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PubMed2004

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. Children with untreated nephrotic syndrome frequently die from infections. The majority of children with nephrotic syndrome respond to corticosteroids. However about 70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Corticosteroid usage has reduced the mortality rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death. However corticosteroids have known adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression. The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. The optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful have not been clarified. OBJECTIVES: The aim of this review was to determine the benefits and harms of different corticosteroid regimens in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2002), Cochrane Renal Group Specialised Register (July 2002), MEDLINE (1966 - July 2002) and EMBASE (1980 - July 2002) without language restriction, reference lists of articles, abstracts from conference proceedings and contact with known investigators in the area. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children (aged three months to 18 years) in their initial or subsequent episode of SSNS, if they compared different durations, total doses or other dose strategies using prednisone or other corticosteroid agent and if they had outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12-24 months. Secondary outcomes sought included the number of children who developed frequently relapsing nephrotic syndrome and adverse events. A random effects model was used to estimate summary effect measures (relative risk (RR), risk difference (RD)) after testing for heterogeneity. Meta-regression was used to explore potential between-study differences due to the baseline risk of relapse, study quality and types of interventions used. MAIN RESULTS: Nineteen trials have been included in this review. A meta-analysis of six trials, which compared two months of prednisone with three months or more in the first episode, showed that the longer duration significantly reduced the risk of relapse at 12 - 24 months (RR 0.70; 95% CI 0.58 to 0.84) without an increase in adverse events. There was an inverse linear relationship between the duration of treatment and risk of relapse (RR = 1.26 - 0.112 duration; r(2) = 0.56; p = 0.03). The number of children who became frequent relapsers and the mean relapse rate/patient/year were also significantly reduced without increase in serious adverse events. In children with frequently relapsing nephrotic syndrome, deflazacort was significantly more effective in maintaining remission than prednisone (RR 0.44; 95% CI 0.25 to 0.78). REVIEWERS' CONCLUSIONS: Children in their first episode of SSNS should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment. In a population with a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 33%. In children who relapse frequently, deflazacort deserves further study.

Adolescent↗
PubMed2005

Is autism caused by early hyperactivity of brain-derived neurotrophic factor?

Autism, a childhood-onset neurodevelopmental disorder, is characterized by disturbances in socialization and language skills, as well as in perception. Several studies indicate the importance of both genetic and environmental factors in the development of idiopathic autism, but the underlying pathogenesis of this disorder is still unknown. Brain-derived neurotrophic factor (BDNF) is important for normal neuronal development. Early BDNF hyperactivity may play an etiological role in autism early in life. This hypothesis is supported by the finding that serum and brain tissue BDNF levels are increased in autism compared with normal controls. Furthermore, BDNF hyperactivity may be associated with early brain outgrowth, increased prevalence of seizures in autism, and similar behaviors observed in autism and fragile X syndrome. Further studies of serum BDNF levels and genetic studies of the BDNF signaling pathway may help to clarify the role of BDNF in the pathogenesis of autism. Attempts to prove the BDNF hyperactivity hypothesis may lead investigators in a new direction for the study of the pathogenesis of autism and the development of an effective intervention of this disorder.

Alleles↗
PubMed2002

Cyclo-oxygenase 2 inhibitors: emerging roles in the gut.

BACKGROUND AND AIMS: Discovery of an isoform of Cyclo-oxygenase (COX) 1, the inducible COX-2, has made it possible to avoid some side effects of non-specific COX inhibitors. The COX-2 gene is over-expressed in reflux oesophagitis, Barrett's oesophagus, gastric and colon cancer, familial adenomatous polyposis, pancreatic cancer, hepatocellular carcinoma, hepatotoxicity, cirrhosis, and inflammatory bowel disease, and specific COX-2 inhibitors have been tried experimentally and clinically and found effective. METHODS: A Medline search was performed of English-language experimental studies and controlled clinical trials from January 1980 to January 2002, and relevant citations were noted. RESULTS: Review of available literature shows that sulindac and COX-2 inhibitors are effective in preventing as well as regressing familial adenomatous polyposis. However, they have not been shown to prevent cancer in these patients. Studies evaluating NSAIDs and COX-2 inhibitors in carcinogen-induced and genetically manipulated animal models of various cancers have been promising especially in conditions such as Barrett's oesophagus, oesophageal and hepatocellular carcinoma and pancreatic cancer. COX-2 inhibitors may be of value in the treatment of reflux oesophagitis, pancreatitis and hepatitis, although carefully planned randomized controlled clinical trials demonstrating their efficacy need to be conducted. At present NSAIDs and COX-2 inhibitors cannot be recommended for average-risk individuals or for those with sporadic colorectal neoplasia (or other forms of cancers) as chemo-preventive agents. CONCLUSION: COX-2 inhibitors may open up a new therapeutic era in which these drugs can be used for chemo-prophylaxis. However, COX-2 selective inhibitors retain renal adverse effects of the non-selective inhibitors and the concern regarding the pro-thrombotic potential of COX-2 inhibitors will limit their value as chemo-preventive agents.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

TransMiner: mining transitive associations among biological objects from text.

