RNA editing signature during myeloid leukemia cell differentiation

Adenosine deaminases acting on RNA (ADARs) are key proteins for hematopoietic stem cell self-renewal and for survival of differentiating progenitor cells. However, their specific role in myeloid cell maturation has been poorly investigated. Here we show that ADAR1 is present at basal level in the primary myeloid leukemia cells obtained from patients at diagnosis as well as in myeloid U-937 and THP1 cell lines and its expression correlates with the editing levels. Upon phorbol-myristate acetate or Vitamin D3/granulocyte macrophage colony-stimulating factor (GM-CSF)-driven differentiation, both ADAR1 and ADAR2 enzymes are upregulated, with a concomitant global increase of A-to-I RNA editing. ADAR1 silencing caused an editing decrease at specific ADAR1 target genes, without, however, interfering with cell differentiation or with ADAR2 activity. Remarkably, ADAR2 is absent in the undifferentiated cell stage, due to its elimination through the ubiquitin–proteasome pathway, being strongly upregulated at the end of the differentiation process. Of note, peripheral blood monocytes display editing events at the selected targets similar to those found in differentiated cell lines. Taken together, the data indicate that ADAR enzymes play important and distinct roles in myeloid cells

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies

The Interplay Between Post-Critical Beliefs and Anxiety: An Exploratory Study in a Polish Sample

The present research investigates the relationship between anxiety and the religiosity dimensions that Wulff (Psychology of religion: classic and contemporary views, Wiley, New York, 1991; Psychology of religion. Classic and contemporary views, Wiley, New York, 1997; Psychologia religii. Klasyczna i współczesna, Wydawnictwo Szkolne i Pedagogiczne, Warszawa, 1999) described as Exclusion vs. Inclusion of Transcendence and Literal vs. Symbolic. The researchers used the Post-Critical Belief scale (Hutsebaut in J Empir Theol 9(2):48–66, 1996; J Empir Theol 10(1):39–54, 1997) to measure Wulff’s religiosity dimensions and the IPAT scale (Krug et al. 1967) to measure anxiety. Results from an adult sample (N = 83) suggest that three dimensions show significant relations with anxiety. Orthodoxy correlated negatively with suspiciousness (L) and positively with guilt proneness (O) factor—in the whole sample. Among women, Historical Relativism negatively correlated with suspiciousness (L), lack of integration (Q3), general anxiety and covert anxiety. Among men, Historical Relativism positively correlated with tension (Q4) and emotional instability (C), general anxiety, covert anxiety and overt anxiety. External Critique was correlated with suspiciousness (L) by men

Early Alterations in Hippocampal Circuitry and Theta Rhythm Generation in a Mouse Model of Prenatal Infection: Implications for Schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic–polyribocytidilic acid (poly I∶C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease

Accuracy of responses from postal surveys about continuing medical education and information behavior: experiences from a survey among German diabetologists

BACKGROUND: Postal surveys are a popular instrument for studies about continuing medical education habits. But little is known about the accuracy of responses in such surveys. The objective of this study was to quantify the magnitude of inaccurate responses in a postal survey among physicians. METHODS: A sub-analysis of a questionnaire about continuing medical education habits and information management was performed. The five variables used for the quantitative analysis are based on a question about the knowledge of a fictitious technical term and on inconsistencies in contingency tables of answers to logically connected questions. RESULTS: Response rate was 52%. Non-response bias is possible but seems not very likely since an association between demographic variables and inconsistent responses could not be found. About 10% of responses were inaccurate according to the definition. CONCLUSION: It was shown that a sub-analysis of a questionnaire makes a quantification of inaccurate responses in postal surveys possible. This sub-analysis revealed that a notable portion of responses in a postal survey about continuing medical education habits and information management was inaccurate

Parameter selection for and implementation of a web-based decision-support tool to predict extubation outcome in premature infants

BACKGROUND: Approximately 30% of intubated preterm infants with respiratory distress syndrome (RDS) will fail attempted extubation, requiring reintubation and mechanical ventilation. Although ventilator technology and monitoring of premature infants have improved over time, optimal extubation remains challenging. Furthermore, extubation decisions for premature infants require complex informational processing, techniques implicitly learned through clinical practice. Computer-aided decision-support tools would benefit inexperienced clinicians, especially during peak neonatal intensive care unit (NICU) census. METHODS: A five-step procedure was developed to identify predictive variables. Clinical expert (CE) thought processes comprised one model. Variables from that model were used to develop two mathematical models for the decision-support tool: an artificial neural network (ANN) and a multivariate logistic regression model (MLR). The ranking of the variables in the three models was compared using the Wilcoxon Signed Rank Test. The best performing model was used in a web-based decision-support tool with a user interface implemented in Hypertext Markup Language (HTML) and the mathematical model employing the ANN. RESULTS: CEs identified 51 potentially predictive variables for extubation decisions for an infant on mechanical ventilation. Comparisons of the three models showed a significant difference between the ANN and the CE (p = 0.0006). Of the original 51 potentially predictive variables, the 13 most predictive variables were used to develop an ANN as a web-based decision-tool. The ANN processes user-provided data and returns the prediction 0–1 score and a novelty index. The user then selects the most appropriate threshold for categorizing the prediction as a success or failure. Furthermore, the novelty index, indicating the similarity of the test case to the training case, allows the user to assess the confidence level of the prediction with regard to how much the new data differ from the data originally used for the development of the prediction tool. CONCLUSION: State-of-the-art, machine-learning methods can be employed for the development of sophisticated tools to aid clinicians' decisions. We identified numerous variables considered relevant for extubation decisions for mechanically ventilated premature infants with RDS. We then developed a web-based decision-support tool for clinicians which can be made widely available and potentially improve patient care world wide

