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Antiplatelet agents for preventing and treating pre-eclampsia.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a platelet-derived vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, and low dose aspirin in particular, might prevent or delay the development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents when given to women at risk of developing pre-eclampsia, and to those with established pre-eclampsia. SEARCH STRATEGY: This review drew on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The Cochrane Controlled Trials Register was also searched, The Cochrane Library 1999 Issue 1, Embase was searched from 1994-1999 and hand searches were performed of the congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent during pregnancy. Quasi random study designs were excluded. Participants were pregnant women considered to be at risk of developing pre-eclampsia, and those with pre-eclampsia before delivery. Women treated postpartum were excluded. Interventions were any comparisons of an antiplatelet agent (such as low dose aspirin or dipyridamole) with either placebo or no antiplatelet agent. DATA COLLECTION AND ANALYSIS: Assessment of trials for inclusion in the review and extraction of data was performed independently and unblinded by two reviewers. Data were entered into the Review Manager software and double checked. MAIN RESULTS: Forty two trials involving over 32,000 women were included in this review, with 30,563 women in the prevention trials. There is a 15% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents [32 trials with 29,331 women; relative risk (RR) 0.85, 95% confidence interval (0.78, 0.92); Number needed to treat (NNT) 89, (59, 167)]. This reduction is regardless of risk status at trial entry or whether a placebo was used, and irrespective of the dose of asprin or gestation at randomisation. Twenty three trials (28,268 women) reported preterm delivery. There is a small (8%) reduction in the risk of delivery before 37 completed weeks [RR 0.92, (0.88, 0.97); NNT 72 (44, 200)]. Baby deaths were reported in 30 trials (30,093 women). Overall there is a 14% reduction in baby deaths in the antiplatelet group [RR 0.86, (0. 75, 0.98); NNT 250 (125, >10000)]. Small for gestational age babies were reported in 25 trials (20,349 women), with no overall difference between the groups, RR 0.92, (0.84, 1.01). There were no significant differences between treatment and control groups in any other measures of outcome. Five trials compared antiplatelet agents with placebo or no antiplatelet agent for the treatment of pre-eclampsia. There are insufficient data for any firm conclusions about the possible effects of these agents when used for treatment of pre-eclampsia. REVIEWER'S CONCLUSIONS: Antiplatelet agents, in this review largely low dose aspirin, have small-moderate benefits when used for prevention of pre-eclampsia. Further information is required to assess which women are most likely to benefit, when treatment should be started, and at what dose.

Aspirin↗

Sympathectomy for neuropathic pain.

BACKGROUND: Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Some examples of this condition are phantom limb pain, post-stroke pain and complex regional pain syndrome type I (reflex sympathetic dystrophy) and type II (causalgia). Treatment options include drugs, physical treatments, surgery and psychological interventions. The concept that many neuropathic pain syndromes, particularly RSD and causalgia are "sympathetically maintained pains" has historically led to attempts to temporarily or permanently interrupt the sympathetic nervous system. Chemical sympathectomies use alcohol or phenol injections to destroy the sympathetic chain, but this effect is temporary until regeneration of the sympathetic chain occurs. Surgical ablation can be performed by open removal or electrocoagulation of the sympathetic chain, or minimally invasive procedures using stereotactic thermal or laser interruption. OBJECTIVES: The review aimed to assess the effects of both chemical and surgical sympathectomy for neuropathic pain. Secondary objectives were to compare the effects of sympathectomy with no treatment, placebo or conventional treatment, and to evaluate whether the technique of sympathectomy influences the outcomes of the procedure. SEARCH STRATEGY: We searched MEDLINE and EMBASE up to February 2003 and the latest issue of the Cochrane Library (Issue 1, 2003). We screened references in the retrieved articles, literature reviews and book chapters. We also contacted experts in the field of neuropathic pain. SELECTION CRITERIA: Clinical trials and observational studies assessing the effects of sympathectomy (surgical or chemical) for neuropathic pain of both central or peripheral origin were included. DATA COLLECTION AND ANALYSIS: Two reviewers applied the selection criteria to titles and abstracts. Full articles of potentially eligible trials were obtained and the same reviewers applied the inclusion criteria to the studies. The methodological quality of the studies was evaluated. The studies were also evaluated for clinical relevance according to a classification developed by our group. Statistical pooling was not possible due to heterogeneity of data; instead a narrative description of each included study was performed. MAIN RESULTS: We included four studies. One randomized trial comparing radiofrequency sympatholysis with phenol sympathectomy was rated as low methodological quality and it showed that radiofrequency sympatholysis does not offer advantage over phenol techniques. However, a modified technique produced sympatholysis comparable to that produced by 6% phenol, with less incidence of post-sympathectomy neuralgia. REVIEWER'S CONCLUSIONS: The practice of surgical and chemical sympathectomy is based on poor quality evidence, uncontrolled studies and personal experience. Furthermore, complications of the procedure may be significant, in terms of both worsening the pain or producing a new pain syndrome; and abnormal forms of sweating (compensatory hyperhidrosis and pathological gustatory sweating). Therefore, more clinical trials of sympathectomy are required to establish the overall effectiveness and potential risks of this procedure.

Humans↗

Compound library development guided by protein structure similarity clustering and natural product structure.

To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11beta-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.

11-beta-Hydroxysteroid Dehydrogenases↗

The measurement and monitoring of surgical adverse events.

BACKGROUND: Surgical adverse events contribute significantly to postoperative morbidity, yet the measurement and monitoring of events is often imprecise and of uncertain validity. Given the trend of decreasing length of hospital stay and the increase in use of innovative surgical techniques--particularly minimally invasive and endoscopic procedures--accurate measurement and monitoring of adverse events is crucial. OBJECTIVES: The aim of this methodological review was to identify a selection of common and potentially avoidable surgical adverse events and to assess whether they could be reliably and validly measured, to review methods for monitoring their occurrence and to identify examples of effective monitoring systems for selected events. This review is a comprehensive attempt to examine the quality of the definition, measurement, reporting and monitoring of selected events that are known to cause significant postoperative morbidity and mortality. METHODS - SELECTION OF SURGICAL ADVERSE EVENTS: Four adverse events were selected on the basis of their frequency of occurrence and likelihood of evidence of measurement and monitoring: (1) surgical wound infection; (2) anastomotic leak; (3) deep vein thrombosis (DVT); (4) surgical mortality. Surgical wound infection and DVT are common events that cause significant postoperative morbidity. Anastomotic leak is a less common event, but risk of fatality is associated with delay in recognition, detection and investigation. Surgical mortality was selected because of the effort known to have been invested in developing systems for monitoring surgical death, both in the UK and internationally. Systems for monitoring surgical wound infection were also included in the review. METHODS - LITERATURE SEARCH: Thirty separate, systematic literature searches of core health and biomedical bibliographic databases (MEDLINE, EMBASE, CINAHL, HealthSTAR and the Cochrane Library) were conducted. The reference lists of retrieved articles were reviewed to locate additional articles. A matrix was developed whereby different literature and study designs were reviewed for each of the surgical adverse events. Each article eligible for inclusion was independently reviewed by two assessors. METHODS - CRITICAL APPRAISAL: Studies were appraised according to predetermined assessment criteria. Definitions and grading scales were assessed for: content, criterion and construct validity; repeatability; reproducibility; and practicality (surgical wound infection and anastomotic leak). Monitoring systems for surgical wound infection and surgical mortality were assessed on the following criteria: (1) coverage of the system; (2) whether or not denominator data were collected; (3) whether standard and agreed definitions were used; (4) inclusion of risk adjustment; (5) issues related to data collection; (6) postdischarge surveillance; (7) output in terms of feedback and wider dissemination. RESULTS - SURGICAL WOUND INFECTION: A total of 41 different definitions and 13 grading scales of surgical wound infection were identified from 82 studies. Definitions of surgical wound infection varied from presence of pus to complex definitions such as those proposed by the Centres for Disease Control in the USA. A small body of literature has been published on the content, criterion and construct validity of different definitions, and comparisons have been made against wound assessment scales and multidimensional indices. There are examples of comprehensive hospital-based monitoring systems of surgical wound infection, mainly under the auspices of nosocomial surveillance. To date, however, there is little evidence of systematic measurement and monitoring of surgical wound infection after hospital discharge. RESULTS - ANASTOMOTIC LEAK: Over 40 definitions of anastomotic leak were extracted from 107 studies of upper gastrointestinal, hepatopancreaticobiliary and lower gastrointestinal surgery. No formal evaluations were found that assessed the validity or reliability of definitions or severity scales of anastomotic leak. One definition was proposed during a national consensus workshop, but no evidence of its use was found in the surgical literature. The lack of a single definition or gold standard hampers comparison of postoperative anastomotic leak rates between studies and institutions. RESULTS - DEEP VEIN THROMBOSIS: Although a critical review of the DVT literature could not be completed within the realms of this review, it was evident that a number of new techniques for the detection and diagnosis of DVT have emerged in the last 20 years. The group recommends a separate review be undertaken of the different diagnostic tests to detect DVT. RESULTS - SURGICAL MORTALITY MONITORING SYSTEMS: The definition of surgical mortality is relatively consistent between monitoring systems, but duration of follow-up of death postdischarge varies considerably. The majority of systems report in-hospital mortality rates; only some have the potential to link deaths to national death registers. Risk assessment is an important factor and there should be a distinction between recording pre-intervention factors and postoperative complications. A variety of risk scoring systems was identified in the review. Factors associated with accurate and complete data collection include the employment of local, dedicated personnel, simple and structured prompts to ensure that clinical input is complete, and accurate and automated data capture and transfer. CONCLUSIONS: The use of standardised, valid and reliable definitions is fundamental to the accurate measurement and monitoring of surgical adverse events. This review found inconsistency in the quality of reporting of postoperative adverse events, limiting accurate comparison of rates over time and between institutions. The duration of follow-up for individual events will vary according to their natural history and epidemiology. Although risk-adjusted aggregated rates can act as screening or warning systems for adverse events, attribution of whether events are avoidable or preventable will invariably require further investigation at the level of the individual, unit or department. CONCLUSIONS - RECOMMENDATIONS FOR RESEARCH: (1) A single, standard definition of surgical wound infection is needed so that comparisons over time and between departments and institutions are valid, accurate and useful. Surgeons and other healthcare professionals should consider adopting the 1992 Centers for Disease Control (CDC) definition for superficial incisional, deep incisional and organ/space surgical site infection for hospital monitoring programmes and surgical audits. There is a need for further methodological research into the performance of the CDC definition in the UK setting. (2) There is a need to formally assess the reliability of self-diagnosis of surgical wound infection by patients. (3) There is a need to assess formally the reliability of case ascertainment by infection control staff. (4) Work is needed to create and agree a standard, valid and reliable definition of anastomotic leak which is acceptable to surgeons. (5) A systematic review is needed of the different diagnostic tests for the diagnosis of DVT. (6) The following variables should be considered in any future DVT review: anatomical region (lower limb, upper limb, pelvis); patient presentation (symptomatic, asymptomatic); outcome of diagnostic test (successfully completed, inconclusive, technically inadequate, negative); length of follow-up; cost of test; whether or not serial screening was conducted; and recording of laboratory cut-off values for fibrinogen equivalent units. (7) A critical review is needed of the surgical risk scoring used in monitoring systems. (8) In the absence of automated linkage there is a need to explore the benefits and costs of monitoring in primary care. (9) The growing potential for automated linkage of data from different sources (including primary care, the private sector and death registers) needs to be explored as a means of improving the ascertainment of surgical complications, including death. This linkage needs to be within the terms of data protection, privacy and human rights legislation. (10) A review is needed of the extent of the use and efficiency of routine hospital data versus special collections or voluntary reporting.

