Ultrastructural alterations in capillaries of the diabetic hypertensive rat retina: protective effects of ACE inhibition.

AIMS/HYPOTHESIS: The ACE inhibitor cilazapril was administered to diabetic hypertensive rats to evaluate its ability to influence the development of retinal capillary alterations. METHODS: Normotensive (strain: Wistar Kyoto) and genetically hypertensive (strain: spontaneously hypertensive) rats were rendered diabetic by intravenous injections of streptozotocin. Half of the diabetic animals received cilazapril with their daily food. At 20 weeks of diabetes, endothelial cells, pericytes and extracellular matrix were assessed by ultrastructural morphometry. Each experimental group consisted of seven animals. RESULTS: Cilazapril normalised systolic arterial pressure in diabetic hypertensive rats (137+/-2 mm Hg compared with 188+/-16 mm Hg in non-medicated diabetic hypertensive rats, p<0.001). The number of endothelial intercellular junctions was reduced in untreated diabetic hypertensive rats (0.15+/-0.05, p<0.02, vs 0.47+/-0.20 in non-diabetic normotensive rats). In diabetic hypertensive animals treated with cilazapril, this loss was attenuated (0.32+/-0.16, p<0.05). The significant thickening of the basement membrane observed in the diabetic normotensive (132.8+/-19.4 nm) and diabetic hypertensive (150.3+/-20.2 nm) groups was decreased by cilazapril in the diabetic hypertensive group (116.7+/-11.0 nm, p<0.01), but was unaffected in the normotensive (131.9+/-17.3 nm) group. No protective effect of the drug was observed in either group on pericytes. CONCLUSIONS/INTERPRETATION: Long-term administration of an effective antihypertensive therapy normalises endothelial alterations and basement membrane thickness in diabetic hypertensive conditions, and thus may account for the well-known improvement of the blood-retinal barrier observed during antihypertensive treatment.

Results of viscocanalostomy for primary open-angle glaucoma.

PURPOSE: Viscocanalostomy is a nonperforating filtering surgical procedure that may avoid postoperative complications common with standard trabeculectomy. This study was conducted to determine the surgical outcome of this procedure after a postoperative observation period of 12 to 36 months. METHODS: Interventional consecutive case series. In a prospective study, a consecutive series of 67 eyes of 67 patients with chronic primary open-angle glaucoma underwent VCS. Excluded were patients with angle closure glaucoma, post-traumatic, uveitic, neovascular, or dysgenetic glaucoma, as well as patients who needed combined cataract-glaucoma procedures. The patients were examined postoperatively on the first day, first week, at 1 month, and then at 3-month intervals through 36 months. At each visit, best-corrected visual acuity, intraocular pressure (IOP), and the appearance of the surgical wound, anterior chamber, and indirect funduscopy were recorded. RESULTS: Complete success was defined as IOP less than or equal to 20 mm Hg and greater than or equal to 30% IOP reduction without medical or additional surgical treatment compared with the IOP from a preoperative level with maximum tolerated medical therapy; qualified success IOP less than or equal to 20 mm Hg with treatment or an IOP reduction less than 30% from preoperative level with maximum tolerated medical therapy; and qualified failure of an IOP greater than 20 mm Hg with glaucoma medication, but no optic nerve or visual field deterioration and complete failure as an eye requiring further glaucoma surgery or lost visual function. The overall success rate was 88% at 1 year, 90% at 2 years, and 88% at 3 years, with a complete success of 68% at 1 year, 60% at 2 and 59% at 3 years. Four eyes had a perforation of the Descemet membrane, three of those needed peripheral iridectomy; six eyes had a microperforation not needing a peripheral iridectomy. Five eyes presented hyphema. Eight eyes presented deterioration of visual function after surgery: three eyes because of corneal astigmatism, one eye because of cataract, and four presented glaucomatous deterioration of the visual field despite pressures under 20 mm Hg. Four eyes had progressive cataract formation judged as independent from surgery. CONCLUSION: VCS provides an overall success rate of 88% and a complete success of 59% 3 years after surgery. The major immediate complication is perforation of the Descemet membrane with a need for peripheral iridectomy. No serious long-term complications were noted in our small series. Visual function remained stable in 55 eyes (82%).

Glial reactivity, an early feature of diabetic retinopathy.

