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Application of Bayesian estimation for the prediction of an appropriate dosage regimen of amikacin.

A Bayesian approach was developed to determine an amikacin dosage regimen to achieve the desired plasma concentrations for each patient. Statistical characteristics of pharmacokinetic parameters were first evaluated in a group of patients (reference population), which when combined with three individual plasma concentrations of drug led to a Bayesian estimation of individual pharmacokinetic parameters. By using these parameters, an individual dosage regimen was then established to avoid residual and peak amikacin concentrations of up to 3 and 25 micrograms/mL, respectively. In a test group of 33 patients, adapted amikacin dosage regimens ranged from 4 to 43 mg/kg/d, with schedules requiring up to four infusions per day. Infusion time varied from 40 min to 4 h. These differences in drug administration protocol result from the wide interindividual variability of amikacin pharmacokinetic parameters. Performance of the developed methodology was evaluated by computing bias and precision of the estimated total body clearance and of the trough and peak amikacin concentrations that were reached after dosage regimen determinations.

Adolescent↗

Quantification of multicontrast vascular MR images with NLSnake, an active contour model: in vitro validation and in vivo evaluation.

Vessel-wall measurements from multicontrast MRI provide information on plaque structure and evolution. This requires the extraction of numerous contours. In this work a contour-extraction method is proposed that uses an active contour model (NLSnake) adapted for a wide range of MR vascular images. This new method employs length normalization for the purpose of deformation computation and offers the advantages of simplified parameter tuning, fast convergence, and minimal user interaction. The model can be initialized far from the boundaries of the region to be segmented, even by only one pixel. The accuracy and reproducibility of NLSnake endoluminal contours were assessed on vascular phantom MR angiography (MRA) and high-resolution in vitro MR images of rabbit aorta. An in vivo evaluation was performed on rabbit and clinical data for both internal and external vessel-wall contours. In phantoms with 95% stenoses, NLSnake measured 94.3% +/- 3.8%, and the accuracy was even better for milder stenoses. In the images of rabbit aorta, variability between NLSnake and experts was less than interobserver variability, while the maximum intravariability of NLSnake was equal to 1.25%. In conclusion, the NLSnake technique successfully quantified the vessel lumen in multicontrast MR images using constant parameters.

Animals↗

Label-free detection methods for protein microarrays.

With the growth of the "-omics" such as functional genomics and proteomics, one of the foremost challenges in biotechnologies has become the development of novel methods to monitor biological process and acquire the information of biomolecular interactions in a systematic manner. To fully understand the roles of newly discovered genes or proteins, it is necessary to elucidate the functions of these molecules in their interaction network. Microarray technology is becoming the method of choice for such a task. Although protein microarray can provide a high throughput analytical platform for protein profiling and protein-protein interaction, most of the current reports are limited to labeled detection using fluorescence or radioisotope techniques. These limitations deflate the potential of the method and prevent the technology from being adapted in a broader range of proteomics applications. In recent years, label-free analytical approaches have gone through intensified development and have been coupled successfully with protein microarray. In many examples of label-free study, the microarray has not only offered the high throughput detection in real time, but also provided kinetics information as well as in situ identification. This article reviews the most significant label-free detection methods for microarray technology, including surface plasmon resonance imaging, atomic force microscope, electrochemical impedance spectroscopy and MS and their applications in proteomics research.

Animals↗

Procedures for the isolation and quantification of the intermediates of the mevalonic acid pathway.

Procedures for the isolation and analysis of all 11 intermediates of the mevalonic acid pathway from acetyl-CoA through geranylgeranyl pyrophosphate were developed. Both acid-labile and base-labile metabolites are simultaneously extracted with good recoveries into 7 M urea at neutral pH and low temperature to minimize hydrolytic and degradative enzyme losses, and the extract is partially purified by adsorption and desorption in high yield from an anion-exchange membrane. With the use of internal standards, the pathway intermediates are subsequently separated and quantified by reversed-phase ion-pair HPLC with on-line radiodetection. Permeable secretory cells specialized for monoterpene biosynthesis were isolated from peppermint (Mentha x piperita) leaves and employed as a model system to test the analytical protocols by examining the incorporation of [14C]pyruvate, [14C]mevalonate, and [3H]isopentenyl pyrophosphate as precursors. This simple new method should be readily adaptable to a wide range of cell and tissue types that can be administered basic metabolic precursors, and should allow measurements of both flux and steady-state levels of the intermediates of the mevalonic acid pathway.

Acetyl Coenzyme A↗

Biology and ecology of mycotoxigenic Aspergillus species as related to economic and health concerns.

