[Successes and complications of rTPA treatment of the anterior eye segment. Comment on the contribution by K.U. Löffler et al].
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Biomedical subjects
Publications and source records attributed to L Hesse.
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The transition metal ion copper(II) has a critical role in chronic neurologic diseases. The amyloid precursor protein (APP) of Alzheimer's disease or a synthetic peptide representing its copper-binding site reduced bound copper(II) to copper(I). This copper ion-mediated redox reaction led to disulfide bond formation in APP, which indicated that free sulfhydryl groups of APP were involved. Neither superoxide nor hydrogen peroxide had an effect on the kinetics of copper(II) reduction. The reduction of copper(II) to copper(I) by APP involves an electron-transfer reaction and could enhance the production of hydroxyl radicals, which could then attack nearby sites. Thus, copper-mediated toxicity may contribute to neurodegeneration in Alzheimer's disease.
The specific binding of the amyloid precursor protein (APP) to extracellular matrix molecules suggests that APP regulates cell interactions and has a function as a cell adhesion molecule and/or substrate adhesion molecule. On the molecular level APP has binding sites for collagen, laminin, and glycosaminoglycans which is a characteristic feature of cell adhesion molecules. We have examined the interactions between the APP and collagen types I and IV and identified the corresponding binding sites on APP and collagen type I. We show that APP bound most efficiently to collagen type I in a concentration-dependent and specific manner in the native and heat-denatured states, suggesting an involvement of a contiguous binding site on collagen. This binding site was identified on the cyanogen bromide fragment alpha 1(I)CB6 of collagen type I, which also binds heparin. APP did not bind to collagen type I-heparin complexes, which suggests that there are overlapping binding sites for heparin and APP on collagen. We localized the site of APP that mediates collagen binding within residues 448-465 of APP695, which are encoded by the ubiquitously expressed APP exon 12, whereas the high affinity heparin binding site of APP is located in exon 9. Since a peptide encompassing this region binds to collagen type I and inhibits APP-collagen type I binding in nanomolar concentrations, this region may comprise the major part of the collagen type I binding site of APP. Moreover, our data also indicate that the collagen binding site is involved in APP-APP interaction that can be modulated by Zn(II) and heparin. Taken together, the data suggest that the regulation of APP binding to collagen type I by heparin occurs through the competitive binding of heparin and APP to collagen.
We have identified and characterized the ligand binding properties of the Alzheimer's disease (AD) beta A4 amyloid protein precursor (APP), mapped the APP ligand binding sites and analyzed the regulation of APP expression, biogenesis and metabolism by components of the extracellular matrix (ECM) and cytokines.
Oxygen radical injury may be a common pathogenic mechanism in several neonatal diseases. The term "oxygen radical disease of prematurity" has been proposed in the face of the greater incidence of intracerebral hemorrhage, bronchopulmonary dysplasia, and retinopathy in premature neonates. To test the hypothesis that overload with ionic iron due to decreased concentrations of iron-oxidizing and iron-binding proteins induces free radical damage in premature asphyxiated newborns suffering periventricular-intraventricular hemorrhage (PIVH), blood plasma of newborns with PIVH (n = 7) was compared with that of controls (n = 10) within the first 12 h of life. We found reduced transferrin (2.05 vs. 2.24 g/l; p < 0.05) and ceruloplasmin (89.9 vs. 126.3 mg/l; p < 0.01) levels and an increased transferrin saturation (54.2 vs. 38.4%; p < 0.05) in those newborns who later developed PIVH. These findings support the theory that iron-catalyzed lipid peroxidation of the brain during reoxygenation after perinatal asphyxia may be involved in the pathogenesis of PIVH.
