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PubMed2006

A computer model for the clearance of insoluble particles from the tracheobronchial tree of the human lung.

A multi-compartment model for the clearance of insoluble particles from the tracheobronchial tree of the human lung was created. As a significant innovation, the model considers specific mass transfer paths that may play an important role for slow bronchial clearance. These include the accumulation of particulate mass in the periciliary sol layer, an uptake of stored particles by airway macrophages, and the endocytosis of deposited mass by epithelial cells. Besides the gel layer representing fast mucociliary clearance, all cellular and extracellular units involved into the slow clearance process are described by respective compartments which are connected by specific transfer paths. The gastrointestinal tract (GIT), lymph nodes (LN), and blood capillaries are included into the model as final accumulation compartments, to which mass is transferred via the airway route and the transepithelial path. Besides a basic version of the model describing the whole tracheobronchial region by one set of compartments, also an advanced approach is introduced which, in accordance with the International Commission on Radiation Protection (ICRP), subdivides the conducting airways into a bronchial (BB) and bronchiolar (bb) part. Preliminary results were generated with MS-Excel from deposition data of 1-mummass median aerodynamic diameter (MMAD) particles, calculating local slow clearance fractions according to mathematical procedures introduced in previous publications. While mucociliary clearance is completely finished within 24h after exposure, slow clearance takes place in distinct phases and needs several days to weeks. This multi-stage event is also reflected in the respective retention curves which correspond well to previously published graphs.

Algorithms↗
PubMed2002

A real-time computer model to assess resident work-hours scenarios.

OBJECTIVE: To accurately model residents' work hours and assess options to forthrightly meet Residency Review Committee-Internal Medicine (RRC-IM) requirements. DESCRIPTION: The requirements limiting residents' work hours are clearly defined by the Accreditation Council for Graduate Medical Education (ACGME) and the RRC-IM: "When averaged over any four-week rotation or assignment, residents must not spend more than 80 hours per week in patient care duties."(1) The call for the profession to realistically address work-hours violations is of paramount importance.(2) Unfortunately, work hours are hard to calculate. We developed an electronic model of residents' work-hours scenarios using Microsoft Excel 97. This model allows the input of multiple parameters (i.e., call frequency, call position, days off, short-call, weeks per rotation, outpatient weeks, clinic day of the week, additional time due to clinic) and start and stop times for post-call, non-call, short-call, and weekend days. For each resident on a rotation, the model graphically demonstrates call schedules, plots clinic days, and portrays all possible and preferred days off. We tested the model for accuracy in several scenarios. For example, the model predicted average work hours of 85.1 hours per week for fourth-night-call rotations. This was compared with logs of actual work hours of 84.6 hours per week. Model accuracy for this scenario was 99.4% (95% CI 96.2%-100%). The model prospectively predicted work hours of 89.9 hours/week in the cardiac intensive care unit (CCU). Subsequent surveys found mean CCU work hours of 88, 1 hours per week. Model accuracy for this scenario was 98% (95% CI 93.2-100%). Thus validated, we then used the model to test proposed scenarios for complying with RRC-IM limits. The flexibility of the model allowed demonstration of the full range of work-hours scenarios in every rotation of our 36-month program. Demonstrations of status-quo work-hours scenarios were presented to faculty as well as real-time demonstrations of the feasibility, or unfeasibility, of their proposed solutions. The model clearly demonstrated that non-call (i.e., short-call) admissions without concomitant decreases in overnight call frequency resulted in substantial increases in total work hours. Attempts to "get the resident out" an hour or two earlier each day had negligible effects on total hours and were unrealistic paper solutions. For fourth-night-call rotations, the addition of a "golden weekend" (i.e., a fifth day off per month) was found to significantly reduce work hours. The electronic model allowed the development of creative schedules for previously third-night-call rotations that limit resident work hours without decreasing continuity of care by scheduling overnight call every sixth night alternating with sixth-night-short-call rotations. DISCUSSION: Our electronic model is sufficiently robust to accurately estimate work hours on multiple and varied rotations. This model clearly demonstrates that it is very difficult to meet the RRC-IM work-hours limitations under standard fourth-night-call schedules with only four days off per month. We are successfully using our model to test proposed alternative scenarios, to overcome faculty misconceptions about resident work-hours "solutions," and to make changes to our call schedules that both are realistic for residents to accomplish and truly diminish total resident work hours toward the requirements of the RRC-IM.

