Single dose oral ibuprofen plus codeine for acute postoperative pain in adults.

BACKGROUND: This is an update of the original Cochrane review published in Issue 3, 2013. There is good evidence that combining two different analgesics in fixed doses in a single tablet can provide better pain relief in acute pain and headache than either drug alone, and that the drug-specific effects are essentially additive. This appears to be broadly true in postoperative pain and migraine headache across a range of different drug combinations and when tested in the same and different trials. Some combinations of ibuprofen and codeine are available without prescription (but usually only from a pharmacy) where the dose of codeine is lower, and with a prescription when the dose of codeine is higher.Use of combination analgesics that contain codeine has been a source of some concern because of misuse from over-the-counter preparations. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus codeine for acute moderate-to-severe postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and the reference lists of articles. The date of the most recent search was 1 December 2014. SELECTION CRITERIA: Randomised, double-blind, placebo- or active-controlled clinical trials of single dose oral ibuprofen plus codeine for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus codeine, placebo, or the same dose of ibuprofen alone with at least 50% pain relief over six hours, using validated equations. We calculated the risk ratio (RR) and number needed to treat to benefit (NNT). We used information on the use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. Analyses were planned for different doses of ibuprofen and codeine, but especially for codeine where we set criteria for low (< 10 mg), medium (10 to 20 mg), and high (> 20 mg) doses. MAIN RESULTS: Since the last version of this review no new studies were found. Information was available from six studies with 1342 participants, using a variety of doses of ibuprofen and codeine. In four studies (443 participants) using ibuprofen 400 mg plus codeine 25.6 mg to 60 mg (high dose codeine) 64% of participants had at least 50% maximum pain relief with the combination compared to 18% with placebo. The NNT was 2.2 (95% confidence interval 1.8 to 2.6) (high quality evidence). In three studies (204 participants) ibuprofen plus codeine (any dose) was better than the same dose of ibuprofen (69% versus 55%) but the result was barely significant with a relative benefit of 1.3 (1.01 to 1.6) (moderate quality evidence). In two studies (159 participants) ibuprofen plus codeine appeared to be better than the same dose of codeine alone (69% versus 33%), but no analysis was done. There was no difference between the combination and placebo in the reporting of adverse events in these acute studies (moderate quality evidence). AUTHORS' CONCLUSIONS: The combination of ibuprofen 400 mg plus codeine 25.6 mg to 60 mg demonstrates good analgesic efficacy. Very limited data suggest that the combination is better than the same dose of either drug alone, and that similar numbers of people experience adverse events with the combination as with placebo.

Single dose oral ibuprofen plus codeine for acute postoperative pain in adults.

BACKGROUND: There is good evidence that combining two different analgesics in fixed doses in a single tablet can provide better pain relief in acute pain and headache than either drug alone, and that the drug-specific effects are essentially additive. This appears to be broadly true in postoperative pain and migraine headache across a range of different drug combinations and when tested in the same and different trials. Some combinations of ibuprofen and codeine are available without prescription (but usually only from a pharmacy) where the dose of codeine is lower, and with a prescription when the dose of codeine is higher. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus codeine for moderate to severe postoperative pain. We compared ibuprofen plus codeine with placebo and with the same dose of ibuprofen alone. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. The date of the most recent search was 30 September 2012. SELECTION CRITERIA: Randomised, double-blind, placebo- or active-controlled clinical trials of single dose oral ibuprofen plus codeine for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus codeine, placebo, or the same dose of ibuprofen alone with at least 50% pain relief over six hours, using validated equations. We calculated the relative risk (RR) and number needed to treat to benefit (NNT). We used information on the use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. Analyses were planned for different doses of ibuprofen and codeine, but especially for codeine where we set criteria for low (< 10 mg), medium (10 to 20 mg), and high (> 20 mg) doses. MAIN RESULTS: Information was available from six studies with 1342 participants, with a variety of doses of ibuprofen and codeine. In four studies (443 participants) using ibuprofen 400 mg plus codeine 25.6 to 60 mg (high dose codeine) 64% of participants had at least 50% maximum pain relief with the combination compared to 18% with placebo. The NNT was 2.2 (95% CI 1.8 to 2.6). In three studies (204 participants) ibuprofen plus codeine (any dose) was better than the same dose of ibuprofen (69% versus 55%) but the result was barely significant with a relative benefit of 1.3 (95% CI 1.01 to 1.6). In two studies (159 participants) ibuprofen plus codeine appeared to be better than the same dose of codeine alone (69% versus 33%), but no analysis was done. There was no difference between the combination and placebo in the reporting of adverse events in these acute studies. AUTHORS' CONCLUSIONS: The combination of ibuprofen 400 mg plus codeine 25.6 to 60 mg demonstrates good analgesic efficacy. Very limited data suggest that the combination is better than the same dose of either drug alone. Use of combination analgesics that contain codeine has been a source of some concern because of misuse from over-the-counter preparations.

Distinctive features of large complex virus genomes and proteomes.

More than a dozen large DNA viruses exceeding 240-kb genome size were recently discovered, including the "giant" mimivirus with a 1.2-Mb genome size. The detection of mimivirus and other large viruses has stimulated new analysis and discussion concerning the early evolution of life and the complexity and mechanisms of evolutionary transitions. This paper presents analysis in three contexts. (i) Genome signatures of large viruses tend to deviate from the genome signatures of their hosts, perhaps indicating that the large viruses are lytic in the hosts. (ii) Proteome composition within these viral genomes contrast with cellular organisms; for example, most eukaryotic genomes, with respect to acidic residue usages, select Glu over Asp, but the opposite generally prevails for the large viral genomes preferring Asp more than Glu. In comparing Phe vs. Tyr usage, the viral genomes select mostly Tyr over Phe, whereas in almost all bacterial and eukaryotic genomes, Phe is used more than Tyr. Interpretations of these contrasts are proffered with respect to protein structure and function. (iii) Frequent oligonucleotides and peptides are characterized in the large viral genomes. The frequent words may provide structural flexibility to interact with host proteins.

Distinguishing features of delta-proteobacterial genomes.

We analyzed several features of five currently available delta-proteobacterial genomes, including two aerobic bacteria exhibiting predatory behavior and three anaerobic sulfate-reducing bacteria. The delta genomes are distinguished from other bacteria by several properties: (i) The delta genomes contain two "giant" S1 ribosomal protein genes in contrast to all other bacterial types, which encode a single or no S1; (ii) in most delta-proteobacterial genomes the major ribosomal protein (RP) gene cluster is near the replication terminus whereas most bacterial genomes place the major RP cluster near the origin of replication; (iii) the delta genomes possess the rare combination of discriminating asparaginyl and glutaminyl tRNA synthetase (AARS) together with the amido-transferase complex (Gat CAB) genes that modify Asp-tRNA(Asn) into Asn-tRNA(Asn) and Glu-tRNA(Gln) into Gln-tRNA(Gln); (iv) the TonB receptors and ferric siderophore receptors that facilitate uptake and removal of complex metals are common among delta genomes; (v) the anaerobic delta genomes encode multiple copies of the anaerobic detoxification protein rubrerythrin that can neutralize hydrogen peroxide; and (vi) sigma(54) activators play a more important role in the delta genomes than in other bacteria. delta genomes have a plethora of enhancer binding proteins that respond to environmental and intracellular cues, often as part of two-component systems; (vii) delta genomes encode multiple copies of metallo-beta-lactamase enzymes; (viii) a host of secretion proteins emphasizing SecA, SecB, and SecY may be especially useful in the predatory activities of Myxococcus xanthus; (ix) delta proteobacteria drive many multiprotein machines in their periplasms and outer membrane, including chaperone-feeding machines, jets for slime secretion, and type IV pili. Bdellovibrio replicates in the periplasm of prey cells. The sulfate-reducing delta proteobacteria metabolize hydrogen and generate a proton gradient by electron transport. The predicted highly expressed genes from delta genomes reflect their different ecologies, metabolic strategies, and adaptations.

