The metabolism and de-bromination of bromotyrosine in vivo

During inflammation, leukocyte-derived eosinophil peroxidase catalyses the formation of hypobromous acid, which can brominate tyrosine residues in proteins to form bromotyrosine. Since eosinophils are involved in the pathogenesis of allergic reactions, such as asthma, urinary bromotyrosine level has been used for the assessment of children with asthma. However, little is known about the metabolism and disposition of bromotyrosine in vivo. The aim of this study was to identify the major urinary metabolites formed during bromotyrosine metabolism and to develop mass spectrometric methods for their quantitation. Deuterium-labeled bromotyrosine was synthesized by deuterium exchange. [D3]bromotyrosine (500 nmole) was injected intraperitoneally into Sprague-Dawley rats and urine was collected for 24 h in a metabolic cage. 13C-labeled derivatives of bromotyrosine and its major urinary metabolite were synthesized and used as internal standards for quantitation. Following solid phase extraction, urine samples were derivatized to the pentafluorobenzyl ester, and analyzed using isotope dilution gas chromatography and negative-ion chemical ionization mass spectrometry. A novel brominated metabolite, 3-bromo-4-hydroxyphenylacetic acid (bromo-HPA), was identified as the major brominated metabolite of bromotyrosine. Bromo-HPA only accounted for 0.43±0.04% of infused [D3]bromotyrosine and 0.12±0.02% of infused [D3]bromotyrosine was excreted in the urine unchanged. However, ~1.3% (6.66±1.33 nmole) of infused [D3]bromotyrosine was excreted in the urine as the de-brominated metabolite, [D3]4-hydroxyphenylacetic acid, which is also a urinary metabolite of tyrosine in mammals. We also tested whether or not iodotyrosine dehalogenase can catalyse de-bromination of bromotyrosine and showed that iodotyrosine dehalogenase is able to de-brominate free bromotyrosine in vitro. We identified bromo-HPA as the main brominated urinary metabolite of bromotyrosine in rats. However, de-halogenation of bromotyrosine is the major metabolic pathway to eliminate free brominated tyrosine in vivo

Early sac shrinkage predicts a low risk of late complications after endovascular aortic aneurysm repair

Background Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). Patients with early postoperative shrinkage may experience fewer subsequent complications, and consequently require less intensive surveillance. Methods Patients undergoing EVAR from 2000 to 2011 at three vascular centres (in 2 countries), who had two imaging examinations (postoperative and after 6-18 months), were included. Maximum diameter, complications and secondary interventions during follow-up were registered. Patients were categorized according to early sac dynamics. The primary endpoint was freedom from late complications. Secondary endpoints were freedom from secondary intervention, postimplant rupture and direct (type I/III) endoleaks. Results Some 597 EVARs (71·1 per cent of all EVARs) were included. No shrinkage was observed in 284 patients (47·6 per cent), moderate shrinkage (5-9 mm) in 142 (23·8 per cent) and major shrinkage (at least 10 mm) in 171 patients (28·6 per cent). Four years after the index imaging, the rate of freedom from complications was 84·3 (95 per cent confidence interval 78·7 to 89·8), 88·1 (80·6 to 95·5) and 94·4 (90·1 to 98·7) per cent respectively. No shrinkage was an independent risk factor for late complications compared with major shrinkage (hazard ratio (HR) 3·11; P < 0·001). Moderate compared with major shrinkage (HR 2·10; P = 0·022), early postoperative complications (HR 3·34; P < 0·001) and increasing abdominal aortic aneurysm baseline diameter (HR 1·02; P = 0·001) were also risk factors for late complications. Freedom from secondary interventions and direct endoleaks was greater for patients with major sac shrinkage. Conclusion Early change in aneurysm sac diameter is a strong predictor of late complications after EVAR. Patients with major sac shrinkage have a very low risk of complications for up to 5 years. This parameter may be used to tailor postoperative surveillance. Towards personalized surveillanc

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk

International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: Device-associated module

