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The effect of metformin on glycemic control, serum lipids and lipoproteins in diet alone and sulfonylurea-treated type 2 diabetic patients with sub-optimal metabolic control.

OBJECTIVE: To see if Metformin Monotherapy affects glycemic control, serum lipid or lipoprotein levels in the treatment of type 2 diabetes who were poorly controlled with diet alone or despite maximal doses of (sulfonylurea) oral glucose lowering agents. DESIGN: A prospective, clinical intervention trial conducted between 1996-1997. SETTING: Two out patient diabetic clinics of Karachi. PATIENTS AND METHODS: A 12-week prospective clinical intervention trial. A total of 30 type 2 diabetic subjects were enrolled, of Whom 21 (12 men and 9 women) completed the study period. Their ages ranged between 35 and 70 years, (mean +/- SD 53.3 +/- 9.31) years, with a mean duration since diagnosis of diabetes was 4.5 +/- 2.3 years, body mass index (mean +/- SD) 26.8 +/- 3.53 kg/m2. They were previously treated with diet alone or had already been taking maximum doses of sulfonylurea monotherapy with suboptimal glycemic control, i.e., raised fasting blood glucose concentrations of 6-15 mmol/L or (108-270 mg/dL) on two occasions, with significant hyperglycemic symptoms. The patients were treated with metformin monotherapy with a follow up of 12 weeks. The initial dosage was 500 mg twice daily, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. By comparing before and after 12 weeks therapy with metformin we assessed the importance of baseline parameters (glycemic control, serum lipid and lipoprotein concentrations, and measures of change in body weight and body mass index). RESULTS: Metformin therapy significantly decreased fasting blood glucose levels in all patients [(mean +/- SD) 227.2 +/- 37.5 to 168.6 +/- 20.5 mg/dl, p < 0.001)]. Serum total cholesterol decreased marginally [(mean +/- SD) 200.3 +/- 18.7 to 181.4 +/- 19.4 mg/dl, p < 0.01)]. Serum total triglycerides concentration also decreased [(mean +/- SD) 195.9 +/- 31.9 to 174.2 +/- 26.6 mg/dl, P < 0.01)]. Low-density lipoproteins declined [(mean +/- SD) 123.5 +/- 16.9 to 105.5 +/- 19.1 mg/dl, P < 0.01)], and very-low density lipoprotein cholesterol also decreased [(mean +/- SD) 39.2 +/- 6.4 to 34.8 +/- to 5.3 mg/dl, P < 0.01)]. Whereas, high-density lipoprotein cholesterol tended to increase [(mean +/- SD) 37.7 +/- 5.1 to 39.5 +/- 4.9 mg/dl, P < 0.01)], while no significant changes occurred in body weight and body mass index. CONCLUSION: Metformin treatment was effective, safe, and generally well tolerated.

Adult↗

Trend detection in control data: optimization and interpretation of Trigg's technique for trend analysis.

A method for trend detection, Trigg's technique [Oper. Res. Q. 15, 271 (1964)], has been investigated for use in monitoring trends in control data produced by multitest continuous-flow analyzers. Simulated trend data were used to optimize the method. Actual control data were analyzed retrospectively to determine the frequency of trends and the accuracy of several parameters obtained from Trigg's method. The prospective use of the technique has successfully uncovered important trends. Criteria for the interpretation of the Trigg's trend data are suggested and an algorithm for the computer implementation of Trigg's calculations is included.

Autoanalysis↗

On optimal velocity during cycling.

This paper focuses on the solution of two problems related to cycling. One is to determine the velocity as a function of distance which minimizes the cyclist's energy expenditure in covering a given distance in a set time. The other is to determine the velocity as a function of the distance which minimizes time for fixed energy expenditure. To solve these problems, an equation of motion for the cyclist riding over arbitrary terrain is written using Newton's second law. This equation is used to evaluate either energy expenditure or time, and the minimization problems are solved using an optimal control formulation in conjunction with the method of Miele [Optimization Techniques with Applications to Aerospace Systems, pp. 69-98 (1962) Academic Press, New York]. Solutions to both optimal control problems are the same. The solutions are illustrated through two examples. In one example where the relative wind velocity is zero, the optimal cruising velocity is constant regardless of terrain. In the second, where the relative wind velocity fluctuates, the optimal cruising velocity varies.

