Biomedical subjects

David G Lloyd

Publications and source records attributed to David G Lloyd.

27 records · Page 2Linked to original sources

PubMed2004

Neuromusculoskeletal modeling: estimation of muscle forces and joint moments and movements from measurements of neural command.

This paper provides an overview of forward dynamic neuromusculoskeletal modeling. The aim of such models is to estimate or predict muscle forces, joint moments, and/or joint kinematics from neural signals. This is a four-step process. In the first step, muscle activation dynamics govern the transformation from the neural signal to a measure of muscle activation-a time varying parameter between 0 and 1. In the second step, muscle contraction dynamics characterize how muscle activations are transformed into muscle forces. The third step requires a model of the musculoskeletal geometry to transform muscle forces to joint moments. Finally, the equations of motion allow joint moments to be transformed into joint movements. Each step involves complex nonlinear relationships. The focus of this paper is on the details involved in the first two steps, since these are the most challenging to the biomechanician. The global process is then explained through applications to the study of predicting isometric elbow moments and dynamic knee kinetics.

Journal Article↗

PubMed2004

De novo drug design: integration of structure-based and ligand-based methods.

Structure-based and ligand-based methods are used to derive predictive models in de novo drug design. Structure-based methods rely exclusively on prior knowledge of a protein structure to derive novel ligands, while ligand-based methods are traditionally used when no protein structure is available. Where there is sufficient information, these methods can be used in conjunction to increase the accuracy of simulation and enhance the drug design process. This review presents developments in the integration of these methods for de novo drug design, and recent results from both systems are highlighted.

Combinatorial Chemistry Techniques↗

PubMed2003

An EMG-driven musculoskeletal model to estimate muscle forces and knee joint moments in vivo.

This paper examined if an electromyography (EMG) driven musculoskeletal model of the human knee could be used to predict knee moments, calculated using inverse dynamics, across a varied range of dynamic contractile conditions. Muscle-tendon lengths and moment arms of 13 muscles crossing the knee joint were determined from joint kinematics using a three-dimensional anatomical model of the lower limb. Muscle activation was determined using a second-order discrete non-linear model using rectified and low-pass filtered EMG as input. A modified Hill-type muscle model was used to calculate individual muscle forces using activation and muscle tendon lengths as inputs. The model was calibrated to six individuals by altering a set of physiologically based parameters using mathematical optimisation to match the net flexion/extension (FE) muscle moment with those measured by inverse dynamics. The model was calibrated for each subject using 5 different tasks, including passive and active FE in an isokinetic dynamometer, running, and cutting manoeuvres recorded using three-dimensional motion analysis. Once calibrated, the model was used to predict the FE moments, estimated via inverse dynamics, from over 200 isokinetic dynamometer, running and sidestepping tasks. The inverse dynamics joint moments were predicted with an average R(2) of 0.91 and mean residual error of approximately 12 Nm. A re-calibration of only the EMG-to-activation parameters revealed FE moments prediction across weeks of similar accuracy. Changing the muscle model to one that is more physiologically correct produced better predictions. The modelling method presented represents a good way to estimate in vivo muscle forces during movement tasks.

Adult↗

PubMed2003

Repeatability of gait data using a functional hip joint centre and a mean helical knee axis.

Repeatability of traditional kinematic and kinetic models is affected by the ability to accurately locate anatomical landmarks (ALs) to define joint centres and anatomical coordinate systems. Numerical methods that define joint centres and axes of rotation independent of ALs may also improve the repeatability of kinematic and kinetic data. The purpose of this paper was to compare the repeatability of gait data obtained from two models, one based on ALs (AL model), and the other incorporating a functional method to define hip joint centres and a mean helical axis to define knee joint flexion/extension axes (FUN model). A foot calibration rig was also developed to define the foot segment independent of ALs. The FUN model produced slightly more repeatable hip and knee joint kinematic and kinetic data than the AL model, with the advantage of not having to accurately locate ALs. Repeatability of the models was similar comparing within-tester sessions to between-tester sessions. The FUN model may also produce more repeatable data than the AL model in subject populations where location of ALs is difficult. The foot calibration rig employed in both the AL and FUN model provided an easy alternative to define the foot segment and obtain repeatable data, without accurately locating ALs on the foot.

Ankle Joint↗

PubMed2003

Muscle activation strategies at the knee during running and cutting maneuvers.

PURPOSE: The purpose of this article was to investigate the activation patterns of muscles surrounding the knee during preplanned (PP) and unanticipated (UN) running and cutting tasks, with respect to the external moments applied to the joint. It was hypothesized that activation strategies during PP tasks would correspond to the magnitude and direction of the external loads applied to the knee joint, and the muscle activation patterns would differ between PP and UN tasks. METHODS: Eleven healthy male subjects performed a series of running and cutting tasks under PP and UN conditions. Activation from 10 knee muscles were determined using full-wave rectified, filtered, and normalized EMG calculated during a precontact phase and two epochs across the stance phase. Knee joint flexor and extensor muscle group ratios indicated the level of co-contraction. Individual muscles were also grouped into medial/lateral and internal/external rotation muscle groups, based upon their ability to counter externally applied varus/valgus and internal/external rotation joint loads, respectively. RESULTS: Selective activation of medial/lateral and internal/external rotation muscles and co-contraction of flexors and extensors were used to stabilize the joint under PP conditions, whereas generalized co-contraction strategies were employed during the UN condition. Net muscle activation during the UN sidestepping tasks increased by 10-20%, compared with an approximately 100% increase in applied varus/valgus and internal/external rotation joint moments. CONCLUSION: In PP conditions, activation patterns appear to be selected to support the external loads experienced at the knee, e.g., medial muscles activated to resist applied valgus moments. Under UN conditions, there was no selective activation of muscles to counter the external knee load, with generalized co-contraction being the activation pattern adopted. These findings have implications for the etiology of noncontact knee ligament injuries.

