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Metabolic control of respiratory neuronal activity and the accompanying changes in breathing movements of the rabbit. III. Phase shifts in respiratory neurons induced by inflation and collapse of the lung, hyperventilation, or metabolic modifiers.

Phase shifts between inspiratory-related and expiratory-related discharge patterns can be reversibly induced in respiratory neurons following volume changes of the lung, hypocapnic apnea as a result of hyperventilation, or superfusion with certain metabolic modifiers. Phase-spanning expiratory-inspiratory or inspiratory-expiratory discharges are frequently induced in those neurons which are activated either by pulmonary stretch receptors or collapse afferents. The same is true for regulatory effectors which activate key steps of the neuronal metabolism such as ADP, 3-phosphoglycerate, L-glutamine, fructose-6-phosphate and fructose-1,6-diphosphate. In contrast, inhibitory vagal inputs or superfusion with citrate, an inhibitory metabolic modifier, revert preexisting expiratory-inspiratory discharges into a phase-coupled inspiratory pattern. It is postulated that the respiratory neuronal networks represents a time-optimal control system which strives to adjust to a new equilibrium value in a minimum of time, following a given mechanical or chemical perturbation. Following the hypothesis advanced by Cohen (1974) that the phase-spanning units modulate the activity of the in-phase neurons, it is suggested that the additional recruitment of expiratory-inspiratory and inspiratory-expiratory units provides a measure of the quality of time-optimal control and hence a performance index of the system.

Animals↗

Quantum computing based on vibrational eigenstates: pulse area theorem analysis.

In a recent paper [D. Babikov, J. Chem. Phys. 121, 7577 (2004)], quantum optimal control theory was applied to analyze the accuracy of quantum gates in a quantum computer based on molecular vibrational eigenstates. The effects of the anharmonicity parameter of the molecule, the target time of the pulse, and the penalty function on the accuracy of the qubit transformations were investigated. We demonstrate that the effects of all the molecular and laser-pulse parameters can be explained utilizing the analytical pulse area theorem, which originates from the standard two-level model. Moreover, by analyzing the difference between the optimal control theory results and those obtained using the pulse area theorem, it is shown that extremely high quantum gate fidelity can be achieved for a qubit system based on vibrational eigenstates.

Comment↗

[Myocardial revascularization after pretreatment with the GPIIb/IIIa receptor blocker abciximab].

AIM: The present prospective study analysis whether preoperative abciximab treatment 1) increases perioperative risks, 2) alters the quality of the surgical treatment, 3) whether secondary organ complications occur and 4) whether and how the perioperative surgical management has to be modified. METHODS: The perioperative results of patients operated upon after preoperative abciximab treatment (n = 31, 1/1994-4/2000) were compared with an optimal control group (elective patients and no preoperative intervention in the hemostaseological system) and with other patients (elective, urgent, emergency operations) receiving different strategies of preoperative hemostaseological interventions (n = 926, 1/1994-4/2000). All patients were operated upon with a well-defined strategy (one surgeon). 1100 perioperative items/patient were prospectively recorded and analyzed. The 30-day and 6 month follow-up was complete. RESULTS: The mean time interval between end of abciximab therapy and onset of operation was 4.3 h (range: 36-0.5 h, median: 2 h). As compared with the optimal control group (n = 81), perioperative blood loss and the need for substitution of blood and blood products was increased. However, as compared with those patients receiving any type of preoperative intervention in the hemostaseological system (the majority of the patients), no difference was observed regarding intraoperative parameters (duration of extracorporeal circulation and of the operation) and postoperative results (neurological, renal complications, myocardial infarction, psychiatric disturbances, etc.) when abciximab patients were compared with the reference populations. No patient of the abciximab group died within 30 days or during the 6 month follow-up period. CONCLUSION: The data show that coronary artery bypass grafting can be performed with similar results in abciximab-pretreated patients as in patients with other types of preoperative anticoagulation. Only slight modifications of the surgical management are recommended. As indicated by similar use IMA-grafts the quality of surgical treatment was not reduced.

Abciximab↗

Low-intensity combination chemotherapy maximizes host survival time for tumors containing drug-resistant cells.

