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1.
J Alzheimers Dis ; 74(4): 1285-1294, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176645

RESUMO

BACKGROUND: Collection of cerebrospinal fluid (CSF) for measurement of amyloid-ß (Aß) species is a gold standard in Alzheimer's disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood Aß test with high AD sensitivity and specificity is of outmost interest. OBJECTIVE: We evaluated the ability of a commercially available plasma Aß assay to distinguish AD patients from biomarker-healthy controls. METHOD: In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A-N-) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain imaging. Total Aß40 and total Aß42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated. RESULTS: Plasma Aß42/40 was weakly positively correlated with CSF Aß42/40 (Spearman's rho 0.22; p = 0.037). Plasma Aß42/40 alone was not able to statistically significantly distinguish between AD patients and controls (AUC 0.58; 95% CI 0.46, 0.70). At a cut-point of 0.076 maximizing sensitivity and specificity, plasma Aß42/40 had a sensitivity of 61.2% and a specificity of 63.6%. CONCLUSION: In this sample, the high-throughput blood Aß assay was not able to distinguish well between AD patients and controls. Whether or not the assay may be useful in large-scale epidemiological settings remains to be seen.

2.
Liver Transpl ; 26(5): 628-639, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32159923

RESUMO

In contrast to donor factors predicting outcomes of liver transplantation (LT), few suitable recipient parameters have been identified. To this end, we performed an in-depth analysis of hospitalization status and duration prior to LT as a potential risk factor for posttransplant outcome. The pretransplant hospitalization status of all patients undergoing LT between 2005 and 2016 at the Charité-Universitätsmedizin Berlin was analyzed retrospectively using propensity score matching. At the time of organ acceptance, 226 of 1134 (19.9%) recipients were hospitalized in an intensive care unit (ICU), 146 (12.9%) in a regular ward (RW) and 762 patients (67.2%) were at home. Hospitalized patients (RW and ICU) compared with patients from home showed a dramatically shorter 3-month survival (78.7% versus 94.4%), 1-year survival (66.3% versus 87.3%), and 3-year survival (61.7% versus 81.7%; all P < 0.001), whereas no significant difference was detected for 3-year survival between ICU and RW patients (61.5% versus 62.3%; P = 0.60). These results remained significant after propensity score matching. Furthermore, in ICU patients, but not in RW patients, survival correlated with days spent in the ICU before LT (1-year survival: 1-6 versus 7-14 days: 73.7% versus 60.5%, P = 0.04; 7-14 days versus >14 days, 60.5% versus 51.0%, P = 0.006). In conclusion, hospitalization status before transplantation is a valuable predictor of patient survival following LT.

3.
BMC Res Notes ; 13(1): 55, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019577

RESUMO

OBJECTIVE: Studies of postoperative cognitive dysfunction (POCD) rely on repeat neuropsychological testing. The stability of the applied instruments, which are affected by natural variability in performance and measurement imprecision, is often unclear. We determined the stability of a neuropsychological test battery using a sample of older adults from the general population. Forty-five participants aged 65 to 89 years performed six computerized and non-computerized neuropsychological tests at baseline and again at 7 day and 3 months follow-up sessions. Mean scores on each test were compared across time points using repeated measures analyses of variance (ANOVA) with pairwise comparison. Two-way mixed effects, absolute agreement analyses of variance intra-class correlation coefficients (ICC) determined test-retest reliability. RESULTS: All tests had moderate to excellent test-retest reliability during 7-day (ICC range 0.63 to 0.94; all p < 0.01) and 3-month intervals (ICC range 0.60 to 0.92; all p < 0.01) though confidence intervals of ICC estimates were large throughout. Practice effects apparent at 7 days eased off by 3 months. No substantial differences between computerized and non-computerized tests were observed. We conclude that the present six-test neuropsychological test battery is appropriate for use in POCD research though small sample size of our study needs to be recognized as a limitation. Trial registration ClinicalTrials.gov Identifier NCT02265263 (15th October 2014).

