Methylprednisolone therapy for retinal laser injury.

OBJECTIVE: Laser photocoagulation treatment of the posterior pole of the retina is often complicated by immediate visual impairment, which is caused by the unavoidable laser-induced destruction of the normal tissue adjacent to the lesion. A neuroprotective therapy aimed at salvaging this normal tissue might enhance the benefit obtained from treatment and permit safe perifoveal photocoagulation. To determine whether corticosteroids can provide neuroprotection during photocoagulation, we examined the effect of methylprednisolone on laser-induced retinal injury in a rat model. METHODS: Argon laser lesions were inflicted on the retinas of 36 rats and were followed immediately by intraperitoneal injections of high-dose methylprednisolone or saline. The animals were sacrificed after 3, 20, or 60 days, and their retinal lesions were evaluated histologically and morphometrically. RESULTS: No histopathologic differences were observed between the treated and control animals. Methylprednisolone treatment was demonstrated to posses some neuroprotective effect for a short time after laser exposure, but was ineffective in ameliorating the long-term results of retinal laser injury. CONCLUSIONS: On the basis of our results, we suggest that high-dose methylprednisolone treatment is ineffective in ameliorating laser-induced retinal injury. Other drugs should be investigated for their potential role as neuroprotective agents to prevent the spread of retinal laser damage.

The role of intraocular lenses in anterior chamber contamination during cataract surgery.

BACKGROUND: Bacterial endophthalmitis is a rare vision-threatening disease, usually caused by microorganisms that are natural inhabitants of the eye lids and conjunctiva. This study was conducted to investigate the role of intraocular lenses (IOLs) in introducing bacterial contamination into the eye during cataract surgery and the efficacy of povidone-iodine solution in prevention this ocular inoculum. METHODS: Fifty patients underwent routine cataract surgery and intraocular lens implantation. One group of the patients was pretreated with external disinfection using povidone-iodine 4% before surgery, while the other group was only pretreated with saline irrigation. Before IOL implantation, a test IOL was placed on the conjunctiva and taken for microbiological studies. Anterior chamber tap was done at the beginning and at the end of each operation. Positive bacterial growth was followed by bacterial identification and sensitivity tests to various antibiotics. RESULTS: Bacterial growth was obtained in 14 of the 50 eyes (28%); in 5 eyes the organism was cultured from tapped aqueous and in 9 eyes from the test IOLs. Prophylactic use of povidone-iodine 4% solution effectively reduced the contamination rate from 34.7% to 16.7%. Coagulase-negative staphylococci were the most common organisms isolated (72%). Most organisms were sensitive to vancomycin (86%) and to fucidic acid (71%). There were no cases of clinical endophthalmitis. CONCLUSIONS: IOLs are apparently potential vehicles for introduction of intraocular bacterial contamination. Instillation of povidone-iodine 4% into the cul-de-sac reduces the risk of bacterial inoculum. Vancomycin is the most effective single agent against intraocular contamination. In order to reduce potential intraocular contamination it is advisable to avoid contact between the IOL and ocular tissues.

The association between cigarette smoking and ocular diseases.

Tobacco smoke is composed of as many as 4,000 active compounds, most of them toxic on either acute or long-term exposure. Many of them are also poisonous to ocular tissues, affecting the eye mainly through ischemic or oxidative mechanisms. The list of ophthalmologic disorders associated with cigarette smoking continues to grow. Most chronic ocular diseases, with the possible exception of diabetic retinopathy and primary open-angle glaucoma, appear to be associated with smoking. Both cataract development and age-related macular degeneration, the leading causes of severe visual impairment and blindness, are directly accelerated by smoking. Other common ocular disorders, such as retinal ischemia, anterior ischemic optic neuropathy, and Graves ophthalmopathy, are also significantly linked to this harmful habit. Tobacco smoking is the direct cause of tobacco-alcohol amblyopia, a once common but now rare disease characterized by severe visual loss, which is probably a result of toxic optic nerve damage. Cigarette smoking is highly irritating to the conjunctival mucosa, also affecting the eyes of nonsmokers by passive exposure (secondhand smoking). The dangerous effects of smoking are transmitted through the placenta, and offspring of smoking mothers are prone to develop strabismus. Efforts should be directed toward augmenting the campaign against tobacco smoking by adding the increased risk of blindness to the better-known arguments against smoking. We should urge our patients to quit smoking, and we must make them keenly aware of the afflictions that can develop when smoke gets in our eyes.