The fungal genus Aspergillus was established in 1729, and includes species that are adapted to a wide range of environmental conditions. Many aspergilli produce mycotoxins in foods that may be toxic, mutagenic or carcinogenic in animals. Most of the Aspergillus species are soil fungi or saprophytes but some are capable of causing decay in storage, disease in plants or invasive disease in humans and animals. Major agricultural commodities affected before or after harvest by fungal growth and mycotoxins include corn, peanuts, cottonseed, rice, tree nuts, cereal grains, and fruits. Animal products (meat, milk and eggs) can become contaminated because of diet. Aspergillus flavus, A. parasiticus, A. ochraceus, A. niger, A. fumigatus and other aspergilli produce mycotoxins of concern. These include the aflatoxins and ochratoxins, as well as cyclopiazonic acid, patulin, sterigmatocystin, gliotoxin, citrinin and other potentially toxic metabolites.

Animals↗

The intensity-dependent changes of the visual evoked responses in man to patterned and blank stimulation.

The visual evoked responses (VERs) to blank and checkerboard-patterned stimuli of 6 degrees angular subtense were recorded referentially (OZ--A2) in 10 dark-adapted subjects using a range of 5.27 log units of intensity (maximum luminance = 6420 cd/m2). The mean peak latencies of the prominent positive-negative deflection of the VERs to the blank stimuli exhibit an exponential shortening with the rise of log stimulation intensity. The peak latencies of the positive-negative deflection of the VERs to the checkerboard-pattern stimulation at low and moderate intensities are by about 50 ms shorter, with the latency of the negative peak of the response to the patterned stimulation corresponding to the positive peak latency of the response to the blank stimuli. Accordingly, the VERs to both types of stimulation are of opposite polarity. With a further increase of the stimulation intensity, the latency of the negative peak of the VER to patterned stimulation gradually lengthens due to the glaring effects of the patterned stimuli. Therefore, at high stimulation intensities the VERs to both types of stimuli are of the same polarity. The mean peak-to-peak amplitudes of the VERs to both types of stimulation differ significantly at high-intensity end of the photostimulation range only, the amplitude of the VER to the patterned stimulation being higher.

Adult↗

Decision analysis in surgical education.

Surgical education can no longer be considered adequate if limited to description of surgical diseases and methods of management. Due to the growth in numbers of surgical diagnostic and therapeutic procedures, the surgeon of the future will find it increasingly necessary to understand the principles by which algorithms are constructed and by which individualized decisions should be made. Several systematic approaches for assisting clinical decision makers have been developed. Decision analysis is particularly appealing because it is flexible and readily adapted to a wide range of clinical situations. It explicitly guides the decision maker in determining the crucial variables in a clinical decision, and permits both objective data and personal preferences to play a part in decision making. Because it provides for personal estimates and preferences, decision analysis is not dehumanizing, even though it is quantitative, explicit, and mathematically rigorous. Topics for a series of seminars or case conferences are suggested. Decision analysis should be part of the intellectual preparation of every clinician.

Decision Support Techniques↗

Endothelial cells as part of a vascular oxygen-sensing system: hypoxia-induced release of autacoids.

Higher developed organisms are equipped with many central and local control mechanisms, which enable an adequate blood and oxygen supply to tissues over a wide range of demands. Global adaptive responses include changes in the circulatory and ventilatory system as well as increases in the oxygen carrying capacity of the blood. At the level of the specialized organs there exist additional control systems for the regulation of local blood flow. Most systems make use of highly specialized cells which are able to sense the oxygen partial pressure of the transport medium, blood, and within the tissues. In the past years, it has been shown that the vascular endothelium lining the entire circulatory system can actively modulate the vascular tone and platelet functions by the release of autacoids, among them prostacyclin and endothelium-derived nitric oxide (EDRF). Recent experiments demonstrate that the release of EDRF is PO2-dependent, which suggests that endothelial cells may act as functional local oxygen sensors within the vascular system.

Adenine Nucleotides↗

Amplifiers for bioelectric events: a design with a minimal number of parts.

A design for an amplifier for bioelectric events is presented that has fewer parts than conventional designs. The design allows the construction of amplifiers of a high quality in terms of noise and common mode rejection, with reduced dimensions and with a lower power consumption. Gain, bandwidth and number of channels are easily adapted to a wide range of biomedical applications. An application example is given in the form of a multichannel EEG amplifier (gain is 20,000), in which each channel consists of three operational amplifiers (one single and one dual), six resistors and two capacitors. The equivalent input noise voltage and current are 0.15 microVrms and 1 pArms, respectively, in a bandwidth of 0.2-40 Hz, and a common mode rejection ratio of 136 dB is achieved without trimming.

