Modelling of the disulphide-swapped isomer of human insulin-like growth factor-1: implications for receptor binding

Insulin-like growth factor-1 (IGF-1) is a serum protein whichunexpectedly folds to yield two stable tertiary structures withdifferent disulphide connectivities; native IGF-1 [18–61,6–48,47–52]and IGF-1 swap [18–61,6–47, 48–52]. Here we demonstratein detail the biological properties of recombinant human nativeIGF-1 and IGF-1 swap secreted from Saccharomyces cerevisiae.IGF-1 swap had a ~30 fold loss in affinity for the IGF-1 receptoroverexpressed on BHK cells compared with native IGF-1.The parallelincrease in dose required to induce negative cooperativity togetherwith the parallel loss in mitogenicity in NIH 3T3 cells impliesthat disruption of the IGF-1 receptor binding interaction ratherthan restriction of a post-binding conformational change isresponsible for the reduction in biological activity of IGF-1swap. Interestingly, the affinity of IGF-1 swap for the insulinreceptor was ~200 fold lower than that of native IGF-1 indicatingthat the binding surface complementary to the insulin receptor(or the ability to attain it) is disturbed to a greater extentthan that to the IGF-1 receptor. A 1.0 ns high-temperature moleculardynamics study of the local energy landscape of IGF-1 swap resultedin uncoiling of the first A-region -helix and a rearrangementin the relative orientation of the A- and B-regions. The modelof IGF-1 swap is structurally homologous to the NMR structureof insulin swap and CD spectra consistent with the model arepresented. However, in the model of IGF-1 swap the C-regionhas filled the space where the first A-region -helix has uncoiledand this may be hindering interaction of Val44 with the secondinsulin receptor binding pocket.     

Integrated MRI assessment of regional function and perfusion in canine myocardial infarction

A single integrated examination using regional measurements of perfusion from contrast-enhanced MRI and three-dimensional (3D) strain from tissue-tagged MRI was developed to differentiate infarcted myocardium from adjacent tissue with functional abnormalities. Ten dogs were studied at baseline and 10 days after a 2-hour occlusion of the left anterior descending coronary artery (LAD). Strain was determined using a 3D finite element model. Two-dimensional measurements of hypoenhancing regions were highly correlated with myocardial viability (r = 0.96). Signal intensity versus time curves obtained from contrast-enhanced MRI were used for quantitative perfusion analysis. The remote and adjacent noninfarcted tissue of the dogs with LAD occlusion, as well as the infarcted tissue, exhibited abnormal deformation patterns as compared to normal dogs (positive predictive value (PPV) of strain determination of infarction = 66%). Integration of contrast-enhanced MRI results with 3D strain analysis enabled the delineation of the myocardial infarction (PPV = 100%) from functionally compromised myocardium. This integrated cardiac examination shows promise for noninvasive serial assessment of potentially jeopardized noninfarcted myocardium to study the process of infarct remodeling and expansion.     

Failure to find homology in rat, cat, and monkey for functions of a subcortical structure in avoidance conditioning.

Notes that electrolytic lesions of the centrum-medianum and parafascicularis complex of the thalamus produce, in the rat, large deficits of both acquisition and retention of active-avoidance responses, especially in the 2-way shuttle-box test. The effect of such lesions on 26 male cats and 6 male and 2 female macaques was examined. It was found that lesions in the cat did not produce significant effects, either with acoustical or visual CS, during postoperative relearning. Moreover, rate of extinction was not affected. Negative results were also found in monkeys. These lesions did not modify the threshold of flinch or jump responses to electric shock in either species. (20 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deriving tabular event-based specifications from goal-oriented requirements models

Goal-oriented methods are increasingly popular for elaborating software requirements. They offer systematic support for incrementally building intentional, structural and operational models of the software and its environment. They also provide various techniques for early analysis, notably, to manage conflicting goals or to anticipate abnormal environment behaviours that prevent goals from being achieved. On the other hand, tabular event-based methods are well-established for specifying operational requirements for control software. They provide sophisticated techniques and tools for late analysis of software behaviour models through simulation, model checking or table exhaustiveness checks. The paper proposes to take the best out of these two worlds to engineer requirements for control software. It presents a technique for deriving event-based specifications, written in the SCR tabular language, from operational specifications built according to the KAOS goal-oriented method. The technique consists of a series of transformation steps each of which resolves semantic, structural or syntactic differences between the KAOS source language and the SCR target language. Some of these steps need human intervention and illustrate the kind of semantic subtleties that need to be taken into account when integrating multiple formalisms. As a result of our technique SCR specifiers may use upstream goal-based processes à la KAOS for the incremental elaboration, early analysis, organization and documentation of their tables, while KAOS modelers may use downstream tables à la SCR for later analysis of the behaviour models derived from goal specifications.     

