The effect of betaxolol on ocular blood flow and visual fields in patients with normotension glaucoma.

PURPOSE: This study investigated the effect of ophthalmic betaxolol, a beta, selective adrenoceptor antagonist, on ocular blood flow and visual function in patients with normotension glaucoma (NTG). METHODS: Thirty-six eyes of eighteen patients with NTG, but otherwise free of systemic disease, were included. Blood fibrinogen, sedimentation rates, Goldmann intraocular pressure, Humphrey automated perimetry, and color Doppler imaging were done at baseline and after one year of twice-daily bilateral topical ocular dosing with 0.5% betaxolol HCI. RESULTS: After treatment, the resistivity index of the ophthalmic artery was significantly reduced, and visual fields were significantly improved. The resistivity indexes of the central retinal artery and posterior ciliary artery were also reduced but did not achieve statistical significance. Intraocular pressure was significantly reduced. There was no change in blood fibrinogen and sedimentation rates. CONCLUSIONS: These findings indicate that long-term treatment with ophthalmic betaxolol improves ocular hemodynamics by lowering the resistivity index of the ophthalmic artery and results in an improvement in the visual fields of patients with NTG. In view of this positive effect on blood flow and visual function, betaxolol is recommended in the management of patients with NTG.

Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1.

We recently reported three truncating mutations of the cytochrome P4501B1 gene (CYP1B1) in five families with primary congenital glaucoma (PCG) linked to the GLC3A locus on chromosome 2p21. This could be the first direct evidence supporting the hypothesis that members of the cytochrome P450 superfamily may control the processes of growth and differentiation. We present a comprehensive sequence analysis of the translated regions of the CYP1B1 gene in 22 PCG families and 100 randomly selected normal individuals. Sixteen mutations and six polymorphisms were identified, illustrating an extensive allelic heterogeneity. The positions affected by these changes were evaluated by building a three-dimensional homology model of the conserved C-terminal half of CYP1B1. These mutations may interfere with heme incorporation, by affecting the hinge region and/or the conserved core structures (CCS) that determine the proper folding and heme-binding ability of P450 molecules. In contrast, all polymorphic sites were poorly conserved and located outside the CCS. Northern hybridization analysis showed strong expression of CYP1B1 in the anterior uveal tract, which is involved in secretion of the aqueous humor and in regulation of outflow facility, processes that could contribute to the elevated intraocular pressure characteristic of PCG.

A second locus (GLC3B) for primary congenital glaucoma (Buphthalmos) maps to the 1p36 region.

Primary congenital glaucoma (gene symbol: GLC3) is an ocular disorder that occurs for 0.01-0.04% of blind people. In the majority of familial cases reported so far, this condition is inherited as an autosomal recessive trait. We have recently used a group of 17 GLC3 families with a minimum of two affected offspring and consanguinity in most of the parental generation and mapped the first GLC3 locus (GLC3A) to the 2p21 region. Six families did not show any linkage to the GLC3A locus and thus provided evidence for genetic heterogeneity of this disorder. A total of eight families unlinked to the 2p21 region were used to search for the chromosomal location of the second GLC3 locus. Herein, we describe mapping of a new locus (designated GLC3B) for primary congenital glaucoma to the short arm of chromosome 1 (1p36.2-36.1) that is situated centromeric to the neuroblastoma and Charcot-Marie-Tooth type 2A (CMT2A) loci. A total of 17 DNA markers were genotyped from this region of chromosome 1. Four families showed no recombination with the two markers D1S2834 and D1S402 with a maximum lod score of 4.510 and 4.157 respectively. Pairwise and multipoint linkage analysis and inspection of the haplotypes revealed that the remaining four families are not linked to this part of chromosome 1, thus providing further evidence that at least one more locus for the autosomal recessive form of GLC3 must exist in the genome. Based on the recombination events, the overall linkage map of this region is: tel-D1S1192-D1S1635-D1S1193 - (D1S1597/-D1S489/D1S228)- [GLC3B/D1S2834/D1S402] - (D1S1176/D1S507/D1S407) - D1S2728-(MFAP2/D1S170) - D1S1368 - D1S436-D1S1592-cen.

Topical cyclosporine as a possible new antimetabolite in trabeculectomy.

BACKGROUND AND OBJECTIVE: The authors conducted a randomized, prospective, and controlled clinical and transmission electron microscopic study to investigate the possible role of cyclosporine in trabeculectomy as an antimetabolite agent. PATIENTS AND METHODS: Twelve patients underwent trabeculectomy with topical cyclosporine and another 12 patients had trabeculectomy without cyclosporine. RESULTS: There was a statistically significant decrease in the postoperative intraocular pressure (P < .05) and in the number of medications needed postoperatively (P < .01) in the cyclosporine group. There were no significant complications in either group. Transmission electron microscopic examinations of the excised trabecular scleral tissue showed that cyclosporine caused inhibition of fibroblasts and led to a disruption in collagen organization at the level of the surgical dissection. Middle scleral layers were generally not affected except in some cyclosporine-treated eyes, which showed only a mild cytopathic effect. CONCLUSION: This study showed that topical cyclosporine was safe and effective for use as an antimetabolite in trabeculectomy. Further studies are needed to substantiate the adjuvant role of cyclosporine in glaucoma filtering operations.

