A computational approach for prediction of donor splice sites with improved accuracy.

Identification of splice sites is important due to their key role in predicting the exon-intron structure of protein coding genes. Though several approaches have been developed for the prediction of splice sites, further improvement in the prediction accuracy will help predict gene structure more accurately. This paper presents a computational approach for prediction of donor splice sites with higher accuracy. In this approach, true and false splice sites were first encoded into numeric vectors and then used as input in artificial neural network (ANN), support vector machine (SVM) and random forest (RF) for prediction. ANN and SVM were found to perform equally and better than RF, while tested on HS3D and NN269 datasets. Further, the performance of ANN, SVM and RF were analyzed by using an independent test set of 50 genes and found that the prediction accuracy of ANN was higher than that of SVM and RF. All the predictors achieved higher accuracy while compared with the existing methods like NNsplice, MEM, MDD, WMM, MM1, FSPLICE, GeneID and ASSP, using the independent test set. We have also developed an online prediction server (PreDOSS) available at http://cabgrid.res.in:8080/predoss, for prediction of donor splice sites using the proposed approach.

Identification of donor splice sites using support vector machine: a computational approach based on positional, compositional and dependency features.

BACKGROUND: Identification of splice sites is essential for annotation of genes. Though existing approaches have achieved an acceptable level of accuracy, still there is a need for further improvement. Besides, most of the approaches are species-specific and hence it is required to develop approaches compatible across species. RESULTS: Each splice site sequence was transformed into a numeric vector of length 49, out of which four were positional, four were dependency and 41 were compositional features. Using the transformed vectors as input, prediction was made through support vector machine. Using balanced training set, the proposed approach achieved area under ROC curve (AUC-ROC) of 96.05, 96.96, 96.95, 96.24 % and area under PR curve (AUC-PR) of 97.64, 97.89, 97.91, 97.90 %, while tested on human, cattle, fish and worm datasets respectively. On the other hand, AUC-ROC of 97.21, 97.45, 97.41, 98.06 % and AUC-PR of 93.24, 93.34, 93.38, 92.29 % were obtained, while imbalanced training datasets were used. The proposed approach was found comparable with state-of-art splice site prediction approaches, while compared using the bench mark NN269 dataset and other datasets. CONCLUSIONS: The proposed approach achieved consistent accuracy across different species as well as found comparable with the existing approaches. Thus, we believe that the proposed approach can be used as a complementary method to the existing methods for the prediction of splice sites. A web server named as 'HSplice' has also been developed based on the proposed approach for easy prediction of 5' splice sites by the users and is freely available at http://cabgrid.res.in:8080/HSplice.

LDL particle size in subjects with previously unsuspected coronary heart disease: relationship with other cardiovascular risk markers.

Low density lipoprotein (LDL) particle diameters were determined by non-denaturing gradient gel electrophoresis in 53 subjects with previously unrecognised coronary heart disease (CHD) and 167 control subjects matched by age, sex and total plasma cholesterol. The mean diameter of the major LDL peak was found not to be significantly different between the two groups, but the CHD subjects were found to have a broader distribution of the predominant LDL species ((25.0 (24.7-25.3)nm versus 24.8 (24.7-24.9)nm)) (median (25-75%)), a greater proportion of larger particles (chi 2 = 19.8, P < 0.001) and to be more likely to have multiple numbers of LDL species than the control subjects (chi 2 = 22.7, P < 0.001). A negative correlation was found between the diameter of the predominant LDL species and fasting plasma triglyceride (r = -0.21, P = 0.0015), waist to hip ratio (WHR) (r = -0.15, P = 0.026) and body mass index (BMI) (r = -0.20, P = 0.002), and in a subgroup of subjects (n = 106), postprandial analysis revealed a negative correlation with the incremental postprandial response of plasma insulin (r = -0.19, P = 0.025). Male subjects had a significantly smaller diameter of the major LDL peak (24.8 +/- 0.0 nm) than female subjects (25.0 +/- 0.0 nm, P < 0.001). The present study failed to confirm an association between small LDL particles and the presence of coronary heart disease but did demonstrate more LDL heterogeneity in those with CHD. In addition, significant relationships were evident between the diameter of the major LDL peak and a number of other risk factors for coronary disease.