[Terror in Japan: mass-intoxication with the nerve-agent sarin].

During 1994/5 the Japanese civilian population suffered 2 terror attacks by the organophosphorus nerve-agent sarin. In these 2 episodes it is estimated that more than 6000 people were injured, of whom 19 died. The quick and efficient response of the civilian emergency systems to these unforeseen, attacks has to be analyzed by local authorities to determine the best solutions in case of another attack. We summarize the events, and note the emergency system's response, the need for rapid and accurate chemical identification of the toxin, the necessity for decontaminating the casualties and for providing protective gear for rescue units in the contaminated area. We also describe the clinical status of the casualties and outline the mode of therapy applied.

MK-801 has neuroprotective and antiproliferative effects in retinal laser injury.

PURPOSE: Treatment of the retina by laser photocoagulation often is complicated by an immediate side effect of visual impairment, caused by unavoidable, laser-induced destruction of healthy tissue adjacent to the lesion. A neuroprotective therapy that salvages this healthy tissue might enhance the benefit obtained from the treatment. This study was proposed to determine whether glutamate-receptor blockers can provide adjuvant neuroprotection during laser photocoagulation. The effect of MK-801, an NMDA-receptor antagonist, on laser-induced retinal injury was examined, in a rat model. METHODS: Argon laser lesions were created in the retinas of 36 DA rats, and were followed immediately by intraperitoneal injections of MK-801 (2 mg/kg) or saline. The animals were killed after 3, 20, or 60 days and the retinal lesions were evaluated histologically and morphometrically. RESULTS: Photoreceptor-cell loss was significantly less in MK-801-treated rats than in control animals. The proliferative membrane composed of retinal pigment epithelial cells and neovascular blood vessels, which was seen at the base of the lesion in control group retinas, was smaller in the MK-801-treated retinas. In rats treated with a higher dose of MK-801, the lesions showed almost no proliferative reaction. CONCLUSIONS: A potent noncompetitive NMDA-receptor blocker, MK-801 exhibits neuroprotective and antiproliferative properties in the retina. Glutamate-receptor blockers should be investigated further as potential adjuvant therapy in retinal photocoagulation treatments.

Effect of corticosteroids on healing of the corneal endothelium in cats.

BACKGROUND: Anterior segment surgery is frequently complicated by damage to the corneal endothelium. We examined the effects of corticosteroids, which are widely used for the suppression of postoperative inflammation, on the process of endothelial cell regeneration. METHODS: The effect of corticosteroids on healing of the corneal endothelium was examined in 10 domestic cats. In both eyes a circular area, 8 mm in diameter, was scraped off at the center of the corneal endothelium without damaging Descemet's membrane. Immediately after scraping, as well as 2 and 5 days later, each animal received a unilateral retrobulbar injection of betamethasone sodium phosphate (2 mg). The other eye served as a control and received a retrobulbar injection of the vehicle only. RESULTS: Evaluation of the corneal endothelium 2, 5 and 7 days after the trauma revealed that relative to the control contralateral eyes, the corticosteroid-treated eyes exhibited a higher mean coefficient of variation of the corneal endothelium cell area, fewer hexagonal cells, a larger number of polygonal cells with 3, 4 7 and 8 cellular facets, thinner corneas and less inflammation. CONCLUSIONS: These findings suggest that corticosteroids unfavorably affect the regeneration of corneal endothelial cells after injury. As corticosteroids appear to have both positive and adverse effects on corneal function after trauma, they should be used with caution.

