Inhibition of IL-10 Production by Maternal Antibodies against Group B Streptococcus GAPDH Confers Immunity to Offspring by Favoring Neutrophil Recruitment

Group B Streptococcus (GBS) is the leading cause of neonatal pneumonia, septicemia, and meningitis. We have previously shown that in adult mice GBS glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extracellular virulence factor that induces production of the immunosuppressive cytokine interleukin-10 (IL-10) by the host early upon bacterial infection. Here, we investigate whether immunity to neonatal GBS infection could be achieved through maternal vaccination against bacterial GAPDH. Female BALB/c mice were immunized with rGAPDH and the progeny was infected with a lethal inoculum of GBS strains. Neonatal mice born from mothers immunized with rGAPDH were protected against infection with GBS strains, including the ST-17 highly virulent clone. A similar protective effect was observed in newborns passively immunized with anti-rGAPDH IgG antibodies, or F(ab')2 fragments, indicating that protection achieved with rGAPDH vaccination is independent of opsonophagocytic killing of bacteria. Protection against lethal GBS infection through rGAPDH maternal vaccination was due to neutralization of IL-10 production soon after infection. Consequently, IL-10 deficient (IL-10−/−) mice pups were as resistant to GBS infection as pups born from vaccinated mothers. We observed that protection was correlated with increased neutrophil trafficking to infected organs. Thus, anti-rGAPDH or anti-IL-10R treatment of mice pups before GBS infection resulted in increased neutrophil numbers and lower bacterial load in infected organs, as compared to newborn mice treated with the respective control antibodies. We showed that mothers immunized with rGAPDH produce neutralizing antibodies that are sufficient to decrease IL-10 production and induce neutrophil recruitment into infected tissues in newborn mice. These results uncover a novel mechanism for GBS virulence in a neonatal host that could be neutralized by vaccination or immunotherapy. As GBS GAPDH is a structurally conserved enzyme that is metabolically essential for bacterial growth in media containing glucose as the sole carbon source (i.e., the blood), this protein constitutes a powerful candidate for the development of a human vaccine against this pathogen

Morphometric assessment of normal, suspect and glaucomatous optic discs with Stratus OCT and HRT II

AIMS: To compare morphometric parameters and diagnostic performance of the new Stratus Optical Coherence Tomograph (OCT) Disc mode and the Heidelberg Retina Tomograph (HRT); to evaluate OCT's accuracy in determining optic nerve head (ONH) borders. METHODS: Controls and patients with ocular hypertension, glaucoma-like discs, and glaucoma were imaged with OCT Disc mode, HRT II, and colour disc photography (DISC-PHOT). In a separate session, automatically depicted ONH shape and size in OCT were compared with DISC-PHOT, and disc borders adjusted manually where required. In a masked fashion, all print-outs and photographs were studied and discs classified as normal, borderline, and abnormal. The Cohen kappa method was then applied to test for agreement of classification. Bland-Altman analysis was used for comparison of disc measures. RESULTS: In all, 49 eyes were evaluated. Automated disc margin recognition failed in 53%. Misplaced margin points were more frequently found in myopic eyes, but only 31/187 were located in an area of peripapillary atrophy. Agreement of OCT with photography-based diagnosis was excellent in normally looking ONHs, but moderate in discs with large cups, where HRT performed better. OCT values were consistently larger than HRT values for disc and cup area. Compared with HRT, small rim areas and volumes tended to be minimized by OCT, and larger ones to be magnified. CONCLUSIONS: Stratus OCT Disc protocol performed overall well in differentiating between normal and glaucomatous ONHs. However, failure of disc border recognition was frequently observed, making manual correction necessary. ONH measures cannot be directly compared between HRT and OCT

Agreement between Heidelberg Retina Tomograph-I and -II in detecting glaucomatous changes using topographic change analysis

