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Several investigators have focused on the source of the angiogenic activity and progress is only now beginning in the assessment of the relative roles of the many potential participants in corneal angiogenesis. In theory the angiogenic factor(s) responsible for corneal vascularization could arise from one or more of the following sources: the denatured tissue, the injurious agent, corneal cells, cells of noncorneal origin, pericorneal vascular cells, serum, tears, or the aqueous humor.

Taken together, all observations suggest that corneal angiogenesis is initiated and controlled by numerous cells and molecules involved in the inflammatory response. Although the precise mechanism of corneal neovascularization remains poorly understood, many of the participants in the drama of corneal angiogenesis have been identified during the past two decades. Despite the possible existence of non-inflammatory angiogenesis in the cornea, convincing evidence to support such a variety of neovascularization in this tissue remains to be presented.

Valuable insights into the pathogenesis of neovascularization in the cornea are gained by an understanding of circumstances that suppress and enhance angiogenesis in this tissue. Studies in a variety of experimental models have demonstrated a suppression of corneal neovascularization in leukopenic animals. Corneal angiogenesis induced by chemical cautery is severely suppressed under situations that inhibit the inflammatory response and most notably the leukocytic infiltration into the cornea. As described below, this occurs following treatment with corticosteroids, non-steroidal anti-inflammatory drugs and irradiation (head irradiation, total body irradiation, total lymphoid irradiation, and total body irradiation followed by bone marrow transplantation) Together these findings add further support to the hypothesis that corneal vascularization is a component of inflammation and that leukocytes play a cardinal role.

A major difficulty facing investigators of angiogenesis has been the lack of a specific, sensitive, in vivo bioassay system for angiogenic factors. A wide variety of systems have been used in assays for angiogenic factors. These include implantations into rabbit ear chambers (138,659,815), hamster cheek pouch chambers (416,674), the chick chorioallantoic membrane (CAM) (23,33,44,223,241,482,642,686,757), the rat kidney capsule (336,623), polyester sponges (10), healing rabbit bone grafts (154,200), the subcutaneous air “pouch” of Selye (625,626,643), epididymal fat pads seeded onto confluent cultures of myofibroblastic cells (660) as well as the subcutaneous implantation of polyvinyl alcohol sponge discs (211,821) or alginate beads containing sequestered cells (602). Vascular endothelial cell cultures derived from different sources have also been used to assess cell replication, DNA synthesis, cell migration, capillary-like tubular structure formation (239,821) as well as other cellular responses to putative angiogenic and anti-angiogenic factors. All of these methods suffer from significant shortcomings not the least of which is a difficulty in quantitation. Assay systems that involve cultured vascular endothelial cells also pose major problems. Because endothelial cells represent a heterogeneous population (210) the responses by certain endothelial cells to biologically active substances may not necessarily reflect reactions of the microvasculature from which new blood vessels arise.

Numerous investigators have studied the ultrastructure of growing blood vessels has been studied in the cornea of the rat (377,666,667,736,737) and rabbit (504,505,728,817,818) but the chain of events that precedes and follows the induction of corneal neovascularization has been studied in relatively few experimental models (18,63,106,108,116,143,194,263–265,416,524,666,694). The endothelial cell-specific tubular organelles (Weibel-Palade bodies) that contain a specific glycoprotein involved in blood coagulation (von Willebrand factor) (523) have been observed in growing corneal blood vessels (326,504).

It is generally accepted that directional growth occurs from a region where a chemical substance is in low concentration toward a zone containing this substance in high concentration. In 1893, Loeb (477) first postulated that some trophic chemical might be responsible for vascularization in general. In 1907 Goldman (298) provided the first clear suggestion that neoplasms produced an angiogenic agent, when he noted that neovascularization could easily be traced to regions in which the tumor had not yet advanced and he stated that “the impetus which gives rise to the proliferation of blood vessels emanates from the invading cell”. That an angiogenic substance might be liberated by nonperfused or ischemic retina was proposed by Michaelson in 1948 (534). Using hamster cheek pouches Greenblatt and Shubik (320) provided convincing evidence that tumors produce a diffusible angiogenic factor in 1968.