PURPOSE: To characterize early structural gliotic reactions in retinal Müller cells, astrocytes, and microglia in experimentally induced diabetes. METHODS: Rats were rendered diabetic by streptozotocin injection and killed after 2, 4, 12, or 20 weeks. Cell densities were determined in flatmounted retinas or transverse semithin sections. Expression of glial fibrillary acidic protein (GFAP) was localized on frozen sections or flatmounts by immunofluorescence and confocal microscopy, and GFAP content was evaluated by Western blot analysis. Microglial cells were visualized by binding of isolectin B4 or staining with antibodies to phosphotyrosine residues. The integrity of the blood-retinal barrier was assessed by intravenous injection of Evans blue. RESULTS: The density of Müller cells and microglia was significantly increased at 4 weeks of diabetes compared with nondiabetic controls. GFAP expression in Müller cells was not detected at 4 weeks but was prominent at 12 weeks. The number of astrocytes was significantly reduced at 4 weeks in the peripapillary and far peripheral retina. Shape changes of microglial cells indicated functional activation. Leakage of the blood-retinal barrier was observed at 2 weeks of hyperglycemia, the earliest time point investigated. CONCLUSIONS: The leakage of the blood-retinal barrier before glial reactivity suggests that glia are early targets of vascular hyperpermeability. The individual glial cell types react differentially to the diabetic state. Müller cells undergo hyperplasia preceding GFAP expression, and microglial cells are activated, whereas astrocytes regress. This glial behavior may contribute decisively to the onset and development of neuropathy in the diabetic retina.

Remodeling of retinal capillaries in the diabetic hypertensive rat.

PURPOSE: To document the effect of sustained systemic hypertension on the integrity and ultrastructural morphology of retinal capillaries in diabetic and nondiabetic rats. METHODS: Normotensive (strain Wistar-Kyoto; WKY) and genetically hypertensive (spontaneously hypertensive; SHR) rats were rendered diabetic by intravenous streptozotocin injection. At 20 weeks of diabetes, endothelial cells, pericytes, and extracellular matrix were evaluated by ultrastructural morphometry. Serum albumin was localized by immunofluorescence microscopy. RESULTS: The endothelial cell layer was markedly thinner in the diabetic normotensive animals. The number of intercellular junctions was reduced in both the nondiabetic and diabetic hypertensive group but less so in the diabetic normotensive group. No significant endothelial cell loss was noted in either of the experimental groups, whereas the number of pericytes and the number of their cytoplasmic processes were reduced in diabetic and hypertensive animals. Significant thickening of the basement membrane and increased permeability to serum albumin were observed in diabetic and hypertensive rats and were strongly enhanced in the combined diseases. CONCLUSIONS: Endothelial thinning and shape changes from an elaborate to a simpler form as well as rounding up of the pericytes and loosening of their vascular sheaths indicate remodeling of the vascular wall during chronic diabetes and sustained hypertension, before a characteristic vasculopathy becomes manifest. The combination of diabetes and hypertension enhances these features, as well as basement membrane thickening and breakdown of the blood-retinal barrier.

Contrast sensitivity in obese dyslipidemic patients with insulin resistance.

OBJECTIVE: To evaluate contrast sensitivity in insulin-resistant obese patients and in aretinopathic diabetic patients. METHODS: Contrast sensitivity was measured at 3 letter sizes (44 x 44, 9 x 9, and 5 x 5 mm) in mesopic (5 candela [cd]/m2) and low photopic (85 cd/m2) vision in 20 dyslipidemic obese patients with insulin resistance, 20 age-matched patients with type 2 diabetes mellitus, and 20 aged-matched healthy control subjects. RESULTS: Significant loss of contrast sensitivity at all 3 letter sizes was observed in low photopic vision (at 44 x 44-mm letter size, control vs obese, P<.002, and control vs diabetic, P<.005; at 9 x 9-mm letter size, control vs obese, P<.02, and control vs diabetic, P<.001; and at 5 x 5-mm letter size, control vs obese, P<.05, and control vs diabetic, P<.005) and mesopic vision (at 44 x 44-mm letter size, control vs diabetic, P<.005; at 9 x 9-mm letter size, control vs obese, P<.005, and control vs diabetic, P<.01; and at 5 x 5-mm letter size, control vs obese, P<.005, and control vs diabetic, P<.001) in insulin-resistant obese and diabetic patients. CONCLUSION: The results suggest that an early neurosensory dysfunction may occur without visible vascular involvement and without overt hyperglycemia.

Exfoliation syndrome and phacoemulsification.

