Reassessment of glucose effectiveness and insulin sensitivity from minimal model analysis: a theoretical evaluation of the single-compartment glucose distribution assumption

Minimal model analysis with the frequently sampled intravenous glucose tolerance test provides an effective way to measure two important metabolic parameters in vivo under non-steady-state conditions: glucose effectiveness (SG) and insulin sensitivity (SI). Two questions regarding the validity of SG and SI have recently emerged. First, SG from the minimal model is suspected to be overestimated. Second, the occurrence of SI values indistinguishable from zero ("zero-SI") is not negligible in large clinical studies, and its physiological meaning is uncertain. In this study, we examined the significance of the assumed single-compartment glucose distribution embedded in the minimal model on the estimation of SG and SI. A more accurate two-compartment model was constructed by incorporating insulin action on hepatic glucose output and uptake into a previously validated construction. The two-compartment results were compared with the one-compartment minimal model results. It was shown that the one-compartment assumption contributes to a systematic deviation of SG (slope = 0.54, y-intercept = 0.014 min[-1]; n = 195 simulations). However, SG from the minimal model was linearly correlated to SG determined from the two-compartment model (r = 0.996). The one-compartment assumption also contributed to the occurrence of zero SI values for insulin-resistant subjects. A similar linear relationship was found between SI estimated by both the minimal model and the two-compartment model (slope = 0.58, y-intercept = -0.57 x 10[-4] min[-1] per pU/ml, r = 0.998). In conclusion, SG and SI from the minimal model are not necessarily equivalent to values emanating from the more accurate two-compartment model. However, the very high correlation between one- and two-compartment results suggests that the minimal model-derived SG and SI are dependable indexes of in vivo glucose effectiveness and insulin sensitivity. Minimal model analysis' advantages of simplicity, minimal invasiveness, reasonable reflection of non-steady-state glucose kinetics, and cost-effectiveness could in many cases outweigh the structural bias introduced by the model simplification.     

Managing heterogeneous multi-system tasks to support enterprise-wide operations

The computing environment in most medium-sized and large enterprises involves old main-frame based (legacy) applications and systems as well as new workstation-based distributed computing systems. The objective of the METEOR project is to support multi-system workflow applications that automate enterprise operations. This paper deals with the modeling and specification of workflows in such applications. Tasks in our heterogeneous environment can be submitted through different types of interfaces on different processing entities. We first present a computational model for workflows that captures the behavior of both transactional and non-transactional tasks of different types. We then develop two languages for specifying a workflow at different levels of abstraction: the Workflow Specification Language (WFSL) is a declarative rule-based language used to express the application-level interactions between multiple tasks, while the Task Specification Language (TSL) focuses on the issues related to individual tasks. These languages are designed to address the important issues of inter-task dependencies, data formatting, data exchange, error handling, and recovery. The paper also presents an architecture for the workflow management system that supports the model and the languages. Recommended by: Omran Bukhres and e. Kühn     

Changing patterns of localization of the tobacco mosaic virus movement protein and replicase to the endoplasmic reticulum and microtubules during infection

Tobacco mosaic virus (TMV) derivatives that encode movement protein (MP) as a fusion to the green fluorescent protein (MP:GFP) were used in combination with antibody staining to identify host cell components to which MP and replicase accumulate in cells of infected Nicotiana benthamiana leaves and in infected BY-2 protoplasts. MP:GFP and replicase colocalized to the endoplasmic reticulum (ER; especially the cortical ER) and were present in large, irregularly shaped, ER-derived structures that may represent "viral factories." The ER-derived structures required an intact cytoskeleton, and microtubules appeared to redistribute MP:GFP from these sites during late stages of infection. In leaves, MP:GFP accumulated in plasmodesmata, whereas in protoplasts, the MP:GFP was targeted to distinct, punctate sites near the plasma membrane. Treating protoplasts with cytochalasin D and brefeldin A at the time of inoculation prevented the accumulation of MP:GFP at these sites. It is proposed that the punctate sites anchor the cortical ER to plasma membrane and are related to sites at which plasmodesmata form in walled cells. Hairlike structures containing MP:GFP appeared on the surface of some of the infected protoplasts and are reminiscent of similar structures induced by other plant viruses. We present a model that postulates the role of the ER and cytoskeleton in targeting the MP and viral ribonucleoprotein from sites of virus synthesis to the plasmodesmata through which infection is spread.     

Anticonvulsant drug concentrations in epileptic patients

Using Wistar stain male rats, it has been shown that 2 atmospheric pressures associated with oxygen saturation, together or singly for 90 minutes daily for successive 46 days, resulted in no significant change on the ratio of testes to body weight. No significant change was observed in the incorporation of 3H-thymidine into testes and pituitary glands between the pressure-treated groups and the control group.     

LAGRANGEAN RELAXATION AND SUBGRADIENT OPTIMIZATION APPLIED TO OPTIMAL DESIGN WITH DISCRETE SIZING

The discrete sizing problem in optimal design is adressed. Lagrangean dual approaches earlier published are briefly reviewed and it is noted that quite sophisticated procedures have been used to solve the dual problems. The simple concept of Lagrangean relaxation combined with subgradient optimization and Lagrangean heuristics has, however, not been applied to the discrete sizing problem. In this paper a scheme based on this concept is described and tested on some small problems. The results indicate that subgradient optimization is completely capable of solving the dual problem. Moreover it is possible to devise heuristics that construct feasible solutions to the original problem, using the Lagrangean subproblem solution.     

Concerted regulation of low density lipoprotein receptor gene expression by follicle-stimulating hormone and insulin-like growth factor I in porcine granulosa cells: promoter activation, messenger ribonucleic acid stability, and sterol feedback

The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 micrograms/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1 beta and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-alpha levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration. It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.