Amplifiers, Electronic↗

Stages of decompensation in combat-related posttraumatic stress disorder: a new conceptual model.

This conceptual article presents a model of severe, chronic combat-related PTSD based on several years of longitudinal clinical observations of Vietnam veterans. The model describes a repeating cycle of decompensation that profoundly disrupts the veteran's life. There appear to be "stages" of decompensation that can be described clinically and may be distinct physiologically. The stages describe a wide range of functioning, from adaptive to totally dysfunctional PTSD core symptoms, as well as several other dimensions of clinical functioning, such as affect regulation, defenses, ego states, interactions with the environment, capacity for self-destruction/suicide and capacity for attachment and insight are described for each stage. Clinical and research implications are discussed.

Adaptation, Psychological↗

Assessing regional variation of environmental fluoride concentrations in western Germany by analysis of antler fluoride content in roe deer (Capreolus capreolus).

To assess regional variation in ambient fluoride levels, we analyzed the fluoride content of 188 antlers of roe deer (Capreolus capreolus) killed between 1990 and 1999 in 14 areas of the federal state of North Rhine-Westphalia, Germany. Individual antler fluoride concentrations ranged between 113 and 11,995 mg x F-/kg bone ash, and sample means differed significantly (p < 0.0001) among the study areas. Low average concentrations (geometric means of 262 and 277 mg x F-/kg bone ash, respectively) were found in antler samples from two control areas, located quite remote to major fluoride emission sources. The highest geometric mean fluoride content (1,677 mg x F-/kg bone ash) was recorded for an antler sample from a study area exposed to fluoride emissions from an aluminium smelter and two mineral coal-fired power stations. In eight antlers obtained from roe deer living in the direct vicinity of the aluminium smelter, fluoride values ranged between 2,067 and 11,995 mg x F-/kg bone ash, thereby demonstrating the strong impact of this emission source on its surroundings. The study showed that by analyzing antler fluoride concentrations, large-scale surveys of environmental contamination by fluoride can be performed in a standardized and cost-effective way in areas inhabited by deer. Due to its rather narrow home range, abundance, and high adaptability, the roe deer is particularly suited for such studies.

Animals↗

A stretching program increases the dynamic passive length and passive resistive properties of the calf muscle-tendon unit of unconditioned younger women.

This study examined the effects of a 6-week stretching program on the dynamic passive elastic properties of the calf muscle-tendon unit (MTU) of unconditioned younger women. After random assignment of 12 women (age 18-31 years) to a stretching group (SG) or to a control group (CG), six subjects in the SG and four subjects in the CG completed the study. For the initial tests, a Kin-Com dynamometer moved the ankle from plantarflexion to maximal dorsiflexion (DF) with negligible surface EMG activity in the soleus, gastrocnemius and tibialis anterior muscles. Angular displacement, passive resistive torque, area under the curve (passive elastic energy) and stiffness variables were reduced from the passive DF torque curves. The SG then completed ten static wall stretches held 15 s each, five times a week for 6 weeks, the CG did not. The tests were repeated and the changes between the tests and retests were examined for group differences (Mann-Whitney U). The SG had significant increases in the maximal passive DF angle (7 degrees +/- 4 degrees ), maximal passive DF torque (11.2 +/- 8.3 N m), full stretch range of motion (23 degrees +/- 24 degrees ), full stretch mean torque (3.4 +/- 2.1 N m), and area under the full stretch curve (22.7 +/- 23.5 degrees N m) compared to the CG (P < or = 0.019). The passive stiffness did not change significantly. The results showed that a stretching program for unconditioned calf MTUs increased the maximal DF angle and length extensibility, as well as the passive resistive properties throughout the full stretch range of motion. The adaptations within the calf MTU provide evidence that stretching enhances the dynamic passive length and passive resistive properties in unconditioned younger women.

Adaptation, Physiological↗

Isolation of secretory cells from plant glandular trichomes and their use in biosynthetic studies of monoterpenes and other gland products.

The natural products that accumulate in or exude from plant glandular trichomes are biosynthesized by secretory cells located at the apex of the trichome. To investigate the formation of glandular trichome constituents in several species of mints (Lamiaceae), a new procedure was developed for isolating large numbers of highly purified secretory cells. In this method, the leaf surface is gently abraded with glass beads in a way that fragments the glandular trichomes and yields clusters of intact secretory cells. The isolated, intact secretory cells and cell-free preparations derived from them are very active in monoterpene biosynthesis and provide useful starting materials for the purification of several key enzymes of monoterpene metabolism. The procedure described is adaptable to a broad range of plant species and should find wide application in the preparation of whole cell and cell-free systems for biosynthetic studies of plant natural products found in glandular trichomes.

