Biomedical subjects

M Mattingly

Publications and source records attributed to M Mattingly.

11 recordsLinked to original sources

PubMed1998

Reduced-order modeling for hyperthermia: an extended balanced-realization-based approach.

Accurate thermal models are needed in hyperthermia cancer treatments for such tasks as actuator and sensor placement design, parameter estimation, and feedback temperature control. The complexity of the human body produces full-order models which are too large for effective execution of these tasks, making use of reduced-order models necessary. However, standard balanced-realization (SBR)-based model reduction techniques require a priori knowledge of the particular placement of actuators and sensors for model reduction. Since placement design is intractable (computationally) on the full-order models, SBR techniques must use ad hoc placements. To alleviate this problem, an extended balanced-realization (EBR)-based model-order reduction approach is presented. The new technique allows model order reduction to be performed over all possible placement designs and does not require ad hoc placement designs. It is shown that models obtained using the EBR method are more robust to intratreatment changes in the placement of the applied power field than those models obtained using the SBR method.

Algorithms↗

PubMed1993

A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies that bind to A2.

Human antibodies that inactivate coagulation factor VIII (fVIII), known as inhibitors, have been shown by immunoblotting or immunoprecipitation assays to bind predominantly to epitopes within the A2 and/or C2 domains of the fVIII protein. Because these assays simply measure antibody binding, a soluble recombinant polypeptide containing the fVIII A2 domain was used to develop a quantitative inhibitor neutralization assay for antibodies that bound only to A2 by immunoblotting assay. Antibodies from six of eight inhibitor plasmas were fully neutralized by A2 (> or = 90%), whereas two were only partially neutralized. These results established the fVIII inhibitor properties of anti-A2 antibodies. In immunoprecipitation assays, five of the eight inhibitors also had significant levels of anti-light-chain antibody. In one case, this light-chain antibody was shown to have inhibitor activity. Because it did not bind to the C2 domain, this antibody appears to define a new inhibitor epitope within the fVIII light chain. Another inhibitor, which was partially neutralized by A2, was not neutralized by the light chain, even though it contained anti-light-chain antibodies by immunoprecipitation assay. Our results show additional complexities of the immune response to fVIII.

Animals↗

PubMed1992

A soluble recombinant factor VIII fragment containing the A2 domain binds to some human anti-factor VIII antibodies that are not detected by immunoblotting.

Human factor VIII (fVIII) inhibitors are pathologic antibodies that inactivate fVIII. A cDNA clone was modified to encode fVIII amino acid residues 373-740 for expression in a baculovirus vector in insect cells. The encoded protein fragment H2 was produced as a soluble, secreted protein, and it was used to test inhibitor plasmas for the presence of antibodies that were not detected by immunoblotting. Seven of 13 inhibitors that bound only to the fVIII light chain by immunoblotting also bound to fragment H2 in an immunoprecipitation assay. Thus multi-chain inhibitor reactivity of inhibitors is more frequent than previously reported. One of these inhibitors was shown to share the epitope for other inhibitors that bind to H2 within amino acid residues 373-541 in immunoblotting assays. The sensitive immunoprecipitation assay described allows determination of relative H2 binding capacity of the total IgG and epitope localization of inhibitors that cannot be similarly characterized by immunoblotting.

Animals↗

PubMed1992

Promotion of murine B cell differentiation by 2-mercaptoethanol in contrast to glutathione.

The role of thiol compounds in B cell proliferation and differentiation was investigated with a stable, homogeneous population of an antigen-specific plasmablastoma, 2C3. This cell line expresses both membrane and secreted forms of immunoglobulin and is arrested at an intermediate stage of B cell development. Attempts to induce its differentiation into plasma cells using antigen, anti-idiotypic antibodies, or mitogens were unsuccessful. However, cultivation of 2C3 in the presence of 2-mercaptoethanol (5 x 10(-5) M) changed its doubling time from 19.8 to 34.9 h. There was also a significant rise in intracellular glutathione and in immunoglobulin production, but little change in non-Ig protein secretion. In contrast, exposure of 2C3 to exogenous glutathione (5 x 10(-3) M) reduced the doubling time to 11.0 h, with marked increases in proliferation. Moreover, there was no significant rise in either intracellular glutathione or immunoglobulin secretion. Distinct morphological differences were also apparent at the ultrastructural level. Thus, there is a dichotomy in the action of the two thiols. Although the effects of 2-mercaptoethanol could not be reversed, the two thiols together abrogated each other's effects, implying that their actions may be mediated through a common regulatory pathway.

