A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1

We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3-p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.     

Gliomatosis cerebri: molecular pathology and clinical course

Gliomatosis cerebri is a rare, diffusely growing neuroepithelial tumor characterized by extensive brain infiltration involving more than two cerebral lobes. Among 13 patients with gliomatosis cerebri (median age, 46 years), biopsies showed features of diffuse astrocytoma (n = 4), oligoastrocytoma (n = 1), anaplastic astrocytoma (n = 5), anaplastic oligoastrocytoma (n = 1), or glioblastoma (n = 2). Molecular genetic investigation showed TP53 mutations in three of seven tumors and both PTEN mutation and epidermal growth factor receptor overexpression in one tumor. Amplification of CDK4 or MDM2 or homozygous deletion of CDKN2A was not detected. Three of 10 patients receiving radiotherapy showed a partial response (one patient) or had stable disease (two patients) lasting for more than 1 year. Four of six patients treated with procarbazine, carmustine, vincristine chemotherapy demonstrated partial remission (one patient), minor response (two patients), or stable disease (one patient). Median survival time from diagnosis was 14 months (range, 4-91+ months). Infratentorial involvement was associated with shorter survival. We conclude that (1) the molecular genetic alterations in gliomatosis cerebri resemble those in diffuse astrocytomas; (2) the prognosis of gliomatosis cerebri is variable but for at least 50% of patients as poor as for glioblastoma; and (3) some patients respond to radiotherapy and/or procarbazine, carmustine, vincristine chemotherapy.     

Modulation of mismatch negativity by stimulus deviance and modality of attention

We studied the effect of attention on the processing of auditory sensory inputs by means of the mismatch negativity (MMN) potential, which can be derived from event-related EEG. A series of frequent standard and rare deviant auditory stimuli were presented to 20 healthy subjects in two recording sessions about five weeks apart. Deviant stimuli were either low or highly deviant as compared to the standard stimulus. While MMN was recorded, subjects were performing a visual and, subsequently, an auditory discrimination task. Directing attention towards the auditory task was associated with increased MMN amplitude only in response to low deviant stimuli and only in the first recording session. No change of MMN amplitude was found when directing attention towards the visual task or when MMN was recorded in response to highly deviant auditory stimuli. The latter may trigger an involuntary switch of attention, thereby overwriting the effect of task-directed attention. Conversely, the effects of attention on the processing of low deviant stimuli appear to be fragile and diminish with increasing automaticity of task execution.     

Pten signaling in gliomas

In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas.     

The involvement of liquid crystals in multichannel implanted neurostimulators,hearing and ENT infections,and cancers

Liquid crystals (LCs) consist of assemblies of molecules, between one and tens of nanometers, grouped in identifiable cohorts according to orientation and structure, which is often lamellar with varying chirality. The term Lo phase designates certain such mesophases. This variety in geometry corresponds to a variety of functions. Some molecules, both organic and inorganic, used in applied engineering, and association with LCs confer new properties. Applying these aspects of LCs in manufacturing implantable material is a growing technology, especially in the interfaces of differentiated multichannel electro-neurostimulation. We highlight the involvement of LCs in the head and neck region, and the role mesophases play in outer hair cell electromotility (mechanotransduction). We summarize implications of LCs this for multichannel electroneurostimulation implant engineering, and highlight their role importance of LCs in early oncogenic process, HPV, and latency in Epstein-Barr and other pathogens. Our approach should help give rise to new therapeutic perspectives. Focusing on upstream nanometric phenomena needs to take on board classic determinism, quantum probability, and statistical complexity.     

Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans

Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Abeta is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated that Abeta40 and Abeta42 interact directly with P-gp. We therefore hypothesized that Abeta accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Abeta, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Abeta40- and Abeta42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 ( ) polymorphisms (exon 2, G-1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Abeta40 and Abeta42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Abeta may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Abeta from brain.