Is anterior leaflet repair always necessary in repair of bileaflet mitral valve prolapse?

BACKGROUND: Traditionally, bileaflet prolapse has been treated by posterior leaflet resection combined with one of a number of procedures designed to support the anterior leaflet. However, most patients with bileaflet prolapse do not have important anterior chordal pathology. This study was undertaken to evaluate the effectiveness of a strategy of posterior leaflet resection and annuloplasty alone for patients with bileaflet prolapse and no anterior chordal rupture or severe anterior chordal elongation. METHODS: From 1993 to 1997, 93 patients with transesophageal echocardiography (TEE) demonstrated bileaflet prolapse and without anterior chordal rupture or important anterior chordal elongation had primary isolated mitral valve repair consisting only of posterior leaflet resection (quadrangular in 28 and sliding in 65) and annuloplasty (Cosgrove-Edwards in 83, pericardial in 9, and Carpentier-Edwards in 1). All patients had severe mitral regurgitation documented by intraoperative TEE. Mean age was 55+/-13 years; 60% were men. RESULTS: Postrepair, mitral regurgitation was 0 to trace in 93% and 1+ in 7%. There were no operative deaths. Late follow-up was available in all patients, with 277 patient-years of follow-up available for analysis. Five-year actuarial survival was 95%. At a mean interval of 2.3+/-1.3 (SD) years, echocardiography demonstrated no or trace mitral regurgitation in 65%, 1+ in 28%, and 2+ in 7%. No correlates of late mitral regurgitation were identified by multivariable analysis. No patient has required reoperation. CONCLUSIONS: In the absence of significant anterior chordal pathology, a strategy of posterior leaflet resection and annuloplasty corrects anterior leaflet prolapse and mitral regurgitation, and provides a durable repair without the necessity of additional procedures on the anterior leaflet.

Aortic regurgitation reduces the accuracy of exercise echocardiography for diagnosis of coronary artery disease.

The association of aortic regurgitation with left ventricular size, hypertrophy, and abnormal coronary flow may influence the accuracy of stress testing techniques for the diagnosis of coronary disease. We examined the diagnostic accuracy of treadmill exercise echocardiography to predict coronary artery disease in 76 patients with moderate to severe aortic regurgitation. Rest and poststress images were interpreted by 2 experienced observers, and accuracy was defined by comparison with stenoses >/=50% diameter at coronary angiography. Results were compared with accuracy in a control group of previously published studies in patients without valvular heart disease. After 6 patients were excluded because of a submaximal heart rate response (<85% age-predicted maximal heart rate), 70 patients were included in the final analysis. Patients with aortic regurgitation were of comparable age to the control group and exercised to similar workload. In 16 (23%) patients with significant coronary artery disease and significant aortic regurgitation, the sensitivity of exercise echocardiography was 56% compared with 83% in the control group (P =.03). The specificity in 54 patients with aortic regurgitation but no significant coronary artery disease was 67% compared with 83% in the control group (P =.02). Accuracy was 64% in aortic regurgitation compared with 83% in the control group (P =.02). In patients with aortic regurgitation, accuracy in the left anterior descending artery territory (76%) marginally exceeded that in the posterior (right + circumflex coronary artery) circulation (70%). Thus the presence of significant aortic regurgitation affects the regional wall motion of the left ventricle during exercise and adversely affects the accuracy of exercise echocardiography for the diagnosis of coronary artery disease.

Accuracy and cost- and time-effectiveness of digital clip versus videotape interpretation of echocardiograms in patients with valvular disease.

