[Functional sites of pro- and eukaryotic genomes: computer modeling and predicting activity].
Explore the source record for details and available documents.
SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
OBJECTIVE: The objective was to determine the role of arcitumomab (CEA-Scan; Immunomedics, Morris Plains, NJ), an anticarcinoembryonic antigen (CEA) Fab' labeled with technetium-99m, in the presurgical evaluation of patients with recurrent or metastatic colorectal carcinoma. SUMMARY BACKGROUND DATA: Surgical resection is the only method known to cure recurrent or metastatic colorectal carcinoma. The location and extent of disease must be determined before surgery. The role of antibody imaging, a new cancer detection modality, in preoperative evaluation for resection of locally recurrent or metastatic colorectal cancer has not been established, either alone or in combination with standard diagnostic modalities. METHODS: In a blinded analysis of 209 patients with known or suspected colorectal cancer, the accuracy of arcitumomab, alone and combined with computed tomography (CT), was compared to that of CT for predicting abdominopelvic tumor resectability by correlating the results with surgical and histopathologic findings. RESULTS: Arcitumomab alone or combined with CT was found to be significantly more accurate for predicting surgical outcome than CT alone. When the results of CT and arcitumomab were concordant for abdominopelvic resectability, nonresectability, or absence of disease, the prediction was accurate in 67%, 100%, and 64%, respectively. Thus, the concordance for nonresectability (100% correct) may obviate the need for other diagnostic modalities or exploratory surgery. When the two tests were discordant, arcitumomab was correct substantially more often than CT. Because the liver is the most common site of distant metastasis in colorectal cancer, a subset of patients with hepatic disease was also analyzed; findings were similar to the overall resectability results. The product's safety profile was excellent: the incidence of induction of an immune response against arcitumomab was <1% and that of potentially adverse events was 1.2%. CONCLUSIONS: The accuracy of arcitumomab for assessing resectability status is greater than that of CT, both in all patients undergoing evaluation for curative abdominopelvic resection of colorectal cancer and in the subset of patients with suspected or proven liver metastases. The additional use of arcitumomab with CT potentially doubles the number of patients who could be saved the cost, morbidity, and mortality of unnecessary abdominopelvic surgery and increases those who are potentially resectable for cure by 40%.
The predictive validity of a computer model of human temperature regulation is tested by comparison with experimental data. Three male subjects were exercised at five different rates (B.M.R., 100 W, 150 W, 200 W, and 250 W) on a cycle ergometer in a controlled-environmental facility. Thermal conditions ranged from 13 degrees to 29 degrees C on the Effective Temperature (E.T.) scale. Two core (rectal and tympanic) and four skin temperature sites (2 torso, 1 leg, and 1 arm) were monitored. Experimental figures for core temperature (TC) and mean body temperature (MBT), evolved from the six monitored sites, were compared with matched simulation data from the computer model. A high negative correlation (r = -0.87) was found for increasing "effective temperature" and mean absolute difference (d) between experimental and simulation data for mean body temperatures. The model has increasing predictive validity as higher heat stress is encountered (E.T. greater than 25 degrees C, d MBT less than 0.3 degrees C), which decreases (E.T. less than 16 degrees C, d MBT greater than 0.8 degrees C) in reduced environmental temperatures.
Explore the source record for details and available documents.
Future alternatives to the presently accepted in vitro paradigm of prediction of intrinsic clearance, which could be used earlier in the drug discovery process, would potentially accelerate efforts to identify better drug candidates with more favorable metabolic profiles and less likelihood of failure with regard to human pharmacokinetic attributes. In this study we describe two computational methods for modeling human microsomal and hepatocyte intrinsic clearance data derived from our laboratory and the literature, which utilize pharmacophore features or descriptors derived from molecular structure. Human microsomal intrinsic clearance data generated for 26 known therapeutic drugs were used to build computational models using commercially available software (Catalyst and Cerius(2)), after first converting the data to hepatocyte intrinsic clearance. The best Catalyst pharmacophore model gave an r of 0.77 for the observed versus predicted clearance. This pharmacophore was described by one hydrogen bond acceptor, two hydrophobic features, and one ring aromatic feature essential to discriminate between high and low intrinsic clearance. The Cerius(2) quantitative structure activity relationship (QSAR) model gave an r(2) = 0.68 for the observed versus predicted clearance and a cross-validated r(2) (q(2)) of 0.42. Similarly, literature data for human hepatocyte intrinsic clearance for 18 therapeutic drugs were also used to generate two separate models using the same computational approaches. The best Catalyst pharmacophore model gave an improved r of 0.87 and was described by two hydrogen bond acceptors, one hydrophobe, and 1 positive ionizable feature. The Cerius(2) QSAR gave an r(2) of 0.88 and a q(2) of 0.79. Each of these models was then used as a test set for prediction of the intrinsic clearance data in the other data set, with variable successes. These present models represent a preliminary application of QSAR software to modeling and prediction of human in vitro intrinsic clearance.