Purpose To evaluate the suitability of including both Heidelberg Retina Tomograph-I (HRT-I) and HRT-II examinations in the same longitudinal series for HRT topographic change analysis (TCA) and to evaluate parabolic error correction (PEC) to improve the agreement between HRT-I and HRT-II examinations. Methods A total of 66 eyes from the University of California San Diego Diagnostic Innovations in Glaucoma Study with baseline HRT-I and HRT-II examinations obtained on the same day and ≥3 HRT-II follow-up examinations were included. Two TCA analyses, HRT-I examination at baseline (HRT-I-mixed series) and HRT-II examination at baseline (HRT-II-only series) were compared. Agreement between the HRT-I-mixed and HRT-II-only series were estimated using Bland-Altman plots. Agreement was assessed: (1) using the current HRT software settings (PEC applied only to HRT-II-only series), and (2) modified HRT settings (PEC also applied to HRT-I-mixed series). Results With current HRT software settings, the HRT-I-mixed series significantly overestimated change locations (ie, red pixels) compared with the HRT-II-only series as indicated by statistically significant proportional biases in the Bland-Altman analysis. By applying PEC to HRT-I-mixed series there were no statistically significant biases in the TCA parameter estimates compared with the HRT-II-only series. Conclusion In some eyes, HRT-I and HRT-II baseline examinations are not interchangeable in TCA analysis without parabolic error correction. HRT-I-mixed series detected more changes characteristic of glaucoma when there were only minimal changes in the HRT-II-only series. Our Results suggest that in the majority of cases, with PEC, HRT-I examinations may be included in a longitudinal series containing HRT-II examinations. & 2011 Macmillan Publishers Limited. All rights reserved

Diagnostic ability of a linear discriminant function for optic nerve head parameters measured with optical coherence tomography for perimetric glaucoma

BACKGROUND/AIMS: To calculate and validate a linear discriminant function (LDF) for optical coherence tomography (OCT) to improve the diagnostic ability of isolated optic nerve head (ONH) parameters to discriminate between healthy individuals and glaucoma patients. METHODS: Two independent samples (teaching and validating sets) were prospectively selected. The teaching set (54 normal eyes and 73 glaucoma patients) was used to calculate the LDF. The validating set (70 healthy individuals and 67 glaucoma patients) was used to test the performance of the LDF in an independent population. Receiver operating characteristic (ROC) curves were plotted and compared with the ONH parameters measured using OCT. RESULTS: The optimized function was: LDF=8.204+(2.59xdisc area)-(9.25xhorizontal rim width). The largest areas under the ROC curve were 0.923 and 0.898 for our LDF and the vertical rim area in the validating population respectively. There were no significant differences between the areas. At 95% fixed specificity, the LDF (71.64%) and the vertical rim area (65.67%) yielded the highest sensitivity values. CONCLUSIONS: All ONH parameters obtained with OCT, except disc area, had a good ability to differentiate between healthy and glaucoma individuals. As judged by the area under the ROC curve, the LDF performed better than any single parameter, although statistics did not prove it better than vertical cup/disc ratio or vertical rim area with the number of subjects we studied

Optic nerve head changes in early glaucoma: a comparison between stereophotography and Heidelberg retina tomography

ObjectiveTo evaluate and compare the diagnostic accuracy of the Heidelberg retina tomograph (HRT) version 3 with that of glaucoma specialists using stereophotography in discriminating between normal eyes and patients with early glaucomatous visual field loss.Methods A total of 105 eyes of 105 individuals were prospectively and consecutively recruited. The sample comprised 51 normal and 54 early glaucomatous eyes, as defined by intraocular pressure and standard automated perimetry results, regardless of optic disc appearance. Receiver operating characteristic (ROC) curves were plotted for the HRT3 parameters and a linear discriminant function (LDF) developed in our hospital. Best sensitivity-specificity pairs were compared between the HRT3 parameters, with the highest areas under the ROC curve (AUCs) and evaluation of optic disc stereophotographs. Agreement between methods for measuring vertical cup-to-disc ratio was evaluated with the Bland-Altman plot.Results The average visual field mean deviation was-2.90 dB. The HRT3 parameters with the largest AUCs were our LDF (0.900), rim volume (0.883), and vertical cup/disk ratio (0.880), with no significant differences between these parameters. Sensitivity-specificity pairs were 79.6-100% (clinical evaluation), 83.3-86.3% (our LDF), 64.8-96.1% (final glaucoma probability score), and 68.5-90.2% (global Moorfields regression analysis).Conclusions The diagnostic accuracy for differentiating normal eyes from those with early visual field defects was similar between clinical evaluation of the optic disc and evaluation with the HRT3. The use of our LDF increased the sensitivity-specificity balance with respect to the HRT-provided parameters. The diagnostic accuracy of the HRT classifications was comparable to that of an experienced glaucoma specialist. © 2010 Macmillan Publishers Limited All rights reserved