Automated measurement of neural foramen cross-sectional area during in vivo functional movement

An automated technique to measure neural foramen cross-sectional area during in vivo, multi-planar movements is presented. This method combines three-dimensional (3D) models of each vertebra obtained from CT scans with in vivo movement data collected using high-speed biplane radiography. A novel computer algorithm that automatically traces a path around the bony boundary that defines the neural foramen at every frame of X-ray data is described. After identifying the neural foramen boundary, the cross-sectional area is calculated. The technique is demonstrated using data collected from a patient with cervical radiculopathy who is tested before and after conservative treatment. The technique presented here can be applied when 3D, dynamic, functional movements are performed. Neural foramen cross-sectional area can be quantified at specific angles of intervertebral rotation, allowing for matched comparisons between two trials or two test sessions. The present technique is ideal for longitudinal studies involving subjects who receive conservative or surgical treatments that may affect spine motion.     

Automated measurement of neural foramen cross-sectional area during in vivo functional movement

An automated technique to measure neural foramen cross-sectional area during in vivo, multi-planar movements is presented. This method combines three-dimensional (3D) models of each vertebra obtained from CT scans with in vivo movement data collected using high-speed biplane radiography. A novel computer algorithm that automatically traces a path around the bony boundary that defines the neural foramen at every frame of X-ray data is described. After identifying the neural foramen boundary, the cross-sectional area is calculated. The technique is demonstrated using data collected from a patient with cervical radiculopathy who is tested before and after conservative treatment. The technique presented here can be applied when 3D, dynamic, functional movements are performed. Neural foramen cross-sectional area can be quantified at specific angles of intervertebral rotation, allowing for matched comparisons between two trials or two test sessions. The present technique is ideal for longitudinal studies involving subjects who receive conservative or surgical treatments that may affect spine motion.     

A novel computational tool for automated structure-based drug design

The computer program LUDI for automated structure-based drug design is described. The program constructs possible new ligands for a given protein of known three-dimensional structure. This novel approach is based upon rules about energetically favourable non-bonded contact geometries between functional groups of the protein and the ligand which are derived from a statistical analysis of crystal packings of organic molecules. In a first step small fragments are docked into the protein binding site in such a way that hydrogen bonds and ionic interactions can be formed with the protein and hydrophobic pockets are filled with lipophilic groups of the ligands. The program can then append further fragments onto a previously positioned fragments or onto an already existing ligand (e.g., a lead structure that one seeks to improve). It is also possible to link several fragments together by bridge fragments to form a complete molecule. All putative ligands retrieved or constructed by LUDI are scored. We use a simple scoring function that was fitted to experimentally determined binding constants of protein–ligand complexes. LUCI is a very fast program with typical execution times of 1–5 min on a work station and is therefore suitable for interactive usage.     

Prototype of a Fully Automated Device for Determination of Bacterial Antibiotic Susceptibility in the Clinical Laboratory

A completely automated system for the performance of antibiotic susceptibility tests in the clinical laboratory is described. With a modicum of personnel involvement, data on 40 specimens tested against 13 antibiotics are obtained every hour after an initial 3-hr period. The step by step explanation of the functioning of this prototype system, based on a thoroughly tested manual model, is presented. The system compares well with the standard diffusion test and has a potential for application to other endeavors of the clinical microbiology laboratory with a comparable saving in time and labor.     

CT-Based Attenuation Correction in I-123-Ioflupane SPECT

Purpose

Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane.

Materials and methods

Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator-characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre.

Results

CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC.

Conclusions

The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure.     

A novel computational method to determine subject-specific bite force and occlusal loading during mastication

The evaluation of three-dimensional occlusal loading during biting and chewing may assist in development of new dental materials, in designing effective and long-lasting restorations such as crowns and bridges, and for evaluating functional performance of prosthodontic components such as dental and/or maxillofacial implants. At present, little is known about the dynamic force and pressure distributions at the occlusal surface during mastication, as these quantities cannot be measured directly. The aim of this study was to evaluate subject-specific occlusal loading forces during mastication using accurate jaw motion measurements. Motion data was obtained from experiments in which an individual performed maximal effort dynamic chewing cycles on a rubber sample with known mechanical properties. A finite element model simulation of one recorded chewing cycle was then performed to evaluate the deformation of the rubber. This was achieved by imposing the measured jaw motions on a three-dimensional geometric surface model of the subject’s dental impressions. Based on the rubber’s deformation and its material behaviour, the simulation was used to compute the resulting stresses within the rubber as well as the contact pressures and forces on the occlusal surfaces. An advantage of this novel modelling approach is that dynamic occlusal pressure maps and biting forces may be predicted with high accuracy and resolution at each time step throughout the chewing cycle. Depending on the motion capture technique and the speed of simulation, the methodology may be automated in such a way that it can be performed chair-side. The present study demonstrates a novel modelling methodology for evaluating dynamic occlusal loading during biting or chewing.     

