Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-gamma-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-gamma expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-gamma production, but also the protective function of iNKT cells in arthritis

Central corneal thickness in the European Glaucoma Prevention Study

Purpose: To measure central corneal thickness (CCT) within the participants of the European Glaucoma Prevention Study (EGPS). This study was designed to test if lowering intraocular pressure (IOP) by means of dorzolamide is able to prevent or delay conversion from ocular hypertension to glaucoma. Design: Randomized, double-masked, controlled, observational clinical trial. Participants: Eight hundred fifty-four of 1077 ocular hypertensive participants within the EGPS were investigated. Four hundred twenty-nine patients were treated with dorzolamide and 425 patients received placebo. Intervention: Treatment with dorzolamide or placebo (the vehicle of dorzolamide) in 1 or both eyes. Main Outcome Measures: Central corneal thickness as measured by ultrasound pachymetry (DGH-500 Pachette; DGH Technologies, Exton, PA). The CCT measurements were obtained in the morning before measuring IOP. Five measurements were taken from each eye of each patient within 5 minutes of application of anesthetic eye drops. Results: Mean CCT was 572.6 +/- 37.4 mu m (range, 458.5-695.6 mu m). The CCT was higher in younger patients, male patients, and diabetic patients. Mean CCTs for the 429 patients receiving dorzolamide were 574.2 +/- 38.48 mu m (range, 458.5-695.6 mu m) and 571.0 +/- 36.21 mu m (469.7-690.1 mu m) for the 425 patients receiving placebo (P = 0.205). Central corneal thickness did not correlate with refraction, baseline IOP, or systemic hypertension. Conclusion: Central corneal thickness measurements within the EGPS were greater than those reported in other studies of normal eyes without ocular hypertension. Larger CCT measurements correlated with male gender, younger age, and diabetes

The European Glaucoma Prevention Study design and baseline description of the participants

Objectives: The European Glaucoma Prevention Study seeks to evaluate the efficacy of reducing intraocular pressure (IOP), with dorzolamide to prevent or delay patients affected by ocular hypertension from developing primary open-angle glaucoma. Design: Randomized, double-blinded, controlled clinical trial. Participants: Patients (age :30 years) were enrolled from 18 European centers. The patients fulfilled a series of inclusion criteria including the measurements of IOP (22-29 mmHg), two normal and reliable visual fields (VFs) (on the basis of mean defect and corrected pattern standard deviation/corrected loss of variance of standard 30/II Humphrey or Octopus perimetry), and normal optic disc as determined by the Optic Disc Reading Center (vertical and horizontal cup-to-disc ratios; asymmetry between the two eyes less than or equal to0.4). Intervention: Patients were randomized to the treatment with dorzolamide or a placebo. Main Outcome Measures: End points are VF and/or optic disc changes. A VF change during the follow-up must be confirmed by two further positive tests. Optic disc change is defined by the agreement of two out of three independent observers evaluating optic disc stereo-slides. Results: One thousand seventy-seven subjects were randomized between January 1, 1997 and May 31, 1999. The mean age was 57.03 +/- 10.3 years; 54.41% were women and 99.9% were Caucasian. Mean IOP was 23.6 +/- 1.6 mmHg in both eyes. Mean visual acuity was 0.97 +/- 0.11 in both eyes; mean refraction was 0.23 +/- 1.76 diopters in the right eye and 0.18 +/- 1.79 diopters in the left eye. Previous use of medication for ocular hypertension was reported by 38.4% of the patients, systemic hypertension by 28.1%, cardiovascular diseases by 12.9%, and diabetes mellitus by 4.7%. The qualifying VFs were normal and reliable according to protocol criteria. Conclusions: The mean IOP of the patients enrolled in the European Glaucoma Prevention Study is consistent with the estimated mean IOP (within the range of 22-29 mmHg) found in a large sample of the European population. The European Glaucoma Prevention Study should be able to better address the clinical question of whether pharmacological reduction of IOP (by means of dorzolamide) in ocular hypertension patients at moderate risk for developing primary open-angle glaucoma effectively lowers the incidence of primary open-angle glaucoma

Reproducibility of evaluation of optic disc change for glaucoma with stereo optic disc photographs

Purpose: To determine the reproducibility of the assessment for glaucomatous change in serial optic disc stereo-slides. Design: Masked interobserver variability study. Participants: Serial optic disc stereo-slides from 40 patients. Methods: Three independent ophthalmologists evaluated for change a set of two serial 20 optic disc color stereo-slides of 40 patients. This test set was not from European Glaucoma Prevention Study (EGPS) patients. Each observer performed two evaluations at least 30 days apart and was masked from the temporal sequence of the slides and his or her previous evaluation. Each patient was graded as changed or stable by two-out-of-three agreement. A K statistic was used to calculate the intra- and interobserver reproducibility as well as the assignment reproducibility (first consensus versus second consensus). The same procedure was followed to test the reproducibility when another experienced ophthalmologist was added to one of the three reading centers. Main Outcome Measures: Reproducibility in evaluating glaucomatous optic disc change. Results: The intraobserver reproducibility (95% confidence interval [CI]) in the evaluation of change ranged between 0.79 (0.45-1.14) and 1.00 (0.69-1.31). The interobserver reproducibility (95% CI) in the evaluation of change ranged between 0.45 (0.15-0.75) and 0.75 (0.44-1.06). The assignment reproducibility (first consensus versus second consensus in the evaluation of change) between the senior EGPS readers was 0.94 (0.63-1.25). The assignment reproducibility when another experienced ophthalmologist replaced one of the readers was 0.94 (0.63-1.25). Conclusions: The assignment reproducibility of three expert readers looking for glaucomatous change in serial optic disc stereo-slides was excellent. It remained so when one of the three experts was replaced by another experienced reader. (C) 2003 by the American Academy of Ophthalmology