Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache?

AIMS: Thrombotic complications after percutaneous coronary intervention procedures have decreased in past years mainly due to the use of clopidogrel antiplatelet therapy. However, the risk of bleeding due to enhanced and irreversible platelet inhibition in patients who will require surgical coronary revascularization instead has not been adequately addressed in the literature. The purpose of this study was to evaluate the effect of pre-operative clopidrogel exposure in haemorrhage-related re-exploration rates, peri-operative transfusion requirements, morbidity, and mortality in patients undergoing coronary artery bypass grafting (CABG) surgery. METHODS AND RESULTS: A study population of 2359 patients undergoing isolated CABG between January 2000 and June 2002 was reviewed. Of these, 415 (17.6%) received clopidogrel prior to CABG surgery, and 1944 (82.4%) did not. A risk-adjusted logistic regression analysis was used to assess the association between clopidogrel pre-medication (vs. no) and haemostatic re-operation, intraoperative and post-operative blood transfusion rates, and multiple transfusions received. Haemorrhage-related pre-operative risk factors identified from the literature and those found significant in a univariate model were used. Furthermore, a sub-cohort, matched-pair by propensity scores analysis, was also conducted. The clopidogrel group had a higher likelihood of haemostatic re-operation [OR = 4.9, (95% CI, 2.63-8.97), P < 0.01], an increase in total packed red blood cell transfusions [OR = 2.2, (95% CI, 1.70-2.84), P < 0.01], multiple unit blood transfusions [OR = 1.9, (95% CI, 1.33-2.75), P < 0.01] and platelet transfusions [OR = 2.6, (95% CI, 1.95-3.56), P < 0.01]. Surgical outcomes and operative mortality [OR = 1.5, (95% CI, 0.36-6.51), P = 0.56] were not significantly different. CONCLUSION: Pre-operative clopidogrel exposure increases the risk of haemostatic re-operation and the requirements for blood and blood product transfusion during, and after, CABG surgery.     

Insulin-sensitive tyrosine kinase activity changes in parallel with plasma insulin and glucose concentrations in humans

Insulin receptor tyrosine kinase is an important step in insulin action. We examined the relationship between diet-induced changes in glucose metabolism and changes in skeletal muscle insulin-sensitive tyrosine kinase activity in 12 nondiabetic subjects. Subjects were fed a traditional, high carbohydrate Pima Indian diet and a modern, high fat western diet for 2 weeks in a randomized cross-over design. At the end of each dietary period, glucose tolerance was assessed, insulin sensitivity (SI) was estimated by Bergman's minimal model method, and insulin receptor concentration and tyrosine kinase activity were determined on lectin-purified extracts from quadriceps femoris muscle. Compared to the traditional diet, the modern diet was associated with a deterioration of glucose tolerance and an increase in glucose-induced plasma insulin levels. As expected, SI changes were associated with opposite changes in plasma insulin levels. However, the changes in maximal tyrosine kinase activity were negatively correlated with changes in SI (r = -0.69; P less than 0.01) and positively correlated with changes in plasma glucose (r = 0.70; P less than 0.01) and insulin response to glucose (r = 0.57; P less than 0.025). These results suggest that the site of diet-induced changes in insulin action is beyond the insulin-sensitive tyrosine kinase. The results further suggest that the kinase activity is modulated by prevailing plasma insulin levels.     

Is Health Care Seeking for Irritable Bowel Syndrome and Functional Dyspepsia a Socially Learned Response to Illness?

In a population-based study of 207 subjects with irritable bowel syndrome (IBS) or functional dyspepsia (FD) and controls (n = 100), we aimed to determine whether dimensions of abnormal illness behavior from the Abnormal Illness Behaviour Questionnaire and aspects of social learning of illness behavior from the Social Learning of Illness Behaviour scale were independent predictors of health care seeking for IBS and FD. Results showed that dimensions of abnormal illness behavior and aspects of social learning of illness behavior (encouragement, reinforcement, and modeling) did not significantly differentiate between consulters and nonconsulters with IBS and/or FD. The Disease Conviction scale (OR = 1.55; 95% CI, 1.15–2.09) of the Abnormal Illness Behaviour Questionnaire was an independent predictor of having a diagnosis of IBS and/or FD, independent of age and gender, psychiatric diagnoses, and symptom severity. We conclude that a belief in the presence of serious pathology characterizes community subjects with IBS and FD, but not health care seeking.     

Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.     

Scoring technique for diagnosis of ventricular hypertrophy from three orthogonal lead electrocardiogram.

A prospective study for the development of scoring techniques for the diagnosis of ventricular hypertrophy from the three orthogonal lead electrocardiogram was undertaken. A total of 51 hearts was examined at necropsy in a training group on which the scoring techniques were developed and a test group of a further 82 hearts was studied to assess the sensitivity and specificity of the method. The hearts were classified as being normal or having left ventricular hypertrophy, right ventricular hypertrophy, biventricular hypertrophy, or were placed in a borderline category. These classifications were based on the measurement of the weight of the left ventricular free wall, the interventricular septum, and the right ventricular free wall. Classical electrocardiographic variables were selected and assigned a point score on the basis of their diagnostic value. The electrocardiographic diagnosis of left ventricular hypertrophy, right ventricular hypertrophy, and biventricular hypertrophy was then made when the relevant score exceeded four points. After excluding 25 cases which showed conduction defects or were regarded as borderline at necropsy, 57 cases remained in the test group for assessing the technique. The sensitivity and specificity for left ventricular hypertrophy were 65 per cent and 91 per cent, respectively. For right ventricular hypertrophy corresponding results were 53 and 90 per cent. For biventricular hypertrophy the sensitivity was lower at 42 per cent, with a corresponding specificity of 93 per cent. These results represent a considerable improvement over older techniques, with up to a tenfold increase in sensitivity being obtained. The technique can be applied with or without computer assistance.     

Metabolic labeling enables selective photocrosslinking of O-GlcNAc-modified proteins to their binding partners

O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible posttranslational modification found on hundreds of nuclear and cytoplasmic proteins in higher eukaryotes. Despite its ubiquity and essentiality in mammals, functional roles for the O-GlcNAc modification remain poorly defined. Here we develop a combined genetic and chemical approach that enables introduction of the diazirine photocrosslinker onto the O-GlcNAc modification in cells. We engineered mammalian cells to produce diazirine-modified O-GlcNAc by expressing a mutant form of UDP-GlcNAc pyrophosphorylase and subsequently culturing these cells with a cell-permeable, diazirine-modified form of GlcNAc-1-phosphate. Irradiation of cells with UV light activated the crosslinker, resulting in formation of covalent bonds between O-GlcNAc-modified proteins and neighboring molecules, which could be identified by mass spectrometry. We used this method to identify interaction partners for the O-GlcNAc-modified FG-repeat nucleoporins. We observed crosslinking between FG-repeat nucleoporins and nuclear transport factors, suggesting that O-GlcNAc residues are intimately associated with essential recognition events in nuclear transport. Further, we propose that the method reported here could find widespread use in investigating the functional consequences of O-GlcNAcylation.     

Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts

Osteoclasts are multinucleated myeloid lineage cells formed in response to macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) by fusion of bone marrow–derived precursors that circulate in the blood and are attracted to sites of bone resorption in response to factors, such as sphingosine‐1 phosphate signaling. Major advances in understanding of the molecular mechanisms regulating osteoclast functions have been made in the past 20 years, mainly from mouse and human genetic studies. These have revealed that osteoclasts express and respond to proinflammatory and anti‐inflammatory cytokines. Some of these cytokines activate NF‐κB and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) signaling to induce osteoclast formation and activity and also regulate communication with neighboring cells through signaling proteins, including ephrins and semaphorins. Osteoclasts also positively and negatively regulate immune responses and osteoblastic bone formation. These advances have led to development of new inhibitors of bone resorption that are in clinical use or in clinical trials; and more should follow, based on these advances. This article reviews current understanding of how bone resorption is regulated both positively and negatively in normal and pathologic states. © 2013 American Society for Bone and Mineral Research.