Summary
A score that can accurately determine the risk of major bleeding during anticoagulant therapy may help to make decisions on anticoagulant use. RIETE is an ongoing registry of consecutive ...patients with acute venous thromboembolism (VTE). We composed a score to predict the risk for major bleeding within three months of anticoagulant therapy. Of 19,274 patients enrolled, 13,057 (67%) were randomly assigned to the derivation sample, 6,572 to the validation sample. In the derivation sample 314 (2.4%) patients bled (fatal bleeding, 105). On multivariate analysis, age >75 years, recent bleeding, cancer, creatinine levels >1.2 mg/dl, anemia, or pulmonary embolism at baseline were independently associated with an increased risk for major bleeding. A score was composed assigning 2 points to recent bleeding, 1.5 to abnormal creatinine levels or anemia, 1 point to the remaining variables. In the derivation sample 2,654 (20%) patients scored 0 points (low risk); 9,645 (74%) 1–4 points (intermediate); 758 (5.8%) >4 points (high risk). The incidences of major bleeding were: 0.3% (95% confidence interval CI: 0.1–0.6), 2.6% (95% CI: 2.3–2.9), and 7.3% (95% CI: 5.6–9.3), respectively. The likelihood ratio test was:0.14 (95% CI:0.07–0.27) for patients at low risk;2.96 (95% CI:2.18–4.02) for those at high risk. In the validation sample the incidence of major bleeding was:0.1%,2.8%,and 6.2%,respectively. In conclusion, a risk score based on six variables documented at entry can identify VTE patients at low, intermediate, or high risk for major bleeding during the first three months of therapy.
The diagnosis of spondylolysis is a major cause of concern for patients and their families, especially when the patients are
young athletes with promising futures in their sports. In this study, 3152 ...case histories of high-level athletes were evaluated
to determine which sports had a higher prevalence of spondylolysis. The overall percentage of spondylolysis among athletes
in this study (8.02%) was not very much higher than that among the general population, which varies between 3% and 7%. However,
when each sport was considered separately we found much higher values for some sports, with the highest percentages occurring
in throwing sports (26.67%), artistic gymnastics (16.96%), and rowing (16.88%). The analysis of the biomechanical movements
involved in the sports with greater prevalence of spondylolysis has led us to include the element of torsion against resistance
as another possible causative factor for spondylolysis that should be added to the already known causative mechanisms, lumbar
hyperextension and rotation. We have divided the sports into three risk groups according to the prevalence of spondylolysis
shown and the characteristics of the sample, and we recommend systematic radiological examination of the lumbar spine in athletes
considered to be at greater risk of developing spondylolysis.
The box H/ACA RNA gene family is one of the largest non-protein-coding gene families in eukaryotes and archaea. Recently, we developed snoGPS, a computational screening program for H/ACA snoRNAs, and ...applied it to Saccharomyces cerevisiae. We report here results of extending our method to screen for H/ACA RNAs in multiple large genomes of related species, and apply it to the human, mouse, and rat genomes. Because of the 250-fold larger search space compared to S. cerevisiae, significant enhancements to our algorithms were required. Complementing extensive cloning experiments performed by others, our findings include the detection and experimental verification of seven new mammalian H/ACA RNAs and the prediction of 23 new H/ACA RNA pseudouridine guide assignments. These assignments include four for H/ACA RNAs previously classified as orphan H/ACA RNAs with no known targets. We also determined systematic syntenic conservation among human and mouse H/ACA RNAs. With this work, 82 of 97 ribosomal RNA pseudouridines and 18 of 32 spliceosomal RNA pseudouridines in mammals have been linked to H/ACA guide RNAs.
It has been suggested that recombination and shuffling between exons has been a key feature in the evolution of proteins. We propose that this strategy could also be used for the artificial evolution ...of proteins in bacteria. As a first step, we illustrate the use of a self-splicing group I intron with inserted lox-Cre recombination site to assemble a very large combinatorial repertoire (> 1011 members) of peptides from two different exons. Each exon comprised a repertoire of 10 random amino acids residues; after splicing, the repertoires were joined together through a central five-residue spacer to give a combinatorial repertoire of 25-residue peptides. The repertoire was displayed on filamentous bacteriophage by fusion to the pIII phage coat protein and selected by binding to several proteins, including β -glucuronidase. One of the peptides selected against β -glucuronidase was chemically synthesized and shown to inhibit the enzymatic activity (inhibition constant: 17 nM); by further exon shuffling, an improved inhibitor was isolated (inhibition constant: 7 nM). Not only does this approach provide the means for making very large peptide repertoires, but we anticipate that by introducing constraints in the sequences of the peptides and of the linker, it may be possible to evolve small folded peptides and proteins.