PATIENT: A 29-year-old white female presented with an episode of recurrent focal toxoplasmic retinochoroiditis in her right eye. Apart from a white active lesion between the temporal vascular arcades, marked vitreous opacification was present. Treatment with oral pyrimethamine and sulfadiazine led to resolution of retinochoroiditis activity including vitreous clearing within 10 weeks. Another 3 weeks later, a fresh peripheral retinal tear was noted on routine fundus examination of the right eye. While the left eye showed no signs of vitreoretinal pathology, biomicroscopy revealed a posterior vitreous detachment and marked vitreous degeneration in the right eye of this emmetropic patient. Prophylactic laser treatment was performed. No further abnormalities were observed during a 5 months follow-up period. CONCLUSION: Retinal tears (and rhegmatogenous retinal detachment) are rare complications of toxoplasmic retinochoroiditis. However, a tear may occur due to vitreoretinal traction following postinflammatory structural alteration of the vitreous. Thus, in toxoplasmic retinochoroiditis the diagnostic attention should not be limited to the evaluation of optical transparency of the vitreous. Vitreous structure should be assessed as well and if structural changes are noted, repeated ophthalmoscopy is mandatory in order to detect retinal tears and rhegmatogenous retinal detachment timely.
Results of pars plana vitrectomy for complications of proliferative diabetic retinopathy were analysed in 32 consecutive patients with a blind fellow eye due to diabetic eye disease. The mean follow-up period was 22.3 months. Only 16% of all eyes examined had received full scatter photocoagulation prior to referral for vitrectomy. Out of 9 eyes with vitreous haemorrhage, 8 improved to a visual acuity of > or = 0.2 postoperatively. Amid 23 eyes which were vitrectomized for advanced traction retinal detachment, only 4 eyes improved to a postoperative visual acuity of > or = 0.02. In this group 12 eyes deteriorated after vitrectomy, 3 eyes progressing to no light perception. The postoperative visual outcome after vitrectomy for traction retinal detachment in this group of diabetics with a blind fellow eye (mean postoperative visual acuity 0.03 +/- 0.05) was significantly worse (p < 0.000) compared to a group of 196 patients with a seeing fellow eye who were vitrectomized for traction retinal detachment at our clinic (mean postoperative visual acuity 0.09 +/- 0.11). Therefore we conclude that traction retinal detachment in this subgroup of patients is a particularly severe presentation of diabetic retinopathy with a guarded functional prognosis after vitrectomy. Our results demonstrate the importance of timely full scatter photocoagulation and early vitrectomy in eyes with progressive fibrovascular proliferation not responding to panretinal photocoagulation. We conclude that especially diabetic patients with a blind fellow eye must be followed closely and assigned to vitrectomy at an earlier stage of their disease in order to improve functional prognosis.
Norrie disease (ND) is a rare X-linked recessive disorder characterized by congenital blindness due to a degenerative and proliferative dysplasia of the neuroretina and, occasionally, by deafness and mental handicap. Here, we report two novel mutations detected in patients with the classical eye features of ND. Both the one-base pair insertion in exon II (544/545 insA) and the two-base pair deletion in the start codon (418delTG) of the ND gene predict a functional 'null allele', i.e. the complete absence of the corresponding gene product.
The aim of the present investigation was to study the clinical course of eyes presenting with retinal redetachment after silicone-oil removal (SOR), with special regard being paid to the long-term visual outcome. Between October 1989 and September 1994, SOR was performed on a consecutive series of 262 eyes that had previously undergone vitrectomy combined with silicone-oil injection for complex retinal detachments. The records of these patients were analyzed retrospectively. The mean follow-up period after redetachment following SOR was 26.3 (range 6-45) months. Redetachment occurred in 35 eyes (13.4%), mostly within 1-3 months of SOR. Redetachment was not dependent on the surgical procedure or the underlying disease. A total of 24 eyes were revitrectomized and a stable flat retina was the result in 23 eyes (65.7%). At the latest follow-up visit, 18 eyes (51.4%) had a visual acuity (VA) of > or = 0.02 and 14 eyes (40%) had a VA of > or = 0.1. In 12 eyes (34.3%) the final VA equalled the best VA recorded before redetachment; an increase in VA occurred in 6 eyes (17.1%) and a deterioration was noted in 17 eyes (48.6%). Only 6 of the 17 eyes that deteriorated had displayed a VA of > or = 0.02 prior to SOR and lost formed vision due to redetachment; these 6 eyes represent 17.1% of the eyes presenting with redetachment after SOR and 2.3% of all 262 eyes that had undergone SOR. These observations demonstrate that revitrectomy is an effective treatment for retinal redetachment after silicone-oil removal. The final failure rate does not appear high enough to justify a contraindication for routine removal of silicone oil, especially since it remains a matter of speculation as to whether these eyes would have fared better had removal of silicone oil been avoided.
