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PubMed2001

Combinatorial approaches to formulation development.

This review describes the use of combinatorial methods for the development of drug formulations. Combinatorial methods are applied to find solutions to various formulation problems, including drug solubilization, controlled release, oral drug administration, and others. Various methods are described, including the synthesis of carrier libraries, high-throughput screening and computational analysis, which are used during the formulation development process, starting from initial assays through the optimization of formulation composition, to the optimization of the manufacturing process. This review also describes an integrated approach to drug formulation development using libraries of block copolymers as the drug carriers.

Animals↗

PubMed2003

Search-based optimization.

The problem of determining the minimum cost hypothetical ancestral sequences for a given cladogram is known to be NP-complete (Wang and Jiang, 1994). Traditionally, point estimations of hypothetical ancestral sequences have been used to gain heuristic, upper bounds on cladogram cost. These include procedures with such diverse approaches as non-additive optimization of multiple sequence alignment, direct optimization (Wheeler, 1996), and fixed-state character optimization (Wheeler, 1999). A method is proposed here which, by extending fixed-state character optimization, replaces the estimation process with a search. This form of optimization examines a diversity of potential state solutions for cost-efficient hypothetical ancestral sequences and can result in greatly more parsimonious cladograms. Additionally, such an approach can be applied to other NP-complete phylogenetic optimization problems such as genomic break-point analysis.

Animals↗

PubMedDate not supplied

[Optimal level of EEG coherence and its importance in evaluating the functional state of the human brain].

The study of EEG by means of computer analysis 46 healthy subjects and more than 100 patients with different disturbances of consciousness showed that one of the necessary conditions for performance of reactions to external stimuli and higher nervous activity consists in the maintainance of optimal level of coherence of brain electric processes, corresponding to the optimal cortical tone. Different depths of disturbances revealed different coherence deviations from the optimal level: its overall decrease in case of deep disturbances (coma), a sharp (pessimal) rise in the low frequency rang in sopor and within a wide frequency range in drowsiness in norm. The recovery of consciousness in the post-coma period and at early stages of coma is accompanied by a discordance between the levels of EEG coherence -- a decline in some cortical parts and a sharp rise -- in other ones.

Alpha Rhythm↗

PubMed2005

Improvement of coagulation-flocculation process using anionic polyacrylamide as coagulant aid.

A physicochemical treatment (coagulation-flocculation) was applied to a slaughterhouse wastewater, using anionic polyacrylamide as coagulant aid to improve the settling velocity of the flocs formed with the coagulants used: ferric sulphate, aluminium sulphate and polyaluminium chloride. The optimum speed and stirring time for the flocculation stage were ascertained along with the optimum pH and coagulant and coagulant aid doses. The speed and coagulation time were initially set according to recommendations in the literature concerning the treatment of this type of water. Chemical oxygen demand (COD), biochemical oxygen demand at 5 days (BOD5) and total suspended solids (TSS) were recorded at the beginning and end of each experiment in order to monitor the process. Once the optimal conditions had been established, several parameters were measured in order to assess the coagulation-flocculation process: particle number and size, sludge volume, nutrients (ammonia nitrogen, total Kjeldahl nitrogen, albuminoid nitrogen, orthophosphate, total phosphorus) and the residual concentration of iron and aluminium in clarified water. Anionic polyacrylamide, when added with ferric sulphate or polyaluminium chloride led to a significant increase in the settling speed.

Acrylic Resins↗

PubMed2000

Requirements for the dGTP-dependent repeat addition processivity of recombinant Tetrahymena telomerase.