Humans↗

Arginine supplementation for prevention of necrotising enterocolitis in preterm infants.

BACKGROUND: Immaturity, ischemia, and disturbances in gut mucosal integrity due to infections or hyperosmolar feeds are some of the suspected mechanisms in the development of necrotising enterocolitis (NEC) in preterm infants. Decreased concentration of nitric oxide is proposed as one of the possible cellular mechanisms for NEC. Plasma arginine concentrations were found to be lower in infants who developed NEC. Arginine can act as a substrate for the production of nitric oxide in the tissues and arginine supplementation may help in preventing NEC. OBJECTIVES: This review examines the efficacy and safety of arginine supplementation in decreasing the incidence of NEC among preterm neonates. SEARCH STRATEGY: A literature search was performed using the following databases: MEDLINE (1966 - June 2004), EMBASE (1980 - June 2004), CINAHL (1982 - June 2004), Cochrane Controlled Trials Register (Issue 2, 2004 of Cochrane Library) and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2004). No language restrictions were applied. SELECTION CRITERIA STUDY DESIGN: randomized or quasi-randomized controlled trials. POPULATION: preterm neonates. INTERVENTION: enteral or parenteral arginine supplementation (in addition to what an infant may be receiving from enteral or parenteral source), compared to placebo or no treatment; arginine administered orally or parenterally for at least 7 days in order to achieve adequate plasma arginine levels (145 umol/l). OUTCOMES: any of the following outcomes - NEC, death prior to discharge, death due to NEC, surgery for NEC, duration of total parenteral nutrition, plasma concentrations of arginine and glutamine at baseline and seven days after intervention, side effects of arginine. DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the author. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and mean difference (MD) as appropriate. MAIN RESULTS: Only one eligible study was identified. The methodological quality of the included study was good. There was a statistically significant reduction in the risk of developing NEC (any stage) in the arginine group compared with the placebo group (RR 0.24 [95% CI 0.10, 0.61], RD -0.21 [95% CI -0.32, -0.09]). No significant side effects directly attributable to arginine were observed. REVIEWERS' CONCLUSIONS: The data are insufficient at present to support a practice recommendation. A multicentre randomized controlled study of arginine supplementation in preterm neonates is needed, focusing on the incidence of NEC, particularly stage 2 or 3.