Associations among biological objects such as genes, proteins, and drugs can be discovered automatically from the scientific literature. TransMiner is a system for finding associations among objects by mining the Medline database of the scientific literature. The direct associations among the objects are discovered based on the principle of co-occurrence in the form of an association graph. The principle of transitive closure is applied to the association graph to find potential transitive associations. The potential transitive associations that are indeed direct are discovered by iterative retrieval and mining of the Medline documents. Those associations that are not found explicitly in the entire Medline database are transitive associations and are the candidates for hypothesis generation. The transitive associations were ranked based on the sum of weight of terms that co-occur with both the objects. The direct and transitive associations are visualized using a graph visualization applet. TransMiner was tested by finding associations among 56 breast cancer genes and among 24 objects in the calpain signal transduction pathway. TransMiner was also used to rediscover associations between magnesium and migraine.

Abstracting and Indexing↗
PubMed2005

GeneSeer: a sage for gene names and genomic resources.

BACKGROUND: Independent identification of genes in different organisms and assays has led to a multitude of names for each gene. This balkanization makes it difficult to use gene names to locate genomic resources, homologs in other species and relevant publications. METHODS: We solve the naming problem by collecting data from a variety of sources and building a name-translation database. We have also built a table of homologs across several model organisms: H. sapiens, M. musculus, R. norvegicus, D. melanogaster, C. elegans, S. cerevisiae, S. pombe and A. thaliana. This allows GeneSeer to draw phylogenetic trees and identify the closest homologs. This, in turn, allows the use of names from one species to identify homologous genes in another species. A website http://geneseer.cshl.org/ is connected to the database to allow user-friendly access to our tools and external genomic resources using familiar gene names. CONCLUSION: GeneSeer allows access to gene information through common names and can map sequences to names. GeneSeer also allows identification of homologs and paralogs for a given gene. A variety of genomic data such as sequences, SNPs, splice variants, expression patterns and others can be accessed through the GeneSeer interface. It is freely available over the web http://geneseer.cshl.org/ and can be incorporated in other tools through an http-based software interface described on the website. It is currently used as the search engine in the RNAi codex resource, which is a portal for short hairpin RNA (shRNA) gene-silencing constructs.

Alternative Splicing↗
PubMed2006

cPath: open source software for collecting, storing, and querying biological pathways.

BACKGROUND: Biological pathways, including metabolic pathways, protein interaction networks, signal transduction pathways, and gene regulatory networks, are currently represented in over 220 diverse databases. These data are crucial for the study of specific biological processes, including human diseases. Standard exchange formats for pathway information, such as BioPAX, CellML, SBML and PSI-MI, enable convenient collection of this data for biological research, but mechanisms for common storage and communication are required. RESULTS: We have developed cPath, an open source database and web application for collecting, storing, and querying biological pathway data. cPath makes it easy to aggregate custom pathway data sets available in standard exchange formats from multiple databases, present pathway data to biologists via a customizable web interface, and export pathway data via a web service to third-party software, such as Cytoscape, for visualization and analysis. cPath is software only, and does not include new pathway information. Key features include: a built-in identifier mapping service for linking identical interactors and linking to external resources; built-in support for PSI-MI and BioPAX standard pathway exchange formats; a web service interface for searching and retrieving pathway data sets; and thorough documentation. The cPath software is freely available under the LGPL open source license for academic and commercial use. CONCLUSION: cPath is a robust, scalable, modular, professional-grade software platform for collecting, storing, and querying biological pathways. It can serve as the core data handling component in information systems for pathway visualization, analysis and modeling.

Computational Biology↗
PubMed2006

Machine learning and word sense disambiguation in the biomedical domain: design and evaluation issues.