Recent clinical trials have shown that for some cancers, high-intensity alternating chemotherapy does not significantly improve either survival times or response rates compared with nonalternating therapy. The current study uses optimal control to determine the best way to treat a tumor that contains drug-resistant cells that cannot be destroyed. The delivery of two non-cross-resistant chemotherapeutic agents is limited by bounds on the drug concentration and the dose intensity. This ensures that the drug toxicity stays within a tolerable range. The aim of the therapy is to maximize the host survival time, defined as the time over which the tumor burden can be kept below a fixed bound. The model is posed as a free terminal time, optimal parameter selection problem in which the constraints are continuously parametrized by time and the number of courses of therapy is free to vary. New theory is developed so that the optimal parameter selection problem can be solved as a sequence of fixed terminal time problems using existing optimal control software. Numerical simulations of Gompertz tumor growth showed that a treatment maintaining a high tumor burden doubled and sometimes tripled with survival time under aggressive therapy. When these simulations were repeated using exponential and logistic tumor growth models, the tumor burden during treatment had little influence upon survival time. In all simulations, survival time was not extended by delivering the anticancer drugs concurrently instead of staggering the treatment arms.

Animals↗

Integral curves and the variational principle of intermittent normal conduction in the tachycardia-dependent right bundle branch block.

Electrocardiographic (ECG) tracings of atrial fibrillation with the tachycardia-dependent right bundle branch block (RBBB) in a patient under digitalis therapy are presented, in which supernormal phase of intraventricular conduction was well-documented. The development of long intervals terminated by a normally conducted beat was attributed to the occurrence of concealed atrio-ventricular (A-V) conduction of atrial fibrillation impulse during the supernormal phase. The ventricular interval caused by a normally conducted beat (x seconds) in the interval of 1.01-1.50 seconds (s) was transformable into from of In(x + a) + l, where parameter a = 0, 0.04, 8.08 and 0.16. The vector differential equation dy/dx = ln (x + a) + 1l which is piecewise continuous and integrable, was assumed to describe the process of optimal control. This is equivalent to the problem of finding Green's function of the region, i.e. to solving, the Dirichlet problem for the region. The solution curves given by y = (x + a) ln(x + a) + l can be interpreted as distributions. This is the first study to apply integral curves and the variational principle to mathematical modelling of normal A-V conduction in tachycardia-dependent RBBB with atrial fibrillation. Furthermore, this is the first topological study to derive some definite properties of states of the phase space of a dynamical system. There are structurally stable vector field points so-called attractors on a differential manifold or surface. The optimal control is characterized by the fixed point property. In general, mathematical modelling may be applicable to the tachycardia-dependent RBBB when the cycle lengths caused by normally conducted beats range from 1.00 to 1.50 s as a feasible region. A solution of Dirichlet problem in the region was found. It was derived from this study that the normally conducted beats appeared as period doubling of 0.38-0.59 s, i.e. the interval of supernormal phase.

Aged↗

[Clinical and experimental control of optimal therapy in epilepsy].

On the basis of a psychopathologically calibrated battery of tests, the effects of four drugs commonly prescribed for the alleviation of epilepsy (Valproinat, Carbamazepin, Diphenylhydantoin, and Primidon) were examined before and after optimisation of therapy. The positive psychotropic effect of Valproinat and Carbamazepin, and probably also of Diphenylhydantoin, consists in the acceleration of the psychic and motor rate and in the reduction of viscosity and perseveration.

Anticonvulsants↗

Optimal noise control in and fast reconstruction of fan-beam computed tomography image.

We proposed a linear approach that exploits statistically complementary information inherent in the projection data of fan-beam computed tomography (CT) for achieving a bias-free image-variance reduction in fan-beam CT. This linear approach leads to the development of infinite classes of hybrid algorithms for image reconstruction in fan-beam CT. These hybrid algorithms are computationally more efficient and numerically less susceptible to data noise and to the effect of finite sampling than the conventional fan-beam filtered back-projection (FFBP) algorithm. We also developed infinite classes of generalized fan-beam filtered back-projection (GFFBP) algorithms, which include the conventional FFBP algorithm as a special member. We demonstrated theoretically and quantitatively that the hybrid and GFFBP algorithms are identical (or different) in the absence (or presence) of data noise and of the effect of finite sampling. More importantly, we identified the statistically optimal hybrid algorithm that may have potentially significant implication to image reconstruction in fan-beam CT. Extensive numerical results of computer-simulation studies validated our theoretical results.