Arginine↗

Mice and men: their promoter properties.

Using the two largest collections of Mus musculus and Homo sapiens transcription start sites (TSSs) determined based on CAGE tags, ditags, full-length cDNAs, and other transcript data, we describe the compositional landscape surrounding TSSs with the aim of gaining better insight into the properties of mammalian promoters. We classified TSSs into four types based on compositional properties of regions immediately surrounding them. These properties highlighted distinctive features in the extended core promoters that helped us delineate boundaries of the transcription initiation domain space for both species. The TSS types were analyzed for associations with initiating dinucleotides, CpG islands, TATA boxes, and an extensive collection of statistically significant cis-elements in mouse and human. We found that different TSS types show preferences for different sets of initiating dinucleotides and cis-elements. Through Gene Ontology and eVOC categories and tissue expression libraries we linked TSS characteristics to expression. Moreover, we show a link of TSS characteristics to very specific genomic organization in an example of immune-response-related genes (GO:0006955). Our results shed light on the global properties of the two transcriptomes not revealed before and therefore provide the framework for better understanding of the transcriptional mechanisms in the two species, as well as a framework for development of new and more efficient promoter- and gene-finding tools.

Animals↗

Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants.

BACKGROUND: Vitamin A is necessary for normal lung growth and the ongoing integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with increased risk of developing chronic lung disease. Several studies have been undertaken to assess whether vitamin A supplementation beyond that routinely given in multivitamin preparations can reduce the incidence of this outcome. OBJECTIVES: To assess the benefit of supplementation with vitamin A in very low birthweight infants. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, Cochrane Controlled Trials Register, and Science Citation Index. The reference lists of relevant trials, recent issues of paediatric and nutrition journals, abstracts and proceedings from relevant conferences in the English language were hand searched. SELECTION CRITERIA: Randomised controlled trials which compared the effects of supplemental vitamin A with standard vitamin A regimes in infants with birthweight </=1500g, and which reported clinical outcomes (death, chronic lung disease or bronchopulmonary dysplasia) and/or vitamin A concentrations were considered for the review. DATA COLLECTION AND ANALYSIS: Data on mortality, requirement for supplemental oxygen at one month of age and at 36 weeks post-menstrual age, retinopathy of prematurity and nosocomial sepsis were excerpted by both reviewers independently. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Six eligible trials were identified, one having a much larger sample size than the others combined. The meta-analysis suggests supplementation with vitamin A results in benefit in terms of reducing oxygen requirement at 36 weeks post-menstrual age [summary RR 0.85 (0.73, 0.98), RD -8.5% (-15.9, -1.1), NNT 11.8 (6.3, 90.9)] and trends towards reduction in death or oxygen requirement at 36 weeks post-menstrual age [summary RR 0.89 (0.79, 1.00)], oxygen use in survivors at one month of age [summary RR 0.93 (0.86, 1.01)], and death or oxygen requirement at one month of age [summary RR 0.93 (0. 86, 1.00)]. Meta-analysis of the two studies which reported on retinopathy of prematurity suggests a trend towards reduced incidence in vitamin A supplemented infants. REVIEWER'S CONCLUSIONS: Supplementing very low birthweight infants with vitamin A is associated with a reduction in oxygen requirement amongst survivors at 36 weeks post-menstrual age. Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in this outcome, balanced against the lack of other proven benefits and the acceptability of treatment. The benefits, in terms of vitamin A status, safety and acceptability of delivering vitamin A in an intravenous emulsion compared with repeat intramuscular injections should be assessed in a further trial.

Dietary Supplements↗

Optimal duration of exclusive breastfeeding.

