MRI and clinical syndrome in dura materrelated Creutzfeldt-Jakob disease

Objective : Iatrogenic Creutzfeldt-Jakob disease (iCJD) is mainly associated with dura mater (DM) grafts and administration of human growth hormones (hGH). Data on disease course in DM-CJD are limited. We describe the clinical and diagnostic findings in this patient group with special emphasis on MRI signal alterations. Methods : Ten DM-CJD patients were studied for their clinical symptoms and diagnostic findings. The MRIs were evaluated for signal increase of the cortical and subcortical structures. Results : DM-CJD patients had a median incubation time of 18 years and median disease duration of 7 months. The majority of patients were MM homozygous at codon 129 of the prion protein gene (PRNP) and presented with gait ataxia and psychiatric symptoms. No correlation between the graft site and the initial disease course was found. The MRI showed cortical and basal ganglia signal increase each in eight out of ten patients and thalamic hyperintensity in five out of ten cases. Of interest, patients with thalamic signal increase were homozygous for methionine. Conclusion : The MRI findings in DM-CJD largely resemble those seen in sporadic CJD, as the cortex and basal ganglia are mainly affecte

Widespread expression of erythropoietin receptor in brain and its induction by injury

Erythropoietin (EPO) exerts potent neuroprotective, neuroregenerative and procognitive functions. However, unequivocal demonstration of erythropoietin receptor (EPOR) expression in brain cells has remained difficult since previously available anti-EPOR antibodies (EPOR-AB) were unspecific. We report here a new, highly specific, polyclonal rabbit EPOR-AB directed against different epitopes in the cytoplasmic tail of human and murine EPOR and its characterization by mass spectrometric analysis of immuno-precipitated endogenous EPOR, Western blotting, immunostaining and flow cytometry. Among others, we applied genetic strategies including overexpression, Lentivirus-mediated conditional knockout of EpoR and tagged proteins, both on cultured cells and tissue sections, as well as intracortical implantation of EPOR-transduced cells to verify specificity. We show examples of EPOR expression in neurons, oligodendroglia, astrocytes and microglia. Employing this new EPOR-AB with double-labeling strategies, we demonstrate membrane expression of EPOR as well as its localization in intracellular compartments such as the Golgi apparatus. Moreover, we show injury-induced expression of EPOR. In mice, a stereotactically applied stab wound to the motor cortex leads to distinct EpoR expression by reactive GFAP-expressing cells in the lesion vicinity. In a patient suffering from epilepsy, neurons and oligodendrocytes of the hippocampus strongly express EPOR. To conclude, this new analytical tool will allow neuroscientists to pinpoint EPOR expression in cells of the nervous system and to better understand its role in healthy conditions, including brain development, as well as under pathological circumstances, such as upregulation upon distress and injury

Mild expression differences of MECP2 influencing aggressive social behavior

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (∼50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2mRNA expression differs in peripheral blood mononuclear cells by ∼50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Multidimensional Conservation Laws: Overview, Problems, and Perspective

Some of recent important developments are overviewed, several longstanding open problems are discussed, and a perspective is presented for the mathematical theory of multidimensional conservation laws. Some basic features and phenomena of multidimensional hyperbolic conservation laws are revealed, and some samples of multidimensional systems/models and related important problems are presented and analyzed with emphasis on the prototypes that have been solved or may be expected to be solved rigorously at least for some cases. In particular, multidimensional steady supersonic problems and transonic problems, shock reflection-diffraction problems, and related effective nonlinear approaches are analyzed. A theory of divergence-measure vector fields and related analytical frameworks for the analysis of entropy solutions are discussed.Comment: 43 pages, 3 figure

Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: Phase 3 study

AbstractBackgroundEvaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.MethodsOpen-label, nonrandomized, multicenter, phase 3 study to validate the 18F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology.ResultsBrain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8–100%], specificity 88.9% [95% CI 77.0–100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively.ConclusionsFlorbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD.Trial registrationClinicalTrials.gov NCT01020838

The design and function of birds’ nests

All birds construct nests in which to lay eggs and/or raise offspring. Traditionally, it was thought that natural selection and the requirement to minimize the risk of predation determined the design of completed nests. However, it is becoming increasingly apparent that sexual selection also influences nest design. This is an important development as while species such as bowerbirds build structures that are extended phenotypic signals whose sole purpose is to attract a mate, nests contain eggs and/or offspring, thereby suggesting a direct tradeoff between the conflicting requirements of natural and sexual selection. Nest design also varies adaptively in order to both minimize the detrimental effects of parasites and to create a suitable microclimate for parents and developing offspring in relation to predictable variation in environmental conditions. Our understanding of the design and function of birds’ nests has increased considerably in recent years, and the evidence suggests that nests have four nonmutually exclusive functions. Consequently, we conclude that the design of birds’ nests is far more sophisticated than previously realized and that nests are multifunctional structures that have important fitness consequences for the builder/s

Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy