0.006%, respectively. CONCLUSIONS: Ocular hemorrhage and, more important, intraocular hemorrhage after thrombolytic therapy for acute myocardial infarction is extremely uncommon. The calculated upper 95% confidence interval for the incidence of intraocular hemorrhage in patients with diabetes was only 0.05%. We conclude that diabetic retinopathy should not be considered a contraindication to thrombolysis in patients with an acute myocardial infarction.
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Intraocular injection of recombinant hirudin to prevent experimental postoperative fibrin.
PURPOSE: To test the efficacy of a single intraocular injection of various doses of recombinant desulphatohirudin variant 1 (Revasc) in a rabbit model after lensectomy-vitrectomy surgery. METHODS: Standard fragmatome lensectomies and core vitrectomies were performed on Dutch Belted rabbits. In a masked fashion, 17 control eyes received single intraocular injections of lactated Ringer's solution, and the treated eyes, with eight eyes per treatment group, received single intraocular injections of hirudin at doses of 0.02 microgram, 2 micrograms, 10 micrograms, 50 micrograms, or 200 micrograms. RESULTS: Intraocular injections of hirudin were effective in preventing postoperative fibrin formation at doses of 2 micrograms. There was no notable intraoperative bleeding. With an injection of 2.0 micrograms hirudin there was no hemorrhage at any time after surgery; with an injection of 200 micrograms hirudin, however, there was notable bleeding. CONCLUSION: Hirudin is effective in the prevention of postoperative fibrin formation with a single intraocular injection of 2.0 micrograms after lensectomy-vitrectomy surgery in the rabbit model. There was no bleeding at the effective dose of 2.0 micrograms; at 100 times the effective dose, however, there was significant postoperative bleeding.
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Pathology of macular lesions from subnanosecond pulses of visible laser energy.
PURPOSE: To demonstrate how current theories regarding ultrashort laser pulse effects may apply to ocular tissue, a prospective clinicopathologic study of macular lesions from ultrashort laser pulses compared the pathologic effects with the clinical and fluorescein angiographic appearance of the laser lesions. METHODS: Ninety-femtosecond, 3-picosecond, and 60-picosecond laser pulses, throughout a range of energies, were delivered to the retina of Macaca mulatta. Clinical examination and fluorescein angiography were performed at 1 hour in all eyes and 24 hours after exposure in selected eyes. Eyes were enucleated at 1 or 24 hours after lesion placement. The structure and extent of retinal lesions were scored for comparison with the clinical findings. RESULTS: Focal retinal pathologic appearance correlated well with a clinically visible lesion observed 24 hours after laser delivery. Retinal lesions were small foci of retinal pigment epithelium (RPE) and retinal disruption, without choriocapillaris involvement. Lesions that contained focal RPE vacuoles or lifting of the RPE also demonstrated leakage, in fluorescein angiographic studies. Suprathreshold laser delivery frequently caused focal columns of retinal injury and intraretinal hemorrhages from retinal vessel bleeding, with no rupture of choroidal blood vessels. CONCLUSIONS: The retinal response to ultrashort laser pulses at moderate energy followed a pattern of focal damage from laser-induced breakdown without significant thermal spread.
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Retinal damage and laser-induced breakdown produced by ultrashort-pulse lasers.
BACKGROUND: In vivo retinal injury studies using ultra-short-pulse lasers at visible wavelengths for both rabbit and primate eyes have shown that the degree of injury to the retina is not proportional to the pulse energy, especially at suprathreshold levels. In this paper we present results of calculations and measurements for laser-induced breakdown (LIB), bubble generation, and self-focusing within the eye. METHODS: We recorded on video and measured the first in vivo LIB and bubble generation thresholds within the vitreous in rabbit and primate eyes, using external optics and femtosecond pulses. These thresholds were then compared with calculations from our LIB model, and calculations were made for self-focusing effects within the vitreous for the high peak power pulses. RESULTS: Results of our nonlinear modeling and calculations for self-focusing and LIB within the eye were compared with experimental results. The LIB ED50 bubble threshold for the monkey eye was measured and found to be 0.56 microJ at 120 fs, compared with the minimum visible lesion (MVL) threshold of 0.43 microJ at 90 fs. Self-focusing effects were found to be possible for pulsewidths below 1 ps and are probably a contributing factor in femtosecond-pulse LIB in the eye. CONCLUSIONS: Based on our measurements for the MVL thresholds and LIB bubble generation thresholds in the monkey eye, we conclude that in the femtosecond pulsewidth regime for visible laser pulses, LIB and self-focusing are contributing factors in the lesion thresholds measured. Our results may also explain why it is so difficult to produce hemorrhagic lesions in either the rabbit or primate eye with visible 100-fs laser pulses even at 100 microJ of energy.
