Sophia Y. Wang

Role of matrix metalloproteinases in delayed cortical responses after stroke.

Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7–14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor–induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.

Protecting Against Cerebrovascular Injury Contributions of 12/15-Lipoxygenase to Edema Formation After Transient Focal Ischemia

Background and Purpose— The concept of the neurovascular unit suggests that effects on brain vasculature must be considered if neuroprotection is to be achieved in stroke. We previously reported that 12/15-lipoxygenase (12/15-LOX) is upregulated in the peri-infarct area after middle cerebral artery occlusion in mice, and 12/15-LOX contributes to brain damage after ischemia–reperfusion. The current study was designed to investigate 12/15-LOX involvement in vascular injury in the ischemic brain. Methods— In cell culture, a human brain microvascular endothelial cell line was subjected to either hypoxia or H2O2-induced oxidative stress with or without lipoxygenase inhibitors. For in vivo studies, mice were subjected to 90 minutes middle cerebral artery occlusion, and the effects of either 12/15-LOX gene knockout or treatment with lipoxygenase inhibitors were compared. Expression of 12/15-LOX and claudin-5 as well as extravasation of immunoglobulin G were detected by immunohistochemistry. Edema was measured as water content of brain hemispheres according to the wet–dry weight method. Results— Brain endothelial cells were protected against hypoxia and H2O2 by the lipoxygenase inhibitor baicalein. After focal ischemia, 12/15-LOX was increased in neurons and endothelial cells. The vascular tight junction protein claudin-5 underwent extensive degradation in the peri-infarct area, which was partially prevented by the lipoxygenase inhibitor baicalein. Leakage of immunoglobulin G into the brain parenchyma was significantly reduced in 12/15-LOX knockout mice as well as wild-type mice treated with baicalein. Likewise, brain edema was significantly ameliorated. Conclusion— 12/15-LOX may contribute to ischemic brain damage not just by causing neuronal cell death, but also by detrimental effects on the brain microvasculature. 12/15-LOX inhibitors may thus be effective as both neuroprotectants and vasculoprotectants.

Reduction of Tissue Plasminogen Activator-Induced Matrix Metalloproteinase-9 by Simvastatin in Astrocytes

Background and Purpose— Hemorrhagic conversion after tissue plasminogen activator (tPA) stroke therapy has been linked with elevations in matrix metalloproteinase-9 (MMP-9) at the neurovascular interface. Here, we test the idea that statins may directly ameliorate tPA-induced MMP-9 dysregulation. Methods— Recombinant human tPA (5 &mgr;g/mL) was added to primary rat cortical astrocytes. Zymography was used to quantify MMP-9 levels in conditioned media. Effects of simvastatin or the Rho kinase inhibitor Y-27632 were assessed by pretreating cells before tPA exposure. Results— Simvastatin (1 to 10 &mgr;mol/L) significantly reduced tPA-induced MMP-9 in cortical astrocytes. This effect may be mediated via the Rho kinase pathway because tPA-induced activation of Rho signaling was suppressed by simvastatin, and tPA-induced MMP-9 levels were similarly reduced by the Rho kinase inhibitor Y-27632 (1 to 10 &mgr;mol/L). Conclusions— Statins reduce tPA-induced MMP-9 dysregulation by inhibiting the Rho signaling pathway. Statins may ameliorate tPA-associated MMP imbalances in stroke.

Prevalence and Predictors of Depression Among Participants With Glaucoma in a Nationally Representative Population Sample

PURPOSE To investigate the prevalence of and risk factors for depression among participants with glaucoma and the predictive value of glaucoma for depression. DESIGN Cross-sectional study. METHODS This study included 6760 participants in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2008, aged ≥40 years, who reported a presence or absence of glaucoma. Demographic and disease-related information was obtained by interview. Self-reported measures of vision were ascertained via items from the Visual Function Questionnaire (VFQ-25). Participants underwent visual acuity examination, fundus photography, and visual field testing with screening frequency-doubling technology (FDT N-30-5). The main outcome was presence of depression, as determined by a score ≥10 on the Patient Health Questionnaire-9 (PHQ-9). RESULTS Prevalence of depression among participants with and without glaucoma was 10.9% (SEM 2.2%) and 6.9% (SEM 0.62%), respectively. While the presence of glaucoma was significantly associated with depression after adjustment for demographic factors (OR 1.80, 95% CI 1.16-2.79), this association was not significant after adjustment for self-reported general health condition (OR 1.35, 95% CI 0.822-2.23). Among participants with glaucoma, objective measures of glaucoma severity were not significant predictors for depression. However, several self-reported measures of visual function were significantly associated with depression. CONCLUSIONS Glaucoma is a significant predictor of depression after adjustment for demographic factors and multiple comorbidities, but not after adjustment for self-reported general health condition. Among participants with glaucoma, self-reported measures of vision were significant risk factors for depression, whereas objective measures of vision were not.

