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Malignant neoplasms of the liver are among the most frequent cancers worldwide. Given the diversity of options for liver cancer therapy, the choice of treatment depends on various parameters including patient condition, tumor size and location, liver function, and previous interventions. To address this issue, we present the first approach to treatment strategy planning based on holistic processing of patient-individual data, practical knowledge (i.e., case knowledge), and factual knowledge (e.g., clinical guidelines and studies). The contributions of this paper are as follows: (1) a formalized dynamic patient model that incorporates all the heterogeneous data acquired for a specific patient in the whole course of disease treatment; (2) a concept for formalizing factual knowledge; and (3) a technical infrastructure that enables storing, accessing, and processing of heterogeneous data to support clinical decision making. Our patient model, which currently covers 602 patient-individual parameters, was successfully instantiated for 184 patients. It was sufficiently comprehensive to serve as the basis for the formalization of a total of 72 rules extracted from studies on patients with colorectal liver metastases or hepatocellular carcinoma. For a subset of 70 patients with these diagnoses, the system derived an average of $$37 \pm 15$$ 37±15 assertions per patient. The proposed concept paves the way for holistic treatment strategy planning by enabling joint storing and processing of heterogeneous data from various information sources.

Abstract: Background and study aims: Patients with achalasia or malignancies of the head and neck are at increased risk for esophageal squamous cell carcinoma. The discussion of a screening and surveillance program is controversial. The aim of the present study was to determine the diagnostic potential of Lugol chromoendoscopy combined with brush cytology to diagnose esophageal squamous cell carcinoma and high-grade dysplasia. Secondly, the benefit of additional biomarkers was investigated. Patients and methods: A total of 61 patients (21 patients with achalasia and 40 patients with malignancies of the head and neck) were included. Chromoendoscopy with 1.2% Lugol iodine solution with targeted biopsies and brush cytology processed by digital image cytometry (DICM) and fluorescence in situ hybridization (FISH) from unstained lesions (USLs) and stained mucosa were performed. Results: Six of the 61 patients had USLs ≥2 cm. Four patients had high-grade dysplasia (HGD) or carcinoma in situ (CIS). One patient with HGD and one patient with CIS were detected only after Lugol chromoendoscopy. The sensitivity and specificity for detected HGD or CIS in USLs ≥2 cm were 100% and 96.5%. No dysplasia was found in USLs <2 cm. DNA ploidy by DNA cytometry and p53 loss of heterozygosity (LOH) by fluorescence in situ hybridization showed no additional impact on diagnostic accuracy. Conclusions: Lugol chromoendoscopy enhances the detection rate of high-risk lesions with dysplasia or carcinoma in situ in large unstained lesions. Biomarkers such as aneuploidy and p53 LOH from brush cytology were not of additional benefit in this setting.

Abstract Despite its explosive growth over the last decade, the Web remains essentially a tool to allow humans to access information. The next generation of the Web, dubbed the ‘Semantic Web’, will extend the Web’s capability through the increased availability machine-processable information. These machine-processable descriptions of Web information resources are called meta-data and are associated with ontologies, or conceptualisations of the domain of application. Meta-data and associated ontologies then allows more intelligent software systems to be written, automating the analysis and exploitation of Web-based information.

Nitric oxide (NO) is generated copiously by articular chondrocytes activated by interleukin-1β (IL-1β). If NO production is blocked, much of the IL-1β inhibition of proteoglycan synthesis is prevented. We tested the hypothesis that this inhibitory effect of NO on proteoglycan synthesis is secondary to changes in chondrocyte transforming growth factor β (TGFβ). Monolayer, primary cultures of lapine articular chondrocytes and cartilage slices were studied. NO production was determined as nitrite accumulation in the medium. TGFβ bioactivity in chondrocyte- and cartilage-conditioned medium (CM) was measured with the mink lung epithelial cell bioassay. Proteoglycan synthesis was measured as the incorporation of ³⁵S-sodium sulfate into macromolecules separated from unincorporated label by gel filtration on PD-10 columns. IL-1β increased active TGFβ in chondrocyte CM by 12 hours; by 24 hours, significant increases in both active and latent TGFβ were detectable. N^G-monomethyl-L-arginine (L-NMA) potentiated the increase in total TGFβ without affecting the early TGFβ activation. IL-1β stimulated a NO-independent, transient increase in TGFβ3 at 24 hours; however, TGFβ1 was not changed. When NO synthesis was inhibited with L-NMA, IL-1β increased CM concentrations of TGFβ1 from 24–72 hours of culture. L-arginine (10 mM) reversed the inhibitory effect of L-NMA on NO production and blocked the increases in TGFβ1. Anti-TGFβ1 antibody prevented the restoration of proteoglycan synthesis by chondrocytes exposed to IL-1β + L-NMA, confirming that NO inhibition of TGFβ1 in IL-1β–treated chondrocytes effected, in part, the decreased proteoglycan synthesis. Furthermore, the increase in TGFβ and proteoglycan synthesis seen with L-NMA was reversed by the NO donor S-nitroso-N-acetylpenicillamide. Similar results were seen with cartilage slices in organ culture. The autocrine increase in CM TGFβ1 levels following prior exposure to TGFβ1 was also blocked by NO. NO can modulate proteoglycan synthesis indirectly by decreasing the production of TGFβ1 by chondrocytes exposed to IL-1β. It prevents autocrine-stimulated increases in TGFβ1, thus potentially diminishing the anabolic effects of this cytokine in chondrocytes.