Acceleration↗

Parameters of good control in diabetes mellitus.

Optimal control of diabetes should achieve not only euglycemia and normal levels of glycosylated hemoglobin but also absence of the reversible concomitants of diabetes such as red cell rigidity, hyperlipidemia, increased capillary permeability, enlargement of the kidneys, proteinuria, etc. Unfortunately, in most patients consistent euglycemia cannot be assured even with two daily injections of insulin. However, self-measurement of blood glucose as a guide to insulin taken before each meal and at bedtime can, in selected patients, increase the frequency of normal glucose levels without undue hypoglycemia.

Blood Glucose↗

Formulation and optimization of controlled release mucoadhesive tablets of atenolol using response surface methodology.

The aim of the current study was to design oral controlled release mucoadhesive compressed hydrophilic matrices of atenolol and to optimize the drug release profile and bioadhesion using response surface methodology. Tablets were prepared by direct compression and evaluated for bioadhesive strength and in vitro dissolution parameters. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile and bioadhesive strength. Carbopol 934P and sodium carboxymethylcellulose were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Compressed matrices exhibited non-Fickian drug release kinetics approaching zero-order, as the value of release rate exponent (n) varied between 0.6672 and 0.8646, resulting in regulated and complete release until 24 hours. Both the polymers had significant effect on the bioadhesive strength of the tablets, measured as force of detachment against porcine gastric mucosa (P < .001). Polynomial mathematical models, generated for various response variables using multiple linear regression analysis, were found to be statistically significant (P < .01). Validation of optimization study, performed using 8 confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (+/- SD) as -0.0072 +/- 1.087. Besides unraveling the effect of the 2 factors on the various response variables, the study helped in finding the optimum formulation with excellent bioadhesive strength and controlled release.

Adrenergic beta-Antagonists↗

Modeling, adaptive control, and optimal drug therapy.

Drug therapy, its clearly development, and the advent of pharmacokinetic models are described, from the original work of Teorell, through that of Augsberger and Kruger-Thiemer, to the present. Adaptive control of such models, long known in engineering, began in therapeutics with methods for linear and nonlinear least-squares regression, and has progressed to the Maximum Aposteriori Probability (MAP) Bayesian method. Strategies for optimal monitoring of serum concentrations are described and their clinical results briefly evaluated. Lastly, the new method of Approximate Optimal Closed-Loop (AOCL) control is described, in which the therapeutic regimen is used at the same time to probe (learn about) the patient's model approximately optimally. The new method considers the expected values of planned future serum concentrations (or other responses), in addition to the traditional measurement of past serum concentrations. This should optimize the process of learning about a patient's model while treating him at the same time.

Bayes Theorem↗

Optimal pH control of batch processes for production of curdlan by Agrobacterium species.

We sought an optimal pH profile to maximize curdlan production in a batch fermentation of Agrobacterium species. The optimal pH profile was calculated using a gradient iteration algorithm based on the minimum principle of Pontryagin. The model equations describing cell growth and curdlan production were developed as functions of pH, sucrose concentration, and ammonium concentration, since the specific rates of cell growth and curdlan production were highly influenced by those parameters. The pH profile provided the strategy to shift the culture pH from the optimal growth condition (pH 7.0) to the optimal production one (pH 5.5) at the time of ammonium exhaustion. By applying the optimal pH profile in the batch process, we obtained significant improvement in curdlan production (64 g L-1) compared to that of constant pH operation (36 g L-1).

Journal Article↗

Modeling epithelial cell homeostasis: assessing recovery and control mechanisms.

