Endothelin receptor-binding subtypes in the human retina and choroid.

PURPOSE: Endothelins (ETs) are a family of vasoconstrictive peptides produced in part by vascular endothelial cells. They are synthesized in the eye, particularly in the uveal tract, and can markedly constrict the iris and preretinal vessels in the rabbit eye. Two ET receptor subtype families have been characterized and cloned, termed ETA and ETB. To better understand the distribution of ocular ET receptors, we localized ET receptor-binding sites in human and rabbit eyes. METHOD: Autoradiography with iodine 125-labeled ET-1 and varying concentrations of unlabeled ET-3 was used to localize ET receptor-binding subtypes in the posterior pole of human and rabbit eyes. RESULTS: The ETA-like receptor-binding sites are localized to the retinal and choroidal blood vessels, whereas the ETB-like receptor-binding sites are localized to the neural and glial substance of the retina. CONCLUSIONS: Endothelin receptor-binding subtypes are differentially located in the posterior pole of human and rabbit eyes. Endothelin peptides released within the retina and choroid may participate in the ocular manifestations of a variety of systemic disorders, including systemic hypertension.

Suture loop to aid in ganciclovir implant removal.

BACKGROUND: The ganciclovir implant (Vitrasert; Bausch & Lomb Inc, Claremont, Calif) has been a useful device in the management of cytomegalovirus retinitis. Seven months after placement, implant exchange is often considered. However, removal may be difficult and may result in vitreous hemorrhage or intraocular dislocation. OBJECTIVE: To describe a suture loop attached to the implant strut and left in the sub-Tenon space to aid in implant removal. METHODS: Twenty-five eyes of 17 patients received a ganciclovir implant with an 8-0 nylon suture loop left beneath the Tenon capsule and underwent at least 6 months of follow-up. Two of these eyes subsequently had a similarly modified ganciclovir implant placed at a separate site (inferonasally) with at least 6 additional months of follow-up. Six eyes of 3 patients had the implant removed as part of an exchange and underwent at least 4 months of follow-up. RESULTS: In the 25 eyes, there were no cases of endophthalmitis, wound leak, suture exposure, or other complications. At implant removal in the 6 eyes previously mentioned, the loop was used for traction on the implant and aided in localization of the implant strut. In these 6 eyes, there were no cases of retinal or choroidal detachment, visually significant vitreous hemorrhage, implant dislocation, or other complications. CONCLUSION: A sub-Tenon capsule suture loop is well tolerated and can assist in ganciclovir implant removal.

Ocular effects of the endothelins. Abundant peptides in the eye.

Endothelins (ETs) are a family of potent vasoactive peptides present in the eye. In the rabbit eye, both ET-1 and ET-3 are present in high concentrations in the iris and ciliary body and in lower concentrations elsewhere. Forty-eight hours after injection of 2.5 micrograms of ET-1 and ET-3 into the anterior vitreous of conscious rabbits, intraocular pressure was reduced by 43% and 45%, respectively, and did not return to normal for at least 5 days. The decrease in intraocular pressure was not due to increased aqueous outflow and was not prevented by pretreatment with indomethacin. Injection of either ET-1 or ET-3 (2.5 to 10 micrograms) into the anterior chamber or posterior vitreous cavity resulted in marked vasoconstriction, which was initiated within seconds and persisted for greater than 4 hours. Both endothelins potently constricted the pupil when added to freshly excised rabbit anterior segments. Endothelins are therefore potential participants in the local regulation of intraocular pressure, ocular blood vessel tone, and iris smooth muscle tone and may be important mediators in ocular pathologic conditions. Endothelins at pharmacologic doses may be useful in the control of intraocular pressure or blood flow.

Treatment of migraine headache after ocular surgery with intravenous metoclopramide hydrochloride.

PURPOSE: To alert ophthalmologists that prolonged or severe postoperative periocular pain and nausea may be caused by migraine. METHODS: We examined two patients who had a history of migraine and had severe episodes of prolonged periocular pain and nausea after ocular procedures. Both patients experienced symptoms similar to their previous migraine attacks. In neither was pain alleviated by routine analgesics. RESULTS: Each patient had relief of symptoms within two minutes after intravenous delivery of metoclopramide hydrochloride. CONCLUSIONS: Ophthalmologists should consider the diagnosis of postoperative migraine in similar patients and provide specific therapy such as intravenous metoclopramide hydrochloride.

Viral sensitivity testing in patients with cytomegalovirus retinitis clinically resistant to foscarnet or ganciclovir.

