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At least 1,243 records · Page 69Linked to original sources
PubMed1998

Utilisation and cost of professional care and assistance according to disability of patients with multiple sclerosis in Flanders (Belgium)

OBJECTIVES: To assess the utilisation of medical services and social (community) assistance in patients with multiple sclerosis of different disability and to calculate the direct healthcare costs to society. METHODS: (1) One hundred and eighty four patients with multiple sclerosis were classified into four grades of disability according to a simplified Kurzke disability status scale. (2) Patients were interviewed with a structured questionnaire containing questions on their sociodemographic status, the use of inpatient and outpatient medical services and pharmaceutical products during the previous year, the use of social assistance, and the purchase of prosthetics and charges for house adaptations during the previous five years. (3) Data were also prospectively collected by means of four week diary annotations of all medical and social acts and their duration. RESULTS: After correction for the disability distribution the yearly costs for the 5500 patients with multiple sclerosis in Flanders was estimated to be ECU 13106000 for ambulatory care including rehabilitation and district nursing and ECU 3234000 for pharmaceutical products. To these direct medical costs ECU 3491000 for social assistance and ECU 4938000 for prosthetics and adaptations should be added. The yearly costs for admissions to hospital including permanent residence in an institution and pharmacy was ECU 26581000 . Home nursing and long term or permanent residence in an institution of the most severely disabled, 17% of the multiple sclerosis population, are responsible for 50% of the total direct healthcare costs and care for the 6.5% institutionalised patients accounts for 23%. Direct costs for medical care and social assistance for patients with multiple sclerosis, who account for about 0.1 % of the total population, amounts to 1% of the total healthcare budget in Flanders. CONCLUSION: This information on utilisation of medical services and social assistance can be used for good healthcare planning and cost effectiveness studies.

Activities of Daily Living↗
PubMed2006

LegumeDB1 bioinformatics resource: comparative genomic analysis and novel cross-genera marker identification in lupin and pasture legume species.

The identification of markers in legume pasture crops, which can be associated with traits such as protein and lipid production, disease resistance, and reduced pod shattering, is generally accepted as an important strategy for improving the agronomic performance of these crops. It has been demonstrated that many quantitative trait loci (QTLs) identified in one species can be found in other plant species. Detailed legume comparative genomic analyses can characterize the genome organization between model legume species (e.g., Medicago truncatula, Lotus japonicus) and economically important crops such as soybean (Glycine max), pea (Pisum sativum), chickpea (Cicer arietinum), and lupin (Lupinus angustifolius), thereby identifying candidate gene markers that can be used to track QTLs in lupin and pasture legume breeding. LegumeDB is a Web-based bioinformatics resource for legume researchers. LegumeDB analysis of Medicago truncatula expressed sequence tags (ESTs) has identified novel simple sequence repeat (SSR) markers (16 tested), some of which have been putatively linked to symbiosome membrane proteins in root nodules and cell-wall proteins important in plant-pathogen defence mechanisms. These novel markers by preliminary PCR assays have been detected in Medicago truncatula and detected in at least one other legume species, Lotus japonicus, Glycine max, Cicer arietinum, and (or) Lupinus angustifolius (15/16 tested). Ongoing research has validated some of these markers to map them in a range of legume species that can then be used to compile composite genetic and physical maps. In this paper, we outline the features and capabilities of LegumeDB as an interactive application that provides legume genetic and physical comparative maps, and the efficient feature identification and annotation of the vast tracks of model legume sequences for convenient data integration and visualization. LegumeDB has been used to identify potential novel cross-genera polymorphic legume markers that map to agronomic traits, supporting the accelerated identification of molecular genetic factors underpinning important agronomic attributes in lupin.

Chromosome Mapping↗
PubMed2004

Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin.

The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT's cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT.

Antineoplastic Agents, Phytogenic↗
PubMed2006

A computational analysis of the three isoforms of glutamate dehydrogenase reveals structural features of the isoform EC 1.4.1.4 supporting a key role in ammonium assimilation by plants.

