Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.

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Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP͞PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated ␤-amyloid, and characterized as CD11b ؉ ͞CD11c ؊ ͞ MHC class II ؊ ͞TNF-␣ ؉ cells, impeded neurogenesis from adult neural stem͞progenitor cells, whereas CD11b ؉ ͞CD11c ؉ ͞MHC class II ؉ ͞TNF-␣ ؊ microglia, a phenotype induced by IL-4, counteracted the adverse ␤-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.␤-amyloid ͉ CD11c ͉ T cell vaccination ͉ immunomodulation ͉ neurodegeneration

The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-g (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-a production, and overcame blockage of IGF-I production caused by IFN-g. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool. IntroductionRecovery from acute insults or chronic inflammatory and noninflammatory degenerative disorders in the CNS has been attributed to a limited capacity for neurogenesis and oligodendrogenesis, poor regeneration of injured nerves, and extreme vulnerability to degenerative conditions. Studies have demonstrated that the adult CNS contains stem cells that can give rise, albeit to a limited extent, both to neurons (1) and to oligodendrocytes (2) throughout life. Knowledge of the factors allowing such stem cells to exist, proliferate, and differentiate in the adult individual is a prerequisite for understanding and promoting the conditions conducive to CNS repair. This in turn can be expected to lead to the development of interventions aimed at boosting neural cell renewal from the endogenous stem cell pool or from exogenously applied stem cells.Studies have shown that inflammation within the CNS blocks neurogenesis (3, 4) and causes structural damage to myelin (5, 6). Moreover, "paralysis" of microglia (MG) and/or macrophages arrests progression of the transient monophasic disease EAE (7, 8). All of those findings were interpreted as evidence in support of the traditional view that the effect of local immune cells in the CNS is detrimental, and hence that recovery would require blockage, arrest, or elimination of local immune responses. Likewise, the limited regeneration and excessive vulnerability of CNS neurons under inflammatory conditions or after an acute insult were put down to the poor ability of the CNS to tolerate the immune-derived defensive activity that is often associated with local inflammation and cytotoxicity mediated, for example, by 9) or nitric oxide (10). More recent studies have shown, however, that although an uncontrolled local immune response indeed impairs

Retinal sensitivity consistently correlated with the status of underlying IS-OS junctional layer in both dry and wet forms of AMD. Loss of IS-OS layer is significantly associated with poor retinal sensitivity, assessed by microperimetry. Compared with visual acuity, functional testing with microperimetry appears to more consistently correlate with changes in the outer retina, such as IS-OS junctional integrity, especially, in patients with wet AMD.

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Purpose To investigate the relationship between postoperative visual acuity and integrity of the external limiting membrane (ELM) and inner segment-outer segment (IS-OS) junction layers, using spectral domain optical coherence tomography (SD-OCT), in eyes with macular holes (MHs) following surgical repair. Methods Medical charts of MH-operated cases were retrospectively identified and reviewed. The primary outcome measures were best-corrected visual acuity (BCVA) and the status of the ELM and IS-OS lines, using SD-OCT, at 6 weeks and 6 months postoperatively. Results Sixty-two eyes of 62 patients were included. At 6 weeks following surgery, out of 56 (90.3%) eyes with successful MH closure: 0 eyes showed the combination of disrupted ELM and continuous IS-OS layers; 7 eyes (12.5%) demonstrated continuity of both ELM and IS-OS (ELM c /IS-OS c group); 29 eyes (51.8%) had continuous ELM with discontinuous IS-OS layers (ELM c /IS-OS d group); and 20 eyes (35.7%) had discontinuities in both the layers (ELM d /IS-OS d group). The ELM d /IS-OS d group had the lowest visual gain at 6 months (P ¼ 0.03). At 6 months, a restoration of the integrity of IS-OS layer was observed in 51.7% eyes in the ELM c /IS-OS d group and in 5% in the ELM d /IS-OS d group (P ¼ 0.001). Conclusions When both ELM and IS-OS layers showed disruptions 6 weeks postoperatively, a significantly worse BCVA was measured at 6 months, compared with the eyes with only IS-OS disruptions, detected 6 weeks following surgery. The integrity of the ELM layer appears to be a critical factor for the restoration of the photoreceptor layer and for predicting a successful visual outcome following MH repair.

Aims: To compare the safety and efficacy of 2 anti-vascular-endothelial-growth-factor agents – bevacizumab (Avastin) versus ranibizumab (Lucentis) – in the treatment of patients with neovascular age-related macular degeneration (AMD). Methods: Retrospective analysis of patients who received intravitreal injections of bevacizumab or ranibizumab for neovascular AMD. Primary outcome measures were best-corrected visual acuity (BCVA) and central foveal thickness (CFT) assessed by Spectral Domain scanning laser ophthalmoscope-optical coherence tomography (SD-OCT). A secondary outcome measure was the report of any adverse events in the 2 groups. Results: The number of injections in the bevacizumab group was 184 (average of 4.7 per eye) compared to 187 in the ranibizumab group (average of 5.5 per eye). The mean logMAR equivalent of BCVA at 1 month after the injection improved by 0.18 in the bevacizumab group (p = 0.009) and by 0.13 in the ranibizumab group (p = 0.004). The average SD-OCT CFT decreased from 325 ± 72 to 300 ± 69 μm in the bevacizumab group (p = 0.016) and from 307 ± 57 to 289 ± 56 μm in the ranibizumab group (p = 0.017). In the bevacizumab group, there was 1 event of lower extremity pain (0.54%) and 1 event of increased arterial blood pressure (0.54%). In the ranibizumab group, there were 2 events of transiently increased intraocular pressure (1.1%) and 1 event (0.53%) of intraocular inflammation following injection. Conclusions: Bevacizumab and ranibizumab treatments resulted in similar gains in visual acuity and reduction in macular thickness, documented each month following injection. Intravitreal bevacizumab appears to be as safe and effective as intravitreal ranibizumab in the treatment of exudative AMD.