Genomic comparisons among gamma-proteobacteria.

Predicted highly expressed (PHX) genes are compared for 16 gamma-proteobacteria and their similarities and differences are interpreted with respect to known or predicted physiological characteristics of the organisms. Predicted highly expressed genes often reflect the organism's predominant lifestyle, habitat, nutrition sources and metabolic propensities. This technique allows to predict principal metabolic activities of the microorganisms operating in their natural habitats. Among our findings is an unusually high number of PHX enzymes acting in cell wall biosynthesis, amino acid biosynthesis and replication in the ant endosymbiont Blochmannia floridanus. We ascribe the abundance of these PHX genes to specific aspects of the relationship between the bacterium and its host. Xanthomonas campestris is unique with a very high number of PHX genes acting in flagellum biosynthesis, which may play a special role during its pathogenicity. Shewanella oneidensis possesses three protein complexes which all can function as complex I in the respiratory chain but only the Na(+)-transporting NADH:ubiquinone oxidoreductase nqr-2 operon is PHX. The PHX genes of Vibrio parahaemolyticus are consistent with the microorganism's adaptation to extremely fast growth rates. Comparative analysis of PHX genes from complex environmental genomic sequences as well as from uncultured pathogenic microbes can provide a novel, useful tool to predict global flux of matter and key intermediates.

Statistical signals in bioinformatics.

The Arthur M. Sackler Colloquium of the National Academy of Sciences, "Frontiers in Bioinformatics: Unsolved Problems and Challenges," organized by David Eisenberg, Russ Altman, and myself, was held October 15-17, 2004, to provide a forum for discussing concepts and methods in bioinformatics serving the biological and medical sciences. The deluge of genomic and proteomic data in the last two decades has driven the creation of tools that search and analyze biomolecular sequences and structures. Bioinformatics is highly interdisciplinary, using knowledge from mathematics, statistics, computer science, biology, medicine, physics, chemistry, and engineering.

Protein length in eukaryotic and prokaryotic proteomes.

We analyzed length differences of eukaryotic, bacterial and archaeal proteins in relation to function, conservation and environmental factors. Comparing Eukaryotes and Prokaryotes, we found that the greater length of eukaryotic proteins is pervasive over all functional categories and involves the vast majority of protein families. The magnitude of these differences suggests that the evolution of eukaryotic proteins was influenced by processes of fusion of single-function proteins into extended multi-functional and multi-domain proteins. Comparing Bacteria and Archaea, we determined that the small but significant length difference observed between their proteins results from a combination of three factors: (i) bacterial proteomes include a greater proportion than archaeal proteomes of longer proteins involved in metabolism or cellular processes, (ii) within most functional classes, protein families unique to Bacteria are generally longer than protein families unique to Archaea and (iii) within the same protein family, homologs from Bacteria tend to be longer than the corresponding homologs from Archaea. These differences are interpreted with respect to evolutionary trends and prevailing environmental conditions within the two prokaryotic groups.

Genomic and proteomic comparisons between bacterial and archaeal genomes and related comparisons with the yeast and fly genomes.

Bacterial, archaeal, yeast, and fly genomes are compared with respect to predicted highly expressed (PHX) genes and several genomic properties. There is a striking difference in the status of PHX ribosomal protein (RP) genes where the archaeal genome generally encodes more RP genes and fewer PHX RPs compared with bacterial genomes. The increase in RPs in archaea and eukaryotes compared with that in bacteria may reflect a more complex set of interactions in archaea and eukaryotes in regulating translation, e.g., differences in structure requiring scaffolding of longer rRNA molecules, expanded interactions with the chaperone machinery, and, in eukaryotic interactions with endoplasmic reticulum components. The yeast genome is similar to fast-growing bacteria in PHX genes but also features several cytoskeletal genes, including actin and tropomyosin, and several signal transduction regulatory proteins from the 14.3.3 family. The most PHX genes of Drosophila encode cytoskeletal and exoskeletal proteins. We found that the preference of a microorganism for an anaerobic metabolism correlates with the number of PHX enzymes of the glycolysis pathway that well exceeds the number of PHX enzymes acting in the tricarboxylic acid cycle. Conversely, if the number of PHX enzymes of the tricarboxylic acid cycle well exceeds the PHX enzymes of glycolysis, an aerobic metabolism is preferred. Where the numbers are approximately commensurate, a facultative growth behavior prevails.