BACKGROUND: There are three isoforms of glutamate dehydrogenase. The isoform EC 1.4.1.4 (GDH4) catalyses glutamate synthesis from 2-oxoglutarate and ammonium, using NAD(P)H. Ammonium assimilation is critical for plant growth. Although GDH4 from animals and prokaryotes are well characterized, there are few data concerning plant GDH4, even from those whose genomes are well annotated. RESULTS: A large set of the three GDH isoforms was built resulting in 116 non-redundant full polypeptide sequences. A computational analysis was made to gain more information concerning the structure-function relationship of GDH4 from plants (Eukaryota, Viridiplantae). The tested plant GDH4 sequences were the two ones known to date, those of Chlorella sorokiniana. This analysis revealed several structural features specific of plant GDH4: (i) the lack of a structure called "antenna"; (ii) the NAD(P)-binding motif GAGNVA; and (iii) a second putative coenzyme-binding motif GVLTGKG together with four residues involved in the binding of the reduced form of NADP. CONCLUSION: A number of structural features specific of plant GDH4 have been found. The results reinforce the probable key role of GDH4 in ammonium assimilation by plants. REVIEWERS: This article was reviewed by Tina Bakolitsa (nominated by Eugene Koonin), Martin Jambon (nominated by Laura Landweber), Sandor Pangor and Franck Eisenhaber.

Journal Article↗
PubMed2002

"A system biology" approach to bioinformatics and functional genomics in complex human diseases: arthritis.

Human and other annotated genome sequences have facilitated generation of vast amounts of correlative data, from human/animal genetics, normal and disease-affected tissues from complex diseases such as arthritis using gene/protein chips and SNP analysis. These data sets include genes/proteins whose functions are partially known at the cellular level or may be completely unknown (e.g. ESTs). Thus, genomic research has transformed molecular biology from "data poor" to "data rich" science, allowing further division into subpopulations of subcellular fractions, which are often given an "-omic" suffix. These disciplines have to converge at a systemic level to examine the structure and dynamics of cellular and organismal function. The challenge of characterizing ESTs linked to complex diseases is like interpreting sharp images on a blurred background and therefore requires a multidimensional screen for functional genomics ("functionomics") in tissues, mice and zebra fish model, which intertwines various approaches and readouts to study development and homeostasis of a system. In summary, the post-genomic era of functionomics will facilitate to narrow the bridge between correlative data and causative data by quaint hypothesis-driven research using a system approach integrating "intercoms" of interacting and interdependent disciplines forming a unified whole as described in this review for Arthritis.

Animals↗
PubMed2003

Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer.

Numerous studies have demonstrated that overexpression of Met, the hepatocyte growth factor(HGF) receptor, plays an important role in tumorigenesis. Met activation can either occur through ligand-independent or -dependent mechanisms, both of which are mediated by a series of proteases and modulators. We studied the protein expression of several components of the HGF/Met pathway on a cohort of 330 node-negative breast carcinomas using a tissue microarray annotated with 30-year, disease-specific patient follow-up data. We examined HGF, matriptase (an activator of HGF expressed on mammary epithelial cell surfaces), HAI-I (the cognate inhibitor of matriptase), and the Met receptor itself. Our studies demonstrate tight correlation between the expression of HGF, matriptase, and Met in breast carcinoma. High-level expression of Met, matriptase, and HAI-I were associated with poor patient outcome. Met and HAI-I showed independent prognostic value when compared with traditional breast markers in a multivariate analysis. Intriguingly, antibodies against the intracellular but not the extracellular domain of Met were prognostic, suggesting that overexpression of the cytoplasmic-tail of Met, perhaps through cleavage or truncating mutation, may play an important role in breast cancer progression.

Breast Neoplasms↗
PubMed2005

Bioinformatics of the Paracoccidioides brasiliensis EST Project.

Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, an endemic mycosis of Latin America. This fungus presents a dimorphic character; it grows as a mycelium at room temperature, but it is isolated as yeast from infected individuals. It is believed that the transition from mycelium to yeast is important for the infective process. The Functional and Differential Genome of Paracoccidioides brasiliensis Project--PbGenome Project was developed to study the infection process by analyzing expressed sequence tags--ESTs, isolated from both mycelial and yeast forms. The PbGenome Project was executed by a consortium that included 70 researchers (professors and students) from two sequencing laboratories of the midwest region of Brazil; this project produced 25,741 ESTs, 19,718 of which with sufficient quality to be analyzed. We describe the computational procedures used to receive process, analyze these ESTs, and help with their functional annotations; we also detail the services that were used for sequence data exploration. Various programs were compared for filtering and grouping the sequences, and they were adapted to a user-friendly interface. This system made the analysis of the differential transcriptome of P. brasiliensis possible.

Brazil↗
PubMed2005

TRED: a Transcriptional Regulatory Element Database and a platform for in silico gene regulation studies.

In order to understand gene regulation, accurate and comprehensive knowledge of transcriptional regulatory elements is essential. Here, we report our efforts in building a mammalian Transcriptional Regulatory Element Database (TRED) with associated data analysis functions. It collects cis- and trans-regulatory elements and is dedicated to easy data access and analysis for both single-gene-based and genome-scale studies. Distinguishing features of TRED include: (i) relatively complete genome-wide promoter annotation for human, mouse and rat; (ii) availability of gene transcriptional regulation information including transcription factor binding sites and experimental evidence; (iii) data accuracy is ensured by hand curation; (iv) efficient user interface for easy and flexible data retrieval; and (v) implementation of on-the-fly sequence analysis tools. TRED can provide good training datasets for further genome-wide cis-regulatory element prediction and annotation, assist detailed functional studies and facilitate the decipher of gene regulatory networks (http://rulai.cshl.edu/TRED).

Animals↗
PubMed2004

Identification of "pathologs" (disease-related genes) from the RIKEN mouse cDNA dataset using human curation plus FACTS, a new biological information extraction system.

BACKGROUND: A major goal in the post-genomic era is to identify and characterise disease susceptibility genes and to apply this knowledge to disease prevention and treatment. Rodents and humans have remarkably similar genomes and share closely related biochemical, physiological and pathological pathways. In this work we utilised the latest information on the mouse transcriptome as revealed by the RIKEN FANTOM2 project to identify novel human disease-related candidate genes. We define a new term "patholog" to mean a homolog of a human disease-related gene encoding a product (transcript, anti-sense or protein) potentially relevant to disease. Rather than just focus on Mendelian inheritance, we applied the analysis to all potential pathologs regardless of their inheritance pattern. RESULTS: Bioinformatic analysis and human curation of 60,770 RIKEN full-length mouse cDNA clones produced 2,578 sequences that showed similarity (70-85% identity) to known human-disease genes. Using a newly developed biological information extraction and annotation tool (FACTS) in parallel with human expert analysis of 17,051 MEDLINE scientific abstracts we identified 182 novel potential pathologs. Of these, 36 were identified by computational tools only, 49 by human expert analysis only and 97 by both methods. These pathologs were related to neoplastic (53%), hereditary (24%), immunological (5%), cardio-vascular (4%), or other (14%), disorders. CONCLUSIONS: Large scale genome projects continue to produce a vast amount of data with potential application to the study of human disease. For this potential to be realised we need intelligent strategies for data categorisation and the ability to link sequence data with relevant literature. This paper demonstrates the power of combining human expert annotation with FACTS, a newly developed bioinformatics tool, to identify novel pathologs from within large-scale mouse transcript datasets.

Animals↗
PubMed2004

A novel method for visualizing nuclear hormone receptor networks relevant to drug metabolism.

The increasing generation of biological data represents a challenge to understanding the complexity of systems, resulting in scientists increasingly focused on a relatively narrow area of study, thereby limiting insight that can be gained from a broader perspective. In the field of drug metabolism and toxicology we are witnessing the characterization of many proteins. Most of the key enzymes and transporters are recognized as transcriptionally regulated by the nuclear hormone receptors such as pregnane X receptor, constitutive androstane receptor, vitamin D receptor, glucocorticoid receptor, and others. There is apparent cross talk in regulation, since multiple receptors may modulate expression of a single enzyme or transporter, representing one of many areas of active research interest. We have used published data on nuclear hormone receptors, enzymes, ligands, and other biological information to manually annotate an Oracle database, forming the basis of a platform for querying (MetaDrug). Using algorithms, we have demonstrated how nuclear hormone receptors alone can form a network of direct interactions, and when expanded, this network increases in complexity to describe the interactions with target genes as well as small molecules known to bind a receptor, enzyme, or transporter. We have also described how the database can be used for visualizing high-throughput microarray data derived from a published study of MCF-7 cells treated with 4-hydroxytamoxifen, to highlight potential downstream effects of molecule treatment. The database represents a novel knowledge mining and analytical tool that, to be relevant, requires continual updating to evolve alongside other key storage systems and sources of biological knowledge.