Computer Simulation↗
PubMed2001

Mathematical modeling and computer simulation of erythrocytapheresis for SCD.

BACKGROUND: Erythrocytapheresis is used to prevent acute chest syndrome and stroke in patients with sickle cell disease (SCD). However, such regimens are associated with significant risks, such as iron overload and potential exposure to transfusion-transmitted infectious diseases. Computer modeling of erythrocytapheresis procedures may help optimize treatments and minimize risks. STUDY DESIGN AND METHODS: Mathematical models based upon material balance equations and patient-specific statistical analyses were developed to estimate HbS levels immediately after erythrocytapheresis and immediately before the next treatment. The equations were incorporated into a software application that was used to model the effects of various treatment values on four patients treated with 90 erythrocytapheresis procedures. RESULTS: Immediate postprocedure HbS values were accurately estimated with correlations between measured and calculated values ranging from R(2) = 0.83 to 0.96. Estimates of HbS just before the next treatment correlated well in three patients (R(2) = 0.71 to 0.83) but poorly in one (R(2) = 0.28 to 0.46). Varying the treatment values by computer simulation led to a wide variation in the number of RBC units and the net RBC volume transfused. CONCLUSION: Computer modeling of erythrocytapheresis can be used to optimize chronic treatment regimens for SCD patients and potentially to minimize the risks of overtransfusion.

Anemia, Sickle Cell↗
PubMed2001

Impaired absorption and omission of insulin: a novel method of detection using the diabetes advisory system computer model.

The Diabetes Advisory System (DIAS) is a decision-support program developed to assist insulin dose adjustment in type 1 diabetes. In this paper, we show how it might be used to identify impaired absorption or omission of insulin in patients with poorly controlled blood glucose. An evaluation of glucose results from four outpatients with persistent hyperglycemia is presented (age 19-48 years with type 1 diabetes for 13-18 years of duration, HbA1c 9.4-13.6%). Each had completed a 4-day record of blood glucose (BG, pre-meal and bedtime), dietary (carbohydrate) intake, and insulin doses (with injection sites). From these data, DIAS modeled a glucose profile (simulated glucose, SG) for the same period. Qualitative assessments were made of differences between BG and SG, and selective reduction or complete removal of insulin doses where BG >> SG. Large improvements in modeling were attributed to either impaired absorption or omission of insulin. Confirmation of these problems was sought from the patients by detailed consultation and physical examination. Impaired insulin absorption was suspected in two patients, both having significant injection site abnormalities. Insulin omission was suspected in the other two subjects. Both had normal injection sites, and one admitted to missing doses. Following retraining, data from three patients showed noticeable improvements in overall modeling as well as glucose control. Using DIAS in the evaluation of patients with type 1 diabetes may highlight previously unrecognized injection site abnormalities or insulin dose omission. This could assist rational optimization of insulin therapy in cases of persistently poor glucose control.

Adult↗
PubMed1996

Three-dimensional finite element computer model of the forward problem of electrocardiology.

This study analyses forward problem of electrocardiology. Premature beats originated from subepicardial layer of myocardium were simulated in order to analyse their shape dependence on the site of origin. The equation governing the propagation of the electrical wave through human thorax together with transition and boundary conditions is derived under the clearly stated simplifying assumptions. The weak formulation of the forward problem of electrocardiology is introduced, too. The Galerkin method as a convenient tool for looking for the numerical solution is mentioned and its practical implementation--finite element method--then used in order to obtain numerical results. The obtained results were presented in the form of isopotential maps and compared with actually measured body surface isopotential maps of the depolarization phase. The parameters of the model were then optimalized in accordance with the measured data. In spite of the lack of quantitative data the model has proved that the presented method was able to be used for the simulation studies of ventricular ectopic beats. It was shown that only a small difference between the site of beat origin can be well distinguished on the simulated body surface maps. (Fig. 3, Ref. 3.)

Computer Simulation↗
PubMed2000

Structure and function of procollagen C-proteinase (mTolloid) domains determined by protease digestion, circular dichroism, binding to procollagen type I, and computer modeling.

