Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs.

ADP plays a critical role in modulating thrombosis and hemostasis. ADP initiates platelet aggregation by simultaneous activation of two G protein-coupled receptors, P2Y1 and P2Y12. Activation of P2Y1 activates phospholipase C and triggers shape change, while P2Y12 couples to Gi to reduce adenylyl cyclase activity. P2Y12 has been shown to be the target of the thienopyridine drugs, ticlopidine and clopidogrel. Recently, we cloned a human orphan receptor, SP1999, highly expressed in brain and platelets, which responded to ADP and had a pharmacological profile similar to that of P2Y12. To determine whether SP1999 is P2Y12, we generated SP1999-null mice. These mice appear normal, but they exhibit highly prolonged bleeding times, and their platelets aggregate poorly in responses to ADP and display a reduced sensitivity to thrombin and collagen. These platelets retain normal shape change and calcium flux in response to ADP but fail to inhibit adenylyl cyclase. In addition, oral clopidogrel does not inhibit aggregation responses to ADP in these mice. These results demonstrate that SP1999 is indeed the elusive receptor, P2Y12. Identification of the target receptor of the thienopyridine drugs affords us a better understanding of platelet function and provides tools that may lead to the discovery of more effective antithrombotic therapies.

HIV in pregnancy: evolution of clinical practice in the UK.

Prior to the introduction of interventions reducing mother-to-child transmission of HIV-1 natural history data reports vertical transmission rates in the order of 25%. The risk of transmission from mother-to-child has been associated with advanced maternal HIV disease, maternal plasma HIV viral load and CD4 lymphocyte count, mode of delivery, length of rupture of membranes, prematurity and breast feeding. During the last 10-15 years the introduction of prelabour cesarean section, formula feeding and antiretroviral therapy has reduced transmission to less than 1% for pregnant women in the UK who are aware of their HIV status. Attention is now turning to the minimization of possible drug side effects for both mother and infant as women are increasingly conceiving on combination antiretroviral therapy. The evolution of current UK guidelines on the prevention of mother-to-child transmission of HIV-1 are discussed.

Differences in the use of vision and proprioception for postural control in autism spectrum disorder.

BACKGROUND: People with autism spectrum disorders (ASDs) also have poorer fundamental motor skills. The development of postural control underlies both social and motor skills. All three elements are facilitated by the active use of visual information. This study compares how adults with ASD and typically developed adults (TDAs) respond to a postural illusion induced using neck vibration. Adults with ASD unlike the TDA, were not expected to correct the illusion using vision. METHODS: The study used intermittent (15off, 5on) posterior neck vibration during 200 s of quiet stance to induce a postural illusion. In TDAs and only in the absence of vision this protocol induces a forward body lean. Participants (12 ASD, 20 TDA) undertook four conditions combining vibration and visual occlusion. RESULTS: As predicted, TDA were only affected by the postural illusion when vision was occluded (vibration condition: vision occluded (n=1) p=0.0001; vision available (n=3) p>0.2466). Adults with ASD were affected by the postural illusion regardless of the availability of vision (all conditions p<0.0007). CONCLUSIONS: Our findings indicated the adults with ASD did not use visual information to control standing posture. In light of existing evidence that vision-for-perception is processed typically in ASD, our findings support a specific deficit in vision-for-action. These findings may explain why individuals with ASD experience difficulties with both social and motor skills since both require vision-for-action. Further research needs to investigate the division of these visual learning pathways in order to provide more specific intervention opportunities in ASD.

Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure-activity relationship studies of methionine and S-alkylcysteine derivatives.

A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C-terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2-methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.

Does the speed of balloon deflation affect the complication rate of coronary angioplasty?

Two hundred consecutive coronary arteries in 157 patients undergoing angioplasty were randomized to fast or slow balloon deflation. Angioplasty was successful in 188 cases (101 with slow and 87 with fast deflation). There was no significant difference between the 2 groups with regard to the total number of dissections, although there was a greater number in the slow deflation group, and no difference in the number of minor dissections (National Heart, Lung, and Blood Institute types A and B). There was a significantly greater number of more severe dissections (types C to F) in the slow deflation group (20 vs 5; p = 0.013). It is proposed that the greater number of severe dissections is due to either increased turbulence or movement of the partially deflated balloon during slow deflation. Thus, slow balloon deflation during coronary angioplasty is associated with a higher complication rate than is conventional rapid deflation.

