Thimerosal generates ethylmercury in aqueous solution and is widely used as preservative. We have investigated the toxicology of Thimerosal in normal human astrocytes, paying particular attention to mitochondrial function and the generation of specific oxidants. We find that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but also concurrent with these phenomena increases the formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated hydroxyl radical. These oxidants increase the levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase in the levels of oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA nicks and blunt-ended breaks. Highly damaged mitochondria are characterized by having very low membrane potentials, increased superoxide/hydrogen peroxide production, and extensively damaged mtDNA and proteins. These mitochondria appear to have undergone a permeability transition, an observation supported by the five-fold increase in Caspase-3 activity observed after Thimerosal treatment.

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Background:The authors present a novel case of a hemangioblastoma of the optic nerve producing bilateral optic tract edema in a patient with von Hippel–Lindau disease (VHL). This is the only case in the literature documenting optic tract edema secondary to a hemangioblastoma of the optic nerve.Case Description:The patient was a 34-year-old female in whom this lesion was causing retro-orbital pain and proptosis. She had previously lost vision in the symptomatic eye secondary to a retinal hemangioblastoma. The optic nerve lesion was excised by sectioning the optic nerve both proximally and distally to the lesion. There were no complications and patient's symptoms resolved postoperatively. A follow-up magnetic resonance imaging (MRI) scan revealed complete excision of the mass and resolution of the optic tract edema.Conclusion:Optic nerve hemangioblastomas in patients with VHL are rare, but are manageable with meticulous microneurosurgery and with appropriate patient expectations. This is the first known case of an optic nerve hemangioblastoma producing bilateral optic tract edema, which resolved after resection of the prechiasmal tumor. Hemangioblastoma should remain in the differential diagnosis of optic nerve tumors, especially in the setting of VHL.

The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

We report an unusual case of a large metastatic lesion from prostate adenocarcinoma with its epicenter located in Meckel's cave. The patient presented with acute neurological deterioration due to pontomesencephalic, cranial nerve, and temporal lobe compression. This lesion radiologically mimicked a giant trigeminal schwannoma. Complete surgical resection was achieved with improvement in the performance status of the patient. The anatomic relevance the extradural neural axis component in the process of dissemination of prostate adenocarcinoma to the skull base is highlighted.

Percutaneous sacroplasty is a procedure adapted from vertebroplasty, which is designed to ameliorate the painful morbidity associated with sacral insufficiency fractures without the invasiveness of open surgery. Early estimates of efficacy, according to several case reports and small series, appear promising, but the procedure is not without risk. Several cases of radiculopathy due to nerve root compression by extravasated polymethylmethacrylate (PMMA) have been reported. The authors present a case of radiculopathy caused by cement leakage from sacroplasty, treated with surgical decompression of the compromised nerve root. The patient presented with left S-1 radiculopathy and was found on CT to have a left S-1 nerve root completely encased in PMMA over a portion of its length. The patient underwent sacral laminectomy with the removal of PMMA and experienced pain relief and the return of function postoperatively. Surgical removal of PMMA extravasated during sacroplasty is feasible and should be considered when nerve root compression or canal stenosis causes pain or neurological deficit refractory to conservative therapy.

Little is known about the role of viral genes in modulating host cytokine responses. Here we report a new functional role of the viral encoded IE1 protein of the murine cytomegalovirus in sculpting the inflammatory response in an acute infection. In time course experiments of infected primary macrophages (MΦs) measuring cytokine production levels, genetic ablation of the immediate-early 1 (ie1) gene results in a significant increase in TNFα production. Intracellular staining for cytokine production and viral early gene expression shows that TNFα production is highly associated with the productively infected MΦ population of cells. The ie1- dependent phenotype of enhanced MΦ TNFα production occurs at both protein and RNA levels. Noticeably, we show in a series of in vivo infection experiments that in multiple organs the presence of ie1 potently inhibits the pro-inflammatory cytokine response. From these experiments, levels of TNFα, and to a lesser extent IFNβ, but not the anti-inflammatory cytokine IL10, are moderated in the presence of ie1. The ie1- mediated inhibition of TNFα production has a similar quantitative phenotype profile in infection of susceptible (BALB/c) and resistant (C57BL/6) mouse strains as well as in a severe immuno-ablative model of infection. In vitro experiments with infected macrophages reveal that deletion of ie1 results in increased sensitivity of viral replication to TNFα inhibition. However, in vivo infection studies show that genetic ablation of TNFα or TNFRp55 receptor is not sufficient to rescue the restricted replication phenotype of the ie1 mutant virus. These results provide, for the first time, evidence for a role of IE1 as a regulator of the pro-inflammatory response and demonstrate a specific pathogen gene capable of moderating the host production of TNFα in vivo.