Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)

Surgical treatment of tricuspid regurgitation after mitral valve surgery: a retrospective study in China

<p>Abstract</p> <p>Background</p> <p>Functional tricuspid regurgitation (TR) occurs in patients with rheumatic mitral valve disease even after mitral valve surgery. The aim of this study was to analyze surgical results of TR after previous successful mitral valve surgery.</p> <p>Methods</p> <p>From September 1996 to September 2008, 45 patients with TR after previous mitral valve replacement underwent second operation for TR. In those, 43 patients (95.6%) had right heart failure symptoms (edema of lower extremities, ascites, hepatic congestion, etc.) and 40 patients (88.9%) had atrial fibrillation. Twenty-six patients (57.8%) were in New York Heart Association (NYHA) functional class III, and 19 (42.2%) in class IV. Previous operations included: 41 for mechanical mitral valve replacement (91.1%), 4 for bioprosthetic mitral valve replacement (8.9%), and 7 for tricuspid annuloplasty (15.6%).</p> <p>Results</p> <p>The tricuspid valves were repaired with Kay's (7 cases, 15.6%) or De Vega technique (4 cases, 8.9%). Tricuspid valve replacement was performed in 34 cases (75.6%). One patient (2.2%) died. Postoperative low cardiac output (LCO) occurred in 5 patients and treated successfully. Postoperative echocardiography showed obvious reduction of right atrium and ventricle. The anterioposterior diameter of the right ventricle decreased to 25.5 ± 7.1 mm from 33.7 ± 6.2 mm preoperatively (P < 0. 05).</p> <p>Conclusion</p> <p>TR after mitral valve replacement in rheumatic heart disease is a serious clinical problem. If it occurs or progresses late after mitral valve surgery, tricuspid valve annuloplasty or replacement may be performed with satisfactory results. Due to the serious consequence of untreated TR, aggressive treatment of existing TR during mitral valve surgery is recommended.</p

Saccharomyces cerevisiae chitin biosynthesis activation by N-acetylchitooses depends on size and structure of chito-oligosaccharides

<p>Abstract</p> <p>Background</p> <p>To explore chitin synthesis initiation, the effect of addition of exogenous oligosaccharides on <it>in vitro </it>chitin synthesis was studied. Oligosaccharides of various natures and lengths were added to a chitin synthase assay performed on a <it>Saccharomyces cerevisiae </it>membrane fraction.</p> <p>Findings</p> <p><it>N</it>-acetylchito-tetra, -penta and -octaoses resulted in 11 to 25% [¹⁴C]-GlcNAc incorporation into [¹⁴C]-chitin, corresponding to an increase in the initial velocity. The activation appeared specific to <it>N</it>-acetylchitooses as it was not observed with oligosaccharides in other series, such as beta-(1,4), beta-(1,3) or alpha-(1,6) glucooligosaccharides.</p> <p>Conclusions</p> <p>The effect induced by the <it>N</it>-acetylchitooses was a saturable phenomenon and did not interfere with free GlcNAc and trypsin which are two known activators of yeast chitin synthase activity <it>in vitro</it>. The magnitude of the activation was dependent on both oligosaccharide concentration and oligosaccharide size.</p

Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation

The CECAM Electronic Structure Library and the modular software development paradigm

First-principles electronic structure calculations are very widely used thanks to the many successful software packages available. Their traditional coding paradigm is monolithic, i.e., regardless of how modular its internal structure may be, the code is built independently from others, from the compiler up, with the exception of linear-algebra and message-passing libraries. This model has been quite successful for decades. The rapid progress in methodology, however, has resulted in an ever increasing complexity of those programs, which implies a growing amount of replication in coding and in the recurrent re-engineering needed to adapt to evolving hardware architecture. The Electronic Structure Library (\esl) was initiated by CECAM (European Centre for Atomic and Molecular Calculations) to catalyze a paradigm shift away from the monolithic model and promote modularization, with the ambition to extract common tasks from electronic structure programs and redesign them as free, open-source libraries. They include ``heavy-duty'' ones with a high degree of parallelisation, and potential for adaptation to novel hardware within them, thereby separating the sophisticated computer science aspects of performance optimization and re-engineering from the computational science done by scientists when implementing new ideas. It is a community effort, undertaken by developers of various successful codes, now facing the challenges arising in the new model. This modular paradigm will improve overall coding efficiency and enable specialists (computer scientists or computational scientists) to use their skills more effectively. It will lead to a more sustainable and dynamic evolution of software as well as lower barriers to entry for new developers

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN

Childhood rhabdomyosarcoma metastatic to bone marrow presenting with disseminated intravascular coagulation and acute tumour lysis syndrome: review of the literature apropos of two cases

The paper presents diagnostic and therapeutic difficulties in two adolescents with widespread rhabdomyosarcoma (RMS) presenting with severe haemorrhages resulting from disseminated intravascular coagulation (DIC) and with laboratory features of acute tumour lysis syndrome (ATLS). Other published cases of childhood RMS with DIC at admission have been listed and reviewed. It has been concluded that the clinical picture of a widespread RMS in children may resemble acute hematologic malignancy and pose a big diagnostic problem. That is why the presence of small blue round cells morphologically similar to lymphoblasts and/or myeloblasts in bone marrow (BM), lacking hematopoietic makers, should prompt the pathologist to consider possible diagnosis of RMS. Inclusion of desmin, MyoD1 and myogenin Myf4 to the immunohistochemical panel is obligatory in such cases. When the representative histopathological tumour specimens are difficult to obtain, the flow cytometric immunophenotyping of BM metastases could help the standard morphological/immunohistological diagnostic procedures and advance the diagnosis. Recently, the flow cytometric CD45− CD56+ immunophenotype together with Myf4 transcript has been assigned to RMS cells infiltrating BM. In children with disseminated RMS complicated with DIC rapid polychemotherapy aimed at diminishing the malignancy-triggered procoagulant activity should be initiated. However, in cases with concomitant ATLS the initial doses of chemotherapy should be reduced and the metabolic disorders and renal function monitored. The prognosis in children with RMS metastatic to BM with signs of DIC or ATLS at admission depends on the response to chemotherapy, however generally it is highly disappointing

Effects of Pre-Natal Vitamin D Supplementation with Partial Correction of Vitamin D Deficiency on Early Life Healthcare Utilisation: A Randomised Controlled Trial

Funded by Asthma UK grant number 09/ 36