Animals↗

PubMed1991

Analysis of diabetic cataractogenesis using chemical-shift nuclear magnetic resonance microscopy.

We here report the analysis of single rabbit lenses under high-glucose stress using four-dimensional 13C nuclear magnetic resonance (NMR) spectroscopy (three spatial and one chemical-shift). We have produced spatial maps of lenticular metabolites (glucose, sorbitol, and lactate) with submillimeter in-plane resolution. The production of sorbitol and its inhibition are also presented. This is the first study to report regional tissue metabolism. We expect further improvements in spatial resolution and acquisition times that will enable localized kinetic studies in intact tissues.

Animals↗

PubMed1989

Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization.

Human factor VIII(FVIII) inhibitors are pathologic, circulating antibodies that inactivate FVIII. We have examined the location of epitopes on the FVIII protein for inhibitors from hemophilia A and nonhemophilic individuals. The inhibitors were of type I or type II in the kinetics of their inactivation of FVIII. A cDNA clone of human FVIII was used to express defined FVIII protein fragments in Escherichia coli for immunoblotting with inhibitor plasma. An epitope for 18 heavy-chain inhibitors was localized to the aminoterminal 18.3 Kd of the A2 domain. Two of these inhibitors also recognized an epitope located between A1 and A2 domains. Similarly, an epitope for 23 light-chain inhibitors was localized to the C2 domain. Weaker epitopes for 13 of the same inhibitors within the C1 and C2 domains were also observed. Four of the 23 inhibitors in addition bound strongly to the A3 domain. Most inhibitors (22 of 23) were neutralized in vitro only by the FVIII fragments to which they bound on immunoblots; however, one inhibitor that was neutralized by a fragment containing the A1 domain did not bind to it on immunoblots. Conversely, 3 of 3 inhibitors that bound to the A3 domain and 5 of 15 that bound to the A2 domain were not neutralized by the corresponding fragments. The epitope specificity of an inhibitor did not depend on its source or type. Our results show that FVIII inhibitors bind to limited areas within the heavy and light chains of FVIII. Some inhibitor plasmas contain additional antibodies that may not be inhibitory.

Autoantibodies↗

PubMed1989

Oropharyngeal mucositis complicating bone marrow transplantation: prognostic factors and the effect of chlorhexidine mouth rinse.

Oral mucosal ulceration complicating bone marrow transplantation interferes with patients' comfort, nutrition and may lead to systemic infection derived from the mouth. The mucosal injury results from epithelial damage due to the cytotoxic effects of chemotherapy and radiation conditioning as well as from superficial oropharyngeal infection. Because chlorhexidine gluconate is a broad spectrum topical antimicrobial which has been demonstrably effective in preventing oral infection and gingivitis, we performed a randomized, placebo controlled, double-blind trial of chlorhexidine as a mouth rinse in BMT recipients to study the severity of oral mucositis and both oral and systemic infectious complications. One hundred patients were randomly assigned to receive either chlorhexidine gluconate 0.12% mouth rinse or placebo three times daily from the initiation (day -8) of chemoradiotherapy conditioning until day +35 post-BMT. Chlorhexidine use resulted in a trend toward improved oral hygiene index (reduced dental plaque) (p = 0.06) but did not modify the oral mucositis. Patients using chlorhexidine developed a maximum ulceration of 18 +/- 22% of their oral mucosa, while placebo patients ulcerated 25 +/- 31% of the mouth. Ulcerative mucositis was significantly worse in adults compared with children, in individuals who received methotrexate for graft-versus-host disease prophylaxis, and was most prominent on non-keratinized epithelium. Overall, there was no clinically demonstrable additional therapeutic advantage to the use of chlorhexidine in either reducing the mucositis, controlling oral pain, facilitating oral nutrition, shortening hospital stay, or reducing oral infection with herpes simplex virus. There was a trend toward diminished oral candidiasis in chlorhexidine users (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli.

