SEARCH · Search PubMed

Results for “Library Collection Development”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 991 records · Page 55Linked to original sources

PubMed2002

Bioinformatics methods for the analysis of expression arrays: data clustering and information extraction.

Expression arrays facilitate the monitoring of changes in the expression patterns of large collections of genes. The analysis of expression array data has become a computationally-intensive task that requires the development of bioinformatics technology for a number of key stages in the process, such as image analysis, database storage, gene clustering and information extraction. Here, we review the current trends in each of these areas, with particular emphasis on the development of the related technology being carried out within our groups.

Abstracting and Indexing↗

PubMed2005

Medical versus surgical interventions for open angle glaucoma.

BACKGROUND: Open angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. OBJECTIVES: To study the relative effects of medical and surgical treatment of OAG. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to February 2005), EMBASE (1988 to February 2005), and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials comparing medications to surgery in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted trial investigators for missing information. MAIN RESULTS: Four trials involving 888 participants with previously untreated OAG were included. Surgery was Scheie's procedure in one trial and trabeculectomy in three trials. In three trials, primary medication was usually pilocarpine, in one trial a beta-blocker. In the most recent trial, participants with mild OAG, progressive visual field (VF) loss, after adjustment for cataract surgery, was not significantly different for medications compared to trabeculectomy (Odds ratio (OR) 0.74; 95% CI 0.54 to 1.01). Reduction of vision, with a higher risk of developing cataract (OR 2.69, 95%% CI 1.64 to 4.42), and more patient discomfort was more likely with trabeculectomy than medication. There is some evidence, from three trials, for people with moderately advanced glaucoma that medication is associated with more progressive VF loss and 6 to 8 mmHg less intraocular pressure (IOP) lowering than surgery, either by a Scheie's procedure or trabeculectomy. There was a trend towards an increased risk of failed IOP control over time for initial pilocarpine treatment compared to trabeculectomy. In the longer-term (two trials) the risk of failure was significantly greater with medication than trabeculectomy (OR 3.90, 95% CI 1.60 to 9.53; HR 7.27, 95% CI 2.23 to 25.71). Medicine and surgery have evolved since these trials were undertaken, and additionally the evidence is potentially subject to detection and attrition bias. AUTHORS' CONCLUSIONS: Evidence from one trial suggests, for mild OAG, that VF deterioration up to five-years is not significantly different whether treatment is initiated with medication or trabeculectomy. Reduced vision, cataract and eye discomfort are more likely with trabeculectomy. There is some evidence, for more severe OAG, that initial medication (pilocarpine, now rarely used as first line medication) is associated with greater VF deterioration than surgery. In general, surgery lowers IOP more than medication. There was no evidence to determine the effectiveness of contemporary medication (prostaglandin analogues, alpha2-agonists and topical carbonic anhydrase inhibitors) compared to surgery in severe OAG, and in people of black African ethnic origin who have a greater risk of more severe open angle glaucoma. More research is required.

Aged↗

PubMed2006

A pooling-deconvolution strategy for biological network elucidation.

The generation of large-scale data sets is a fundamental requirement of systems biology. But despite recent advances, generation of such high-coverage data remains a major challenge. We developed a pooling-deconvolution strategy that can dramatically decrease the effort required. This strategy, pooling with imaginary tags followed by deconvolution (PI-deconvolution), allows the screening of 2(n) probe proteins (baits) in 2 x n pools, with n replicates for each bait. Deconvolution of baits with their binding partners (preys) can be achieved by reading the prey's profile from the 2 x n experiments. We validated this strategy for protein-protein interaction mapping using both proteome microarrays and a yeast two-hybrid array, demonstrating that PI-deconvolution can be used to identify interactions accurately with fewer experiments and better coverage. We also show that PI-deconvolution can be used to identify protein-small molecule interactions inferred from profiling the yeast deletion collection. PI-deconvolution should be applicable to a wide range of library-against-library approaches and can also be used to optimize array designs.

Computational Biology↗

PubMed1994

Developmental expression of mucin genes MUC1 and MUC2.

The mucin gene MUC1, is expressed in a number of human ductal epithelia in vivo including those within the pancreas, mammary gland, kidney and genital ducts. Further it is expressed at a high level in certain tumours and tumour-derived cell lines. MUC2 was initially isolated from a human jejunum cDNA library and is thought to be one of the major intestinal mucin genes, though it is also expressed in the trachea. We have examined the developmental expression of these two mucin genes in human tissues. High level expression of MUC1 has been seen by 12.5 weeks of gestation in the epithelial of the distal respiratory tract and the collecting ducts in the kidney. By 18 weeks MUC1 mRNA is detectable in the colon but pancreatic expression of MUC1 is not seen until late in gestation. MUC2 mRNA is seen by 12 weeks of gestation in the jejunum, ileum and colon, and in large bronchioles of the lung by 18 weeks. The pattern of expression of MUC1 suggests that this mucin may not be involved in early ductal obstruction in the CF pancreas, but both MUC1 and MUC2 may play a role in the development of intestinal disease and MUC1 in early respiratory disease associated with CF.

Cystic Fibrosis↗

PubMed2006

Inhaled nitric oxide for respiratory failure in preterm infants.

BACKGROUND: Inhaled nitric oxide has been proven effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure, and the potential risks, differ substantially in preterm infants. Analysis of the efficacy and toxicities of inhaled nitric oxide in infants born before 35 weeks is therefore necessary. OBJECTIVES: To determine whether, in preterm newborn infants (< 35 weeks gestation) who have hypoxic respiratory failure, treatment with inhaled nitric oxide improves oxygenation within 2 hours and reduces the rates of death, bronchopulmonary dysplasia, intraventricular haemorrhage, or neurodevelopmental disability SEARCH STRATEGY: Standard methods of the Cochrane Neonatal Review Group were used. We searched MEDLINE, EMBASE, Healthstar and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), using the following keywords: nitric oxide, clinical trial, newborn, and covering years from 1985 to 2005. In addition, we searched the abstracts of the Pediatric Academic Societies. SELECTION CRITERIA: Randomised and quasi randomised studies in preterm infants with hypoxic respiratory failure. Administration of inhaled nitric oxide compared to control with or without placebo. Clinically relevant outcomes that were analysed included death, bronchopulmonary dysplasia (defined as oxygen dependence at 36 weeks postconceptional age), intraventricular haemorrhage, long term neurodevelopmental outcome and short term effects on oxygenation. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Neonatal Review Group were used. Two investigators extracted, assessed and coded separately all data for each study. Any disagreement was resolved by discussion. MAIN RESULTS: Seven randomised controlled trials of inhaled nitric oxide therapy in preterm infants were found. One study consisted of infants determined to have a high risk of developing bronchopulmonary dysplasia (Subhedar 1997). One study studied routine use of inhaled NO in all ventilated preterm infants (Schreiber 2003). The remaining studies consisted of infants with high predicted mortality based on poor oxygenation (Kinsella 1999; Hascoet 2005; INNOVO 2005; Van Meurs 2005; Mercier 1999). No significant effect of inhaled nitric oxide on mortality or bronchopulmonary dysplasia was demonstrated. There was no evidence of effect on the risk of intraventricular haemorrhage. There may be short term improvements in oxygenation. Two studies (Schreiber 2003; INNOVO 2005) have so far presented data on long term neurodevelopmental outcome, one of which demonstrated improved outcome at two years corrected age. AUTHORS' CONCLUSIONS: The currently published evidence from randomised trials does not support the use of inhaled nitric oxide in preterm infants with hypoxic respiratory failure. Further studies may need to be performed to evaluate the potential benefit of routine use of this therapy in infants with milder forms of respiratory failure, and these trials will need to be designed to evaluate not only neonatal survival, and the occurrence of neonatal morbidities, but should be powered to evaluate neurodevelopmental outcome at a minimum of two years of age.

Administration, Inhalation↗

PubMed2000

Telemedicine versus face to face patient care: effects on professional practice and health care outcomes.

BACKGROUND: Telemedicine is the use of telecommunications technology for medical diagnosis and patient care. From its beginnings telemedicine has been used in a variety of health care fields, although widespread interest among healthcare providers has only now become apparent with the development of more sophisticated technology. OBJECTIVES: To assess the effects of telemedicine as an alternative to face-to-face patient care. SEARCH STRATEGY: We searched the Effective Practice and Organisation of Care Group's specialised register, The Cochrane Library, MEDLINE (1966-August 1999), EMBASE (to 1996), Cinahl (to August 1999), Inspec (to August 1996), Healthstar (1983-1996), OCLC, Sigle (to 1999), Assia, SCI (1981-1997), SSCI (1981-1997), DHSS-Data. We hand searched the Journal of Telemedicine and Telecare (1995-1999), Telemedicine Journal (1995-1999) and reference lists of articles. We also hand searched conference proceedings and contacted experts in countries identified as having an interest in telemedicine. SELECTION CRITERIA: Randomised trials, controlled before and after studies and interrupted time series comparing telemedicine with face-to-face patient care. The participants were qualified health professionals and patients receiving care through telemedicine. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Seven trials involving more than 800 people were included. One trial was concerned with telemedicine in the emergency department, one with video-consultations between primary health care and the hospital outpatients department, and the remainder were concerned with the provision of home care or patient self-monitoring of chronic disease. The studies appeared to be well conducted, although patient numbers were small in all but one. Although none of the studies showed any detrimental effects from the interventions, neither did they show unequivocal benefits and the findings did not constitute evidence of the safety of telemedicine. None of the studies included formal economic analysis. All the technological aspects of the interventions appear to have been reliable, and to have been well accepted by patients. REVIEWER'S CONCLUSIONS: Establishing systems for patient care using telecommunications technologies is feasible, but there is little evidence of clinical benefits. The studies provided variable and inconclusive results for other outcomes such as psychological measures, and no analysable data about the cost effectiveness of telemedicine systems. The review demonstrates the need for further research and the fact that it is feasible to carry out randomised trials of telemedicine applications. Policy makers should be cautious about recommending increased use and investment in unevaluated technologies.

Communication↗

PubMed2005

Surgical sealant for preventing air leaks after pulmonary resections in patients with lung cancer.

BACKGROUND: Postoperative air leak is a frequent complication after pulmonary resection for lung cancer. It may cause serious complications, such as empyema, or prolong the need for chest tube and hospitalisation. Surgical sealants of different types have been developed to prevent or to reduce postoperative air leaks. A systematic review was therefore undertaken to evaluate the evidence on their effectiveness. OBJECTIVES: To evaluate the effectiveness of surgical sealants in preventing or in reducing postoperative air leaks after pulmonary resection for lung cancer. SEARCH STRATEGY: The electronic databases MEDLINE (1966 to 2004), EMBASE (1974 to 2004), Cancerlit (1993 to 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3/2004) and listed references were searched, and handsearching of conference proceedings was conducted to identify published and unpublished trials. SELECTION CRITERIA: Randomised controlled clinical trials were included in which standard closure techniques plus a sealant were compared with the same intervention with no use of any sealant in patients undergoing elective pulmonary resection provided that a large proportion of the patients included in the studies had undergone pulmonary resection for lung cancer. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials to be included in the review, assessed methodological quality of each trial and extracted data using a standardised form. Because of several limitations, narrative synthesis was used at this stage. MAIN RESULTS: Twelve trials, with 1097 patients in total, were included. In eight trials there was a statistically significant difference between treatment and control patients in reducing postoperative air leaks. However this reduction only proved a significant reduction of hospital stay in one trial. Only in one trial reduction of time of chest drain removal and reduction of percentage of patient with persistent air leak were significantly smaller in the treatment group. AUTHORS' CONCLUSIONS: Although surgical sealants seem to reduce postoperative air leaks, length of hospitalisation is not affected and infectious complications may be increased. Therefore, systematic use of surgical sealants in clinical practice cannot be recommended at the moment. More randomised controlled clinical trials are needed.

Air↗

PubMed2003

Cot-nursing versus incubator care for preterm infants.

BACKGROUND: An optimal thermal environment is desirable for preterm infants. These infants are usually nursed in incubators, but cot-nursing may provide an alternative. Measures to assist the maintenance of body temperature for smaller infants in open cots include extra clothing/bedding, warming up the nursery and heating the cot mattress. Recently a heated water-filled mattress has been developed to maintain the temperature of a cot-nursed preterm infant. While there may be benefits of nursing preterm infants in open cots, there may be potential risks such as nosocomial infection caused by more handling due to easier access. OBJECTIVES: Among preterm infants allocated to cot-nursing vs incubator care in neonatal period, to assess effects on their temperature control and weight gain. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of electronic databases: Oxford Database of Perinatal Trials; Cochrane Controlled Trials Register (Cochrane Library Issue 4 2001); MEDLINE (1966-2001); and CINAHL (1982-2001), previous reviews including cross references. SELECTION CRITERIA: All trials using random or quasi-random patient allocation in which infants receiving care in standard newborn cots were compared to infants managed in a conventional air heated incubator. DATA COLLECTION AND ANALYSIS: The authors independently assessed trial quality and extracted data for the primary outcomes of temperature control and weight gain. Meta-analysis was conducted using a fixed effects model. Results are presented as relative risk (RR) for categorical data and mean difference (MD) and weighted mean differences (WMD) for data measured on a continuous scale. MAIN RESULTS: Nine potential studies were identified of which four, involving 173 babies, were included in this review. When compared to incubator care, cot-nursing resulted in a statistically significantly higher mean body temperature (MD 0.30 degrees C; 95% CI 0.10, 0.50, one trial) and a decrease in proportion of infants not breast feeding at hospital discharge (RR 0.52; 95% CI 0.28, 0.94, two trials, 77 infants). No statistically significant difference was shown in weight gain, reported by two trials involving 69 infants. The comparison of cot-nursing using a heated water-filled mattress versus incubator care, which included four trials and a total of 149 infants, produced similar results. Cot-nursing with warming of the nursery resulted in statistically significantly smaller weight gain during week one compared to the incubator group in one trial that involved 49 infants (MD -5.90 g/kg/day; 95% CI -11.13, -0.67) with no significant difference found for weeks two and three. REVIEWER'S CONCLUSIONS: Due to the small numbers of trials included and infants studied, and the resulting imprecision in the measures of effect for all outcomes, the review does not give a clear indication for the role of cot-nursing for preterm infants. Further assessment of the role of cot nursing for preterm infants using randomised controlled trials is necessary.

Beds↗

PubMed2006

Autologous cartilage implantation for full thickness articular cartilage defects of the knee.