BACKGROUND: Word sense disambiguation (WSD) is critical in the biomedical domain for improving the precision of natural language processing (NLP), text mining, and information retrieval systems because ambiguous words negatively impact accurate access to literature containing biomolecular entities, such as genes, proteins, cells, diseases, and other important entities. Automated techniques have been developed that address the WSD problem for a number of text processing situations, but the problem is still a challenging one. Supervised WSD machine learning (ML) methods have been applied in the biomedical domain and have shown promising results, but the results typically incorporate a number of confounding factors, and it is problematic to truly understand the effectiveness and generalizability of the methods because these factors interact with each other and affect the final results. Thus, there is a need to explicitly address the factors and to systematically quantify their effects on performance. RESULTS: Experiments were designed to measure the effect of "sample size" (i.e. size of the datasets), "sense distribution" (i.e. the distribution of the different meanings of the ambiguous word) and "degree of difficulty" (i.e. the measure of the distances between the meanings of the senses of an ambiguous word) on the performance of WSD classifiers. Support Vector Machine (SVM) classifiers were applied to an automatically generated data set containing four ambiguous biomedical abbreviations: BPD, BSA, PCA, and RSV, which were chosen because of varying degrees of differences in their respective senses. Results showed that: 1) increasing the sample size generally reduced the error rate, but this was limited mainly to well-separated senses (i.e. cases where the distances between the senses were large); in difficult cases an unusually large increase in sample size was needed to increase performance slightly, which was impractical, 2) the sense distribution did not have an effect on performance when the senses were separable, 3) when there was a majority sense of over 90%, the WSD classifier was not better than use of the simple majority sense, 4) error rates were proportional to the similarity of senses, and 5) there was no statistical difference between results when using a 5-fold or 10-fold cross-validation method. Other issues that impact performance are also enumerated. CONCLUSION: Several different independent aspects affect performance when using ML techniques for WSD. We found that combining them into one single result obscures understanding of the underlying methods. Although we studied only four abbreviations, we utilized a well-established statistical method that guarantees the results are likely to be generalizable for abbreviations with similar characteristics. The results of our experiments show that in order to understand the performance of these ML methods it is critical that papers report on the baseline performance, the distribution and sample size of the senses in the datasets, and the standard deviation or confidence intervals. In addition, papers should also characterize the difficulty of the WSD task, the WSD situations addressed and not addressed, as well as the ML methods and features used. This should lead to an improved understanding of the generalizablility and the limitations of the methodology.

Algorithms↗
PubMed2004

A graph-theoretic modeling on GO space for biological interpretation of gene clusters.

MOTIVATION: With the advent of DNA microarray technologies, the parallel quantification of genome-wide transcriptions has been a great opportunity to systematically understand the complicated biological phenomena. Amidst the enthusiastic investigations into the intricate gene expression data, clustering methods have been the useful tools to uncover the meaningful patterns hidden in those data. The mathematical techniques, however, entirely based on the numerical expression data, do not show biologically relevant information on the clustering results. RESULTS: We present a novel methodology for biological interpretation of gene clusters. Our graph theoretic algorithm extracts common biological attributes of the genes within a cluster or a group of interest through the modified structure of gene ontology (GO) called GO tree. After genes are annotated with GO terms, the hierarchical nature of GO terms is used to find the representative biological meanings of the gene clusters. In addition, the biological significance of gene clusters can be assessed quantitatively by defining a distance function on the GO tree. Our approach has a complementary meaning to many statistical clustering techniques; we can see clustering problems from a different viewpoint by use of biological ontology. We applied this algorithm to the well-known data set and successfully obtained the biological features of the gene clusters with the quantitative biological assessment of clustering quality through GO Biological Process.

Algorithms↗
PubMed1994

Macromolecular query language (MMQL): prototype data model and implementation.

Macromolecular query language (MMQL) is an extensible interpretive language in which to pose questions concerning the experimental or derived features of the 3-D structure of biological macromolecules. MMQL portends to be intuitive with a simple syntax, so that from a user's perspective complex queries are easily written. A number of basic queries and a more complex query--determination of structures containing a five-strand Greek key motif--are presented to illustrate the strengths and weaknesses of the language. The predominant features of MMQL are a filter and pattern grammar which are combined to express a wide range of interesting biological queries. Filters permit the selection of object attributes, for example, compound name and resolution, whereas the patterns currently implemented query primary sequence, close contacts, hydrogen bonding, secondary structure, conformation and amino acid properties (volume, polarity, isoelectric point, hydrophobicity and different forms of exposure). MMQL queries are processed by MMQLlib; a C++ class library, to which new query methods and pattern types are easily added. The prototype implementation described uses PDBlib, another C(++)-based class library from representing the features of biological macromolecules at the level of detail parsable from a PDB file. Since PDBlib can represent data stored in relational and object-oriented databases, as well as PDB files, once these data are loaded they too can be queried by MMQL. Performance metrics are given for queries of PDB files for which all derived data are calculated at run time and compared to a preliminary version of OOPDB, a prototype object-oriented database with a schema based on a persistent version of PDBlib which offers more efficient data access and the potential to maintain derived information. MMQLlib, PDBlib and associated software are available via anonymous ftp from cuhhca.hhmi.columbia.edu.