Ocular injury by mustard gas.

Sulfur mustard is a chemical warfare agent which was widely used during World War I and more recently in conflicts in the Middle East. This highly toxic compound causes severe dermal, gastrointestinal, respiratory and ocular injuries. It acts as an alkylating agent that induces structural changes and, hence, destruction of nucleic acids and proteins, impairing the cell's normal homeostasis and eventually causing its death. Sulfur mustard reacts rapidly with ocular tissues, and after a latent period of a few hours the patient starts suffering from severe eye pain, photophobia, excessive lacrimation and blindness. The injury, which is restricted to the anterior segment of the eye, may cause long-lasting incapacity in large numbers of casualties. Approximately 0.5% of the severely wounded victims may develop late complications which require prolonged ophthalmologic observation and therapy. In light of the ever-present threat of mustard chemical warfare against military and civilians, physicians worldwide should be aware of its grave effects and know how to care for its victims.

Neuroprotective therapy for argon-laser induced retinal injury.

Laser photocoagulation treatment of the central retina is often complicated by an immediate side effect of visual impairment, caused by the unavoidable laser-induced destruction of the normal tissue lying adjacent to the lesion and not affected directly by the laser beam. Furthermore, accidental laser injuries are at present untreatable. A neuroprotective therapy for salvaging the normal tissue might enhance the benefit obtained from treatment and allow safe perifoveal photocoagulation. We have developed a rat model for studying the efficacy of putative neuroprotective compounds in ameliorating laser-induced retinal damage. Four compounds were evaluated: the corticosteroid methylprednisolone, the glutamate-receptor blocker MK-801, the anti-oxidant enzyme superoxide dismutase, and the calcium-overload antagonist flunarizine. The study was carried out in two steps: in the first, the histopathological development of retinal laser injuries was studied. Argon laser lesions were inflicted in the retinas of 18 pigmented rats. The animals were killed after 3, 20 or 60 days and their retinal lesions were evaluated under the light microscope. The laser injury mainly involved the outer layers of the retina, where it destroyed significant numbers of photoreceptor cells. Over time, evidence of two major histopathological processes was observed: traction of adjacent normal retinal cells into the central area of the lesion forming an internal retinal bulging, and a retinal pigmented epithelial proliferative reaction associated with subretinal neovascularization and invasion of the retinal lesion site by phagocytes. The neuroprotective effects of each of the four compounds were verified in a second step of the study. For each drug tested, 12 rats were irradiated with argon laser inflictions: six of them received the tested agent while the other six were treated with the corresponding vehicle. Twenty days after laser exposure, the rats were killed and their lesions were subjected to image-analysis morphometry. The extent of retinal destruction was assessed by measuring the lesion diameter and the amount of photoreceptor cell loss in the outer nuclear layer. Methylprednisolone and MK-801 were shown to ameliorate laser-induced retinal damage, whereas both superoxide dismutase and flunarizine were ineffective. Furthermore, MK-801 diminished the proliferative reaction of the retinal pigment epithelial cells. On the basis of our results we suggest that the pigmented rat model is suitable for studying and screening various compounds for their neuroprotective efficacy in treating retinal laser injury. We further suggest that glutamate might play a key role in mediating retinal injury induced by laser irradiation.

[Advances in ophthalmological photodynamic therapy].

Photodynamic therapy is a new experimental therapeutic technique which is attracting increasing attention. Its biopharmacological basis of action is the specific interaction of a photosensitizing compound with the cellular elements of pathological lesions. The photosensitizer is thought to enter specifically into the pathologic cells, where it accumulates. The lesion is then irradiated with a sensitizing laser-beam of specific wave-length to activate the photosensitizer, which then becomes a generator of free oxygen radicals. These radicals destroy the sensitizer-harboring pathological cells. The advantage of specifically destroying pathological lesions without affecting surrounding normal tissue is obvious. Recently, many experimental studies have been conducted to test the usefulness of photodynamic therapy for ocular disorders, mainly advanced age-related macular degeneration and uveal melanoma. Results so far are encouraging.