PURPOSE: Resistance to antiviral therapy is a potential cause of progression of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. We investigated the results of viral sensitivity testing in a series of patients with clinically resistant retinitis who had positive results of blood or urine cytomegalovirus cultures. METHODS: All patients with newly diagnosed cytomegalovirus retinitis between January 1990 and December 1991 were prospectively studied. Blood and urine cultures for cytomegalovirus were obtained in a nonrandomized subgroup of this group. The results of in vitro sensitivity to foscarnet and ganciclovir, determined by a DNA hybridization assay, were then analyzed in seven patients with clinically resistant cytomegalovirus retinitis and whose blood or urine culture results, or both, were positive for cytomegalovirus while on a treatment regimen. RESULTS: Foscarnet-resistant cytomegalovirus (ID50 > 300 microM) was isolated from two patients, one of whom was being treated with foscarnet. Ganciclovir-resistant cytomegalovirus (ID 50 > 6.0 microM) was isolated from four patients, three of whom were being treated with ganciclovir. Foscarnet- and ganciclovir-resistant cytomegalovirus occurred with previous ganciclovir therapy in one patient. Clinical improvement occurred in three patients whose change in therapy was based on viral sensitivity testing. In general, prolonged therapy with one drug was associated with a progressive increase in the ID 50 for that drug. CONCLUSIONS: Viral resistance to foscarnet or ganciclovir may explain refractory cytomegalovirus retinitis in some patients.

Open globe injuries in children: a retrospective analysis.

PURPOSE: To study the outcome of open globe injuries in patients aged <14 years and compare the results between patients who presented approximately 30 years ago and a recent series. METHODS: Between January 1970 and January 1993, 180 eyes of children who presented with an open globe injury were retrospectively analyzed. Patients were divided into two groups. One group of children underwent treatment of an open globe injury between January 1970 and December 1981 (group A) and another between December 1985 and January 1993 (group B). Main outcome measures studied were final visual acuity and enucleation rates. Risk factors studied included age, race, sex, visual acuity, type of trauma, and various injury characteristics at presentation. RESULTS: The factors associated with visual outcomes included: age, type of injury, wound size, initial visual acuity, and retinal detachment. Final visual outcome and enucleation rates were not significantly different between the older series (group A) and the recent series (group B). Lenticular damage, location, posterior extent of the injury, and presence of an intraocular foreign body had been significant prognostic factors in the older series, but were not statistically associated with the prognosis in the recent series. CONCLUSION: The nature of the injury and the patient's age are the main determining factors in the outcome of open globe injuries in children.

Progress in the treatment of posterior segment trauma.

Ocular trauma remains a common cause of vision loss worldwide. Progress appears to have been made in the treatment of intraocular foreign bodies and traumatic endophthalmitis particularly with the use of early vitrectomy and intravitreal antibiotics. Recent work increasingly supports the benefit of vitrectomy in conjunction with other modern surgical techniques for the treatment of other injuries of the posterior segment. This review highlights much of the literature on ocular trauma from the previous year and discusses the merits of current and future approaches to surgical intervention.

Carboxypeptidase E (enkephalin convertase): mRNA distribution in rat brain by in situ hybridization.

Carboxypeptidase E (CPE), also referred to as enkephalin convertase or carboxypeptidase H (EC 3.4.17.10), is present in neurotransmitter secretory granules and can remove C-terminal basic residues following endopeptidase cleavage during peptide processing. Using in situ hybridization with 35S-labeled oligonucleotide probes, we have mapped the localization of CPE mRNA in the rat brain. Specificity for CPE was confirmed by control experiments, which included production of identical patterns hybridization with 3 different antisense oligonucleotide probes, loss of label with RNase pretreatment of sections or co-incubation with excess unlabeled probe, and lack of labeling with sense orientation probes. In addition, the regional distribution of CPE mRNA by Northern blot analysis corresponded with distribution of labeling by in situ hybridization. The highest levels of CPE mRNA were found to be present in the pyramidal cells of the hippocampus, the pituitary anterior and intermediate lobes, the ependymal cells of the lateral ventricle, the endopiriform nucleus, the basolateral amygdala, the supraoptic nucleus, and the paraventricular nucleus. Intermediate levels were present in the thalamus, medial geniculate nucleus, lateral septal nucleus, piriform and entorhinal cortex, nucleus of the tractus solitarius, cerebellar cortex, pontine nuclei, and inferior olive. The lowest levels were found in the hippocampal granule cell layer, lateral hypothalamus, globus pallidus, and brain stem reticular formation. Ibotenic acid lesions of the hippocampus eliminated the majority of the label, which had been present over pyramidal cells, though labeling was increased over areas of reactive gliosis, suggesting that activated astrocytes can also synthesize CPE mRNA. In general, the localization of CPE mRNA in the rat brain corresponded to the distribution of enkephalin and other peptide neurotransmitter-synthesizing neurons, though CPE mRNA was also present in neurons that do not secrete known peptides and in reactive glia. The widespread yet specific localization of CPE mRNA in the rat brain suggests it may be an excellent marker for peptide synthesizing cells in the CNS.