Comparison of fixed-wire and over-the-wire balloon dilatation systems for percutaneous transluminal coronary angioplasty.

There is controversy concerning the relative safety and efficacy of the 2 currently available percutaneous transluminal coronary angioplasty dilatation systems--fixed-wire (FW) and over-the-wire (OW). A randomized, prospective trial comparing the 2 systems was performed to examine this controversy. Of 1,513 patients undergoing percutaneous transluminal coronary angioplasty at 3 centers between June 1990 and October 1991, 602 (40%) fulfilled the eligibility criteria for the study. There were 643 lesions, of which 327 were randomized to FW and 316 to OW systems. There was no difference in the success rate between FW (92%) and OW (94%) systems. Inability to cross with a wire was infrequent with either system (FW: 1.8%; and OW: 1.6%). Inability to cross with a balloon when the wire crossed the lesion did not occur. An FW system was successful in 6 cases (1.9%) in which the OW system had been unsuccessful, whereas an OW system succeeded in 14 (4.3%) after the FW system had been unsuccessful (p = NS). Time to cross stenoses was 200 +/- 21 and 233 +/- 22 seconds, procedural time was 21 +/- 1.3 and 21 +/- 1.0 minutes, fluoroscopy time was 6.7 +/- 0.4 and 7.1 +/- 0.4 minutes, contrast used was 89.0 +/- 4.2 and 84.0 +/- 3.5 ml, and number of cine runs was 5.9 +/- 3.0 and 6.3 +/- 3.4 in the FW and OW systems, respectively. Complications were infrequent with either system (FW: 10.4%; and OW: 9.5%). Acute closure occurred in 1.8 and 2.2% of cases in the FW and OW systems, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Production of a monoclonal antibody to human liver alkaline phosphatase.

A monoclonal antibody to human liver alkaline phosphatase (ALP) has been produced by the mouse-hybridoma method using a partially purified enzyme preparation as antigen. The particular hybridoma secreting the antibody was detected by a screening procedure based on the retention of enzyme activity by the enzyme/antibody complex. The antibody cross-reacts strongly with human kidney and bone ALPs but not with human placental or intestinal ALPs. It also cross-reacts with liver and kidney ALPs from gorilla, chimpanzee and orangutan. It shows no significant reaction, under the conditions used, with liver or kidney ALPs from several lower primates. An antibody affinity column was prepared and shown to be effective for the final stages of liver ALP purification.

Percutaneous removal of ventricular pacemaker electrodes using a Dormier basket.

Four permanent ventricular endocardial pacemaker electrodes which could not be removed via their insertion site have been retrieved via the femoral vein using a Dormier basket. Apart from short-lived ventricular arrhythmias no complications occurred in any case. Where removal of an otherwise unaccessible ventricular pacemaker electrode is considered essential the use of a Dormier basket percutaneously appears to be effective and more acceptable than surgical removal.

Amiodarone in pregnancy. Case report and review of the literature.

A case of the use of amiodarone in pregnancy is reported and the literature on this subject reviewed. The data available to date show: there is no risk of teratogenic effects, the QT interval is prolonged during infancy (no associated arrhythmias noted), infant bradycardia occurs and should be monitored and thyroid function can be affected and should be monitored at birth. If fetal electrocardiographic monitoring is performed before and during labour and after birth, and thyroid function is assessed, then, to date, there does not appear to be any significant contraindication to the use of amiodarone during pregnancy. In view of the potential side effects, however, the use of amiodarone should be restricted to arrhythmias which are life-threatening or not controlled by conventional therapy.

Cross-sectional echocardiographic demonstration of biventricular thrombus.

Nine months following extensive myocardial infarction, a 60-year-old man presented with intermittent right heart failure. Cross-sectional echocardiography demonstrated biventricular thrombi, the right ventricular thrombus being very close to the tricuspid valve and possibly interfering with its function. Post-mortem examination confirmed the echocardiographic findings.

Evaluation of myocardial thallium tomography in patients with chest pain.