Many factors influence capillary growth and numerous theories have been proposed to account for the formation of new capillaries in different situations (114,649).

A wide variety of disorders of the cornea culminate in angiogenesis and a considerable amount of information has accumulated about the circumstances under which newly formed blood vessels sprout and extend centripetally into the cornea. In man corneal neovascularization complicates numerous infections (including trachoma, herpes simplex keratitis, leishmaniasis and onchocerciasis), immunologic processes (Stevens-Johnson’s syndrome, graft rejection), alkali burns, as well as traumatic, inflammatory, toxic and nutritional deficiency states and the wearing of some contact lenses (11,104,130,184,190,273,388,638,645). It is noteworthy that corneal vascularization is relatively uncommon in fungal keratitis (184).

Numerous methods have been used to quantitate corneal angiogenesis but almost all lack sufficient precision to provide reliable data suitable for biostatistical analysis. Many investigators of corneal neovascularization have only indicated whether a particular injury or intracorneal inoculation did or did not induce angiogenesis. In some studies the incidence of an angiogenic response has been used as an indication of the angiogenicity. Because it has become abundantly clear that the frequency and degree of corneal neovascularization varies in different situations the extent of induced corneal vascularization must be quantitated for meaningful comparisons between different experimental groups and their appropriate controls. To achieve this end some authors have graded the degree of corneal vascularization subjectively (61,174,266). Such methods have included the measuring of the vascular ingrowth from the corneoscleral limbus with a caliper and grading the extent of the vascularization subjectively (266); others have based the grading system on the number and length of the vascular loops (174) or on the distance that the blood vessels extended towards a burn from the corneoscleral limbus (494). Surprisingly, many authors have either not described their grading system or have simply illustrated representative photographs. A commonly used non-objective scoring of corneal vascularization on a 1+ to 4+ basis is insensitive and difficult to standardize. Efforts have also been made to grade angiogenesis according to the density of vascular growth (385).

Using a 193-nm excimer laser, we produced wide-area, refractive keratectomies on 18 cynomolgus monkey corneas and followed them up for up to 18 months. All corneas developed some subepithelial haze by one month. Electron microscopy disclosed epithelial thickening, absence of Bowman's layer, and subepithelial activated fibroblasts surrounded by disorganized collagen. By six months, the haze faded to a variable degree, the epithelium regained normal thickness, and the collagen was more organized. Persistent corneal haze at 12 months in some corneas correlated with electronlucent spaces in the subepithelial zone. Corneas were 90 microns thinner centrally two weeks after myopic ablation, but returned to preoperative thickness by six months. Myopic flattening and hyperopic steepening of 6 diopters were targeted, and over 7 diopters of each were achieved initially. Regression of induced curvature stabilized over several months. At 18 months, 4.4 diopters of myopic flattening and 5.2 diopters of hyperopic steepening remained.

To review 30 years' clinical experience with Fuchs corneal endothelial dystrophy leading to penetrating keratoplasty (PK).We reviewed the clinical records of patients diagnosed histopathologically as having Fuchs corneal endothelial dystrophy who underwent PK at Duke University Medical Center between January 1, 1972, and December 31, 2001. This observational case series included 424 patients (546 eyes).Women represented 77.6% of patients. Mean age at the time of PK for all patients was 69.2 years. Bilateral PK was required in 28.8% of patients, and the mean interval between the 2 PKs was 3.2 years. There was no difference with regard to sex in the likelihood of requiring bilateral PK (P=.59). Among 376 documented family histories, 13.6% were known to be positive for Fuchs dystrophy. Patients with a positive family history underwent PK a mean of 5 years earlier (P.002) and were more likely to require bilateral PK (P.003). Patients who underwent bilateral PK were twice as likely to have a positive family history compared with those undergoing unilateral PK (P.001). Mean visual acuities at corneal thicknesses of 539 to 650 microm, 651 to 750 microm, and greater than 750 microm were 20/60, 20/60, and 20/80, respectively. Patients who underwent bilateral PK and had a preceding cataract extraction on 1 eye required PK of the pseudophakic eye on average 3.2 years earlier than the fellow eye. The mean time from cataract extraction to PK was 2.2 years.This large study affirms that Fuchs dystrophy is a disorder of aging that predominantly affects women (3.5:1) and is often familial. Pachymetry-determined corneal thickness was a poor predictor of visual acuity until extreme levels of corneal edema were reached. Cataract extraction in an eye with Fuchs dystrophy leads to earlier PK.

