Showing papers by "Uppsala University published in 1997"

A spatial scan statistic

Abstract: The scan statistic is commonly used to test if a one dimensional point process is purely random, or if any clusters can be detected. Here it is simultaneously extended in three directions:(i) a spatial scan statistic for the detection of clusters in a multi-dimensional point process is proposed, (ii) the area of the scanning window is allowed to vary, and (iii) the baseline process may be any inhomogeneous Poisson process or Bernoulli process with intensity pro-portional to some known function. The main interest is in detecting clusters not explained by the baseline process. These methods are illustrated on an epidemiological data set, but there are other potential areas of application as well.

UPPAAL in a Nutshell

Abstract: This paper presents the overal structure, the design criteria, and the main features of the tool box Uppaal. It gives a detailed user guide which describes how to use the various tools of Uppaal version 2.02 to construct abstract models of a real-time system, to simulate its dynamical behavior, to specify and verify its safety and bounded liveness properties in terms of its model. In addition, the paper also provides a short review on case-studies where Uppaal is applied, as well as references to its theoretical foundation.

Hyaluronan: its nature, distribution, functions and turnover

Abstract: Hyaluronan is a polysaccharide found in all tissues and body fluids of vertebrates as well as in some bacteria. It is a linear polymer of exceptional molecular weight, especially abundant in loose connective tissue. Hyaluronan is synthesized in the cellular plasma membrane. It exists as a pool associated with the cell surface, another bound to other matrix components, and a largely mobile pool. A number of proteins, the hyaladherins, specifically recognize the hyaluronan structure. Interactions of this kind bind hyaluronan with proteoglycans to stabilize the structure of the matrix, and with cell surfaces to modify cell behaviour. Because of the striking physicochemical properties of hyaluronan solutions, various physiological functions have been assigned to it, including lubrication, water homeostasis, filtering effects and regulation of plasma protein distribution. In animals and man, the half-life of hyaluronan in tissues ranges from less than 1 to several days. It is catabolized by receptor-mediated endocytosis and lysosomal degradation either locally or after transport by lymph to lymph nodes which degrade much of it. The remainder enters the general circulation and is removed from blood, with a half-life of 2-5 min, mainly by the endothelial cells of the liver sinuoids.

Experiential knowledge and cost in the internationalization process

Abstract: In furthering our understanding of the dynamics of the internationalization of firms, process models have played a significant role [Bilkey and Tesar 1977; Cavusgil 1980, 1984; Czinkota 1982; Johanson and Vahlne 1977, 1990; Luostarinen 1980; Reid 1983]. In these models, market-specific experiential knowledge is central in explaining the firm’s internationalization process. A vast amount of research, using the concept of experiential knowledge, on the internationalization process and the choice of mode for entering foreign markets has been accumulated [Barkema, Bell and Pennings 1996; Beamish 1990; Calof and Beamish 1995; Erramilli 1990, 1991; Erramilli and Rao 1990, 1993; Hirsch 1993; Kogut and Singh 1988; O’Grady and Lane 1996; Reid 1984; Root 1987; Sharma and Johanson 1987; Wiedersheim-Paul, Olson and Welch 1978]. Surprisingly, none of the above-mentioned work has explicitly dealt with the cost of the internationalization process. This is surprising since the management of internationalization unavoidably gives rise to the question of cost [Carlson 1974]. An internationalization process entails risk and the investment of resources. Here the issue of the effects of the critical experiential knowledge on the cost of the internationalization process becomes important. Cost aspects have a bearing on the profit generated by firms [Bilkey 1982], on a firm’s inclination to enter foreign markets [Dichtl, Koeglmayr and Mueller 1990], and on the selection or changing of foreign market entry mode [Calof and Beamish 1995].

Li+ Ion Insertion in TiO2 (Anatase). 2. Voltammetry on Nanoporous Films

Abstract: Electrochemical properties of Li+ ion insertion in nanoporous TiO2 (anatase) electrodes were studied by voltammetry. Linear and cyclic potential scans were recorded as a function of electrolyte con ...

Experiential Knowledge and Costs in the Internationalization Process

Abstract: Using a behavioral approach, this study identifies and delineates components of experiential knowledge in the internationalization process. Three hypotheses are developed and tested. They center around the lack of knowledge in the areas of foreign business, foreign institutions and firm internationalization, as well as the effect that this lack of knowledge has on managers' perceived cost in the internationalization process. With the help of a LISREL-based structural model, the three hypotheses are tested on a sample of 362 service firms. The analysis shows that lack of internationalization knowledge has a strong impact on the lack of both business and institutionalization. But there is no direct effect of lack of internationalization knowledge on perceived cost of internationalization.