4.
BMC Bioinformatics ; 21(1): 36, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000657

RESUMO

BACKGROUND: In methylation analyses like epigenome-wide association studies, a high amount of biomarkers is tested for an association between the measured continuous outcome and different covariates. In the case of a continuous covariate like smoking pack years (SPY), a measure of lifetime exposure to tobacco toxins, a spike at zero can occur. Hence, all non-smokers are generating a peak at zero, while the smoking patients are distributed over the other SPY values. Additionally, the spike might also occur on the right side of the covariate distribution, if a category "heavy smoker" is designed. Here, we will focus on methylation data with a spike at the left or the right of the distribution of a continuous covariate. After the methylation data is generated, analysis is usually performed by preprocessing, quality control, and determination of differentially methylated sites, often performed in pipeline fashion. Hence, the data is processed in a string of methods, which are available in one software package. The pipelines can distinguish between categorical covariates, i.e. for group comparisons or continuous covariates, i.e. for linear regression. The differential methylation analysis is often done internally by a linear regression without checking its inherent assumptions. A spike in the continuous covariate is ignored and can cause biased results. RESULTS: We have reanalysed five data sets, four freely available from ArrayExpress, including methylation data and smoking habits reported by smoking pack years. Therefore, we generated an algorithm to check for the occurrences of suspicious interactions between the values associated with the spike position and the non-spike positions of the covariate. Our algorithm helps to decide if a suspicious interaction can be found and further investigations should be carried out. This is mostly important, because the information on the differentially methylated sites will be used for post-hoc analyses like pathway analyses. CONCLUSIONS: We help to check for the validation of the linear regression assumptions in a methylation analysis pipeline. These assumptions should also be considered for machine learning approaches. In addition, we are able to detect outliers in the continuous covariate. Therefore, more statistical robust results should be produced in methylation analysis using our algorithm as a preprocessing step.


Assuntos
Metilação de DNA , Fumar/genética , Adulto , Algoritmos , Análise de Variância , Humanos , Modelos Lineares , Aprendizado de Máquina , Pessoa de Meia-Idade , Fumar/metabolismo
5.
Allergy ; 75(2): 346-356, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31386204

RESUMO

BACKGROUND: miRNAs are master regulators of signaling pathways critically involved in asthma and are transferred between cells in extracellular vesicles (EV). We aimed to investigate whether the miRNA content of EV secreted by primary normal human bronchial epithelial cells (NHBE) is altered upon asthma development. METHODS: NHBE cells were cultured at air-liquid interface and treated with interleukin (IL)-13 to induce an asthma-like phenotype. EV isolations by precipitation from basal culture medium or apical surface wash were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blot, and EV-associated miRNAs were identified by a RT-qPCR-based profiling. Significant candidates were confirmed in EVs isolated by size-exclusion chromatography from nasal lavages of children with mild-to-moderate (n = 8) or severe asthma (n = 9), and healthy controls (n = 9). RESULTS: NHBE cells secrete EVs to the apical and basal side. 47 miRNAs were expressed in EVs and 16 thereof were significantly altered in basal EV upon IL-13 treatment. Expression of miRNAs could be confirmed in EVs from human nasal lavages. Of note, levels of miR-92b, miR-210, and miR-34a significantly correlated with lung function parameters in children (FEV1 FVC%pred and FEF25-75%pred ), thus lower sEV-miRNA levels in nasal lavages associated with airway obstruction. Subsequent ingenuity pathway analysis predicted the miRNAs to regulate Th2 polarization and dendritic cell maturation. CONCLUSION: Our data indicate that secretion of miRNAs in EVs from the airway epithelium, in particular miR-34a, miR-92b, and miR-210, might be involved in the early development of a Th2 response in the airways and asthma.

6.
BMJ Open ; 9(10): e032695, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666276

RESUMO

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS: The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. ETHICS AND DISSEMINATION: The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité - Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03510650.

7.
BMC Anesthesiol ; 19(1): 146, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395011

RESUMO

BACKGROUND: Emergence-delirium is the most frequent brain dysfunction in children recovering from general anaesthesia, though the pathophysiological background remains unclear. The presented study analysed an association between emergence delirium and intraoperative Burst Suppression activity in the electroencephalogram, a period of very deep hypnosis during general anaesthesia. METHODS: In this prospective, observational cohort study at the Charité - university hospital in Berlin / Germany children aged 0.5 to 8 years, undergoing planned surgery, were included between September 2015 and February 2017. Intraoperative bi-frontal electroencephalograms were recorded. Occurrence and duration of Burst Suppression periods were visually analysed. Emergence delirium was assessed using the Pediatric Assessment of Emergence Delirium Score. RESULTS: From 97 children being analysed within this study, 40 children developed emergence delirium, and 57 children did not. Overall 52% of the children displayed intraoperative Burst Suppression periods; however, occurrence and duration of Burst Suppression (Emergence delirium group 55% / 261 + 462 s vs. Non-emergence delirium group 49% / 318 + 531 s) did not differ significantly between both groups. CONCLUSIONS: Our data reveal no correlation between the occurrence and duration of intraoperative Burst Suppression activity and the incidence of emergence delirium. Burst Suppression occurrence is frequent; however, it does not seem to have an unfavourable impact on cerebral function at emergence from general anaesthesia in children. TRAIL REGISTRATION: NCT02481999, June 25, 2015.