Objective To characterize the relation of the βig-h3 protein to the diagnostic corneal deposits in the hereditary corneal dystrophies recently shown to have mutations in the βig-h3 gene on chromosome 5q31. Methods Corneas with lattice, granular, mixed granular-lattice ("Avellino"), and 2 types of Reis-Bucklers dystrophy were diagnosed by the histochemical and ultrastructural characteristics of their abnormal aggregates. Dystrophic and normal corneas were compared for immunolocalization of βig-h3 protein. Results In normal corneas, immunoreactivity for βig-h3 protein was strongest in the Bowman layer, and next strong along stromal interlamellar junctions and attachment sites of collagen to the Descemet membrane. Antibody binding was intense on all dystrophic aggregates, mimicking somewhat the normal protein distribution. Mixed granular-lattice dystrophy had the most variation in βig-h3–immunopositive forms. The aggregates in both the "rod-shaped" Reis-Bucklers type and the "curly fiber" Thiel-Behnke type were strongly stained for βig-h3 protein, consistent with mutations on the βig-h3 gene. Conclusions The marked immunopositivity for βig-h3 protein in the abnormal deposits in these dystrophies indicates that βig-h3 protein is a major component. The variety and quantity of immunopositive forms suggests that they consist primarily of the mutant protein, self-polymerizing and/or incorrectly binding to other corneal components. Variability of forms may relate to both the specific mutation and regional interactions of this protein.

Objective: To measure the levels of sulfotransferase activity for keratan sulfate and chondroitin sulfate in serum of patients with macular corneal dystrophy type I, an inherited disorder that is characterized by the absence of sulfate esters on keratan sulfate in the corneal stroma. Methods: The amount of sulfur-35 transferred from 3′-phosphoadenosine 5′-phosphosulfate to partially sulfated keratan sulfate and partially sulfated chondroitin sulfate by the sulfotransferase present in serum from patients with macular corneal dystrophy and agematched controls was determined under conditions where only the added enzyme was rate limiting. Results: Serum from patients with macular corneal dystrophy type I has the same level of sulfotransferase activity for keratan sulfate and chondroitin sulfate as found in age-matched controls. Conclusions: Patients with macular corneal dystrophy type I have sulfotransferase activity for sulfating at least 1 of the 2 sugars in keratan sulfate. It is proposed that the sulfotransferase for N -acetylglucosamine may be deficient.

PURPOSE: Synchrotron x-ray diffraction experiments indicate that corneas with macular corneal dystrophy (MCD) contain unusual 4.6-A periodic repeats thought to reside in proteoglycans or glycosaminoglycans. Recently the 4.6-A x-ray reflection was found to be significantly diminished after incubation of MCD specimens in buffer containing chondroitinase ABC or N-glycanase. We examined the sulfated proteoglycans in these glycosidase-digested MCD corneas. METHODS: Transmission electron microscopy was used in conjunction with cuprolinic blue-staining for sulfated proteoglycans. RESULTS: Incubation of an MCD specimen in enzyme buffer left both small and large proteoglycan filaments in the stromal matrix, whereas incubation in the presence of chondroitinase ABC removed these molecules from the tissue. Incubation in buffer containing N-glycanase, on the other hand, removed the large proteoglycan filaments from the MCD stroma but left unaffected the small collagen-associated proteoglycans. CONCLUSION: These results are consistent with the interpretation that 4.6-A periodic repeats in MCD corneas reside in large sulfated proteoglycan filaments (or aggregates thereof) that may contain chondroitin/dermatan sulfate and keratan sulfate or keratan components.

