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PubMed2005

Optimized model tuning in medical systems.

In medical systems it is often advantageous to utilize specific problem situations (cases) in addition to or instead of a general model. Decisions are then based on relevant past cases retrieved from a case memory. The reliability of such decisions depends directly on the ability to identify cases of practical relevance to the current situation. This paper discusses issues of automated tuning in order to obtain a proper definition of mutual case similarity in a specific medical domain. The main focus is on a reasonably time-consuming optimization of the parameters that determine case retrieval and further utilization in decision making/ prediction. The two case studies - mortality prediction after cardiological intervention, and resource allocation at a spa - document that the optimization process is influenced by various characteristics of the problem domain.

Computer Simulation↗

PubMed1999

Biological barriers to cellular delivery of lipid-based DNA carriers.

Although lipid-based DNA delivery systems are being assessed in gene therapy clinical trials, many investigators in this field are concerned about the inefficiency of lipid-based gene transfer technology, a criticism directed at all formulations used to enhance transfer of plasmid expression vectors. It is important to recognize that many approaches have been taken to improve transfection efficiency, however because of the complex nature of the formulation technology being developed, it has been extremely difficult to define specific carrier attributes that enhance transfection. We believe that these optimization processes are flawed for two reasons. First, a very defined change in formulation components affects the physical and chemical characteristics of the carrier in many ways. As a consequence, it has not been possible to define structure/activity relationships. Second, the primary endpoint used to assess plasmid delivery has been transgene expression, an activity that is under the control of cellular processes that have nothing to do with delivery. Gene expression following administration of a plasmid expression vector involves a number of critical steps: (i) DNA protection, (ii) binding to a specific cell population, (iii) DNA transfer across the cell membrane, (iv) release of DNA into the cytoplasm, (v) transport through the cell and across the nuclear membrane as well as (vi) transcription and translation of the gene. The objective of this review is to describe lipid-based DNA carrier systems and the attributes believed to be important in regulating the transfection activity of these formulations. Although membrane destabilization activity of the lipid-based carriers plays an important role, we suggest here that a critical element required for efficient transfection is dissociation of lipids bound to the plasmid expression vector following internalization.

Journal Article↗

PubMed2000

A theoretical approach to the mechanism of biological oxidation of organophosphorus pesticides.

Organophosphorus pesticides are the most common classes involved in poisonings related to pesticides. We used enzymatic activity of chloroperoxidase on the metabolism of some phosphorothioate pesticides published previously and molecular mechanics methods to perform a theoretical approach of the mechanism of biological oxidation of this class of pesticides. The molecular structure of eight pesticides were optimized by molecular mechanics methods using the CAChe program package for biomolecules, ver. 3.11 (Oxford Molecular Ltd., Campbell, CA). Total energy resulted from the structure optimization process and the partial charges of both phosphorus and sulfur were computed for every pesticide. Phosphorus partial charge and enzymatic activity were significantly related by linear regression analysis (r=0.82, P<0.05). Analyzing our results and using previously reported enzymatic activity of chloroperoxidase on these pesticides, we deduced chemical events involved in activation of the active site of chloroperoxidase and proposed a novel mechanism of oxidation for this class of pesticides. This mechanism will also help to understand the oxidation process of pesticides by cytochrome P450, and production of toxic metabolites.

Chemical Phenomena↗

PubMed2001

Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization.