BACKGROUND: : Although the health benefits of breastfeeding are widely acknowledged, opinions and recommendations are strongly divided on the optimal duration of exclusive breastfeeding. Much of the debate has centered on the so-called 'weanling's dilemma' in developing countries: the choice between the known protective effect of exclusive breastfeeding against infectious morbidity and the (theoretical) insufficiency of breast milk alone to satisfy the infant's energy and micronutrient requirements beyond four months of age. The debate over whether to recommend exclusive breastfeeding for four to six months versus 'about six months' has recently become heated and acrimonious. OBJECTIVES: : The primary objective of this review was to assess the effects on child health, growth, and development, and on maternal health, of exclusive breastfeeding for six months versus exclusive breastfeeding for three to four months with mixed breastfeeding (introduction of complementary liquid or solid foods with continued breastfeeding) thereafter through six months. A secondary objective was to assess the child and maternal health effects of prolonged (greater than six months) exclusive breastfeeding versus exclusive breastfeeding for six months followed by mixed breastfeeding thereafter. SEARCH STRATEGY: : Two independent literature searches were carried out, together comprising the following databases: MEDLINE (as of 1966), Index Medicus (prior to 1966), CINAHL, HealthSTAR, BIOSIS, CAB Abstracts, EMBASE-Medicine, EMBASE-Psychology, Econlit, Index Medicus for the WHO Eastern Mediterranean Region, African Index Medicus, Lilacs (Latin American and Caribbean literature), EBM Reviews-Best Evidence, the Cochrane Database of Systematic Reviews (The Cochrane Library Issue 3, 2000), and the Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2000). No language restrictions were imposed. The two searches yielded a total of 2,668 unique citations. Contacts with experts in the field yielded additional published and unpublished studies. SELECTION CRITERIA: : We selected all internally-controlled clinical trials and observational studies comparing child or maternal health outcomes with exclusive breastfeeding for six or more months versus exclusive breastfeeding for at least three to four months with continued mixed breastfeeding until at least six months. Studies were stratified according to study design (controlled trials versus observational studies), provenance (developing versus developed countries), and timing of compared feeding groups (three to seven months versus later). DATA COLLECTION AND ANALYSIS: : Two reviewers independently assessed study quality (using a priori assessment criteria) and extracted data. MAIN RESULTS: : Twenty independent studies meeting the selection criteria were identified by the literature search: nine from developing countries (two of which were controlled trials in Honduras) and 11 from developed countries (all observational studies). The two trials did not receive high methodologic quality ratings but were nonetheless superior to any of the observational studies included in this review. The observational studies were of variable quality; in addition, their nonexperimental designs were not able to exclude potential sources of confounding and selection bias. Definitions of exclusive breastfeeding varied considerably across studies. Neither the trials nor the observational studies suggest that infants who continue to be exclusively breastfed for six months show deficits in weight or length gain, although larger sample sizes would be required to rule out modest differences in risk of undernutrition. The data are conflicting with respect to iron status, but at least in developing country settings where newborn iron stores may be suboptimal, suggest that exclusive breastfeeding without iron supplementation through six months may compromise hematologic status. Based primarily on an observational analysis of a large randomized trial in Belarus, infants who continue exclusive breastfeeding for six months or more appear to have a significantly reduced risk of one or more episodes of gastrointestinal infection. No significant reduction in risk of atopic eczema, asthma, or other atopic outcomes has been demonstrated in studies from Finland, Australia, and Belarus. Data from the two Honduran trials suggest that exclusive breastfeeding through six months is associated with delayed resumption of menses and more rapid postpartum weight loss in the mother. REVIEWER'S CONCLUSIONS: : We found no objective evidence of a 'weanling's dilemma'. Infants who are exclusively breastfed for six months experience less morbidity from gastrointestinal infection than those who are mixed breastfed as of three or four months, and no deficits have been demonstrated in growth among infants from either developing or developed countries who are exclusively breastfed for six months or longer. Moreover, the mothers of such infants have more prolonged lactational amenorrhea. Although infants should still be managed individually so that insufficient growth or other adverse outcomes are not ignored and appropriate interventions are provided, the available evidence demonstrates no apparent risks in recommending, as a general policy, exclusive breastfeeding for the first six months of life in both developing and developed country settings. Large randomized trials are recommended in both types of setting to rule out small effects on growth and to confirm the reported health benefits of exclusive breastfeeding for six months or beyond.

Breast Feeding↗

TRIPLES: a database of gene function in Saccharomyces cerevisiae.