Amino Acid Sequence↗
PubMed2001

Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.

PURPOSE: To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease. DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease. STUDY SELECTION: Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997. DATA EXTRACTION: Data on 1860 nondiabetic patients were analyzed. DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 and P = 0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d. CONCLUSION: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Enamel matrix derivative (Emdogain) for periodontal tissue regeneration in intrabony defects.

BACKGROUND: Periodontitis is a chronic infective disease of the gums caused by bacteria present in dental plaque. This condition induces the breakdown of the tooth supporting apparatus until teeth are lost. Surgery may be indicated to arrest disease progression and regenerate lost tissues. Several surgical techniques have been developed to regenerate periodontal tissues including guided tissue regeneration (GTR), bone grafting (BG) and the use of enamel matrix derivative (EMD). EMD is an extract of enamel matrix and contains amelogenins of various molecular weights. There is evidence to show that amelogenins are involved not only in enamel formation, but also in the formation of the periodontal attachment during tooth formation. OBJECTIVES: To test the efficacy of EMD in comparison with open flap debridement, GTR and various BG procedures for the treatment of intrabony defects. SEARCH STRATEGY: We searched the Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Several journals were handsearched. No language restrictions were applied. Authors of randomised controlled trials (RCTs) identified, personal contacts and the manufacturer were contacted to identify unpublished trials. Most recent search: January 2003. SELECTION CRITERIA: RCTs on patients affected by periodontitis having intrabony defects treated with EMD compared with open flap debridement, GTR and various BG procedures with at least one year follow up. The outcome measures considered were: tooth loss, changes in probing attachment levels (PAL), pocket depths (PPD), gingival recessions (REC), marginal bone levels on intraoral radiographs and postoperative infections. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two reviewers. Results were expressed as random effect models using weighted mean differences for continuous outcomes and relative risk for dichotomous outcomes with 95% confidence interval (CI). Heterogeneity was investigated including both clinical and methodological factors. MAIN RESULTS: No difference in tooth loss was observed. A meta-analysis including eight trials showed that Emdogain treated sites displayed statistically significant PAL improvements (mean difference 1.3 mm, 95%CI: 0.8 to 1.8) and PPD reduction (1 mm, 95%CI: 0.5 to 1.4) when compared to flap surgery. Comparing Emdogain with GTR (six trials), GTR showed a statistically significant reduction of PPD (0.6 mm) and increase of REC (0.5 mm). No difference in postoperative infections was observed. REVIEWER'S CONCLUSIONS: Emdogain is able to significantly improve PAL levels (1.3mm) and PPD reduction (1mm) when compared to flap surgery, however these results may not have a great clinical impact, since it has not been shown that more periodontally compromised teeth could be saved. There was no evidence of clinically important differences between GTR and Emdogain.

Alveolar Bone Loss↗
PubMed2003

AnaBench: a Web/CORBA-based workbench for biomolecular sequence analysis.

BACKGROUND: Sequence data analyses such as gene identification, structure modeling or phylogenetic tree inference involve a variety of bioinformatics software tools. Due to the heterogeneity of bioinformatics tools in usage and data requirements, scientists spend much effort on technical issues including data format, storage and management of input and output, and memorization of numerous parameters and multi-step analysis procedures. RESULTS: In this paper, we present the design and implementation of AnaBench, an interactive, Web-based bioinformatics Analysis workBench allowing streamlined data analysis. Our philosophy was to minimize the technical effort not only for the scientist who uses this environment to analyze data, but also for the administrator who manages and maintains the workbench. With new bioinformatics tools published daily, AnaBench permits easy incorporation of additional tools. This flexibility is achieved by employing a three-tier distributed architecture and recent technologies including CORBA middleware, Java, JDBC, and JSP. A CORBA server permits transparent access to a workbench management database, which stores information about the users, their data, as well as the description of all bioinformatics applications that can be launched from the workbench. CONCLUSION: AnaBench is an efficient and intuitive interactive bioinformatics environment, which offers scientists application-driven, data-driven and protocol-driven analysis approaches. The prototype of AnaBench, managed by a team at the Université de Montréal, is accessible on-line at: http://malawimonas.bcm.umontreal.ca:8091/anabench. Please contact the authors for details about setting up a local-network AnaBench site elsewhere.