Mental function has as its cerebral basis a specific dynamic structure. In particular, cortical and limbic areas involved in "higher brain functions" such as learning, memory, perception, self-awareness and consciousness continuously need to be self-adjusted even after development is completed. By this lifelong self-optimization process, the cognitive, behavioural and emotional reactivity of an individual is stepwise remodelled to meet the environmental demands. While the presence of rigid synaptic connections ensures the stability of the principal characteristics of function, the variable configuration of the flexible synaptic connections determines the unique, non-repeatable character of an experienced mental act. With the increasing need during evolution to organize brain structures of increasing complexity, this process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. These mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodelling according to experience, are accompanied, however, by increasing inherent possibilities of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time provide the basis for a variety of neuropsychiatric disorders. It is the objective of the present paper to outline the hypothesis that it might be the disturbance of structural brain self-organization which, based on both genetic and epigenetic information, constantly "creates" and "re-creates" the brain throughout life, that is the defect that underlies Alzheimer's disease (AD). This hypothesis is, in particular, based on the following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated with aberrant sprouting at both the presynaptic (axonal) and postsynaptic (dendritic) site. (3) The spatial and temporal distribution of AD pathology follows the pattern of structural neuroplasticity in adulthood, which is a developmental pattern. (4) AD pathology preferentially involves molecules critical for the regulation of modifications of synaptic connections, i.e. "morphoregulatory" molecules that are developmentally controlled, such as growth-inducing and growth-associated molecules, synaptic molecules, adhesion molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc. (5) Life events that place an additional burden on the plastic capacity of the brain or that require a particularly high plastic capacity of the brain might trigger the onset of the disease or might stimulate a more rapid progression of the disease. In other words, they might increase the risk for AD in the sense that they determine when, not whether, one gets AD. (6) AD is associated with a reactivation of developmental programmes that are incompatible with a differentiated cellular background and, therefore, lead to neuronal death. From this hypothesis, it can be predicted that a therapeutic intervention into these pathogenetic mechanisms is a particular challenge as it potentially interferes with those mechanisms that at the same time provide the basis for "higher brain function".

Alzheimer Disease↗

PubMed2002

An investigation of a video-based patient repositioning technique.

PURPOSE: We have investigated a video-based patient repositioning technique designed to use skin features for radiotherapy repositioning. We investigated the feasibility of the clinical application of this system by quantitative evaluation of performance characteristics of the methodology. METHODS AND MATERIALS: Multiple regions of interest (ROI) were specified in the field of view of video cameras. We used a normalized correlation pattern-matching algorithm to compute the translations of each ROI pattern in a target image. These translations were compared against trial translations using a quadratic cost function for an optimization process in which the patient rotation and translational parameters were calculated. RESULTS: A hierarchical search technique achieved high-speed (compute correlation for 128 x 128 ROI in 512 x 512 target image within 0.005 s) and subpixel spatial accuracy (as high as 0.2 pixel). By treating the observed translations as movements of points on the surfaces of a hypothetical cube, we were able to estimate accurately the actual translations and rotations of the test phantoms used in our experiments to less than 1 mm and 0.2 degrees with a standard deviation of 0.3 mm and 0.5 degrees respectively. For human volunteer cases, we estimated the translations and rotations to have an accuracy of 2 mm and 1.2 degrees. CONCLUSION: A personal computer-based video system is suitable for routine patient setup of fractionated conformal radiotherapy. It is expected to achieve high-precision repositioning of the skin surface with high efficiency.

Algorithms↗

PubMed2002

Application of constrained least-squares techniques to IMRT treatment planning.

PURPOSE: The purpose of this work was to apply the method of constrained least-squares to inverse treatment planning and to explore its potential for providing a fast interactive planning environment for intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: The description of the dose inside a patient is a linear matrix transformation of beamlet weights. The constrained least-squares method adds additional matrix operators and produces beamlet weights by a direct linear transformation. These matrix operators contain a priori knowledge about the radiation distribution. The constrained least-squares technique was applied to obtain IMRT plans for prostate and paraspinal cancer patients and compared with the corresponding plans optimized using the CORVUS inverse planning system. RESULTS: It was demonstrated that a constrained least-squares technique is suitable for IMRT plan optimization with significantly increased computing speed. For the two cases we have tested, the constrained least-squares method was an order of magnitude faster than conventional iterative techniques because of the avoidance of the iterative calculations. We also found that the constrained least-squares method is capable of generating clinically acceptable treatment plans with less trial-and-error adjustments of system variables, and with improved target volume coverage as well as sensitive structure sparing in comparison with that obtained using CORVUS. CONCLUSIONS: The constrained least-squares method has the advantage that it does not require iterative calculation and thus significantly speeds up the therapeutic plan optimization process. Besides shedding important insight into the inverse planning problem, the technique has strong potential to provide a fast and interactive environment for IMRT treatment planning.

Algorithms↗

PubMed1997

Optimized beam planning for linear accelerator-based stereotactic radiosurgery.

PURPOSE: Current treatment planning for linear accelerator-based stereotactic radiosurgery and radiotherapy is a lengthy and iterative procedure. The planner has to manually select the beam arcs and carefully consider many different selections to ensure target volume coverage while sparing dose to critical organs. In this article we report an optimization procedure that can automatically select the beam arcs based on geometric and dosimetric analysis of the treatment parameters. METHODS AND MATERIALS: The optimization problem is introduced by using a Beam's Eye View (BEV) map where a pattern of lines represents a beam arc combination for a treatment plan. The collection of all possible treatment plans is described by using the concept of phase space where each point corresponds to a particular configuration of the system under consideration, and in this case, a particular beam arc combination. A geometric reduction of the phase space is performed by excluding static beam ports that irradiate too much critical organs and too little target volume. The phase space is further reduced by excluding beam arc combinations that do not comply with treatment convenience considerations and established planning experiences. These reductions significantly reduces the number of beam arc combinations to be considered and thus dramatically simplifies the computational complexity. The method of simulated annealing is then used to the reduced phase space to select the set of beam arcs that provides the best surface dose distribution for the target volume. The optimization procedure is applied to a radiosurgery case to compare the optimized beam arcs with the previously manually planned beam arcs. The procedure is also applied to 10 randomly selected cases for a comparison in terms of tissue-volume ratio calculations. RESULTS: The system is a highly automated beam arc planning tool for stereotactic radiosurgery and stereotactic radiotherapy. Its interactive nature allows the planner to rapidly consider many treatment plans to search for the best option. For the case presented, it is shown that the optimized beams substantially reduce the dose to the postrema. The tissue-volume ratio calculations demonstrate that the optimization often produces clinically superior treatment plans than the manual beam planning method. CONCLUSIONS: Our method of phase space reduction proves to be very useful in approaching the complex problem of treatment planning optimization. Not only does it substantially reduce the number of beam arcs that need to be considered, but it also simplifies the evaluation of the beam arc options. Both of these greatly reduce the computational complexity of the optimization and make the procedure fast and efficient. Moreover, the reduction of phase space adds another layer of interaction between the user and the beam selection procedure, so that the optimization process is well controlled and thus very effective.

Brain Neoplasms↗

PubMed2000

Cation-exchange high-performance liquid chromatography of recombinant adeno-associated virus type 2.

There has been much interest recently in the development of recombinant viruses as vectors for gene therapy applications. We have constructed a recombinant adeno-associated viral (AAV) vector containing the gene encoding CFTR (cystic fibrosis transmembrane chloride regulator). This vector is currently being used in clinical trials as a treatment for cystic fibrosis. In the course of scale-up and process optimization efforts, a variety of analyses have been developed to characterize yield and quality. Although these methods produce quantitative and highly reproducible results, most are very time intensive. For example, a standard bioassay requires a 72-h incubation period followed by an additional day of analysis. Other tests such as UV spectrophotometry are fast, but unable to distinguish between whole virus, free protein, and DNA. Here, we describe an analytical cation-exchange high-performance liquid chromatographic method utilizing a TSKgel SP-NPR strong cation-exchange column. Unlike the bioassay which requires a 96-h wait for information, this method yields data in less than 20 min. In addition to the quick assay turn-around, the material eluting in the single peak was found to be intact, infectious, nuclease resistant AAV particles. This offers a significant advantage over the limited information one gains from UV spectrophotometry. This demonstrates the utility of chromatography for analysis and purification of viral vectors.

Blotting, Western↗

PubMed2003

Use of cultured cells of kidney origin to assess specific cytotoxic effects of nephrotoxins.

During drug discovery, assessment of renal safety for a compound is important for further development of a candidate drug. In this study, we describe an in vitro cell-based assay capable of discerning nephrotoxicity. Three cell types, two of kidney origin and one of liver origin, were used to examine the effects of nephrotoxins. The cell types were the porcine normal kidney tubular epithelial cell line (LLC-PK1), the primary human renal proximal tubular epithelial cells (hRPTEC) and the human liver cell line (HepG2). Cytotoxicity was measured using a luciferin/luciferase assay that measures cellular ATP levels. Four known nephrotoxins, 4-aminophenol, cisplatin, cyclosporin A and paraquat, were tested in this cell-based assay to evaluate cytotoxicity on drug exposure. Kidney-derived LLC-PK1 cells and hRPTECs were found to be sensitive to selected nephrotoxins while liver-derived HepG2 cells were insensitive. Human RPTEC cells obtained from three individual donors demonstrated highly reproducible effects on drug exposure. With respect to drug discovery efforts, integration of the cell models described here are valuable for evaluation of nephrotoxic potentials during lead selection and optimization processes.

Adenosine Triphosphate↗

PubMed2000

Production of viral vectors for gene therapy applications.

Advances in cell culture engineering, cell metabolism, bioreactor design and operation, and downstream processing will all positively impact the bioprocessing of viral vectors. Design of appropriate vectors and tailoring of packaging cells to support more productive infections will be of paramount importance for production of high-titer and high-quality vectors. Furthermore, quantitative analysis of the infection parameters during virus propagation, such as time of infection, multiplicity of infection, the length of replication cycle, virus half-life, and burst size, will also be important to the process optimization. Finally, procedures for separation, purification and formulation of vector preparations have to be further developed.

Adenoviridae↗

PubMed2001

Influence of the liquid-phase mass transfer on the performance of a packed-bed bioreactor for wastewater treatment.

This paper reports on the influence of the liquid-phase mass transfer on the performance of a horizontal-flow, anaerobic, immobilized-biomass (HAIB) reactor treating low-strength wastewater. The HAIB reactor was subjected to liquid superficial velocities (vs) ranging from 10 to 50 cm h(-1), corresponding to hydraulic detention time (theta h) of 10-2 h. The best performance was achieved at an overall theta h of 3.3 h due to the interdependence of biochemical reactions and mass transfer mechanisms for process optimization. The HAIB reactor was provided with four intermediate sampling ports, and the values of v(s) were fixed to permit sampling at different ports corresponding to thetah of 2 h as vs increased. The chemical oxygen demand removal (COD) efficiencies increased from 68% to 82% with the increase of v(s) from 10 to 50 cm h(-1). It could be concluded that the performance of the HAIB reactor was improved significantly by increasing vs, thus decreasing the liquid-phase mass transfer resistance.

Bioreactors↗

PubMed2001

Moderator-collimator-shielding design for neutron radiography systems using 252Cf.

This paper is concerned with the presentation of a study of the general design of an optimized neutron radiography system that utilizes 252Cf. Moderation, collimation and shielding aspects are considered. A Monte Carlo code, MCNP, was used to obtain a maximum and more homogeneous neutron flux in the collimator outlet next to the image plane, taking into account geometric characteristics and an adequate radiation shielding strategy that complies with the radiological protection rules. Among the various moderator materials investigated, the high density polyethylene proved to be the most efficient, with a thermalization factor of 56 cm2. Using a collimator design assembly it was possible to obtain a normalized thermal neutron flux, at the image plane, equals 6 x 10(-6) n cm(-2) s(-1) at an effective collimator ratio of 7.5, or 3.2 x 10(-7) n cm(-2) s(-1) at an effective collimator ratio of 50. The total dose equivalent rates were significantly reduced by the shielding optimization process.

Journal Article↗

PubMed1996

Control of the dehydration process in production of intermediate-moisture meat products: a review.

IM meat products are produced by lowering the aw to 0.90 to 0.60. Such products are stable at ambient temperature and humidity and are produced in nearly every country in the world, especially in developing areas where refrigeration is limited or unavailable. Traditionally IM meats use low cost sources of energy for drying, such as sun drying, addition of salt, or fermentation. Products produced by different processes are of interest since they do not require refrigeration during distribution and storage. Many different IM meat products can be produced by utilizing modern processing equipment and methods. Production can be achieved in a relatively short period of time and their advantages during marketing and distribution can be utilized. Nevertheless, a better understanding of the principles involved in heat transfer and efficiency of production are still needed to increase efficiency of processing. A basic understanding of the influence of water vapor pressure and sorption phenomena on water activity can materially improve the efficiency of drying of IM meats. Predrying treatments, such as fermentation and humidity control, can also be taken advantage of during the dehydration process. Such information can lead to process optimization and reduction of energy costs during production of IM meats. The development of sound science-based methods to assure the production of high-quality and nutritious IM meats is needed. Finally, such products also must be free of pathogenic microorganisms to assure their success in production and marketing.

