Tumour necrosis factor (TNF)-induced death of oligodendrocytes, the cell type targeted in multiple sclerosis, is mediated by TNF receptor p55 (TNFR-p55). The ligation of TNFR-p55 induces several signal transduction pathways; however, the precise mechanism involved in human oligodendrocyte (hOL) death is unknown. We defined that TNF-induced death of hOLs is non-caspase dependent, as evidenced by lack of generation of caspases 8, 1 and 3 active subunits; lack of cleavage of caspases 1 and 3 fluorogenic substrates; and lack of hOL death inhibition by the general caspase inhibitor, ZVAD.FMK. Electrophoresis of TNF-exposed hOL DNA revealed large-scale DNA fragmentation characteristic of apoptosis-inducing factor (AIF)-mediated cell death, and co-localization experiments showed that AIF translocation to the nucleus occurred upon exposure to TNF. AIF depletion by an antisense strategy prevented TNF-induced hOL death. These results indicate that TNF-induced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination.

Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH(2)-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.

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The aim of our study was to establish the effectiveness of the functional MRI (fMRI) technique in comparison with intraoperative cortical stimulation (ICS) in planning cortex-saving neurosurgical interventions. The combination of sensory and motor stimulation during fMRI experiments was used to improve the exactness of central sulcus localization. The study subjects were 30 volunteers and 33 patients with brain tumors in the rolandic area. Detailed topographical relations of activated areas in fMRI and intraoperative techniques were compared. The agreement in the location defined by the two methods for motor centers was found to be 84%; for sensory centers it was 83%. When both kinds of activation are taken into account this agreement increases to 98%. A significant relation was found between fMRI and ICS for the agreement of the distance both for motor and sensory centers (p=0.0021-0.0024). Also a strong dependence was found between the agreement of the location and the agreement of the distance for both kinds of stimulation. The spatial correlation between fMRI and ICS methods for the sensorimotor cortex is very high. fMRI combining functional and structural information is very helpful for preoperative neurosurgical planning. The sensitivity of the fMRI technique in brain mapping increases when using both motor and sensory paradigms in the same patient.

We present a case of a 29-year-old male with a calcifying pseudoneoplasm of the neuraxis (CAPNON) located in the region of the foramen magnum, treated successfully by complete resection. After a 2-year follow-up the patient remains recurrence free. Clinical and histopathological characterization of CAPNON is provided with special emphasis on the intraoperative and neuroradiological features of the lesion.