Algorithms↗

Simulation on an optimal combustion control strategy for 3-D temperature distributions in tangentially pc-fired utility boiler furnaces.

The control of 3-D temperature distribution in a utility boiler furnace is essential for the safe, economic and clean operation of pc-fired furnace with multi-burner system. The development of the visualization of 3-D temperature distributions in pc-fired furnaces makes it possible for a new combustion control strategy directly with the furnace temperature as its goal to improve the control quality for the combustion processes. Studied in this paper is such a new strategy that the whole furnace is divided into several parts in the vertical direction, and the average temperature and its bias from the center in every cross section can be extracted from the visualization results of the 3-D temperature distributions. In the simulation stage, a computational fluid dynamics (CFD) code served to calculate the 3-D temperature distributions in a furnace, then a linear model was set up to relate the features of the temperature distributions with the input of the combustion processes, such as the flow rates of fuel and air fed into the furnaces through all the burners. The adaptive genetic algorithm was adopted to find the optimal combination of the whole input parameters which ensure to form an optimal 3-D temperature field in the furnace desired for the operation of boiler. Simulation results showed that the strategy could soon find the factors making the temperature distribution apart from the optimal state and give correct adjusting suggestions.

Algorithms↗

Surface electrostatic effects in oligonucleotide microarrays: control and optimization of binding thermodynamics.

We present a theoretical thermodynamic framework for the design of more efficient oligonucleotide microarrays. A general thermodynamic relation is derived to describe the electrostatic surface effects on the binding of the assayed biomolecule to a surface-tethered molecular probe. The relation is applied to analyze how the nucleic acid target, the oligonuleotide probe, and their DNA duplex electrostatic interactions with the surface affect the hybridization on DNA arrays. Taking advantage of a closed form exact solution of the linear Poisson-Boltzmann equation for a charged ion-penetrable sphere in electrolyte solution interacting with a plane wall, we study the effects of the surface and solution conditions. Binding free energy is found as a function of the surface material, dielectric or metal, the surface charge density, linker molecule length, temperature, and added salt content. The charge or electric potential of the dielectric or metal surface, respectively, is shown to dominate the hybridization, especially at low added salt or short linker length. We predict that substantial enhancement of sensitivity, selectivity, and reliability of microarrays can be achieved by control of the surface conditions. As examples, we discuss how to overcome two limitations of current technologies: nonequal sensitivity of the probes with different GC and AT bases content, and poor match/mismatch discrimination. In addition, we suggest the design of microarray conditions where the tested nucleic acid is unfolded, thus making possible the screening of a larger sequence with single nucleotide resolution. These promising findings are discussed and further experimental tests suggested.

Base Sequence↗

A comparative efficacy and safety study of long-acting risperidone injection and risperidone oral tablets among hospitalized patients: 12-week randomized, single-blind study.

OBJECTIVE: The superiority of risperidone long-acting injection (RLAI) over oral typical and atypical antipsychotics demonstrated in previous studies may be related to the improved drug compliance. The aim of the 12-week randomized, single-blind study was to test whether the superiority of RLAI remained among hospitalized patients that drug compliance could be optimally controlled. METHODS: Fifty hospitalized stable schizophrenic patients, who had maintained on oral risperidone for more than 3 months, were randomized to the RLAI and oral risperidone group. Finally 49 patients (98 %) completed the study, and no dose change of oral risperidone, or RLAI was noted among all patients. RESULTS: The RLAI group showed significantly increased positive score of Positive and Negative Syndrome Scale (PANSS) than the risperidone group (0.72 +/- 3.52 vs. -1.24 +/- 3.81, p = 0.022), but without significance difference for the PANSS total, negative and general psychopathology scores. The RLAI group also showed a significantly improved Udvalg for Kliniske Undersogelser (UKU) Scale (p = 0.037), social life domains of Short-Form Health Survey (SF-36) (p = 0.011), and reduced prolactin level (p = 0.001). CONCLUSION: The results indicated that with optimal controlling of drug compliance among hospitalized patients, RLAI showed no benefit of efficacy over oral risperidone, but with advantages of improved side-effect profiles, social life ratings, and reduced prolactin levels.

