Surgical reconstruction of the left main coronary artery with patch-angioplasty

<p>Abstract</p> <p>Background</p> <p>Conventional coronary artery bypass grafting (CABG) has been established as the treatment of choice for left main coronary artery (LMCA) stenosis However, the conventional grafting provides a retrograde perfusion to extensive myocardial area and leads prospectively to competitive flow of the non-occluded coronaries thus consuming the grafts. Surgical reconstruction of the LMCA with patch-angioplasty is an alternative method that eliminates these drawbacks.</p> <p>Methods</p> <p>Between February 1997 and July 2007, 37 patients with isolated LMCA stenosis were referred for surgical ostial reconstruction. In 27 patients (73%) surgical angioplasties have been performed. All patients were followed up clinically and with transesophageal echocardiography (TEE) and coronary angiography when required.</p> <p>Results</p> <p>In 10 patients (27%) a LMCA stenosis could not be confirmed. There were no early mortality or perioperative myocardial infarctions. The postoperative course was uneventful in all patients. In 25 patients, TEE demonstrated a wide open main stem flow pattern one to six months after reconstruction of the left main coronary artery with one patch mild aneurysmal dilated.</p> <p>Conclusions</p> <p>The surgical reconstruction with patch-angioplasty is a safe and effective method for the treatment of proximal and middle LMCA stenosis. Almost one third of the study group had no really LMCA stenosis: antegrade flow pattern remained sustained and the arterial grafts have been spared. In the cases of unclear or suspected LMCA stenosis, cardio-CT can be performed to unmask catheter-induced coronary spasm as the underlying reason for isolated LMCA stenosis.</p

Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1–/– mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1–/– mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Polymorphisms of TP53 codon 72 with breast carcinoma risk: evidence from 12226 cases and 10782 controls

<p>Abstract</p> <p>Background</p> <p>Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. A number of studies have conducted on the association of TP53 codon 72 polymorphisms with susceptibility to breast carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship.</p> <p>Methods</p> <p>We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Jan 2009. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications.</p> <p>Results</p> <p>A total of seventeen case-control studies, including 12226 cases and 10782 controls, met the included criteria and thus were selected. Ultimately, the relevant data were extracted and further analyzed using systematic meta-analyses. Overall, no associations of TP53 codon 72 polymorphisms with breast carcinoma were observed (for Arg/Arg vs Pro/Pro: OR = 1.20; 95%CI = 0.96–1.50; for dominant model: OR = 1.12; 95%CI = 0.96–1.32; for recessive model: OR = 1.13; 95%CI = 0.98–1.31). In the subgroup analysis by ethnicity, statistically similar results were obtained when the data were stratified as Asians, Caucasians and Africans.</p> <p>Conclusion</p> <p>Collectively, the results of the present study suggest that <it>TP53 codon 72 </it>polymorphisms might not be a low-penetrant risk factor for developing breast carcinoma.</p

A systematic review of the clinical effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of suspected coronary artery disease

<p>Abstract</p> <p>Background</p> <p>This systematic review summarized recent evidence pertaining to the clinical effectiveness of 64-slice or higher computed tomography angiography (CTA) in patients with suspected coronary artery disease (CAD). If CTA proves to be a successful diagnostic performance measure, it could prevent the use of invasive diagnostic procedures in some patients. This would provide multiple health and cost benefits, particularly for under resourced areas where invasive coronary angiography is not always available.</p> <p>Methods</p> <p>A systematic method of literature searching and selection was employed with searches limited to December 2006 to March 2009. Included studies were quality assessed using National Health and Medical Research Council (NHMRC) diagnostic levels of evidence and a modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Individual and pooled diagnostic performance measures were calculated using standard meta-analytic techniques at the patient, vessel and segment level. A positive result was defined as greater than or equal to 50% stenosis.</p> <p>Results</p> <p>Twenty-eight studies were included in the systematic review examining 3,674 patients. The primary meta-analysis at the patient-level indicated a sensitivity of 98.2% and specificity of 81.6%. The median (range) positive predictive value (PPV) was 90.5% (76%-100%) and negative predictive value (NPV) 99.0% (83%-100%). In all vessels, the pooled sensitivity was 94.9%, specificity 89.5%, and median (range) PPV 75.0% (53%-95%) and NPV 99.0% (93%-100%). At the individual artery level, overall diagnostic accuracy appeared to be slightly higher in the left main coronary artery and slightly lower in the left anterior descending and circumflex artery. In all segments, the sensitivity was 91.3%, specificity 94.0% and median (range) PPV 69.0% (44%-86%) and NPV 99.0% (98%-100%).</p> <p>Conclusions</p> <p>The high sensitivity indicates that CTA can effectively identify the majority of patients with significant coronary artery stenosis. The high NPV at the patient, vessel and segment level establishes CTA as an effective non-invasive alternative to invasive coronary angiography (ICA) for the exclusion of stenosis.</p