The importance of shear stress in the initiation and progression of atherosclerosis has been recognized for some time. A novel way to quantify wall shear stress under physiologically realistic conditions is to combine magnetic resonance imaging (MRI) and computational fluid dynamics. The present study aims to investigate the reproducibility of the simulated flow by using this combined approach. The right carotid bifurcations of eight healthy subjects were scanned twice with MRI within a few weeks. Three-dimensional geometries of the vessels were reconstructed for each scan and each subject. Pulsatile flows through these models were calculated to assess errors associated with the predicted flow parameters. This was done by comparing various wall shear stress indices, including the time-averaged wall shear stress (WSS), oscillating shear index (OSI), WSS Gradients (WSSG) and WSS Angle Deviation (WSSAD). Qualitatively, all the wall shear parameters proved to be highly reproducible. Quantitatively, the reproducibility was over 90% for OSI and WSSAD, but less impressive (60%) for other parameters. Our results indicated that WSS and WSSG values were extremely sensitive to subtle variations in local geometry and mesh design, particularly in regions around the bifurcation apex where WSS values were high and least reproducible.
Vaccination with peptides recognized by antigen-specific CTLs can prevent lethal virus infections and tumor growth. In order to avoid the synthesis and testing of the numerous overlapping peptide of long AA sequences of proteins of interest, we developed a computer program which utilizes the rules, "motifs" which govern how peptides bind to HLA class I molecules, to derive a predicted binding score for each overlapping peptide. Correlations between the predicted and actual binding results to HLA-A*0201 for 100 peptides selected from six early and two late protein sequences of human papillomavirus type 1a revealed an acceptable level (61%) of concordance. The program is very flexible with regard to the input of protein sequences and motif definitions and is able to handle various motif and peptide lengths.
Two designs of total knee replacements were analysed to determine how the geometry of their bearing surface would affect the susceptibility of their ultra high molecular weight polyethylene tibial inserts to delamination. Orientations of the femoral components on the tibial surfaces were calculated with use of rigid body analysis for discrete intervals during the stance phase of gait. For each successive orientation, finite element analysis was used to compress the components together to determine the stresses in the tibial inserts. A damage function analogous to strain energy density was defined to account for the accumulated amplitudes and frequencies of the maximum shear stress cycles and hence to predict fatigue failure. The damage function was applied to each polyethylene element in the tibial insert, and the highest value calculated for each design was its damage score. One knee had a damage score more than three times less than that of the other because of lower stresses and because the contact points moved in the medial-lateral as well as anterior-posterior directions during internal-external rotation. The femoral and tibial components of this knee had large outer frontal radii and close conformity in the frontal plane. We propose that this method, which accounts for the motions and stresses endured during walking, makes different predictions regarding the likelihood of delamination compared with the predictions made by conventional static compression tests performed when the knee is in a neutral position.
BACKGROUND AND PURPOSE: Current guidelines recommend the use of head CT in the evaluation of patients with transient ischemic attack (TIA), but data supporting its value are sparse. METHODS: Patients who presented to 1 of 16 emergency departments of a large Northern California health maintenance organization and received a diagnosis of TIA from November 1997 through February 1998 were enrolled and followed up for 90 days. Clinical, demographic, and outcome data were obtained from computerized databases and medical records. Physicians blinded to patient characteristics and outcomes abstracted head CT findings from radiology reports. Abstracted findings included evidence of old or new infarct, periventricular white-matter disease, cerebral atrophy, cerebral vascular calcification, and nonischemic lesions. RESULTS: Head CT was performed in 67% of eligible patients (n=322) diagnosed with TIA. Evidence of a new infarct was seen on head CT in 13 patients (4%). A nonischemic cause of TIA symptoms was found in 4 patients (1.2%). During follow-up, 10.9% of TIA patients experienced subsequent stroke. After adjustment for confounders, risk for stroke during follow-up was significantly higher in those with a new infarct on head CT compared with others with TIA (odds ratio, 4.06; 95% confidence interval, 1.16 to 14.14; P=0.028). Old infarction, periventricular white-matter disease, cerebral atrophy, and cerebral vascular calcification were not predictors of subsequent risk of stroke. CONCLUSIONS: Evidence of a new infarct on head CT in patients presenting with TIA is associated with increased short-term risk for stroke. Head CT appears to have prognostic value in patients with TIA and, for this reason alone, may be justified in their evaluation.
