Whole-body mathematical model for simulating intracranial pressure dynamics

A whole-body mathematical model (10) for simulating intracranial pressure dynamics. In one embodiment, model (10) includes 17 interacting compartments, of which nine lie entirely outside of intracranial vault (14). Compartments (F) and (T) are defined to distinguish ventricular from extraventricular CSF. The vasculature of the intracranial system within cranial vault (14) is also subdivided into five compartments (A, C, P, V, and S, respectively) representing the intracranial arteries, capillaries, choroid plexus, veins, and venous sinus. The body's extracranial systemic vasculature is divided into six compartments (I, J, O, Z, D, and X, respectively) representing the arteries, capillaries, and veins of the central body and the lower body. Compartments (G) and (B) include tissue and the associated interstitial fluid in the intracranial and lower regions. Compartment (Y) is a composite involving the tissues, organs, and pulmonary circulation of the central body and compartment (M) represents the external environment

Pallidal stimulation-induced psychosis and suicidality in Parkinson’s disease

Neuropsychiatric adverse events have been previously reported following deep brain stimulation (DBS) for Parkinson’s disease (PD). Most cases described have involved DBS of the subthalamic nucleus (STN). We report a unique case of acute-onset and reversible psychosis, suicidality, and depressive symptoms following DBS of the globus pallidus internus (GPi) and review the relevant literature

Cav1.2 splice variant with exon 9* is critical for regulation of cerebral artery diameter

L-type voltage-dependent Ca2+ channels (VDCCs) are essential for numerous processes in the cardiovascular and nervous systems. Alternative splicing modulates proteomic composition of Cav1.2 to generate functional variation between channel isoforms. Here, we describe expression and function of Cav1.2 channels containing alternatively spliced exon 9* in cerebral artery myocytes. RT-PCR showed expression of Cav1.2 splice variants both containing (α1C9/9*/10) and lacking (α1C9/10) exon 9* in intact rabbit and human cerebral arteries. With the use of laser capture microdissection and RT-PCR, expression of mRNA for both α1C9/9*/10 and α1C9/10 was demonstrated in isolated cerebral artery myocytes. Quantitative real-time PCR revealed significantly greater α1C9/9*/10 expression relative to α1C9/10 in intact rabbit cerebral arteries compared with cardiac tissue and cerebral cortex. To demonstrate a functional role for α1C9/9*/10, smooth muscle of intact cerebral arteries was treated with antisense oligonucleotides targeting α1C9/9*/10 (α1C9/9*/10-AS) or exon 9 (α1C-AS), expressed in all Cav1.2 splice variants, by reversible permeabilization and organ cultured for 1–4 days. Treatment with α1C9/9*/10-AS reduced maximal constriction induced by elevated extracellular K+ ([K+]o) by ∼75% compared with α1C9/9*/10-sense-treated arteries. Maximal constriction in response to the Ca2+ ionophore ionomycin and [K+]o EC50 values were not altered by antisense treatment. Decreases in maximal [K+]o-induced constriction were similar between α1C9/9*/10-AS and α1C-AS groups (22.7 ± 9% and 25.6 ± 4% constriction, respectively). We conclude that although cerebral artery myocytes express both α1C9/9*/10 and α1C9/10 VDCC splice variants, α1C9/9*/10 is functionally dominant in the control of cerebral artery diameter

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors