Diabetic macular edema-like ocular lesions in male spontaneously diabetic torii fatty rats.

Diabetic macular edema (DME) is a major factor contributing to visual disabilities in diabetic patients, and the number of patients is increasing. Animal models play a key role in the development of novel therapies. In this study, pathophysiological analyses of ocular lesions in Spontaneously Diabetic Torii (SDT) fatty rats were performed. First, vascular endothelial growth factor (VEGF) concentrations in vitreous humor, retinal vascular permeability and retinal thickness were measured in SDT fatty rats (Experiment 1). Furthermore, the pharmacological effects of two anti-diabetic drugs, phlorizin and pioglitazone, on retinal lesions were evaluated (Experiment 2). As results, the SDT fatty rats exhibited VEGF increase in vitreous humor at 8 and 16 weeks of age, and both retinal vascular hyperpermeability and retinal thickening at 16 weeks of age. In particular, the layers between the retinal internal limiting membrane and the outer nuclear layer were thickened. Phlorizin treatment from 4 to 16 weeks of age improved hyperglycemia and normalized retinal thickness; however, the effect of pioglitazone on retinal thickness was not strong despite the normalization of hyperglycemia. These data demonstrate that the male SDT fatty rat is a useful model for developing new therapeutic approaches in DME.

Protein kinase C beta inhibitor prevents diabetic peripheral neuropathy, but not histopathological abnormalities of retina in Spontaneously Diabetic Torii rat.

Spontaneously Diabetic Torii (SDT) rat shows severe ocular complications such as tractional retinal detachment. In the present study, effect of protein kinase C beta (PKCbeta) inhibitor JTT-010 was evaluated to clarify the involvement of PKCbeta in complications of SDT rat. SDT rats were administered JTT-010 (10 or 50 mg/kg/day) for 48 weeks. SDT rats showed delayed oscillatory potentials in electroretinogram. Delayed motor nerve conduction velocity, decreased coefficients of variation of R-R intervals in electrocardiogram and thermal hypoalgesia were also observed. These functional disorders were prevented by administration of JTT-010. Abnormal retinal vascular was formed and the optic disc was protruded in SDT rat; however, JTT-010 did not prevent these hyperglycaemia-induced retinal abnormalities. These findings indicate that PKCbeta is intimately involved in diabetic complications; however, it seems that other factor(s) are primary contributors to histopathological abnormalities in retina. Therefore, PKCbeta inhibitors require concurrent administration of antihyperglycaemic drugs to achieve maximum effect on diabetic complications.

Nicorandil improves diabetes and rat islet beta-cell damage induced by streptozotocin in vivo and in vitro.

OBJECTIVE: N-(2-hydroxyethyl)-nicotinamide nitrate (nicorandil) is a unique anti-anginal agent, reported to act as both an ATP-sensitive K(+) channel opener (PCO) and a nitric oxide donor. It also has an anti-oxidant action. We examined the effects of nicorandil on streptozotocin (STZ)-induced islet beta-cell damage both in vivo and in vitro. DESIGN AND METHODS: STZ-induced diabetic Brown Norway rats (STZ-DM) were fed with nicorandil-containing chow from day 2 (STZ-DM-N48), 3 (STZ-DM-N72), and 4 (STZ-DM-N96) to day 30. Body weight, blood glucose, and plasma insulin were measured every week. For the in vitro assay, neonatal rat islet-rich cultures were performed and cells were treated with nicorandil from 1 h before to 2 h after exposure to STZ for 30 min. Insulin secretion from islet cells was assayed after an additional 24 h of culture. We also observed the effect of nicorandil on the generation of reactive oxygen species (ROS) from rat inslinoma cells (RINm5F). RESULTS: Body weight loss and blood glucose levels of STZ-DM-N48 rats were significantly lower than those of STZ-DM rats. Immunohistochemical staining of insulin showed preservation of insulin-secreting islet beta-cells in STZ-DM-N48 rats. Nicorandil also dose-dependently recovered the insulin release from neonatal rat islet cells treated with STZ in in vitro experiments. Nicorandil did not act as a PCO on neonatal rat islet beta-cells or RINm5F cells, and did not show an inhibitory effect on poly(ADP-ribose) polymerase-1. However, the drug inhibited the production of ROS stimulated by high glucose (22.0 mmol/l) in RINm5F cells. CONCLUSIONS: These results suggested that nicorandil improves diabetes and rat islet beta-cell damage induced by STZ in vivo and in vitro. It protects islet beta-cells, at least partly, via a radical scavenging effect.