Telomerase is a reverse transcriptase responsible for adding simple sequence repeats to chromosome 3'-ends. The template for telomeric repeat synthesis is carried within the RNA component of the telomerase ribonucleoprotein complex. Telomerases can copy their internal templates with repeat addition processivity, reusing the same template multiple times in the extension of a single primer. For some telomerases, optimal repeat addition processivity requires high micromolar dGTP concentrations, a much higher dGTP concentration than required for processive nucleotide addition within a repeat. We have investigated the requirements for dGTP-dependent repeat addition processivity using recombinant Tetrahymena telomerase. By altering the template sequence, we show that repeat addition processivity retains the same dGTP-dependence even if dGTP is not the first nucleotide incorporated in the second repeat. Furthermore, no dNTP other than dGTP can stimulate repeat addition processivity, even if it is the first nucleotide incorporated in the second repeat. Using structural variants of dGTP, we demonstrate that the stimulation of repeat addition processivity is specific for dGTP base and sugar constituents but requires only a single phosphate group. However, all nucleotides that stimulate repeat addition processivity also inhibit or compete with dGTP incorporation into product DNA. By assaying telomerase complexes reconstituted with a variety of altered templates, we find that repeat addition processivity has an unanticipated template or product sequence specificity. Finally, we show that a novel, nascent product DNA binding site establishes dGTP-dependent repeat addition processivity.

Animals↗

PubMed2004

Microcapsules based on glycinin-sodium dodecyl sulfate complex coacervation.

Microcapsules processed by complex coacervation were prepared using hexadecane for the oil phase and glycinin (a soybean storage protein)-sodium dodecyl sulfate (SDS) as the main wall-forming material. The study underlines the essential role of SDS, which, by the way of [glycinin(+)-SDS(-)] insoluble complex formation, allowed the precipitation of proteins around oil droplets. Moreover, particular attention was attributed to the study of suitable conditions of glycinin cross-linking with glutaraldehyde. The reticulation step was performed at pH 4.0 and it was observed that the precipitated state of proteins increased considerably the efficiency of the cross-linking reaction. Analysis of the reactional medium after each main step of the process (emulsification, complex coacervation, cross-linking) allowed the follow-up and characterization of microcapsule formation. Optimization of different process parameters such as glycinin concentration, glycinin/SDS/glutaraldehyde ratios, pH and the kinetics of cross-linking allowed the encapsulation of the totality of oil and the use of more than 98% of initially introduced proteins for the microcapsule wall formation.

Capsules↗

PubMed2001

Optimal filtering of whole nerve signals.

Electroneurographic recordings suffer from low signal to noise (S/N) ratios. The S/N ratio can be improved by different signal processing methods including optimal filtering. A method to design two types of optimal filters (Wiener and Matched filters) was developed for use with neurographic signals, and the calculated filters were applied to nerve cuff recordings from the cat S1 spinal root that were recorded during the activation of cutaneous, bladder, and rectal mechanoreceptors. The S1 spinal root recordings were also filtered using various band-pass (BP) filters with different cut-off frequencies, since the frequency responses of the Wiener and Matched filters had a band-pass character. The mean increase in the S/N ratio across all recordings was 54, 89, and 85% for the selected best Wiener, Matched, and band-pass filters, respectively. There were no statistically significant differences between the performance of the selected filters when all three methods were compared. However, Matched filters yielded a greater increase in S/N ratio than Wiener filters when only two filtering techniques were compared. All three filtering methods have in most cases also improved the selectivity of the recordings for different sensory modalities. This might be important when recording nerve activity from a mixed nerve innervating multiple end-organs to increase the modality selectivity for the nerve fibers of interest. The mean Modality Selectivity Indices (MSI) over different receptor types and for the same selected filters as above were 1.12, 1.27, and 1.29, respectively, and indicate increases in modality selectivity (MSI>1). Improving the S/N ratio and modality selectivity of neurographic recordings is an important development to increase the utility of neural signals for understanding neural function and for use as feedback or control signals in neural prosthetic devices.

Action Potentials↗

PubMed2006

Nonuniform distribution of reach-related and torque-related activity in upper arm muscles and neurons of primary motor cortex.