Explore the source record for details and available documents.
OBJECTIVE: Hyperperfusion after carotid endarterectomy (CEA) has been proposed as the main mechanism of intracerebral hemorrhage, which is a disastrous complication. The aim of this study was to compare the predictive value of cerebral blood flow (CBF) abnormalities for hyperperfusion after CEA with the conventional region of interest (ROI) analysis and statistical brain mapping analysis. METHODS: For 46 patients with unilateral carotid stenosis of 70% or more, CBF and cerebral vasoreactivity were investigated with resting and acetazolamide-challenge single-photon emission computed tomography before CEA and 1 day after CEA. Three-dimensional stereotactic surface projection (3-D-SSP) analysis of CBF changes was performed by automatic quantification with a predefined template. RESULTS: Logistic regression analysis demonstrated CBF reduction (z-score) to be the only significant variable for postoperative hyperperfusion on 3-D-SSP with thalamic normalization but no significant variable with the ROI method. Receiver operating characteristic (ROC) analysis demonstrated significant improvement in the predictive value of CBF reduction (z-score) on 3-D-SSP (area under the ROC curve = 0.93) in comparison with the ROI method (area under the ROC curve = 0.78) (P = 0.049). According to the optimal cutoff values provided by ROC analysis, patients were categorized into two groups: Type I (CBF decrease < 20%, n = 23) and Type II (CBF decrease > or = 20%, n = 23) on ROI analysis and Type A (z-score < or = 2, n = 40) and Type B (z-score > 2, n = 6) on 3-D-SSP. There was a significant difference in incidence of hyperperfusion between Type A (1 of 40) and Type B (5 of 6) on 3-D-SSP (P = 0.00003) but not between Type I (1 of 23) and Type II (5 of 23) on ROI analysis. Cerebral vasoreactivity did not show significant value in the prediction of hyperperfusion with either the ROI or the 3-D-SSP method. CONCLUSION: Objective assessment of CBF status, especially baseline CBF reduction (z-score), with automatic quantification by 3-D-SSP with normalization had a higher diagnostic value than conventional ROI analysis to identify patients at risk for hyperperfusion after CEA.
Explore the source record for details and available documents.
The Bohr/Riley model of CO2 homeostasis describes the relationship between CO2 production, ventilation, and arterial PCO2 and assumes that ventilation and CO2 delivery to the lung are both anatomically and temporally well matched. In contrast to normal breathing, periodic patterns of ventilation show temporal mismatch of ventilation to CO2 delivery. We developed a computer model of lung CO2 clearance that uses CO2 transfer equations to generate iterative solutions for PCO2 in multiple body compartments as a function of time. During continuous ventilatory patterns our model predicts steady-state arterial PCO2 identical to that of the Bohr model. During periodic ventilation, we predict mean PCO2 will be elevated unless mean ventilation is increased above that required by the Bohr model. Waxing and waning tidal volumes, low functional residual capacity, and low capillary blood volume potentiate the hypercapnia. However, if cardiac output oscillates in phase with breathing, hypercapnia is minimized. This analysis suggests a new mechanism for the development of sustained hypercapnia, separate from absolute hypoventilation or the presence of lung disease.