Endothelin in brain: receptors, mitogenesis, and biosynthesis in glial cells.

We have explored the cellular loci of endothelin (ET) actions and formation in the brain, using cerebellar mutant mice as well as primary and continuous cell cultures. A glial role is favored by several observations: (i) mutant mice lacking neuronal Purkinje cells display normal ET receptor binding and enhanced stimulation by ET of inositolphospholipid turnover; (ii) in weaver mice lacking neuronal granule cells, ET stimulation of inositolphospholipid turnover is not significantly diminished; (iii) C6 glioma cells and primary cultures of cerebellar astroglia exhibit substantial ET receptor binding and ET-induced stimulation of inositolphospholipid turnover; (iv) ET promotes mitogenesis of C6 glioma cells and primary cerebellar astroglia; and (v) primary cultures of cerebellar astroglia contain ET mRNA. ET also appears to have a neuronal role, since it stimulates inositolphospholipid turnover in primary cultures of cerebellar granule cells, and ET binding declines in granule cell-deficient mice. Thus, ET can be produced by glia and act upon both glia and neurons in a paracrine fashion.

Brain phospholipase C isozymes: differential mRNA localizations by in situ hybridization.

mRNAs for isozymes of phospholipase C (PLC) were localized in rat brain by in situ hybridization with oligonucleotide probes for PLC isozymes I, II, and III of Rhee's group [Suh, P.-G., Ryu, S. H., Moon, K. H., Suh, H. W. & Rhee, S. G. (1988) Proc. Natl. Acad. Sci. USA 85, 5419-5423 and (1988) Cell 54, 161-169], and isozyme I of Bennett and Crooke [Bennett, C. F., Balcarek, J. M., Varrichio, A. & Crooke, S. T. (1988) Nature (London) 334, 268-270], which we designate PLC-A. The isozymes displayed different localizations. PLC-A mRNA was highest in the mitral cell layer of the olfactory bulb, choroid plexus, hippocampus and dentate gyrus, magnocellular hypothalamic nuclei, rostral raphe nuclei, and cerebellar Purkinje cells. PLC-I was highest in the internal granular cell layer of the olfactory bulb, cerebral cortex, caudate, nucleus of the lateral olfactory tract, reticular nucleus of thalamus, hippocampus and dentate gyrus, and granule cell layer of the cerebellum. PLC-II had a more widespread distribution, with relatively high levels in the internal granular layer of the olfactory bulb, hippocampus and dentate gyrus, and cerebellar Purkinje and granule cells. PLC-III label was low throughout the brain. These distributions suggest selective coupling of individual PLC isozymes with particular postsynaptic receptors. PLC-A may be preferentially associated with 5-hydroxytryptamine 1C receptors, vasopressin V1 receptors, and a subtype of glutamate receptors. PLC-I may be linked to muscarinic m1 and m3 receptors as well as other receptors. The distribution of PLC-II mRNA resembles that of src protooncogene, with which it displays sequence homology.

Endothelin: visualization of mRNAs by in situ hybridization provides evidence for local action.

Endothelin (ET) is a recently identified vasoactive peptide with three isoforms for which three genes have been cloned. The cellular sites of synthesis of this peptide have not yet been identified in vivo. Using Northern blot analysis, we have detected two forms of ET mRNA in rat tissues: a 3.7-kilobase form in the kidney, eye, and brain, a 2.5-kilobase form in the intestine, and both forms in the lung. We have localized these forms of ET mRNA in several rat tissues using in situ hybridization. In the 19-day rat fetus, ET mRNA is highest in the lung, intestine, and meninges. At high resolution, ET mRNA is localized in the lung to respiratory epithelial cells of bronchioles and apparently in blood vessels. In adult tissues, ET mRNA is present throughout the lung, in the renal medulla vasa recta, and in the iris of the eye. ET mRNA is synthesized in close proximity to ET binding sites in many organs (e.g., lung, kidney, intestine, and eye), suggesting a local action of this peptide. However, in other areas (e.g., heart and renal cortex), ET binding sites are present in the absence of ET mRNA, suggesting an action of ET from the bloodstream or from neurons. Northern blot analysis of ET mRNA in microvascular endothelial cells in culture indicates that ET is synthesized in small blood vessels and regulated similarly to its regulation in large vessels. Our results provide evidence that ET, like other regulatory peptides, may serve in several tissues as a neuromodulator or local hormone.

