Epileptogenic Tubers Are Associated with Increased Kurtosis of Susceptibility Values: A Combined Quantitative Susceptibility Mapping and Stereoelectroencephalography Pilot Study

BACKGROUND AND PURPOSE: Prior studies have found an association between calcification and the epileptogenicity of tubers in tuberous sclerosis complex. Quantitative susceptibility mapping is a novel tool sensitive to magnetic susceptibility alterations due to tissue calcification. We assessed the utility of quantitative susceptibility mapping in identifying putative epileptogenic tubers in tuberous sclerosis complex using stereoelectroencephalography data as ground truth. MATERIALS AND METHODS: We studied patients with tuberous sclerosis complex undergoing stereoelectroencephalography at a single center who had multiecho gradient-echo sequences available. Quantitative susceptibility mapping and R2* values were extracted for all tubers on the basis of manually drawn 3D ROIs using T1- and T2-FLAIR sequences. Characteristics of quantitative susceptibility mapping and R2* distributions from implanted tubers were compared using binary logistic generalized estimating equation models designed to identify ictal (involved in seizure onset) and interictal (persistent interictal epileptiform activity) tubers. These models were then applied to the unimplanted tubers to identify potential ictal and interictal tubers that were not sampled by stereoelectroencephalography. RESULTS: A total of 146 tubers were identified in 10 patients, 76 of which were sampled using stereoelectroencephalography. Increased kurtosis of the tuber quantitative susceptibility mapping values was associated with epileptogenicity (P = .04 for the ictal group and P = .005 for the interictal group) by the generalized estimating equation model. Both groups had poor sensitivity (35.0% and 44.1%, respectively) but high specificity (94.6% and 78.6%, respectively). CONCLUSIONS: Our finding of increased kurtosis of quantitative susceptibility mapping values (heavy-tailed distribution) was highly specific, suggesting that it may be a useful biomarker to identify putative epileptogenic tubers in tuberous sclerosis complex. This finding motivates the investigation of underlying tuber mineralization and other properties driving kurtosis changes in quantitative susceptibility mapping values

TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters

<p>Abstract</p> <p>Background</p> <p>Exposure of cancer cells to chemotherapeutic agents may result in reduced sensitivity to structurally unrelated agents, a phenomenon known as multidrug resistance, MDR. The purpose of this study is to investigate cell growth inhibition of wild type and the corresponding MDR cells by Tumor Treating Fields - TTFields, a new cancer treatment modality that is free of systemic toxicity. The TTFields were applied alone and in combination with paclitaxel and doxorubicin.</p> <p>Methods</p> <p>Three pairs of wild type/MDR cell lines, having resistivity resulting from over-expression of ABC transporters, were studied: a clonal derivative (C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant sub-line Emt^R1; human breast cancer cells MCF-7 and their mitoxantrone-resistant sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours with and without the chemotherapeutic agents. The numbers of viable cells in the treated cultures and the untreated control groups were determined using the XTT assay. Student t-test was applied to asses the significance of the differences between results obtained for each of the three cell pairs.</p> <p>Results</p> <p>TTFields caused a similar reduction in the number of viable cells of wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a similar increased reduction in cell survival of wild type and MDR cells. TTFields had no effect on intracellular doxorubicin accumulation in both wild type and MDR cells.</p> <p>Conclusions</p> <p>The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors.</p

Neuropathology of 16p13.11 Deletion in Epilepsy

16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically

Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P,0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a $2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions: Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set o

Migrant health in French Guiana: Are undocumented immigrants more vulnerable?

<p>Abstract</p> <p>Background</p> <p>Few data exist on the health status of the immigrant population in French Guiana. The main objective of this article was to identify differences in its health status in relation to that of the native-born population.</p> <p>Methods</p> <p>A representative, population-based, cross-sectional survey was conducted in 2009 among 1027 adults living in Cayenne and St-Laurent du Maroni. Health status was assessed in terms of self-perceived health, chronic diseases and functional limitations. The migration variables were immigration status, the duration of residence in French Guiana and the country of birth. Logistic regression models were conducted.</p> <p>Results</p> <p>Immigrants account for 40.5% and 57.8% of the adult population of Cayenne and St-Laurent du Maroni, respectively. Most of them (60.7% and 77.5%, respectively) had been living in French Guiana for more than 10 years. A large proportion were still undocumented or had a precarious legal status. The undocumented immigrants reported the worst health status (OR = 3.18 [1.21-7.84] for self-perceived health, OR = 2.79 [1.22-6.34] for a chronic disease, and OR = 2.17 [1.00-4.70] for a functional limitation). These differences are partially explained by socioeconomic status and psychosocial factors. The country of birth and the duration of residence also had an impact on health indicators.</p> <p>Conclusion</p> <p>Data on immigrant health are scarce in France, and more generally, immigrant health problems have been largely ignored in public health policies. Immigrant health status is of crucial interest to health policy planners, and it is especially relevant in French Guiana, considering the size of the foreign-born population in that region.</p

