Erucic acid, a nutritional PPAR delta-ligand may influence Huntington's disease pathogenesis

Increasing recent evidence suggests a key role of oligodendroglial injury and demyelination in the pathophysiology of Huntington's Disease (HD) and the transcription factor PPAR delta is critical for oligodendroglial regeneration and myelination. PPAR delta directly involves in the pathogenesis of HD and treatment with a brain-permeable PPAR delta-agonist (KD3010) alleviates its severity in mice. Erucic acid (EA) is also a PPAR delta-ligand omega 9 fatty acid which is highly consumed in Asian countries through ingesting cruciferous vegetables such as rapeseed (Brassica napus) and indian mustard (Brassica juncea). EA is also an ingredient of Lorenzo's oil employed in the medical treatment of adrenoleukodystrophy and can be converted to nervonic acid, a component of myelin. HD pathogenesis also involves oxidative and inflammatory injury and EA exerts antioxidative and antiinflammatory efficacies including inhibition of thrombin and elastase. Consumption of rapeseed, indian mustard, and Canola oils (containing EA) improves cognitive parameters in animal models, as well as treatment with pure EA. Moreover, erucamide, an endogenous EA-amide derivative regulating angiogenesis and water balance, exerts antidepressive and anxiolytic effects in mice. Hitherto, no study has investigated the therapeutic potential of EA in HD and we believe that it strongly merits to be studied in animal models of HD as a potential therapeutic.</p

A hypothetical proposal to employ meperidine and tamoxifen in treatment of glioblastoma. Role of P-glycoprotein, ceramide and metabolic pathways

Meperidine (pethidine) is a µ-opioid receptor (MOR) agonist widely used in the treatment of cancer pain. While MOR agonists in experimental models have demonstrated both pro- and antitumorigenic properties, meperidine has unique features which may be predominantly anticancer in nature. Meperidine both inhibits NMDA (N-methyl-D-Aspartate) receptors, which are involved in the progression of glioblastoma, and blocks NADH:Ubiquinone Oxidoreductase, which may hinder mitochondrial respiration. In the developing embryonic neural tissue, meperidine reduces cell proliferation around the neural tube and lowers the expression of the B RE (brain and reproductive organ-expressed). This is notable given that the B RE gene is implicated in cancer chemoresistance and gliomagenesis. Further, meperidine inhibits P-glycoprotein, which is involved in cancer multidrug resistance and the degradation of the sphingolipid backbone, ceramide. By enhancing the pro-autophagic and pro-apoptotic ceramide levels in cancer cells, meperidine stimulates cell death and reverses multidrug resistance. Tamoxifen, a safe medication employed in the treatment of breast cancer, directly blocks P-glycoprotein and boosts levels of ceramide both via inhibition of glycosylceramide synthase and ceramidase. Further, tamoxifen blocks NMDA-neurotoxicity and therefore it may act synergistically with meperidine in reducing glioblastoma progression associated with NMDA-activation. Finally, tamoxifen blocks glycolysis which may enhance the mitochondrial-blocking activity of meperidine to shut down energy metabolism of glioblastoma cells. Because of these properties, we believe that the combination of meperidine and tamoxifen merits study in cell culture and animal models to investigate a potential synergistic relationship in the treatment of glioblastoma.</p

Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettre first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-kappa B, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy

Volume-outcome relationships in neurosurgery

For a variety of neurosurgical conditions, increasing surgeon and hospital volumes correlate with improved outcomes, such as mortality, complication rates, length of stay, hospital charges, and discharge disposition. Neurosurgeons can improve patient outcomes at the population level by changing practice and referral patterns to regionalize care for select conditions at high-volume specialty treatment centers. Individual practitioners should be aware of where they fall on the volume spectrum and understand the implications of their practice and referral habits on their patients

Epidemiology, clinical presentation, diagnostic evaluation, and prognosis of spinal arteriovenous malformations

Spinal arteriovenous malformations (sAVM) are rare vascular pathologies whose natural history remains incompletely understood. Advances in diagnostic imaging, coupled with the evolution of endovascular and microsurgical techniques have led to the description of a number of classification schemes for these lesions. An updated method has changed AVM classification from five categories of lesion based on source and location of feeder vessels to three categories based on pathophysiology. These categories include extradural arteriovenous fistulae (AVFs), intradural AVFs, extradural-intradural AVFs, intramedullary AVMs, and conus medullaris AVM each with individual subclassifications. Treatment outcomes have been shown to differ based on classification criteria. The increased use of advanced imaging prior to surgical intervention has facilitated the treatment of AVFs. Definitive diagnosis and characterization have traditionally required digital subtraction angiography, which is now being supplemented with other forms of noninvasive imaging such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA). Epidemiologically, intradural dorsal AVFs account for 80% of all sAVMs, and are characterized by low-pressure shunts located in the sleeve of the dorsal nerve root. Microsurgical treatment has been shown to be highly effective in cases of intradural dorsal AVFs, although many cases are also amenable to durable occlusion using liquid embolics. Conus medullaris AVMs, which has only been recently characterized as a separate category of sAVM, is best treated using a combination of embolization and microsurgery. Successful treatment of sAVM mandates a thorough understanding of the anatomy and classification of these lesions. The purpose of this chapter is to review and summarize the classification, natural history, and prognosis of sAVMs