To determine the frequency of ocular metastases in the general population, we conducted a prospective histopathologic study of 716 eyes obtained from patients who had malignant neoplasms at the time of death. Fifty-two patients had ocular metastases; all of these individuals had widespread metastases that contributed to their deaths. The overall incidence of ocular metastases among all fatal cases of cancer was 9.3%. Thirty-three of the 117 patients with various types of leukemia and four of the 60 patients dying with lymphoma had ocular involvement. The total incidence of ocular metastases in patients dying of all types of carcinoma was 4.0%. In the nine patients dying of sarcoma, no ocular metastases were detected. We estimate that about 22,000 patients who will die of cancer in the United States during 1983 will have ocular metastases.

The clinical and morphologic features of a pigmented squamous cell carcinoma of the bulbar conjunctiva in a 57-year-old black man are reported. The tumor resembled the more usual epibulbar squamous cell carcinoma but had many melanin containing cells within it. Transmission electron microscopy disclosed melanosomes within squamous epithelium, melanocytes, and macrophages. The only cells within the tumor with morphologic features of a malignant neoplasm were squamous in type. The literature on this rare conjunctival tumor, which has a good prognosis following complete excision, is reviewed. Pigmented squamous cell carcinomas need to be distinguished from the more common nodular melanomas, which have a more ominous outlook.

The first ten blind human eyes in the United States to receive excimer laser (ArFl 193 nm) lamellar keratectomy (reprofiling) are presented. Seven of these patients were followed 6 to 12 months after ablation. All eyes are grossly clear in the region of ablation. Results of slit-lamp examination of all flattened ablated areas show mild superficial haze at the epithelial/stromal interface. This haze might not interfere significantly with vision in patients 7 to 10. Serial pachymetry and keratometry measurements, refraction, and digital keratoscopy show a progressive filling in of the excavated area by approximately two thirds but a loss of initial diopteric correction of only one third. Histopathologic analysis was obtained for four eyes. Transmission electron microscopy of three eyes enucleated 3 to 12 days after ablation shows 40-microns ablation depths through Bowman's layer and superficial stroma with minimal adjacent tissue damage and no inflammatory cells. The epithelium is increased in thickness by 50%, and firmly attached to the underlying stroma. A 4-month postablation specimen shows keratocyte activation with increased protein synthesis (presumed collagen and ground substance).

The clinical presentation of an 11-year-old boy with unilateral posterior internal ophthalmomyiasis is described. Ophthalmoscopy of the affected eye in this individual disclosed characteristic subretinal depigmented linear tracks and a larva within the vitreous. The intravitreal larva was retrieved successfully by pars plana vitrectomy and identified as the first instar of Cuterebra sp. (rodent botfly) by scanning electron microscopy. This was done by examining the external features of the larva by scanning electron microscopy and comparing them to scanning electron micrographs that were prepared on other first instar larvae of flies known to be implicated in internal ophthalmomyiasis. The study demonstrates the usefulness of scanning electron microscopy for taxonomic identification of fly larvae. Since even a small fragment of these organisms may contain characteristic features of external morphology, scanning electron microscopy may be useful in cases where the specimen is damaged or incomplete.

Severe progressive ocular enlargement of late onset accompanying chronic uveitis and secondary glaucoma occurred in an 18-year-old man. Electron microscopy of the thin sclera from the unusually large eye (40x40x37 mm) disclosed collagen fibrils with mean widths that exceeded that of controls, but that were within the range of the fibril size typically present in the outer sclera. Thinner fibrils that normally occur particularly within the inner sclera were conspicuously absent. Morphologic observations on corneal and cutaneous collagen from the patient were unremarkable. No abnormality was detected on chemical analysis of cutaneous collagen. The abnormal morphologic pattern of the scleral collagen is interpreted as a probable arrest in scleral collagen synthesis.

An elevated pigmented mass of the choroid remained stable for 6 1/2 years and then was documented photographically to have increased in size. The tumor stained on fluorescein angiography, produced a visual field defect, and differentially took up radioactive phosphorus. The eye was enucleated and on histologic examination contained a nevus of the choroid. This case shows that enlargement of a choroidal nevus may occur during adulthood, and suggests that despite newer and more sophisticated diagnostic techniques, large nevi and small melanomas of the choroid may be clinically indistinguishable.