BACKGROUND: Although digital and videotaped images are known to be comparable for the evaluation of left ventricular function, their relative accuracy for assessment of more complex anatomy is unclear. We sought to compare reading time, storage costs, and concordance of video and digital interpretations across multiple observers and sites. METHODS: One hundred one patients with valvular (90 mitral, 48 aortic, 80 tricuspid) disease were selected prospectively, and studies were stored according to video and standardized digital protocols. The same reviewer interpreted video and digital images independently and at different times with the use of a standard report form to evaluate 40 items (e.g., severity of stenosis or regurgitation, leaflet thickening, and calcification) as normal or mildly, moderately, or severely abnormal. Concordance between modalities was expressed at kappa. Major discordance (difference of >1 level of severity) was ascribed to the modality that gave the lesser severity. CD-ROM was used to store digital data (20:1 lossy compression), and super-VHS videotape was used to store video data. The reading time and storage costs for each modality were compared. RESULTS: Measured parameters were highly concordant (ejection fraction was 52% +/- 13% by both). Major discordance was rare, and lesser values were reported with digital rather than video interpretation in the categories of aortic and mitral valve thickening (1% to 2%) and severity of mitral regurgitation (2%). Digital reading time was 6.8 +/- 2.4 minutes, 38% shorter than with video (11.0 +/- 3.0, range 8 to 22 minutes, P <.001). Compressed digital studies had an average size of 60 +/- 14 megabytes (range 26 to 96 megabytes). Storage cost for video was A$0.62 per patient (18 studies per tape, total cost A$11.20), compared with A$0.31 per patient for digital storage (8 studies per CD-ROM, total cost A$2.50). CONCLUSION: Digital and video interpretation were highly concordant; in the few cases of major discordance, the digital scores were lower, perhaps reflecting undersampling. Use of additional views and longer clips may be indicated to minimize discordance with video in patients with complex problems. Digital interpretation offers a significant reduction in reading times and the cost of archiving.

Effect of cardiac output on mitral valve area in patients with mitral stenosis: validation and pitfalls of the pressure half-time method.

BACKGROUND AND AIM OF THE STUDY: The non-invasive evaluation of mitral valve area is often used in the assessment of patients with mitral stenosis. The pressure half-time method is commonly used to calculate valve area, but is inaccurate in many clinical scenarios. We sought to quantify the effects of changing cardiac output on the accuracy of mitral valve area determination. METHODS: Thirteen patients with mitral stenosis underwent routine stress echocardiography with resting and peak exercise results compared. A previously described and clinically validated mathematical model of the cardiovascular system was used to validate the clinical results. Seven different loading conditions for each of four different stenotic valve areas were modeled. RESULTS: In patients, with increasing cardiac output, pressure half-time decreased (-30.6+/-35.3 ms/l/min) and calculated valve area increased by 0.25+/-0.30 cm2/l/min. By continuity, it appeared that approximately half of this increase was due to actual valve orifice stretching, the remainder reflecting fundamental changes in the relationship between half-time and valve area. Mathematical modeling resulted in similar changes in pressure half-time and calculated valve area (0.06 to 0.12 cm2/l/min, p = 0.20 versus clinical results). CONCLUSION: Changes in cardiac output result in predictable changes in pressure half-time, and should be considered when performing serial examinations in patients with mitral stenosis.

Neutrophil oxygen free radical production proportionates with the degree of myocardial ischemia.

OBJECTIVE: To assess the production of oxygen free radicals by chemiluminescence and to assess leukocyte aggregation, in patients with acute myocardial infarction and angina pectoris, and to compare these to creatine kinase-MB levels. DESIGN: Prospective study with serial estimation at presentation and 72 h later. SETTING: Referral, tertiary care hospital. PATIENTS: Group 1, acute myocardial infarction (n = 18); group 2, stable angina pectoris (n = 8); and age-and sex-matched normal healthy persons (n = 12). All patients included had pain of less than 24 h duration with typical electrocardiographic and laboratory abnormalities. Patients or controls who had any inflammatory disease in the preceding two weeks or who were on anti-inflammatory drugs, calcium channel or beta-adrenoceptor blockers, were excluded. TESTS: Venous blood samples taken at presentation and 72 h later were analyzed for creatine kinase-MB using a standard kit, neutrophilic chemiluminescence and leukocyte aggregation. MAIN RESULTS: In group 1 there were significant rises in both creatine kinase-MB and chemiluminescence, which subsequently regressed (P less than 0.02). There was, however, no statistical correlation between the two. The qualitative pattern of the rise and fall of chemiluminescence was similar in group 2. Changes in leukergy in both groups were not significant. CONCLUSIONS: Oxygen free radical generation occurs early in myocardial ischemia with regression by 72 h. Neutrophilic chemiluminescence may provide an alternative method for assessment of myocardial ischemia.