Critical to epithelial cell viability is prompt and direct recovery, following a perturbation of cellular conditions. Although a number of transporters are known to be activated by changes in cell volume, cell pH, or cell membrane potential, their importance to cellular homeostasis has been difficult to establish. Moreover, the coordination among such regulated transporters to enhance recovery has received no attention in mathematical models of cellular function. In this paper, a previously developed model of proximal tubule (Weinstein, 1992, Am. J. Physiol. 263, F784-F798), has been approximated by its linearization about a reference condition. This yields a system of differential equations and auxiliary linear equations, which estimate cell volume and composition and transcellular fluxes in response to changes in bath conditions or membrane transport coefficients. Using the singular value decomposition, this system is reduced to a linear dynamical system, which is stable and reproduces the full model behavior in a useful neighborhood of the reference. Cost functions on trajectories formulated in the model variables (e.g., time for cell volume recovery) are translated into cost functions for the dynamical system. When the model is extended by the inclusion of linear dependence of membrane transport coefficients on model variables, the impact of each such controller on the recovery cost can be estimated with the solution of a Lyapunov matrix equation. Alternatively, solution of an algebraic Riccati equation provides the ensemble of controllers that constitute optimal state feedback for the dynamical system. When translated back into the physiological variables, the optimal controller contains some expected components, as well as unanticipated controllers of uncertain significance. This approach provides a means of relating cellular homeostasis to optimization of a dynamical system.

Biological Transport↗

Optimal posture control of a musculo-skeletal arm model.

In this paper maximal performance posture control of the human arm is investigated by means of model simulations. Recent experiments (F.C.T. van der Helm, submitted, 2000) have shown that the reflexive feedback during postural control varies with the bandwidth of the applied force disturbances. This paper focusses on the influence of the frequency content of force disturbances on the reflexive feedback gains by means of optimization. The arm is modelled by a nonlinear musculo-skeletal model with two degrees of freedom and six muscles. To facilitate the optimization of the model parameters, the arm model is linearized. A performance criterion is minimized for stochastic force disturbances in a two-step procedure: (1) optimization of static muscle activations using an additional energy criterion to obtain a unique and energy-efficient solution; antid (2) optimization of reflex gains using an additional control effort criterion to obtain a unique solution. The optimization reveals that for the given task and posture, the shoulder muscles have the largest contribution, whereas the bi-articular muscles have a relatively small contribution to the behaviour. The dynamics at the endpoint level are estimated so that a comparison can be made with the experiments. Compared to the experiments, the intrinsic damping of the model is relatively large (about 150%), whereas the intrinsic stiffness is relatively small (about 60%). These differences can be attributed to unmodelled mechanical effects of crossbridges in Hill-type muscle models. The optimized reflex gains show remarkable similarities with the values found in the experiments, implying that humans can adjust their reflexive feedback gains in an optimal way, weighting the performance and energy. The approach in this paper could be useful in the study of various posture tasks, for example in the prediction of the relation between the control parameters of various musculo-skeletal models and different experimental variables.

Arm↗

A model of optimal voluntary muscular control.

In the absence of detailed knowledge of how the CNS controls a muscle through its motor fibers, a reasonable hypothesis is that of optimal control. This hypothesis is studied using a simplified mathematical model of a single muscle, based on A.V. Hill's equations, with series elastic element omitted, and with the motor signal represented by a single input variable. Two cost functions were used. The first was total energy expended by the muscle (work plus heat). If the load is a constant force, with no inertia, Hill's optimal velocity of shortening results. If the load includes a mass, analysis by optimal control theory shows that the motor signal to the muscle consists of three phases: (1) maximal stimulation to accelerate the mass to the optimal velocity as quickly as possible, (2) an intermediate level of stimulation to hold the velocity at its optimal value, once reached, and (3) zero stimulation, to permit the mass to slow down, as quickly as possible, to zero velocity at the specified distance shortened. If the latter distance is too small, or the mass too large, the optimal velocity is not reached, and phase (2) is absent. For lengthening, there is no optimal velocity; there are only two phases, zero stimulation followed by maximal stimulation. The second cost function was total time. The optimal control for shortening consists of only phases (1) and (3) above, and is identical to the minimal energy control whenever phase (2) is absent from the latter. Generalization of this model to include viscous loads and a series elastic element are discussed.