A light microscopic, histochemical, and ultrastructural study was performed on tissue obtained from a pigmented squamous cell carcinoma of the cornea and conjunctiva. To the best of our knowledge this is the first time that one of these rare pigmented squamous cell carcinomas of the ocular mucous membrane has been described in detail. The occurrence of this neoplasm, which needs to be differentiated from other pigmented lesions, and particularly epibulbar melanomas, underscores the fact that all pigmented tumors are not melanomas. The study revealed that melanin granules, which accounted for the pigmentation of the neoplasm, were present in variable numbers in neoplastic squamous cells, Langerhans cells, macrophages, and stellate cells identified as melanocytes with mature melanosomes. Premelanosomes were not observed in any of these cells types. Current concepts concerning the common association of Langerhans cells with their characteristic intracytoplasmic "Birbeck granules" and melanocytes are discussed.

A significant, but transient corneal edema followed inadvertent intracameral irrigation of acetic acid in two patients. Since postsurgical corneal edema generally indicates corneal endothelial dysfunction, the effects of acetic acid on corneal endothelium were studied in the cat where the endothelial regenerative capacity is thought to be comparable to that of humans. The anterior chambers of feline eyes were irrigated with 0.25% acetic acid or balanced salt solution in a double-masked manner. Marked corneal opacification and thickening were evident following exposure to the acetic acid but did not occur following irrigation with balanced salt solution alone. Following intracameral acetic acid irrigation, a few endothelial cells were found in the anterior chamber angle but could not be found on Descemet's membrane. Over an 8-week period gradual repopulation of Descemet's membrane by endothelial cells occurred, first in the periphery and later in the central cornea, coincident with resolution of corneal edema.

Of 532 cases of sarcoidosis in the southeastern United States, ocular manifestations were a prominent feature of the disease in 202 (38%) of the patients. Approximately one fifth of them sought medical attention because of ocular complaints. This was the second most frequent clinical manifestation, exceeded only by pulmonary symptoms. When ocular segment structures were affected, the anterior segment was involved in 171 (84.7%) of cases. Chronic granulomatous uveitis was the most common abnormality in 106 cases (52.5%). Posterior segment disease occurred in 51 (25.3%) of cases, usually in the form of chorioretinitis or preiphlebitis; it was sometimes the sole manifestation of ocular sarcoidosis, but usually accompanied abnormalities in the anterior part of the eye. The incidence of central nervous system sarcoidosis was increased when posterior segment involvement was observed. Orbital and adnexal structures, primarily lacrimal gland, were affected in 53 (27.7%) of cases.

An otherwise normal adult Charles River rat (CD strain) was observed to have no recognizable eyes. Breeding and morphological studies were undertaken to determine the nature of the ocular defect, as well as its cause and pathogenesis. The anomaly was found to be inherited as an autosomal recessive trait with variable expressivity. It was characterized by unilateral or bilateral congenital microphthalmia with multiple associated ocular abnormalities including a neuroepithelial cyst, optic nerve aplasia, and cataract. In several elderly rats, no eye was found histologically in the orbit, suggesting reabsorption of malformed tissues as the basis of the anophthalmia. Study of the prenatal morphogenesis of the microphthalmia suggested that the primary disorder reflects a disturbance of the neuroepithelium of the retinal anlage and results in defective early formation of the optic cup. The abnormalities in other ocular structures, particularly in the lens, are considered secondary. This ocular malformation emphasizes the early interactions and interdependence of the lens and retina in normal morphogenesis and provides an animal model for study of lens-retinal relationships in abnormal morphogenesis. It is particularly relevant in understanding the pathogenesis of microphthalmia with cysts in the human eye.