A new form of retinopathy associated with myocardial infarction treated with percutaneous coronary intervention.

AIM: To report a new form of retinopathy that was observed in patients who had undergone percutaneous coronary intervention (PCI) following acute myocardial infarction (AMI). METHODS: Serial ophthalmological examinations were conducted in 40 patients who underwent PCI. Thirty patients were diagnosed with AMI, and another 10 had stable angina pectoris. RESULTS: Cotton wool spots developed in 17 (57%) patients from the group with AMI undergoing PCI (n = 30) within 2 months. Of these, 41% (seven patients) also developed superficial haemorrhages. Retinopathy was most prominent 1-2 months after AMI and then tended to become quiescent afterwards, without treatment. CONCLUSION: We have identified a new form of retinopathy in patients with AMI that spontaneously subsides without treatment.

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide.

AIMS/HYPOTHESIS: Early stage leukocyte entrapment in the retinal microcirculation (retinal leukostasis) is considered to be one of the important pathogenetic events in diabetic retinopathy. Gliclazide, a sulphonylurea, was reported to reduce leukocyte adhesion to endothelial cells in hyperglycaemia in vitro, thus suggesting possible selective efficacy of this sulphonylurea in preventing leukostasis in diabetic patients. This study evaluated the effectiveness and selectivity of gliclazide treatment on retinal leukostasis of diabetic rats in vivo. METHODS: Streptozotocin (STZ) (65 mg/kg)-induced diabetic rats were divided into three groups (n = 8 each): an untreated diabetic group, a gliclazide-treated diabetic group, and a glibenclamide-treated diabetic group. Gliclazide or glibenclamide was administered orally during a 3-week period. Non-diabetic rats were used as a control (n = 8). Retinal leukostasis was quantitatively evaluated in vivo by acridine orange leukocyte fluorography using a scanning laser ophthalmoscope. RESULTS: The number of leukocytes trapped in the area around the optic disc in the untreated diabetic group (36.9 +/- 5.1 cells) increased significantly compared with the non-diabetic control group (21.9 +/- 2.9 cells; p = 0.0007). The number of leukocytes trapped in the gliclazide-treated diabetic group (23.5 +/- 4.0 cells) decreased significantly compared with untreated diabetic group ( p = 0.0008). In contrast, no reduction of retinal leukostasis was found in the glibenclamide-treated diabetic group (37.8 +/- 5.8 cells; p = 0.7923). CONCLUSION/INTERPRETATION: This suggests that gliclazide could directly improve abnormalities in the retinal microcirculation independent of blood glucose control and possibly have selective therapeutic benefits in preventing early, critical events in diabetic retinopathy compared with other sulphonylurea drugs.

A new spontaneously diabetic non-obese Torii rat strain with severe ocular complications.

A new spontaneously diabetic strain of the Sprague-Dawley rat was established in 1997 and named the SDT (Spontaneously Diabetic Torii) rat. In this research, we investigated the characteristics of the disease condition in the SDT rats. The time of onset of glucosuria was different between male and female SDT rats; glucosuria appeared at approximately 20 weeks of age in male rats and at approximately 45 weeks of age in female rats. A cumulative incidence of diabetes of 100% was noted by 40 weeks of age in male rats, while it was only 33.3% even by 65 weeks of age in female rats. The survival rate up to 65 weeks of age was 92.9% in male rats and 97.4% in female rats. Glucose intolerance was observed in male rats from 16 weeks of age. The clinical characteristics of the male SDT rats were (1) hyperglycemia and hypoinsulinemia (from 25 weeks of age); (2) long-term survival without insulin treatment; (3) hypertriglyceridemia (by 35 weeks of age); however, no obesity was noted in any of the male rats. The histopathological characteristics of the male rats with diabetes mellitus (DM) were (1) fibrosis of the pancreatic islets (by 25 weeks of age); (2) cataract (by 40 weeks of age); (3) tractional retinal detachment with fibrous proliferation (by 70 weeks of age) and (4) massive hemorrhaging in the anterior chamber (by 77 weeks of age). These clinical and histopathological characteristics of the disease in SDT rats resemble those of human Type 2 diabetes with insulin hyposecretion. In conclusion, SDT rat is considered to be a potentially useful model for studies of diabetic retinopathy encountered in humans.