Administration, Oral↗

Mechanism of membrane fluidity optimization: isothermal control of the Bacillus subtilis acyl-lipid desaturase.

The Des pathway of Bacillus subtilis regulates the expression of the acyl-lipid desaturase, Des, thereby controlling the synthesis of unsaturated fatty acids (UFAs) from saturated phospholipid precursors. Previously, we showed that the master switch for the Des pathway is a two-component regulatory system composed of a membrane-associated kinase, DesK, and a soluble transcriptional regulator, DesR, which stringently controls transcription of the des gene. Activation of this pathway takes place when cells are shifted to low growth temperature. Here, we report on the mechanism by which isoleucine regulates the Des pathway. We found that exogenous isoleucine sources, as well as its alpha-keto acid derivative, which is a branched-chain fatty acid precursor, negatively regulate the expression of the des gene at 37 degrees C. The DesK-DesR two-component system mediates this response, as both partners are required to sense and transduce the isoleucine signal at 37 degrees C. Fatty acid profiles strongly indicate that isoleucine affects the signalling state of the DesK sensor protein by dramatically increasing the incorporation of the lower-melting-point anteiso-branched-chain fatty acids into membrane phospholipids. We propose that both a decrease in membrane fluidity at constant temperature and a temperature downshift induce des by the same mechanism. Thus, the Des pathway would provide a novel mechanism to optimize membrane lipid fluidity at a constant temperature.

Bacillus subtilis↗

Adaptive environmental control for optimal results during plant microgravity experiments.

The SVET Space Greenhouse (SG)--the first and the only automated plant growth facility onboard the MIR Space Station in the period 1990-2000 was developed on a Russian-Bulgarian Project in the 80s. The aim was to study plant growth under microgravity in order to include plants as a link of future Biological Life Support Systems for the long-term manned space missions. An American developed Gas Exchange Measurement System (GEMS) was added to the existing SVET SG equipment in 1995 to monitor more environmental and physiological parameters. A lot of long-duration plant flight experiments were carried out in the SVET+GEMS. They led to significant results in the Fundamental Gravitational Biology field--second-generation wheat seeds were produced in the conditions of microgravity. The new International Space Station (ISS) will provide a perfect opportunity for conducting full life cycle plant experiments in microgravity, including measurement of more vital plant parameters, during the next 15-20 years. Nowadays plant growth facilities for scientific research based on the SVET SG functional principles are developed for the ISS by different countries (Russia, USA, Italy, Japan, etc.). A new Concept for an advanced SVET-3 Space Greenhouse for the ISS, based on the Bulgarian experience and "know-how" is described. The absolute and differential plant chamber air parameters and some plant physiological parameters are measured and processed in real time. Using the transpiration and photosynthesis measurement data the Control Unit evaluates the plant status and performs adaptive environmental control in order to provide the most favorable conditions for plant growth at every stage of plant development in experiments. A conceptual block-diagram of the SVET-3 SG is presented.

Brassica↗

Quality control and optimized procedure of hybridization capture-PCR for the identification of Mycobacterium avium subsp. paratuberculosis in faeces.

Nucleic acid sequence capture techniques are used to improve both the sensitivity and specificity of PCR for the diagnosis of plant, animal and human diseases. Hybridization capture-PCR (HC-PCR) was first reported as a method for the detection of Mycobacterium avium subsp. paratuberculosis in 1995 and was successfully trialed on a small number of faecal samples from cattle with Johne's disease. A locally optimized HC-PCR method was evaluated on faeces from infected and non-infected animals. However, sample to sample cross contamination during the DNA purification step highlighted that the original format of the test was unsuitable for routine diagnostic use. Here, we report modifications and optimization of HC-PCR, particularly with respect to DNA purification from faeces, hybridization and capture steps. We also identified procedurally sensitive critical points in the test during capture and washing of magnetic beads. Southern blotting was omitted from the protocol to preserve specificity but this resulted in analytical sensitivity of 5000 organisms per 200 mg faecal sample. Nevertheless, HC-PCR detected M.paratuberculosis in pellets from infected sheep diluted at rates of up to 1 in 100 in normal faeces, suggesting that the technique should be evaluated further for low-cost diagnosis in flocks/herds using pooled samples.