Clinicopathologic correlation of the multiple recurrent serosanguineous retinal pigment epithelial detachments syndrome.

PURPOSE: Ocular clinicopathologic correlation in a patient with bilateral multiple recurrent hemorrhagic detachments of the sensory retina and retinal pigment epithelium (RPE), which eventually led to rubeosis and loss of useful vision in one eye, is described. The clinical appearance was most consistent with multiple recurrent serosanguineous RPE detachments syndrome (which may be similar to posterior uveal bleeding, or PUB, syndrome). METHODS: Light microscopic examination of 450 serial sections through a 3.7-mm area including the macula, optic nerve head, and superior and inferior peripapillary region of the eye that underwent diagnostic enucleation was performed. One fresh cap was used for immunohistochemical staining. Tissue from the posterior aspect of the other cap was prepared for electron microscopy. RESULTS: Microscopic examination disclosed extensive fibrovascular proliferation in the subretinal space and within Bruch's membrane, and the presence of at least 23 choroidal blood vessels that traversed defects in Bruch's membrane. Immunohistochemical studies of inflammatory infiltrates within the choroid and fibrovascular tissue demonstrated both a B- and T-cell response. CONCLUSION: In this case, recurrent serosanguineous detachments of the sensory retina and RPE were secondary to choroidal neovascularization with extensive fibrovascular proliferation in the subretinal space and within Bruch's membrane. Marked lymphocytic infiltration was present throughout the choroid and the fibrovascular tissue. Clinical improvement in the fellow eye after immunosuppressive therapy suggested that an immunologic component might be a causative factor, although the waxing and waning course in this condition precludes any definitive evaluation for its use in multiple recurrent serosanguineous RPE detachments syndrome.

Open-globe injury. Update on types of injuries and visual results.

PURPOSE: The purpose of the study is to evaluate a recent series of patients who presented with open-globe injuries and to compare this series with a previous series collected at the authors' institution to determine whether prognostic factors or visual outcomes have changed. METHODS: A retrospective review of 290 eyes of consecutive patients who presented to the Wilmer Ophthalmological Institute with open-globe injuries between December 1985 and January 1993 (group B) was compared with a series of 476 eyes with open-globe injury treated and evaluated at this institute between January 1970 and December 1981 (group A). For comparison, the outcomes evaluated included rates of enucleation and final visual acuity. RESULTS: Several factors identified previously in group A to correlate with visual outcomes also were found to correlate significantly (P < 0.001) with visual outcome in group B, including: (1) type of injury, (2) location and extent of injury, (3) initial visual acuity, (4) presence of an afferent pupillary defect, (5) lenticular involvement, (6) vitreous hemorrhage, and (7) type of intraocular foreign body. Overall visual outcomes differed significantly between the groups (P = 0.02). The incidence of enucleation was lower in group B (24%) than in group A (30%). However, the percentage of patients who achieved ambulatory visual acuity (5/200) or better was similar in both groups (57%, group A versus 55%, group B). CONCLUSION: Prognostic factors identified previously proved valid in this recent series. Visual outcomes have improved at this institution in the last 20 years for patients with severe ocular trauma, although visual potential for these patients is still limited.

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.

Ophthalmic involvement in aggressive histiocytosis X.

The authors report the clinicopathologic features of an unusually aggressive form of histiocytosis X (Langerhans' cell histiocytosis) in a 36-year-old man who presented with diplopia and early development of pituitary failure from presumed involvement of the hypothalamus. Results of postmortem examination showed infiltrates of histiocytes and mixed inflammatory cells, with a variably dense desmoplastic tissue within the orbit and sclera bilaterally, the left optic nerve, choroid, emissary canals, and many other body systems including the pituitary, heart, lung, and gastrointestinal tract. Diagnosis was confirmed by immunohistochemical staining of large histiocytes within diseased areas, with anti-T6 and anti-S-100 antibodies.