Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD mice by syngeneic splenocytes treated with cytotoxic drugs.

Infusions of syngeneic T-cells, lethally damaged with ultraviolet A light (UVA) and 8-methoxypsoralen (8-MOP), have been reported to prevent or ameliorate a number of autoimmune diseases in humans and in animal models of autoimmune disease. We previously demonstrated that the combination of UVA/8-MOP, or deoxycoformycin and deoxyadenosine (dCF/dAdo), damaged human lymphoid cells by inducing DNA strand breakage and stimulating poly (ADP-ribosyl)ation. These cells subsequently underwent programmed cell death ("apoptosis"). These findings suggested a common mechanism of lymphocyte damage, and that in vitro treatment of T-cells with cCF/dAdo might substitute for UVA/8-MOP. This hypothesis was tested in a model of autoimmune diabetes in the NOD mouse. Young adult female NOD/Wehi mice were given 350 mg/kg cyclophosphamide (CP) on day 1 to induce rapid-onset diabetes and divided into five treatment groups. Four groups received approximately 50 x 10(6) syngeneic mouse splenocytes that had been treated with various cytotoxic agents. 27/40 (68%) of the CP-only control group and 14/30 (48%) of the group given untreated splenocytes developed diabetes. By contrast, only 2/20 (10%) mice of UVA/8-MOP and 3/23 (14%) of dCF/dAdo-treated splenocyte groups developed diabetes (P < 0.01). Diabetes in high spontaneous-diabetes incidence NOD/Lt female mice was also greatly reduced (4/8 untreated vs 1/7 treated; (< 0.05). We postulate that cytotoxic damage to activated splenic T-cells allows their recognition by host T-cells and results in a protective response against autoreactive cells as a form of T-cell vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)

Accuracy and implications of a reported family history of glaucoma: experience from the Glaucoma Inheritance Study in Tasmania.

OBJECTIVES: To ascertain the prevalence of previously undiagnosed primary open-angle glaucoma (POAG) within 5 large POAG pedigrees and to evaluate the reliability of a reported family history of glaucoma within these pedigrees. METHODS: The Glaucoma Inheritance Study in Tasmania (GIST) identified several large adult POAG pedigrees. Intraocular pressure (IOP), optic disc stereophotography, and automated perimetry were performed on all adult pedigree members. Participants were classified as normal (IOP <22 mm Hg and normal optic disc and field); glaucoma suspect (normal field, but an IOP >/=22 mm Hg and/or suspicious optic disc); or POAG (field defect and glaucomatous optic disc). Some individuals with POAG had been previously diagnosed by their local ophthalmologist; others were diagnosed as a result of the GIST project. Family members with a prior diagnosis of POAG were asked to report if they were aware of any relatives with POAG. This reported family history was then directly compared with the actual pedigree (before the diagnosis of new cases) to calculate agreement. MAIN OUTCOME MEASURE: The rate of glaucoma in pedigrees and percentage of previously diagnosed glaucoma cases who were aware of the positive family history of POAG. RESULTS: Four hundred forty-two subjects (mean age, 54 years [range, 13-97 years]) from 5 pedigrees were examined: 316 subjects (71%) were normal, 47 (11%) were previously diagnosed with POAG, and 8 (2%) were previously diagnosed glaucoma suspects; 30 cases (7%) of POAG and 41 suspects (9%) were newly diagnosed as a direct result of the GIST examination. Of the 47 previously diagnosed POAG cases, 41 were questioned about their prior knowledge of any family history and 11 (27%) were unaware of their family history of POAG. CONCLUSIONS: Examination of all adult subjects from POAG families yields new cases. Even in large POAG pedigrees, 27% of previously diagnosed POAG patients were unaware of their positive family history. These findings suggest that a higher percentage of adult POAG may be inherited than hitherto reported. Arch Ophthalmol. 2000;118:900-904

The 'GIST' score: ranking glaucoma for genetic studies. Glaucoma Inheritance Study of Tasmania.

The 'GIST' score was developed to facilitate linkage analysis of adult-onset primary open angle glaucoma (POAG) pedigrees in the Glaucoma Inheritance Study of Tasmania (GIST). Previous genetic linkage studies on juvenile open angle glaucoma pedigrees have relied upon an analysis of definitely affected individuals using the 'single best diagnosis' convention. Studies of adult-onset POAG have been complicated by limited numbers of unequivocally affected members identified even in very large pedigrees due to the later onset of the disease. Many members of the pedigree may have equivocal clinical features or are too young to show signs of the disease. The 'GIST score' is a numeric value between zero and one where zero is clinical certainty of absence of the disease and one is the definitive diagnosis of POAG. The score is developed by assigning relative weighting to key clinical features which results in a 'pedigee probability' of the diagnosis being present or absent in a member of a pedigree. Ranking of borderline and unaffected glaucoma subjects allows the laboratory more flexibility in the use of the members of the pedigree for linkage analysis. The score is not intended to have clinical usefulness in management of glaucoma.