Specific C-Receptors for Itch in Human Skin

Abstract: In microneurography experiments 56 unmyelinated nerve fibers were studied in the cutaneous branch of the peroneal nerve of healthy volunteers. Units were identified with the “marking” technique as mechanically and heat-responsive (CMH; n = 30), heat-responsive (CH; n = 13), or unresponsive to mechanical and heat stimulation (CM i H i ; n = 13). None of the units showed spontaneous activity. These units were tested for responsiveness to iontophoresis of histamine (1 mA, 20 sec) from a small probe (diameter, 6 mm), which induced itch sensations lasting several minutes. Twenty-three units were unresponsive to histamine, and 25 units responded weakly with a few spike discharges after iontophoresis. Eight units, however, responded with sustained discharges to histamine, and their discharge patterns were matching the time course of the itch sensations. All C-units in this group were mechanically insensitive, and five of them were heat-responsive. They had very low conduction velocities of only 0.5 m/sec, on average, which is significantly lower than conduction velocities of the “polymodal” CMH units. This slow conduction velocities attributable to small axon diameters may be one reason why these units have not been encountered in previous studies. Histamine-sensitive C-units had very large innervation territories extending up to a diameter of 85 mm on the lower leg. We conclude that these C-fibers represent a new class of afferent nerve fibers with particularly thin axons but excessive terminal branching. This type of C-fiber probably represents the afferent units long searched for mediating itch sensations.

Neutralino relic density including coannihilations

Abstract: We evaluate the relic density of the lightest neutralino, the lightest supersymmetric particle, in the minimal supersymmetric extension of the standard model. For the first time, we include all coannihilation processes between neutralinos and charginos for any neutralino mass and composition. We use the most sophisticated routines for integrating the cross sections and the Boltzmann equation. We properly treat (sub)threshold and resonant annihilations. We also include one-loop corrections to neutralino masses. We find that coannihilation processes are important not only for light Higgsino-like neutralinos, as pointed out before, but also for heavy Higgsinos and for mixed and gauginolike neutralinos. Indeed, coannihilations should be included whenever {vert_bar}{mu}{vert_bar}{approx_lt}2{vert_bar}M{sub 1}{vert_bar}, independently of the neutralino composition. When {vert_bar}{mu}{vert_bar}{approximately}{vert_bar}M{sub 1}{vert_bar}, coannihilations can increase or decrease the relic density in and out of the cosmologically interesting region. We find that there is still a window of light Higgsino-like neutralinos that are viable dark matter candidates and that coannihilations shift the cosmological upper bound on the neutralino mass from 3 to 7 TeV. {copyright} {ital 1997} {ital The American Physical Society}

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

Abstract: Purpose A theoretical method has been devised for prediction of drug absorption after oral administration to humans Methods Twenty structurally diverse model drugs, ranging from 03 to 100% absorbed, were investigated The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility Results An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSAd) (r2 = 094) The relationship was stronger than those obtained for more established predictors of drug absorption Drugs that are completely absorbed (FA > 90%) had a PSAd ≤ 60 A2 while drugs that are 140 A2 Conclusions The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process

Chitosans as Absorption Enhancers for Poorly Absorbable Drugs 2: Mechanism of Absorption Enhancement

Abstract: Purpose. It has recently been shown that the absorption enhancing and toxic effects of chitosans are dependent on their chemical composition. In this study, the mechanisms underlying these effects were investigated at the cellular level.

Stable knot-like structures in classical field theory

Abstract: In 1867, Lord Kelvin proposed that atoms—then considered to be elementary particles—could be described as knotted vortex tubes in either1. For almost two decades, this idea motivated an extensive study of the mathematical properties of knots, and the results obtained at that time by Tait2 remain central to mathematical knot theory3,4. But despite the clear relevance of knots to a large number of physical, chemical and biological systems, the physical properties of knot-like structures have not been much investigated. This is largely due to the absence of a theoretical means for generating stable knots in the nonlinear field equations that can be used to describe such systems. Here we show that knot-like structures can emerge as stable, finite-energy solutions in one such class of equations—local, three-dimensional langrangian field-theory models. Our results point to several experimental and theoretical situations where such structures may be relevant, ranging from defects in liquid crystals and vortices in superfluid helium to the structure-forming role of cosmic strings in the early Universe.

A measure of restorative quality in environments

Abstract: Restorative environments help renew psychological resources depleted in environments that do not fully support intended functions The design of restorative environments can be aided and underlying theory elaborated with a means for measuring psychological factors thought to work in restorative experiences This paper reports on four studies carried out to develop such a measure, the Perceived Restorativeness Scale (PRS) Each study employed several strategies for assessing reliability and validity Factor analysis was used to examine the stability of the measure's factor structure across different sites and studies To assess criterion, convergent, and discriminant validities, measures of emotional states and other environmental qualities were also completed for each site The sites selected for evaluation differed on theoretically relevant dimensions (natural‐urban; outdoor‐indoor), enabling checks on the PRS's sensitivity to meaningful differences among environments The results were consistent across

Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.

