Developing and validating a cardiovascular risk score for patients in the community with prior cardiovascular disease

OBJECTIVE: Patients with atherosclerotic cardiovascular disease (CVD) vary significantly in their risk of future CVD events; yet few clinical scores are available to aid assessment of risk. We sought to develop a score for use in primary care that estimates short-term CVD risk in these patients. METHODS: Adults aged <80 years with prior CVD were identified from a New Zealand primary care cohort study (PREDICT), and linked to national mortality, hospitalisation and dispensing databases. A Cox model with an outcome of myocardial infarction, stroke or CVD death within 2 years was developed. External validation was performed in a cohort from the UK. RESULTS: 24 927 patients, 63% men, 63% European, median age 65 years (IQR 58-72 years), experienced 1480 CVD events within 2 years after a CVD risk assessment. A risk score including ethnicity, comorbidities, body mass index, creatine creatinine and treatment, in addition to established risk factors used in primary prevention, predicted a median 2-year CVD risk of 5.0% (IQR 3.5%-8.3%). A plot of actual against predicted event rates showed very good calibration throughout the risk range. The score performed well in the UK cohort but overestimated risk for those at highest risk, who were predominantly patients defined as having heart failure. CONCLUSIONS: The PREDICT-CVD secondary prevention score uses routine measurements from clinical practice that enable it to be implemented in a primary care setting. The score will facilitate risk communication between primary care practitioners and patients with prior CVD, particularly as a resource to show the benefit of risk factor modification

Regions identity between the genome of vertebrates and non-retroviral families of insect viruses

<p>Abstract</p> <p>Background</p> <p>The scope of our understanding of the evolutionary history between viruses and animals is limited. The fact that the recent availability of many complete insect virus genomes and vertebrate genomes as well as the ability to screen these sequences makes it possible to gain a new perspective insight into the evolutionary interaction between insect viruses and vertebrates. This study is to determine the possibility of existence of sequence identity between the genomes of insect viruses and vertebrates, attempt to explain this phenomenon in term of genetic mobile element, and try to investigate the evolutionary relationship between these short regions of identity among these species.</p> <p>Results</p> <p>Some of studied insect viruses contain variable numbers of short regions of sequence identity to the genomes of vertebrate with nucleotide sequence length from 28 bp to 124 bp. They are found to locate in multiple sites of the vertebrate genomes. The ontology of animal genes with identical regions involves in several processes including chromatin remodeling, regulation of apoptosis, signaling pathway, nerve system development and some enzyme-like catalysis. Phylogenetic analysis reveals that at least some short regions of sequence identity in the genomes of vertebrate are derived the ancestral of insect viruses.</p> <p>Conclusion</p> <p>Short regions of sequence identity were found in the vertebrates and insect viruses. These sequences played an important role not only in the long-term evolution of vertebrates, but also in promotion of insect virus. This typical win-win strategy may come from natural selection.</p

Minimal Absent Words in Prokaryotic and Eukaryotic Genomes

Minimal absent words have been computed in genomes of organisms from all domains of life. Here, we explore different sets of minimal absent words in the genomes of 22 organisms (one archaeota, thirteen bacteria and eight eukaryotes). We investigate if the mutational biases that may explain the deficit of the shortest absent words in vertebrates are also pervasive in other absent words, namely in minimal absent words, as well as to other organisms. We find that the compositional biases observed for the shortest absent words in vertebrates are not uniform throughout different sets of minimal absent words. We further investigate the hypothesis of the inheritance of minimal absent words through common ancestry from the similarity in dinucleotide relative abundances of different sets of minimal absent words, and find that this inheritance may be exclusive to vertebrates

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Burst of Young Retrogenes and Independent Retrogene Formation in Mammals

Retroposition and retrogenes gain increasing attention as recent studies show that they play an important role in human new gene formation. Here we examined the patterns of retrogene distribution in 8 mammalian genomes using 4 non-mammalian genomes as a contrast. There has been a burst of young retrogenes not only in primate lineages as suggested in a recent study, but also in other mammalian lineages. In mammals, most of the retrofamilies (the gene families that have retrogenes) are shared between species. In these shared retrofamilies, 14%–18% of functional retrogenes may have originated independently in multiple mammalian species. Notably, in the independently originated retrogenes, there is an enrichment of ribosome related gene function. In sharp contrast, none of these patterns hold in non-mammals. Our results suggest that the recruitment of the specific L1 retrotransposons in mammals might have been an important evolutionary event for the split of mammals and non-mammals and retroposition continues to be an important active process in shaping the dynamics of mammalian genomes, as compared to being rather inert in non-mammals

RsaI repetitive DNA in Buffalo Bubalus bubalis representing retrotransposons, conserved in bovids, are part of the functional genes