The problem of overlapping glaucoma families in the Glaucoma Inheritance Study in Tasmania (GIST).

The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australia's island state, Tasmania (population 450,000). Its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucoma (POAG) suitable for genetic linkage analysis. POAG is relatively common, affecting around 3% of the Australian population. By finding the large families with POAG and identifying all the descendants in a captive population, it is possible that there may be overlap of different glaucoma pedigrees. Three of the first thirteen families in the study were composed of overlapping pedigrees. In one GIST family, GTas3, there has been intermarriage with other pedigrees with glaucoma on five occasions. The possibility of multiple genotypes was also reinforced by the inability to determine a single glaucoma phenotype in this family. When finding large families of POAG for linkage analysis, researchers must be aware of the risk of affected individuals inheriting their gene from the alternate parent. Thus, the alternate parents or their families must be examined, especially if the phenotype is atypical for the rest of the family.

Topical prostaglandin analogues do not affect selective laser trabeculoplasty outcomes.

PURPOSE: To investigate the effect of topical prostaglandin analogue use on the efficacy of selective laser trabeculoplasty (SLT) intraocular pressure (IOP) lowering in patients with open-angle glaucoma. PATIENTS AND METHODS: This retrospective study included 123 consecutive patients who underwent 180 degrees SLT for the first time. Eyes were grouped into those that received prostaglandin analogues before and after SLT (n=74) and those that did not (n=49). The main outcome measure was IOP lowering after SLT. Success was defined as > or =20% reduction in IOP without further glaucoma intervention. RESULTS: There was no significant difference in IOP lowering at 6 months post-laser between the prostaglandin and non-prostaglandin groups (3.9+/-4.8 vs 4.6+/-3.6 mm Hg, P=0.43). Long-term SLT success rates were also not significantly different between the treatment groups (Kaplan-Meier survival analysis, P=0.68). IOP lowering at 6 months was similar in eyes that received no glaucoma medications, monotherapy with or without a prostaglandin analogue, or combination therapy with or without prostaglandin analogues (P=0.81). Logistic regression analysis showed that various patient characteristics including age, sex, type of glaucoma, previous glaucoma surgery, and other glaucoma risk factors did not predict a successful SLT outcome. However, higher pre-operative IOP was found to predict SLT success (odds ratio=1.12, 95% CI=1.02-1.24, P=0.02). CONCLUSION: The IOP lowering efficacy of SLT is not influenced by the use of topical prostaglandin analogues.

Risk factors for delayed suprachoroidal haemorrhage following glaucoma surgery.

AIM: To determine the incidence, risk factors and outcomes of delayed suprachoroidal haemorrhage (DSCH) after glaucoma surgery. METHODS: A retrospective case-control study was performed at a tertiary referral eye hospital on patients who presented with DSCH following glaucoma surgery. Cases were compared with a matched-control population that underwent equivalent procedures but did not develop DSCH. The main outcome parameters were incidence of DSCH, risk factors associated with its occurrence, visual outcome and prognostic factors. RESULTS: Of the 2752 glaucoma surgeries performed during the 10-year recruitment period, 29 cases of DSCH (1%) were identified. An increased incidence of DSCH was observed after glaucoma drainage device implantation compared with trabeculectomy-associated DSCH (p<0.0001; odds ratio 3.4; 95% CI 1.9 to 5.4). Risk factors for DSCH included low postoperative intraocular pressure (< or =3 mm Hg; p<0.001), aphakia (p<0.001), prior intraocular surgery (p<0.002), hypertension (p<0.001), anticoagulation (p = 0.002), ischaemic heart disease (p = 0.001) and respiratory disease (p = 0.008). The visual outcome of patients with haemorrhage was poor (logMAR 1.34 (SD 0.41)) and was significantly worse when compared with the control group (p = 0.002). CONCLUSIONS: In this study cohort, DSCH occurred more frequently after glaucoma drainage device implantation compared with trabeculectomy. Caution should be exercised when operating on patients with known ocular and systemic risk factors.

Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A)

BACKGROUND: A substantial proportion of cases of glaucoma have a genetic basis. Mutations causing glaucoma have been identified in the chromosome 1 open-angle glaucoma gene (GLC1A), which encodes a 57-kd protein known as myocilin. The normal role of this protein and the mechanism by which mutations cause glaucoma are not known. METHODS: We screened 716 patients with primary open-angle glaucoma and 596 control subjects for sequence changes in the GLC1A gene. RESULTS: We identified 16 sequence variations that met the criteria for a probable disease-causing mutation because they altered the predicted amino acid sequence and they were found in one or more patients with glaucoma, in less than 1 percent of the control subjects. These 16 mutations were found in 33 patients (4.6 percent). Six of the mutations were found in more than 1 subject (total, 99). Clinical features associated with these six mutations included an age at diagnosis ranging from 8 to 77 years and maximal recorded intraocular pressures ranging from 12 to 77 mm Hg. CONCLUSIONS: A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma.