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At least 253 records · Page 14Linked to original sources
PubMed2002

Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV.

Carbonic anhydrase inhibitors are effective in lowering intraocular pressure, the primary indication of glaucoma. Human carbonic anhydrase II, and possibly carbonic anhydrase IV (CAII and CAIV, respectively), help regulate fluid secretion into the anterior chamber of the eye. Because inhibitors currently formulated as drugs to treat glaucoma were designed to target CAII, an understanding of the structural basis of CAII-CAIV discrimination by inhibitors would be useful for probing the role of each isozyme in the etiology of the disease. Here, we report the X-ray crystal structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides complexed with CAII and the computationally predicted structures of the same compounds complexed with CAIV. All three compounds bind with similar affinity to CAII, but they bind with up to 100-fold lower affinities to CAIV. Comparisons of experimentally determined structures of CAII-inhibitor complexes and computationally predicted structures of CAIV-inhibitor complexes allow us to rationalize these affinity trends and outline molecular features that may contribute to high-affinity inhibitor binding to CAIV. This study demonstrates how experimental structure determination methods and computational structure prediction methods can be used together to answer questions that cannot be answered by either method alone.

Carbonic Anhydrase II↗
PubMed2004

Prediction of aqueous solubility of organic salts of diclofenac using PLS and molecular modeling.

Organic salts of diclofenac were predicted by using computed molecular descriptors and multivariate partial least squares (PLS). The molecular descriptors including binding energy and surface area of salts were calculated by the use of Hyperchem and ChemPlus QSAR programs for Windows. Other physicochemical properties such as hydrogen acceptor for oxygen atoms, hydrogen acceptor for nitrogen atoms, hydrogen bond donors, hydrogen bond-forming ability, molecular weight, and log partition coefficient (logP) of bases were also used as descriptors. Good statistical models were derived that permit simple computational prediction of salt solubility of a same parent structure. The final models derived had R2 value = 0.96 and root mean square error for prediction (RMSEP) values ranging from 0.021 to 0.054 (log scale). Preferably all utilized descriptors in the final models can readily obtain from the chemical structure of salt and base. Molecular weight of base is one of the important factors associated with salt solubility. While increased molecular weight of base, surface area of salt and hydrogen bonding ability of base increase solubility, and increased binding energy and logP of base have negative effect on salt solubility.

Diclofenac↗
PubMed1994

An analytic calculation of the energy fluence spectrum of a linear accelerator.

Calculation of photon dose by convolution methods requires a knowledge of the fluence spectrum of photons produced by the linear accelerator treatment head. But this spectrum is very difficult to measure accurately, and is often derived by Monte Carlo calculations modeling the elements of the treatment head. In this paper an analytic calculation technique and the corresponding computer tool for calculating the photon energy fluence spectral distribution at any point in a bremsstrahlung field are presented. Primary bremsstrahlung photon distributions are computed by modeling electron dispersion in layers in a thick target and using the thin target bremsstrahlung cross section formulas of Schiff. The first Compton scatter from all materials in a linear accelerator treatment head is computed analytically. Higher-order Compton scatter events and pair production annihilation photons are ignored, but the attenuation of both primary and first scattered photon fluence is computed. Predictions of the computer implementation of the model are compared to measurements of bremsstrahlung production in a thick target and to Monte Carlo calculations of the energy fluence emerging from a linear accelerator. Finally, the computer tool is used to investigate the source of collimator-dependent fluence fluctuations in air. In agreement with other measurements, the principal contribution to fluence outside the geometric field is found to be from scatter in the flattening filter.

Biophysical Phenomena↗
PubMedDate not supplied

[Prediction and computer analysis of the exon-intron structure of human genes].

This review of the original works on computer analysis of the human genome considers the development of methods to predict the exon-intron structure of genes and analysis of alternative splicing. Prediction of the gene structure is based on homology between the gene product and a known protein or between the genomic sequences of the gene and its homolog from another organism. The methods were tested and proved highly efficient. Human gene splicing was analyzed with original methods and EST databases. Genes with alternative splicing were for the first time shown to account for no less than 35% total genes. Alternative splicing was compared for the human and mouse genomes. Species-specific isoforms were demonstrated for 50% alternatively spliced genes (25% total genes).

