Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

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.

Endovascular management of six simultaneous intracranial dural arteriovenous fistulas in a single patient.

A 64-year-old man with a history of traumatic brain injury 4 years previously presented with progressive cognitive decline and gait abnormality. MRI revealed diffusion restriction in the bilateral centrum semiovale and multiple serpiginous flow voids. Cerebral angiogram revealed a total of six intracranial dural arteriovenous fistulas with separate fistulas of the right and left sphenoid bones, left clival plexus, right transverse sinus, right sigmoid sinus, and superior sagittal sinus. A diffuse pseudophlebitic pattern of venous drainage indicating severe venous hypertension was also observed. The patient underwent a series of endovascular treatments over the next 10 months to achieve resolution of all arteriovenous shunting. Repeat MRI showed resolution of the diffusion restriction and marked reduction in T2 vascular flow voids. The patient's clinical status improved significantly over the course of treatment, paralleling the improvement in venous hypertension.

Treatment of 14 intracranial aneurysms with the FRED system.

BACKGROUND: Endovascular treatment of intracranial aneurysms via flow diversion has become increasingly popular over the past several years. The flow redirection endoluminal device (FRED; Microvention, Tustin, California, USA) system is a next generation closed cell paired stent flow diversion device. OBJECTIVE: Our initial clinical experience with the FRED system is described. We believe this series to be the first use of the FRED system in the western hemisphere. METHODS: 14 aneurysms were treated utilizing the FRED system in 13 patients. Post-deployment angiography and fluoro CTs were obtained in all cases. RESULTS: Immediate post-treatment angiography demonstrated reduced flow into all aneurysms although no long term angiographic data are yet available. The device proved technically easy to deploy and recapture after partial deployment if needed. No complications, technical or otherwise, were encountered. Radiographic visibility and ability to maintain its internal cylindrical shape in tortuous arteries, as demonstrated by fluoro CT, was at least as good as the pipeline embolization device. CONCLUSIONS: The FRED system was technically easy to deploy with no procedural complications occurring in this first reported series of 14 aneurysms. The ability of the FRED system to be recaptured after partial deployment and to maintain its internal shape in tortuous vessels was demonstrated well. Long term clinical and angiographic follow-up along with prospective studies are now needed to ascertain the role of the FRED in intracranial aneurysm treatment.

Alterations in sensitivity to estrogen, dihydrotestosterone, and xenogens in B-lymphocytes from children with autism spectrum disorder and their unaffected twins/siblings.

It has been postulated that androgen overexposure in a susceptible person leads to excessive brain masculinization and the autism spectrum disorder (ASD) phenotype. In this study, the responses to estradiol (E2), dihydrotestosterone (DHT), and dichlorodiphenyldichloroethylene (DDE) on B-lymphocytes from ASD subjects and controls are compared. B cells were obtained from 11 ASD subjects, their unaffected fraternal twins, and nontwin siblings. Controls were obtained from a different cell bank. Lactate dehydrogenase (LDH) and sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction levels were measured after incubation with different concentrations of E2, DHT, and DDE. XTT/LDH ratio, representative of mitochondria number per cell, was calculated. E2, DHT, and DDE all cause "U"-shaped growth curves, as measured by LDH levels. ASD B cells show less growth depression compared to siblings and controls (P < 0.01). They also have reduced XTT/LDH ratios (P < 0.01) when compared to external controls, whereas siblings had values of XTT/LDH between ASD and external controls. B-lymphocytes from people with ASD exhibit a differential response to E2, DHT, and hormone disruptors in regard to cell growth and mitochondrial upregulation when compared to non-ASD siblings and external controls. Specifically, ASD B-lymphocytes show significantly less growth depression and less mitochondrial upregulation when exposed to these effectors. A mitochondrial deficit in ASD individuals is implied.

B-lymphocytes from a population of children with autism spectrum disorder and their unaffected siblings exhibit hypersensitivity to thimerosal.

The role of thimerosal containing vaccines in the development of autism spectrum disorder (ASD) has been an area of intense debate, as has the presence of mercury dental amalgams and fish ingestion by pregnant mothers. We studied the effects of thimerosal on cell proliferation and mitochondrial function from B-lymphocytes taken from individuals with autism, their nonautistic twins, and their nontwin siblings. Eleven families were examined and compared to matched controls. B-cells were grown with increasing levels of thimerosal, and various assays (LDH, XTT, DCFH, etc.) were performed to examine the effects on cellular proliferation and mitochondrial function. A subpopulation of eight individuals (4 ASD, 2 twins, and 2 siblings) from four of the families showed thimerosal hypersensitivity, whereas none of the control individuals displayed this response. The thimerosal concentration required to inhibit cell proliferation in these individuals was only 40% of controls. Cells hypersensitive to thimerosal also had higher levels of oxidative stress markers, protein carbonyls, and oxidant generation. This suggests certain individuals with a mild mitochondrial defect may be highly susceptible to mitochondrial specific toxins like the vaccine preservative thimerosal.

Endovascular management of six simultaneous intracranial dural arteriovenous fistulas in a single patient.

A 64-year-old man with a history of traumatic brain injury 4 years previously presented with progressive cognitive decline and gait abnormality. MRI revealed diffusion restriction in the bilateral centrum semiovale and multiple serpiginous flow voids. Cerebral angiogram revealed a total of six intracranial dural arteriovenous fistulas with separate fistulas of the right and left sphenoid bones, left clival plexus, right transverse sinus, right sigmoid sinus, and superior sagittal sinus. A diffuse pseudophlebitic pattern of venous drainage indicating severe venous hypertension was also observed. The patient underwent a series of endovascular treatments over the next 10 months to achieve resolution of all arteriovenous shunting. Repeat MRI showed resolution of the diffusion restriction and marked reduction in T2 vascular flow voids. The patient's clinical status improved significantly over the course of treatment, paralleling the improvement in venous hypertension.