Using a novel multipurpose mini-transposon, we have generated a collection of defined mutant alleles for the analysis of disruption phenotypes, protein localization, and gene expression in Saccharomyces cerevisiae. To catalog this unique data set, we have developed TRIPLES, a Web-accessible database of TRansposon-Insertion Phenotypes, Localization and Expression in Saccharomyces. Encompassing over 250 000 data points, TRIPLES provides convenient access to information from nearly 7800 transposon-mutagenized yeast strains; within TRIPLES, complete data reports of each strain may be viewed in table format, or if desired, downloaded as tab-delimited text files. Each report contains external links to corresponding entries within the Saccharomyces Genome Database and International Nucleic Acid Sequence Data Library (GenBank). Unlike other yeast databases, TRIPLES also provides on-line order forms linked to each clone report; users may immediately request any desired strain free-of-charge by submitting a completed form. In addition to presenting a wealth of information for over 2300 open reading frames, TRIPLES constitutes an important medium for the distribution of useful reagents throughout the yeast scientific community. Maintained by the Yale Genome Analysis Center, TRIPLES may be accessed at http://ycmi.med.yale.edu/ygac/triples.htm

DNA Transposable Elements↗

[Subtractive gene cloning using dynabeads oligo(dT)25 for elucidation of pseudohyphal formation in Candida tropicalis].

The dimorphic transition from yeast to pseudohyphae in Candida tropicalis occurs following the addition of ethanol to a synthetic medium containing glucose. We developed a method of subtractive gene cloning to isolate genes, of which the expression was apparently specific for pseudohyphal formation in this organism. Subtraction was performed between sense-strand cDNAs instead of mRNAs from cells of the ethanol culture and anti-sense cDNAs linking to Dynabeads oligo(dT)25 from those of the control culture. Dynabeads oligo(dT)25 are paramagnetic beads with 25 nucleotide-long chains of deoxythymidines covalently linked to their surface and were expected to be easily collected using a magnet. This method using Dynabeads oligo(dT)25 minimizes the degradation of mRNA and makes it easy to construct a cDNA library sufficient to analyze the genetic information on the yeast-to-hyphae transition. Using this strategy, we identified several genes including a homologue of CPP1 coding tyrosine phosphatase and a homologue of nmt1+ encoding protein, which was reported to regulate thiamine biosynthesis.

Candida↗

The subsystems approach to genome annotation and its use in the project to annotate 1000 genomes.

The release of the 1000th complete microbial genome will occur in the next two to three years. In anticipation of this milestone, the Fellowship for Interpretation of Genomes (FIG) launched the Project to Annotate 1000 Genomes. The project is built around the principle that the key to improved accuracy in high-throughput annotation technology is to have experts annotate single subsystems over the complete collection of genomes, rather than having an annotation expert attempt to annotate all of the genes in a single genome. Using the subsystems approach, all of the genes implementing the subsystem are analyzed by an expert in that subsystem. An annotation environment was created where populated subsystems are curated and projected to new genomes. A portable notion of a populated subsystem was defined, and tools developed for exchanging and curating these objects. Tools were also developed to resolve conflicts between populated subsystems. The SEED is the first annotation environment that supports this model of annotation. Here, we describe the subsystem approach, and offer the first release of our growing library of populated subsystems. The initial release of data includes 180 177 distinct proteins with 2133 distinct functional roles. This data comes from 173 subsystems and 383 different organisms.

Acyl Coenzyme A↗

Haemophilus influenzae oral whole cell vaccination for preventing acute exacerbations of chronic bronchitis.

BACKGROUND: Acute bronchitis leading to ongoing exacerbations is a serious condition predisposed to by viruses, bacteria or environmental factors. It can be fatal. Antibiotic therapy is not particularly useful. An oral Haemophilus influenzae vaccine has been developed. OBJECTIVES: To assess the effects of an oral, monobacterial whole-cell, killed, nontypeable H. influenzae vaccine in protecting against recurrent acute episodes in chronic bronchitis. SEARCH STRATEGY: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to January Week 4 2006), EMBASE (1990 to September 2005) and ISI Current Contents (2004 to May 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of the H. influenzae vaccine on patients with recurrent acute exacerbations of chronic bronchitis were included when there was overt matching of the vaccine and placebo groups on clinical grounds. DATA COLLECTION AND ANALYSIS: Three authors extracted data and assessed trial quality independently from original records and publications for incidence and severity of bronchitis episodes and carriage rate of nontypeable H. influenzae measured in the upper respiratory tract every three months following vaccination. MAIN RESULTS: Six trials were included in the study with a total of 440 participants. The vaccine reduced the incidence of bronchitic episodes at three months after vaccination (rate ratio is 0.69; 95% CI 0.41 to 1.14) and at six months after vaccination (rate ratio 0.82; 95% CI 0.62 to 1.09). If these results been statistically significant, they would have represented a reduction in acute bronchitic attacks for vaccinated individuals of 31% at three months, and 18% at six. The effect had disappeared by nine months. The severity of exacerbations in the treatment group, as measured by requirement to prescribe antibiotics, was likewise reduced by 58% at three months (Peto odds ratio = 0.42; 95% CI 0.16 to 1.13), and by 65% at six months (Peto odds ratio = 0.35; 95% CI 0.16 to 0.75). AUTHORS' CONCLUSIONS: Vaccinating patients with recurrent acute exacerbations of chronic bronchitis in the autumn may reduce the number and severity of exacerbations over the following winter. A large clinical trial is needed.