Databases, Factual↗
PubMed2005

A scan for positively selected genes in the genomes of humans and chimpanzees.

Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.

Animals↗
PubMed2004

ProSight PTM: an integrated environment for protein identification and characterization by top-down mass spectrometry.

ProSight PTM (https://prosightptm.scs.uiuc.edu/) is a web application for identification and characterization of proteins using mass spectra data from 'top-down' fragmentation of intact protein ions (i.e. without any tryptic digestion). ProSight PTM has many tools and graphical features to facilitate analysis of single proteins, proteins in mixtures and proteins fragmented in parallel. Sequence databases from across the phylogenetic tree are supported, with a new database strategy of 'shotgun annotation' used to assist characterization of wild-type proteins. During a database search, data from divergent sources regarding potential mass differences such as polymorphisms, alternate splicing and post-translational modifications are utilized. The user can optionally control how much of this biological variability should be searched.

Alternative Splicing↗
PubMed2003

Reconciling gene expression data with known genome-scale regulatory network structures.

The availability of genome-scale gene expression data sets has initiated the development of methods that use this data to infer transcriptional regulatory networks. Alternatively, such regulatory network structures can be reconstructed based on annotated genome information, well-curated databases, and primary research literature. As a first step toward reconciling the two approaches, we examine the consistency between known genome-wide regulatory network structures and extensive gene expression data collections in Escherichia coli and Saccharomyces cerevisiae. By decomposing the regulatory network into a set of basic network elements, we can compute the local consistency of each instance of a particular type of network element. We find that the consistency of network elements is influenced by both structural features of the network such as the number of regulators acting on a target gene and by the functional classes of the genes involved in a particular element. Taken together, the approach presented allows us to define regulatory network subcomponents with a high degree of consistency between the network structure and gene expression data. The results suggest that targeted gene expression profiling data can be used to refine and expand particular subcomponents of known regulatory networks that are sufficiently decoupled from the rest of the network.

Computational Biology↗
PubMed2003

Automated DNA chip annotation tables at IFOM: the importance of synchronisation and cross-referencing of sequence databases.

The increasing popularity of DNA chip technology for the study of gene expression is producing, for each experiment, a sizable quantity of numerical data to analyse and an accompanying large number of gene identifiers that should be associated with the relevant biological annotation. We describe here a website at IFOM (FIRC Institute of Molecular Oncology) where we release regularly updated annotation tables for the most used Affymetrix oligonucleotide DNA chips and for the whole Research Genetics 46K clone collection for cDNA arrays. These tables are synchronised with every new release of the mouse and human UniGene databases (NCBI; National Center for Biotechnology Information), allowing fast and easy preliminary annotation of DNA array experiments. We also report some comparative evidence about the importance of biological database synchronisation and cross-references in the process of generating annotation tables for DNA chips.

Abstracting and Indexing↗
PubMed2005

Computational and comparative analyses of 150 full-length cDNA sequences from the oomycete plant pathogen Phytophthora infestans.

Phytophthora infestans is a devastating phytopathogenic oomycete that causes late blight on tomato and potato. Recent genome sequencing efforts of P. infestans and other Phytophthora species are generating vast amounts of sequence data providing opportunities to unlock the complex nature of pathogenesis. However, accurate annotation of Phytophthora genomes will be a significant challenge. Most of the information about gene structure in these species was gathered from a handful of genes resulting in significant limitations for development of ab initio gene-calling programs. In this study, we collected a total of 150 bioinformatically determined near full-length cDNA (FLcDNA) sequences of P. infestans that were predicted to contain full open reading frame sequences. We performed detailed computational analyses of these FLcDNA sequences to obtain a snapshot of P. infestans gene structure, gauge the degree of sequence conservation between P. infestans genes and those of Phytophthora sojae and Phytophthora ramorum, and identify patterns of gene conservation between P. infestans and various eukaryotes, particularly fungi, for which genome-wide translated protein sequences are available. These analyses helped us to define the structural characteristics of P. infestans genes using a validated data set. We also determined the degree of sequence conservation within the genus Phytophthora and identified a set of fast evolving genes. Finally, we identified a set of genes that are shared between Phytophthora and fungal phytopathogens but absent in animal fungal pathogens. These results confirm that plant pathogenic oomycetes and fungi share virulence components, and suggest that eukaryotic microbial pathogens that share similar lifestyles also share a similar set of genes independently of their phylogenetic relatedness.