Computational Biology↗
PubMed1997

Nutritional factors and colon carcinoma: a case-control study involving French Canadians in Montréal, Quebec, Canada.

BACKGROUND: In a population-based case-control study of colon carcinoma and nutrition involving the francophone community in Greater Montreal, a total of 402 cases (200 males and 202 females) and 668 controls (239 males and 429 females) were interviewed. METHODS: Cases from 1989-1993 were identified through the admission offices of 5 major francophone teaching hospitals in Montreal and were ages 35-79 years. Controls matched by age, place of residence, and language were selected by a modified random digit dialing method. Information on dietary intake was collected with a quantitative food frequency questionnaire. RESULTS: No associations were evident between colon carcinoma and total energy, protein, or carbohydrate consumption, whereas a suggestive inverse association was found with total fat intake, with an odds ratio (OR) of 0.78 (P = 0.0637), and with saturated fat intake as well (OR = 0.71, P = 0.0893). A strongly significant inverse association was found with dietary fiber (OR = 0.50, P = 0.0018). The strongest inverse association concerning fiber was found with fiber from vegetable sources (OR = 0.57, P = 0.0096), and a suggestive (although nonsignificant) inverse association (OR = 0.74, P = 0.0687) was found with fiber from fruits. Calcium was inversely associated with risk (OR = 0.69, P = 0.0411), as was dietary intake of vitamin A (OR = 0.67, P = 0.0162), retinol, (OR = 0.069, P = 0.0409), vitamin E (OR = 0.53, P = 0.0028), and alphatocopherol (OR = 0.63, P = 0.0256). Although there was no association demonstrated between dietary beta-carotene intake and risk, a suggestive (although nonsignificant) inverse association with intake of other types of carotene was observed (OR = 0.76, P = 0.0740). No association was found between intake of other nutrients investigated in this study and risk of colon carcinoma. CONCLUSIONS: There is strong evidence from epidemiologic studies that high intake of fat and meat are risk factors for colorectal carcinoma in humans, whereas high intake of vegetable and fruit are inversely associated with risk of colon carcinoma. The findings from this study are in agreement with this observation.

Adult↗
PubMed2004

Genomic analysis of regulatory network dynamics reveals large topological changes.

Network analysis has been applied widely, providing a unifying language to describe disparate systems ranging from social interactions to power grids. It has recently been used in molecular biology, but so far the resulting networks have only been analysed statically. Here we present the dynamics of a biological network on a genomic scale, by integrating transcriptional regulatory information and gene-expression data for multiple conditions in Saccharomyces cerevisiae. We develop an approach for the statistical analysis of network dynamics, called SANDY, combining well-known global topological measures, local motifs and newly derived statistics. We uncover large changes in underlying network architecture that are unexpected given current viewpoints and random simulations. In response to diverse stimuli, transcription factors alter their interactions to varying degrees, thereby rewiring the network. A few transcription factors serve as permanent hubs, but most act transiently only during certain conditions. By studying sub-network structures, we show that environmental responses facilitate fast signal propagation (for example, with short regulatory cascades), whereas the cell cycle and sporulation direct temporal progression through multiple stages (for example, with highly inter-connected transcription factors). Indeed, to drive the latter processes forward, phase-specific transcription factors inter-regulate serially, and ubiquitously active transcription factors layer above them in a two-tiered hierarchy. We anticipate that many of the concepts presented here--particularly the large-scale topological changes and hub transience--will apply to other biological networks, including complex sub-systems in higher eukaryotes.

Algorithms↗
PubMed1994

Busulfan.