Administration, Oral↗

Iodised salt for preventing iodine deficiency disorders.

BACKGROUND: Iodine deficiency is the main cause for potentially preventable mental retardation in childhood, as well as causing goitre and hypothyroidism in people of all ages. It is still prevalent in large parts of the world. OBJECTIVES: To assess the effects of iodised salt in comparison with other forms of iodine supplementation or placebo in the prevention of iodine deficiency disorders. SEARCH STRATEGY: We searched the Cochrane Library, Medline, the Register of Chinese trials developed by the Chinese Cochrane Centre, and the Chinese Med Database. We performed handsearching of a number of journals (Chinese Journal of Control of Endemic Diseases, Chinese Journal of Epidemiology, Chinese Journal of Preventive Medicine, and Studies of Trace Elements and Health up to February 2001), and searched reference lists, databases of ongoing trials and the Internet. Date of latest search: November 2001. SELECTION CRITERIA: We included prospective controlled studies of iodised salt versus other forms of iodine supplementation or placebo in people living in areas of iodine deficiency. Studies reported mainly goitre rates and urinary iodine excretion as outcome measures. DATA COLLECTION AND ANALYSIS: The initial data selection and quality assessment of trials was done independently by two reviewers. Subsequently, after the scope of the review was slightly widened from including only randomised controlled trials to including non-randomised prospective comparative studies, a third reviewer repeated the trials selection and quality assessment. As the studies identified were not sufficiently similar and not of sufficient quality, we did not do a meta-analysis but summarised the data in a narrative format. MAIN RESULTS: We found six prospective controlled trials relating to our question. Four of these were described as randomised controlled trials, one was a prospective controlled trial that did not specify allocation to comparison groups, and one was a repeated cross-sectional study comparing different interventions. Comparison interventions included non-iodised salt, iodised water, iodised oil, and salt iodisation with potassium iodide versus potassium iodate. Numbers of participants in the trials ranged from 35 to 334; over 20,000 people were included in the cross-sectional study. Three studies were in children only, two investigated both groups of children and adults and one investigated pregnant women. There was a tendency towards goitre reduction with iodised salt, although this was not significant in all studies. There was also an improved iodine status in most studies (except in small children in one of the studies), although urinary iodine excretion did not always reach the levels recommended by the WHO. None of the studies observed any adverse effects of iodised salt. REVIEWER'S CONCLUSIONS: The results suggest that iodised salt is an effective means of improving iodine status. No conclusions can be made about improvements in other, more patient-oriented outcomes, such as physical and mental development in children and mortality. None of the studies specifically investigated development of iodine-induced hyperthyroidism, which can be easily overlooked if just assessed on the basis of symptoms. High quality controlled studies investigating relevant long term outcome measures are needed to address questions of dosage and best means of iodine supplementation in different population groups and settings.

Cross-Sectional Studies↗

An empirical process for the design of high-throughput screening deck filters.

A process for objective identification and filtering of undesirable compounds that contribute to high-throughput screening (HTS) deck promiscuity is described. Two methods of mapping hit promiscuity have been developed linking SMARTS-based structural queries with historical primary HTS data. The first compares an expected assay hit rate to actual hit rates. The second examines the propensity of an individual compound to hit multiple assays. Statistical evaluation of the data indicates a correlation between the resultant functional group filters and compound promiscuity. These data corroborate a number of commonly applied filters as well as producing some unexpected results. Application of these models to HTS collection triage reduced the number of in-house compounds considered for screening by 12%. The implications of these findings are further discussed in the context of the HTS screening set and combinatorial library design as well as compound acquisition.

Drug Design↗

Using SERVQUAL in health libraries across Somerset, Devon and Cornwall.

This study provides the results of a survey conducted in the autumn of 2001 by ten NHS library services across Somerset, Devon and Cornwall. The aim of the project was to measure the service quality of each individual library and to provide an overall picture of the quality of library services within the south-west peninsula. The survey was based on SERVQUAL, a diagnostic tool developed in the 1980s, which measures service quality in terms of customer expectations and perceptions of service. The survey results have provided the librarians with a wealth of information about service quality. The service as a whole is perceived to be not only meeting but also exceeding expectations in terms of reliability, responsiveness, empathy and assurance. For the first time, the ten health library services can measure their own service quality as well as benchmark themselves against others.

