Copying letters to patients with cystic fibrosis (CF): Letter content and patient perceptions of benefit

Background: Copying letters involves generating an extra copy of all correspondence between healthcare professionals about the patient, to the patient.

Complete Sudoku - extra rules for more symmetry

We propose some extra rules to add to the well-known Sudoku puzzle and present an argument to justify their inclusion. The rules mean that puzzles can be created with fewer cells completed initially yet which still have only one solution. We have created a Web-based program which can be used to generate and solve both standard and extended (Complete) puzzles.

The DUB/USP17 deubiquitinating enzymes: A gene family within a tandemly repeated sequence, is also embedded within the copy number variable Beta-defensin cluste

Background: The DUB/USP17 subfamily of deubiquitinating enzymes were originally identified as immediate early genes induced in response to cytokine stimulation in mice (DUB-1, DUB-1A, DUB-2, DUB-2A). Subsequently we have identified a number of human family members and shown that one of these (DUB-3) is also cytokine inducible. We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the 'CAAX' box protease RCE1.

Results: Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable betadefensin cluster. In addition, we show that the multiple genes observed in humans and other distantly related mammals have arisen due to the independent expansion of an ancestral sequence within each species. However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating.

Conclusions: The observation that the DUB/USP17 genes, which can influence cell growth and survival, have evolved from an unstable ancestral sequence which has undergone multiple and varied duplications in the species examined marks this as a unique family. In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

Estimating the masses of extra-solar planets

All extra-solar planet masses that have been derived spectroscopically are lower limits since the inclination of the orbit to our line-of-sight is unknown except for transiting systems. In theory, however, it is possible to determine the inclination angle, i, between the rotation axis of a star and an observer's line-of-sight from measurements of the projected equatorial velocity (v sin i), the stellar rotation period (P(rot)) and the stellar radius (R(*)). For stars which host planetary systems this allows the removal of the sin i dependency of extra-solar planet masses derived from spectroscopic observations under the assumption that the planetary orbits lie perpendicular to the stellar rotation axis.
We have carried out an extensive literature search and present a catalogue of v sin i, P(rot) and R(*) estimates for stars hosting extra-solar planets. In addition, we have used Hipparcos parallaxes and the Barnes-Evans relationship to further supplement the R(*) estimates obtained from the literature. Using this catalogue, we have obtained sin i estimates using a Markov-chain Monte Carlo analysis. This technique allows proper 1 Sigma two-tailed confidence limits to be placed on the derived sin i's along with the transit probability for each planet to be determined.
While we find that a small proportion of systems yield sin i's significantly greater than 1, most likely due to poor P(rot) estimations, the large majority are acceptable. We are further encouraged by the cases where we have data on transiting systems, as the technique indicates inclinations of similar to 90 degrees and high transit probabilities. In total, we are able to estimate the true masses of 133 extra-solar planets. Of these 133 extra-solar planets, only six have revised masses that place them above the 13M(J) deuterium burning limit; four of those six extra-solar planet candidates were already suspected to lie above the deuterium burning limit before correcting their masses for the sin i dependency. Our work reveals a population of high-mass extra-solar planets with low eccentricities, and we speculate that these extra-solar planets may represent the signature of different planetary formation mechanisms at work. Finally, we discuss future observations that should improve the robustness of this technique.

Targets of genome copy number reduction in primary breast cancers identified by integrative genomics

The identification of specific oncogenes and tumor suppressor genes in regions of recurrent aneuploidy is a major challenge of molecular cancer research. Using both oligonucleotide single-nucleotide polymorphism and mRNA expression arrays, we integrated genomic and transcriptional information to identify and prioritize candidate cancer genes in regions of increased and decreased chromosomal copy number in a cohort of primary breast cancers. Confirming the validity of this approach, several regions of previously-known copy number (CN) alterations in breast cancer could be successfully reidentified. Focusing on regions of decreased CN, we defined a prioritized list of eighteen candidate genes, which included ARPIN, FBNI, and LZTSI, previously shown to be associated with cancers in breast or other tissue types, and novel genes such as P29, MORF4LI, and TBCID5. One such gene, the RUNX3 transcription factor, was selected for further study. We show that RUNX3 is present at reduced CNs in proportion to the rest of the tumor genome and that RUNX3 CN reductions can also be observed in a breast cancer series from a different center. Using tissue microarrays, we demonstrate in an independent cohort of over 120 breast tissues that RUNX3 protein is expressed in normal breast epithelium but not fat and stromal tissue, and widely down-regulated in the majority of breast cancers (> 85%). In vitro, RUNX3 overexpression suppressed the invasive potential of MDA-MB-231 breast cancer cells in a matrigel assay. Our results demonstrate the utility of integrative genomic approaches to identify novel potential cancer-related genes in primary tumors. This article contains Supplementary Material available at http:// www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2006 Wiley-Liss, Inc.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1-4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.