Centromere-associated protein-E (CENP-E) is an essential mitotic kinesin that is required for efficient, stable microtubule capture at kinetochores. It also directly binds to BubR1, a ...kinetochore-associated kinase implicated in the mitotic checkpoint, the major cell cycle control pathway in which unattached kinetochores prevent anaphase onset. Here, we show that single unattached kinetochores depleted of CENP-E cannot block entry into anaphase, resulting in aneuploidy in 25% of divisions in primary mouse fibroblasts in vitro and in 95% of regenerating hepatocytes in vivo. Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal.
Background Left ventricular end-diastolic pressure (LVEDP) is frequently measured during primary percutaneous coronary intervention (PCI). However, little is known of this measurement's utility in ...predicting outcomes or informing treatment decisions. We sought to determine the prognostic value of LVEDP measured during primary PCI for ST-segment elevation myocardial infarction (STEMI). Methods We studied 1,909 (33.2%) of 5,745 STEMI patients in whom LVEDP was measured during primary PCI in the APEX-AMI trial. Cox regression analysis was used to evaluate whether LVEDP was an independent predictor of mortality and the composite of death, cardiogenic shock, or congestive heart failure (CHF) at 90 days. Results The median (25th, 75th percentiles) LVEDP level was 22 mm Hg (16, 29); compared with patients with LVEDP ≤22 mm Hg, those with LVEDP >22 mm Hg had higher rates of CHF (7.3% vs 3.1%, P < .001), cardiogenic shock (4.6% vs 1.7%, P < .001), and death (4.1% vs 2.2%, P = .014) at 90 days. After multivariable adjustment, LVEDP was associated with increased risk of mortality through 90 days (adjusted hazard ratio 1.22, 95% CI 1.02-1.46, per 5-mmHg increase, P = .044) and the composite of death, cardiogenic shock, or CHF within the first 2 days (adjusted hazard ratio 1.40, 95% CI 1.23-1.59, per 5-mm Hg increase, P < .001), but not from day 3 to 90 ( P = .25). Conclusions Left ventricular end-diastolic pressure measured during primary PCI for STEMI is an independent predictor of inhospital and longer term cardiovascular outcomes. Measuring LVEDP may be useful to stratify patient risk and guide postinfarct treatment.
Abnormal chromosome content - also known as aneuploidy - is the most common characteristic of human solid tumours. It has therefore been proposed that aneuploidy contributes to, or even drives, ...tumour development. The mitotic checkpoint guards against chromosome mis-segregation by delaying cell-cycle progression through mitosis until all chromosomes have successfully made spindle-microtubule attachments. Defects in the mitotic checkpoint generate aneuploidy and might facilitate tumorigenesis, but more severe disabling of checkpoint signalling is a possible anticancer strategy.
Diagnostic strategies with ECG and serum cardiac markers have been used to rule out acute myocardial infarction in 6 to 12 hours. The present study evaluated whether a multimarker strategy that used ...point-of-care measurement of myoglobin, creatine kinase (CK)-MB, and troponin I could exclude acute myocardial infarction in </=3 hours.
We prospectively enrolled consecutive patients (n=817) in the emergency department who were evaluated for possible acute myocardial infarction. In patients with nondiagnostic ECGs, we measured CK-MB, troponin I, and myoglobin with a point-of-care device at presentation and at 90 minutes, 3 hours, and 9 hours. Standard central laboratory testing of CK-MB was done at the same time intervals, and triage decisions were made by emergency physicians who were unaware of point-of-care results. Sensitivity and negative predictive value were compared for both the multimarker, point-of-care approach and the central laboratory strategy. Sensitivity and negative predictive value for point-of-care combination of myoglobin and troponin I by 90 minutes was 96.9% and 99.6%, respectively. CK-MB measurements and blood sampling at 3 hours did not improve sensitivity or negative predictive value. Median time from sampling to reporting of results was 71.0 minutes for the central laboratory versus 24.0 minutes for the point-of-care device (P<0.001).
Acute myocardial infarction can be excluded rapidly in the emergency department by use of point-of-care measurements of myoglobin and troponin I during the first 90 minutes after presentation.
5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzodoxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular ...dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.
Complement activation mediates myocardial damage that occurs during ischemia and reperfusion through multiple pathways. We performed 2 separate, parallel, double-blind, placebo-controlled trials to ...determine the effects of pexelizumab (a novel C5 complement monoclonal antibody fragment) on infarct size in patients receiving reperfusion therapy: COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) and COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA). The COMPLY trial is reported here.
Overall, 943 patients with acute ST-segment elevation myocardial infarction (MI) (20% with isolated inferior MI) receiving fibrinolysis were randomly assigned <6 hours after symptom onset to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg per h for 20 hours. Infarct size determined by creatine kinase-MB area under the curve was the primary analysis, which included patients who received at least some study drug and fibrinolysis (n=920). The median infarct size did not differ by treatment (placebo, 5230; bolus, 4952; bolus plus infusion, 5557 ng/mL x h; bolus versus placebo, P=0.85; bolus plus infusion versus placebo, P=0.81), nor did the 90-day composite incidence of death, new or worsening congestive heart failure, shock, or stroke (placebo, 18.6%; bolus, 18.4%; bolus plus infusion, 19.7%). Pexelizumab inhibited complement for 4 hours with bolus-only dosing and for 20 to 24 hours with bolus-plus-infusion dosing, with no increase in infections.
When used adjunctively with fibrinolysis, pexelizumab blocked complement activity but reduced neither infarct size by creatine kinase-MB assessment nor adverse clinical outcomes.
Within the NDACC (Network for the Detection of Atmospheric Composition Change), more than 20 FTIR (Fourier-transform infrared) spectrometers, spread worldwide, provide long-term data records of many ...atmospheric trace gases. We present a method that uses measured and modelled XCO2 for assessing the consistency of these NDACC data records. Our XCO2 retrieval setup is kept simple so that it can easily be adopted for any NDACC/FTIR-like measurement made since the late 1950s. By a comparison to coincident TCCON (Total Carbon Column Observing Network) measurements, we empirically demonstrate the useful quality of this suggested NDACC XCO2 product (empirically obtained scatter between TCCON and NDACC is about 4‰ for daily mean as well as monthly mean comparisons, and the bias is 25 ‰). Our XCO2 model is a simple regression model fitted to CarbonTracker results and the Mauna Loa CO2 in situ records. A comparison to TCCON data suggests an uncertainty of the model for monthly mean data of below 3 ‰. We apply the method to the NDACC/FTIR spectra that are used within the project MUSICA (multi-platform remote sensing of isotopologues for investigating the cycle of atmospheric water) and demonstrate that there is a good consistency for these globally representative set of spectra measured since 1996: the scatter between the modelled and measured XCO2 on a yearly time scale is only 3 ‰.
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