A self-administered questionnaire for detection of unrecognised coronary heart disease.

On an individual and a population basis, an increased incidence of coronary heart disease is associated with classical cardiovascular risk factors, but many cases occur in people not identified as at high risk. Conversely, many people at high statistical risk do not develop coronary disease. We used a questionnaire to identify unrecognised coronary heart disease in people attending large-scale health survey centres. Participants were required to report the presence and characteristics of any chest pain. Those returning responses consistent with myocardial ischaemia were offered treadmill exercise ECG tests. Over 18 months, 4070 questionnaires were returned. Of 475 respondents offered testing, 229 (198 male, 131 female) accepted. Thirty-two subjects (15 male, 17 female: a detection rate of 13.9 per cent of those assessed as likely on questionnaire, or 0.8 per cent of all respondents) had results consistent with significant coronary heart disease. Follow-up was available in 30 cases. There was no difference in classical risk-factor distribution (including multivariate risk percentiles: 42.4 (male) and 46.7 (female)) between those newly diagnosed with coronary heart disease and their community counterparts. More women than men were identified as suffering from unrecognised coronary heart disease, with a preponderance of younger women. Cost per case identified was A$1220. Screening by self-administered questionnaire is a useful and relatively cost-effective means of identifying unrecognised coronary heart disease.

Is a hypertensive always a hypertensive?

Forty two patients of uncomplicated essential hypertension with well controlled and stable blood pressure for the last six months have been followed up for 2 years after withdrawal of therapy. Drug therapy was reinstituted if they became hypertensive again. Thirty four (89.9%) and 33 patients remained normotensive at 4 and 8 weeks respectively. At the end of 6 months, 26 (61.9%) patients were drug free, 9 (21.4%) were back on therapy and 7 (16.5%) were lost to follow up. At the end of one year, 18 (42.8%) were drug free, 14 (33.3%) were on drugs and 10 (23.8%) had dropped out. At the end of 2 years, the figures were 14 (drug free), 15 (on drugs) and 13 (drop-outs). No cardiovascular or any other complication was recorded during the period. These observations suggest that there may be a subgroup of mild or moderate hypertensives in whom it may be possible to withdraw therapy under observation. However, there is a risk of substantial drop out rate possibly under a false sense of security. Considering the large number of hypertensives in our country and the world over, its economic and therapeutic implications are obvious.

Questioning a universal theory of mind: mental-real distinctions made by Indian children.

The purposes of this experiment were to investigate the effects of age, item type, and culture on the mental-real distinction made by children. A sample of 42 children (21 affluent and 21 deprived) in three age ranges (3- and 4-year-olds, 5- and 6-year-olds, and 7- and 8-year-olds) participated. Nine items were used. The behavioral-sensory and public-existence criteria (Wellman & Estes, 1986) were used to gauge the children's ability to make the distinction. Contrary to previous research findings, the 3- and 4-year-olds in this study were unable to make the mental-real distinction. An age-related improvement in making this distinction was observed, and item type affected the mental-real distinction. The affluent children consistently outperformed their deprived counterparts. This finding was partly construed as evidence for the influence of culture on the ability to make this distinction in these age groups.

Evolution and outcome of diastolic dysfunction.