8.
Eur J Anaesthesiol ; 36(9): 683-687, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306183

RESUMO

BACKGROUND: Recent guidelines on postoperative delirium (POD) recommend POD screening in all patients, using a validated tool, starting in the recovery room. An operationalisation of the Confusion Assessment Method (CAM) criteria, the 3-Minute Diagnostic Interview for CAM-defined Delirium (3D-CAM), has been developed for use in general medical units. OBJECTIVES: The aim of this study was to evaluate 3D-CAM performance in an adult patient population to detect POD in the recovery room. DESIGN: A prospective diagnostic study. SETTING: Recovery room of a tertiary care university hospital in Berlin, Germany, in 2017. PATIENTS: Patients at least 18 years of age undergoing elective surgery. MAIN OUTCOME MEASURES: Patients were subjected to evaluation by blinded investigators using the 3D-CAM and the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5, reference standard). Sensitivity, specificity and positive predictive value (PPV) and negative predictive value (NPV) were analysed for 3D-CAM, in addition to test-retest and inter-rater reliability analyses. RESULTS: Sixteen out of 176 patients (9.1%) developed POD. The 3D-CAM demonstrated strong test performance (specificity 0.88, sensitivity 1.0, area under the curve 0.94, PPV 0.44 and NPV 1.0), with a test-retest reliability of 90% (n = 10) and inter-rater reliability of 80% (n = 10). CONCLUSION: In this diagnostic study, 3D-CAM showed strong performance for detection of POD in the recovery room. Due to the low training requirements, fast application and high sensitivity, it might be particularly appropriate for clinical staff with limited experience in the assessment of POD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02992717.

9.
Clin Epigenetics ; 11(1): 105, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331382

RESUMO

BACKGROUND: The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. RESULTS: Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1; best p = 5.5 × 10-8) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p = 5.9 × 10-9). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p = 4.0 × 10-10. RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p = 2.2 × 10-14), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. CONCLUSION: This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.

10.
Emerg Microbes Infect ; 7(1): 201, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30514855

RESUMO

Cetacean morbillivirus (CeMV) has emerged as the pathogen that poses the greatest risk of triggering epizootics in cetacean populations worldwide, and has a high propensity for interspecies transmission, including sporadic infection of seals. In this study, we investigated the evolutionary history of CeMV by deep sequencing wild-type viruses from tissue samples representing cetacean species with different spatiotemporal origins. Bayesian phylogeographic analysis generated an estimated evolutionary rate of 2.34 × 10-4 nucleotide substitutions/site/year and showed that CeMV evolutionary dynamics are neither host-restricted nor location-restricted. Moreover, the dolphin morbillivirus strain of CeMV has undergone purifying selection without evidence of species-specific mutations. Cell-to-cell fusion and growth kinetics assays demonstrated that CeMV can use both dolphin and seal CD150 as a cellular receptor. Thus, it appears that CeMV can readily spread among multiple cetacean populations and may pose an additional spillover risk to seals.


Assuntos
Cetáceos/virologia , Evolução Molecular , Genoma Viral , Infecções por Morbillivirus/veterinária , Morbillivirus/genética , Animais , Teorema de Bayes , Golfinhos/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Mar Mediterrâneo , Infecções por Morbillivirus/transmissão , Mar do Norte , Filogeografia , Receptores Virais/metabolismo , Focas Verdadeiras/virologia , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
11.
Infect Genet Evol ; 66: 180-187, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30292006