Metabolic profile of fetal dopamine neurons transplanted to the adult rat striatum.

In the present study, we have examined the expression and distribution of the metabolic marker neuron-specific enolase (NSE) in solid-tissue transplants of fetal substantia nigra (SN) to the striatum of intact and 6-hydroxydopamine lesioned mature rats. Immunocytochemistry was applied to label NSE and tyrosine hydroxylase (TH) respectively. Cellular content of NSE is indicative of metabolic activity as well as synaptogenesis/maturation. Three months after implantation, the fetal grafts exhibited intensely TH-immunoreactive neurons, typically organized in elongated clusters, especially along the graft-host border and along blood vessels penetrating into the graft interior. Moderate to high metabolic activity as indicated by NSE immunoreactivity was observed in neuronal perikarya, principally in non-TH immunoreactive areas. In contrast to these immunohistochemical findings, in situ hybridization for TH mRNA, carried out exclusively on grafts into the intact striatum, demonstrated DA cell bodies both at the graft-host interface and, significantly, throughout the graft interior. The number of transcripts per cell, moreover, did not differ significantly in these two locations. We propose that conditions at the graft-host border promote tissue-specific regulation of nigral DA neurons, and that this regulation occurs post-transcriptionally. Thus, DA neurons relatively distant from the host parenchyma are underregulated, resulting in a higher level of metabolic activity and an increased turnover of TH in the grafted neurons.

Prenatal ontogeny of tyrosine hydroxylase gene expression in the rat ventral mesencephalon.

We have examined the development of dopaminergic (DA) neurons in the embryonic mesencephalon with regard to the expression of the gene coding for tyrosine hydroxylase (TH). Mesencephalic DA neurons from rat embryos aged E13 to E21 were analyzed using a quantitative in situ hybridization protocol featuring a 35S-labeled RNA probe complimentary to TH mRNA. In the early-to-mid stage embryonic brains, the expression of the TH gene was examined relative to the position of individual, migrating DA cells in the caudal-rostral and dorsal-ventral axes of the mesencephalon. In the later embryonic subjects, neurons were analyzed according to their position in one of the midbrain DA nuclei. The ontogeny of TH gene expression in the rat mesencephalon exhibited two phases: during the early phase (E13-E15), we observed major fluctuations in the level of TH gene expression accompanying the differentiation and maturation processes of the DA cells. Later, in the mid-to-late gestation fetus (E18-E21), TH gene expression generally stabilized as TH mRNA-expressing neurons reached their final anatomical positions within the mesencephalic DA complex. Our data demonstrate the complex dynamics which characterize the ontogeny of TH gene expression in the prenatally developing mesencephalon, and suggest a connection between the maturational level of DA neurons and the expression of the key gene regulating their principle neurotransmitter.

Differential expression of tyrosine hydroxylase mRNA in the developing rat mesencephalon.

1. With respect to the mesostriatal projection, the mesencephalon is composed of two dopaminergic (DA) cell populations, called dorsal tier and ventral tier. Strong evidence suggests differences in both the spatial and the temporal sequence of the innervation of the striatum between the two groups, with the ventral tier neurons innervating striatal patches prenatally and dorsal tier cells innervating striatal matrix postnatally. 2. Using in situ hybridization, we have examined the expression of the gene coding for tyrosine hydroxylase (TH) in mesencephalic DA neurons with respect to their postnatal development. Two ontogenic patterns of expression were observed: (a) dorsal tier neurons of the medial mesencephalon exhibited a sharp increase in expression beginning after birth, peaking on day 14, then decreasing and, finally, stabilizing; and (b) ventral tier neurons and dorsal tier cells from the lateral and the medial-dorsal mesencephalon showed only a slight increase in TH mRNA, reaching a plateau at P10. 3. The time course of the observed increase in TH gene expression in the first group, generally parallels the innervation of their target cells in the striatal matrix, suggesting that TH gene expression in these cells may be influenced by their postsynaptic cells or by the innervation process.