Algorithms↗
PubMed2005

Effects of Bcl-2 levels on Fas signaling-induced caspase-3 activation: molecular genetic tests of computational model predictions.

Fas-induced apoptosis is a critical process for normal immune system development and function. Although many molecular components in the Fas signaling pathway have been identified, a systematic understanding of how they work together to determine network dynamics and apoptosis itself has remained elusive. To address this, we generated a computational model for interpreting and predicting effects of pathway component properties. The model integrates current information concerning the signaling network downstream of Fas activation, through both type I and type II pathways, until activation of caspase-3. Unknown parameter values in the model were estimated using experimental data obtained from human Jurkat T cells. To elucidate critical signaling network properties, we examined the effects of altering the level of Bcl-2 on the kinetics of caspase-3 activation, using both overexpression and knockdown in the model and experimentally. Overexpression was used to distinguish among alternative hypotheses for inhibitory binding interactions of Bcl-2 with various components in the mitochondrial pathway. In comparing model simulations with experimental results, we find the best agreement when Bcl-2 blocks the release of cytochrome c by binding to both Bax and truncated Bid instead of Bax, truncated Bid, or Bid alone. Moreover, although Bcl-2 overexpression strongly reduces caspase-3 activation, Bcl-2 knockdown has a negligible effect, demonstrating a general model finding that varying the expression levels of signal molecules frequently has asymmetric effects on the outcome. Finally, we demonstrate that the relative dominance of type I vs type II pathways can be switched by varying particular signaling component levels without changing network structure.

Apoptosis↗
PubMed1999

Predictive medicine: computational techniques in therapeutic decision-making.

The current paradigm for surgery planning for the treatment of cardiovascular disease relies exclusively on diagnostic imaging data to define the present state of the patient, empirical data to evaluate the efficacy of prior treatments for similar patients, and the judgement of the surgeon to decide on a preferred treatment. The individual variability and inherent complexity of human biological systems is such that diagnostic imaging and empirical data alone are insufficient to predict the outcome of a given treatment for an individual patient. We propose a new paradigm of predictive medicine in which the physician utilizes computational tools to construct and evaluate a combined anatomic/physiologic model to predict the outcome of alternative treatment plans for an individual patient. The predictive medicine paradigm is implemented in a software system developed for Simulation-Based Medical Planning. This system provides an integrated set of tools to test hypotheses regarding the effect of alternate treatment plans on blood flow in the cardiovascular system of an individual patient. It combines an Internet-based user interface developed using Java and VRML, image segmentation, geometric solid modeling, automatic finite element mesh generation, computational fluid dynamics, and scientific visualization techniques. This system is applied to the evaluation of alternate, patient-specific treatments for a case of lower extremity occlusive cardiovascular disease.

Arterial Occlusive Diseases↗
PubMed1995

Antibody humanization predicted by computer graphic analysis.

Humanized antibodies continue to be evaluated in clinical trials, and each trial will yield valuable information for the design of the next generation of humanized antibodies. More attention will be given to the use of antibody fragments and the selection of human antibody specificities from phage libraries for human antibody therapeutics. Computer graphic analysis and molecular modeling of antibody structures will continue to be invaluable for predicting structural modifications for humanization of antibodies and for extracting structural information from antigen binding sites that can ultimately lead to small molecule therapeutics.