Thirty-seven patients with chest pain have been studied by exercise thallium tomography and coronary arteriography to assess the accuracy of thallium tomography in the identification of patients with coronary artery disease and to evaluate whether knowledge of clinical data improves this accuracy. Thallium tomography was also used to identify which coronary arteries were stenosed. Thallium tomography when compared with coronary arteriography has a sensitivity of 97%, a specificity of 75%, and an overall accuracy of 92% for the detection of coronary artery disease. When clinical information was made available, these results improved to a sensitivity of 100%, a specificity of 75%, and an overall accuracy of 95%. In the identification of which coronary arteries were stenosed, thallium tomography had a sensitivity of 85%, a specificity of 89%, and an overall accuracy of 86%. These results show that exercise thallium tomography can be an accurate non-invasive screening test in patients with chest pain thought to be angina.

Digital subtraction angiography of the left ventricle.

Twenty-eight patients have been studied by left ventricular angiography and digital subtraction angiography, using either a peripheral venous injection (16) or a central venous injection (12) of contrast medium. Digital subtraction angiography compared favourably to angiography in the qualitative assessment of left ventricular size and function. Measurement of ejection fraction demonstrated a good correlation (r = 0.83) between digital subtraction angiography and left ventricular angiography. In the assessment of left ventricular segmental wall motion the use of a central venous injection, particularly in those patients with severely impaired ventricular function, proved superior to the use of a peripheral injection.

Identification of intracardiac thrombus: comparison of computed tomography and cross-sectional echocardiography.

Thirty-eight patients with conditions predisposing to intracardiac thrombus have been studied by computed tomography and cross-sectional echocardiography. Computed tomography identified 22 cases of intracardiac thrombus (13 left ventricular, eight left atrial and one right atrial). Cross-sectional echocardiography identified five of these left ventricular thrombi and the right atrial thrombus, but none of the left atrial thrombi. In addition, measurements of thrombus density on computed tomography identified a significant difference (p less than 0.02) between the density of a new compared with an organized thrombus.

A comparison of angiographic and electrocardiographically gated computed tomographic measurements of left-ventricular function.

Fifty patients with ischaemic heart disease have been studied by electrocardiographically gated computed tomography (CT) and left-ventricular angiography to assess the accuracy of the former in the measurement of left-ventricular volumes and ejection fraction. There was no significant difference in the measurements of end-diastolic volume (p = 0.9, r = 0.81). Computed tomography significantly overestimated end-systolic volume (p less than 0.001, r = 0.89) and significantly underestimated ejection fraction (p less than 0.001, r = 0.74). Although there is some variation between the two sets of measurements, the correlation between the two techniques is good, indicating that electrocardiographically gated CT could be a useful noninvasive technique for assessing left-ventricular function.

Detection of coronary artery bypass graft patency as assessed by magnetic resonance imaging.

In a study of 22 patients with 60 coronary artery bypass grafts, magnetic resonance imaging (MRI) correctly assessed graft patency or occlusion in 90% of cases when compared with selective coronary graft angiography and computed tomography. It is concluded that MRI can detect a normally functioning coronary artery bypass graft and could be used as a non-invasive technique to assess graft patency in patients presenting with post-operative angina.

Is coronary angioplasty safe in the elderly?

OBJECTIVE: To evaluate the use of percutaneous transluminal coronary angioplasty (PTCA) and the immediate procedural outcomes in the elderly at a tertiary care centre. PATIENTS AND METHODS: Between January 1992 and December 1997, a total retrospective cohort study of 2322 consecutive patients aged 60 years or older underwent PTCA. Patients were categorized into three age groups: group A (60 to 69 years of age), which included 1294 patients; group B (70 to 79 years), which included 895 patients; and group C (80 years of age or older), which included 133 patients. PTCA was performed using the newest catheter technology as it became available. RESULTS: Men comprised 63% of the patients in groups A and B combined, and 44% of group C (P<0.001). Canadian Cardiovascular Society angina class IV was present in 45% of group C compared with 30% and 35% in groups A and B, respectively (P<0.001). The proportion of patients with diabetes mellitus and hypertension was similar among the three groups. Acute myocardial infarction before PTCA was twice as common at 4.5% (95% CI 3.7% to 5.3%) in group C, compared with 2.9% (95% CI 2.7% to 3.1%) and 2.2% (95% CI 2.0% to 2.3%) in groups A and B, respectively. The procedural success rate was similar at 93%, 92.7% and 91.7% in groups A, B and C, respectively. A total of five (0.2%) deaths and eight (0.34%) myocardial infarctions occurred in groups A and B combined, while none occurred in group C (not significant). More patients in groups A and B underwent emergency coronary artery bypass graft than in group C: group A - 22, 3.4% (95% CI 3.2% to 3.6%); group B - 16, 3.4% (95% CI 3.2% to 3.6%) and group C - one, 0.75% (95% CI 0.6% to 0.9%). CONCLUSIONS: In this retrospective series of patients, it was shown that PTCA may be performed in the very elderly with high procedural success and acceptable risk. Age alone should not be the criterion to limit the use of PTCA.