Expression of tyrosine hydroxylase mRNA in transplanted fetal dopamine neurons.

Expression of genes coding for synthesis of secretory products has been shown to be an important index of neuronal activity. Gene expression in transplanted fetal substantia nigra (SN) was examined for the first time, utilizing in situ hybridization with a probe for tyrosine hydroxylase mRNA. Three months after implantation, the grafts contained many labeled neurons. Compared to host SN neurons, the grafted dopaminergic cells expressed more message for the enzyme, while they showed lower amounts of the enzyme itself. This result suggests that a molecular approach applied to neural transplantation can detect important if subtle differences in graft cell activity.

Types and distribution of glutamic acid decarboxylase (GAD)-immunoreactive neurons in mouse motor cortex.

Neuronal structures in mouse motor cortex that contain gamma-aminobutyric acid (GABA), were identified by an immunocytochemical method, using an antiserum to glutamic acid decarboxylase (GAD). GAD-positive cell bodies occurred in all layers of the motor cortex, but were more concentrated in layers III and VI. GAD-positive puncta, presumably axon terminals, were also distributed throughout the cortical layers; a high density of puncta occurred in layer III, whereas a somewhat lower density characterized layer VI. Based on the shapes of their somata and dendritic trees we concluded that all GAD-positive cells were of the non-pyramidal type.

Perfume allergy due to oak moss and other lichens.

During a period of 2 1/2 years, 7 of 2000 patients routinely tested at our laboratory revealed contact allergy to oak moss in perfumes. All reacted to a mixture of different lichens and to some specific lichen compounds. The sensitivity was probably induced by cosmetics containing lichen substances. The following 3 compounds caused reactions in all patients tested: atranorin, evernic and usnic acids. 3 patients were photosensitive, but stronger reactions were elicited by prolonged contact during occlusion of the patches and complete protection against light, rather than by irradiation alone. The data suggest that the sensitizing capacity of the lichen compounds is primarily of a contact rather than of a photocontact nature.

Photosensitivity and allergy to aromatic lichen acids, Compositae oleoresins and other plant substances.

Sixteen patients with verified light sensitivity to both UVB and UVA wavebands showed allergic reactions to various lichen plants (Parmelia spp., Hypogymnia spp., Pseudovernia spp., Cladonia spp., Platismatia spp., Physcia spp., Umbilicaria spp. and Cetraria spp.). Among the aromatic lichen compounds, atranorin was observed to be the most frequently involved allergen, but also several other isolated lichen acids were immunologically active: d-usnic, evernic, stictic, fumarprotocetraric, lobaric, salazinic, diffractaic and physodic/physodalic acid. Several patients showed allergy to other plant substances from other sources such as seven different species from the Compositae family, alantolactone, balsam of Peru, colophony and wood tars. Sensitivity to known photosensitizers was observed in four patients. Aromatic lichen acids are UV-absorbing substances and several are evidently able to photosensitize human skin.

Photosensitivity and allergy to aromatic lichen acids, Compositae oleoresins and other plant substances.

Sixteen patients with verified light sensitivity to both UVB and UVA wavebands showed allergic reactions to various lichen plants (Parmelia spp., Hypogymnia spp., Pseuodovernia spp., Cladonia spp., Platismatia spp., Physcia spp., Umbilicaria spp. and Cetraria spp.). Among the aromatic lichen compounds, atranorin was observed to be the most frequently involved allergen but also several other isolated lichen acids were immunologically active: d-usnic, evernic, stictic, fumarprotocetraric, lobaric, salazinic, diffractaic and physodic/physodalic acid. Several patients showed allergy to other plant substances from other sources such as seven different species from the Compositae family, alantolactone, balsam of Peru, colophony and wood tars. Sensitivity to known photosensitizers was observed in four patients. Aromatic lichen acids are UV-absorbing substances and several are evidently able to photosensitive human skin.