Assignment of a locus (GLC3A) for primary congenital glaucoma (Buphthalmos) to 2p21 and evidence for genetic heterogeneity.

Primary congenital glaucoma (GLC3) is an inherited eye disorder that accounts for 0.01-0.04% of total blindness. Although a large number of chromosomal abnormalities have already been reported in patients with congenital glaucoma, the precise location and pathogenesis of this condition remain elusive. By using a group of 17 GLC3 families and a combination of both candidate regional and general positional mapping strategies, we have mapped a locus for GLC3 to the short arm of chromosome 2. Eleven families showed no recombination with 3 tightly linked markers of D2S177 (Z = 9.40), D2S1346 (Z = 8.83), and D2S1348 (Z = 8.90) with a combined haplotype lod score of 11.50. Haplotype and multipoint linkage analyses of 14 DNA markers from 2p indicated that the disease gene is located in the 2p21 region and is flanked by DNA markers D2S1788/D2S1325 (theta = 0.03; Z = 5.42) and D2S1356 (theta = 0.05; Z = 4.69). Inspection of haplotype and heterogeneity analysis confirmed that 6 families are not linked to the 2p21 region, thus providing the first proof of genetic heterogeneity for this phenotype. We therefore designated the locus on 2p21 GLC3A and positioned it in the overall linkage map of Tel-D2S405-D2S367-(D2S1788/D2S1325)-[(GLC3A++ +, D2S177)/(D2S1346/D2S1348)]-D2S1356-D2S119- D2S1761-D2S1248-D2S1352-D2S406- D2S441-Cen. Of the seven genes mapping to the 2p21 region, CAD, CALM2, and LHCGR are centromeric to D2S119 and can be excluded as a candidate for GLC3A, but mutations in PRKR, TIK, SOS1, or SPTBN1 may still be accountable for this phenotype. As human 2p21 shows homology with mouse chromosomes 11 and 17, the homolog of GLC3A is expected to reside on one of these two chromosomes.

Ophthalmic screening of school children in Ankara.

Ophthalmic screening was done on 23,810 children visited at schools in different regions of Ankara. Children with below normal visual acuity were invited to the outpatient department and had a full routine ocular examination. Thirty-nine nursery and primary schools were selected, ten of them private, eleven average state schools, seven good state schools and eleven village schools. Among the 23,810 children, 3095 (13%) had various pathology; 1516 were girls, 1579 boys. Refractive errors were found in 85% of the children (2630). This equals 11% of the total screened population. Refractive errors were myopia 32%, hypermetropia 21%, astigmatism 47%. Strabismic children were 2.5%, and amblyopia was found in 1.1%. The purpose of the study was to assess the place of an ocular screening program in primary school children and to discuss the differences encountered in different urban areas.

Trabeculectomy with mitomycin C: an electron microscopic and clinical study.

A prospective and randomized clinical trial was conducted to investigate the pressure-lowering effect of mitomycin C-aided trabeculectomy in the Turkish population. The scleral tissues excised during the operation were examined by light and electron microscopy. The study population consisted of 26 patients undergoing mitomycin C-aided trabeculectomy and another 26 patients subjected to trabeculectomy without mitomycin C serving as controls. The treatment groups consisted of primary open-angle and closed-angle glaucomas, congenital glaucomas, various types of secondary glaucomas and prior failed trabeculectomies. The decrease in IOP was more marked (P < 0.01) and the number of additional medications needed post-operatively was less in the mitomycin C group (P < 0.01). There were no serious complications except for transient hypotony in one mitomycin-treated eye. Transmission electron microscopic examinations showed differences between the control and mitomycin applied trabecular blocks. At the scleral dissection plane where mitomycin was applied, collagen fibrils were frayed with a loss of proteoglycan cross-links. Fibroblasts demonstrated pyknotic nuclei and loss of cell processes. In the control group, active fibroblasts and regular collagen structure were observed at this level. The middle and inner scleral layers were generally unaffected except for minor changes in some of the mitomycin-treated eyes. Our study showed mitomycin C to be safe and effective as adjunct to trabeculectomy in both primary open-angle, primary angle-closure, various secondary glaucomas and prior failed trabeculectomies. Transmission electron microscopic examinations of excised blocks showed disruption in collagen organization and cytopathic effects to fibroblasts. Mitomycin seemed to affect the proteoglycan cross-links between collagen fibrils after its application.

Therapeutical and genetical aspects of congenital glaucomas.

Therapy for congenital glaucoma is primarily surgical. We have investigated 249 cases who have undergone trabeculectomy. There was a 79% success rate as regards to control of the IOP. Vision could be saved among the patients who had applied relatively early. At the end of the follow up which was 5 years IOP remained normal in the successful group. All the patients and their families were analysed genetically by their pedigrees and caryotypes. An autosomal recessive pattern with variable penetrance was found. The majority of the patients came from families with consanguineous marriages giving a rate of 66.6%. It was suggested that the course of the disease is highly affected by and related to parental consanguinity. An early age of onset and an accelerated clinical course could be well correlated.