This paper proposes a method for decoupling a multi-variable linear system with prescribed degree of stability. The properties of the resulting optimal feedback system and conditions for steady state decoupling by state feedback are discussed. An interactive computer program is then shortly described, which allows to compute the feedback and prefilter gains necessary for decoupling the system. The same interactive computer aided design program is also used for performing time simulations and a sensitivity analysis if required.

Using the Quicksort Algortihm, given by van Emden, an analysis is made how Hoare's method of program verification can be applied to already existing programs. Changes to these programs become necessary to adopt them to the proving method and to the existing axioms. The interdependencies between these changes and the verification method are discussed and conclusions are draw about the applicability of Hoare's Methods for proving already existing programs.

The paper describes the MIKE (Model-based and Incremental Knowledge Engineering) approach for developing knowledge-based systems. MIKE integrates semiformal and formal specification techniques together with prototyping into a coherent framework. All activities in the building process of a knowledge-based system are embedded in a cyclic process model. For the semiformal representation we use a hypermedia-based formalism which serves as a communication basis between expert and knowledge engineer during knowledge acquisition. The semiformal knowledge representation is also the basis for formalization, resulting in a formal and executable model specified in the Knowledge Acquisition and Representation Language (KARL). Since KARL is executable, the model of expertise can be developed and validated by prototyping. A smooth transition from a semiformal to a formal specification and further on to design is achieved because all the description techniques rely on the same conceptual model to describe the functional and nonfunctional aspects of the system. Thus, the system is thoroughly documented at different description levels, each of which focuses on a distinct aspect of the entire development effort. Traceability of requirements is supported by linking the different models to each other.

The aim of this study was to examine the relationship between sarcolemmal Na^+-Ca^2^+ exchangers and sarcoplasmic reticulum (SR) Ca^2^+-ATPase (SERCA2) expression and the developmental differences in cardiac Ca^2^+ handling. Postnatal steady-state mRNA and protein levels were analysed in rat ventricular myocardium by Northern and immunoblot analysis, respectively. This was compared to Na^+ gradient-induced and SR oxalate-supported Ca^2^+ transport in isolated membranes. Na^+-Ca^2^+ exchanger mRNA declined by 75% between day 1 and 30, whereas SR Ca^2^+-ATPase mRNA levels increased by 97% during this period. The Na^+-Ca^2^+ exchanger mRNA/Ca^2^+-ATPase mRNA ratio was found to be inversely related to postnatal age. The changes in mRNA levels were associated with corresponding developmental differences in the Ca^2^+ transport activities of the respective membrane proteins. In crude membranes, the Na^+-dependent Ca^2^+ transport activity (at 75 @mm Ca^2^+) declined gradually (P<0.01; mean+/-s.e.) from 17.7+/-2.4 nmoles Ca^2^+/g wet tissue/2s at day 1-3 (n=5) to a value of 4.2+/-1.1 at day 40 (n=4). Conversely, SR Ca^2^+ uptake increased (P<0.01) 2.6-fold during this period. The inversely related changes in the post-natal expression and function of the Na^+-Ca^2^+ exchanger and SR Ca^2^+-ATPase suggest a coordinated control at the pretranslational level of the cellular Ca^2^+ transport processes mediated by the two membrane proteins.