An ELISA assay using a monoclonal antibody (ET-4-A-4) that recognizes a sulfated carbohydrate epitope in both keratan sulfate type I (corneal) and type II (skeletal) was employed to quantify keratan sulfate in serum and corneal tissue from patients with macular corneal dystrophy (MCD). This assay disclosed significant quantities of keratan sulfate in the serum in 45 healthy individuals (251 +/- 78 ng/ml), and in 66 patients with various corneal diseases (273 +/- 101 ng/ml). In contrast keratan sulfate was not detected (less than 2 ng/ml) in the serum of 16 patients with histopathologically confirmed MCD. Keratan sulfate was also detected in extracts of normal corneas and corneal tissue with a variety of pathologic conditions, but was virtually absent in corneal tissue from five patients with MCD. In corneas with MCD the chondroitin sulfate/keratan sulfate ratio was considerably higher than that of all normal and pathologic corneas studied. Since keratan sulfate in the serum appears to be derived predominantly from the normal turnover of cartilage these studies strongly suggest that the defect in keratan sulfate synthesis in MCD is not restricted to corneal cells and that MCD is one manifestation of a systemic disorder of keratan sulfate. The cartilage changes, however, do not have clinical significance. Moreover, since keratan sulfate can be detected in the blood of newborns it should be possible to diagnose MCD prior to corneal opacification.

At autopsy we examined eight eyes of six infants with Potter's syndrome, an idiopathic multisystem condition with a constellation of ocular anomalies, to explore its ocular component more fully and systematically. A striking abnormality in some cases was the presence of dilated intraocular blood vessels, and these were sometimes associated with retinal and preretinal neovascularization reminiscent of the vaso-proliferative stage of retrolental fibroplasia. Since oxygen therapy cannot be implicated in these cases, other causes, either genetic or environmental, must be sought. The presence of nonretinal ocular vascular anomalies, such as iris capillary dilation, peripapillary angioma formation, and vascular anomalies in nonocular tissue, point to a generalized derangement in the control of ocular angiogenesis. Our study indicated that an understanding of the pathogenesis of the vascular anomalies in Potter's syndrome is clearly relevant to other more common retinopathies that are associated with neovascularization.

In a clinical study of the essential iris atrophies, corneal edema occurred in 49 of 90 patients, and a characteristic hammered-silver appearance of the posterior cornea was visible in 54 cases. Intraocular pressure in the eyes with corneal edema ranged from normal to extreme elevation with glaucomatous damage, and lowering the pressure relieved the corneal edema in many cases with penetrating keratoplasty being effective when other measures failed. Electron microscopy of two keratoplasty specimens revealed extremely few, distinctly abnormal cells lining a collagenous layer posterior to Descemet's membrane.

Corrosion casts provide three dimensional replicas that can be examined readily by scanning electron microscopy (SEM). They are prepared by filling vascular networks with polymerizing plastic and then digesting away the tissue. As based on our studies of ocular vessels, this report describes the vascular anatomy, as well as the artifacts, that are encountered during SEM studies of such preparations.

The clinical and morphologic features of a unique intraorbital cartilaginous tumor are described. This lesion was excised from the orbit of an 11-year-old girl who was known to have a mild prominence of the right eye since at least age 6 years. This mass was not situated in the vicinity of the trochea or adjacent to the orbital bones, and we speculate that it arose from primitive orbital mesenchyme, which normally only differentiates into cartilage in the trochlea. We have designated this lesion as a cartilaginous hamartoma because it seems to be a tumor-like malformation composed of tissues that are constituents of the normal orbit rather than a true chondroma.

Thirty preretinal membranes excised from diabetic patients during pars plana vitrectomy were examined by transmission electron microscopy, scanning electron microscopy, or both. All the specimens were still correctly orientated after removal from the eyes. All the specimens contained collagen in varying amounts and most had blood vessels with a thickened basal lamina and adjacent pericytes. Fenestrated capillaries were identified in only four of the 21 membranes containing blood vessels. A wide variety of cell types were scattered within the membranes, including polymorphonuclear leukocytes, lymphocytes, plasma cells, macrophages (containing melanin and hemosiderin), glial cells, retinal pigment epithelium, and cells of uncertain derivation. Scanning electron microscopy showed the retinal side of the membranes to be smoother than the vitreal side and disclosed preretinal cells on the vitreal side of the membranes, either as individual stellate cells or as a monolayer of flattened cells with microvilli. Membranes stripped from the surface of the retina had a smooth, generally acellular surface on the retinal side.