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Recombinant hirudin for prevention of experimental postoperative intraocular fibrin.
PURPOSE: To determine the efficacy of a specific antithrombin agent (recombinant desulphatohirudin variant 1 [Revasc, Ciba-Geigy, Ltd., Basel, Switzerland]) administered in the infusion fluid to prevent early postoperative fibrin formation in a rabbit lensectomy and vitrectomy model. METHODS: Standard fragmatome lensectomies and core vitrectomies were performed prospectively in a masked fashion on ten control eyes with lactated Ringer's infusion and on ten eyes treated with 10 microgram of recombinant hirudin/ml in the infusate. The amounts of fibrin and hemorrhage were graded in a masked fashion by using slit-lamp examination and indirect ophthalmoscopy on postoperative days 1 through 5 and on day 7. RESULTS: The difference in the mean grade of fibrin formed on the first postoperative day in the eyes treated with recombinant hirudin (mean, 0.9) in relation to the mean grade of fibrin in the control eyes (mean, 3.5) was statistically significant (P = .004). This difference was also significant on the second postoperative day (P = .01). None of the treated eyes developed intraoperative or postoperative hemorrhage. CONCLUSIONS: Recombinant desulphatohirudin variant 1 is an effective inhibitor of postoperative fibrin formation in a rabbit model and is not associated with an increased risk of intraoperative or postoperative bleeding at the tested dose. This drug may be a useful adjunct in vitreous surgery for both proliferative vitreoretinopathy and the complications of proliferative diabetic retinopathy.
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Tissue plasminogen activator for preserving inferior peripheral iridectomy patency in eyes with silicone oil.
PURPOSE: An inferior peripheral iridectomy (IPI) was used to prevent forward migration of silicone oil in vitrectomized eyes; however, in approximately one third of eyes, the IPI closed spontaneously. Occlusion of the IPI by fibrin is believed to be an early event in permanent IPI closure by scar tissue. The authors determined whether intraocular tissue plasminogen activator (tPA) would restore and maintain IPI patency in eyes that had early occlusion of the IPI by fibrin. METHODS: Between November 1993 and January 1995, 12 patients who underwent vitrectomy with silicone tamponade and IPI for complicated retinal detachment received an anterior chamber injection of tPA (6.25 or 12.5 microgram) for occlusion of the IPI by fibrin. RESULTS: All 12 patients had lysis of fibrin and maintained a patent IPI at the last follow-up (124+/-95 days). One patient required multiple tPA injections for recurrent fibrin formation. In another patient, a small hyphema developed after the tPA injection, which did not occlude the IPI. When compared with the natural course in a very similar group of patients previously reported, tPA had a statistically significant beneficial effect in the maintenance of IPI patency (P = 0.040). CONCLUSIONS: Intraocular tPA can be safely used to lyse postoperative fibrin occluding the IPI in eyes with silicone oil tamponade. Early lysis of this fibrin maintains IPI patency.
Adult↗
Recombinant soluble human complement receptor type 1 inhibits antisperm antibody- and neutrophil-mediated injury to human sperm.