Summary: Whole-body microvibrations (MV) in three dimensions were measured in 51 volunteers, all medical students, 26 without and 25 with beta-receptor blockade (propranolol), immediately before a practical physiology examination and during the ensuing vacation. Propranolol impeded the increase in MV values in all three axes, significantly those in the z axis (vertical), the differences in MV values between the two measurements being minimal in the beta-receptor blocked group. On the other hand, propranolol enhanced MV in the x axis (anteroposterior) and the y axis (transverse), the y axis difference being significant only in females. Propranolol obviously relieves examination stress: the majority of candidates (52%) felt “quieter≓ in the examination with than in other similar situations without beta-receptor blockade. Propranolol was, however, without effect on the examination results. The rectified impulse in the z axis when related to body weight (Jz) correlates linearly with the calculated cardiac output. Propranolol, however, reduced cardiac output more than Jz, pointing to a Jz component non-sensitive to beta-receptor blockade. The part played by muscle tonus, mainly reflected in the y axis, thus remains unknown. The large and slow oscillations in the x and y axes, observed particularly in beta-receptor blocked females, might be attributed to diminution in standing ability.

Myocardial function, intracellular calcium and levels of calcium cycling proteins were analyzed in failing and nonfailing human myocardium. Myocardial function was evaluated by the isometric force-frequency relation, and intracellular calcium was studied by aequorin light emission. When stimulation frequency was increased above 30 min-1, there was a continuous increase in isometric tension development in the nonfailing myocardium. In contrast, in failing myocardium, frequency potentiation of contractile force was blunted or inverse. As a consequence, at higher rates of stimulation, twitch tension was reduced significantly in failing compared to nonfailing human myocardium. Aequorin measurements indicated that the contractile deficit in the failing myocardium at higher rates of stimulation is associated with decreased free intracellular calcium concentration. Western blot analysis indicated that in the failing myocardium protein levels of SR-Ca2+-ATPase are significantly reduced and protein levels of Na+-Ca2+-exchanger are significantly increased. Levels of phospholamban are slightly reduced in the failing myocardium, and ryanodine receptor and calsequestrin protein levels are unchanged. There was a close positive correlation between the protein levels of SR-Ca2+-ATPase and frequency potentiation of contractile force. From these data, we conclude that in failing compared to nonfailing human myocardium 1) force-frequency relation is blunted or inverse. 2) Frequency-dependence of contractile force is closely correlated with frequency-dependence of intracellular calcium cycling. 3) Protein levels of SR-Ca2+-ATPase may determine frequency-dependence of sarcoplasmic reticulum calcium release. 4) Calcium elimination by an increased number of Na+-Ca2+-exchanger molecules may be a compensatory mechanism to prevent diastolic calcium accumulation in failing myocardium with a reduced number of SR calcium pumps.

The mechanisms underlying enhanced vascular reactivity in pregnancy are not yet defined. In this study we have investigated the potential role of endothelium-derived vasodilator nitric oxide (EDNO). EDNO-mediated dilatory responses in vitrowere markedly increased in aorta of pregnant as compared with nonpregnant rats. This increase in EDNO-releasability was accompanied by a two-fold increase in mRNA of endothelial constitutive nitric oxide synthase (NOS-III). Chronically substituted estrogen, but neither progesterone nor testosterone induced an upregulation of NOS-III mRNA in aorta of gonadectomized rats which amounted to about half that induced in aorta of pregnant rats. Thus, increased EDNO-releasability and increased NOS-III mRNA contribute to enhanced vascular reactivity in pregnancy.

Sex-reversed XX male mice that carry the variant form of the testis-determining Sxr region, Sxr', do not express male-specific H-Y antigen. In a stock of mice segregating for Sxr', we detected an exceptional XX male that proved positive for H-Y antigen. DNA fingerprinting revealed that the banding pattern characteristic of Sxr' had been replaced by the pattern associated with the native testis-determining region of the normal Y chromosome of that stock, presumably by pairing and crossing-over between the two testis-determining regions of the father's Y Sxr' chromosome. Pairing between the two ends of such a chromosome in a loop-like configuration has been observed by electron microscopy. However, an anomalous crossing-over event of this kind would only give rise to the observed result if the native homologue of the Sxr region were situated on the very minute short arm of the Y chromosome. We therefore conclude that the two linked genes Tdy and Hya, controlling testis determination and H-Y antigen expression, respectively, are located on the short arm of the mouse Y chromosome.