Procollagen C-proteinase-2 (pCP-2, mTld) is derived from the longest splicing variant of the gene encoding bone morphogenetic protein 1 (BMP-1). The variants have identical amino terminal signal peptides, prodomains and astacin-like protease domains. However, they differ in the length of their carboxy terminal part, which in pCP-2 has the composition CUB1, CUB2, EGF-like1, CUB3, EGF-like2, CUB4, CUB5, and C-tail. In the shorter form, pCP-1 (i.e., BMP-1), the sequence ends after the CUB3-domain. Using a combination of mutagenesis and structural approaches, we have investigated the structure and function of subfragments of pCP-2. The full-length latent recombinant enzyme and its N-terminally truncated form lacking the prodomain were tested for their enzymic activity. The intact protein showed only partial processing of procollagen type I, whereas the truncated form expressed enzymic activity indistinguishable from its native counterpart purified from chick embryo tendons. These results clearly demonstrated that the prodomain is required for the latency of the enzyme but not for its correct folding. Limited proteolysis of the recombinant protein with alpha-chymotrypsin produced four discrete fragments revealing the location of cleavage sites between the repetitive CUB/EGF domains. The results provide evidence that the CUB sequences form independently folded modules that are stabilized by two pairs of internal disulfide bridges. The modules are linked to each other by more flexible, hinge-like peptides. Solid-phase binding assays with isolated CUB domains and immobilized procollagen type I demonstrated that the first three but not the last two CUB domains specifically bound to the substrate. To define putative sites for CUB-CUB or CUB-substrate interactions, we generated molecular models for pCP-2 CUB domains. The models were obtained using as a template the structure of CUB domain in zona pellucida adhesion protein PSP-I/PSP-II from porcine sperm. The predicted conformations for homology models were, subsequently, confirmed by circular dichroism spectroscopy of polypeptide domains isolated following limited proteolysis with alpha-chymotrypsin.

Amino Acid Sequence↗
PubMed2006

ATX-II effects on the apparent location of M cells in a computational model of a human left ventricular wedge.

INTRODUCTION: The apparent location of the myocytes (M cells) with the longest action potential duration (APD) in a canine left ventricular (LV) wedge have been reported to shift after application of a sea anemone toxin, ATX-II. This toxin slows inactivation of I(Na) and thus prolongs APD. Thus, M cells may exhibit dynamic functional states, rather than being a static, anatomically discrete, myocyte population. In this study, we attempted to further define and understand this phenomenon using a mathematical model of the human ventricular myocyte action potential incorporated into an in silico "wedge" preparation. Our simulations demonstrate that even under conditions of a fixed population and ratio of epicardial, M, and endocardial myocytes, the apparent anatomical position (transmural location) of the myocytes with the longest APD can shift following ATX-II treatment. This arises because the ATX-II effect, modeled as a small increase in the late or persistent Na(+) current, and consequent prolongation of APD significantly changes the electrotonic interactions between ventricular myocytes in this LV wedge preparation. METHODS AND RESULTS: This LV wedge model is based on bidomain equations. It corresponds to a rectangular tissue immersed in a passive and isotropic medium that represents the superfusion bath. In this theoretical work, the three known different and discrete populations of myocytes in the human left ventricle have been included: the epicardial, M, and endocardial cells. The effects of ATX-II on I(Na) were simulated by altering the voltage-dependent steady-state inactivation of the parameters h (fast gate) and j (slow gate). As a result, in these ATX-II simulations a persistent late Na(+) current was generated in all three types of ventricular myocytes. However, the APDs were prolonged in a heterogeneous pattern. Our simulations demonstrate that after the ATX-II effects develop, alterations in transmural electrotonic interactions can produce changes in the transmural location of myocytes with the longest APD. CONCLUSIONS: The combination of intercellular electrotonic interactions, which tend to reduce and smooth out the discrete transmural APD variations, and the heterogeneous effects of ATX-II, which preferentially prolong the APD of M cells, can shift the location of the ventricular myocytes. This shift results in significantly altered transmural patterns of action potential durations, which would be expected to change localized refractory period and excitability. These cellular changes give rise to alterations in the corresponding surface electrograms and may change the overall substrates for conduction and rhythm disturbances.

Action Potentials↗
PubMed2006

How can (-)-epigallocatechin gallate from green tea prevent HIV-1 infection? Mechanistic insights from computational modeling and the implication for rational design of anti-HIV-1 entry inhibitors.