Abstract: Hypercholesterolaemia plays a crucial role in the development of atherosclerotic diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerotic process to coronary heart disease increases progressively with increasing levels of total serum cholesterol or low density lipoprotein (LDL) cholesterol at both the individual and the population level. The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoAto mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by statins decreases intracellular cholesterol biosynthesis, which then leads to transcriptionally upregulated production of microsomal HMG-CoA reductase and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance. There are no simple methods to investigate the concentration-dependent inhibition of HMG-CoA reductase in human pharmacodynamic studies. The main clinical variable is plasma LDL-cholesterol, which takes 4 to 6 weeks to show a reduction after the start of statin treatment. Consequently, a dose-effect rather than a concentration-effect relationship is more appropriate to use in describing the pharmacodynamics. Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins. The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDLcatabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins. Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised. The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (>90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.

Electron-density map interpretation.

Abstract: Publisher Summary Any errors that occur in a crystallographic project usually will be found before publication. Often, if an error has been made, the project will stall and there will be no publication. Introducing a serious error in a model can be different. This chapter discusses the kinds of error that might be made and why these errors are made. It discusses some of the features of the crystallographic model-building program O. Real errors in models occur with frequencies that are, fortunately, inversely proportional to the seriousness of the error. Building a molecular model from electron density is a complicated process. During the interpretation of an electron-density map, the basic function of the molecular graphics program is to assist the scientist in imagining, and then remembering, the three-dimensional folding and features of the structure. Thus, it is important to be able to change the model quickly and not to be interrupted by the details of operating a computer program. To facilitate the rapid building and rebuilding of molecular models, O incorporates autobuild options, allowing the user to create a molecular structure quickly from a rough three-dimensional sketch. This has the drawback of possibly making it even easier to build a wrong structure.

Towards an explanation of regional specialization and industry agglomeration

Abstract: The main argument advanced in this paper is that proximity matters. Product innovations, new forms of organization or new skills are arrived at in interactive processes within industrial systems. Such systems are embedded in a broader cultural and institutional context. Everything else being equal, interactive collaboration will be less costly and more smooth, the shorter the distance between the participants. The benefits of proximity can be translated into a force of spatial agglomeration in relation to firms engaged in interactive learning. Thus, agglomerations of related economic activity are not just reminiscents of previously cost efficient spatial configurations, but are currently being recreated as a result of an increasing demand for rapid knowledge transfer between firms. In this finding, we argue, lies the foundation for explaining the observed durability in otherwise incomprehensible patterns of specialization and competitiveness between countries and regions.

Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women

Abstract: Purpose. To chemically characterize the fluids available for drug dissolution in the upper gastrointestinal tract during the fasted state in humans, and to examine variations and potential gender differences regarding the physico-chemical properties of these fluids.

Body Size and Prostate Cancer: A 20-Year Follow-up Study Among 135006 Swedish Construction Workers

Abstract: Background: Obesity is associated with endocrine changes (e.g., increased estrogen and decreased testosterone in the blood) that have been implicated in the cause of prostate cancer and, therefore, ...

Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation.

Abstract: The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin. Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the reaction of a tripeptide, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV), and dioxygen to form isopenicillin N and two water molecules. Mechanistic studies suggest the reaction is initiated by ligation of the substrate thiolate to the iron centre, and proceeds through an enzyme-bound monocyclic intermediate. Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 A resolution. Based on the structure, we propose a mechanism for penicillin formation that involves ligation of ACV to the iron centre, creating a vacant iron coordination site into which dioxygen can bind. Subsequently, iron-dioxygen and iron-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues. The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis.

Low-Molecular-Weight Heparin (Fragmin) During Instability in Coronary Artery Disease (FRISC)

Abstract: This study evaluated whether the low-molecular-weight (LMW) heparin dalteparin sodium (Fragmin) had protective effects against cardiac events in aspirin-treated patients with unstable coronary artery syndromes. Patients (n = 1,506) with unstable angina or non-Q-wave myocardial infarction were randomized to double-blind, placebo-controlled treatment with LMW heparin. The treatment was given as subcutaneous injections: 120 U/kg body weight/12 hours during the first 5-7 days and 7,500 U once daily during the following 35-45 days. The primary endpoint, death or myocardial infarction after 6 days, showed a 3% (4.7%-1.7%) absolute and a 65% relative reduction in the LMW heparin group. There was a 6.8% (15.5%-8.7%) absolute and a 47% relative reduction of urgent revascularization or need for heparin or nitroglycerin infusions in combination with the primary endpoint. After 40 days there was an absolute reduction of death or myocardial infarction of 2.8% (10.7%-7.9%) and its combination with incapacitating angina was reduced by 5.9% (30.7%-24.8%). The survival analysis indicated a reactivation of the instability soon after lowering the dose at 5-7 days. With long-term follow-up, 3-4 months after termination of LMW heparin, the differences between groups were no longer statistically significant. However, the cumulative reduction in death, myocardial infarction, and revascularization because of incapacitating angina of 5.1% (25.3%-20.4%) was maintained. No cerebral and few major bleeds occurred. Compliance was adequate. Thus, subcutaneous LMW heparin protects against cardiac events in the acute phase of unstable coronary artery disease. The subcutaneous regimen also allows prolongation of treatment in the outpatient setting, which might maintain the initial benefits over a longer period.