The diastolic and systolic dysfunction in the failing heart appear to be related to the altered Ca2+ handling of the cardiac myocyte. Disturbed Ca2+ handling might also affect influx and efflux of other ions, including Na+. In this context, the cardiac sarcolemmal Na+/Ca2+ exchanger represents an important exchange mechanism of Ca2+ versus Na+ transport across the sarcolemma. Expression and function of cardiac Na+/Ca2+ exchanger is highest in newborn rats and declines gradually in postnatal development. In pressure overload-induced hypertrophy, expression of cardiac Na+/Ca2+ exchanger is increased and translated into increased Na+/Ca2+ exchanger activity similar to the early phase of postnatal development in the rat. This suggests a common underlying mechanism in the control of Na+/ Ca2+ exchanger expression in the immature and the hypertrophied myocardium. Similar to experimental-induced hypertrophy, mRNA, protein and activity of Na+/Ca2+ exchanger is increased in the failing human heart suggesting an increase in the number of functional exchanger molecules rather than an enhanced exchange rate by preexisting exchanger molecules. The potential functional implications of an increased cardiac Na+/Ca2+ exchanger activity in human heart failure may be limitation of diastolic intracellular Ca2+ overload. However, this may increase the arrhythmogenic potential of the failing heart, since additional Na+ influx via Na+/Ca2+ exchanger may affect the membrane potential.

To pursue our studies of the effects of adrenalectomy on the adrenergic regulation of phosphorylase a, cAMP, cell calcium, and Ca2+ signaling in rat hepatocytes (Studer, R.K., and Borle, A.B. (1984) Biochim. Biophys. Acta 804, 377-385; Freudenrich, C.C., and Borle, A.B. (1988) J. Biol. Chem. 263, 8604-8610), we have further examined the alpha 1-adrenergic pathway in adrenalectomized and sham-operated male rats. We measured the number and affinity of alpha 1-adrenergic receptors, the cytosolic free Ca2+ concentration [(Ca2+]i) of hepatocytes with aequorin, inositol triphosphate (IP3) accumulation, and Ca2+ influx and efflux across the plasma membrane. We also compared the effects of vasopressin with those obtained with epinephrine. We found that the number of alpha 1-adrenergic receptors was slightly depressed (-23%), but that their affinity was unchanged. However, IP3 accumulation evoked by epinephrine was decreased 50%. This is probably the main cause for the depressed peak rise in [Ca2+]i we previously observed and reported. We also found that the basal resting Ca2+ influx was increased after adrenalectomy. Experiments with the beta-blocker propranolol, which abolished the epinephrine-evoked increase in Ca2+ influx, suggest that this effect may be mediated by cAMP, at least in adrenalectomized animals. The effects of vasopressin on IP3 [Ca2+]i and Ca2+ influx and efflux were also significantly decreased after adrenalectomy, indicating that alpha 1-adrenergic-mediated and other IP3-dependent Ca2+ signaling pathways are depressed after adrenalectomy.

The relative importance of alpha- and beta-adrenergic pathways and of their respective intracellular mediators, calcium and cAMP, in the stimulation of phosphorylase alpha induced by catecholamines was studied in hepatocytes isolated from mature male and female rats. The fractional efflux of 45Ca was used as an index of intracellular calcium activity. Our results show that, in females: 1) the activation of phosphorylase alpha induced by 10(-8) to 10(-5) M epinephrine correlates with a rise in cellular cAMP as well as with an increase in 45Ca fractional efflux, 2) both alpha- and beta-agonists stimulate phosphorylase, 3) neither alpha- nor beta-antagonists effectively block the rise in phosphorylase caused by epinephrine, and 4) propranolol suppresses the rise in cAMP while phenoxybenzamine blocks the rise in calcium efflux. On the other hand, we found that in the male: 1) phosphorylase alpha activity is exclusively correlated with a rise in fractional calcium efflux, 2) epinephrine (10(-8) to 10(-7) M) does not increase cAMP and it causes a greater rise in calcium efflux than in the female at all concentrations, 3) phenylephrine increases calcium efflux and phosphorylase activity without affecting cAMP, 4) phenoxybenzamine totally blocks epinephrine action, and 5) beta-agonists and beta-antagonists are without effects. We conclude that, in females, epinephrine utilizes both alpha- and beta-adrenergic pathways which activate phosphorylase by calcium or cAMP, respectively, while, in adult male rats, epinephrine increases phosphorylase alpha activity by an alpha-mediated, calcium-dependent and cAMP-independent pathway.