Diagnoses and visit length in complementary and mainstream medicine

<p>Abstract</p> <p>Background</p> <p>The demand for complementary medicine (CM) is growing worldwide and so is the supply. So far, there is not much insight in the activities in Dutch CM practices nor in how these activities differ from mainstream general practice. Comparisons on diagnoses and visit length can offer an impression of how Dutch CM practices operate.</p> <p>Methods</p> <p>Three groups of regularly trained physicians specialized in CM participated in this study: 16 homeopathic physicians, 13 physician acupuncturists and 11 naturopathy physicians. Every CM physician was asked to include a maximum of 75 new patients within a period of six months. For each patient an inclusion registration form had to be completed and the activities during a maximum of five repeat visits were subsequently registered. Registrations included patient characteristics, diagnoses and visit length. These data could be compared with similar data from general practitioners (GPs) participating in the second Dutch national study in general practice (DNSGP-2). Differences between CM practices and between CM and mainstream GP data were tested using multilevel regression analysis.</p> <p>Results</p> <p>The CM physicians registered activities in a total of 5919 visits in 1839 patients. In all types of CM practices general problems (as coded in the ICPC) were diagnosed more often than in mainstream general practice, especially fatigue, allergic reactions and infections. Psychological problems and problems with the nervous system were also diagnosed more frequently. In addition, each type of CM physician encountered specific health problems: in acupuncture problems with the musculoskeletal system prevailed, in homeopathy skin problems and in naturopathy gastrointestinal problems. Comparisons in visit length revealed that CM physicians spent at least twice as much time with patients compared to mainstream GPs.</p> <p>Conclusions</p> <p>CM physicians differed from mainstream GPs in diagnoses, partly related to general and partly to specific diagnoses. Between CM practices differences were found on specific domains of complaints. Visit length was much longer in CM practices compared to mainstream GP visits, and such ample time may be one of the attractive features of CM for patients.</p

Children’s rights online: challenges, dilemmas and emerging directions

In debates over internet governance, the interests of children figure unevenly, and only partial progress has been made in supporting children’s rights online globally. This chapter examines how the UN Convention on the Rights of the Child is helpful in mapping children’s rights to provision, protection and participation as they apply online as well as offline. However, challenges remain. First, opportunities and risks are positively linked, policy approaches are needed to resolve the potential conflict between protection on the one hand, and provision and participation on the other. Second, while parents may be relied on to some degree to balance their child’s rights and needs, the evidence suggests that a minority of parents are ill-equipped to manage this. Third, resolution is needed regarding the responsibility for implementing digital rights, since many governments prefer self-regulation in relation to internet governance. The chapter concludes by calling for a global governance body charged with ensuring the delivery of children’s rights

Comparative Membranome Expression Analysis in Primary Tumors and Derived Cell Lines

Despite the wide use of cell lines in cancer research, the extent to which their surface properties correspond to those of primary tumors is poorly characterized. The present study addresses this problem from a transcriptional standpoint, analyzing the expression of membrane protein genes - the Membranome – in primary tumors and immortalized in-vitro cultured tumor cells. 409 human samples, deriving from ten independent studies, were analyzed. These comprise normal tissues, primary tumors and tumor derived cell lines deriving from eight different tissues: brain, breast, colon, kidney, leukemia, lung, melanoma, and ovary. We demonstrated that the Membranome has greater power than the remainder of the transcriptome when used as input for the automatic classification of tumor samples. This feature is maintained in tumor derived cell lines. In most cases primary tumors show maximal similarity in Membranome expression with cell lines of same tissue origin. Differences in Membranome expression between tumors and cell lines were analyzed also at the pathway level and biological themes were identified that were differentially regulated in the two settings. Moreover, by including normal samples in the analysis, we quantified the degree to which cell lines retain the Membranome up- and down- regulations observed in primary tumors with respect to their normal counterparts. We showed that most of the Membranome up-regulations observed in primary tumors are lost in the in-vitro cultured cells. Conversely, the majority of Membranome genes down-regulated upon tumor transformation maintain lower expression levels also in the cell lines. This study points towards a central role of Membranome genes in the definition of the tumor phenotype. The comparative analysis of primary tumors and cell lines identifies the limits of cell lines as a model for the study of cancer-related processes mediated by the cell surface. Results presented allow for a more rational use of the cell lines as a model of cancer