An integrated approach to patient-specific predictive modeling for single ventricle heart palliation

In patients with congenital heart disease and a single ventricle (SV), ventricular support of the circulation is inadequate, and staged palliative surgery (usually 3 stages) is needed for treatment. In the various palliative surgical stages individual differences in the circulation are important and patient-specific surgical planning is ideal. In this study, an integrated approach between clinicians and engineers has been developed, based on patient-specific multi-scale models, and is here applied to predict stage 2 surgical outcomes. This approach involves four distinct steps: (1) collection of pre-operative clinical data from a patient presenting for SV palliation, (2) construction of the pre-operative model, (3) creation of feasible virtual surgical options which couple a three-dimensional model of the surgical anatomy with a lumped parameter model (LPM) of the remainder of the circulation and (4) performance of post-operative simulations to aid clinical decision making. The pre-operative model is described, agreeing well with clinical flow tracings and mean pressures. Two surgical options (bi-directional Glenn and hemi-Fontan operations) are virtually performed and coupled to the pre-operative LPM, with the hemodynamics of both options reported. Results are validated against postoperative clinical data. Ultimately, this work represents the first patient-specific predictive modeling of stage 2 palliation using virtual surgery and closed-loop multi-scale modeling.     

Simulation of the aging face

A three-dimensional finite element program is described which attempts to simulate the nonlinear mechanical behavior of an aging human face with specific reference to progressive gravimetric soft tissue descent. A cross section of the facial structure is considered to consist of a multilayered composite of tissues with differing mechanical behavior. Relatively short time (elastic-viscoplastic) behavior is governed by equations previously developed which are consistent with mechanical tests. The long time response is controlled by the aging elastic components of the tissues. An aging function is introduced which, in a simplified manner, models the observed loss of stiffness of these aging elastic components due to the history of straining as well as other physiological and environmental influences. Calculations have been performed for 30 years of exposure to gravitational forces. The deformations and stress distributions in the layers of the soft tissues are described. Overall, the feasibility of using constitutive relations which reflect the highly nonlinear elastic-viscoplastic behavior of facial soft tissues in finite element based three-dimensional mechanical analyses of the human face is demonstrated. Further developments of the program are discussed in relation to possible clinical applications. Although the proposed aging function produces physically reasonable long-term response, experimental data are not yet available for more quantitative validation.     

A calculator program for clinical application of the Bayesian method of predicting plasma drug levels

A pharmacokinetic program that allows individualization of drug dosage regimens through the Bayesian method is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based upon the one-compartment open model with either instantaneous or zero-order absorption. Individualized estimation of the patient's kinetic parameters (clearance and volume of distribution) is performed by analyzing the plasma levels measured in the patient as well as considering the population data of the drug. After estimating the individual kinetic parameters by the Bayesian method, the program predicts the dosage regimen that will elicit the desired peak and trough plasma levels at steady state. For comparison purposes, the least-squares estimates for clearance and volume of distribution are calculated, and dosage prediction can also be made on the basis of the least-squares estimates. The least-squares estimates can be used to calculate population pharmacokinetic parameters according to the Standard Two-Stage method. Several examples of clinical use of the program are presented. The examples refer to patients with classic hemophilia who were treated with Factor VIII concentrates. In these patients, the Bayesian kinetic parameters of Factor VIII have been estimated through the calculator program. The Bayesian parameter estimates generated by the HP-41 have been compared with those determined by a Bayesian program (ADVISE) designed for microcomputers.     

Modeling of protein binary complexes using structural mass spectrometry data

In this article, we describe a general approach to modeling the structure of binary protein complexes using structural mass spectrometry data combined with molecular docking. In the first step, hydroxyl radical mediated oxidative protein footprinting is used to identify residues that experience conformational reorganization due to binding or participate in the binding interface. In the second step, a three-dimensional atomic structure of the complex is derived by computational modeling. Homology modeling approaches are used to define the structures of the individual proteins if footprinting detects significant conformational reorganization as a function of complex formation. A three-dimensional model of the complex is constructed from these binary partners using the ClusPro program, which is composed of docking, energy filtering, and clustering steps. Footprinting data are used to incorporate constraints-positive and/or negative-in the docking step and are also used to decide the type of energy filter-electrostatics or desolvation-in the successive energy-filtering step. By using this approach, we examine the structure of a number of binary complexes of monomeric actin and compare the results to crystallographic data. Based on docking alone, a number of competing models with widely varying structures are observed, one of which is likely to agree with crystallographic data. When the docking steps are guided by footprinting data, accurate models emerge as top scoring. We demonstrate this method with the actin/gelsolin segment-1 complex. We also provide a structural model for the actin/cofilin complex using this approach which does not have a crystal or NMR structure.     