The effects of 10(-10) to 10(-7) M glucagon on cAMP, phosphorylase a, cell calcium, and glucose production, and glucagon interactions with epinephrine were studied in isolated hepatocytes from adult male and female rats. At physiological concentrations (10(-10) - 10(-9) M), glucagon activated phosphorylase by increasing cAMP and not by raising the cytosolic free calcium. At supra-physiologic concentrations (and in the male only), glucagon slightly increased the cytosolic free calcium, the fractional efflux of calcium, and, after 2 h, decreased the cell calcium content. Exposure of hepatocytes to the simultaneous administration of 10(-9) M glucagon and 10(-7) M epinephrine resulted in a prolongation of the activation of phosphorylase a and a greater release of glucose from glycogen stores than exposure to either agonist alone. In the male, the effects of low concentrations of the two hormones on phosphorylase a activity were additive. Cytosolic free calcium was increased by 10(-6) M epinephrine from 280 to 500 nM while physiological concentrations of glucagon did not change it. In these intact cells, there was no evidence of an alpha 2-adrenergic inhibition of adenyl cyclase and no indication that cAMP depresses the rise in cell calcium induced by alpha-adrenergic stimuli.

Es wird der Einfluß der Ringstruktur, der Ringgröße und der Anzahl der N-Methylgruppen auf die mikrobiologische Aktivität der Enniatine untersucht. Alle diese Faktoren scheinen für die Aktivität wichtig zu sein.

Activated articular chondrocytes produce large amounts of nitric oxide (NO), and there is increasing evidence that this is involved in the etiopathogenesis of osteoarthritis (OA). Because of its short half-life, the biological effects of endogenously produced NO are likely to occur locally within the cartilage. We have observed that inhibitors of NO synthases relieve the inhibition of matrix synthesis that otherwise occurs in response to IL-1. To avoid the use of inhibitors, we have recently transduced chondrocytes with the iNOS (NOS-2) gene and confirmed the ability of the endogenously produced NO to inhibit matrix synthesis. Despite the high levels of NO made by these cells, there was no evidence of apoptosis or other forms of cell death. NO was also shown to inhibit the production of TGF-β1by cells treated with IL-1, as well as to decrease matrix production in response to IGF-1. The hypothesis that NO inhibits matrix production by interfering with important autocrine and paracrine factors should be entertained.

En Suisse, la thématique des risques psychosociaux est en essor. Trente-quatre pour cent des salariés se disent stressés avec des répercussions sur leur santé. Mise en place en 2009 à l’IST, la consultation travail et souffrance vise à faire émerger les déterminants du processus de déstabilisation, dans une perspective d’élargissement des scénarios de lecture, d’optimisation des soins, d’aide à la décision et restauration de la capacité d’action. Pluridisciplinaire, collaborative, elle permet d’entrevoir la dynamique psychique du collaborateur, en particulier à travers son rapport au travail. L’objectif est de préciser ses besoins et apports.

<$O_ST_ABS>Background<$C_ST_ABS>Cardiac hypertrophy is associated with altered Ca2+ handling and may predispose to the development of LV dysfunction and cardiac failure. At the cellular level, the re-expression of ANF represents a well-established marker of myocyte hypertrophy while the decreased expression of the sarcoplasmatic reticulum (SR) Ca2+-ATPase is thought to play a crucial role in the alterations of Ca2+ handling and LV function. We assessed the dose-dependent effect of chronic ACE inhibition or AT₁ receptor blockade on cardiac function in relation to the cardiac expression of the SR Ca2+-ATPase and ANF. <$O_ST_ABS>Methods and Results<$C_ST_ABS>Renal hypertensive rats (2K-1C) were treated for 12 weeks with three different doses of the ACE inhibitor benazepril, the AT₁-receptor antagonist valsartan (each drug 0.3, 3, and 10 mg/kg per day i.p.) or placebo. LV dimensions, hypertrophy and wall stress were determined in vivo by magnetic resonance imaging and the gene expressions of ANF and SR Ca2+-ATPase were quantified by Northern blot. Low doses of both drugs did not affect blood pressure, hypertrophy, systolic wall stress and the ANF and SR Ca2+-ATPase gene expression. High doses of each drug reduced systolic blood pressure, wall stress, and LV hypertrophy to a similar extent and to values comparable to normotensive, age-matched rats. In addition, high dose treatment reduced LV end-systolic and end-diastolic volume as compared to untreated 2K-1C animals and normalized the mRNA levels of both ANF and SR Ca2+-ATPase (as compared to normotensive animals). <$O_ST_ABS>Conclusions<$C_ST_ABS>We conclude that in this model, high doses of ACE inhibition and AT₁-receptor blockade are necessary to normalize systolic blood pressure, LV hypertrophy and systolic LV wall stress which, in turn, is associated with restoration of a normal cardiac phenotype with respect to SR Ca2+-ATPase and ANF and normalization of cardiac function.