PURPOSE: To evaluate intraoperative and postoperative complications of phacoemulsification and intraocular lens (IOL) implantation in eyes with exfoliation syndrome. SETTING: Eye Clinic, University Hospital of Geneva, Switzerland. METHODS: This prospective study evaluated 20 consecutive patients with exfoliation syndrome and 20 consecutive patients without the syndrome (control group) who had phacoemulsification and posterior chamber IOL implantation. One year later, the incidence of zonular tears, operating time, and fibrinoid reaction were studied in another group of 23 consecutive patients who had the same type of surgery by the same surgeon. RESULTS: Maximal pupil dilation was significantly smaller (P < .0001) in the exfoliation than in the control group. Intraoperatively, the incidence of zonular tears was the same in both groups (10%). In the 23 patients who had surgery 1 year later, no zonular tears occurred. The incidence of postoperative complications was similar in both groups. The exfoliation group had a significant decrease in intraocular pressure over preoperative levels at 1 week and 3 months postoperatively. CONCLUSION: Phacoemulsification with posterior chamber IOL implantation appears to be safe in eyes with exfoliation syndrome.

Expression and release of tumor necrosis factor-alpha by explants of mouse cornea.

PURPOSE: To elucidate a possible target of immunosuppressive agents widely used in the treatment of corneal disorders, the authors determined whether corneal cells are capable of expressing and releasing tumor necrosis factor-alpha (TNF alpha) on lipopolysaccharide (LPS) stimulation, and they investigated whether TNF alpha production can be modulated by pharmacologic agents. METHODS: Trephined central corneas from C57BL/6 mice were kept in culture for 3 days. Release of TNF alpha after a 24-hour stimulation with LPS (1 microgram/ml) into the culture medium was determined both by bioassay and by enzyme-linked immunosorbent assay. Expression of TNF alpha mRNA after 6-hour stimulation was examined by polymerase chain reaction. Immunofluorescent staining on cryostat sections of cultured corneas was performed to localize TNF alpha in the tissue. Corneal explants were pretreated with immunosuppressive agents (prednisolone, budesonide, cyclosporin A) for 48 hours, followed by 6-or 24-hour stimulation with LPS in the continuous presence of the agents. RESULTS: Lipopolysaccharide stimulated TNF alpha release into the culture medium. The addition of budesonide (10(-7) M) or prednisolone (10(-6) M) significantly inhibited LPS-induced TNF alpha release, whereas cyclosporin A (10(-7) - 10(-5) M) had no marked effect. Levels of TNF alpha mRNA in corneal explants increased fivefold after stimulation with LPS. Immunohistochemical staining revealed that TNF alpha was expressed in the epithelial cells. Budesonide markedly decreased mRNA expression and abolished immunostaining of TNF alpha stimulated by LPS. CONCLUSIONS: TNF alpha is produced and released by the epithelial cells of mouse central cornea in response to LPS. Contrary to cyclosporin A, corticosteroids such as prednisolone and budesonide potently inhibit TNF alpha production.

[Apropos of a case of bilateral perforating corneal ulcer in a patient with Portugese amyloidosis]. / A propos d'un cas d'ulcère cornéen perforant bilatéral chez un patient atteint d'amyloidose portugaise.

PURPOSE: Corneal ulcer is a very rare clinical manifestation in hereditary familial amyloidosis of the Portuguese type, from which only one case has been reported previously. The case of a 35-year-old man illustrates the diagnostic findings and the difficulties encountered in understanding the physiopathology of such a complication. PATIENT: The patient was referred by his general practician because of bilateral visual impairment since few days. Examination disclosed bilateral central perforating corneal ulceration. Corneal sensitivity was normal in both eyes, BUT (break-up time) was 2 sec. and Schirmer II test abolished. RESULTS/CONCLUSION: Corneal ulceration is an unusual complication consecutive to a massive dry eye syndrome.

Risk factors associated with contrast sensitivity loss in diabetic patients.

BACKGROUND: Psychophysical tests in patients with diabetes mellitus reveal deficits of central vision before the development of overt retinopathy. We evaluated the contrast sensitivity thresholds in 30 patients with type II diabetes mellitus and without retinopathy, taking into account the crystalline lens density. Risk factors for contrast sensitivity deficits were investigated. METHODS: Contrast sensitivity was compared in 30 aretinopathic diabetic patients and age-matched controls. Contrast thresholds were determined for stationary gratings at three spatial frequencies (6, 15, and 27 cycles/deg) and for mesopic (5 cd/m2) and low photopic (85 cd/m2) vision. Lens density was measured using a IntraOptics opacity lensmeter. RESULTS: Significant contrast sensitivity losses at all three spatial frequencies were observed in low photopic and mesopic vision in diabetic patients. The optical density of the lens in the diabetic group did not differ from that in the controls. Contrast sensitivity deficits were positively correlated with patient's age, systolic blood pressure and nephropathy at all three spatial frequencies. No relationship between cardiovascular autonomic neuropathy and contrast sensitivity defects was observed. CONCLUSIONS: These data suggest that contrast sensitivity deficits in diabetic patients without retinopathy are not solely explained by a diabetes-induced increases in lens optical density. Abnormalities of the retina or its neural connections occurring before the onset of clinically detectable retinopathy may be involved. Risk factors for these deficits are advanced age, high systolic blood pressure, and nephropathy.