The objective behind the Euro Heart Survey on diabetes and the heart was to study the prevalence of abnormal glucose regulation in adult patients with coronary artery disease (CAD).
The survey ...engaged 110 centres in 25 countries recruiting 4196 patients referred to a cardiologist due to CAD out of whom 2107 were admitted on an acute basis and 2854 had an elective consultation. Patient data were collected via a web-based case record form. An oral glucose tolerance test (OGTT) was used for the characterisation of the glucose metabolism. Thirty-one per cent of the patients had diabetes. An OGTT was performed on the 1920 patients without known diabetes, of whom 923 had acute and 997 had a stable manifestation of CAD, respectively. In patients with acute CAD, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group these proportions were 37% and 14%.
This survey demonstrates that normal glucose regulation is less common than abnormal glucose regulation in patients with CAD. OGTT easily discloses the glucometabolic state and should be a routine procedure. The knowledge of glucometabolic state among these patients should influence their future management because it has great potential to improve the outcome.
The circular dichroism (CD) spectrum of the denatured state of barstar has been analyzed as a function of urea and temperature. The near- and far-UV CD spectra change very rapidly in magnitude and ...shape with increasing temperature, unlike those of native protein, suggesting the presence of residual structure that changes with denaturing conditions. The effect of mutations indicates that there is residual structure in helix1 of the protein, consistent with NMR data. The changes in CD with conditions are consistent with the denatured state being a mixture of conformations of similar energy.
Our study aimed to evaluate the patients diagnosed of thrombotic thrombocytopenic purpura in our hospital during the last 23 years.
We have made a retrospective study of the clinical records of 25 ...patients diagnosed of TTP between 1983-2005, describing the clinical, epidemiological and laboratory data.
Twenty-five cases were diagnosed. Mean age was 39 years, 64% women and 36% men, 44% had suffered headaches, 4% fever, 32% neurological focality, 12% renal disorders, 36% hemorrhagic disease and 16% thromboembolic disease. TTP etiology was: 72% idiopathic, 8% pregnancy, 4% Human Immunodeficiency Virus, 4% myasthenia gravis, 4% pulmonary neoplasm and 4% puerperium. Medium hemoglobin level was 9 g/dl, leucocytes 8700/mm3 and platelets 12000/mm3. Patients received a median of 5 plasmapheresis. Mean time to relapse was two months. Other treatments for TTP were aspirin (16%), cyclosporine (4%), vincristine (4%) and splenectomy (4%).
PTT incidence in our region has increased in recent years, probably due to an increase in the immigrant population not included in the census, among the most relevant reasons. In our study, renal disorders and presence of fever were less frequently described than in other reports. There was no correlation between the number of plasmapheresis and likelihood of relapse. Most relapses were in idiopathic TTP.
Activation of mammalian sterile 20–like kinase 1 (Mst1) by genotoxic compounds is known to stimulate apoptosis in some cell types. The importance of Mst1 in cell death caused by clinically relevant ...pathologic stimuli is unknown, however. In this study, we show that Mst1 is a prominent myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes and that Mst1 causes cardiac myocyte apoptosis in vitro in a kinase activity–dependent manner. In vivo, cardiac-specific overexpression of Mst1 in transgenic mice results in activation of caspases, increased apoptosis, and dilated cardiomyopathy. Surprisingly, however, Mst1 prevents compensatory cardiac myocyte elongation or hypertrophy despite increased wall stress, thereby obscuring the use of the Frank-Starling mechanism, a fundamental mechanism by which the heart maintains cardiac output in response to increased mechanical load at the single myocyte level. Furthermore, Mst1 is activated by ischemia/reperfusion in the mouse heart in vivo. Suppression of endogenous Mst1 by cardiac-specific overexpression of dominant-negative Mst1 in transgenic mice prevents myocyte death by pathologic insults. These results show that Mst1 works as both an essential initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes, resulting in a previously unrecognized form of cardiomyopathy.
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