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death

Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway

The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases

Biochemical, structural and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) to be a 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 to be more closely related to the JmjC hydroxylases than to the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the translation factor (TRAFAC) family of GTPases, developmentally regulated GTP-binding proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(ii)- and 2OG-dependent hydroxylation of a highly conserved lysine residue in DRG1/2; amino-acid analyses reveal that JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.Fil: Markolovic, Suzana. University of Oxford; Reino UnidoFil: Zhuang, Qinqin. University Of Birmingham; Reino UnidoFil: Wilkins, Sarah E.. University of Oxford; Reino UnidoFil: Eaton, Charlotte D.. University Of Birmingham; Reino UnidoFil: Abboud, Martine I.. University of Oxford; Reino UnidoFil: Katz, Maximiliano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: McNeil, Helen E.. University Of Birmingham; Reino UnidoFil: Leśniak, Robert K.. University of Oxford; Reino UnidoFil: Hall, Charlotte. University Of Birmingham; Reino UnidoFil: Struwe, Weston B.. University of Oxford; Reino UnidoFil: Konietzny, Rebecca. University of Oxford; Reino UnidoFil: Davis, Simon. University of Oxford; Reino UnidoFil: Yang, Ming. The Francis Crick Institute; Reino Unido. University of Oxford; Reino UnidoFil: Ge, Wei. University of Oxford; Reino UnidoFil: Benesch, Justin L. P.. University of Oxford; Reino UnidoFil: Kessler, Benedikt M.. University of Oxford; Reino UnidoFil: Ratcliffe, Peter J.. University of Oxford; Reino Unido. The Francis Crick Institute; Reino UnidoFil: Cockman, Matthew E.. The Francis Crick Institute; Reino Unido. University of Oxford; Reino UnidoFil: Fischer, Roman. University of Oxford; Reino UnidoFil: Wappner, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Chowdhury, Rasheduzzaman. University of Stanford; Estados Unidos. University of Oxford; Reino UnidoFil: Coleman, Mathew L.. University Of Birmingham; Reino UnidoFil: Schofield, Christopher J.. University of Oxford; Reino Unid

The effects of repeated-sprint training on field-based fitness measures: a meta-analysis of controlled and non-controlled trials

Background: Repeated-sprint training appears to be an efficient and practical means for the simultaneous development of different components of fitness relevant to team sports. Objective: Our objective was to systematically review the literature and meta-analyse the effect of repeated-sprint training on a selection of field-based measures of athletic performance, i.e. counter-movement jump, 10 m sprint, 20 m sprint, 30 m sprint, repeated-sprint ability and high-intensity intermittent running performance. Data Sources: The SPORTDiscus, PubMed, MEDLINE and Web of Science databases were searched for original research articles. Search terms included 'repeated-sprint training', 'sprint training', 'aerobic endurance', 'repeated-sprint ability', 'counter-movement jump' and 'sprint performance'. Study Selection: Inclusion criteria included intervention consisting of a series of ≤10 s sprints with ≤60 s recovery; trained participants; intervention duration of 2–12 weeks; field-based fitness measures; running- or cycling-based intervention; published up to, and including, February 2014. Data Extraction: Our final dataset included six trials for counter-movement jump (two controlled trials), eight trials for 10 m sprint, four trials for 20 m sprint (three controlled trials), two trials for 30 m sprint, eight trials for repeated-sprint ability and three trials for high-intensity intermittent running performance. Analyses were conducted using comprehensive meta-analysis software. Uncertainty in the meta-analysed effect of repeated-sprint training was expressed as 95 % confidence limits (CL), along with the probability that the true value of the effect was trivial, beneficial or harmful. Magnitude-based inferences were based on standardised thresholds for small, moderate and large changes of 0.2, 0.6 and 1.2 standard deviations, respectively. Results: Repeated-sprint training had a likely small beneficial effect in non-controlled counter-movement jump trials (effect size 0.33; 95 % CL ±0.30), with a possibly moderate beneficial effect in controlled trials (0.63; 95 % CL ±0.44). There was a very likely small beneficial effect on 10 m sprint time in non-controlled trials (−0.42; 95 % CL ±0.24), with a possibly moderate beneficial effect on 20 m sprint time in non-controlled (−0.49; 95 % CL ±0.46) and controlled (−0.65; 95 % CL ±0.61) trials. Repeated-sprint training had a possibly large beneficial effect on 30 m sprint performance in non-controlled trials (−1.01; 95 % CL ±0.93), with possibly moderate beneficial effects on repeated-sprint ability (−0.62; 95 % CL ±0.25) and high-intensity intermittent running performance (−0.61; 95 % CL ±0.54). Conclusions: Repeated-sprint training can induce small to large improvements in power, speed, repeated-sprint ability and endurance, and may have relevance for training in team sports