Phosphatidic acid (PA) is an obligate intermediate in the phosphatidylinositol (PI) cycle and may serve as a sensitive marker for this pathway of reactions. Previously, we have shown that acetylcholine (ACh) stimulates formation of labeled PA in whole rat corneas whose phospholipids were prelabeled with [14C]arachidonate. To determine which layer of the cornea exhibits the ACh effect, intact epithelium was isolated from the rest of the corneal tissue (designated "stroma/endothelium") by incubating rat corneas with neutral protease and then stripping off the epithelium using forceps. The epithelium was ultrastructurally normal and avidly incorporated [14C]arachidonate into phospholipids; the stroma/endothelium had only trace incorporation. [14C]Arachidonyl-PA formation by the epithelium was significantly increased after a 37 second (+58%) and was maximal after a 5.0 minute (+188%) incubation in the presence of 1 mM ACh. The stimulation by ACh was blocked by atropine and scopolamine but not by d-tubocurarine. The epithelium also incorporated significant quantities of [3H]inositol into phosphatidylinositol (PI), phosphatidylinositol monophosphate (PIP), and phosphatidyl-inositol bisphosphate (PIP 2). When [3H]inositol-labeled epithelia were incubated for 5 minutes with 1 mM ACh, [3H]inositol monophosphate (IP) was increased 200%, [3H]inositol bisphosphate (IP2) was increased 225%, and [3H]inositol 2 trisphosphate (IP3) was increased 74%. These results suggest that muscarinic cholinergic receptors may be an important regulator of the PI cycle in corneal epithelium and thus may affect intracellular calcium mobilization and epithelial proliferation and regeneration.

The morphology of the tentorium cerebelli was investigated in representatives of the chordata. A tentorium cerebelli characterized birds and mammals but was regularly absent in fishes, amphibians, and reptiles. The data suggest that the tentorium cerebelli emerged relatively late in phylogeny as bilateral folds of dura mater on either side of the brainstem in the cerebro-cerebellar fissure. Subsequent evolution was characterized by the union of these septa behind the brainstem and by a progressive lengthening of the straight sinus. Tentorial ossification distinguished a further evolutionary step in some mammalian lines. The inferred evolutionary pattern of the tentorium cerebelli resembles the successive stages which the human tentorium undergoes during ontogeny.

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Actinic granuloma is a condition showing actinic elastosis accompanied by a chronic inflammatory cell infiltrate and multinucleated giant cells absorbing elastotic fibers. 1 It differs from granuloma annulare by the absence of necrobiotic collagen and palisading histiocytes. 1,2 Lesions typically occur in the skin and begin as papules that progress to plaques and then to incomplete or complete annular lesions. In the conjunctiva, actinic elastosis is the hallmark of Pingueculae 3 and to the best of our knowledge has been noted in association with a granulomatous reaction in only one previous report. 4 We recently studied a conjunctival lesion with the histologic features of actinic granuloma.

• The effect of topically administered rabbit fibronectin on the rate of corneal epithelial wound healing was assessed in rabbits. Two types of epithelial defects were created, a "standard" 7-mm-diameter scraped central wound and a "persistent epithelial wound" secondary to post-scraping application of alcian blue. In a masked fashion, eyes were treated with either fibronectin or balanced salt solution. Areas of the photographically documented fluorescein-stained defects were measured by computerized planimetry. The mean healing rate in fibronectin-treated eyes with standard wounds was linear but not significantly different from the rate in control eyes. The healing rate in persistent epithelial wounds treated with fibronectin was slower than that in standard wounds and was not linear, but it was not statistically significantly different from that of control eyes with persistent epithelial wounds. These results conflict with those of previous studies and indicate that the topical application of fibronectin in rabbits does not necessarily promote corneal epithelial wound healing.

