Effect of carbon black nanomaterial on biological membranes revealed by shape of human erythrocytes, platelets and phospholipid vesicles

Background: We studied the effect of carbon black (CB) agglomerated nanomaterial on biological membranes as revealed by shapes of human erythrocytes, platelets and giant phospholipid vesicles. Diluted human blood was incubated with CB nanomaterial and observed by different microscopic techniques. Giant unilamellar phospholipid vesicles (GUVs) created by electroformation were incubated with CB nanomaterial and observed by optical microscopy. Populations of erythrocytes and GUVs were analyzed: the effect of CB nanomaterial was assessed by the average number and distribution of erythrocyte shape types (discocytes, echinocytes, stomatocytes) and of vesicles in test suspensions, with respect to control suspensions. Ensembles of representative images were created and analyzed using computer aided image processing and statistical methods. In a population study, blood of 14 healthy human donors was incubated with CB nanomaterial. Blood cell parameters (concentration of different cell types, their volumes and distributions) were assessed.Results: We found that CB nanomaterial formed micrometer-sized agglomerates in citrated and phosphate buffered saline, in diluted blood and in blood plasma. These agglomerates interacted with erythrocyte membranes but did not affect erythrocyte shape locally or globally. CB nanomaterial agglomerates were found to mediate attractive interaction between blood cells and to present seeds for formation of agglomerate - blood cells complexes. Distortion of disc shape of resting platelets due to incubation with CB nanomaterial was not observed. CB nanomaterial induced bursting of GUVs while the shape of the remaining vesicles was on the average more elongated than in control suspension, indicating indirect osmotic effects of CB nanomaterial.Conclusions: CB nanomaterial interacts with membranes of blood cells but does not have a direct effect on local or global membrane shape in physiological in vitro conditions. Blood cells and GUVs are convenient and ethically acceptable methods for the study of effects of various substances on biological membranes and therefrom derived effects on organisms.</div

Visualized exploratory spatiotemporal analysis of hand-foot-mouth disease in southern China

Objectives: In epidemiological research, major studies have focused on theoretical models; however, few methods of visual analysis have been used to display the patterns of disease distribution.Design: For this study, a method combining the space-time cube (STC) with space-time scan statistics (STSS) was used to analyze the pattern of incidence of hand-foot-mouth disease (HFMD) in Guangdong Province from May 2008 to March 2009. In this research, STC was used to display the spatiotemporal pattern of incidence of HFMD, and STSS were used to detect the local aggregations of the disease.Setting: The hand-foot-mouth disease data were obtained from Guangdong Province from May 2008 to March 2009, with a total of 68,130 cases.Results: The STC analysis revealed a differential pattern of HFMD incidence among different months and cities and also showed that the population density and average precipitation are correlated with the incidence of HFMD. The STSS analysis revealed that the most likely aggregation includes the Shenzhen, Foshan and Dongguan populations, which are the most developed regions in Guangdong Province.Conclusion: Both STC and STSS are efficient tools for the exploratory data analysis of disease transmission. STC clearly displays the spatiotemporal patterns of disease. Using the maximum likelihood ratio, the STSS model precisely locates the most likely aggregation

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Contains fulltext : 79699.pdf (publisher's version ) (Closed access)BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity

Global, local and focused geographic clustering for case-control data with residential histories

BACKGROUND: This paper introduces a new approach for evaluating clustering in case-control data that accounts for residential histories. Although many statistics have been proposed for assessing local, focused and global clustering in health outcomes, few, if any, exist for evaluating clusters when individuals are mobile. METHODS: Local, global and focused tests for residential histories are developed based on sets of matrices of nearest neighbor relationships that reflect the changing topology of cases and controls. Exposure traces are defined that account for the latency between exposure and disease manifestation, and that use exposure windows whose duration may vary. Several of the methods so derived are applied to evaluate clustering of residential histories in a case-control study of bladder cancer in south eastern Michigan. These data are still being collected and the analysis is conducted for demonstration purposes only. RESULTS: Statistically significant clustering of residential histories of cases was found but is likely due to delayed reporting of cases by one of the hospitals participating in the study. CONCLUSION: Data with residential histories are preferable when causative exposures and disease latencies occur on a long enough time span that human mobility matters. To analyze such data, methods are needed that take residential histories into account