In proliferative diabetic retinopathy the indication of early vitrectomy remains controversial. At present, no decision rule exists for the assessment of the various factors predicting the postoperative visual outcome. We reviewed 75 vitrectomies in 68 diabetics from our clinic. All vitrectomies were done by one surgeon. In all cases, vitrectomy was indicated because of nonclearing vitreous hemorrhage and/or fibrovascular proliferation. A linear regression model was used to identify factors correlating with the visual outcome. By means of univariate analysis, six of nine clinical variables were found to be associated with the final visual outcome. Dividing the patients into two groups according to their preoperative visual acuity (group 1 hand movement, group 2 better than hand movement), we identified two predictors that were independently associated with the postoperative visual acuity: group 1-the visual acuity of the fellow eye (P < 0.05) and rubeosis iridis (P < 0.05); group 2-the visual acuity of the fellow eye (P < 0.001) and preexisting systemic diabetic vascular disorders (P < 0.01). Based on this model, a formula was derived to predict the visual acuity at 6 months postsurgery. For easier handling the prognostic factors of a poor visual outcome (less than 0.1) were summarized in a flow chart. The test is a useful tool for the preoperative evaluation of various risk factors and, hence, for more reliable prediction of a poor visual outcome. Thus, it may be especially useful to objectify the risk-benefit ratio for early vitrectomy in diabetics.
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We studied the effect of intraoperative fibrinolysis prior to surgical evacuation of subretinal hemorrhage, which has been recommended as a valuable adjunct in the surgical treatment of submacular hemorrhage. We analyzed retrospectively the records of eight patients who underwent pars plana vitrectomy combined with subretinal injection of tissue plasminogen activator (TPA). The duration of symptoms ranged from 2 h to 14 days (median 1.5 days). During vitrectomy, TPA (6-75 micrograms) was injected subretinally through a retinotomy. After 20 min the liquified blood was surgically drained. The residual clot had to be extracted mechanically through an enlarged retinotomy site. In all patients, fibrinolysis was incomplete and an additional mechanical clot extraction was necessary. The postoperative visual acuity improved slightly in four patients, stabilized at the preoperative level in three patients, and worsened in one patient. During follow-up, one patient suffered from retinal detachment. In four patients a cataract developed. In all eyes, large defects of the retinal pigment epithelium resulted. In contrast to other authors, we did not find an acceptable liquefaction of the subretinal clot that would have facilitated surgical extraction of the hemorrhage. Therefore, a therapeutic benefit from the injection of TPA before removal of a subretinal hemorrhage was not distinct.
The purpose of this study was to compare the regeneration of corneal nerves after photorefractive keratectomy (PRK) versus laser in situ keratomileusis (LASIK) in vivo with a confocal videomicroscope. In all, 15 eyes that had undergone PRK and 15 eyes that had been subjected to LASIK were compared with a confocal in vivo slit-scanning video-microscope. The subepithelial nerves were observed preoperatively and at 3, 6, and 12 months postoperatively. In all eyes, good microscope images of the subepithelial nerve plexus could be obtained preoperatively. Because of postoperative light reflection and scattering in the treated area, subepithelial nerve-fiber regeneration could be followed satisfactorily only in seven eyes after PRK and in five eyes following LASIK. In the eyes treated with PRK, recovery of subepithelial reinnervation started from the margin of the ablation zone, being directed toward the center of the cornea. At 8 weeks postoperatively, rarefied subepithelial nerve fibers were visible at the edges, and after 3 months, single nonbranched nerve fibers could be visualized in the center of the ablation zone. At 6-8 months following PRK, subepithelial nerve regeneration seemed to be completed; however, abnormal branching and accessory thin nerve fibers were present without exception. After LASIK, corneal nerve-fiber regeneration followed the same course described for PRK except that regenerated subepithelial nerve fibers were barely visible in the center after 6 months. Further changes in nerve structure were visible for up to 12 months postoperatively. Recovery of corneal sensitivity in humans has been reported to start at 4-6 weeks after PRK and is said to be completed within 6-12 months of surgery. Slit-scanning videomicroscope findings were in accordance with these observations.
