Optic neuropathy is the leading cause of irreversible blindness, and a paradigm for central nervous system axonal disease. The primary event is damage to retinal ganglion cell axons, with subsequent death of the cell body by apoptosis. Trials of neuroprotection for these and other neuronal diseases have mostly failed, primarily because mechanisms of neuroprotection in animals do not necessarily translate to humans. We developed a methodology for imaging an intracellular transduction pathway that signals neuronal death in the living animal. Using longitudinal confocal scanning multilaser ophthalmoscopy, we identified the production of superoxide within retrograde-labelled rat retinal ganglion cells after optic nerve transection. Superoxide was visualized by real-time imaging of its reaction product with intravitreally administered hydroethidine and confirmed by differential spectroscopy of the specific product 2-hydroxyethidium. Retinal ganglion cell superoxide increased within 24 h after axotomy, peaking at 4 days, and was not observed in contralateral untransected eyes. The superoxide signal preceded phosphatidylserine externalization, indicating that superoxide generation was an early event and preceded apoptosis. Intravitreal pegylated superoxide dismutase blocked superoxide generation after axotomy and delayed retinal ganglion cell death. Together, these results are consistent with superoxide being an upstream signal for retinal ganglion cell apoptosis after optic nerve injury. Early detection of axonal injury with superoxide could serve as a predictive biomarker for patients with optic neuropathy.
The pharmacological and medical management of complex chemotherapy regimens are vast and complex, requiring an intimate understanding of physiology, particularly when novel biologic agents are utilized with commonly used regimens. The molecular classification in patients with diffuse large B-cell lymphoma (DLBCL) is multifaceted, particularly with the expansion of novel molecular聽targets. The pharmacological and medical management of hematologic malignancies with a tendency to have central nervous system (CNS) involvement is complex and requires an understanding of physiology and pharmacology. Many chemotherapy regimens used to treat hematologic malignancies with either CNS involvement or high risk for CNS disease will include the administration of high dose methotrexate. This requires having physiological understanding with respect to the standard regimens for DLBCL in addition to understanding cytogenetic markers, such as c-myc and bcl-2, the expression of which displays increased likelihood of CNS involvement. In patients with documented CNS disease and active neurological manifestations such as myclonus, headaches, nystagmus, and blurred vision, the utilization of high dose methotrexate has become an essential standard of care. We examine the pharmacologic mechanisms of high dose methotrexate in patients with hematologic malignancies such as DLBCL and review the most common toxicities on a multidisciplinary level.
There are a wide variety of new and emerging biological agents currently being used in the treatment of uveitis which has expanded the therapeutic horizons far beyond previous limitations.
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