The present study examined the activity of primate shoulder and elbow muscles using a novel reaching task. We enforced similar patterns of center-out movement while the animals countered viscous loads at their shoulder, elbow, both joints, or neither joint. Accordingly, we could examine reach-related activity during the unloaded condition and torque-related activity by comparing activity across load conditions. During unloaded reaching the upper arm muscles exhibited a bimodal distribution of preferred hand direction. Maximal reach-related activity occurred with hand movements mostly toward or away from the body. Arm muscles also exhibited a bimodal distribution of their preferred torque direction. Maximal torque-related activity typically occurred with shoulder-extension/elbow-flexion torque or shoulder-flexion/elbow-extension torque. Similar biases in reach-related and torque-related activity could be reproduced by optimizing a global measure of muscle activity. These biases were also observed in the neural activity of primary motor cortex (M1). The parallels between M1 and muscular activity demonstrate another link between motor cortical processing and the motor periphery and may reflect an optimization process performed by the sensorimotor system.

Algorithms↗

PubMed1988

On working through: a model from artificial intelligence.

Working through is centrally important to clinical psychoanalysis. It is inadequately explained in analytic theory. An artificial intelligence model of the process is proposed. Models of problem solving show that the complexity of necessary computation is an important determinant of how a problem is solved. Not optimal, but only good enough solutions are usually found. The quality of solutions depends on the time and resources available. Generally it is far easier to use existing methods than to develop new approaches. When problems must be solved in an emergency fashion, as in trauma, poor solutions are likely to emerge. In studying the annealing of metals and other complex optimization problems, a process, the Boltzman algorithm, was discovered, which continues the search for better solutions while gradually developing a coherent structure of the overall solution. The algorithm provides a model both for psychoanalytic working through and for the normally ongoing process of psychological development and reworking whose deficiency is characteristic of much psychopathology. Working through in the analytic situation is the reactivation of this normal process, and a good analytic outcome is achieved when the process can continue without the analyst. Properties of the Boltzman algorithm clarify such concepts as "optimal" frustration and anxiety which correspond to working in the area where the stable but not rigid structures emerge in the algorithms operation. These studies are an example of how computer science and artificial intelligence are a potentially rich source for psychoanalytic theory.

Algorithms↗

PubMed1978

[Optimal dental radiography by means of expert film processing].

The processing of the dental radiographic films in the darkroom is decisive of the optimal information content of dental radiographs. Proper storage of the films, darkroom lighting according to regulations and standardized film developing are the basic conditions for stable film quality. The indications given are above all intended for aiding the stomatological nurse in taking dental radiographs.

Radiography, Dental↗

PubMed2000

Flow cytometric screening of cell-based libraries.

Flow cytometry is a powerful, high-throughput library screening tool in numerous applications including the isolation of bioactive molecules from synthetic combinatorial libraries, the identification of virulence genes in microorganisms, and the study and engineering of protein functions. Using flow cytometry, large libraries of protein mutants expressed in microorganisms can be screened quantitatively for desired functions, including ligand binding, catalysis, expression level, and stability. Rare target cells, occurring at frequencies below 10(-6), can be detected and isolated from heterogeneous library populations using one or more cycles of cell sorting and amplification by growth. Flow cytometry is particularly powerful because it provides the unique opportunity to observe and quantitatively optimize the screening process. However, the ability to isolate cells occurring at such low frequencies within a population requires consideration and optimization of screening parameters. With this aim, an analysis of the various parameters involved in screening cell-based libraries for rare target cells possessing a desired trait is presented.

Cell Separation↗

PubMed2005

The process of decision making in reproductive medicine.

The decision-making process regarding the optimal infertility treatment strategy is influenced by several factors. In addition to the underlying cause of infertility, the process of decision making is also influenced by other factors. These factors are mainly (1) the duration of infertility, (2) patient's age, and (3) the number of previously performed treatment cycles of intrauterine insemination (IUI) or in vitro fertilization (IVF). The duration of infertility influences diagnostic steps as well as therapeutic options. With an infertility of at least 5 years the benefit of intrauterine insemination is limited and couples should be counseled to go forward with IVF. Patients age >or= 40 years should be treated with IVF, whereas patients age >or= 43 years should be counseled about their very limited chance to conceive even through IVF. The number of insemination cycles should be limited to four. Couples who have undergone at least six IVF cycles should be counseled to discontinue therapy. The treatment program should be as individualized as possible, with individual counseling that is adapted after each single treatment cycle.