Benchmarking↗

Complementary DNA cloning and characterization of rat spergen-1, a spermatogenic cell-specific gene-1, containing a mitochondria-targeting signal.

To elucidate the molecular mechanisms involved with spermiogenesis in testis, we performed differential display screening to isolate genes that are developmentally up-regulated during rat testis development. One of the cDNAs isolated by differential display was highly expressed in testis. Both reverse transcription-polymerase chain reaction and Northern blot analysis showed that the expression level of the gene developmentally increased. By screening the rat testis cDNA library, we successfully isolated rat cDNA clones encoding the entire open-reading frame of 462 base pairs coding a small protein of 154 amino acids. Because in situ hybridization revealed that the gene was specifically expressed in haploid spermatids in the rat seminiferous tubules, it was designated as spergen-1 (spermatogenic cell-specific gene-1). The recently opened database of the full-length mouse cDNA collection contains a mouse gene that is homologous to rat spergen-1. Subcellular fractionation followed by immunoblot analysis revealed that spergen-1 protein was associated with mitochondria. The transfection experiments performed in COS-7 cells suggested that spergen-1 has a N-terminal mitochondria-targeting signal. We suggest that spergen-1 might be involved in spermiogenesis by transiently associating with spermatid mitochondria.

Amino Acid Sequence↗

IVE (Image Visualization Environment): a software platform for all three-dimensional microscopy applications.

IVE (Image Visualization Environment) is a software platform designed from the outset to handle all aspects of modern computerized multidimensional microscopy. This platform provides users with an execution environment in which 5D data (XYZ, wavelength, and time) can be easily manipulated for the purpose of data collection, processing, display, and analysis. During the entire process, powerful data display functions are readily available for extracting complicated three-dimensional information through data visualization. By employing both the shared memory and multitasking features of the UNIX operation system, individual functions can be implemented as separate programs, and multiple programs can access the same data pool simultaneously. This enables users to combine the functionalities of different programs to facilitate each unique data analysis task. Furthermore, by defining an appropriate program execution model, commonly shared functional components such as data display, data I/O and user interface, etc. can be implemented using simple IVE library calls. This dramatically reduces the program development time and ensures consistency throughout the entire software system. As a result, users can quickly master the microscopy software system and new functions can be easily integrated, as different functional requirements arise for different research projects.

Chromosomes↗

A physical map of human chromosome 7: an integrated YAC contig map with average STS spacing of 79 kb.

The construction of highly integrated and annotated physical maps of human chromosomes represents a critical goal of the ongoing Human Genome Project. Our laboratory has focused on developing a physical map of human chromosome 7, a approximately 170-Mb segment of DNA that corresponds to an estimated 5% of the human genome. Using a yeast artificial chromosome (YAC)-based sequence-tagged site (STS)-content mapping strategy, 2150 chromosome 7-specific STSs have been established and mapped to a collection of YACs highly enriched for chromosome 7 DNA. The STSs correspond to sequences generated from a variety of DNA sources, with particular emphasis placed on YAC insert ends, genetic markers, and genes. The YACs include a set of relatively nonchimeric clones from a human-hamster hybrid cell line as well as clones isolated from total genomic libraries. For map integration, we have localized 260 STSs corresponding to Genethon genetic markers and 259 STSs corresponding to markers orders by radiation hybrid (RH) mapping on our YAC contigs. Analysis of the data with the program SEGMAP results in the assembly of 22 contigs that are "anchored" on the Genethon genetic map, the RH map, and/or the cytogenetic map. These 22 contigs are ordered relative to one another, are (in all but 3 cases) oriented relative to the centromere and telomeres, and contain > 98% of the mapped STSs. The largest anchored YAC contig, accounting for most of 7p, contains 634 STSs and 1260 YACs. An additional 14 contigs, accounting for approximately 1.5% of the mapped STSs, are assembled but remain unanchored on either the genetic or RH map. Therefore, these 14 "orphan" contigs are not ordered relative to other contigs. In our contig maps, adjacent STSs are connected by two or more YACs in > 95% of cases. With 2150 mapped STSs, our map provides an average STS spacing of approximately 79 kb. The physical map we report here exceeds the goal of 100-kb average STS spacing and should provide an excellent framework for systematic sequencing of the chromosome.

Chromosome Mapping↗