Adolescent↗

PubMed2002

Murine model of autosomal dominant retinitis pigmentosa generated by targeted deletion at codon 307 of the rds-peripherin gene.

We introduced a targeted single base deletion at codon 307 of the rds-peripherin gene in mice, similar mutations being known to cause autosomal dominant retinitis pigmentosa (RP) in man. Histopathological and electroretinographic analysis indicate that the retinopathy in mice homozygous for the codon 307 mutation appears more rapid than that in the naturally occurring null mutant, the rds(-/-) mouse, suggesting that the rds-307 mutation displays a dominant negative phenotype in combination with that due to haplosufficiency. RP is the most prevalent cause of registered visual handicap in those of working age in developed countries, the 50 or so mutations so far identified within the RDS-peripherin gene accounting for up to 10% of dominant cases of the disease. Given the sequence homologies that exist between the murine rds-peripherin and the human RDS-peripherin gene, this disease model, the first to be generated for peripherin-based RP using gene targeting techniques, should in principle be of value in the work-up in mice of therapeutics capable of targeting transcripts derived from the human gene.

Amino Acid Sequence↗

PubMed2002

A topological study of prodrugs of 5-fluorouracil.

Various physicochemical properties are correlated with the first-order connectivity index for a series of prodrug derivatives of 5-fluorouracil. Partition coefficient data available in the literature were complemented by calculated logP values using the CLOGP program. The first-order connectivity index correlated quite well with the experimental logP values (n=16) while the correlation with ClogP improved with the removal of compounds VI, VII and XVII. A molecular modelling study provided data for the molecular area and volume of all prodrugs studied. The regression equations obtained showed that there was good correlation between the topological index and the molecular area and volume. The connectivity index is an adequate topological descriptor. The first-order valence index was preferred over that of order two. Comparison of ClogP values provides group contribution values while the comparison of molecular volume data provides information on the volumes of individual substituents relative to that of hydrogen.

Antimetabolites↗

PubMed2002

A real-time EMG-driven virtual arm.

An EMG-driven virtual arm is being developed in our laboratories for the purposes of studying neuromuscular control of arm movements. The virtual arm incorporates the major muscles spanning the elbow joint and is used to estimate tension developed by individual muscles based on recorded electromyograms (EMGs). It is able to estimate joint moments and the corresponding virtual movements, which are displayed in real-time on a computer screen. In addition, the virtual arm offers artificial control over a variety of physiological and environmental conditions. The virtual arm can be used to examine how the neuromuscular system compensates for the partial or total loss of a muscle's ability to generate force as might result from trauma or pathology. The purpose of this paper is to describe the design objectives, fundamental components and implementation of our real-time, EMG-driven virtual arm.

Arm↗

PubMedDate not supplied

Considerations in compound database preparation--"hidden" impact on virtual screening results.

Structure-based virtual screening (SBVS) utilizing docking algorithms has become an essential tool in the drug discovery process, and significant progress has been made in successfully applying the technique to a wide range of receptor targets. In silico validation of virtual screening protocols before application to a receptor target using a corporate or commercially available compound collection is key to establishing a successful process. Ultimately, retrieval of a set of active compounds from a database of inactives is required, and the metric of enrichment (E) is habitually used to discern the quality of separation of the two. Numerous reports have addressed the performance of docking algorithms with regard to the quality of binding mode prediction and the issue of postprocessing "hit lists" of docked ligands. However, the impact of ligand database preprocessing has yet to be examined in the context of virtual screening and prioritization of compounds for biological evaluation. We provide an insight into the implications of cheminformatic preprocessing of a validation database of compounds where multiple protonated, tautomeric, stereochemical, and conformational states have been enumerated. Several commonly used methods for the generation of ligand conformations and conformational ensembles are examined, paired with an exhaustive rigid-body algorithm for the docking of different "multimeric" compound representations to the ligand binding site of the human estrogen receptor alpha. Chemgauss, a shapegaussian scoring function with intrinsic chemical knowledge, was combined with PLP as a consensus-scoring scheme to rank output from the docking protocol and enrichment rates calculated for each screen. The overheads of CPU consumption and the effect on relative database size (disk requirement) for each of the protocols employed are considered. Assessment of these parameters indicates that SBVS enrichments are highly dependent on the initial cheminformatic treatment(s) used in database construction. The interplay of SMILES representations, stereochemical information, protonation state enumeration, and ligand conformation ensembles are critical in achieving optimum enrichment rates in such screening.

Computer Simulation↗