BACKGROUND: Treatments for managing articular cartilage defects of the knee, including drilling and abrasion arthroplasty, are not always effective. When they are, long-term benefits may not be maintained and osteoarthritis may develop, resulting in the need for a total knee replacement. An alternative is the surgical implantation of healthy cartilage cells into damaged areas (autologous cartilage implantation). OBJECTIVES: To determine the effectiveness of autologous cartilage implantation (ACI) in people with full thickness articular cartilage defects of the knee. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (15 December 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to December 2005), CINAHL (1982 to December Week 2, 2004), EMBASE (1988 to 2005 Week 50), SPORTDiscus (1830 to January 2005) and the National Research Register Issue 3, 2005. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing ACI with any other type of treatment (including no treatment or placebo) for symptomatic cartilage defects of the medial or lateral femoral condyle, femoral trochlea or patella. DATA COLLECTION AND ANALYSIS: Two review authors selected studies for inclusion independently. We assessed study quality based on adequacy of the randomisation process, adequacy of the allocation concealment process, potential for selection bias after allocation and level of masking. Data was not pooled due to clinical and methodological heterogeneity in the studies. MAIN RESULTS: We included four randomised controlled trials (266 participants). One trial of ACI versus mosaicplasty reported statistically significant results for ACI at one year, but only in a post-hoc subgroup analysis of participants with medial condylar defects; 88% had excellent or good results with ACI versus 69% with mosaicplasty. A second trial of ACI versus mosaicplasty found no statistically significant difference in clinical outcomes at two years. There was no statistically significant difference in outcomes at two years in a trial comparing ACI with microfracture. In addition, one trial of matrix-guided ACI versus microfracture did not contain enough long-term results to reach definitive conclusions. AUTHORS' CONCLUSIONS: The use of ACI and other chondral resurfacing techniques is becoming increasingly widespread. However, there is at present no evidence of significant difference between ACI and other interventions. Additional good quality randomised controlled trials with long-term functional outcomes are required.

Cartilage, Articular↗

PubMed2006

A high throughput fluorescent assay for measuring the activity of fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH) is the enzyme responsible for the rapid degradation of fatty acid amides such as the endocannabinoid anandamide. Inhibition of FAAH activity has been suggested as a therapeutic approach for the treatment of chronic pain, depression and anxiety, through local activation of the cannabinoid receptor CB1. We have developed a high throughput screening assay for identification of FAAH inhibitors using a novel substrate, decanoyl 7-amino-4-methyl coumarin (D-AMC) that is cleaved by FAAH to release decanoic acid and the highly fluorescent molecule 7-amino-4-methyl coumarin (AMC). This assay gives an excellent signal window for measuring FAAH activity and, as a continuous assay, inherently offers improved sensitivity and accuracy over previously reported endpoint assays. The assay was validated using a panel of known FAAH inhibitors and purified recombinant human FAAH, then converted to a 384 well format and used to screen a large library of compounds (>600,000 compounds) to identify FAAH inhibitors. This screen identified numerous novel FAAH inhibitors of diverse chemotypes. These hits confirmed using a native FAAH substrate, anandamide, and had very similar rank order potency to that obtained using the D-AMC substrate. Collectively these data demonstrate that D-AMC can be successfully used to rapidly and effectively identify novel FAAH inhibitors for potential therapeutic use.

Amidohydrolases↗

PubMed2005

Selection of tumor-targeting agents on freshly excised human breast tumors using a phage display library.

The selective delivery of therapeutic agents to tumor site without harming rest of the body is a major challenge in clinical oncology today. Phage display approach has been used for searching ligands for cell-surface macromolecules on cancer cells so that they can be employed as drug targeting agents. Although basic protocols for biopanning cells are available, they are not as such suitable for screening highly complex and diverse target as whole tumor. Present study is an attempt to select peptide ligands specific to whole tumors. The cells from freshly collected human breast tumors were biopanned with phage displayed disulfide-constrained random heptapeptide library, following subtraction on normal human breast cells. Comparative analysis of amino acid frequencies in tumor-selected peptides and in random peptides from unselected library showed that selection was not random. The binding assessment of tumor-selected clones, using highly sensitive chemiluminescence ELISA, demonstrated that 47-75% of selected clones, depending on a tumor, bound to tumor cells they were panned on. Furthermore, several clones bound exclusively or preferentially to tumor cells in comparison to normal breast cells. It was interesting to note that insert sequences of tumor-binding clones from different tumors shared significant motifs. It shows the possibility of identifying ligands that may bind to tumor-specific targets common in certain tumors. The results of this investigation on seven human breast tumors demonstrated that, using procedures developed in the present study, whole tumors can be panned successfully with phage displayed library and tumor-binding ligands can be identified rapidly in high throughput manner. This is an important enabling step in identifying lead molecules for developing novel, specific, and effective agents that can be used for the diagnosis and treatment of cancer.