Faecal contamination of greywater and associated microbial risks

The faecal contamination of greywater in a local treatment system at Viby?sen, north of Stockholm, Sweden was quantified using faecal indicator bacteria and chemical biomarkers. Bacterial indicator densities overestimated the faecal load by 100-1000-fold when compared to chemical biomarkers. Based on measured levels of coprostanol, the faecal load was estimated to be 0.04 g person(-1) day(-1). Prevalence of pathogens in the population and the faecal load were used to form the basis of a screening-level quantitative microbial risk assessment (QMRA) that was undertaken for rotavirus, Salmonella typhimurium, Campylobacter jejuni, Giardia lamblia and Cryptosporidium parvum. The different exposure scenarios simulated--direct contact, irrigation of sport fields and groundwater recharge--gave unacceptably high rotavirus risks (0.04 < Pinf < 0.60) despite a low faecal load. The poor reduction of somatic coliphages, which were used as a virus model, in the treatment was one main reason and additional treatment of the greywater is suggested. Somatic coliphages can under extreme circumstances replicate in the wastewater treatment system and thereby underestimate the virus reduction. An alternative QMRA method based on faecal enterococci densities estimated similar risks as for rotavirus. Growth conditions for Salmonella in greywater sediments were also investigated and risk modelling based on replication in the system increased the probability of infection from Salmonella 1000-fold, but it was still lower than the risk of a rotavirus infection.     

Rate of evolution of the specific surface area of surface snow layers

The snowpack can impact atmospheric chemistry by exchanging adsorbed or dissolved gases with the atmosphere. Modeling this impact requires the knowledge of the specific surface area (SSA) of snow and its variations with time. We have therefore measured the evolution of the SSA of eight recent surface snow layers in the Arctic and the French Alps, using CH4 adsorption at liquid nitrogen temperature (77 K). The SSA of fresh snow layers was found to decrease with time, from initial values in the range 613-1540 cm2/g to values as low as 257 cm2/g after 6 days. This is explained by snow metamorphism, which causes modifications in crystal shapes, here essentially crystal rounding and the disappearance of microstructures. A parametrization of the rate of SSA decrease is proposed. We fit the SSA decrease to an exponential law and find that the time constant alpha(exp) (day(-1)) depends on temperature according to alpha(exp) = 76.6 exp (-1708/7), with Tin kelvin. Our parametrization predicts that the SSA of a snow layer evolving at -40 degrees C will decrease by a factor of 2 after 14 days, while a similar decrease at -1 degrees C will only require 5 days. Wind was found to increase the rate of SSA decrease, but insufficient data did not allow a parametrization of this effect.     

A data model for managing drug therapy within a patient data management system for intensive care units

The major intent of this article was to describe the design principles of the drug-therapy documentation module of the Patient Data Management System (PDMS) ICUData, in routine use at the intensive care unit (ICU) of the Department of Anesthesiology and Intensive Care Medicine at the University Hospital of Giessen, Germany, since February 1999. The new drug management system has been in routine use since March 2000. Until 8 January 2001, 1140 patients have been documented using this approach. It could be demonstrated that it was possible to transform the formerly unstructured text-based documentation into a detailed and structured model. The mediated benefit resulted in the automatic calculation of fluid balance. Further, detailed statistical analyses of therapeutic behavior in drug administration are now possible.     

Strategic technology planning in hospital management

Abstract. Hospital managers regularly are confronted with their patients' demand for increased service performance on the one hand and tight budgets on the other. As medical technologies influence both the costs and the service spectrum, strategic technology planning is among the critical tasks in hospital management. This paper addresses the corresponding problem of selecting the “best” portfolio of medical devices and proposes an appropriate decision support system. It starts with a multiobjective mathematical programming model that determines the solution space of all efficient portfolios of medical technology investments. The members of the planning committee with their diverging interests then are supported by their interactive exploration of that space until they jointly reach a satisfying portfolio and are not willing to make any further compromises between its objective levels. As one of its salient features the system does not require a priori preference information. RID="*" ID="*" A previous version of this paper has been presented at the Wiesbaden 2000 Meeting of the GOR-Working Group “Operations Research in Health Care”. The authors thank Andrea Lührs and Thomas Rollins, both from Siemens AG, for their valuable support. Moreover, thanks are due to the anonymous referees for their comments on a previous version of this paper. Correspondence to: C. Stummer