The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family.

Apoptosis is essential for normal development and maintenance of homeostasis, and disruption of apoptotic pathways is associated with multiple disease states, including cancer. Although initially identified as central regulators of apoptosis at the level of mitochondria, an important role for BCL-2 proteins at the endoplasmic reticulum is now well established. Signaling pathways emanating from the endoplasmic reticulum (ER) are involved in apoptosis initiated by stimuli as diverse as ER stress, oncogene expression, death receptor (DR) ligation and oxidative stress, and the BCL-2 family is almost invariably implicated in the regulation of these pathways. This also includes Ca(2+)-mediated cross talk between ER and mitochondria during apoptosis, which contributes to the mitochondrial dynamics that support the core mitochondrial apoptosis pathway. In addition to the regulation of apoptosis, BCL-2 proteins at the ER also regulate autophagy, a survival pathway that limits metabolic stress, genomic instability and tumorigenesis. In cases where apoptosis is inhibited, however, prolonged autophagy can lead to cell death. This review provides an overview of ER-associated apoptotic and autophagic signaling pathways, with particular emphasis on the BCL-2 family proteins.

Transesophageal echocardiography in the diagnosis of branch retinal artery obstruction.

We examined a 28-year-old man and a 19-year-old woman with branch retinal artery obstruction. Both were examined exhaustively. In each patient, a patent foramen ovale was demonstrated by transesophageal echocardiography after a transthoracic study disclosed no abnormalities. These observations suggest that transesophageal echocardiography is valuable in examining young patients with retinal emboli in whom cardiac abnormalities are suspected.

Primary open angle glaucomas in the rhesus monkey.

Rhesus monkeys from the closed Cayo Santiago colony of the University of Puerto Rico demonstrate elevated (> or = 22 mm Hg) intraocular pressure in a pattern which significantly favours certain maternal lineage groupings. The colony had remained genetically pure since 1938. Of nine matriarchal lineages (matrilines) examined, two had an incidence of ocular hypertension of more than 40% and six of more than 10%. Information on 18 matrilines is currently located in the colony data base which identifies each individual and its vital statistics. In 1990, six animals were moved to the laboratory in Florida. Among those from a low incidence matriline, we found abnormal optic nerve cups, pallor, reduced function of (mainly peripheral) fields, progression and loss of optic nerve axons in the presence of ocular hypertension. In another individual where the cup/disc ratio for the right eye was 0.7 and left eye 0.4 and outflow facility was normal, we excluded all other causes of optic nerve atrophy, and low tension glaucoma was diagnosed. This female was from a matriline with a low incidence of ocular hypertension. Relatively rapid aging (3-4 years/human year) monkeys with ocular hypertension and familial clustering produce a near ideal glaucoma research model.

A primate model for age related macular drusen.

A closed colony of semi-free-ranging rhesus monkeys maintained in isolation since 1938 by the Caribbean Primate Research Center (CPRC) is being studied as a model for age related macular drusen. Of examined colony animals 57.7% of the monkeys and 47.3% of their eyes have drusen. The prevalence and severity of drusen are linearly related to increasing age and are significantly higher in specific maternal lineages (matrilines). An electrophysiological estimate indicates loss of function associated with drusen. Prevalence of drusen in CPRC females is almost twice that of males, while the prevalence among CPRC animals in general appears to be several times that of monkeys from continental US facilities. Evidence suggests that the frequency of endstage lesions is also similar to that in human populations. The CPRC matriline monkeys appear to provide the best model yet reported for human age related macular drusen.

Recurrent postoperative endophthalmitis.

We treated five patients for postoperative endophthalmitis who demonstrated an initially good response to intravitreal management of their infection and then suffered a later recurrence. Four of the five patients received a single intravitreal injection of antibiotics as the only intravitreal therapy, and the fifth patient received a single antibiotic injection in addition to a partial vitrectomy. All recurrent infections occurred between 10 and 21 days after the original intravitreal injection of antibiotics. At the time of the recurrence, all five patients remained culture positive with the same organism that was initially isolated. The bacterial species isolated were S. epidermidis, group D streptococcus, P. acnes, P. mirabilis, and P. aeruginosa. All patients were ultimately sterilized with repeated intravitreal injections of antibiotics, vitrectomy, and/or intraocular lens removal. Factors that were related to recurrent infection were marginal susceptibility of the organism to the originally injected antibiotics, infection with a slowly replicating organism, and infection with a gram-negative bacillus. A single intravitreal injection of antibiotics may only partially treat bacterial endophthalmitis. Patients should be observed for at least 3 weeks following treatment of endophthalmitis for recurrence of their infection, and aggressive management, including vitrectomy and repeated intravitreal injections of antibiotics, should be used to treat recurrent infections.

Acquired contralateral oculomotor synkinesis.

A patient with a traumatic right third nerve paresis had a contralateral oculomotor synkinesis develop that involved the left upper eyelid. With infraduction in adduction of the nonparetic left globe, the left upper eyelid was elevated. Elevation of the right upper eyelid was present in adduction of the paretic eye but absent in downgaze. To our knowledge this is the first description of the pseudo-Graefe phenomenon developing contralateral to the regenerating paretic third nerve.