Combined system of biomicroscopic vitreous videography and photography.

PURPOSE: To combine the techniques of biomicroscopic vitreous videography and vitreous photography when examining patients with age- or disease-related vitreous changes. METHODS: We performed biomicroscopic vitreous videography and photography using the newly developed digital photo camera (one-half-inch three-charged coupled device camera with high resolution of 800 x 800 television lines) connected to a slit-lamp biomicroscope and compared it with conventional 35-mm slit-lamp photography in 24 consecutive eyes of 19 patients with idiopathic macular breaks. RESULTS: Stage 1 macular breaks were found in three eyes, stage 2 in four eyes, stage 3 in 11 eyes, and stage 4 in six eyes. Both vitreous videographs and still photographs were recorded and reviewed rapidly in one system. Using this system, dynamic vitreous changes and still vitreous images were documented clearly with real-time television monitoring without using flash illumination. The still images obtained from this system were better than those obtained using conventional 35-mm slit-lamp photography in cases with stage 1, 2, and 3 macular breaks (P = 0.0000000001 by Fisher's exact test). CONCLUSION: This combined system of biomicroscopic vitreous videography and photography may become the standard system of biomicroscopic vitreous examination.

Predictive value of floaters in the diagnosis of posterior vitreous detachment.

PURPOSE: To evaluate Weiss ring and floaters as indexes of posterior vitreous detachment. METHODS: Using biomicroscopy and indirect ophthalmoscopy, we examined the posterior vitreous in 200 consecutive eyes with posterior vitreous detachment. RESULTS: In 200 eyes with posterior vitreous detachment, biomicroscopy disclosed complete, incomplete, and no Weiss ring in 102 (51%), 72 (36%), and 26 (13%) eyes, respectively. Indirect ophthalmoscopy showed the glial ring in 58 (56.9%) and 16 (22.2%) of the eyes, with a complete (102 eyes) and incomplete (72 eyes) Weiss ring, respectively. Although the incidence of floaters was significantly correlated with the presence of the glial ring (P = .0014), 60 (58.8%) and 49 (68.1%) of the eyes with a complete (102 eyes) and incomplete (72 eyes) glial ring, respectively, had no floaters. CONCLUSION: Detecting the detached posterior vitreous cortex by biomicroscopy is essential regardless of the presence of Weiss ring or floaters.

Abnormal vitreous structure in optic nerve pit.

A 37-year-old man presented with an optic nerve pit and serous macular detachment of the left eye. Scanning laser ophthalmoscopy revealed a cyst-like structure terminating at the pit in the premacular vitreous. During ocular movement, this structure moved vigorously and seemed to exert traction on the pit. We believe that it is part of an anomalous Cloquet's canal, and that traction on the pit may be a significant factor in the development of serous macular detachment in this patient.

Variations of posterior vitreous detachment.

AIMS: To identify variations in posterior vitreous detachment (PVD) and establish a clinical classification system for PVD. METHODS: 400 consecutive eyes were examined using biomicroscopy and vitreous photography and classified the PVD variations-complete PVD with collapse, complete PVD without collapse, partial PVD with thickened posterior vitreous cortex (TPVC), or partial PVD without TPVC. RESULTS: In each PVD type, the most frequently seen ocular pathologies were as follows: in complete PVD with collapse (186 eyes), age related changes without vitreoretinal diseases (77 eyes, 41.4%) and high myopia (55 eyes, 29.6%); in complete PVD without collapse (39 eyes), uveitis (23 eyes, 59.0%) and central retinal vein occlusions (8 eyes, 20.5%); in partial PVD with TPVC (64 eyes), proliferative diabetic retinopathy (30 eyes, 46.9%); and inpartial PVD without TPVC (111 eyes), age related changes without vitreoretinal diseases (62 eyes, 55.9%). This PVD categorisation was significantly associated with the prevalence of each vitreoretinal disease (p < 0.0001, chi 2 test on contingency table). CONCLUSIONS: PVD variations can be classified into four types, which is clinically useful because each type corresponds well to specific vitreoretinal changes.

Copper-ion-catalyzed vitreous liquefaction in vivo.