Calcium-Activated Potassium Channels BK and IK1 Are Functionally Expressed in Human Gliomas but Do Not Regulate Cell Proliferation

Gliomas are morbid brain tumors that are extremely resistant to available chemotherapy and radiology treatments. Some studies have suggested that calcium-activated potassium channels contribute to the high proliferative potential of tumor cells, including gliomas. However, other publications demonstrated no role for these channels or even assigned them antitumorogenic properties. In this work we characterized the expression and functional contribution to proliferation of Ca2+-activated K+ channels in human glioblastoma cells. Quantitative RT-PCR detected transcripts for the big conductance (BK), intermediate conductance (IK1), and small conductance (SK2) K+ channels in two glioblastoma-derived cell lines and a surgical sample of glioblastoma multiforme. Functional expression of BK and IK1 in U251 and U87 glioma cell lines and primary glioma cultures was verified using whole-cell electrophysiological recordings. Inhibitors of BK (paxilline and penitrem A) and IK1 channels (clotrimazole and TRAM-34) reduced U251 and U87 proliferation in an additive fashion, while the selective blocker of SK channels UCL1848 had no effect. However, the antiproliferative properties of BK and IK1 inhibitors were seen at concentrations that were higher than those necessary to inhibit channel activity. To verify specificity of pharmacological agents, we downregulated BK and IK1 channels in U251 cells using gene-specific siRNAs. Although siRNA knockdowns caused strong reductions in the BK and IK1 current densities, neither single nor double gene silencing significantly affected rates of proliferation. Taken together, these results suggest that Ca2+-activated K+ channels do not play a critical role in proliferation of glioma cells and that the effects of pharmacological inhibitors occur through their off-target actions

Diagnostic thinking and information used in clinical decision-making: a qualitative study of expert and student dental clinicians

<p>Abstract</p> <p>Background</p> <p>It is uncertain whether the range and frequency of Diagnostic Thinking Processes (DTP) and pieces of information (concepts) involved in dental restorative treatment planning are different between students and expert clinicians.</p> <p>Methods</p> <p>We video-recorded dental visits with one standardized patient. Clinicians were subsequently interviewed and their cognitive strategies explored using guide questions; interviews were also recorded. Both visit and interview were content-analyzed, following the Gale and Marsden model for clinical decision-making. Limited tests used to contrast data were t, χ², and Fisher's. Scott's π was used to determine inter-coder reliability.</p> <p>Results</p> <p>Fifteen dentists and 17 senior dental students participated in visits lasting 32.0 minutes (± 12.9) among experts, and 29.9 ± 7.1 among students; contact time with patient was 26.4 ± 13.9 minutes (experts), and 22.2 ± 7.5 (students). The time elapsed between the first and the last instances of the clinician looking in the mouth was similar between experts and students. Ninety eight types of pieces of information were used in combinations with 12 DTPs. The main differences found in DTP utilization had dentists conducting diagnostic interpretations of findings with sufficient certainty to be considered definitive twice as often as students. Students resorted more often to more general or clarifying enquiry in their search for information than dentists.</p> <p>Conclusions</p> <p>Differences in diagnostic strategies and concepts existed within clearly delimited types of cognitive processes; such processes were largely compatible with the analytic and (in particular) non-analytic approaches to clinical decision-making identified in the medical field. Because we were focused on a clinical presentation primarily made up of non-emergency treatment needs, use of other DTPs and concepts might occur when clinicians evaluate emergency treatment needs, complex rehabilitative cases, and/or medically compromised patients.</p

Genetic Detection and Characterization of Lujo Virus, a New Hemorrhagic Fever–Associated Arenavirus from Southern Africa

Lujo virus (LUJV), a new member of the family Arenaviridae and the first hemorrhagic fever–associated arenavirus from the Old World discovered in three decades, was isolated in South Africa during an outbreak of human disease characterized by nosocomial transmission and an unprecedented high case fatality rate of 80% (4/5 cases). Unbiased pyrosequencing of RNA extracts from serum and tissues of outbreak victims enabled identification and detailed phylogenetic characterization within 72 hours of sample receipt. Full genome analyses of LUJV showed it to be unique and branching off the ancestral node of the Old World arenaviruses. The virus G1 glycoprotein sequence was highly diverse and almost equidistant from that of other Old World and New World arenaviruses, consistent with a potential distinctive receptor tropism. LUJV is a novel, genetically distinct, highly pathogenic arenavirus