Risk factors for nonunion after nonoperative treatment of displaced midshaft fractures of the clavicle.

BACKGROUND: Identification of patients at higher risk of nonunion after diaphyseal clavicular fractures is desirable to improve patient counseling and enable targeted surgical treatment. METHODS: Seventy-nine percent (941 of 1196) of diaphyseal clavicular fractures were followed to union or nonunion. Demographic, injury, and radiographic characteristics associated with nonunion were determined with use of bivariate and multivariate statistical analyses. RESULTS: In patients who were eighteen years of age or older, 125 (13.3%) of the fractures had clinical and radiographic evidence of nonunion. Factors significantly associated with nonunion on bivariate analysis were sex, smoking status, overall fracture displacement, overlap, translation, and comminution. The factors that maintained significance on multivariate analysis were smoking (odds ratio, 3.76), comminution (odds ratio, 1.75), and fracture displacement (odds ratio, 1.17). If all displaced midshaft fractures were managed operatively, 7.5 procedures would need to be undertaken to prevent a single nonunion. If only fractures with a predicted probability of ≥40% were managed operatively, the number of patients managed operatively to prevent a single nonunion would fall to 1.7. CONCLUSIONS: Thirteen percent of displaced diaphyseal fractures in patients who were at least eighteen years of age did not heal. Smoking was the strongest risk factor, and smoking cessation should be an integral part of treatment. The probability of nonunion in a particular individual can be estimated with use of a statistical model based on known risk factors. This information can be useful when counseling the patient even though nonunion remains difficult to predict accurately in that individual. The number who would need to be treated to prevent a single nonunion can be reduced by identifying those at higher risk.

Open reduction and plate fixation versus nonoperative treatment for displaced midshaft clavicular fractures: a multicenter, randomized, controlled trial.

BACKGROUND: There is a growing trend to treat displaced midshaft clavicular fractures with primary open reduction and plate fixation; whether such treatment results in improved patient outcomes is debatable. The aim of this multicenter, single-blinded, randomized controlled trial was to compare union rates, functional outcomes, and economic costs for displaced midshaft clavicular fractures that were treated with either primary open reduction and plate fixation or nonoperative treatment. METHODS: In a prospective, multicenter, stratified, randomized controlled trial, 200 patients between sixteen and sixty years of age who had an acute displaced midshaft clavicular fracture were randomized to receive either primary open reduction and plate fixation or nonoperative treatment. Functional assessment was conducted at six weeks, three months, six months, and one year with use of the Disabilities of the Arm, Shoulder and Hand (DASH) and Constant scores. Union was evaluated with use of three-dimensional computed tomography. Complications were recorded, and an economic evaluation was performed. RESULTS: The rate of nonunion was significantly reduced after open reduction and plate fixation (one nonunion) as compared with nonoperative treatment (sixteen nonunions) (relative risk = 0.07; p = 0.007). Group allocation to nonoperative treatment was independently predictive of the development of nonunion (p = 0.0001). Overall, DASH and Constant scores were significantly better after open reduction and plate fixation than after nonoperative treatment at the time of the one-year follow-up (DASH score, 3.4 versus 6.1 [p = 0.04]; Constant score, 92.0 versus 87.8 [p = 0.01]). However, when patients with nonunion were excluded from analysis, there were no significant differences in the Constant scores or DASH scores at any time point. Patients were less dissatisfied with symptoms of shoulder droop, local bump at the fracture site, and shoulder asymmetry in the open reduction and plate fixation group (p < 0.0001). The cost of treatment was significantly greater after open reduction and plate fixation (p < 0.0001). CONCLUSIONS: Open reduction and plate fixation reduces the rate of nonunion after acute displaced midshaft clavicular fracture compared with nonoperative treatment and is associated with better functional outcomes. However, the improved outcomes appear to result from the prevention of nonunion by open reduction and plate fixation. Open reduction and plate fixation is more expensive and is associated with implant-related complications that are not seen in association with nonoperative treatment. The results of the present study do not support routine primary open reduction and plate fixation for the treatment of displaced midshaft clavicular fractures.