Adult-onset macular degeneration in the Cayo Santiago macaques.

Since 1985 a group from the University of Florida has examined 136 rhesus monkeys from the Cayo Santiago colony. From the sample, 97 are older than nine years (approximately 30 human years) and 39 are younger. Drusen were found in 17% of the younger eyes and in 46% of the older eyes. All animals over 25 years of age had drusen in the central fundus. The incidence of drusen varied from 19-77% between five social groups. Incidence reported in random-source colonies in the continental U.S.A. is about six percent. Compared to near-age matched controls without drusen, selected rhesus exhibited visual resolution losses amounting to two Snellen-lines or more. The end-stage disciform changes and ultrastructural similarities are comparable with human macular disease. Future prospective studies may include therapies, surgical intervention, environmental manipulation and genetic research.

Macular disease in related rhesus monkeys.

During (January) 1986-(May) 1988, we examined 272 eyes in 136 rhesus monkeys in the closed Cayo Santiago colony of the Caribbean Primate Research Center of the University of Puerto Rico. Seventy-eight eyes were less than 10 years of age. One hundred and ninety-four were aged 10-28 years. The fundi were examined and photographed. Fluorescein angiography was performed in some eyes. Selected cases were evaluated for 'acuity' loss by recording of pattern-evoked retinal and cortical signals. Light and electron microscopy were used to evaluate the pigment epithelium of some animals. Thirty-eight percent of all eyes had posterior pole drusen. Incidence was highly age-related. When late-stage lesions were found, we did not see neovascularization, but late hyperfluorescence was consistent with degenerative scarring and atrophy. Electrophysiology demonstrated moderately reduced acuity in the presence of numerous macular drusen. Electrooculograms were low normal. Histopathology showed changes identical to those reported in human age-related macular degeneration. No eyes less than 10 years of age had confluent drusen or disciform-like lesions. The incidence of drusen in samples of some social groups was much higher than others.

The treatment of postoperative endophthalmitis. Results of differing approaches to treatment.

The authors treated 26 patients with postoperative endophthalmitis over a 4-year period, between 1983 and 1986. Nineteen patients were culture-positive and seven were culture-negative. All patients received intravitreal antibiotics as part of their treatment regimen. Culture-negative patients generally responded well to a single intravitreal antibiotic injection. Five of seven (71.4%) culture-positive patients who were treated with a single intravitreal antibiotic injection and no vitrectomy suffered either a recurrence of their infection or did not respond to treatment. Four of five patients who received a vitrectomy in addition to a single intravitreal antibiotic injection were cured of their infections; the one patient who received repeated intravitreal antibiotic injections alone and all six patients who received repeated intravitreal antibiotic injections in combination with vitrectomy were cured of their infections. Although the intravitreal injection of antibiotics provides an extremely high initial level of antibiotics inside the eye, a single intravitreal antibiotic injection may only partially treat bacterial endophthalmitis. In culture-negative cases, a single intravitreal injection of antibiotics appears to be sufficient treatment. In culture-positive cases, a higher cure rate is achieved with an aggressive approach which includes the use of repeated intravitreal antibiotic injections and/or vitrectomy.

Electroretinograms in early fungal endophthalmitis.

To facilitate the early diagnosis of exogenous fungal endophthalmitis, we developed a rabbit model for Aspergillus fumigatus endophthalmitis. Six eyes of six New Zealand white rabbits were inoculated with forty spores of A. fumigatus. A control group of their six contralateral eyes received a similar but sterile inoculum. The rabbit eyes were evaluated with respect to clinical appearance and the electroretinogram. Clinically evident endophthalmitis developed in all six infected eyes at an average of five days after injection (range 3-7 days). Data samples each 48 hours showed transient b-wave amplitude elevations in three infected eyes. These were greater than two standard deviations above the mean pre-injection values (p less than 0.05). These amplitude increases preceded the onset of ophthalmoscopically recognizable infection and were observed at 2 to 5 days after injection (mean = 4 days). B-wave amplitudes in the infected eyes fell below two standard deviations of pre-injection values (p less than 0.05) at an average of 5 days (range 3-7 days) after injection, a corresponding to the onset of clinically obvious infection. At an average of 7 days after injection, all the infected eyes exhibited unmeasurable electroretinogram waveforms and severe infection. Histopathologic study of infected eyes showed extensive fungal infiltration of retina and vitreous tissues. The electroretinogram may be helpful in the early diagnosis of fungal endophthalmitis.

Degenerative changes in maculas of rhesus monkeys.

In the hope of identifying an animal model for age-related macular degeneration (AMD) we undertook a pilot investigation of aged rhesus monkeys. Twenty-nine monkeys from a seminatural colony were examined at the Caribbean Primate Research Center. Macular drusen were found in 74% of the monkey eyes. Alterations of the retinal pigment epithelium within the macula were noted in 45% of the eyes. Fluorescein angiography in selected animals revealed window defects consistent with drusen. None of this sample showed the exudative form of AMD or disciform scarring. One typical monkey underwent special studies including measurement of visual resolution by electrophysiological study of the retinal and visual cortex. Application of human criteria to this animal supported the diagnosis of early AMD. Histopathologic study of one eye by transmission electron microscopy confirmed the presence of drusen with nearly identical ultrastructural features to those found in the human pigment epithelium in AMD.