Base Composition↗
PubMed2005

Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data.

Genome-wide expression profiling is a powerful tool for implicating novel gene ensembles in cellular mechanisms of health and disease. The most popular platform for genome-wide expression profiling is the Affymetrix GeneChip. However, its selection of probes relied on earlier genome and transcriptome annotation which is significantly different from current knowledge. The resultant informatics problems have a profound impact on analysis and interpretation the data. Here, we address these critical issues and offer a solution. We identified several classes of problems at the individual probe level in the existing annotation, under the assumption that current genome and transcriptome databases are more accurate than those used for GeneChip design. We then reorganized probes on more than a dozen popular GeneChips into gene-, transcript- and exon-specific probe sets in light of up-to-date genome, cDNA/EST clustering and single nucleotide polymorphism information. Comparing analysis results between the original and the redefined probe sets reveals approximately 30-50% discrepancy in the genes previously identified as differentially expressed, regardless of analysis method. Our results demonstrate that the original Affymetrix probe set definitions are inaccurate, and many conclusions derived from past GeneChip analyses may be significantly flawed. It will be beneficial to re-analyze existing GeneChip data with updated probe set definitions.

Alleles↗
PubMed1997

Recruitment for controlled clinical trials: literature summary and annotated bibliography.

This article is a literature summary and annotated bibliography of research on recruitment for controlled clinical trials published through 1995. It extends and revises a similar review published in this journal a decade ago. The current commentary focuses on intervening developments in recruitment, including diverse populations, HIV trials, primary prevention trials, recruitment strategies, overall planning and management, patient and physician attitudes, adherence, generalizability, and cost. Profound barriers may exist in the recruitment of diverse populations, involving language, cultural factors, beliefs about medical research, and the appropriateness of available protocols. Extensive literature exists on patient and physician barriers to participation. Trials in HIV-infected or AIDs-diagnosed individuals introduce special considerations, including issues of confidentiality, parallel track design, and populations difficult to define and track. Recruitment strategies such as patient registries, occupational screening, direct mail, and the media are now prominent in the literature. Successful planning and management of an overall recruitment plan include piloting strategies, monitoring recruitment by data tracking systems, and hiring quality staff. Generalizability of study results is influenced by the characteristics of participants and by their adherence to study protocol. With increasingly limited funding to conduct clinical trials, efforts to quantify and reduce recruitment costs are being made. While over 4000 titles were identified, primarily by MEDLINE literature search, the articles summarized emphasize data-supported and -confirmed conclusions, and broad coverage of disease areas. We annotate here 91 outstanding articles useful for formulation of overall recruitment approaches in clinical trials.

Clinical Trials as Topic↗
PubMed2001

Functional and structural genomics using PEDANT.

MOTIVATION: Enormous demand for fast and accurate analysis of biological sequences is fuelled by the pace of genome analysis efforts. There is also an acute need in reliable up-to-date genomic databases integrating both functional and structural information. Here we describe the current status of the PEDANT software system for high-throughput analysis of large biological sequence sets and the genome analysis server associated with it. RESULTS: The principal features of PEDANT are: (i) completely automatic processing of data using a wide range of bioinformatics methods, (ii) manual refinement of annotation, (iii) automatic and manual assignment of gene products to a number of functional and structural categories, (iv) extensive hyperlinked protein reports, and (v) advanced DNA and protein viewers. The system is easily extensible and allows to include custom methods, databases, and categories with minimal or no programming effort. PEDANT is actively used as a collaborative environment to support several on-going genome sequencing projects. The main purpose of the PEDANT genome database is to quickly disseminate well-organized information on completely sequenced and unfinished genomes. It currently includes 80 genomic sequences and in many cases serves as the only source of exhaustive information on a given genome. The database also acts as a vehicle for a number of research projects in bioinformatics. Using SQL queries, it is possible to correlate a large variety of pre-computed properties of gene products encoded in complete genomes with each other and compare them with data sets of special scientific interest. In particular, the availability of structural predictions for over 300 000 genomic proteins makes PEDANT the most extensive structural genomics resource available on the web.

Arabidopsis↗