<p>Abstract</p> <p>Background</p> <p>Repetitive sequences are the major components of the eukaryotic genomes. Association of these repeats with transcribing sequences and their regulation in buffalo <it>Bubalus bubalis </it>has remained largely unresolved.</p> <p>Results</p> <p>We cloned and sequenced <it>RsaI </it>repeat fragments pDp1, pDp2, pDp3, pDp4 of 1331, 651, 603 and 339 base pairs, respectively from the buffalo, <it>Bubalus bubalis</it>. Upon characterization, these fragments were found to represent retrotransposons and part of some functional genes. The resultant clones showed cross hybridization only with buffalo, cattle, goat and sheep genomic DNA. Real Time PCR, detected ~2 × 10⁴copies of pDp1, ~ 3000 copies of pDp2 and pDp3 and ~ 1000 of pDp4 in buffalo, cattle, goat and sheep genomes, respectively. <it>RsaI </it>repeats are transcriptionally active in somatic tissues and spermatozoa. Accordingly, pDp1 showed maximum expression in lung, pDp2 and pDp3 both in Kidney, and pDp4 in ovary. Fluorescence <it>in situ </it>hybridization showed repeats to be distributed all across the chromosomes.</p> <p>Conclusions</p> <p>The data suggest that <it>RsaI </it>repeats have been incorporated into the exonic regions of various transcribing genes, possibly contributing towards the architecture and evolution of the buffalo and related genomes. Prospects of our present work in the context of comparative and functional genomics are highlighted.</p

The over-representation of binary DNA tracts in seven sequenced chromosomes

BACKGROUND: DNA tracts composed of only two bases are possible in six combinations: A+G (purines, R), C+T (pyrimidines, Y), G+T (Keto, K), A+C (Imino, M), A+T (Weak, W) and G+C (Strong, S). It is long known that all-pyrimidine tracts, complemented by all-purines tracts ("R.Y tracts"), are excessively present in analyzed DNA. We have previously shown that R.Y tracts are in vast excess in yeast promoters, and brought evidence for their role in gene regulation. Here we report the systematic mapping of all six binary combinations on the level of complete sequenced chromosomes, as well as in their different subregions. RESULTS: DNA tracts composed of the above binary base combinations have been mapped in seven sequenced chromosomes: Human chromosomes 21 and 22 (the major contigs); Drosophila melanogaster chr. 2R; Caenorhabditis elegans chr. I; Arabidopsis thaliana chr. II; Saccharomyces cerevisiae chr. IV and M. jannaschii. A huge over-representation, reaching million-folds, has been found for very long tracts of all binary motifs except S, in each of the seven organisms. Long R.Y tracts are the most excessive, except in D. melanogaster, where the K.M motif predominates. S (G, C rich) tracts are in excess mainly in CpG islands; the W motif predominates in bacteria. Many excessively long W tracts are nevertheless found also in the archeon and in the eukaryotes. The survey of complete chromosomes enables us, for the first time, to map systematically the intergenic regions. In human and other chromosomes we find the highest over-representation of the binary DNA tracts in the intergenic regions. These over-representations are only partly explainable by the presence of interspersed elements. CONCLUSIONS: The over-representation of long DNA tracts composed of five of the above motifs is the largest deviation from randomness so far established for DNA, and this in a wide range of eukaryotic and archeal chromosomes. A propensity for ready DNA unwinding is proposed as the functional role, explaining the evolutionary conservation of the huge excesses observed

A Critical Analysis of Atoh7 (Math5) mRNA Splicing in the Developing Mouse Retina

The Math5 (Atoh7) gene is transiently expressed during retinogenesis by progenitors exiting mitosis, and is essential for ganglion cell (RGC) development. Math5 contains a single exon, and its 1.7 kb mRNA encodes a 149-aa polypeptide. Mouse Math5 mutants have essentially no RGCs or optic nerves. Given the importance of this gene in retinal development, we thoroughly investigated the possibility of Math5 mRNA splicing by Northern blot, 3′RACE, RNase protection assays, and RT-PCR, using RNAs extracted from embryonic eyes and adult cerebellum, or transcribed in vitro from cDNA clones. Because Math5 mRNA contains an elevated G+C content, we used graded concentrations of betaine, an isostabilizing agent that disrupts secondary structure. Although ∼10% of cerebellar Math5 RNAs are spliced, truncating the polypeptide, our results show few, if any, spliced Math5 transcripts exist in the developing retina (<1%). Rare deleted cDNAs do arise via RT-mediated RNA template switching in vitro, and are selectively amplified during PCR. These data differ starkly from a recent study (Kanadia and Cepko 2010), which concluded that the vast majority of Math5 and other bHLH transcripts are spliced to generate noncoding RNAs. Our findings clarify the architecture of the Math5 gene and its mechanism of action. These results have implications for all members of the bHLH gene family, for any gene that is alternatively spliced, and for the interpretation of all RT-PCR experiments

Mapping the prion protein distribution in marsupials: insights from comparing opossum with mouse CNS

The cellular form of the prion protein (PrP(C)) is a sialoglycoprotein widely expressed in the central nervous system (CNS) of mammalian species during neurodevelopment and in adulthood. The location of the protein in the CNS may play a role in the susceptibility of a species to fatal prion diseases, which are also known as the transmissible spongiform encephalopathies (TSEs). To date, little is known about PrP(C) distribution in marsupial mammals, for which no naturally occurring prion diseases have been reported. To extend our understanding of varying PrP(C) expression profiles in different mammals we carried out a detailed expression analysis of PrP(C) distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). We detected lower levels of PrP(C) in white matter fiber bundles of opossum CNS compared to mouse CNS. This result is consistent with a possible role for PrP(C) in the distinct neurodevelopment and neurocircuitry found in marsupials compared to other mammalian species