Predicted highly expressed genes in archaeal genomes.

Based primarily on 16S rRNA sequence comparisons, life has been broadly divided into the three domains of Bacteria, Archaea, and Eukarya. Archaea is further classified into Crenarchaea and Euryarchaea. Archaea generally thrive in extreme environments as assessed by temperature, pH, and salinity. For many prokaryotic organisms, ribosomal proteins (RP), transcription/translation factors, and chaperone genes tend to be highly expressed. A gene is predicted highly expressed (PHX) if its codon usage is rather similar to the average codon usage of at least one of the RP, transcription/translation factors, and chaperone gene classes and deviates strongly from the average gene of the genome. The thermosome (Ths) chaperonin family represents the most salient PHX genes among Archaea. The chaperones Trigger factor and HSP70 have overlapping functions in the folding process, but both of these proteins are lacking in most archaea where they may be substituted by the chaperone prefoldin. Other distinctive PHX proteins of Archaea, absent from Bacteria, include the proliferating cell nuclear antigen PCNA, a replication auxiliary factor responsible for tethering the catalytic unit of DNA polymerase to DNA during high-speed replication, and the acidic RP P0, which helps to initiate mRNA translation at the ribosome. Other PHX genes feature Cell division control protein 48 (Cdc48), whereas the bacterial septation proteins FtsZ and minD are lacking in Crenarchaea. RadA is a major DNA repair and recombination protein of Archaea. Archaeal genomes feature a strong Shine-Dalgarno ribosome-binding motif more pronounced in Euryarchaea compared with Crenarchaea.

Predicting coding potential from genome sequence: application to betaherpesviruses infecting rats and mice.

Prediction of protein-coding regions and other features of primary DNA sequence have greatly contributed to experimental biology. Significant challenges remain in genome annotation methods, including the identification of small or overlapping genes and the assessment of mRNA splicing or unconventional translation signals in expression. We have employed a combined analysis of compositional biases and conservation together with frame-specific G+C representation to reevaluate and annotate the genome sequences of mouse and rat cytomegaloviruses. Our analysis predicts that there are at least 34 protein-coding regions in these genomes that were not apparent in earlier annotation efforts. These include 17 single-exon genes, three new exons of previously identified genes, a newly identified four-exon gene for a lectin-like protein (in rat cytomegalovirus), and 10 probable frameshift extensions of previously annotated genes. This expanded set of candidate genes provides an additional basis for investigation in cytomegalovirus biology and pathogenesis.

Comparative analysis of gene expression among low G+C gram-positive genomes.

We present a comparative analysis of predicted highly expressed (PHX) genes in the low G+C Gram-positive genomes of Bacillus subtilis, Bacillus halodurans, Listeria monocytogenes, Listeria innocua, Lactococcus lactis, Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Clostridium acetobutylicum, and Clostridium perfringens. Most enzymes acting in glycolysis and fermentation pathways are PHX in these genomes, but not those involved in the TCA cycle and respiration, suggesting that these organisms have predominantly adapted to grow rapidly in an anaerobic environment. Only B. subtilis and B. halodurans have several TCA cycle PHX genes, whereas the TCA pathway is entirely missing from the metabolic repertoire of the two Streptococcus species and is incomplete in Listeria, Lactococcus, and Clostridium. Pyruvate-formate lyase, an enzyme critical in mixed acid fermentation, is among the highest PHX genes in all these genomes except for C. acetobutylicum (not PHX), and B. subtilis, and B. halodurans (missing). Pyruvate-formate lyase is also prominently PHX in enteric gamma-proteobacteria, but not in other prokaryotes. Phosphotransferase system genes are generally PHX with selection of different substrates in different genomes. The various substrate specificities among phosphotransferase systems in different genomes apparently reflect on differences in habitat, lifestyle, and nutrient sources.