RESUMO

Discovery of novel viruses in host samples is a multidisciplinary process which relies increasingly on next-generation sequencing (NGS) followed by computational analysis. A crucial step in this analysis is to separate host sequence reads from the sequence reads of the virus to be discovered. This becomes especially difficult if no reference genome of the host is available. Furthermore, if the total number of viral reads in a sample is low, de novo assembly of a virus which is a requirement for most existing pipelines is hard to realize. We present a new modular, computational pipeline for discovery of novel viruses in host samples. While existing pipelines rely on the availability of the hosts reference genome for filtering sequence reads, our new pipeline can also cope with cases for which no reference genome is available. As a further novelty of our method a decoy module is used to assess false classification rates in the discovery process. Additionally, viruses with a low read coverage can be identified and visually reviewed. We validate our pipeline on simulated data as well as two experimental samples with known virus content. For the experimental samples, we were able to reproduce the laboratory findings. Our newly developed pipeline is applicable for virus detection in a wide range of host species. The three modules we present can either be incorporated individually in other pipelines or be used as a stand-alone pipeline. We are the first to present a decoy approach within a virus detection pipeline that can be used to assess error rates so that the quality of the final result can be judged. We provide an implementation of our modules via Github. However, the principle of the modules can easily be re-implemented by other researchers.


Assuntos
Genoma Viral , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Viroses/diagnóstico , Viroses/virologia , Vírus/genética , Algoritmos , Sequência de Aminoácidos , Animais , Sequência de Bases , Biologia Computacional/métodos , Bases de Dados de Produtos Farmacêuticos , Genômica/métodos , Humanos , Metagenômica/métodos , Vírus/classificação
12.
Emerg Infect Dis ; 24(9): 1691-1695, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30124416

RESUMO

We isolated Batai virus from the brain of a euthanized, 26-year-old, captive harbor seal with meningoencephalomyelitis in Germany. We provide evidence that this orthobunyavirus can naturally infect the central nervous system of a mammal. The full-genome sequence showed differences from a previously reported virus isolate from a mosquito in Germany.


Assuntos
Infecções por Bunyaviridae/veterinária , Encefalite/veterinária , Orthobunyavirus/isolamento & purificação , Phoca , Animais , Animais de Zoológico , Infecções por Bunyaviridae/complicações , Infecções por Bunyaviridae/diagnóstico , Culicidae , Diagnóstico Diferencial , Encefalite/complicações , Encefalite/diagnóstico , Alemanha , Insetos Vetores , Masculino , Mar do Norte , Orthobunyavirus/genética , Filogenia
13.
J Clin Transl Endocrinol ; 13: 26-38, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30003044

RESUMO

Background: Crohn's disease (CD) is associated with a higher prevalence of osteoporosis, a complication that is recognized as a significant cause of morbidity. Its pathogenesis is controversial, but the activity of CD is one contributing factor. Methods: We stimulated SCP-1 cells (mesenchymal stem cell line) under osteogenic conditions with serum from adult patients with CD in the symptomatic phase (SP) and in remission (R) and with control sera. Concentrations of IL-6, IL-1 beta, and TNF alpha in the sera were measured. Patients were classified as normal or osteopenic/osteoporotic based on bone mineral density (BMD) T-score measurements. After 14 days in culture, protein expression and gene ontology (GO) annotation analysis was performed. Results: Cytokine concentrations (IL-6, IL-1 beta, TNF alpha) varied within sera groups. None of the cytokines were significantly increased in the symptomatic phase compared to remission. Protein analysis revealed 17 proteins regulated by the SP versus R phase sera of disease. A linear relationship between CDAI (Crohn's disease activity index) and normalized protein expression of APOA1 and 2, TTR, CDKAL1 and TUBB6 could be determined. Eleven proteins were found to be differentially regulated comparing osteoporosis-positive and osteoporosis-negative sera. Gene annotation and further analysis identified these genes as part of heme and erythrocyte metabolism, as well as involved in hypoxia and in endocytosis. A significant linear relationship between bone mineral density and normalized protein expression could be determined for proteins FABP3 and TTR. Conclusion: Our explorative results confirm our hypothesis that factors in serum from patients with CD change the protein expression pattern of human immortalized osteoblast like cells. We suggest, that these short time changes indeed influence factors of bone metabolism.