To investigate copper-ion (Cu2+)-catalyzed vitreous liquefaction in vivo, Cu2+ solution (10 mumol) was injected into the vitreous cavity of rabbits. At 24 h after the injection, the gel and liquid vitreous were weighed, and the percent of vitreous liquefaction was calculated. Cu2+ injection resulted in liquefaction of 58% of the vitreous, although control eyes had 12% liquefaction (p < 0.1). The vitreous liquefaction was more pronounced in the presence of exogenous ascorbic acid. However, the addition of mannitol, a hydroxyl-radical-specific scavenger, significantly suppressed the Cu(2+)-catalyzed vitreous liquefaction. The free radicals generated by the Cu(2+)-catalyzed oxidation system may cause vitreous liquefaction in vivo.

Vitreomacular observations. II. Data on the pathogenesis of idiopathic macular breaks.

BACKGROUND: The pathogenesis of idiopathic macular breaks is still uncertain. Their formation has been ascribed to anteriorly oriented intravitreous traction and to shrinkage of the prefoveal cortical vitreous. The validity of both hypotheses is considered in this paper. METHODS: In order to clarify the pathogenesis of idiopathic macular breaks 127 consecutive patients had their vitreous examined and photographed with the El Bayadi-Kajiura precorneal lens and a slit-lamp microscope. RESULTS: A comparison with 127 matched controls demonstrated that the vitreous was significantly more often attached in eyes with a macular break than in controls (P < 0.01). In eyes with a macular break the vitreous was significantly more often attached in early cases (Gass stage 1) than in Gass stages 3 and 4 (P < 0.01). Still photographs and observation of the movements of the operculum demonstrated that, in some cases of stage 3 and also in stage 4, it moved inside the partially liquefied posterior vitreous, anteriorly to the retinal surface and frequently without evidence of posterior vitreous detachment over the macular area. The following anatomical features characterize the vitreomacular area: extremely thin hyaloid membrane (< 100 microns) and inner limiting lamina (10 nm) that adhere strongly to each other and to the underlying Mueller cells. There is no evidence that these structures can shrink selectively to cause a macular break. The premacular vitreous gel contains collagen fibers that attach posteriorly to the macula and anteriorly to the vitreous base. CONCLUSIONS: Our working hypothesis is that when detachment of the posterior vitreous is abnormally delayed, anteroposterior traction by collagen fibers may pull a foveal operculum off the retina. Our observations make this hypothesis attractive. However, the generally accepted hypothesis of Johnson and Gass cannot be entirely dismissed. In reality, since the two hypotheses are not mutually exclusive, they may both the partially correct.

Differential diagnosis of macular breaks by microperimetry using the scanning laser ophthalmoscope.

To improve the differential diagnosis of macular breaks by microperimetry using the scanning laser ophthalmoscope (SLO), we studied 50 consecutive breaks detected by biomicroscopy and indirect ophthalmoscopy. The full-thickness macular break was easily diagnosed using only biomicroscopy and indirect ophthalmoscopy because the macular break had a cuff in 22 of the eyes. SLO microperimetry also showed an absolute scotoma within the macular break and a relative scotoma on the cuff in these 22 eyes. However, in the other 28 eyes it was impossible to distinguish between the full-thickness macular breaks and pseudo-macular breaks or lamellar macular breaks using only biomicroscopy and indirect ophthalmoscopy because of the absence of a cuff. However, SLO microperimetry differentiated full-thickness macular breaks from pseudomacular breaks or lamellar macular breaks in these 28 eyes. SLO microperimetry is indispensable for determining the prognosis of and the surgical indication requirements for idiopathic macular breaks.

Clinical characteristics of traumatic macular holes.

The clinical characteristics of 20 eyes of 20 consecutive patients with traumatic macular hole were studied retrospectively. The macular holes were elliptical with irregular edges in 19 eyes (95%) and ranged in size from 0.2 to 0.5 DD (disc diameter). Posterior vitreous detachment (PVD) was found in only 3 eyes (15%); the vitreous was detached from the macula in only one of these 3. Other conditions found in the 20 patients included commotio retinae, vitreous hemorrhage, hyphema, and choroidal rupture. These findings strongly suggest that most traumatic macular holes develop in the absence of PVD and that the pathogenesis is independent of the occurrence of PVD. We believe that the macular rupture (hole) is caused mechanically by the force of the impact on the posterior pole and the ocular deformity which result from blunt trauma.