Decision Making↗

PubMed2003

Strength nutrition.

Muscle strength is determined by muscle size and factors related to neural recruitment. Resistance training is a potent stimulus for increasing muscle size and strength. These increases are, to a large extent, influenced and mediated by changes in hormones that regulate important events during the recovery process following exercise. Provision of nutrients in the appropriate amounts and at the appropriate times is necessary to optimize the recovery process. This review discusses the results of research that has examined the potential for nutrition and dietary supplements to impact the acute response to resistance exercise and chronic adaptations to resistance training. To date, the most promising strategies to augment gains in muscle size and strength appear to be consumption of protein-carbohydrate calories before and after resistance exercise, and creatine supplementation.

Adaptation, Physiological↗

PubMed1990

[Characterization of the asynergic myocardium in acute coronary syndrome using simultaneous dual radionuclide emission computed tomography].

The purpose of the present study was to evaluate the tissue characterization of the ischemic myocardium by dual single photon emission computed tomography (SPECT) with thallium-201 (Tl-201) and technetium-99m pyrophosphate (Tc-99m PYP) using the simultaneous collection method. The subjects consisted of 84 patients with acute coronary syndrome followed by protracted left ventricular asynergy. For precise interpretation of clinical scintigraphy, we used phantom experiments and the results were as follows: 1. The residual myocardium in the infarcted area could be evaluated to some extent from the severity of the defect on Tl-201 SPECT with optimal and unified image processing standardized by maximal pixel counts in the myocardium. 2. The influence of cross talk between two radionuclides on each tomographic image was negligible under usual clinical conditions. 3. In a subendocardial infarction model where the Tc-99m layer was located within 50% inside the phantom wall and the other space was filled with 201TlCl solution, the Tc-99m layer was clearly visualized inwardly as compared with the Tl-201 layer on dual SPECT with optimal image processing. 4. Transmural infarction could be visualized as a total defect on Tl-201 SPECT only when its diameter was greater than 2 to 2.5 cm. Taking these results into account, we evaluated clinical cases. According to the peak CK value and Tl-201 SPECT in the chronic phase, the subjects were categorized as transmural infarction (TMI), nontransmural infarction (NTMI) and unstable angina pectoris (UAP), and the scintigraphic characteristics of each group were compared. Short-axis tomographic features of all lesions were classified in nine types from 1A to IIIC by the combination of Tl-201 uptake grades (total defect: I, reduced uptake: II, normal: III) and the condition of Tc-99m PYP accumulation (negative: A, transmural: B, subendocardial: C). The relationship between recovery from asynergy and the dual scintigraphic findings was also evaluated and 17 patients in whom asynergy had nearly resolved in the chronic phase was especially classified in a reversible ischemic myocardial damage (RIMD) group. The clinical results were as follows: 1. In cases without reinfarction, a Tl-201 uptake in ischemically-injured lesions was variably improved in the chronic phase. In 9% of all the lesions of NTMI, a Tl-201 uptake showed total defects in the acute phase. 2. Type IIC lesions were most frequently observed, accounting for 43% of all lesions of NTMI.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMed2006

Genotoxic activity of nitroarene-contaminated industrial sludge following large-scale treatment in aerated and non-aerated sacs.