Association between Myopia and Glaucoma in the United States Population

PURPOSE To investigate the association between myopia and the prevalence of glaucoma. METHODS This cross-sectional study included 5277 participants from the 2005 to 2008 National Health and Nutrition Examination Survey, greater than or equal to 40 years old, without history of cataract or refractive surgery, who underwent auto-refraction measurement. The predictor was refractive status; emmetropia (-0.99 to +0.99 diopters [D]), mild myopia (-1.00 to -2.99 D), moderate myopia (-3.00 to -5.99 D), severe myopia (> -6.00 D), and hyperopia (> 1.00 D). The outcomes were self-reported glaucoma, vertical cup-to-disc ratio and visual field defects as found on frequency doubling technology (FDT) testing RESULTS Odds of self-reported glaucoma were not significantly increased in mild (odds ratio [OR] 0.90, confidence interval [CI] 0.56-1.45), moderate (OR 1.40, CI 0.62-3.16), or severe (OR 0.26, CI 0.08-0.80) myopes compared with emmetropes. Odds of vertical cup-to-disc ratio greater than or equal to 0.7 were not significantly increased in mild (OR 0.84, CI 0.31-2.25), moderate (OR 0.37, CI 0.04-3.57), or severe (OR 0.85, CI 0.09-8.42) myopes compared with emmetropes. Odds of any visual field defects were significantly increased in mild (OR 2.02, CI 1.28-3.19), moderate (OR 3.09, CI 1.42-6.72), and severe (OR 14.43, CI 5.13-40.61) myopes compared with emmetropes. The χ(2) test indicated a significant difference (P = 0.001) in the distribution of subjects with each category of visual field status across subjects with each refractive status; the proportion of subjects with worse visual field defects increased with worsening myopia severity. CONCLUSIONS The association between myopia and visual field defects may represent an increased risk of glaucoma among myopes, and the lack of association with self-reported glaucoma may suggest a need for greater glaucoma surveillance in this population.

Rapid Deletional Peripheral CD8 T Cell Tolerance Induced by Allogeneic Bone Marrow: Role of Donor Class II MHC and B Cells

Mixed chimerism and donor-specific tolerance are achieved in mice receiving 3 Gy of total body irradiation and anti-CD154 mAb followed by allogeneic bone marrow (BM) transplantation. In this model, recipient CD4 cells are critically important for CD8 tolerance. To evaluate the role of CD4 cells recognizing donor MHC class II directly, we used class II-deficient donor marrow and were not able to achieve chimerism unless recipient CD8 cells were depleted, indicating that directly alloreactive CD4 cells were necessary for CD8 tolerance. To identify the MHC class II+ donor cells promoting this tolerance, we used donor BM lacking certain cell populations or used positively selected cell populations. Neither donor CD11c+ dendritic cells, B cells, T cells, nor donor-derived IL-10 were critical for chimerism induction. Purified donor B cells induced early chimerism and donor-specific cell-mediated lympholysis tolerance in both strain combinations tested. In contrast, positively selected CD11b+ monocytes/myeloid cells did not induce early chimerism in either strain combination. Donor cell preparations containing B cells were able to induce early deletion of donor-reactive TCR-transgenic 2C CD8 T cells, whereas those devoid of B cells had reduced activity. Thus, induction of stable mixed chimerism depends on the expression of MHC class II on the donor marrow, but no requisite donor cell lineage was identified. Donor BM-derived B cells induced early chimerism, donor-specific cell-mediated lympholysis tolerance, and deletion of donor-reactive CD8 T cells, whereas CD11b+ cells did not. Thus, BM-derived B cells are potent tolerogenic APCs for alloreactive CD8 cells.

The Association between Glaucoma Prevalence and Supplementation with the Oxidants Calcium and Iron

PURPOSE To investigate the relationship between supplementary consumption of the oxidants calcium and iron and the prevalence of glaucoma. METHODS This cross-sectional study included 3833 participants in the National Health and Nutrition Examination Survey (NHANES) for 2007 and 2008, ≥ 40 years of age, who reported a presence or absence of glaucoma. Participants were interviewed regarding the use of dietary supplements and antacids during the preceding 30-day period. Data pertaining to the supplementary intake of calcium and iron was aggregated and divided into quintiles. Information regarding the presence or absence of glaucoma and demographics, comorbidities, and health-related behavior was obtained via interview. RESULTS Participants who consumed ≥ 800 mg/d of supplementary calcium or ≥ 18 mg/d of supplementary iron had significantly higher odds of having been diagnosed with glaucoma than did those who had not consumed supplementary calcium or iron, after adjustment for potential confounders (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.25-4.76 for calcium; OR 3.80, 95% CI 1.79-8.06 for iron). Concurrent consumption of both calcium and iron above these levels was associated with still greater odds of having been diagnosed with glaucoma (OR 7.24, 95% CI 2.42-21.62). A clear dose-response relationship between quintiles of supplementary calcium or iron intake and glaucoma prevalence was not found. CONCLUSIONS These results suggest that there may be a threshold intake of iron and calcium above which there is an increased risk of development of glaucoma. Prospective longitudinal studies are needed, to assess whether oxidant intake is a risk factor for development and progression of glaucoma.