Genome comparisons and analysis.

As we enter the post-genomic era, with the accelerating availability of complete genome sequences, new theoretical approaches and new experimental techniques, our ability to dissect cellular processes at the molecular level continues to expand. Recent advances include the application of RNA interference methods to characterize loss-of-function phenotype genes in higher eukaryotes, comparative analysis of the human and mouse genome sequences, and methods for reconciling contradictory phylogenetic reconstructions. New developments feed into the increasingly rich content of databases such as the COG database. The next phase of research will be increasingly dominated by efforts to integrate the deluge of data into our understanding of biological systems.

Predicting gene expression levels from codon biases in alpha-proteobacterial genomes.

Predicted highly expressed (PHX) genes in five currently available high G+C complete alpha-proteobacterial genomes are analyzed. These include: the nitrogen-fixing plant symbionts Sinorhizobium meliloti (SINME) and Mesorhizobium loti (MESLO), the nonpathogenic aquatic bacterium Caulobacter crescentus (CAUCR), the plant pathogen Agrobacterium tumefaciens (AGRTU), and the mammalian pathogen Brucella melitensis (BRUME). Three of these genomes, SINME, AGRTU, and BRUME, contain multiple chromosomes or megaplasmids (>1 Mb length). PHX genes in these genomes are concentrated mainly in the major (largest) chromosome with few PHX genes found in the secondary chromosomes and megaplasmids. Tricarboxylic acid cycle and aerobic respiration genes are strongly PHX in all five genomes, whereas anaerobic pathways of glycolysis and fermentation are mostly not PHX. Only in MESLO (but not SINME) and BRUME are most glycolysis genes PHX. Many flagellar genes are PHX in MESLO and CAUCR, but mostly are not PHX in SINME and AGRTU. The nonmotile BRUME also carries many flagellar genes but these are generally not PHX and all but one are located in the second chromosome. CAUCR stands out among available prokaryotic genomes with 25 PHX TonB-dependent receptors. These are putatively involved in uptake of iron ions and other nonsoluble compounds.

Associations between human disease genes and overlapping gene groups and multiple amino acid runs.

Overlapping gene groups (OGGs) arise when exons of one gene are contained within the introns of another. Typically, the two overlapping genes are encoded on opposite DNA strands. OGGs are often associated with specific disease phenotypes. In this report, we identify genes with OGG architecture and genes encoding multiple long amino acid runs and examine their relations to diseases. OGGs appear to be susceptible to genomic rearrangements as happens commonly with the loci of the DiGeorge syndrome on human chromosome 22. We also examine the degree of conservation of OGGs between human and mouse. Our analyses suggest that (i) a high proportion of genes in OGG regions are disease-associated, (ii) genomic rearrangements are likely to occur within OGGs, possibly as a consequence of anomalous sequence features prevalent in these regions, and (iii) multiple amino acid runs are also frequently associated with pathologies.

Frequent oligonucleotide motifs in genomes of three streptococci.

Complete genomes of three closely related Gram-positive bacteria Streptococcus pyogenes, Streptococcus pneumoniae and Lactococcus lactis are analyzed for abundances of short DNA sequence motifs (frequent words). The character and extent of frequent words are strikingly different among these genomes. The frequent words of S.pneumoniae split into three categories: parts of the previously characterized RUP and BOX repetitive elements and a 24 bp tandem repeat in the gene SP1772. The most abundant frequent words of L.lactis are all related to the 13 bp motif, WWNTTACTGACRR or its inverted complement YYGTCAGTAANWW. Distributional analysis of this motif, which we called highly repetitive motif (HRM), indicates its possible dual role. Frequent occurrences immediately downstream of genes suggest a possible role in transcription termination whereas spacings of consecutive HRMs consistent with the DNA helical period are indicative of a protein-binding site. Two regions of the L.lactis genome feature an intriguing pattern of several periodically occurring HRMs separated by precisely 59 bp. In a striking contrast to S.pneumoniae and L.lactis, S.pyogenes contains hardly any frequent words.