An industrial sludge containing a complex mixture of nitroaromatic compounds was treated in industrial large-scale aerobic and anaerobic biodegradation processes, performed in compost sacs. The goal was to study changes in genotoxicity during the two different oxygen regimes using the umuC genotoxicity assay. The composting sac was actively aerated during 3 months and allowed to mature for another 3 months. The anaerobic sac was not aerated for 5 months and aerated during the last month in order to enhance degradation of remaining organic carbon. The sludge was obtained from the wastewater treatment plant at an industrial area in Karlskoga, Sweden. The biodegradation study was performed at a commercial waste treatment plant in Stockholm, according to the company routine procedure when treating household waste in sealed sacs. The material from the non-aerated system showed increased genotoxicity in the acetone-soluble fraction after treatment, as did the water-soluble fraction. The subsequent aeration period did not decrease the toxicity below the genotoxicity limit. The increase in the water-soluble genotoxic compounds may pose an environmental problem during secondary storage or use of sludge treated this way, since leakage of water-dissolved genotoxic compounds may occur. The composting process also generated genotoxicity, but this was restricted to acetone-soluble compounds, while the water-soluble compounds remained low in genotoxicity. The aerated process therefore seems more favorable in term of risk reduction of this industrial sludge, although it is necessary to optimize the aerated process in order to achieve non-toxic levels of potential genotoxic compounds extractable by organic solvents.

Bacteria↗

PubMed2002

A distributed simulation technique for multiple input multiple output systems.

Distributed computing concepts have been attempted in the realm of real-time process control for a long time. This started with the systolic arrays of processors and an enormous amount of research has been done in this field. This paper proposes a methodology by which a multiple input multiple output system representing a plant and defined in terms of connected blocks of transfer functions can be decomposed into a set of parallel simulation processes in a message passing environment viz. a network of work stations. The paper also analyzes the scope of optimization of the processing time associated with each task. The methodology includes online reconfiguration of the system.

Algorithms↗

PubMed2006

Column experiments to assess the effects of electron donors on the efficiency of in situ precipitation of Zn, Cd, Co and Ni in contaminated groundwater applying the biological sulfate removal technology.