Presumed bilateral cytomegalovirus-induced optic neuropathy in an immunocompetent person. A case report.

Ocular manifestations of an acquired cytomegalovirus (CMV) infection are often associated with the patient being in an immunocompromised state. In the vast majority of cases, the affliction appears as a necrotic retinitis; an isolated optic nerve lesion is seen less frequently. To date, only two cases of CMV retinitis and one case of bilateral acute retinal necrosis have been reported in healthy individuals. We describe a 32-year-old healthy woman who developed bilateral papillitis. Tests were positive for acute CMV infection but negative for an immunocompromised state. We changed the antiviral therapy from acyclovir to foscarnet in association with corticosteroids, and resolution of the papillitis and recovery of visual acuity were obtained.

[Foldable implants in cataract surgery at the Geneva Ophthalmological Clinic]. / Les implants pliables dans la chirurgie de la cataracte à la clinique ophtalmologique de Genève.

PURPOSE: Since 1993, foldable intraocular lenses (Adatomed 90 D, Allergan SI26NB et SI30NB, Chiron C10, Medilas 127) have been implanted through a corneal or scleral tunel after phakoemulsification of the cataract. This retrospective study is made for evaluating the advantages and the disadvantages of these new silicon implants. PATIENTS AND METHOD: The first 250 implantations of a silicon foldable lens compared to 50 rigid PMMA lenses. Problems during implantation, final visual acuity, opacification of the anterior and posterior capsule, decentration of the lens and the stability of the refraction during the 3-19 months following cataract extraction were evaluated. RESULTS: 4 breaks of the capsule, 2 desinsertions of the capsular bag during the implantation of a foldable lens, a difference of less than 0.5 diopter in favour of the foldable lenses, no difference in the incidence of the secondary cataract (p = 0.3) and a more marqued postoperative opacification of the anterior capsule (p = 0.0275) among the foldable silicon lenses were observed. CONCLUSIONS: These results are very encouraging for the visual outcome, but the time of postoperative observations is too short to determine on a long term basis, which is the most important factor for a new implant. To avoid an early opacification of the anterior capsule, a large capsulorhexis, as wide as the optic of the silicon lens, is recommended.

Cardiovascular autonomic neuropathy in diabetic patients with macular oedema.

We performed a case-control study to investigate the determinants of macular oedema in patients with diabetes mellitus. Patients with macular oedema (n = 20) were selected for study, together with a random sample of subjects without macular oedema (controls, n = 21). Both groups were similar for sex, type of diabetes, treatment and glycaemic control. Patients with maculopathy had higher systolic and diastolic blood pressure than controls (P < 0.006 and P < 0.03, respectively). Impaired renal function was proportionally higher in patients with maculopathy than in controls (60% vs 47%). Vibratory perception was more impaired in the maculopathy group than the control group (P < 0.02), and maculopathy was associated with the presence of cardiovascular autonomic neuropathy. R-R variation and the brake index were significantly lower in patients than control subjects (P < 0.01 for both). Moreover, the group with maculopathy had a greater fall in systolic blood pressure after standing than did the control group (P < 0.0001). Autonomic neuropathy may be associated with the development of maculopathy and retinopathy, although additional evidence is required to confirm this association. Conditions associated with high blood pressure may accelerate progression and aggravate maculopathy.

In vitro inhibition of midazolam and quinidine metabolism by flavonoids.

Studies in humans in vivo have demonstrated that substances found in grapefruit juice may increase the bioavailability of dihydropyridine derivatives as a result of the inhibition of liver enzyme activities by flavonoids found in grapefruit. Since the metabolism of dihydropyridine drugs is mediated by cytochrome P-450 (CYP) 3A4, it has been hypothesized that flavonoids may also influence the metabolism of other drugs, such as midazolam and quinidine, which are biotransformed by the same CYP isoform. Three flavonoids, kaempferol, naringenin and quercetin, are found in grapefruit juice but not in orange juice. The effect of these substances on the metabolism of midazolam and quinidine has been investigated in human liver microsomes. In the concentration range 10-160 microM the inhibitory potential of flavonoids was the same for both of the tested drugs; it decreased in the order quercetin >> kaempferol > naringenin. The data suggest that the flavonoids found in grapefruit juice may influence the kinetics of midazolam and quinidine in man.