Biophysical Phenomena↗

Bridging process-based and empirical approaches to modeling tree growth.

The gulf between process-based and empirical approaches to modeling tree growth may be bridged, in part, by the use of a common model. To this end, we have formulated a process-based model of tree growth that can be fitted and applied in an empirical mode. The growth model is grounded in pipe model theory and an optimal control model of crown development. Together, the pipe model and the optimal control model provide a framework for expressing the components of tree biomass in terms of three standard inventory variables: tree height, crown height and stem cross-sectional area. Growth rates of the inventory variables and the components of biomass are formulated from a carbon balance. Fundamentally, the parameters of the model comprise physiological rates and morphological ratios. In principle, the values of these parameters may be estimated by lower-level process models. Alternatively, the physiological and morphological parameters combine, under reasonable assumptions, into a set of aggregate parameters, whose values can be estimated from inventory data with a statistical fitting procedure.

Biomass↗

How we will go to Mars.

This article studies the efficiency of ejecting waste generated by the life support system (LSS) of a manned spacecraft to reduce initial mass on low earth orbit. The spacecraft is used for a long-duration interplanetary mission and is equipped with either a chemical or a nuclear-thermal propulsion system. For this study we simulate an optimal control problem for a given spacecraft maneuver. An impulsive approximation of the optimal interplanetary spacecraft trajectory is assumed, which allows us to reduce the general optimal control problem to hierarchic structure of 'outer' and 'inner' subproblems. This structure is analyzed using the Pontryagin's Maximum principle. Numerical results, illustrating the efficiency of waste ejection are shown for typical Earth-Mars transfer trajectories. This results confirm in theory that using a waste ejection system makes an early manned Mars mission possible without having to design and build new, advanced biological LSS.

Ecological Systems, Closed↗

A technique for sequential segmental neuromuscular stimulation with closed loop feedback control.

In dynamic myoplasty, dysfunctional muscle is assisted or replaced with skeletal muscle from a donor site. Electrical stimulation is commonly used to train and animate the skeletal muscle to perform its new task. Due to simultaneous tetanic contractions of the entire myoplasty, muscles are deprived of perfusion and fatigue rapidly, causing long-term problems such as excessive scarring and muscle ischemia. Sequential stimulation contracts part of the muscle while other parts rest, thus significantly improving blood perfusion. However, the muscle still fatigues. In this article, we report a test of the feasibility of using closed-loop control to economize the contractions of the sequentially stimulated myoplasty. A simple stimulation algorithm was developed and tested on a sequentially stimulated neo-sphincter designed from a canine gracilis muscle. Pressure generated in the lumen of the myoplasty neo-sphincter was used as feedback to regulate the stimulation signal via three control parameters, thereby optimizing the performance of the myoplasty. Additionally, we investigated and compared the efficiency of amplitude and frequency modulation techniques. Closed-loop feedback enabled us to maintain target pressures within 10% deviation using amplitude modulation and optimized control parameters (correction frequency = 4 Hz, correction threshold = 4%, and transition time = 0.3 s). The large-scale stimulation/feedback setup was unfit for chronic experimentation, but can be used as a blueprint for a small-scale version to unveil the theoretical benefits of closed-loop control in chronic experimentation.

Algorithms↗

Feature-based, automated segmentation of cerebral infarct patterns using T2- and diffusion-weighted imaging.