Spontaneous resolution of foveal detachments and macular breaks.

PURPOSE: To evaluate the mechanism of spontaneous resolution of foveal detachments and idiopathic macular breaks. METHODS: We reviewed the records of 139 consecutive eyes (94 patients) with either a foveal detachment or a macular break in patients who were examined between 1989 and 1992. There were 26 men and 68 women (mean age, 66.9 +/- 6.9 years). They were either unoperated on or observed during the period that preceded surgery. Each patient underwent complete ophthalmic examination in addition to slit-lamp photography of the vitreomacular interface and microperimetry with the scanning laser ophthalmoscope. RESULTS: Eight eyes demonstrated spontaneous resolution. A foveal detachment was noted in five eyes (five patients) and a stage 2 macular break in three eyes (three patients). The mean duration of observation was 33 months (range, one to 144 months). Resolution of the foveal detachments occurred without the development of posterior vitreous detachment. In each eye, the presence of a pseudo-operculum, indicating vitreofoveal separation, was accompanied by flattening of the foveal detachment without detectable posterior vitreous detachment. The three eyes with stage 2 macular break resolved after premature development of a posterior vitreous detachment. CONCLUSIONS: Foveal detachment and macular break resolution seem to result from the release or weakening of vitreous traction on the fovea. Reattachment of the foveal retina preserves fair to good visual acuity. Surgical intervention is contraindicated (1) in eyes in which foveal detachment flattens and develops a pseudo-operculum and (2) when a posterior vitreous detachment develops in an eye with a stage 2 macular break. Careful biomicroscopic vitreous examination and microperimetry with the scanning laser ophthalmoscope are extremely useful methods for adequate examination of these patients.

[Traumatic macular hole and posterior vitreous].

We studied retrospectively the clinical features of 18 eyes of 18 patients with traumatic macular hole. The macular hole was elliptical with irregular edges in 17 eyes (94%) and its size ranged from 1/5 to 1/2 of the disc diameter. Posterior vitreous detachment was found in 3 eyes (17%); the vitreous was detached from the macula in only one of these 3 eyes. Commotio retinae, vitreous hemorrhage, hyphema, or choroidal rupture was also found in several eyes. These findings suggest that traumatic macular hole develops usually in the absence of posterior vitreous detachment and its pathogenesis is independent of the occurrence of posterior vitreous detachment. We speculate that blunt trauma-induced deformity of the eyeball or impact on the posterior pole provides a mechanical cause for the macular rupture.

[Differential diagnosis of macular breaks by microperimetry with a scanning laser ophthalmoscope].

To improve differential diagnosis of macular breaks, microperimetry with a scanning laser ophthalmoscope (SLO) was performed. Fifty consecutive macular breaks were detected by biomicroscopy and indirect ophthalmoscopy, and SLO microperimetry was performed on each. Of the 50 eyes, 22 eyes were diagnosed with idiopathic macular breaks by biopmicroscopy and indirect ophthalmoscopy because of a cuff. SLO microperimetry also showed dense scotoma within the macular break and relative scotoma on the cuff in the 22 eyes. However, diagnosis was not done only by biomicroscopy and indirect ophthalmoscopy in the other 28 eyes because of the absence of a cuff. SLO microperimetry differentiated the full thickness macular breaks from pseudo-or lamellar breaks in these eyes. SLO microperimetry is useful for differentiating their prognosis, and determining the need for surgical treatment.

Serum-induced collagen gel contraction.

PURPOSE: To understand the molecular events underlying disease-related vitreous gel contraction, the effect of serum components on collagen was investigated. METHODS: Bovine vitreous or dermal collagen was incubated with a mixture of transglutaminase (TG; factor XIIIa) and fibronectin (FN), and the biochemical changes of collagen were monitored by gel electrophoresis. In addition, serum-induced changes in the volume of the collagen gel were monitored. RESULTS: Gel electrophoresis revealed a new high-molecular-weight band (M(r) 240,000) presumably due to intermolecular cross-links of collagen peptides and FN. The serum components also were shown to cause a significant decrease in the volume of the collagen gel. CONCLUSION. Collagen gel contraction could be attributed to the collagen-FN-collagen cross-links catalyzed by TG.