Amino Acid Motifs↗

PubMed2001

Teaching critical appraisal skills in health care settings.

BACKGROUND: Critical appraisal is the process of assessing and interpreting evidence by systematically considering its validity, results and relevance to an individual's work. Within the last decade critical appraisal has been added as a topic to many medical school and UK Royal College curricula, and several continuing professional development ventures have been funded to provide further training. OBJECTIVES: To assess the effects of teaching critical appraisal skills to health professionals, on the process of care, patient outcomes and knowledge of health professionals. SEARCH STRATEGY: We searched The Cochrane Library (to Issue 2 2000), MEDLINE (1966 to 1997), EMBASE (1980 to 1997), Eric (1966 to 1997), Cinahl (1982 to 1997), Lisa (1976 to 1997), Sigle (1980 to 1997), Science Citation Index (1981 to 1997), PsycLit (1974 to 1997), the world-wide-web, and reference lists of articles. We also contacted major medical education centres. SELECTION CRITERIA: Randomised trials, controlled clinical trials, controlled before and after studies and interrupted time series analyses of educational interventions teaching critical appraisal to health professionals. The outcomes were: process of care; patient mortality, quality of life, and satisfaction; and health professional knowledge/awareness based upon objective, standardised, validated instruments. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and three reviewers independently assessed study quality. MAIN RESULTS: One USA hospital-based randomised trial was included involving 44 doctors. The outcome assessed was critical appraisal knowledge. Process of care, patient health or attitude/awareness outcomes were not assessed. Critical appraisal teaching was reported to have resulted in a 25% improvement (adjusted figure) in critical appraisal knowledge in the intervention group compared to a 6% improvement in the control group, which was statistically significant (p=0.02). REVIEWER'S CONCLUSIONS: There is evidence that critical appraisal teaching has positive effects on participants' knowledge, but as only one study met the inclusion criteria the validity of drawing general conclusions about the effects of teaching critical appraisal is debatable. There are large gaps in the evidence as to whether teaching critical appraisal impacts on decision-making or patient outcomes. It is also unclear whether the size of benefit seen is large enough to be of practical significance, or whether this varies according to participant background or teaching method. The evidence supporting all outcomes is weakened by the generally poorly designed, executed and reported studies that we found.

Decision Making↗

PubMed2006

Weight reduction for primary prevention of stroke in adults with overweight or obesity.

BACKGROUND: Obesity is seen as a worldwide chronic disease with high prevalence that has been associated with increased morbidity from many conditions including stroke, which is the third leading cause of death in developed countries and a leading cause of severe long-term disability. The causal association between overweight or obesity and stroke is unclear and there is no definite study clarifying the role of obesity treatment in the prevention of a first stroke (primary prevention). Given the prevalence of stroke and the enormous health and economic cost of the disease, it is important to establish the possible impact of weight reduction per se on stroke incidence. OBJECTIVES: To assess the effects of weight reduction in people with overweight or obesity on stroke incidence. SEARCH STRATEGY: MEDLINE, EMBASE, The Cochrane Library, LILACS, databases of ongoing trials and reference lists were used to identify relevant trials. The last search was conducted in April 2006. SELECTION CRITERIA: Randomised controlled trials comparing any intervention for weight reduction (single or combined) with placebo or no intervention in overweight or obese people. DATA COLLECTION AND ANALYSIS: No trials were found in the literature for inclusion in this review. MAIN RESULTS: There are currently no results to be reported. AUTHORS' CONCLUSIONS: Obesity seems to be associated with an increased risk of stroke and it has been suggested that weight loss may lead to a reduction of stroke occurrence. However, this hypothesis is not based on strong scientific evidence resulting from randomised controlled clinical trials. This systematic review identified the urgent need for well-designed, adequately-powered, multi centre randomised controlled trials assessing the effects of weight reduction in persons with overweight or obesity on stroke occurrence.