Animals↗
PubMed2006

Aortic valve calcification as quantified with multislice computed tomography predicts short-term clinical outcome in patients with asymptomatic aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Aortic valve calcification may be an independent risk factor for adverse clinical outcome. The study aim was to assess the predictive value of possible risk factors, including the severity of aortic valve calcification as quantified with 16-multislice computed tomography (MSCT) for adverse short-term clinical outcome in patients with asymptomatic, degenerative aortic stenosis (AS). METHODS: Possible risk factors for adverse short-term clinical outcome were prospectively tested in 34 consecutive patients with asymptomatic AS as follows: (i) aortic valve calcium (AVC) score as quantified with MSCT; (ii) echocardiographic parameters--aortic valve area (AVA) calculated with continuity equation, mean and maximal transvalvular pressure gradients, end-diastolic septal wall diameter; and (iii) laboratory tests (brain natriuretic peptide (BNP), C-reactive protein (CRP)). RESULTS: Within 18-24 months of follow up, 11 of 34 patients developed a major adverse clinical outcome. Ten patients suffered from onset of symptoms accompanied by hemodynamic progression, and one patient died from sudden cardiac death. Six of these 10 patients underwent aortic valve replacement, one patient declined surgery, and three patients were not accepted for surgery (one of these died suddenly shortly afterwards). The aortic valve calcium score was the strongest predictor of a major adverse clinical event (p < 0.001) among all parameters assessed (1,928 +/- 789 versus 5,111 +/- 2,409 Agatston units). The plasma level of BNP (p = 0.003), mean transvalvular pressure gradient (p = 0.002) and AVA (p = 0.003) were also risk factors for adverse clinical outcome. CONCLUSION: The AVC score as quantified with MSCT predicted adverse short-term clinical outcome in patients with asymptomatic AS. In patients with severe aortic valve calcification, close follow up examinations are mandatory, and early elective surgery may be considered even in the absence of symptoms. MSCT provides a comprehensive non-invasive imaging approach for risk stratification in patients with asymptomatic AS.

Aortic Valve↗
PubMed2000

Infarct size determination by technetium 99m sestamibi single-photon emission computed tomography predicts survival in patients with chronic coronary artery disease.

BACKGROUND: The prognostic value of infarct size quantification by technetium 99m sestamibi single-photon emission computed tomography (SPECT) in patients with chronic coronary artery disease (CAD) has not been established. Methods And Results Between September 1994 and May 1995, 1323 patients with known or suspected CAD were referred for perfusion imaging for clinical reasons and had infarct size determined by quantitative SPECT imaging. Patients underwent exercise stress (61%), pharmacologic stress (37%), and rest imaging (3%). Patients were excluded if they had cardiomyopathy, valvular heart disease, or myocardial infarction within 3 weeks of the SPECT study. There were 1224 patients who formed the study group. Follow-up was 94% complete at a median of 1.9 +/- 0.4 years. Sixty-five percent of patients had no measurable infarct. Among the patients with measurable infarcts, the mean infarct size by sestamibi imaging was 15.0% +/- 14.5% of the left ventricle (25% of infarcts </=5% of the left ventricle and 25% of infarcts >/=19% of the left ventricle). By using stepwise regression analysis, age, diabetes, and hypercholesterolemia were all clinical predictors of overall death (P <.05). For cardiac death, only age and diabetes were significant. After adjusting for these clinical variables, infarct size remained an independent predictor of overall death (P =. 001) and survival free of cardiac death (P =.0002). However, when first-pass left ventricular ejection fraction was added to the models, infarct size was no longer significant. CONCLUSIONS: Infarct size determination by SPECT (99m)Tc sestamibi can predict subsequent death in patients with chronic CAD, although ejection fraction appears to have greater prognostic value.

Adult↗
PubMed1987

Theoretical, computer-assisted prediction versus SRK prediction of postoperative refraction after intraocular lens implantation.

The postoperative refraction prediction was evaluated in 99 patients with a 19.0-diopter standard power anterior chamber lens using a theoretical, computer-assisted method based on Gaussian optics and an empirical intraocular lens calculation method based on the SRK formula. Both the theoretical and the empirical predictions accorded with the observed values in the near emmetropia region. In the prediction of ametropia, the SRK method showed a tendency to predict refractions that were lower than the actual values in hyperopic eyes and higher than the actual values in myopic eyes. The bias of the SRK method may be due to the use of an erroneous refraction factor that converts the ametropia to the deviation in implant power from the emmetropia power. By introducing an individual refraction factor, the accuracy of the SRK method approached that of the theoretical method.

Aged↗
PubMed2004

Coronary calcium by spiral computed tomography predicts cardiovascular events in high-risk hypertensive patients.