Absorption↗

PubMed2002

[Probabilities of controlling tumors and complications (TCP/NTCP) after radiotherapy: methodologic, physical, and biological aspects].

Radiotherapy is aimed at getting the best possible therapeutic ratio (tumor local control versus morbidity). Physicists and radiation oncologists have to evaluate explicitly or implicitly the probability of induced complications to normal surrounding tissues. This is based on published data and clinician's experience. Quantitative methods have been introduced with different models in order to predict the impact of partial or global irradiation on a normal organ. These models correspond to the Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP). These biological models may be useful to evaluate the quality of a treatment planning or for the optimization process. The methodologies used and the clinical data are developed and discussed.

Dose-Response Relationship, Radiation↗

PubMed2001

Microwave-assisted high-speed chemistry: a new technique in drug discovery.

In both lead identification and lead optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds. The fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery; within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry.

Journal Article↗

PubMed2003

Chemistry challenges in lead optimization: silicon isosteres in drug discovery.

During the lead optimization phase of drug discovery projects, the factors contributing to subsequent failure might include poor portfolio decision-making and a sub-optimal intellectual property (IP) position. The pharmaceutical industry has an ongoing need for new, safe medicines with a genuine biomedical benefit, a clean IP position and commercial viability. Inherent drug-like properties and chemical tractability are also essential for the smooth development of such agents. The introduction of bioisosteres, to improve the properties of a molecule and obtain new classes of compounds without prior art in the patent literature, is a key strategy used by medicinal chemists during the lead optimization process. Sila-substitution (C/Si exchange) of existing drugs is an approach to search for new drug-like candidates that have beneficial biological properties and a clear IP position. Some of the fundamental differences between carbon and silicon can lead to marked alterations in the physicochemical and biological properties of the silicon-containing analogues and the resulting benefits can be exploited in the drug design process.

Chemistry, Pharmaceutical↗

PubMed2002

Structure and function of auditory cortex: music and speech.

We examine the evidence that speech and musical sounds exploit different acoustic cues: speech is highly dependent on rapidly changing broadband sounds, whereas tonal patterns tend to be slower, although small and precise changes in frequency are important. We argue that the auditory cortices in the two hemispheres are relatively specialized, such that temporal resolution is better in left auditory cortical areas and spectral resolution is better in right auditory cortical areas. We propose that cortical asymmetries might have developed as a general solution to the need to optimize processing of the acoustic environment in both temporal and frequency domains.

Journal Article↗

PubMed1999

Steady-state oxidation model by horseradish peroxidase for the estimation of the non-inactivation zone in the enzymatic removal of pentachlorophenol.

A theoretical model for the rate of oxidation of pentachlorophenol (PCP) catalyzed by horseradish peroxidase (HRP), was investigated to account for the influence of hydrogen peroxide (H2O2) concentration on the catalytic activity. To evaluate the maximum allowable H2O2 concentration, a relatively simple steady-state model was developed based on the Ping-Pong Bi-Bi mechanism considering the effect of excess H2O2. Several sets of experimental data obtained from batch reactions using an equimolar concentration of H2O2 and PCP were used to estimate the kinetic parameters by a nonlinear regression method. The model profiles acquired using the estimated parameters were in good agreement with experimental data at different initial enzyme and substrate concentrations. The best-fitted parameters were used to predict the initial rate of the enzyme reaction. The model prediction was coincident with the experimental results of other studies, indicating that the proposed model could be used for the optimization of reaction conditions. The maximum allowable H2O2 concentration to prevent H2O2 inhibition was calculated from the proposed model equation: [H2O2](0,max) = (square root)KmH2O2Ki[PCP]0/KmPCP+[PCP]0. Using this equation, a curve depicting the non-inactivation zone for the two substrates (hydrogen peroxide and PCP) was plotted and it could be used for experimental design and optimal process operation. To minimize enzyme inactivation by H2O2, it was determined that the concentration of H2O2 should be lower than 2.78 mM, regardless of the stoichiometric ratio.

Journal Article↗