Macular degeneration in a community of rhesus monkeys. Ultrastructural observations.

The eyes of 29 aged adult, (mean age, 20 years) rhesus monkeys were examined for the presence of age-related macular degeneration (AMD). This sample represented approximately 25% of the aged population in the seminatural colony at the Caribbean Primate Research Center (CPRC) of the University of Puerto Rico. Approximately 75% of the animals examined had drusen in the posterior pole. Ultrastructural analysis was used to determine whether the pathologic alteration of Bruch's membrane and drusen in the colony resembled those noted in aged or AMD-afflicted human retinas. There were abnormalities in all layers of Bruch's membrane. Deposits of heterogeneous material, comprised of membranous, granular, and cellular components, were seen in both the inner collagenous zone (ICZ) and the outer collagenous zone (OCZ). Accumulation of this drusenoid material in the ICZ produced a scalloping of the basal border of the retinal pigment epithelium (RPE). Dense bodies were seen in both Bruch's membrane and RPE cytoplasm near the basal infoldings. Cytoplasmic processes, as well as whole cells, were seen with regularity within the drusenoid material. In one case there was a cell with a basement membrane crossing the middle elastic layer of Bruch's membrane. These changes are consistent with those reported in human aging and AMD. Aged individuals in this colony appear to be predisposed to macular degenerative changes and may prove to be an invaluable animal model for studying AMD in humans.

Tissue responses of the monkey retina: tuning and dependence on inner layer integrity.

Recent technical and conceptual advances have made it possible to experiment with models of local human inner retinal disease and changes in very small, tissue-specific signals. Local retrograde degeneration of the ganglion cells was induced in four rhesus monkeys by 160 degrees microdiathermy fiber layer burns at the nasal or temporal edges of the optic disc. There were no abnormalities of the classical electroretinograms (ERGs) during the following 210 days. With nasal lesions, pattern-evoked retinal (PERR) and cortical responses over a range of grating contrasts and spatial frequencies were largely normal. The authors found a cortical spatial tuning peak near 0.5 cycles/deg (cpd) and a retinal peak at 0.25-0.3 cpd. With temporal lesions, the retinal signals to high frequency stimuli (greater than 1.0 cpd) approached zero between 20-60 days. The cortical evoked signal declined with a course similar to the retinal components. Histological evidence was found for extensive loss of ganglion cells and fibers in a central 30-40 degrees temporal area, including the macula, 210 days after the temporal lesions. This is strong evidence that local ganglion cell-dependent electrical potentials, bearing little relation to the ERG, can be measured in response to selected stimuli.

Orbital Burkitt's lymphoma in a homosexual man with acquired immune deficiency.

A 22-year-old homosexual man had persistent systemic lymphadenopathy and a three-week history of rapid swelling and induration of his right upper eyelid. Acquired immune deficiency leading to the development of lymphoma was suspected. A biopsy specimen of the mass revealed Burkitt's lymphoma and treatment with systemic chemotherapy and radiation therapy resulted in remission. A significant number of patients with acquired immune deficiency are developing Burkitt's lymphoma. The three separate syndromes of acquired immune deficiency and their associated ophthalmic manifestations are discussed.

Diagnostic vitrectomy.

The histopathologic and cytopathologic study of ocular fluids obtained for diagnostic purposes is presented. The analysis of fluid specimens with millipore filter, celloidin bag-cell block, and transmission electron microscopy techniques has proved to be effective for establishing and confirming clinical diagnoses. Diagnostic vitrectomy can be readily used to evaluate such conditions as intraocular tumors, lens and blood-induced glaucoma, inflammatory conditions, amyloidosis, persistent hyperplastic primary vitreous (PHPV), epithelial ingrowth, and tractional vitreoretinal membranes.

A histopathologic study of macular cysts and holes.

Forty-four eyes from 39 patients with either lamellar macular holes (17 eyes), full-thickness macular holes (18 eyes), and/or macular cysts (9 eyes) were studied histopathologically. Lamellar and full-thickness holes were frequently found in eyes with a history of trauma or ocular surgery. Diabetes mellitus was the most common condition associated with macular cysts. Four lamellar holes and four full-thickness holes occurred in eyes with senile macular degeneration. Six lamellar holes, eight full-thickness holes, and one macular cyst developed on an idiopathic basis. Residual cystoid macular edema was the most prevalent accompanying pathologic feature. Cystoid macular edema was also noted in the opposite eye in seven cases of lamellar and full-thickness holes. A preretinal glial membrane, thought to be a secondary change, was found at or near the edges of the lamellar or full-thickness holes or over the macular cyst in the majority of cases. Wrinkling of the internal limiting membrane (ILM) was present in five cases. Vitreous traction, with or without an operculum, was infrequently associated with these entities.