BACKGROUND: Diastolic dysfunction (DD) is highly prevalent and associated with increased morbidity and mortality, but its natural history remains poorly defined. OBJECTIVE: This cohort study sought to characterise the influence of clinical features, medical therapy and echocardiographic parameters on the progression of DD. METHODS: We identified 926 consecutive patients (aged 62 (14) years, 221 women) with DD and preserved systolic function. A repeat echocardiogram was performed in 199 patients > or =1 year after the baseline study (average 3.6 (1.4) years). Follow-up for 4.8 (2.5) years was 97% complete for the major endpoint of all-cause mortality. Cox regression analyses were performed to identify the associations of mortality. RESULTS: Over follow-up, 142 patients died and 22 were admitted with heart failure. The independent predictors of death were age, hyperlipidaemia, co-morbid disease and restrictive filling. The degree of diastolic dysfunction remained stable in 52%, deteriorated in 27% and improved in 21%. There was a greater use of medical therapy in those with stable or worsening diastolic function; when the protective effects of these agents were taken into account in a multivariate model, improvement in diastolic dysfunction was associated with a survival benefit. CONCLUSION: DD is associated with all-cause mortality, independent of the presence of a major co-morbidity. The degree of DD remains stable in about 50% of patients, the population whose diastolic function improves over time has a more favourable outcome.

Cost-effectiveness and accuracy of exercise stress echocardiography in the non-invasive diagnosis of coronary heart disease.

BACKGROUND: Exercise stress echocardiography (ESE) is a more recent form of totally non-invasive stress testing which like exercise thallium SPECT scintigraphy (ETS) was developed to overcome the known limitations of ECG stress testing, namely the limited diagnostic accuracy and the inability of ECG stress testing to site the region of coronary artery disease (CAD) induced ischaemia. AIMS: To determine the sensitivity and specificity (and overall accuracy) of ESE in a group of patients referred for ETS imaging and compare the relative costs of each technique. METHODS: One hundred and fifteen patients referred for ETS consented to a simultaneous ESE. Of this group, 59 patients underwent coronary angiography which was utilised as the gold standard. RESULTS: The feasibility of ESE was 97% (112 of 115 patients of the total study population and 57 of the 59 patients who underwent coronary angiography). Of the 59 patients undergoing coronary angiography, the sensitivity of ESE and ETS were not significantly different (84.1% versus 91.3% respectively). However, despite the apparent marked difference in specificity (92.3% versus 61.5% respectively), p = NS (Fisher's exact test) as there were only 13 normals in the group who underwent coronary angiography. Overall accuracy was also closely similar (86.0% versus 84.7% respectively) and therefore also not significantly different. By contrast, agreement with coronary angiography as measured by the kappa statistic (kappa +/- SEk) was good for ESE (0.66 +/- 0.11) but only moderate for ETS (0.54 +/- 0.13). Moreover, there was a cost saving of at least $594.00 per patient in favour of ESE. CONCLUSION: ESE is a totally non-invasive, sensitive, specific and cost-effective imaging modality for the detection and localisation of CAD.

Anatomical M-mode: A novel technique for the quantitative evaluation of regional wall motion analysis during dobutamine echocardiography.

Recognition of abnormal wall motion during dobutamine echocardiography requires an expert observer. Anatomical M-mode echocardiography may offer a novel quantitative approach to interpretation, amenable to less expert readers. We studied the application of this new modality to 124 patients (80 with known coronary anatomy and 44 patients at low probability of coronary disease) who underwent dobutamine echocardiography, using a standard protocol. Wall motion was interpreted by an experienced reader, using digitally stored 2-dimensional echocardiographic images at rest and peak stress. Percentage of systolic thickening was measured offline using anatomical M-mode echocardiography in the basal and mid segments at rest and peak dose, and compared with wall motion scores and coronary angiography. Of 729 segments, wall motion was identified as normal in 449, ischemic or viable in 171 and showed resting WM abnormalities only in 109 segments. After exclusion of the apex, anatomical M-mode measurements were feasible in 729 of 960 possible basal- and mid-zone segments (76%). Measurement of systolic thickening at peak dose was reproducible within (r2 = 0.83) and between observers (r2 = 0.93). Systolic thickening was significantly greater in segments with normal wall motion (37 +/- 2%) compared with ischemic or viable segments (30 +/- 2%, p < 0.001), and scar segments (23 +/- 3%, p < 0.001). There was an increment of thickening from rest to stress in normal and viable segments, no change in scar, and a decrement in ischemic segments. Significant coronary artery disease (defined by stenoses >70% diameter) was present in 59 patients. Systolic thickening showed significant variation between segments interpreted by wall motion scoring and angiography as true and false positive and true and false negative (p < 0.05). Measurement of systolic thickening using anatomical M-mode echocardiography offers an objective method to quantify systolic thickening at dobutamine echocardiography but has limited clinical feasibility.

