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In view of coexistence of opioid and cholecystokinin (CCK) in the brain areas concerned with pain processing, some semirigid racemic and chiral analogues of a potent CCK receptor antagonist (benzotript) have been synthesized and tested for their modulatory role on opioid antinociception, which may be mediated by CCK-B receptor. Some of these compounds, 3e, 3g, 3h, 4a, 4b and 4h, exhibited antinociceptive potentiation comparable to benzotript and proglumide. In order to identify the essential chemical structural features important for this potentiation, molecular modeling and quantitative structure activity relationship (QSAR) studies have been carried out in the S and R enantiomers of some of these semi-rigid compounds. The 3D-biophore models, common to all molecules of the training set have been derived. These models with superimposition (match value >0.25) depicted three biophoric sites one each for, pi/hydrophobic interactions, hydrogen bonding and ionic interactions among the phenyl/pyrrole ring, indole nitrogen, amidic oxygen, pyridyl nitrogen and lone pair of amidic oxygen. The total hydrophobicity and S absolute stereochemistry are found to positively contribute to potentiation of antinociception induced by morphine and the resulting quantitative pharmacophoric model with good correlation is found to well describe the observed activity.

Fuchs' endothelial dystrophy of the cornea is a significant cause of corneal blindness in the United States. The disease is characterized by a slow, continuous loss of morphologically and physiologically altered endothelial cells, eventually leading to corneal edema. The endothelial cells synthesize a thickened Descemet's membrane with focal excrescences of altered basement membrane material (guttae). This review details the epidemiological, clinical, and laboratory data that have accumulated on Fuchs' dystrophy. Several hypotheses regarding the pathogenesis of Fuchs' dystrophy are discussed, including the possible influences of aberrant embryogenesis, hormones, and injury on the development of the disease. The current state of medical and surgical management is summarized, along with the future prospects for treatment.

A family with total (internal and external) ophthalmoplegia had associated iris transillumination. No abnormal visual-evoked response brain lateralization indicative of albinism was found. On the basis of avian chimera experiments showing iris muscles to be derived from neural crest cells, we proposed a neurocristopathic theory to explain all clinical findings in this family.

Epidermal growth factor (EGF) is a naturally occurring mitogen which, in its recombinant form, is under intensive investigation for therapeutic use. Receptor activation by EGF induces up-regulation of synthesis of specific proteins as well as proliferation and differentiation of the corneal epithelium, keratocytes, and endothelium both in vivo and in vitro. With topical application of EGF, corneal wounds could possibly heal within hours, and the strength of the stromal scars is also increased; this may lead to the prospect of sutureless surgery. It may be possible to treat degenerative and dystrophic disorders of the cornea, especially of the endothelium, and to enhance the density of endothelial cells in donor corneas prior to transplantation. Combination therapy with EGF, fibroblast growth factor, and corticosteroids may be advantageous in producing a synergistic effect. It is possible that, with increased knowledge of the pharmacokinetics and the development of appropriate delivery systems, EGF could become an integral part of the next generation of ophthalmic pharmaceuticals.

The levels of the minor hemoglobin A1 components were measured in a consecutive series of 102 diabetic patients who were extensively studied for signs of diabetic retinopathy. We found a statistically significant relationship between metabolic control, as reflected by the hemoglobin A1 level, and the severity of diabetic retinopathy in patients with diabetes diagnosed before 30 years of age (P less than or equal to .001). We did not demonstrate a significant correlation between metabolic control and the severity of retinopathy in patients with diabetes diagnosed after the age of 30 years. We found significantly more severe retinopathy among patients with longer duration of the disease, in men, in whites, in diabetics diagnosted before 30 years of age who were treated with lower insulin doses, and in obses patients with the onset of diabetes after the age of 30 years.

A previously healthy 10-year-old girl suffered sudden, binocular visual deterioration. During the next few years her neurologic and visual condition progressively worsened and she developed hypertension, seizures, ataxia, and lactic acidemia, leading to death at the age of 16 years. Bilateral optic disk pallor was followed by the loss of the foveal reflex and pigmentary maculopathy, manifested as disorganization of the retinal layers, loss of ganglion cells, degeneration of the photoreceptors and nuclei, and irregular infiltration of the retina by pigment epithelial cells. The optic nerves and tracts showed central axonal loss. Bilateral, multifocal symmetric areas of cerebral atrophy and necrosis of the neuropil and neurons in the cerebral cortex, basal ganglia, and thalamus were observed; neurons persisted in the dorsal medulla, despite neuropil degeneration.