The pathogenesis of antisperm antibody (ASA)-mediated infertility is postulated to be related in part to complement (C)-dependent sperm dysfunction in the female genital tract. We have previously demonstrated that C can be involved in ASA-mediated sperm injury by the deposition of activated C3 fragments and the assembly of terminal membrane attack complex (C5b-9) leading to C3-mediated sperm binding to neutrophils or C5b-9-mediated sperm motility loss. This study evaluated the protective effect of recombinant soluble C receptor type 1 (sCR1) on ASA-and C-mediated neutrophil/sperm interaction, neutrophil aggregation, and sperm motility loss. Motile sperm with or without neutrophils were incubated in the presence of 10% C-fixing ASA+ serum or ASA- control sera in the presence or absence of sCR1. After defined incubation periods, the following neutrophil and sperm parameters were evaluated: 1) neutrophil aggregation (by the flow cytometric pulse processing method), 2) sperm phagocytosis (by light microscopy), 3) the deposition of C3 cleavage fragments (C3b, iC3b, and C3d) on motile sperm (by immunofluorescence flow cytometry), and 4) the relation between sperm motility loss and sperm-bound C3d. Only the coincubation of neutrophils with sperm in the presence of C-fixing ASA+ sera resulted in marked neutrophil aggregation (20.5 +/- 0.26% vs. 2.4% +/- 1.6; p < 0.0001) and a concomitant increase in neutrophils containing ingested sperm (71 +/- 5.8% vs. 3.5%; p < 0.0001). Soluble CR1 inhibited ASA- and C-mediated neutrophil aggregation by 46% and sperm phagocytosis by 57%. Motile sperm incubated with C-fixing ASA- sera showed a time-dependent increase in the binding of C3 fragments as detected by flow cytometry using anti-iC3b neoantigen, anti-C3c, and anti-C3d monoclonal antibodies (mAbs). A negative correlation (r2 = -0.930; p < 0.001) was found between the increase in sperm-associated C3d fluorescence and the percentage motile sperm in the presence of ASA- sera. Soluble CR1 (200 micrograms/ml) maximally inhibited the binding of anti-C3b, anti-C3c, and anti-C3d mAbs to sperm by 96%, 83%, and 72%, respectively. Thus, sCR1 abrogated the binding of C3 fragments to human sperm and fully protected sperm from C5b-9-mediated sperm immobilization. These findings suggested the therapeutic potential of sCR1 as an intravaginal pharmacophore to prevent C-dependent sperm dysfunction and related inflammatory events in the female genital tract.
Acrosome↗
Extended in vivo half-life of human soluble complement receptor type 1 fused to a serum albumin-binding receptor.
A new approach has been used to extend the T(1/2) of human soluble complement receptor type 1 (sCR1) in rats. The albumin-binding domains B2A3 (BA) and B1A2B2A3 (BABA) from Streptococcal protein G were fused to the carboxyl terminus of sCR1, and the recombinant genes were expressed and amplified in Chinese hamster ovary cells. Western blot analysis and surface plasmon resonance measurements demonstrated the binding of rat serum albumin to both sCR1-BA and sCR1-BABA but not to sCR1. The in vitro complement inhibitory activity of the fusion proteins was shown to be similar to that of sCR1, indicating that neither the albumin-binding domains nor the presence of bovine serum albumin interfere with sCR1 function. Pharmacokinetic analysis showed that the T(1/2) of the distribution phase (T(1/2alpha)) was 3.3, 20.0 and 6.0 min for sCR1, sCR1-BA and sCR1-BABA, respectively. The T(1/2) of the elimination phase (T(1/2beta)) was 103, 297 and 170 min for sCR1, sCR1-BA and sCR1-BABA, respectively. The plasma elimination of sCR1-BA and sCR1-BABA was significantly (P < .05) prolonged as compared to sCR1. The proteins showed similar tissue distribution; at 4-hr postdosing, the highest levels of 125I-radioactivity per gram of tissue were localized in the urine, blood, liver, stomach, and small intestine.
Animals↗
Diabetic retinopathy in a cat.
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Animals↗
Clinicopathologic correlation of spontaneous retinal pigment epithelial tears with choroidal neovascular membranes in age-related macular degeneration.
BACKGROUND: A correlation of the clinical and histopathologic features of age-related macular degeneration (AMD), complicated by choroidal neovascular membrane (CNVM) with spontaneous tears of retinal pigment epithelial (RPE) detachment, has not been reported. METHODS: Two patients with vision loss from AMD and spontaneous pigment epithelial detachment tears, involving the fovea with serous or hemorrhagic neurosensory retinal detachments, were examined clinically. The surgically excised CNVM from each patient was examined with light microscopy. RESULTS: The authors present two patients with clinicopathologic correlation of the ophthalmoscopic, fluorescein angiographic, and pathologic findings of spontaneous pigment epithelial detachment tears. In the surgical specimens from these two eyes, the removed tissue, presumed to be the spontaneous RPE tear with CNVMs, demonstrated a fibrovascular membrane surrounding RPE with adjacent abnormally thickened basement membrane. The RPE-basement membrane complex was folded redundantly and scrolled beneath itself. CONCLUSION: The authors found RPE-basement membrane abnormalities and CNVMs associated with clinically evident spontaneous pigment epithelial detachment tears. These findings support the current theories of their pathogenesis.
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Effect of soluble complement receptor-1 on neutrophil accumulation after traumatic brain injury in rats.