BACKGROUND, AIMS AND SCOPE: In a previous study, we explored the use of acetate, lactate, molasses, Hydrogen Release Compound (HRC, which is based on a biodegradable poly-lactate ester), methanol and ethanol as carbon source and electron donor to promote bacterial sulfate reduction in batch experiments, this with regards to applying an in situ metal precipitation (ISMP) process as a remediation tool to treat heavy metal contaminated groundwater at the site of a nonferrous metal work company. Based on the results of these batch tests, column experiments were conducted with lactate, molasses and HRCI as the next step in our preliminary study for a go-no go decision for dimensioning an on site application of the ISMP process that applies the activity of the endogenous population of sulfate-reducing bacteria (SRB). Special attention was given to the sustainability of the metal precipitation process under circumstances of changing chemical oxygen demand (COD) to [SO4(2-)] ratios or disrupted substrate supply. METHODS: To optimize the ISMP process, an insight is needed in the composition and activity of the indigenous SRB community, as well as information on the way its composition and activity are affected by process conditions such as the added type of C-source/ electron donor, or the presence of other prokaryotes (e.g. fermenting bacteria, methane producing Archaea, acetogens). Therefore, the biological sulfate reduction process in the column experiments was evaluated by combining classical analytical methods [measuring heavy metal concentration, SO4(2-)-concentration, pH, dissolved organic carbon (DOC)] with molecular methods [denaturing gradient gel electrophoresis (DGGE) fingerprinting and phylogenetic sequence analysis] based on either the 16S rRNA-gene or the dsr (dissimilatory sulfite reductase) gene, the latter being a specific biomarker for SRB. RESULTS AND DISCUSSION: All carbon sources tested promoted SRB activity, which resulted within 8 weeks in a drastic reduction of the sulfate and heavy metal contents in the column effluents. However, unexpected temporal decreases in the efficiency of the ISMP process, accompanied by the release of precipitated metals, were observed for most conditions tested. The most dramatic observation of the failing ISMP process was observed within 12 weeks for the molasses amended column. Subsequent lowering the COD/ SO4(2-) ratio from 1.9 to 0.4 did not alter the outcome of sulfate reduction and metal precipitation efficiency in this set-up. Remarkably, after 6 months of inactivity, bacterial sulfate reduction was recovered in the molasses set up when the original COD/ SO4(2-) ratio of 1.9 was applied again. Intentional disruption of the lactate and HRC supplies resulted in an immediate stagnation of the ISMP processes and in a rapid release of precipitated metals into the column effluents. However, the ISMP process could be restored after substrate amendment. 16S rDNA-based DGGE analysis revealed that the SRB population, in accordance with the results of the previously performed batch experiments, consisted exclusively of members of the genus Desulfosporosinus. The community of Archaea was characterized by sequencing amplicons of archaeal and methanogen-specific PCR reactions. This approach only revealed the presence of non-thermophilic Crenarchaeota, a novel group of organisms which is only distantly related to methane producing Euryarchaeota. DGGE on the dsrB genes was successfully used to link the results of the ISMP process to the community composition of the sulfate reducing bacteria. CONCLUSIONS: In the case of an intentional disruption of substrate supply, the ISMP process failed most likely because the growth and activity of the indigenous SRB community stopped due to a lack of a carbon and electron donor. On the other hand, the cause of the sudden temporal shortcomings of the ISMP process in the presence of different substrates was not immediately clear. It was first thought to be the result of competition between methanogenic prokaryotes (MP) and sulfate reducers, since the formation of small amounts of CH4 (0.01-0.03 ppm ml(-1) was detected. However, the results of molecular analyzes indicate that methanogens do not constitute a major fraction of the microbial communities that were enriched in the column experiments. Therefore, we postulate that the SRB population becomes inhibited by the formed metal sulfides. RECOMMENDATION AND PERSPECTIVE: Our results indicate that the ISMP process is highly dependent on SRB-stimulation by substrate amendments and suggest that this remedial approach might not be viable for long-term application unless substrate amendments are continued and environmental conditions are strictly controlled. This will include the removal of affected aquifer material from the metal precipitation zone at the end of the remediation process, or removal of metal precipitates when the microbial activity decreases. Additional tests are necessary to investigate what will happen when clear groundwater passes through the reactive zone while no more C-sources are amended and all indigenous carbon is consumed. Also, the effects of dramatic increases in sulfate- or HM-concentrations on the SRB-community and the concomitant ISMP process need to be studied in more detail.

Bacteria↗

PubMed2005

Comparison of the granulation behavior of three different excipients in a laboratory fluidized bed granulator using statistical methods.

The granulation process and, subsequently, the tableting behavior of the resulting granules of alpha-lactose-monohydrate, dicalcium phosphate anhydrous, and potato starch were investigated using statistical designs. The three substances were chosen due to their differences in granulation and tableting behavior, such as water solubility, swelling, and compressional properties. Granulation process variables, namely the inlet air temperature, spray rate, binder concentration of granulating solution, and inlet air flow rate were investigated. A central composite design was applied to study the granulation of alpha-lactose-monohydrate. Granulations of dicalcium phosphate and potato starch were investigated using a 2(3) factorial design, in which the effects of the inlet air temperature, spray rate, and binder concentration were considered. To compare the granulation behavior of theses substances the particle size distribution, angle of repose, and yield of the granules were used as responses for the statistical designs. The granules were compressed into tablets and the tensile strength was used as an additional statistical response. Based on the process parameters, models were developed using multiple regression modeling for each examined response. These models were then used to optimize the granulation process that provides granules with a Sauter mean diameter of D32 between 300 and 500 microm, an angle of repose smaller than 36 degrees and a granule yield above 90%. Moreover, the values of the tensile strength of the tablets should be between 1.6 and 2.5 N/mm2. The intersections of the response surfaces of each examined substance were compared using contour plots. To achieve the largest "satisfactory zone," the granulations of milled alpha-lactose-monohydrate, dicalcium phosphate, or potato starch should be performed at low inlet air temperatures.

Calcium Phosphates↗