We used an immunohistochemical method to examine the distribution of neuronal-specific enolase in the trabecular meshwork of adult normal human eyes, as well as in primary cultures of human trabecular cells maintained in vitro for up to 44 days with or without the addition of nerve growth factor. In tissue sections of the globes, neuronal-specific enolase was present in the cells of the anterior region of the meshwork and those of the inner uveal beams. The cells of the posterior region of the meshwork stained variably with antiserum against neuronal-specific enolase. Cultured trabecular cells were initially neuronal-specific enolase-positive, but became negative after 18 to 21 days in vitro. The addition of nerve growth factor restored the expression of neuronal-specific enolase in these cultured cells. Because the presence of neuronal-specific enolase in normal cells is believed to indicate their differentiation from neuroectoderm, our results provide evidence that the trabecular cells in human eyes are derived from the embryonic neural crest. Our finding also supports the hypothesis that abnormal migration or a defective terminal induction of the neural crest cells has a role in certain ocular diseases that are characterized by chamber angle anomalies or primary glaucoma.

Microwaves most commonly cause anterior and/or posterior subcapsular lenticular opacities in experimental animals and, as shown in epidemiologic studies and case reports, in human subjects. The formation of cataracts seems to be related directly to the power of the microwave and the duration of exposure. The mechanism of cataractogenesis includes deformation of heat-labile enzymes, such as glutathione peroxide, that ordinarily protect lens cell proteins and membrane lipids from oxidative damage. Oxidation of protein sulfhydryl groups and the formation of high-molecular-weight aggregates cause local variations in the orderly structure of the lens cells. An alternative mechanism is thermoelastic expansion through which pressure waves in the aqueous humor cause direct physical damage to the lens cells. Cataracts induced by ionizing radiation (e.g., X-rays and gamma rays) usually are observed in the posterior region of the lens, often in the form of a posterior subcapsular cataract. Increasing the dose of ionizing radiation causes increasing opacification of the lens, which appears after a decreasing latency period. Like cataract formation by microwaves, cataractogenesis induced by ionizing radiation is associated with damage to the lens cell membrane. Another possible mechanism is damage to lens cell DNA, with decreases in the production of protective enzymes and in sulfur-sulfur bond formation, and with altered protein concentrations. Until further definitive conclusions about the mechanisms of microwaves and ionizing radiation induced cataracts are reached, and alternative protective measures are found, one can only recommend mechanical shielding from these radiations to minimize the possibility of development of radiation-induced cataracts.

Corneal mucus plaques adhered to the anterior corneal surface in 17 of 67 advanced cases of keratoconjunctivitis sicca. The plaques were translucent to opaque and varied in size and shape, from multiple isolated islands to bizarre patterns involving more than half the corneal surface. Ultrastructurally, they consisted of mucus mixed with desquamated degenerating epithelial cells and proteinaceous and lipoidal material. The condition may be symptomatic but can be controlled and prevented in most cases by topical ocular application of 10% acetylcysteine.

Of a family with 40 members, 12 had autosomal dominant optic atrophy. The affected members were aware of reduced vision from the first decade. Visual loss was moderate to severe, 6/12 (20/40) to 3/60 (10/200). The affected members showed similar centrocecal scotomata. Most affected patients had severe unclassified color defects. Electroretinography measurements were normal in all but one patient who had a small reduction in the scotopic response. The pathologic changes in a patient with autosomal dominant optic atrophy showed diffuse atrophy of the ganglion cell layer of the retina with a loss of myelin and nerve tissue within the optic nerves. We suggest that autosomal dominant atrophy is a primary degeneration of retinal ganglion cells.

By using an enzyme-linked immunosorbent assay, we detected a significant amount of tissue plasminogen activator (0.8 +/- 0.17 ng/ml) in the aqueous humor of ten normal human eyes. It was also identified on Western blot analysis. The ratio of tissue plasminogen activator to total protein in aqueous humor was about 30 times greater than the ratio of tissue plasminogen activator to total protein in plasma. There was evidence that at least some of the tissue plasminogen activator in the aqueous humor was synthesized locally by the structures bordering the anterior chamber of the eye. Tissue plasminogen activator may be a useful therapeutic modality in clinical conditions of delayed dissolution of fibrin in the eye.