14.
Sci Rep ; 8(1): 7524, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29760429

RESUMO

Canine circoviruses (CanineCV's), belonging to the genus Circovirus of the Circoviridae family, were detected by next generation sequencing in samples from Thai dogs with respiratory symptoms. Genetic characterization and phylogenetic analysis of nearly complete CanineCV genomes suggested that natural recombination had occurred among different lineages of CanineCV's. Similarity plot and bootscaning analyses indicated that American and Chinese viruses had served as major and minor parental viruses, respectively. Positions of recombination breakpoints were estimated using maximum-likelihood frameworks with statistical significant testing. The putative recombination event was located in the Replicase gene, intersecting with open reading frame-3. Analysis of nucleotide changes confirmed the origin of the recombination event. This is the first description of naturally occurring recombinant CanineCV's that have resulted in the circulation of newly emerging CanineCV lineages.


Assuntos
Infecções por Circoviridae/veterinária , Circovirus/classificação , Doenças do Cão/virologia , Sequenciamento de Nucleotídeos em Larga Escala/veterinária , Doenças Respiratórias/veterinária , Animais , Infecções por Circoviridae/virologia , Circovirus/genética , Circovirus/isolamento & purificação , Cães , Evolução Molecular , Tamanho do Genoma , Genoma Viral , Filogenia , Recombinação Genética , Doenças Respiratórias/virologia , Análise de Sequência de DNA/veterinária , Tailândia
15.
Genetics ; 209(1): 321-333, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29545467

RESUMO

Important traits in agricultural, natural, and human populations are increasingly being shown to be under the control of many genes that individually contribute only a small proportion of genetic variation. However, the majority of modern tools in quantitative and population genetics, including genome-wide association studies and selection-mapping protocols, are designed to identify individual genes with large effects. We have developed an approach to identify traits that have been under selection and are controlled by large numbers of loci. In contrast to existing methods, our technique uses additive-effects estimates from all available markers, and relates these estimates to allele-frequency change over time. Using this information, we generate a composite statistic, denoted [Formula: see text] which can be used to test for significant evidence of selection on a trait. Our test requires pre- and postselection genotypic data but only a single time point with phenotypic information. Simulations demonstrate that [Formula: see text] is powerful for identifying selection, particularly in situations where the trait being tested is controlled by many genes, which is precisely the scenario where classical approaches for selection mapping are least powerful. We apply this test to breeding populations of maize and chickens, where we demonstrate the successful identification of selection on traits that are documented to have been under selection.


Assuntos
Modelos Genéticos , Característica Quantitativa Herdável , Seleção Genética , Algoritmos , Animais , Galinhas/genética , Mapeamento Cromossômico , Simulação por Computador , Genótipo , Fenótipo , Locos de Características Quantitativas , Zea mays/genética
16.
Vet Pathol ; 55(3): 434-441, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29421972

RESUMO

Bocaviruses are small nonenveloped DNA viruses belonging to the Bocaparvovirus genus of the Parvoviridae family and have been linked to both respiratory and enteric disease in humans and animals. To date, 3 bocaviruses, canine bocaviruses 1 to 3 (CBoV-1-3), have been shown to affect dogs with different disease manifestations reported for infected animals. We used next-generation sequencing to identify a novel strain of canine CBoV-2 (CBoV TH-2016) in a litter of puppies that died in Thailand from acute dyspnea and hemoptysis, for which no causal pathogen could be identified in routine assays. Analysis of the complete coding sequences of CBoV TH-2016 showed that this virus was most closely related to a strain previously identified in South Korea (isolate 14D193), with evidence of genetic recombination in the VP2 gene with related strains from South Korea and Hong Kong. Use of quantitative polymerase chain reaction showed the presence of CBoV TH-2016 in several tissues, suggesting hematogenous virus spread, while only intestinal tissue was found to be positive by in situ hybridization and electron microscopy. Histologic small intestinal lesions associated with CBoV TH-2016 infection were eosinophilic intranuclear inclusion bodies within villous enterocytes without villous atrophy or fusion, similar to those previously considered pathognomonic for CBoV-1 infection. Therefore, this study provides novel insights in the pathogenicity of canine bocavirus infections and suggests that a novel recombinant CBoV-2 may result in atypical findings of CBoV infection. Although the specific cause of death of these puppies remained undetermined, a contributory role of enteric CBoV TH-2016 infection is possible.