Animals↗

Autologous red cells derived from cord blood: collection, preparation, storage and quality controls with optimal additive storage medium (Sag-mannitol).

To investigate whether packed red cells (PRCs) prepared from autologous cord blood-packed red cells (AC-PRCs) could be used as an alternative for homologous-packed red cells (H-PRCs), we developed a system to collect and prepare AC-PRCs and determined standard storage parameters during 35 days of storage in extended storage medium (Sag-mannitol). We collected and fractionated cord blood from 390 newborns. The amount and quality of the AC-PRCs were analysed. The bacterial contamination rate was 1.84%. Twelve AC-PRCs were stored for 35 days, and standard laboratory parameters were measured at day 1 and day 35. The initial laboratory parameters of the AC-PRCs were similar to the parameters of the H-PRCs. After 35 days, the AC-PRCs displayed an increased haemolysis rate compared to H-PRCs (1.1 versus 0.2%) and also a significant decreased adenosine triphosphate value (1.2 versus 2.3 micromol L(-1)). Haemoglobin, haematocrit and pH were comparable in both groups. AC-PRCs meet the quality criteria for H-PRCs after 35 days. Utilizing a closed collection system for cord blood and an extended storage medium will increase safety and quality and facilitate the routine transfusion of autologous red cells derived from cord blood.

Adenosine Triphosphate↗

Capillary zone electrophoresis with optimized temperature control for studying thermal denaturation of proteins at various pH.

Capillary electrophoresis (CE) was used to analyze the thermal denaturation of bovine beta-lactoglobulin at different pH. This model protein exhibits complex pH- and temperature association/dissociation dependence balances in its quaternary structure. The study was possible after modification and improvement of a capillary electrophoresis apparatus. The improvement allowed both efficient control (temperature fluctuations <0.05 degrees C) and accurate measurement of the temperature (+/- 0.1 degrees C) within the capillary cartridge. CE allowed the thermodynamic parameters of beta-lactoglobulin thermal denaturation to be estimated. The transition temperature, Tm, was determined at acidic, neutral and alkaline pH. Van't Hoff analysis was performed through direct measurement of native and unfolded protein populations in the slow-time regime. This allowed estimation of thermodynamic parameters (deltaH, deltaS, deltaCp). Finally, the stability curve, i.e., the temperature dependence of the free energy change (deltaG) of protein unfolding was drawn. The accuracy of the parameters values compares with parameters obtained by calorimetric measurements. The available parameters and the requirement of minute amount of protein sample are of potential interest in the field of protein engineering and biological pharmaceuticals. Accordingly, CE can be proposed as a convenient tool to study protein stability and denaturation processes.

Animals↗

Achieving optimal diabetic control in adolescence: the continuing enigma.

The transition from childhood through adolescence to adulthood is a difficult stage, particularly for patients with type 1 diabetes. The yearning for autonomy and independence, as well as the hormonal changes around the time of puberty, can manifest in poor glycaemic control. The focus on diet and weight increases the prevalence of eating disorders, compounding the difficulties in supervising diabetes patients. This can be exacerbated by the realisation that hyperglycaemia induces weight loss and the use of this knowledge to further manipulate diabetes control to gain a desired body image. The management of adolescents with type 1 diabetes is therefore challenging and requires close collaboration between psychological medicine and diabetes teams. This review describes the difficulties frequently encountered, with a description of four cases illustrating these points. Case 1 demonstrates the problem of needle phobia in a newly diagnosed patient with type 1 diabetes leading to persistent hyperglycaemia, the recognition of weight loss associated with this and the development of bulimia. The patient's overall management was further complicated by risk-taking behaviour. By the age of 24 years, she has developed diabetic retinopathy and autonomic neuropathy and continues to partake in risk-taking behaviour. Case 2 illustrates how the lack of parental support shortly after the development of type 1 diabetes led to poor glycaemic control and how teenagers often omit insulin to accommodate lifestyle and risk-taking behaviour. Case 3 further exemplifies the difficulty in managing patients with needle phobia and the fear of hypoglycaemia. Case 4 adds further weight to the need for parental support and the impact of deleterious life events on glycaemic control by manipulation of insulin dosage.

Adolescent↗