Iris Elens

G37R SOD1 mutant alters mitochondrial complex I activity, Ca(2+) uptake and ATP production.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the molecular mechanisms whereby these mutations induce motor neuron death remain controversial. Here, we show that stable overexpression of mutant human SOD1 (G37R) - but not wild-type SOD1 (wt-SOD1) - in mouse neuroblastoma cells (N2a) results in morphological abnormalities of mitochondria accompanied by several dysfunctions. Activity of the oxidative phosphorylation complex I was significantly reduced in G37R cells and correlated with lower mitochondrial membrane potential and reduced levels of cytosolic ATP. Using targeted chimeric aequorin we further analyzed the consequences of mitochondrial dysfunction on cellular Ca(2+) handling. Mitochondrial Ca(2+) uptake, elicited by IP(3)-induced Ca(2+) release from endoplasmic reticulum (ER) was significantly reduced in G37R cells, while uptake induced by a brief Ca(2+) pulse was not affected in permeabilized cells. The decreased mitochondrial Ca(2+) uptake resulted in increased cytosolic Ca(2+) transients, whereas ER Ca(2+) load and resting cytosolic Ca(2+) levels were not affected. Together, these findings suggest that the mechanism linking mutant G37R SOD1 and ALS involves mitochondrial respiratory chain deficiency resulting in ATP loss and impairment of mitochondrial and cytosolic Ca(2+) homeostasis.

Ring chromosome 20 syndrome: Electroclinical description of six patients and review of the literature

BACKGROUND Ring chromosome 20 syndrome is a rare chromosomal disorder. METHODS In six patients, we focused on the presenting epileptic phenotype, the behavioral and mental problems and the relationship between the ratio of mosaicism and the age at onset of the epilepsy. RESULTS All patients presented with pharmacoresistant frontal lobe complex partial seizures. The earliest onset of epilepsy was seen in patients without mosaicism. There were three patients out of six with behavioral disturbances before the onset of seizures. All patients had mild to moderate cognitive impairment. Electroencephalogram recordings showed rhythmic theta waves with frontal predominance and non-convulsive status epilepticus (NCSE). CONCLUSIONS The ring chromosome 20 syndrome is characterized by childhood-onset refractory epilepsy continuing throughout adult life, mental disability, and behavioral disturbances which can originate before seizure onset. Ictal EEG reveals a unique pattern. Our findings indicate a possible link between the percentage of affected cells and the age of epilepsy onset.

Resection and Immunotherapy for Recurrent Grade III Glioma

Background. Despite surgery, radiotherapy, and chemotherapy, the prognosis of relapsed grade III gliomas remains poor. After promising results of immunotherapy in grade IV gliomas, we investigated its safety and efficacy in recurrent grade III gliomas. Methods. Thirty-nine patients received vaccines containing dendritic cells loaded with autologous tumor lysate after tumor resection. Progression-free survival (PFS) and overall survival (OS) were compared with those obtained after temozolomide (TMZ) treatment as found in the literature. Results. Median PFS and OS were 4.6 and 20.5, 3.4 and 18.8, 7.8 and 13.3 months in recurrent grade III astrocytoma, oligodendroglioma, and oligoastrocytoma, respectively. Compared with TMZ, no grade III/IV toxicity was reported and median OS tended to be higher although there was no difference in median PFS. The perceived benefit of immunotherapy was more pronounced in astrocytic tumors. Conclusions. We provide the first description of immunotherapy in recurrent grade III glioma as safe, promising, and feasible.

Brain Connectivity and Cognitive Flexibility in Nonirradiated Adult Survivors of Childhood Leukemia

Background This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Methods Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearmans rank and Pearsons correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Results Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Conclusions Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.