Correlations between Shine-Dalgarno sequences and gene features such as predicted expression levels and operon structures.

This work assesses relationships for 30 complete prokaryotic genomes between the presence of the Shine-Dalgarno (SD) sequence and other gene features, including expression levels, type of start codon, and distance between successive genes. A significant positive correlation of the presence of an SD sequence and the predicted expression level of a gene based on codon usage biases was ascertained, such that predicted highly expressed genes are more likely to possess a strong SD sequence than average genes. Genes with AUG start codons are more likely than genes with other start codons, GUG or UUG, to possess an SD sequence. Genes in close proximity to upstream genes on the same coding strand in most genomes are significantly higher in SD presence. In light of these results, we discuss the role of the SD sequence in translation initiation and its relationship with predicted gene expression levels and with operon structure in both bacterial and archaeal genomes.

Heterogeneity of genome and proteome content in bacteria, archaea, and eukaryotes.

Our analysis compares bacteria, archaea, and eukaryota with respect to a wide assortment of genome and proteome properties. These properties include ribosomal protein gene distributions, chaperone protein contrasts, major variation of transcription/translation factors, gene encoding pathways of energy metabolism, and predicted protein expression levels. Significant differences within and between the three domains of life include protein lengths, information processing procedures, many metabolic and lipid biosynthesis pathways, cellular controls, and regulatory proteins. Differences among genomes are influenced by lifestyle, habitat, physiology, energy sources, and other factors.

Genes, pseudogenes, and Alu sequence organization across human chromosomes 21 and 22.

Human chromosomes 21 and 22 (mainly the q-arms) were the first complete parts of the human genome released. Our analysis of genes, pseudogenes (Psig), and Alu repeats across these chromosomes include the following findings: The number of gene structures containing untranslated exons exceeds 25%; the terminal exon tends to be the largest among exons, whereas, the initial intron tends to be the largest among introns; single-exon gene length is approximately the mean gene exon number times the mean internal exon length; processed Psig lengths are on average approximately the same as single-exon gene length; and the G+C content and length of genes are uncorrelated. The counts and distribution of genes, Psig, and Alu sequences and G+C variation are evaluated with respect to clusters and overdispersions. Other assessments concern comparisons of intergenic lengths, properties of Psig sequences, and correlations between Alu and Psig sequences.

Amino acid runs in eukaryotic proteomes and disease associations.

We present a comparative proteome analysis of the five complete eukaryotic genomes (human, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana), focusing on individual and multiple amino acid runs, charge and hydrophobic runs. We found that human proteins with multiple long runs are often associated with diseases; these include long glutamine runs that induce neurological disorders, various cancers, categories of leukemias (mostly involving chromosomal translocations), and an abundance of Ca(2 +) and K(+) channel proteins. Many human proteins with multiple runs function in development and/or transcription regulation and are Drosophila homeotic homologs. A large number of these proteins are expressed in the nervous system. More than 80% of Drosophila proteins with multiple runs seem to function in transcription regulation. The most frequent amino acid runs in Drosophila sequences occur for glutamine, alanine, and serine, whereas human sequences highlight glutamate, proline, and leucine. The most frequent runs in yeast are of serine, glutamine, and acidic residues. Compared with the other eukaryotic proteomes, amino acid runs are significantly more abundant in the fly. This finding might be interpreted in terms of innate differences in DNA-replication processes, repair mechanisms, DNA-modification systems, and mutational biases. There are striking differences in amino acid runs for glutamine, asparagine, and leucine among the five proteomes.