PATIENT: A 57-year-old patient with diabetes mellitus presented with therapy-resistant superficial punctate keratitis in his only eye. Finally self-injury was suspected. After unsuccessful medical treatment of three weeks' duration the disease could be healed promptly after application of an eyepad: the patient admitted self-manipulation. CONCLUSION: In all patients with ocular pathology of uncertain origin, especially in corneal lesions, self-inflicted injury should be part of the diagnostic consideration.
BACKGROUND: Rhegmatogenous retinal detachment (RD) has a strong bilateral tendency. It results from a chronic degenerative process, wherein both eyes are involved. However, simultaneous RD of both eyes is a rare finding. In a retrospective study we investigated the clinical course as well as risk factors in this kind of manifestation. METHODS: From 1989 to 1994, 931 patients underwent operation because of RD in our ophthalmologic department. Eleven of these patients presented a simultaneous bilateral RD exceeding one hour. We excluded patients with consecutive retinal detachments and retinal detachments deriving from intraocular surgery, trauma, tractive hole formation or heredodegeneration. RESULTS: Seven out of 11 patients with simultaneous bilateral retinal detachment were under 35 years of age. All of these presented multiple round holes (3-19). Horse-shoe tears were causative in 6 eyes; these patients all were over 50 years of age. There was a preponderance of males (73%) in our study. Nine patients were myopic with diopters ranging from -0.5 to -11.25. Retinal reattachment by a single intervention was achieved in 21 eyes, whereas 3 eyes had to undergo a second operation for a redetachment. CONCLUSION: Simultaneous bilateral RD, the most severe type of a retinal resp. vitreoretinal degenerative process, occurs predominantly in patients under the age of 35 with multiple bilateral round holes. We therefore conclude that multiple round holes in this group of patients are not to be regarded as a benign form of degeneration.
Tissue plasminogen activator (TPA) converts plasminogen to plasmin, thereby inducing fibrinolysis. In ophthalmologic surgery of subretinal hemorrhages, it is used to dissolve blood clots. As the blood-retina barrier of diabetic patients has broken down, plasminogen can enter the vitreous compartment in these cases. It is known that plasmin dissolves extracellular matrix protein in the vitreous interface. For that reason se used TPA in pars plana vitrectomy (ppV) of proliferative diabetic vitreous retinopathy (PDVR). Ten patients undergoing ppV for PDVR of stage A or B (Kroll classification) were included in a prospective study. At 15 min prior to vitrectomy, 100 microliters balanced salt solution was injected into the vitreous cavity. As randomized, the injection fluid contained either 25 micrograms TPA or only buffer solution. At this stage, the operating surgeon did not know whether TPA was injected or not. The grade of difficulty and complications of the operation were scored and documented. In all cases the operating surgeon correctly classified verum or placebo after surgery. Preparation of vitreous cortex and pathological membranes proved to be less difficult when TPA had been injected. Moreover, no severe bleeding occurred in this group in spite of marked PDVR. We conclude that TPA can be used in ppV without producing severe side effects. Disintegration of the vitreous interface causes a posterior detachment of the vitreous body, thus facilitating ppV.
Previously it has been shown that the extracellular domain of transmembrane beta A4 amyloid precursor protein (APP) includes binding sites for zinc(II) and for molecules of the extracellular matrix such as collagen, laminin and the heparin sulfate chains of proteoglycans (HSPGs). Here we report that APP also binds copper ions. A copper type II binding site was located within residues 135-155 of the cysteine-rich domain of APP695 which is present in all eight APP splice isoforms known so far. The two essential histidines in the type II copper binding site of APP are conserved in the related protein APLP2. Copper(II) binding is shown to inhibit homophilic APP binding. The identification of a copper(II) binding site in APP suggests that APP and APLP2 may be involved in electron transfer and radical reactions.
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