Possible inhibitors preventing human immunodeficiency virus type 1 (HIV-1) entry into the cells are recognized as hopeful next-generation anti-HIV-1 drugs. It is highly desirable to develop a potent inhibitor blocking binding of glycoprotein CD4 of the cell with glycoprotein gp120 of HIV-1, because the gp120-CD4 binding is the initial step of HIV-1 entry into the cells. It has been recently reported that (-)-epigallocatechin gallate (EGCG) from green tea is an inhibitor blocking gp120-CD4 binding. But the inhibitory mechanism remains unknown. For understanding the inhibitory mechanism, extensive molecular docking, molecular dynamics simulations, and binding free-energy calculations have been performed in this study to predict the most favorable structures of CD4-EGCG, gp120-CD4, and gp120-CD4-EGCG binding complexes in water. The results reveal that EGCG binds with CD4 in such a way that the calculated binding affinity of gp120 with the CD4-EGCG complex is negligible. So, the favorable binding of EGCG with CD4 can effectively block gp120-CD4 binding. The calculated CD4-EGCG binding affinity (DeltaG(bind) = -5.5 kcal/mol, K(d) = 94 microM) is in excellent agreement with available experimental data suggesting IC(50) approximately 100 microM for EGCG-blocking CD4-gp120 binding. These results and insights provide a rational basis for future design of novel, more potent inhibitors to block gp120-CD4 binding.

Anti-HIV Agents↗
PubMed2005

Computer modelling of antifolate inhibition of folate metabolism using hybrid functional petri nets.

Antifolates are used in the treatment of various human malignancies and exert their cytotoxic activity by inhibiting folate-dependent enzymes resulting in disruption of DNA synthesis and cell death. Here we devised a computerized hybrid functional petri nets (HFPN) modelling of folate metabolism under physiological and antifolate inhibitory conditions. This HFPN modelling proved valid as a good agreement was found between the simulated steady-state concentrations of various reduced folates and those published for cell extracts; consistently, the simulation derived total folate pool size (11.3 microM) was identical to that published for cell extracts. In silico experiments were conducted to characterize the inhibitory profile of four distinct antifolates including methotrexate (MTX), tomudex, and LY309887, which inhibit dihydrofolate reductase (DHFR), thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTFase), respectively, as well as pemetrexed which has the capacity to inhibit all three enzymes. In order to assess the inhibitory activity of antifolates on purines and pyrimidines, the biosynthesis rates of IMP (20.53 microM/min) and dTMP (23.8 microM/min) were first simulated. Whereas the biochemical inhibitory profile of MTX was characterized by increased dihydrofolate and decreased tetrahydrofolate (THF) concentrations, the remaining antifolates did not decrease THF levels. Furthermore, MTX was 766- and 10-fold more potent in decreasing the production rates of IMP and dTMP, respectively, than pemetrexed. LY309887 indirectly decreased the rate of dTMP production by reducing the levels of 5-CH2-THF, a folate cofactor for TS. Surprisingly, pemetrexed failed to inhibit DHFR even at high concentrations. This HFPN-based simulation offers an inexpensive, user-friendly, rapid and reliable means of pre-clinical evaluation of the inhibitory profiles of antifolates.

Antimetabolites, Antineoplastic↗
PubMed2006

Computational modeling of polyoxotungstates by relativistic DFT calculations of (183)W NMR chemical shifts.

The (183)W nuclear shielding in a variety of tungsten polyoxometalates (POM) (Lindqvist, Anderson, decatungstates, Keggin) of different shapes and charges has been modeled by DFT calculations that take into account relativistic effects, by means of the zero-order regular approximation (ZORA), and solvent effects, by the conductor-like screening model (COSMO) continuum method. The charge/surface area ratio (q/A) is proposed as an indicator of the charge density to which the solvation energies of all POMs are correlated in a satisfactory way. Among the various theoretical levels tested (ZORA scalar or spin-orbit, frozen-core or all-electron basis set, geometry optimization in the gas phase or in the continuum solvent, etc.), the best results are obtained when both geometry optimization in solvent and spin-orbit shielding are included (mean absolute error of delta=35 ppm). The quality of the computed chemical shifts depends systematically on the charge density as expressed by q/A; thus, POMs with low q/A ratios display the best agreement with experimental data. The performance of the method is such that computed values can aid the assignment of the (183)W NMR spectra of polyoxotungstates, as shown by the case of alpha-[PW(11)TiO(40)](5-), whose six signals are ranked computationally so as to almost reproduce the experimental ordering even though the signals are spaced by as little as 5 ppm.

Journal Article↗
PubMed2003

A computational model of direct interstitial infusion of macromolecules into the spinal cord.

