Analysis of genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in Induced Pluripotent Stem Cells (iPSCs) from patients with Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a malformation of cortical development which is strongly associated with drug-refractory epilepsy. Certain studies have demonstrated an increase in mTOR signaling in patients with FCD on the basis of observation of phosphorylated molecules. The aim of the present study was to verify the differences in genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in iPSCs derived from the Focal Cortical Dysplasia. Fibroblasts were obtained from the skin biopsies of patients with FCD (n = 2) and controls (n = 2). iPSCs were generated by exposing the fibroblasts to viral vectors that contained the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC genes) responsible for promoving cell reprogramation. The fibroblasts and iPSCs were tested during different phases of neurodifferentiation for migration capacity and expression of the genes involved in the PI3K pathway. Fibroblasts of patients with FCD migrated with greater intensity during the first two time points of analyses. iPSCs did not exhibit any difference in cell migration between the groups. Fibroblasts, brain tissue, and iPSCs of the patients with FCD exhibited a significant reduction in the relative expression values of 4EBP-1. During neurodevelopment, the iPSCs from patients with FCD exhibited a reduction in the expression of cIAP-1, cIAP-2, PI3K, ß-Catenin and 4EBP-1 gene. We suggest that the differences observed in the migration potential of adult cells and in the gene expression related to the fundamental processes involved in normal brain development during the neurodifferentiation process might be associated with cortical alteration in the patients with FCD.

Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas.

Glioblastoma (GBM) is a very aggressive tumor that has not had substantial therapeutic improvement since the introduction of temozolomide (TMZ) in combination with radiotherapy. Combining TMZ with other chemotherapeutic agents is a strategy that could be further explored for GBM. To search for molecular predictors of TMZ resistance, the TCGA (The Cancer Genome Atlas) database was utilized to assess the impact of specific genes on TMZ response. Patients whose tumors expressed low levels of FGFR3 and AKT2 responded poorly to TMZ. Combination treatment of vinblastine (VBL) plus mebendazole (MBZ) with TMZ was more effective in reducing cell number in most cultures when compared to TMZ alone, especially in cells with low expression levels of FGFR3 and AKT2. Cell cycle distribution and nuclear morphometric analysis indicated that the triple combination of TMZ, VBL and MBZ (TVM) was able to induce polyploidy and senescence, in addition to increasing the Notch3 RNA level in patient-derived gliomas. Thus, this set of data suggests that the triple combination of TMZ, VBL and MBZ may be a considerable therapeutic alternative for the TMZ-tolerant gliomas that harbor low expression of FGFR3/AKT2.

Microsurgical Clipping of Low-Riding Basilar Bifurcation Aneurysm.

Basilar bifurcation is a challenging site for aneurysm clipping. Anatomical factors such as size and projection of the aneurysm, distance between the aneurysm neck and the dorsum sellae, and location of the basilar bifurcation contribute to surgical complexity. Endovascular treatment has been used more frequently than microsurgical clipping, especially for posterior circulation lesions. Thus, the upcoming generation of neurosurgeons will have increasingly less access to the microsurgical treatment of such lesions. We present the case of a 45-year-old female patient who presented sudden mental confusion characterized by disorientation in time, space, and person. Investigative acute cerebral magnetic resonance imaging revealed diffusion restriction in the left posterior cerebral and superior cerebellar arteries. The clinical and cardiologic investigations revealed no abnormalities, but computed tomographic angiography and digital arteriography revealed a low-riding basilar bifurcation aneurysm and a very small aneurysm in the right internal carotid artery. The wide neck precluded coil embolization, and the appropriate stent was not covered by our public health insurance. Considering the young age, surgical treatment was proposed. Microsurgical clipping was performed using the right pre-temporal approach. In this two-dimensional video, we show the steps to reach the low-riding basilar bifurcation aneurysm neck. The positioning, transzygomatic pterional craniotomy, intradural anterior clinoidectomy, and posterior cavernous sinus opening are shown, and the surrounding anatomy is illustrated.

The antiepileptic activity of JSTX-3 is mediated by N-methyl-D-aspartate receptors in human hippocampal neurons.

We analyzed the effect of the acylpolyaminetoxin JSTX-3 on the epileptogenic discharges induced by perfusion of human hippocampal slices with artificial cerebrospinal fluid lacking Mg2+ or N-methyl-D-aspartate. Hippocampi were surgically removed from patients with refractory medial temporal lobe epilepsy, sliced in the surgical room and taken to the laboratory immersed in normal artificial cerebrospinal fluid. Epileptiform activity was induced by perfusion with Mg2+-free artificial cerebrospinal fluid or by iontophoretically applied N-methyl-D-aspartate and intracellular and field recordings of CA1 neurons were performed. The ictal-like discharges induced by Mg2+-free artificial cerebrospinal fluid and N-methyl-D-aspartate were blocked by incubation with JSTX-3. This effect was similar to that obtained with the N-methyl-D-aspartate receptor antagonist DL (-)2-amino-5 phosphonovaleric acid. Our findings suggest that in human hippocampal neurons, the antiepileptic effect of JSTX-3 is mediated by its action on N-methyl-D-aspartate receptor.

Functional variability of the human cortical motor map: electrical stimulation findings in perirolandic epilepsy surgery.

The purpose of this study was to assess the cortical representation of sensorimotor functions in patients undergoing perirolandic epilepsy surgery, focusing on somatotopy, mosaicism, and variability of function in relation to the classic motor homunculus. The authors studied 36 patients in whom intraoperative or extraoperative electrical cortical stimulation to map motor functions was performed. A computer program was devised to register electrode number, stimulation parameters, and response to each stimulus. Electrode position was represented graphically whenever a stimulus was delivered. A total of 43 maps from 36 patients were analyzed. The authors found variations in the organization of M1 (primary motor cortex) in seven patients (19.4%). Four patients (11.1%) presented mosaicism (overlapping of functional areas), two (5.6%) presented variability (inverted disposition of M1 functional areas), and one (2.8%) had both. The results of this study challenge the notion of orderly topographic relationships between the human sensorimotor functions and their representation in the primary motor cortex. These results confirm those of other studies with animals and humans using novel imaging techniques, suggesting that the motor homunculus may not always be considered a definite and absolute representation of M1.