Parenchymal hypodensity is a proposed risk factor for hemorrhage after recombinant tissue plasminogen activator (TPA) thrombolysis for ischemic stroke. In Buffalo, NY, and Houston, TX, the authors reviewed 70 patients who were treated with intravenous TPA for acute middle cerebral artery (MCA) stroke. Two observers blinded to clinical outcome analyzed initial noncontrast head computed tomography (CT) scans. Basal ganglia CT hypodensity was quantitated in Hounsfield units (HUs). Contralateral-ipsilateral difference in density was calculated using the asymptomatic side as a control. Ictus time to TPA averaged 2.5 hours. Six patients developed symptomatic intraparenchymal hematomas (2 fatal). The hemorrhage group had more severe basal ganglia hypodensity (mean 7.5 +/- 1.4, range 6-10 HU) than the nonhemorrhage group (2.2 +/- 1.4, range 0-9 HU) (P < .0001). The hemorrhage group had hypodensity of > 5 HU; the nonhemorrhage group had hypodensity of < or = 4 HU, except 1 patient with hypodensity of 9 HU. In predicting hemorrhage, the positive predictive value of hypodensity > 5 HU was 86%; the negative predictive value was 100%. Prethrombolysis NIH Stroke Scale (NIHSS) deficit (P = .0007) and blood glucose (P = .005) were also higher in the hemorrhage group. Age, gender, smoking, hypertension, and ictus time to TPA infusion did not differ between the 2 groups. Logistic regression indicated that basal ganglia hypodensity was the best single predictor of hemorrhage. Hypodensity and NIHSS score together predicted all cases of hemorrhage. The authors conclude that basal ganglia hypodensity quantified by CT may be a useful method of risk stratification to select acute MCA stroke patients for thrombolytic therapy.
Explore the source record for details and available documents.
The use of computed tomography (CT) to confirm femoral head position after closed reduction and spica cast immobilization in the treatment of developmental dysplasia of the hip (DDH) has become a common practice. We retrospectively reviewed postreduction CT scans of 38 children younger than 24 months of age with unilateral DDH to determine whether they could predict acetabular remodeling potential. The measurements analyzed from the postreduction CT scans were the acetabular index, axial acetabular index, anterior and posterior acetabular angles, acetabular anteversion, and axial reduction index; the standard acetabular index was measured from the plain radiographs. The average age at reduction was 11 months and at follow-up was 61 months. No angle measured on the postreduction CT scan was found to be predictive of acetabular remodeling.
OBJECTIVE: The South Bay Heart Watch is a cohort study designed to determine the significance of coronary calcium in high-risk asymptomatic patients. This is a report of the relative risk (RR) for outcomes of coronary artery calcium in diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS: A total of 1312 diabetic and nondiabetic subjects underwent risk factor screening and computed tomography testing for coronary calcium at baseline and were followed clinically for 6.3 +/- 1.4 years. End points were either 1). hard events of nonfatal myocardial infarction (MI) or coronary death or 2). any cardiovascular event (nonfatal MI, coronary death, coronary revascularization, or stroke). RESULTS: The incidence rates of a hard event and any cardiovascular event for diabetic and nondiabetic subjects were 14.5 and 6.1% and 23.8 and 12.2%, respectively (P < 0.001). Cox regression analyses of the combined risk relationship of diabetes status and calcium score demonstrated that relative to nondiabetic subjects with low calcium scores (<2.8), diabetic subjects with calcium scores >or=2.8 exhibited at least a fourfold increase in the risk of either a hard or any cardiovascular event (P < 0.001). Cox regression analyses conducted separately for nondiabetic and diabetic subjects revealed that coronary calcium score risk groups were significantly associated with events in nondiabetic subjects (RR >or= 2.6, P 0.05). CONCLUSIONS: The risk of coronary heart disease increases with increasing calcium scores and diabetes status. Calcium scores have less prognostic value in diabetic subjects.
Background: In plastic and reconstructive craniofacial surgery, careful preoperative planning is essential. In complex cases of craniofacial synostosis, rapid prototyping models are used to simulate the surgery and reduce operating time. Recently, 3-D CT model surgery has been introduced for presurgical planning and prediction of the postoperative result. Objective: For simulation of craniofacial surgery a computer-based system was developed that allows visualization and manipulation of CT-data using computer graphics techniques. Surgical procedures in all areas of the bony skull can be performed interactively. Results: The case of a child with scaphocephalus is presented. Surgery is planned using the craniofacial surgery simulator described above. Conclusion: The computer-based interactive surgery simulation systems presented here allow precise visualization of craniofacial surgery. The accurate computer-aided 3-D simulation of bone displacements is also the prerequisite for transfer of the simulated surgery using a navigation system for surgery. Thus the preoperatively planned procedure could be transferred directly to the operating table. Copyright 2001 European Association for Cranio-Maxillofacial Surgery.