Adult↗

PubMed1997

All in one: a highly detailed rotamer library improves both accuracy and speed in the modelling of sidechains by dead-end elimination.

BACKGROUND: About a decade ago, the concept of rotamer libraries was introduced to model sidechains given known mainchain coordinates. Since then, several groups have developed methods to handle the challenging combinatorial problem that is faced when searching rotamer libraries. To avoid a combinatorial explosion, the dead-end elimination method detects and eliminates rotamers that cannot be members of the global minimum energy conformation (GMEC). Several groups have applied and further developed this method in the fields of homology modelling and protein design. RESULTS: This work addresses at the same time increased prediction accuracy and calculation speed improvements. The proposed enhancements allow the elimination of more than one-third of the possible rotameric states before applying the dead-end elimination method. This is achieved by using a highly detailed rotamer library allowing the safe application of an energy-based rejection criterion without risking the elimination of a GMEC rotamer. As a result, we gain both in modelling accuracy and in computational speed. Being completely automated, the current implementation of the dead-end elimination prediction of protein sidechains can be applied to the modelling of sidechains of proteins of any size on the high-end computer systems currently used in molecular modelling. The improved accuracy is highlighted in a comparative study on a collection of proteins of varying size for which score results have previously been published by multiple groups. Furthermore, we propose a new validation method for the scoring of the modelled structure versus the experimental data based upon the volume overlap of the predicted and observed sidechains. This overlap criterion is discussed in relation to the classic RMSD and the frequently used +/- 40 degrees window in comparing chi 1 and chi 2 angles. CONCLUSIONS: We have shown that a very detailed library allows the introduction of a safe energy threshold rejection criterion, thereby increasing both the execution speed and the accuracy of the modelling program. We speculate that the current method will allow the sidechain prediction of medium-sized proteins and complex protein interfaces involving up to 150 residues on low-end desktop computers.

Algorithms↗

PubMed2001

Complex gel permeation assays for screening combinatorial libraries.

Gel permeation methods have been commonly used to screen combinatorial libraries synthesized on a solid support. We report here three screens of combinatorial libraries using gel permeation assays. These include a simple enzymatic assay to identify inhibitors of the influenza enzyme neuraminidase, and two more complex assays designed to screen for inhibitors of the interleukin-8 (IL-8)-IL-8 receptor and the urokinase-urokinase receptor interactions, respectively. The IL-8 ligand-receptor assay makes use of IL-8 receptor-expressing cells attached to a membrane, thus enabling washing steps as part of the assay. The urokinase ligand-receptor assay employs an enzyme-linked immunosorbent assay-type format, previously thought to be amenable only to well-based assays. The results of these three screens are reported here, including the discovery of a novel series of acyclic inhibitors of neuraminidase. The development of complex assays in a gel permeation format allows for the routine screening of combinatorially as well as noncombinatorially made compound collections against virtually any kind of target, and is being widely used in our high throughput screening operations.

Chromatography, Gel↗

PubMed2003

Mixed-genome microarrays reveal multiple serotype and lineage-specific differences among strains of Listeria monocytogenes.

Epidemiological studies and analysis of putative virulence genes have shown that Listeria monocytogenes has diverged into several phylogenetic divisions. We hypothesize that similar divergence has occurred for many genes that influence niche-specific fitness and virulence and that identifying these differences may offer new opportunities for the detection, treatment, and control of this important pathogen. To explore this issue further, we developed a microarray composed of fragmented DNA taken from 10 strains of L. monocytogenes. We then hybridized genomic DNA from 50 different strains to replicate arrays and analyzed the resulting hybridization patterns. A simple Euclidean distance metric permitted the reconstruction of previously described genetic relationships between serotypes, and only four microarray probes were needed to discriminate between the most important serotypes (1/2a, 1/2b, 1/2c, and 4). We calculated an index of linkage equilibrium from the microarray data and confirmed that L. monocytogenes has a strongly clonal population structure (I(A) = 3.85). Twenty-nine informative probes were retrieved from the library and sequenced. These included genes associated with repairing UV-damaged DNA, salt tolerance, biofilm formation, heavy metal transport, ferrous iron transport, and teichoic acid synthesis. Several membrane-bound lipoproteins and one internalin were identified, plus three phage sequences and six sequences with unknown function. Collectively, these data confirm that many genes have diverged between lineages of L. monocytogenes. Furthermore, these results demonstrate the value of mixed-genome microarrays as a tool for deriving biologically useful information and for identifying and screening genetic markers for clinically important microbes.