[Postoperative endophthalmitis at the Geneva Ophthalmologic Clinic]. / Les endophtalmies post-opératoires à la Clinique Ophtalmologique de Genève.

The postoperative endophthalmitis is a rare and serious complication of the intraocular surgery, which may result in the loss of the visual function. Retrospectively, the authors reviewed the 14 postoperative endophthalmitis cases at the department of ophthalmology of Geneva between 1983 and 1992. For cataract extractions, the following incidence was observed: 0.115% (8 of 6954 cases). In 36% (5 of 14 cases), the culture was positive. The best treatment was a early vitrectomy associated with antibiotherapy. In 57% (8 of 14 cases), the visual outcome was equal to or better than 0.2.

[Effectiveness of treatment of diabetic macular edema by laser photocoagulation]. / Efficacité du traitement de l'oedème maculaire diabétique par photocoagulation au laser.

BACKGROUND: Diabetic macular edema is the most frequent cause of visual loss in patients with diabetic retinopathy. Laser photocoagulation of clinically significant macular edema is effective in reducing the risk of visual loss. METHODS AND RESULTS: Sixty three eyes of 42 diabetic patients with macular edema were included in a clinical study to determine the short-term visual outcome (9 months) of laser photocoagulation. The results suggest that laser photocoagulation is less effective in diabetic patients with high blood pressure and in patients with low visual acuity at treatment time.

[Diagnostic aspects and frequency of retrocorneal precipitates in diagnosis of cytomegalovirus retinitis in the HIV+ patient]. / Aspect et fréquence des précipités rétrocornéens lors du diagnostic de la rétinite à CMV chez le patient VIH+.

Cytomegalovirus retinitis (CMV) is the most common ocular opportunistic infection seen in patients with acquired immune deficiency syndrome. The anterior segment is usually quiet or with minimal aqueous humour flare and cell reaction. Nevertheless, in this prospective study of 30 eyes with CMV retinitis, 22 (73%) had white, small and filamentous keratic precipitates (KPS) which seem to corroborate this inflammation. The positivity of the KPS depends upon the extent of CMV retinitis.

Aqueous humor penetration of ofloxacin given by various routes.

We studied the aqueous humor penetration of ofloxacin after topical, oral, and intravenous administration in 51 consecutive patients undergoing cataract surgery. Aqueous humor concentration (mean +/- SD) was 0.53 +/- 0.35 mg/l when ofloxacin 0.3% eyedrops were instilled topically six times, one drop every three hours, until 90 minutes preoperatively, and 0.63 +/- 0.29 mg/l (P = .45) when two additional instillations were made, one drop every 30 minutes, until 30 minutes before aqueous humor aspiration. Aqueous humor concentration two hours after a single 200-mg oral dose (0.38 +/- 0.15 mg/l) was significantly lower (P = .048) than that 12 hours after the same oral dose (0.58 +/- 0.24 mg/l). Two hours following an intravenous infusion of 200 mg of ofloxacin, aqueous humor concentration was 0.33 +/- 0.19 mg/l. Our results suggest that therapeutic levels above the minimum inhibitory concentration for many bacteria cultured in endophthalmitis can be achieved in aqueous humor after either topical or oral administration, which indicates that this antibiotic passes easily through the corneal and the blood aqueous barriers.

[Diabetic maculopathy: clinical aspects, risk factors and therapeutic possibilities]. / La maculopathie diabétique: aspects cliniques, facteurs de risque et possibilités thérapeutiques.

Edema of the macula is a frequent component of diabetic retinopathy, as well as a common cause of visual impairment in this disorder. It is strongly associated with high blood pressure and the presence of proteinuria. Correction of these risk factors may reduce macular edema and should be included as part of the total management of patients with diabetic maculopathy. The benefit of a focal treatment for focal macular edema has been established but the results are not so good when a grid treatment for diffuse macular edema is performed.

[Phacoemulsification: technical initiation at what price?]. / Phacoémulsification: initiation a quel prix?

Phacoemulsification of the cataract is perhaps technically superior which is considered "classic". This technic consists however of a number of difficulties that may be mastered during an apprentiship. Considerable complications may arise during this initiation periods; imposing this surgical method on patients is thus an ethical problem. If the risks encountered during the apprentiship of phacoemulsification appear comparable to those during the classic extracapsular technique, phacoemulsification may be recommended with less reservation. We have compared 250 initial cases of classic extracapsular extraction with 250 "initial cases" of phacoemulsification, taking into account operative and post-operative complications and final functional results.