ESyPred3D: Prediction of proteins 3D structures

MOTIVATION: Homology or comparative modeling is currently the most accurate method to predict the three-dimensional structure of proteins. It generally consists in four steps: (1) databanks searching to identify the structural homolog, (2) target-template alignment, (3) model building and optimization, and (4) model evaluation. The target-template alignment step is generally accepted as the most critical step in homology modeling. RESULTS: We present here ESyPred3D, a new automated homology modeling program. The method gets benefit of the increased alignment performances of a new alignment strategy. Alignments are obtained by combining, weighting and screening the results of several multiple alignment programs. The final three-dimensional structure is build using the modeling package MODELLER. ESyPred3D was tested on 13 targets in the CASP4 experiment (Critical Assessment of Techniques for Proteins Structural Prediction). Our alignment strategy obtains better results compared to PSI-BLAST alignments and ESyPred3D alignments are among the most accurate compared to those of participants having used the same template. AVAILABILITY: ESyPred3D is available through its web site at http://www.fundp.ac.be/urbm/bioinfo/esypred/ CONTACT: christophe.lambert@fundp.ac.be; http://www.fundp.ac.be/~lambertc     

Implementing a regulation-complaint quality improvement program on a commercial laboratory information system.

Implementing a quality improvement (QI) program on an automated laboratory information system (LIS) in the current regulatory climate requires first that the QI program be defined and second that the selected LIS be able to capture important events and use flexible vendor-provided or user-defined routines to prepare reports. Reports key on specific monitors and thresholds defined in the QI program. The product of a pathology laboratory is communicated information. The QI program focuses on the accuracy, clarity and timeliness with which the whole information-generating process functions. To support peer review the LIS must be able to select reports for evaluation based on user-defined parameters, such as diagnosis keyed through Systematized Nomenclature of Medicine codes, or by random or pattern selection by accession number. Counting and review of revised reports will focus attention on accuracy and skill in communication since these indicators often reflect client satisfaction with the report. To link services--e.g., cytology with surgical pathology--the LIS must be able to gather cases from the accession lists of both services and to flag diagnostic inconsistencies. LIS transaction logging at every step in the information process allows tracking of work load, productivity and resource utilization by functional areas and by individual, thus meeting regulatory requirements. Transaction logging also provides management information, such as segmented turnaround time audits, pinpointing sources of delay by kind and location of work or individual involved. Critical data must be held on-line for at least five years.     

Simultaneous and multivariate alignment of protein sequences: correspondence between physicochemical profiles and structurally conserved regions (SCR)

A general protein sequence alignment methodology for detecting a priori unknown common structural and functional regions is described. The method proposed in this paper is based on two basic requirements for a meaningful alignment. First, each sequence or segment of a sequence is characterized by a multivariate physicochemical profile. Second, the alignment is performed by considering all the sequences simultaneously, and the algorithm detects those regions that form a set of similar profiles. In order to test the structural meaning of the alignment obtained from the sequences, quantitative comparisons are performed with structurally conserved regions (SCR) determined from the X-ray structures of three serine proteases. Results suggest that the limits of the SCR may be predicted from the similarities between the physicochemical profiles of the sequences. The procedures are not completely automated. The final step requires a visual screening of alternative pathways in order to determine an optimal alignment.     

Metabolomics spectral formatting, alignment and conversion tools (MSFACTs)

MOTIVATION: The amplified interest in metabolic profiling has generated the need for additional tools to assist in the rapid analysis of complex data sets. RESULTS: A new program; metabolomics spectral formatting, alignment and conversion tools, (MSFACTs) is described here for the automated import, reformatting, alignment, and export of large chromatographic data sets to allow more rapid visualization and interrogation of metabolomic data. MSFACTs incorporates two tools: one for the alignment of integrated chromatographic peak lists and another for extracting information from raw chromatographic ASCII formatted data files. MSFACTs is illustrated in the processing of GC/MS metabolomic data from different tissues of the model legume plant, Medicago truncatula. The results document that various tissues such as roots, stems, and leaves from the same plant can be easily differentiated based on metabolite profiles. Further, similar types of tissues within the same plant, such as the first to eleventh internodes of stems, could also be differentiated based on metabolite profiles. AVAILABILITY: Freely available upon request for academic and non-commercial use. Commercial use is available through licensing agreement http://www.noble.org/PlantBio/MS/MSFACTs/MSFACTs.html.     