An Open-Ended Finite Domain Constraint Solver

Abstract: We describe the design and implementation of a finite domain constraint solver embedded in a Prolog system using an extended unification mechanism via attributed variables as a generic constraint interface. The solver is essentially a scheduler for indexicals, i.e. reactive functional rules encoding local consistency methods performing incremental constraint solving or entailment checking, and global constraints, i.e. general propagators which may use specialized algorithms to achieve a higher degree of consistency or better time and space complexity.

Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes

Abstract: o-Quinones are physiological oxidation products of catecholamines that contribute to redox cycling, toxicity and apoptosis, i.e. the neurodegenerative processes underlying Parkinson's disease and schizophrenia. The present study shows that the cyclized o-quinones aminochrome, dopachrome, adrenochrome and noradrenochrome, derived from dopamine, dopa, adrenaline and noradrenaline respectively, are efficiently conjugated with glutathione in the presence of human glutathione transferase (GST) M2-2. The oxidation product of adrenaline, adrenochrome, is less active as a substrate for GST M2-2, and more efficiently conjugated by GST M1-1. Evidence for expression of GST M2-2 in substantia nigra of human brain was obtained by identification of the corresponding PCR product in a cDNA library. Glutathione conjugation of these quinones is a detoxication reaction that prevents redox cycling, thus indicating that GSTs have a cytoprotective role involving elimination of reactive chemical species originating from the oxidative metabolism of catecholamines. In particular, GST M2-2 has the capacity to provide protection relevant to the prevention of neurodegenerative diseases.

On the growth rates of human malignant tumors: Implications for medical decision making

Abstract: Testicular carcinomas, pediatric tumors, and some mesenchymal tumors are examples of rapidly proliferating cell populations, for which the tumor volume doubling time (TVDT) can be counted in days. Cancers from the breast, prostate, and colon are frequently slow-growing, displaying a TVDT of months or years. Irrespective of their growth rates, most human tumors have been found: to start from one single cell, to have a long subclinical period, to grow at constant rates for long periods of time, to start to metastasize often even before the primary is detected, and to have metastases that often grow at approximately the same rate as the primary tumor. The recognition of basic facts in tumor cell kinetics is essential in the evaluation of important present-day strategies in oncology. Among the facts emphasized in this review are: (1) Screening programs. Most tumors are several years old when detectable by present-day diagnostic methods. This makes the term "early detection" questionable. (2) Legal trials. The importance of so-called doctor's delay is often discussed, but the prognostic value of "early" detection is overestimated. (3) Analyses of clinical trials. Such analysis may be differentiated depending on the growth rates of the type of tumor studied. Furthermore, uncritical analysis of survival data may be misleading if the TVDT is not taken into consideration. (4) Analyses of epidemiological data. If causes of malignant tumors in humans are searched for, the time of exposure must be extended far back in the subject's history. (5) Risk estimations by insurance companies. For the majority of human cancers, the 5-year survival rate is not a valid measurement for cure. Thus, basic knowledge of tumor kinetics may have important implications for political health programs, legal trials, medical science, and insurance policies.

Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids.

Abstract: Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired beta cell function, peripheral insulin resistance, and increased hepatic glucose production Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production In addition, they may directly inhibit insulin release To evaluate that possible role of glucocorticoids in beta cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their beta cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic beta cell as an important target for the diabetogenic action of glucocorticoids

Search for neutral heavy leptons produced in Z decays

Abstract: Weak isosinglet Neutral Heavy Leptons (m) have been searched for using data collected by the DELPHI detector corresponding to 3:3 106 hadronic Z0 decays at LEP1. Four separate searches have been performed, for short-lived m production giving monojet or acollinear jet topologies, and for long-lived m giving detectable secondary vertices or calorimeter clusters. No indication of the existence of these particles has been found, leading to an upper limit for the branching ratio BR(Z0 ! m) of about 1:310−6 at 95% confidence level for m masses between 3.5 and 50 GeV/c2. Outside this range the limit weakens rapidly with the m mass. The results are also interpreted in terms of limits for the single production of excited neutrinos.