Epitopes for antibodies that inhibit factor VIII procoagulant protein were analyzed by deletion mapping of factor VIII protein fragments expressed in Escherichia coli. A human factor VIII cDNA clone was used to generate E. coli expression vectors encoding fragments containing the 80-kDa factor VIII light chain (A3, C1, and C2 domains) and the 44-kDa carboxyl-terminal half of the factor VIII heavy chain (A2 domain). A series of deletions of each fragment was constructed and tested by immunoblotting for the binding of alloantibody and autoantibody inhibitors. Analysis of derivatives of the 80-kDa fragment showed that six inhibitors recognized a major epitope(s) within the carboxyl-terminal 17.3 kDa of factor VIII. These inhibitors also recognized weaker epitopes nearby and one inhibitor recognized epitopes scattered throughout the 80-kDa fragment. Deletions within the heavy chain fragment revealed one epitope-containing region confined to the amino-terminal 18.3 kDa recognized by six inhibitors. Bacterially produced factor VIII fragments containing the major epitopes were capable of neutralizing inhibitors in vitro but fragments containing weaker or no epitopes did not. These data suggest a potential therapeutic use of factor VIII fragments for neutralization of inhibitor antibodies.

Autoantibodies↗

PubMedDate not supplied

A dynamic two-dimensional phantom for ultrasound hyperthermia controller testing.

A new thin layer phantom for testing hyperthermia controllers has been constructed and evaluated using an ultrasound hyperthermia system. The phantom's thermal behaviour agrees with the characteristics of the Pennes' bio-heat transfer equation (BHTE). In particular, the experimental and theoretical results agree in the following ways. First, with respect to the power deposition: for a given power magnitude and scan radius, the shape of the temperature distribution across the phantom corresponds to the shape predicted by the BHTE and the experimental and theoretical temperature values agree closely; when the power magnitude is varied at a fixed scan radius, the average temperature of the phantom varies linearly with the applied power, and as the scan radius is varied at a fixed power magnitude, the average temperature increases with decreasing scan radius size. Secondly, with respect to perfusion: increasing or decreasing the flow rate over the phantom simulates an increase or decrease in the BHTE perfusion term, and the estimated perfusion values are dependent on flow rate only, and are not functions of power or geometry. The combination of these experimental and theoretical results validate the phantom's potential for testing feedback control systems, particularly for future use in the development and verification of model-based controllers. The use of this phantom should improve and accelerate the testing and evaluation of feedback control systems, and reduce the need for animal and human testing.

Animals↗

PubMedDate not supplied

A comparison of reduced-order modelling techniques for application in hyperthermia control and estimation.

Reduced-order modelling techniques can make important contributions in the control and state estimation of large systems. In hyperthermia, reduced-order modelling can provide a useful tool by which a large thermal model can be reduced to the most significant subset of its full-order modes, making real-time control and estimation possible. Two such reduction methods, one based on modal decomposition and the other on balanced realization, are compared in the context of simulated hyperthermia heat transfer problems. The results show that the modal decomposition reduction method has three significant advantages over that of balanced realization. First, modal decomposition reduced models result in less error, when compared to the full-order model, than balanced realization reduced models of similar order in problems with low or moderate advective heat transfer. Second, because the balanced realization based methods require a priori knowledge of the sensor and actuator placements, the reduced-order model is not robust to changes in sensor or actuator locations, a limitation not present in modal decomposition. Third, the modal decomposition transformation is less demanding computationally. On the other hand, in thermal problems dominated by advective heat transfer, numerical instabilities make modal decomposition based reduction problematic. Modal decomposition methods are therefore recommended for reduction of models in which advection is not dominant and research continues into methods to render balanced realization based reduction more suitable for real-time clinical hyperthermia control and estimation.

Algorithms↗

PubMedDate not supplied

Optimal actuator placement for large scale systems: a reduced-order modelling approach.

A recently developed, extended balanced realization, reduced order modelling technique for large-scale distributed systems is applied to the problem of optimal actuator placement for hyperthermia treatments. Extended balanced realization develops low-order models whose state reconstructions are robust to actuator and sensor placement changes, and hence can be effectively used to find optimal placements in a computationally efficient manner. This optimization approach has been tested on simulations of a scanned focused, ultrasound hyperthermia system and found to be robust and accurate over a wide range of models, and the savings in computational costs were found to be significant.

Equipment Design↗