•We report INICC device-associated module data of 50 countries from 2010-2015.•We collected prospective data from 861,284 patients in 703 ICUs for 3,506,562 days.•DA-HAI rates and bacterial resistance were higher in the INICC ICUs than in CDC-NHSN's.•Device utilization ratio in the INICC ICUs was similar to CDC-NHSN's. Background: We report the results of International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2010-December 2015 in 703 intensive care units (ICUs) in Latin America, Europe, Eastern Mediterranean, Southeast Asia, and Western Pacific. Methods: During the 6-year study period, using Centers for Disease Control and Prevention National Healthcare Safety Network (CDC-NHSN) definitions for device-associated health care-associated infection (DA-HAI), we collected prospective data from 861,284 patients hospitalized in INICC hospital ICUs for an aggregate of 3,506,562 days. Results: Although device use in INICC ICUs was similar to that reported from CDC-NHSN ICUs, DA-HAI rates were higher in the INICC ICUs: in the INICC medical-surgical ICUs, the pooled rate of central line-associated bloodstream infection, 4.1 per 1,000 central line-days, was nearly 5-fold higher than the 0.8 per 1,000 central line-days reported from comparable US ICUs, the overall rate of ventilator-associated pneumonia was also higher, 13.1 versus 0.9 per 1,000 ventilator-days, as was the rate of catheter-associated urinary tract infection, 5.07 versus 1.7 per 1,000 catheter-days. From blood cultures samples, frequencies of resistance of Pseudomonas isolates to amikacin (29.87% vs 10%) and to imipenem (44.3% vs 26.1%), and of Klebsiella pneumoniae isolates to ceftazidime (73.2% vs 28.8%) and to imipenem (43.27% vs 12.8%) were also higher in the INICC ICUs compared with CDC-NHSN ICUs. Conclusions: Although DA-HAIs in INICC ICU patients continue to be higher than the rates reported in CDC-NSHN ICUs representing the developed world, we have observed a significant trend toward the reduction of DA-HAI rates in INICC ICUs as shown in each international report. It is INICC's main goal to continue facilitating education, training, and basic and cost-effective tools and resources, such as standardized forms and an online platform, to tackle this problem effectively and systematically

ILC Reference Design Report Volume 1 - Executive Summary

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization

ILC Reference Design Report Volume 4 - Detectors

This report, Volume IV of the International Linear Collider Reference Design Report, describes the detectors which will record and measure the charged and neutral particles produced in the ILC's high energy e+e- collisions. The physics of the ILC, and the environment of the machine-detector interface, pose new challenges for detector design. Several conceptual designs for the detector promise the needed performance, and ongoing detector R&D is addressing the outstanding technological issues. Two such detectors, operating in push-pull mode, perfectly instrument the ILC interaction region, and access the full potential of ILC physics.This report, Volume IV of the International Linear Collider Reference Design Report, describes the detectors which will record and measure the charged and neutral particles produced in the ILC's high energy e+e- collisions. The physics of the ILC, and the environment of the machine-detector interface, pose new challenges for detector design. Several conceptual designs for the detector promise the needed performance, and ongoing detector R&D is addressing the outstanding technological issues. Two such detectors, operating in push-pull mode, perfectly instrument the ILC interaction region, and access the full potential of ILC physics

ILC Reference Design Report Volume 3 - Accelerator

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2 s^-1. The complex includes a polarized electron source, an undulator-based positron source, two 6.7 km circumference damping rings, two-stage bunch compressors, two 11 km long main linacs and a 4.5 km long beam delivery system. This report is Volume III (Accelerator) of the four volume Reference Design Report, which describes the design and cost of the ILC.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2 s^-1. The complex includes a polarized electron source, an undulator-based positron source, two 6.7 km circumference damping rings, two-stage bunch compressors, two 11 km long main linacs and a 4.5 km long beam delivery system. This report is Volume III (Accelerator) of the four volume Reference Design Report, which describes the design and cost of the ILC

International Linear Collider Reference Design Report Volume 2: PHYSICS AT THE ILC

This article reviews the physics case for the ILC. Baseline running at 500 GeV as well as possible upgrades and options are discussed. The opportunities on Standard Model physics, Higgs physics, Supersymmetry and alternative theories beyond the Standard Model are described.This article reviews the physics case for the ILC. Baseline running at 500 GeV as well as possible upgrades and options are discussed. The opportunities on Standard Model physics, Higgs physics, Supersymmetry and alternative theories beyond the Standard Model are described