OBJECTIVE: To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients. DATA SOURCES: English-language literature published between 1953 and 1993 was analyzed; pertinent literature was reviewed. STUDY SELECTION: Emphasis was placed on pharmacologic studies and clinical trials involving busulfan therapy both in myeloproliferative disorders and in conditioning regimens for autologous or allogeneic bone marrow transplantation. DATA EXTRACTION: Data from both pediatric and adult studies were evaluated; emphasis was placed on the relationship between plasma concentrations of busulfan and its efficacy and toxicity. DATA SYNTHESIS: Busulfan has been used widely at conventional dosages (1-12 mg/d) for the treatment of patients with chronic myelogenous leukemia (CML). Busulfan at high doses (usually 16 mg/kg) given with other cytotoxic drugs (especially cyclophosphamide) is a common preparative regimen in patients undergoing allogeneic or autologous bone marrow transplantation (BMT) for acute or chronic leukemia and other nonmalignant disorders (e.g., hemoglobinopathies, inborn error of immune system, congenital metabolic disorders). Pharmacokinetics of high-dose busulfan are age-dependent. Busulfan systemic exposure and, thus, tissue and tumor exposure are lower in children than with adults. Relationships between toxicity (principally neutropenia, hepatic veno-occlusive disease, incidence of seizures) and drug exposure were found for busulfan. CONCLUSIONS: Busulfan is a useful, sufficiently safe drug in the treatment of patients with CML. At higher dosages, busulfan is a fundamental part of myeloablative therapies for patients undergoing BMT. As the pharmacokinetics and metabolism of busulfan is further understood, there is great potential for improving treatment outcome. An assessment of maximal tolerated exposure determined by therapeutic drug monitoring may decrease the incidence and lethality of regimen-related toxicities.

Age Factors↗
PubMed2005

Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.

Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at 17q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5' noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism.

Alanine↗
PubMed2003

Genome-wide prediction, display and refinement of binding sites with information theory-based models.

BACKGROUND: We present Delila-genome, a software system for identification, visualization and analysis of protein binding sites in complete genome sequences. Binding sites are predicted by scanning genomic sequences with information theory-based (or user-defined) weight matrices. Matrices are refined by adding experimentally-defined binding sites to published binding sites. Delila-Genome was used to examine the accuracy of individual information contents of binding sites detected with refined matrices as a measure of the strengths of the corresponding protein-nucleic acid interactions. The software can then be used to predict novel sites by rescanning the genome with the refined matrices. RESULTS: Parameters for genome scans are entered using a Java-based GUI interface and backend scripts in Perl. Multi-processor CPU load-sharing minimized the average response time for scans of different chromosomes. Scans of human genome assemblies required 4-6 hours for transcription factor binding sites and 10-19 hours for splice sites, respectively, on 24- and 3-node Mosix and Beowulf clusters. Individual binding sites are displayed either as high-resolution sequence walkers or in low-resolution custom tracks in the UCSC genome browser. For large datasets, we applied a data reduction strategy that limited displays of binding sites exceeding a threshold information content to specific chromosomal regions within or adjacent to genes. An HTML document is produced listing binding sites ranked by binding site strength or chromosomal location hyperlinked to the UCSC custom track, other annotation databases and binding site sequences. Post-genome scan tools parse binding site annotations of selected chromosome intervals and compare the results of genome scans using different weight matrices. Comparisons of multiple genome scans can display binding sites that are unique to each scan and identify sites with significantly altered binding strengths. CONCLUSIONS: Delila-Genome was used to scan the human genome sequence with information weight matrices of transcription factor binding sites, including PXR/RXRalpha, AHR and NF-kappaB p50/p65, and matrices for RNA binding sites including splice donor, acceptor, and SC35 recognition sites. Comparisons of genome scans with the original and refined PXR/RXRalpha information weight matrices indicate that the refined model more accurately predicts the strengths of known binding sites and is more sensitive for detection of novel binding sites.

Binding Sites↗
PubMed2005

Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's.

BACKGROUND: Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels. RESULTS: We found that the serial pattern of this instinctive behavioral sequence becomes strengthened as an entire entity in hyper-dopaminergic mutants, and more resistant to interruption. Hyper-dopaminergic mutant mice have stronger and more rigid syntactic grooming chain patterns than wild-type control mice. Mutants showed sequential super-stereotypy in the sense of having more stereotyped and predictable syntactic grooming sequences, and were also more likely to resist disruption of the pattern en route, by returning after a disruption to complete the pattern from the appropriate point in the sequence. By contrast, wild-type mice exhibited weaker forms of the fixed action pattern, and often failed to complete the full sequence. CONCLUSIONS: Sequential super-stereotypy occurs in the complex fixed action patterns of hyper-dopaminergic mutant mice. Elucidation of the basis for sequential super-stereotypy of instinctive behavior in DAT knockdown mutant mice may offer insights into neural mechanisms of overly-rigid sequences of action or thought in human patients with disorders such as Tourette's or OCD.

Animals↗