Pharmacognostical studies on leaf of polygonum glabrum willd.

Pharmacognostic studies on leaf of Polygonum glabrum Willd. has been carried out along with its numerical values, fluorescence characteristics and ash and extractive values.

Free radicals in myocardial injury: experimental and clinical studies.

The exposure of cardiac cells to OFR generated artificially, showed a marked decrease (p less than 0.01) in cellular utilization of glucose along with a significant decrease in calcium uptake (p less than 0.05). We have also provided evidence for a direct relationship of neutrophil OFR production with the extent of myocardial ischemia in patients of myocardial infarction. Our data provides evidence for implication of OFR in myocardial injury and the pivotal role played by modulators like calcium, ECGF and prostaglandins in potentiating damage to the myocardium.

Exercise echocardiography predicts development of left ventricular dysfunction in medically and surgically treated patients with asymptomatic severe aortic regurgitation.

OBJECTIVE: To assess resting and exercise echocardiography for prediction of left ventricular dysfunction in patients with significant asymptomatic aortic regurgitation. DESIGN: Cohort study of patients with aortic regurgitation. SETTING: Tertiary referral centre specialising in valvar surgery. PATIENTS: 61 patients (38 men, 23 women; mean (SD) age 53 (14) years) with asymptomatic or minimally symptomatic aortic regurgitation and no known coronary artery disease; 35 were treated medically and 26 had aortic valve replacement. INTERVENTIONS: Exercise echocardiography was used to evaluate ejection fraction, which was measured on the resting and post-stress images using the modified Simpson method. Patients with an increment of ejection fraction after exercise were denoted as having contractile reserve (CR+); those without an increment were labelled CR-. MAIN OUTCOME MEASURES: Standard univariate and multivariate methods and receiver operating characteristic analyses were used to assess the ability of contractile reserve to predict follow up ejection fraction. RESULTS: In the 35 medically treated patients, 13 of 21 (62%) with CR+ (mean (SD) ejection fraction increment 7 (3)%) had preserved ejection fraction on follow up. In the 14 patients with CR- (ejection fraction decrement 8 (4)%), 13 (93%) had a decrement of ejection fraction on follow up from 60 (5)% at baseline to 54 (3)% on follow up (p = 0.005). Age, resting left ventricular dimensions, medical treatment, aortic regurgitation severity, exercise capacity, and rate-pressure product were similar in both CR+ and CR- groups. Among the 26 surgical patients, 13 showed CR+ (ejection fraction increase 9 (5)%), all of whom had an increase in ejection fraction on follow up (from 49% to 59%). Of 13 surgical patients with CR- (ejection fraction decrease 7 (5)%), 10 (77%) showed the same or worse ejection fraction on postoperative follow up. CONCLUSIONS: Contractile reserve on exercise echocardiography is a better predictor of left ventricular decompensation than resting indices in asymptomatic patients with aortic regurgitation. In patients undergoing aortic valve replacement, contractile reserve had a better correlation with resting ejection fraction on postoperative follow up. Measurement of contractile reserve may be useful to monitor the early development of myocardial dysfunction in asymptomatic patients with aortic regurgitation, and may help to optimise the timing of surgery.