As part of the acute inflammatory response, neutrophils accumulate in the central nervous system after injury. Recently, a soluble human recombinant complement receptor (sCR1; BRL 55730; T Cell Sciences, Inc., Cambridge, MA, U.S.A.) has been developed that inhibits the activation of both the classical and the alternative pathways of complement. sCR1 attenuates the effects of the acute inflammatory response in several models of injury outside the central nervous system. The role of complement in traumatic brain injury, however, remains undefined. We hypothesized that treatment with sCR1 would attenuate neutrophil accumulation in the brain after cerebral trauma. Using a randomized, blinded protocol, 18 anesthetized Sprague-Dawley rats were pre-treated with sCR1 or saline (control) at both 2 h and 2 min before trauma (weight drop) to the exposed right parietal cortex. A third dose of sCR1 (or saline) was given 6 h after trauma. Coronal brain sections centered on the site of trauma were obtained at 24 h after trauma and analyzed for myeloperoxidase (MPO) activity as a marker of neutrophil accumulation. Complete blood counts with differential were obtained before treatment with sCR1 and at 24 h after trauma. At 24 h after trauma, brain MPO activity was reduced by 41% in sCR1-treated rats compared with control rats [0.1599 +/- 0.102 versus 0.2712 +/- 0.178 U/g (mean +/- SD); p = 0.02]. The neutrophil count in peripheral blood increased approximately twofold in both groups. Neutrophil accumulation occurring in the brain after trauma is inhibited by sCR1 treatment. This suggests that complement activation is involved in the local inflammatory response to traumatic brain injury and plays an important role in neutrophil accumulation in the injured brain.
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The effects of soluble recombinant complement receptor 1 on complement-mediated experimental glomerulonephritis.
Complement is a major mediator of tissue injury in several types of glomerulonephritis. However, no therapeutic agents that inhibit complement activation are available for human use. sCR1 (TP10, BRL 55736) is a recombinant, soluble human complement receptor 1 (CR1) molecule lacking transmembrane and cytoplasmic domains that inhibits C3 and C5 convertase activity by preferentially binding C4b and C3b. To test the efficacy of sCR1 on complement-mediated glomerulonephritis, rats were pretreated with sCR1 (60 mg/kg per day) before and during the induction of three models of complement-dependent glomerulonephritis (concanavalin A and antithymocyte serum models of proliferative glomerulonephritis, passive Heyman nephritis). Daily sCR1 and complement hemolytic activity levels were measured, and renal histology and urine protein excretion were examined. Mean serum sCR1 levels of 100 to 200 micrograms/mL were maintained with a reduction in complement hemolytic activity to less than 15% in most animals. In the antithymocyte serum model, sCR1-treated animals had significant reductions in mesangiolysis, glomerular platelet and macrophage infiltrates, and proteinuria at 48 h. In the concanavalin A model, sCR1 significantly reduced glomerular C3 and fibrin deposits, platelet infiltrates, and proteinuria at 48 h. In passive Heymann nephritis, proteinuria was also significantly reduced (199 +/- 8.5 versus 125 +/- 16 mg/day, P < 0.002) at 5 days. It was concluded that sCR1 significantly reduces both morphologic and functional consequences of several different types of complement-mediated glomerulonephritis and deserves evaluation as a potential therapeutic agent in complement-mediated immune glomerular disease in humans.
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Retinal effects of ultrashort laser pulses in the rabbit eye.
PURPOSE: To evaluate the effects of ultrashort laser pulses from femtoseconds to nanoseconds on the retinas of live rabbit eyes and to determine the energy requirements for visible lesion development. METHODS: The retinal effects of laser exposures were examined for laser exposures with pulsewidths ranging from 4 ns to 90 fs, with visible wavelengths of 532 nm for durations > 5 ps and 580 nm for durations < 5 ps. The authors examined and scored all laser impact sites in the retina ophthalmoscopically--with fundus photography and with fluorescein angiography--to identify evidence of visible laser effects. RESULTS: The laser energy required for retinal minimal visible lesions was found to be slightly less for pulsewidths < 5 ps and varied from 5 microJ at 4 ns to 1.1 microJ at 90 fs for the 1-hour ophthalmoscopic reading. Lesions from higher energy pulses (7 to 120 microJ) were examined at all pulsewidths. For 90-fs high-energy pulse delivery, an increased intensity of retinal lesions and the development of several subretinal hemorrhages were demonstrated at peak energies of 30 microJ. Fluorescein angiography was found to be much more sensitive as an indicator of retinal damage for both femtosecond pulsewidths. CONCLUSIONS: The low energies required for visible lesion production in live rabbit eyes raise new questions surrounding ultrashort pulse propagation in ocular media, energy deposition at the retina, and mechanisms limiting retinal damage from ultrashort laser pulses.
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