Cell-Free System↗

Development and validation of an automated enzyme assay for paracetamol (acetaminophen).

A rapid, enzymatic assay for serum or plasma paracetamol has been developed with the potential for adaptation to a wide range of clinical analysers. The method involves the action of an amidase enzyme to produce 4-aminophenol from paracetamol, which in turn reacts with 8-hydroxyquinoline in the presence of manganese ions to form a blue dye. Two stable reagents are used and excellent precision is achieved over the drug concentration range 0-2.5 mmol/l. The method, which is complete within 6 min, has been validated using a Monarch centrifugal analyser and shows no significant interference from endogenous serum compounds, drugs or paracetamol metabolites.

Acetaminophen↗

Mechanical simulation of shear stress on the walls of peripheral arteries.

In the last few years many attempts were made to line artificial vascular grafts with in vitro grown endothelial cell layers and thereby to minimize the risk of thromboembolism. However, adherence and resistance against shear stress forces were not tested under physiological pulsatile shear stress forces. In this paper, a mock-circulation apparatus is described, which simulates various forms of pulsatile shear stress, and which at the same time meets the requirements of cell cultivation. It can be sterilized and needs less than 700 ml of culture medium for priming. The generated flow profile can be adapted to a wide range of shear stress and also to different viscosities of used media. To take account of the different viscosities of culture medium and blood, a computerized calculation of the shear stress pattern was performed. Using the results of this computer model, the flow pattern was modified to obtain normal physiological shear stress when using culture medium. Results of pulse generation and simulation for the superficial femoral artery are presented.

Arteries↗

The glucose stimulus-response curve of the beta-cell in physically trained humans, assessed by hyperglycemic clamps.

In order to examine the effect of habitual exercise on beta-cell responses over a wide range of plasma glucose levels, plasma insulin and C-peptide responses to 2 1/2-hour hyperglycemic clamps at 7.5, 10, and 15 mmol/L glucose were assessed in six trained athletes and six age- and weight-matched sedentary controls. Athletes were significantly fitter than controls (estimated maximal oxygen uptake [VO2 max] mean 44 v 30 mL.kg-1.min-1, P less than .05) and were more sensitive to insulin as assessed by dividing the mean glucose infusion rate over the last 20 minutes of the clamp by the steady-state plasma insulin (mean 0.44 v 0.19 mg.min-1.kg-1.nmol-1. L, respectively, P less than .01). Plasma C-peptide responses were lower in the athletes, both fasting (geometric mean 0.28 v 0.62 nmol/L, P less than .05), and at the end of all clamps (at 7.5, 10, and 15 mmol/L plasma glucose, respectively, 0.65 v 1.43, 1.25 v 2.85, and 2.40 v 4.46 nmol/L each, P less than .05). First-phase plasma C-peptide responses were lower in the athletes at the 10 and 15 mmol clamp levels. The slope of the glucose-C-peptide stimulus-response curve was approximately linear over the range examined, the slope being significantly shallower in athletes than controls for both first phase (P less than .01) and second phase (P less than .01). Plasma insulin responses were similar to C-peptide responses. The attenuation of beta-cell responsiveness over a wide glucose range may be an adaptation to the enhanced peripheral insulin sensitivity seen in athletes.

Adult↗

Intravenous infusion system for chronic drug administration in unrestrained rats.

This paper describes a system for long-term intravenous infusion studies in relatively unrestrained rats. It has the advantage of allowing continual 24 hr studies to be run without the problems of having the infusion cable tangle or interfere with the normal activity of the rats, and most of the components are either easily made or readily available from commercial sources. The apparatus itself incorporates the features of several reported chronic infusion systems using modifications to produce a feed-through swivel and infusion cable which can be adapted to a wide range of experimental chambers. In addition, a skull implant is described which minimizes the restraining features inherent in harnesses and provides a secure link between the rat and the infusion cable. The implant mates directly with the infusion cable and is readily detachable. The entire system is inexpensive and requires a minimum of construction.

Animals↗

The Lake Casitas wild mouse: evolving genetic resistance to retroviral disease.

A small colony of feral mice from California continues to flourish in spite of a virulent epizootic of pathological retrovirus. Epidemiological and genetic studies revealed that the viral infection is strongly balanced by the polymorphic resistance locus, Fv-4, a transcriptionally active but truncated provirus that originated in the East Asian ancestors of the Californian mice. The natural history of these populations represents a graphic example of genomic adaptation in free-ranging populations to regulate and delimit infectious disease.

Animals↗