Diffusion-weighted imaging enables the diagnosis of cerebral ischemias very early, thus supporting therapies such as thrombolysis. However, morphology and tissue-characterizing parameters (e.g. relaxation times or water diffusion) may vary strongly in ischemic regions, indicating different underlying pathologic processes. As the determination of the parameters by a supervised segmentation is very time consuming, we evaluated whether different infarct patterns may be segmented by an automated, multidimensional feature-based method using a unified segmentation procedure. Ischemias were classified into 5 characteristic patterns. For each class, a 3D histogram based on T(2)- and diffusion-weighted images as well as calculated apparent diffusion coefficients (ADC) was generated from a representative data set. Healthy and pathologic tissue classes were segmented in the histogram as separate, local density maxima with freely shaped borders. Segmentation control parameters were optimized in a 3-step procedure. The method was evaluated using synthetic images as well as results of a supervised segmentation. For the analysis of cerebral ischemias, the optimal control parameter set led to sensitivities and specificities between 1.0 and 0.9.

Algorithms↗

Prediction of quality of life after coronary artery bypass graft surgery: a review and evaluation of multiple, recent studies.

OBJECTIVE: To review studies predicting psychosocial outcome after coronary artery bypass graft surgery (CABG). METHODS: Seventeen prospective studies, appearing in the MEDLINE and PsycLIT data bases between 1986 and 1996, were reviewed regarding objectives, methodological issues, results, and clinical relevance. RESULTS: All studies reported that psychological factors bad predictive value. In particular, preoperative anxiety and depression predicted postoperative psychological maladjustment; social support, preoperative feelings of control, denial, and optimism contributed to psychological adjustment. CONCLUSIONS: Many specific psychological outcomes seem to be best predicted by preoperative assessment of functions in that specific area, especially in the case of anxiety and depression. Furthermore, personality factors including denial, optimism, control, and the need for support appear to be predictors of psychological outcome. Appropriate identification of predictive factors might improve the development of individually tailored interventions for patients at risk of postoperative psychological problems.

Adult↗

Visually guided hand movements in children with minor neurological dysfunction: response time and movement organization.

Many children with signs of minor neurological dysfunction (MND) are unable to adapt precisely their movements to external goals, in particular when they are under time pressure. Pilot studies in our laboratories suggested that response times in various sorts of tapping tasks were longer in such children than in controls with an optimal neurological status. In the present study an experimental tapping task, presented in 'self-paced mode', is applied to explore further the relationships between response time and spatio-temporal organization of movements in children with MND as compared to optimal controls. Differences were found with respect to inter-response intervals as well as to the organization of the movements; children with MND have longer overall response times than controls, more movement elements per tap and shorter first movement elements. Further, the moment of maximal acceleration comes later in the children with MND than in the controls. Such differences in response time and movement organization may be due to information processing limitations and increased attentional demands for the execution of movements in MND children.

Attention↗

Clinicoepidemiological and biochemical profile of malnutrition-modulated diabetes mellitus.

Malnitrition-modulated diabetes mellitus ((MMDM) was previously known as protein-deficient diabetes mellitus (PDDM). Its clinical picture is similar to that of type 1 diabetes, but it develops over a background of chronic malnutrition from childhood. In spite of severe hyperglycemia, ketonuria never occurs. MMDM patients are extremely lean and require high doses of insulin-over 2.0 U/kg/day for good glycemic control. Even when optimally controlled, these patients maintain their leanness. Infections of the skin and soft tissues and pulmonary tuberculosis are often seen, whereas micro- and macrovascular complications are rare, even after long-term follow-up. Ultrasonographic evaluation of the abdomen clearly differentiates MMDM from fibrocalculous pancreatic diabetes. Absence of ketonuria and ketosis despite very severe hyperglycemia in emaciated young subjects is the most significant marker of MMDM.

Adolescent↗

[Quality control and optimization of therapeutic activity with the use of thermoanalytic methods].

Thermogravimetry, differential scanning calorimetry, thermomicroscopy, transparency measure permit drug quality control: knowledge of solvated or unsolvated mole, thermal stability, identification of crystalline form (polymorphism) quick determination of total impurity with graphs. These methods can be used for therapeutic activity optimization of very weakly soluble drugs: research of the polymorph showing the best kinetic dissolution, establishment of phase diagram drug/inert substance by example for determination invariant composition particularly eutectic for which the drug solubility is increased.

Calorimetry, Differential Scanning↗