Convection-enhanced interstitial infusion can deliver macromolecular drugs to large tissue volumes of the central nervous system. To characterize infusion into the spinal cord, an image-based three-dimensional finite element model of the rat spinal cord was developed. The model incorporated convection and diffusion through white and gray matter, including anisotropic transport due to alignment of white matter tracts. Spatial and temporal distribution of the marker substance albumin within the interstitial space was determined. Consistent with previous experiments, predicted distribution was highly anisotropic. Infusing into the dorsal column, albumin was primarily confined to, white matter with limited penetration into adjacent gray matter. Distribution was determined primarily by the ratio of fiber-parallel to fiber-perpendicular hydraulic conductivity tensor components (k(wm-z)/k(wm-x)), the ratio of transverse white and gray matter hydraulic conductivity (k(wm-x)/k(gm)), and tissue porosity. Fits to previous experimental measures of axial and transverse spread, distribution volume, and protein recovery yielded an optimum k(wm-z)/k(wm-x) of approximately 20 at 0.1 microl/min. k(wm-x)/k(gm) of 100 was sufficient to match experimental transverse distribution data. Best fits to data at 0.1 microl/min were achieved by porosities characteristic of moderate edema (e.g., 0.26). Distribution also varied with catheter placement with more medial placement resulting in greater distribution volumes.

Albumins↗
PubMed2002

[The research on computer modeling for artificial bio-valve].

In this paper, the structure parameters and the equations to calculate these parameters are presented for the model design of the artificial bio-valve on the basis of heart anatomy, shell theory and the optimal flow of heart valve. No-root bio-valve is designed and manufactured according to the above theoies and technology. Its perfect property has been confirmed by measurement in vitro and clinical application in vivo.

Algorithms↗
PubMedDate not supplied

Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart.

Blockade of the delayed rectifier potassium channel current, I(Kr), has been associated with drug-induced QT prolongation in the electrocardiogram and life-threatening cardiac arrhythmias. However, it is increasingly clear that compound-induced interactions with multiple cardiac ion channels may significantly affect QT prolongation that would result from inhibition of only I(Kr) [Redfern, W.S., Carlsson, L., et al., 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58(1), 32-45]. Such an assessment may not be feasible in vitro, due to multi-factorial processes that are also time-dependent and highly non-linear. Limited preclinical data, I(Kr) hERG assay and canine Purkinje fiber (PF) action potentials (APs) [Gintant, G.A., Limberis, J.T., McDermott, J.S., Wegner, C.D., Cox, B.F., 2001. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J. Cardiovasc. Pharmacol. 37(5), 607-618], were used for two test compounds in a systems-based modeling platform of cardiac electrophysiology [Muzikant, A.L., Penland, R.C., 2002. Models for profiling the potential QT prolongation risk of drugs. Curr. Opin. Drug. Discov. Dev. 5(1), 127-35] to: (i) convert a canine myocyte model to a PF model by training functional current parameters to the AP data; (ii) reverse engineer the compounds' effects on five channel currents other than I(Kr), predicting significant IC(50) values for I(Na+), sustained and I(Ca2+), L-type , which were subsequently experimentally validated; (iii) use the predicted (I(Na+), sustained and I(Ca2+), L-type) and measured (I(Kr)) IC(50) values to simulate dose-dependent effects of the compounds on APs in endocardial, mid-myocardial, and epicardiac ventricular cells; and (iv) integrate the three types of cellular responses into a tissue-level spatial model, which quantifiably predicted no potential for the test compounds to induce either QT prolongation or increased transmural dispersion of repolarization in a dose-dependent and reverse rate-dependent fashion, despite their inhibition of I(Kr) in vitro.

Action Potentials↗
PubMed2006

Interaction of epithelium with mesenchyme affects global features of lung architecture: a computer model of development.

Lung airway morphogenesis is simulated in a simplified diffusing environment that simulates the mesenchyme to explore the role of morphogens in airway architecture development. Simple rules govern local branching morphogenesis. Morphogen gradients are modeled by four pairs of sources and their diffusion through the mesenchyme. Sensitivity to lobar architecture and mesenchymal morphogen are explored. Even if the model accurately represents observed patterns of local development, it could not produce realistic global patterns of lung architecture if interaction with its environment was not taken into account, implying that reciprocal interaction between airway growth and morphogens in the mesenchyme plays a critical role in producing realistic global features of lung architecture.