Protection against Lethal Aspergillus fumigatus Infection in Mice by Allogeneic Myeloid Progenitors Is Not Major Histocompatibility Complex Restricted

Invasive fungal infections are a leading cause of morbidity and mortality after myelotoxic chemotherapy or radiation exposure. The resulting depletion of myeloid precursors under these conditions appears to be the factor that limits approaches to accelerate immune reconstitution. In a murine model of myeloablation after radiation exposure, we demonstrated that highly purified common myeloid and granulocyte-monocyte progenitors (CMPs/GMPs) accelerated myeloid recovery and, thus, enhanced innate immunity as measured by survival after a lethal challenge with Aspergillus fumigatus. Of greatest significance was the demonstration that the protection afforded by CMPs/GMPs was not major histocompatibility complex restricted. Furthermore, the effect of CMP/GMP cellular therapy was additive with that of liposomal amphotericin B treatment. These observations greatly expand the potential donor pool and, thus, the clinical utility of CMP/GMP cellular therapy in patients with myeloid depletion.

Association between Visual Field Defects and Quality of Life in the United States

PURPOSE To investigate the association between visual field defects and quality of life in the United States population. DESIGN Cross-sectional study. PARTICIPANTS A total of 5186 participants in the 2005 through 2008 National Health and Nutrition Examination Survey 40 years of age and older without a self-reported history of age-related macular degeneration or prior refractive surgery who had undergone frequency doubling technology perimetric testing. METHODS Frequency doubling technology perimetry was performed in both eyes. Results from the better eye were used to categorize subjects as normal or having mild, moderate, or severe visual field loss. Subjects completed surveys about their visual and physical functioning ability. MAIN OUTCOME MEASURES Disability pertaining to 6 vision-related activities, 2 visual function questions, and 5 physical functioning domains. RESULTS Eighty-one percent of subjects had normal visual fields and 10%, 7%, and 2% demonstrated mild, moderate, and severe visual field defects, respectively. Subjects with greater severity of visual field defects had greater difficulty with vision-related activities. Subjects with severe visual field defects demonstrated the greatest odds of difficulty with all 6 activities. The 2 activities impacted most adversely were daytime driving in familiar places (odds ratio [OR], 12.4; 95% confidence interval [CI], 6.1-25.1) and noticing objects off to the side when walking (OR, 7.7; 95% CI, 4.7-12.7). Subjects with severe visual field defects had greater odds of worrying about eyesight (OR, 3.4; 95% CI, 2.0-5.8) and being limited by vision in the time spent on daily activities (OR, 5.1; 95% CI, 3.0-8.5). Subjects with severe visual field defects demonstrated the greatest odds of difficulty with 3 physical function domains, including activities of daily living (OR, 2.45; 95% CI, 1.37-4.38), instrumental activities of daily living (OR, 2.45; 95% CI, 1.37-4.38), as well as leisure and social activities (OR, 3.29; 95% CI, 1.87-5.77). CONCLUSIONS Greater severity of visual field abnormality was associated with significantly greater odds of disability with vision-related function and physical function. These findings support the necessity of routine screening to find those who may benefit from therapy to prevent progressive glaucomatous vision loss.

Glaucoma and vitamins A, C, and E supplement intake and serum levels in a population-based sample of the United States

PurposeTo investigate the potential association between glaucoma prevalence and supplemental intake, as well as serum levels of vitamins A, C and E.MethodsThis cross-sectional study included 2912 participants in the 2005–2006 National Health and Nutrition Examination Survey, age ≥40 years, who self-reported a presence or absence of glaucoma. Participants were interviewed regarding the use of dietary supplements during the preceding 30-day period. Participants also underwent serum measurements of vitamins A, C, and E (both alpha- and gamma-tocopherol). Information on the primary outcome measure, presence or absence of glaucoma, as well as demographic information, comorbidities and health-related behaviors, was assessed via interview.ResultsMultivariate odds ratios for self-reported glaucoma, comparing the highest quartile of consumption to no consumption, and adjusted for potential confounding variables were 0.48 (95% confidence interval (CI) 0.13–1.82) for vitamin A, 0.47 (95% CI 0.23–0.97) for vitamin C, and 2.59 (95% CI 0.89–7.56) for vitamin E. Adjusted odds ratios for self-reported glaucoma comparing the highest vs lowest quintiles of vitamin serum levels were 1.44 (95% CI 0.79–2.62) for vitamin A, 0.94 (95% CI 0.42–2.11) for vitamin C, 1.40 (95% CI 0.70–2.81) for alpha-tocopherol, and 0.64 (95% CI 0.24–1.70) for gamma-tocopherol.ConclusionNeither supplementary consumption with nor serum levels of vitamins A and E were found to be associated with glaucoma prevalence. While low- and high-dose supplementary consumption of vitamin C was found to be associated with decreased odds of glaucoma, serum levels of vitamin C did not correlate with glaucoma prevalence.