A study of 11 consecutive patients with anterior uveal melanomas from one institution demonstrated the wide variation in the clinical and histopathologic manifestations of the tumors. The intraocular pressure in the involved eye compared with the fellow eye was elevated in five cases, equal in four, and reduced in two. Histologic studies suggest that the anterior uveal melanomas influence intraocular pressure through their effect on the balance between aqueous production and outflow. Three of the four patients with ciliary body melanomas and glaucoma died of metastatic disease within 3 years of enucleation.

Transgenic mice carrying the murine granulocyte-macrophage colony stimulating factor (GM-CSF) gene expressed from a retroviral promoter exhibit elevated levels of GM-CSF in the serum, urine, peritoneal cavity, and eye. The eyes of transgenic mice are opaque, contain accumulations of macrophages, and develop retinal damage. Similarly, lesions containing macrophages develop in striated muscle. The mice also display an accumulation of large, often multinucleate, activated macrophages in the peritoneal and pleural cavities. The transgene is transcribed in peritoneal cells, as well as in eyes and infiltrated striated muscle. A high proportion of transgenic mice die with muscle wasting when aged 2-4 months, possibly because of macrophage activation resulting from the high levels of GM-CSF.

A 63-year-old man, in good health previously, developed swelling and erythema of the right upper eyelid which progressed to involve both eyelids and surrounding tissues. After one month, he had a 9.0 × 9.0 × 3.5 cm mass despite two attempts at incisional drainage and treatment with antibiotics. Multiple asymptomatic erythematous nodules (2–3 cm in diameter) developed on his back, trunk, and arms four weeks after onset of the eyelid erythema and swelling. Biopsies of two upper back papules and the eyelid disclosed cutaneous T-cell lymphoma, a lymphoproliferative malignancy of thymus derived lymphocytes originating in the skin. Systemic chemotherapy resulted in a marked decrease in the ocular adnexal mass but lymphomatous meningitis and quadriplegia developed. The patient died four months later; an autopsy was not performed. This case demonstrates that cutaneous T-cell lymphoma may rarely have its initial manifestation as a rapidly enlarging eyelid tumor.

The clinical and histopathologic features of Axenfeld's anomaly and Rieger's anomaly and syndrome are reviewed, and recent findings regarding the pathogenesis of this spectrum of developmental disorders are discussed. Based on these observations, it has been suggested that a developmental arrest, in the third trimester of gestation, of tissues derived from the neural crest cells accounts for the ocular and most of the nonocular abnormalities in this group of disorders. Since previous collective terms, such as mesodermal dysgenesis and anterior chamber cleavage syndrome, are not consistent with these new observations, the alternative name, Axenfeld-Rieger syndrome, has been proposed. The differential diagnosis of the syndrome includes two additional spectra of disorders: the iridocorneal endothelial syndrome and the posterior polymorphous dystrophies. The most serious ocular problem in Axenfeld-Rieger syndrome is the associated glaucoma, which occurs in a high percentage of patients and is typically difficult to control. Recent observations regarding the mechanism of the glaucoma, as reviewed in this paper, provide guidance in the management of this aspect of Axenfeld-Rieger syndrome.

Two cases of malignant syringoma of the eyelid are reported. The first patient, a 20-year-old woman, presented with a one year history of a slowly growing nodule in the left lower eyelid. The lesion recurred five months after excision, slowly grew over the ensuing two and one-half years, and was reexcised. The second case was an 18-year-old man who was first examined by an ophthalmologist because of a slowly enlarging, painless induration of his right lower eyelid for two years. Histologic examination of the excised lesions from both patients disclosed proliferated ducts lined by two layers of epithelium infiltrating the dermis and subcutaneous tissue; there was skeletal muscle and perineural invasion, but only minimal cellular atypia. Malignant syringomas are rare forms of sweat gland carcinoma, which most often occur on the upper lip and to our knowledge have not been reported on the eyelid. These tumors probably arise from eccrine ducts, are more common in women, and have a peak incidence in the fifth decade. The histologic feature that best indicates prognosis is the degree of cellular atypia. Patients with cytologically well-differentiated tumors do well following complete local excision. Features that help to distinguish malignant syringoma from its benign counterpart are the larger size, solitary nature, and subcutaneous, muscular, and perineural invasion.