OBJECTIVE: The ability of coronary artery calcium (CAC) to predict coronary events has been shown in several studies. We aimed to investigate the hypothesis that CAC as assessed by dual slice spiral computed tomography (DSCT), is an independent risk factor for cardiovascular events in hypertensive patients. METHODS: We followed 446 participants of INSIGHT (International Nifedipine Study Intervention as Goal for Hypertension Therapy) calcification study, for the incidence of cardiovascular events as a function of CAC and other factors. All were hypertensive, without coronary artery disease (CAD), ages > 55 years and with at least one more major cardiovascular risk factor. All underwent a baseline DSCT and were followed for a mean period of 3.8 +/- 0.4 years. All events were documented while the scheduled visits and confirmed by the INSIGHT critical event committee. RESULTS: Follow-up was conducted on all participants. 294 patients (66%) had CAC at baseline. Forty-seven patients experienced a first cardiovascular event: acute myocardial infarction (MI), 16; sudden cardiac death, two; unstable angina resulting in revascularization, 14; stroke, 15. The incidence of first cardiovascular events was 3.7 times higher among those who had CAC at baseline than among those who had no CAC (14.5% (41 of 294) versus 3.9% (6 of 152)). Patients who experienced an event were more likely to be males, had had higher prevalence of peripheral vascular disease, longer duration of hypertension, and had higher levels of systolic blood pressure (SBP), glucose, creatinine and uric acid. Adjusting for these covariates, CAC (total coronary calcium score (TCS) > 0) independently predicted cardiovascular events with an odds ratio (OR) of 2.76 [95% confidence interval (CI) 1.09-6.99, P = 0.032]. CONCLUSION: The presence of CAC predicts cardiovascular events in high-risk asymptomatic hypertensive patients.

Aged↗
PubMed2005

Does pelvic hematoma on admission computed tomography predict active bleeding at angiography for pelvic fracture?

Pelvic angiography plays an increasing role in the management of pelvic fractures (PFs). Little has been written regarding the size of pelvic hematoma on admission computed tomography (CT) and how it relates to angiography results after PF. This is a retrospective review of trauma patients with PF who underwent an admission abdominal/pelvic CT scan and pelvic angiography from 2001 to 2003. CT pelvic hematoma was measured and classified as minimal or significant based on hematoma dimensions. Presence of a contrast blush on CT scan was also documented. Thirty-seven patients underwent an admission CT scan and went on to pelvic angiography. Of the 22 patients with significant pelvic hematoma, 73 per cent (n = 16) had bleeding at angiography. Fifteen patients had minimal pelvic hematoma, with 67 per cent (n = 10) showing active bleeding at angiography. In addition, five of six patients (83%) with no pelvic hematoma had active bleeding at angiography. Six patients had a blush on CT scan, with five of these (83%) having a positive angiogram. But, 22 of 31 (71%) patients with no blush on CT scan had bleeding at angiography. The absence of a pelvic hematoma or contrast blush should not alter indications for pelvic angiography, as they do not reliably exclude active pelvic bleeding.

Adult↗
PubMed1976

A symptomatic discriminant to identify recurrent ulcer in patients with dysperpsia after gastric surgery.

A questionnaire has been completed by 99 patients referred for investigation of symptoms after gastric operations. The replies were analysed in an attempt to distinguish patients with a recurrent peptic ulcer from those with no recurrent ulcer. All cases were investigated by barium meal, endoscopy, and oral cholecystography. All recurrent ulcers were confirmed by reoperation and patients with gastric carcinoma, gallstones, or symptomatic hiatus hernia were excluded. The study was retrospective in 40 patients in whom the diagnosis was already confirmed when the questionnaire was analysed and prospective in 59 in whom the diagnosis was originally unknown. The replies were analysed with (a) a small computer using Bayes' theorem, (b) weighted tables, and (c) a discriminant analysis. The computer prediction of the prospective data was 85% accurate. The results of simpler methods were almost as good as the computer prediction, and questions related only to the severity of pain and vomiting accurately distinguished recurrent ulcer from other causes of dyspepsia in 81% of patients.

Diagnosis, Computer-Assisted↗