Bronchi↗
PubMed2006

In silico structure-based design of a potent and selective small peptide inhibitor of protein tyrosine phosphatase 1B, a novel therapeutic target for obesity and type 2 diabetes mellitus: a computer modeling approach.

Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator of insulin signaling by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor. Recent gene knockout studies in mice have shown the mice to have increased insulin sensitivity and improved glucose tolerance. Furthermore, these mice also exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have the potential of enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. In addition, recent clinical studies have shown that the haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling evidence that small molecule inhibitors of PTP1B may be effective in treating insulin resistance at an early stage, thereby leading to a prevention strategy for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence WKPD. Docking calculations indicate that this peptide is as potent as the existing inhibitors. Moreover, the peptide is also found to be selective for PTP1B with a greatly reduced potency against other biologically important protein tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a suitable lead compound for the development of new drugs against type 2 diabetes and obesity.

Amino Acid Sequence↗
PubMed2004

Hemispheric specialization and independence for word recognition: a comparison of three computational models.

Two findings serve as the hallmark for hemispheric specialization during lateralized lexical decision. First is an overall word advantage, with words being recognized more quickly and accurately than non-words (the effect being stronger in response latency). Second, a right visual field advantage is observed for words, with little or no hemispheric differences in the ability to identify non-words. Several theories have been proposed to account for this difference in word and non-word recognition, some by suggesting dual routes of lexical access and others by incorporating separate, and potentially independent, word and non-word detection mechanisms. We compare three previously proposed cognitive theories of hemispheric interactions (callosal relay, direct access, and cooperative hemispheres) through neural network modeling, with each network incorporating different means of interhemispheric communication. When parameters were varied to simulate left hemisphere specialization for lexical decision, only the cooperative hemispheres model showed both a consistent left hemisphere advantage for word recognition but not non-word recognition, as well as an overall word advantage. These results support the theory that neural representations of words are more strongly established in the left hemisphere through prior learning, despite open communication between the hemispheres during both learning and recall.

Dominance, Cerebral↗
PubMed1986

In vitro measurement and computer modelling of the diffusion of antibiotic in bone cement.

The diffusion coefficient for a particular antibiotic (benzyl penicillin) in various types of bone cement has been calculated from direct measurement of the passage of radio-labelled penicillin through thin sections of cement at intervals over a period of 90 days, assuming the transport processes to be Fickian. Since the concentration gradient across the test sample is not uniform in the earlier stages of the experiment, a finite-difference approximation to the diffusion equation was used to take account of the transient behaviour in determining the coefficient. This method of analysis may also be used to predict the release, as a function of time, from the surface of antibiotic-loaded bone cement and from implanted pre-loaded PMMA beads used to provide antibiotic cover following bone or joint surgery. Our computer-generated predictions appear to agree very well with previously published figures arising from in vivo and in vitro studies and we conclude therefore, that Fick's Law accurately describes the process, even when the cement mix is inhomogeneous. We have by this means a reliable method by which the diffusion coefficients for various combinations of cement, antibiotic and other additives may be retrospectively determined and compared.

Anti-Bacterial Agents↗
PubMed2004

A computer model of field potential responses for the study of short-term plasticity in hippocampus.

Activity-dependent synaptic plasticity has important implications for network function. The previously developed model of the hippocampal CA1 area, which contained pyramidal cells (PC) and two types of interneurons involved in feed-forward and recurrent inhibition, respectively, and received synaptic inputs from CA3 neurons via the Schaffer collaterals, was enhanced by incorporating dynamic synaptic connections capable of changing their weights depending on presynaptic activation history. The model output was presented as field potentials, which were compared with those derived experimentally. The parameters of Schaffer collateral-PC excitatory model synapse were determined, with which the model successfully reproduced the complicated dynamics of train-stimulation sequential potentiation/depression observed in experimentally recorded field responses. It was found that the model better reproduces the time course of experimental field potentials if the inhibitory synapses on PC are also made dynamic, with expressed properties of frequency-dependent depression. This finding supports experimental evidence that these synapses are subject to activity-dependent depression. The model field potentials in response to various randomly generated and real (derived from recorded CA3 unit activity) long stimulating trains were calculated, illustrating that short-term plasticity with the observed characteristics could play specific roles in frequency processing in hippocampus and thus providing a new tool for the theoretical study of activity-dependent synaptic plasticity.

Animals↗