Assuntos
Bocavirus/classificação , Doenças do Cão/patologia , Infecções por Parvoviridae/veterinária , Animais , Doenças do Cão/virologia , Cães , Infecções por Parvoviridae/patologia , Infecções por Parvoviridae/virologia , Reação em Cadeia da Polimerase
17.
Comput Biol Med ; 92: 1-8, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29132014

RESUMO

Correlated binary data arise in a large variety of biomedical research. In order to evaluate methods for their analysis, computer simulations of such data are often required. Existing methods can often not cover the full range of possible correlations between the variables or are not available as implemented software. We propose a genetic algorithm that approaches the desired correlation structure under a given marginal distribution. The procedure generates a large representative matrix from which the probabilities of individual observations can be derived or from which samples can be drawn directly. Our genetic algorithm is evaluated under different specified marginal frequencies and correlation structures, and is compared against two existing approaches. The evaluation checks the speed and precision of the approach as well as its suitability for generating also high-dimensional data. In an example of high-throughput glycan array data, we demonstrate the usability of our approach to simulate the power of global test procedures. An implementation of our own and two other methods were added to the R-package 'RepeatedHighDim'. The presented algorithm is not restricted to certain correlation structures. In contrast to existing methods it is also evaluated for high-dimensional data.


Assuntos
Algoritmos , Pesquisa Biomédica/métodos , Biologia Computacional/métodos , Modelos Genéticos , Simulação por Computador , Humanos , Informática Médica
18.
Bioinformatics ; 33(19): 3115-3116, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28633391

RESUMO

Summary: Bioinformatics methods often incorporate the frequency distribution of nulecobases or k-mers in DNA or RNA sequences, for example as part of metagenomic or phylogenetic analysis. Because the frequency matrix with sequences in the rows and nucleobases in the columns is multi-dimensional it is hard to visualize. We present the R-package 'kmerPyramid' that allows to display each sequence, based on its nucleobase or k-mer distribution projected to the space of principal components, as a point within a 3-dimensional, interactive pyramid. Using the computer mouse, the user can turn the pyramid's axes, zoom in and out and identify individual points. Additionally, the package provides the k-mer frequency matrices of about 2000 bacteria and 5000 virus reference sequences calculated from the NCBI RefSeq genbank. The 'kmerPyramid' can particularly be used for visualization of intra- and inter species differences. Availability and implementation: The R-package 'kmerPyramid' is available from the GitHub website at https://github.com/jkruppa/kmerPyramid. Contact: klaus.jung@tiho-hannover.de. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Software , Bactérias/genética , Gráficos por Computador , Análise de Componente Principal , Vírus/genética
19.
BMC Bioinformatics ; 18(1): 232, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28464790

RESUMO

BACKGROUND: Analyses of molecular high-throughput data often lack in robustness, i.e. results are very sensitive to the addition or removal of a single observation. Therefore, the identification of extreme observations is an important step of quality control before doing further data analysis. Standard outlier detection methods for univariate data are however not applicable, since the considered data are high-dimensional, i.e. multiple hundreds or thousands of features are observed in small samples. Usually, outliers in high-dimensional data are solely detected by visual inspection of a graphical representation of the data by the analyst. Typical graphical representation for high-dimensional data are hierarchical cluster tree or principal component plots. Pure visual approaches depend, however, on the individual judgement of the analyst and are hard to automate. Existing methods for automated outlier detection are only dedicated to data of a single experimental groups. RESULTS: In this work we propose to use bagplots, the 2-dimensional extension of the boxplot, to automatically identify outliers in the subspace of the first two principal components of the data. Furthermore, we present for the first time the gemplot, the 3-dimensional extension of boxplot and bagplot, which can be used in the subspace of the first three principal components. Bagplot and gemplot surround the regular observations with convex hulls and observations outside these hulls are regarded as outliers. The convex hulls are determined separately for the observations of each experimental group while the observations of all groups can be displayed in the same subspace of principal components. We demonstrate the usefulness of this approach on multiple sets of artificial data as well as one set of gene expression data from a next-generation sequencing experiment, and compare the new method to other common approaches. Furthermore, we provide an implementation of the gemplot in the package 'gemPlot' for the R programming environment. CONCLUSIONS: Bagplots and gemplots in subspaces of principal components are useful for automated and objective outlier identification in high-dimensional data from molecular high-throughput experiments. A clear advantage over other methods is that multiple experimental groups can be displayed in the same figure although outlier detection is performed for each individual group.


Assuntos
Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Componente Principal/métodos , Análise por Conglomerados , Bases de Dados Genéticas , Humanos
20.
J Clin Invest ; 127(5): 1798-1812, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28394258

RESUMO

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Cardiopatias , Miocárdio , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Feminino , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Humanos , Masculino
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