Impact d’une méthode originale de synchronisation respiratoire sur la détection des lésions hépatiques en TEP/TDM au F-FDG

In ¹⁸F-Fluoro-Desoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT), respiratory motion induces bias in image interpretations. These movements can introduce organs misregistration between both modalities yielding erroneous attenuation correction and thus wrong maximum standardized uptake values (SUV_max). We present here the results of a clinical study which aims to assess the benefits of a novel respiratory gating method (CT-based) for liver lesions detection. Forty-nine patients planed to undergo hepatic surgery were addressed to our department for PET/CT examination before surgery. Each patient had both standard and CT-based protocols. Hepatic lesions described by two observers on PET images were compared with pathological analysis and intra-operative ultrasound. Sensitivities calculated for observer 1 were 60 and 64% for standard and CT-based, respectively. For the second observer, sensitivities were 58.7 and 72%. CT-based showed a significant increase (P < 0.01) of sensitivity on a per-lesion basis for one observer. CT-based did not improve inter-observer variability. At last, SUV_max were significantly higher with CT-based method (P < 0.001). Respiratory gating CT-based method is easily bearable by the patients. This procedure ensures good matching between both modalities and reduces motion-blurring effect in PET data. CT-based method improves liver lesions detectability and allows more accurate quantitation compared to non-gated FDG-PET/CT examinations.     

A calculator program for least-squares parameter estimation according to the one-compartment kinetic model with zero-order input

A calculator program that performs a nonlinear least-squares fit to data conforming to the one-compartment model with zero-order input is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based on the Gauss-Newton iterative algorithm as modified by Hartley. A subroutine for calculation of initial parameter estimates is incorporated into the program. Plasma concentration data relative to a single oral dose of a sustained-release theophylline formulation are used to demonstrate the practical application of the program.     

Mechanical properties of brain tissue in-vivo: experiment and computer simulation

Realistic computer simulation of neurosurgical procedures requires incorporation of the mechanical properties of brain tissue in the mathematical model. Possible applications of computer simulation of neurosurgery include non-rigid registration, virtual reality training and operation planning systems and robotic devices to perform minimally invasive brain surgery. A number of constitutive models of brain tissue, both single-phase and bi-phasic, have been proposed in recent years. The major deficiency of most of them, however, is the fact that they were identified using experimental data obtained in vitro and there is no certainty whether they can be applied in the realistic in vivo setting. In this paper we attempt to show that previously proposed by us hyper-viscoelastic constitutive model of brain tissue can be applied to simulating surgical procedures. An in vivo indentation experiment is described. The force-displacement curve for the loading speed typical for surgical procedures is concave upward containing no linear portion from which a meaningful elastic modulus might be determined. In order to properly analyse experimental data, a three-dimensional, non-linear finite element model of the brain was developed. Magnetic resonance imaging techniques were used to obtain geometric information needed for the model. The shape of the force-displacement curve obtained using the numerical solution was very similar to the experimental one. The predicted forces were about 31% lower than those recorded during the experiment. Having in mind that the coefficients in the model had been identified based on experimental data obtained in vitro, and large variability of mechanical properties of biological tissues, such agreement can be considered as very good. By appropriately increasing material parameters describing instantaneous stiffness of the tissue one is able, without changing the structure of the model, to reproduce experimental curve almost perfectly. Numerical studies showed also that the linear, viscoelastic model of brain tissue is not appropriate for the modelling brain tissue deformation even for moderate strains.     

Disease cost in a surgical ward.

Data relating to the cost of caring for individual patients were collected for all patients in a general surgical ward over a six-month period. From this the cost per patient was calculated for various diseases and was found to be related to duration of stay. Postoperative morbidity was important in determining cost. A system that calculates cost by means of units based on the use of resources rather than by cash cost accounting is probably the most suitable for a clinician who has to monitor resources.     

Automated and assisted RNA resonance assignment using NMR chemical shift statistics

The three-dimensional structure determination of RNAs by NMR spectroscopy relies on chemical shift assignment, which still constitutes a bottleneck. In order to develop more efficient assignment strategies, we analysed relationships between sequence and ¹H and ¹³C chemical shifts. Statistics of resonances from regularly Watson–Crick base-paired RNA revealed highly characteristic chemical shift clusters. We developed two approaches using these statistics for chemical shift assignment of double-stranded RNA (dsRNA): a manual approach that yields starting points for resonance assignment and simplifies decision trees and an automated approach based on the recently introduced automated resonance assignment algorithm FLYA. Both strategies require only unlabeled RNAs and three 2D spectra for assigning the H2/C2, H5/C5, H6/C6, H8/C8 and H1′/C1′ chemical shifts. The manual approach proved to be efficient and robust when applied to the experimental data of RNAs with a size between 20 nt and 42 nt. The more advanced automated assignment approach was successfully applied to four stem-loop RNAs and a 42 nt siRNA, assigning 92–100% of the resonances from dsRNA regions correctly. This is the first automated approach for chemical shift assignment of non-exchangeable protons of RNA and their corresponding ¹³C resonances, which provides an important step toward automated structure determination of RNAs.