Cluster Analysis↗

PubMed1996

Identifying a core set of medical informatics serials: an analysis using the MEDLINE database.

A study was undertaken to test the hypothesis that a core set of medical informatics serials could be identified by using standard bibliometric techniques. All journal articles indexed by the National Library of Medicine between 1990 and 1994 were included. Articles were identified by using the "MEDICAL INFORMATICS" Medical Subject Heading (MeSH) term. Each serial title containing articles was then ranked according to (1) the total number of medical informatics journal articles indexed and (2) the percentage of medical informatics journal articles indexed. Twenty-eight serials had more than 100 articles indexed under the "MEDICAL INFORMATICS" MeSH term. Thirty serials had more than 40% of their articles indexed under the "MEDICAL INFORMATICS" MESH term. A "core" set of fourteen serials had 100 or more medical informatics articles indexed, including more than 70% of all articles they published. The methodology described provides librarians with another tool to use in the difficult task of journal selection. The set of "core" serials identified provides librarians with a ranked list of serials, based on which a medical informatics collection can be developed.

Abstracting and Indexing↗

PubMed2004

Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease may be refractory to conventional treatments such as corticosteroids, enteral nutrition and immuno-suppressive agents. A number of patients with the disease may also become steroid-dependent leading to increased risk of developing steroid-related adverse effects. Recent studies suggest that TNF-a blocking agents may be effective in inducing remission in Crohn's disease. OBJECTIVES: To conduct a systematic review to evaluate the effectiveness of TNF-a blocking agents in inducing remission in patients with active Crohn's disease. SEARCH STRATEGY: We searched MEDLINE (1966-June 2003), EMBASE (1984-June 2003), the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 2, 2003) and the IBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication obtained. SELECTION CRITERIA: We included only randomised controlled trials in which patients with active Crohn's disease (defined by a validated Crohn's disease activity index) were randomly allocated to receive a TNF-a blocking agent in the treatment arm, or to receive placebo or another treatment in the comparison arm. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of the methodological quality of each trial were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. Outcome measures reported in the primary studies included clinical remission, clinical response and changes in disease activity index. MAIN RESULTS: Ten studies were identified of which 4 met the inclusion criteria. The included studies either differed in the type of TNF-a blocking agent used or in the way outcomes were assessed to such an extent that we considered it inappropriate to combine the data statistically. There is evidence from one randomised controlled trial that suggests that a single intravenous infusion of the monoclonal antibody cA2, infliximab, may be effective for induction of remission in Crohn's disease. There was no difference in response rates among infliximab doses of 5, 10 or 20 mg/kg. The results of two other trials suggested that CDP571, the genetically engineered human TNF monoclonal antibody, may also be effective in reducing disease activity index at 2 weeks after an infusion. We did not find any evidence to support the use of etanercept in Crohn's disease. REVIEWER'S CONCLUSIONS: Evidence from one randomized controlled trial suggests that a single infusion of infliximab may be effective for induction of remission in Crohn's disease. Based on this study, we can recommend a dose of 5 mg/kg. There is also some evidence that CDP571 may be effective in inducing remission in Crohn's disease. We did not find any evidence that supports the use of etanercept in Crohn's disease. The period of follow up for the patients in these studies was probably too short to allow adequate assessment of recently reported serious adverse effects such as tuberculosis and lymphoma.

Antibodies, Monoclonal↗