Identifying Causal Genes and Dysregulated Pathways in Complex Diseases

In complex diseases, various combinations of genomic perturbations often lead to the same phenotype. On a molecular level, combinations of genomic perturbations are assumed to dys-regulate the same cellular pathways. Such a pathway-centric perspective is fundamental to understanding the mechanisms of complex diseases and the identification of potential drug targets. In order to provide an integrated perspective on complex disease mechanisms, we developed a novel computational method to simultaneously identify causal genes and dys-regulated pathways. First, we identified a representative set of genes that are differentially expressed in cancer compared to non-tumor control cases. Assuming that disease-associated gene expression changes are caused by genomic alterations, we determined potential paths from such genomic causes to target genes through a network of molecular interactions. Applying our method to sets of genomic alterations and gene expression profiles of 158 Glioblastoma multiforme (GBM) patients we uncovered candidate causal genes and causal paths that are potentially responsible for the altered expression of disease genes. We discovered a set of putative causal genes that potentially play a role in the disease. Combining an expression Quantitative Trait Loci (eQTL) analysis with pathway information, our approach allowed us not only to identify potential causal genes but also to find intermediate nodes and pathways mediating the information flow between causal and target genes. Our results indicate that different genomic perturbations indeed dys-regulate the same functional pathways, supporting a pathway-centric perspective of cancer. While copy number alterations and gene expression data of glioblastoma patients provided opportunities to test our approach, our method can be applied to any disease system where genetic variations play a fundamental causal role

Coherence Potentials: Loss-Less, All-or-None Network Events in the Cortex

Transient associations among neurons are thought to underlie memory and behavior. However, little is known about how such associations occur or how they can be identified. Here we recorded ongoing local field potential (LFP) activity at multiple sites within the cortex of awake monkeys and organotypic cultures of cortex. We show that when the composite activity of a local neuronal group exceeds a threshold, its activity pattern, as reflected in the LFP, occurs without distortion at other cortex sites via fast synaptic transmission. These large-amplitude LFPs, which we call coherence potentials, extend up to hundreds of milliseconds and mark periods of loss-less spread of temporal and amplitude information much like action potentials at the single-cell level. However, coherence potentials have an additional degree of freedom in the diversity of their waveforms, which provides a high-dimensional parameter for encoding information and allows identification of particular associations. Such nonlinear behavior is analogous to the spread of ideas and behaviors in social networks

Old Questions and New Evidence from Social Sequence Analysis

In what ways do dual-earner couples organize their workdays and how do they (de)synchronize their daily activities? Using a multichannel sequence analysis approach, the paper tackles these questions. We consider the couples' division of work-family activities in holistic terms by setting it within the context of everyday life, that is, the overall temporal pattern of combination of His and Her multiple activities. Our multichannel sequence analysis approach is based on a Lexicographic Index that seeks to overcome some optimal matching limits of the sequence analysis. The case-study concerns how Italian dual-earner couples organize their daily activities (sleep, personal care, work, moving, housework, free time), during a typical Monday to Friday work day, 7.00 am to 10.00 pm. The analysis, carried out using the data from the 2008 Italian Census on Time Use (the last one available), involves 873 couples where both partners filled the given diaries on the very same day. All the analyses confirm the idea that dual-earner couples package their life time mainly in accordance with their jobs and eventual children management. Moreover, the analyses show that this time packaging changes in relation to the level of education, social class and the occupational sector of the couple

Protein tyrosine phosphatases in glioma biology

Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic strategies. The drastically increased knowledge about the molecular underpinnings of gliomas during the last decade has elicited high expectations for a more rational and effective therapy for these tumors. Most studies on the molecular pathways involved in glioma biology thus far had a strong focus on growth factor receptor protein tyrosine kinase (PTK) and phosphatidylinositol phosphatase signaling pathways. Except for the tumor suppressor PTEN, much less attention has been paid to the PTK counterparts, the protein tyrosine phosphatase (PTP) superfamily, in gliomas. PTPs are instrumental in the reversible phosphorylation of tyrosine residues and have emerged as important regulators of signaling pathways that are linked to various developmental and disease-related processes. Here, we provide an overview of the current knowledge on PTP involvement in gliomagenesis. So far, the data point to the potential implication of receptor-type (RPTPδ, DEP1, RPTPμ, RPTPζ) and intracellular (PTP1B, TCPTP, SHP2, PTPN13) classical PTPs, dual-specific PTPs (MKP-1, VHP, PRL-3, KAP, PTEN) and the CDC25B and CDC25C PTPs in glioma biology. Like PTKs, these PTPs may represent promising targets for the development of novel diagnostic and therapeutic strategies in the treatment of high-grade gliomas