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Background:Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWFgene and show high variability among different populations. Methods:Twenty‐five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWFgene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Results:Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1‐3) of the 5′‐region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730–10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. Conclusion:We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.

Currently, three MAPPER multi-electron beam lithography tools are operational. Two are located at customers, TSMC and LETI, and one is located at MAPPER. The tools at TSMC and LETI are used for process development. These tools each have 110 parallel electron beams and have demonstrated sub-30 nm half pitch resolution in chemically amplified resists. One important step towards the high volume tool is the capability to stitch the exposure of one electron beam to the next. The pre-alpha tool at MAPPER has been upgraded with an interferometer to enable exposures with a scanning stage and demonstrate first beam-to-beam stitching. A scan of 200 micrometers has been used to create a stitch area of 50 x 3 microns. The stitch error over all stitches was found to be below 25 nm. The electron beam position stability during the 10 seconds required for beam-to-beam stitching showed a contribution to the stitch error of 2.3 nm. The beam separation measurement, used to correct the static error, adds about 2.2 nm and the stage stability and linearity adds another 5 nm in the scan (interferometer) direction. In the perpendicular direction the stage instability gives the largest contribution to the stitch error (15 nm) due to the use of capacitive sensors. Overall, the electron beam stability and the beam position correction method work correctly and with sufficient accuracy for the high volume tool, 'Matrix'. The wafer stage for the Matrix system will incorporate full interferometer control to attain the needed positioning accuracy and stability.

Clonal hematopoiesis triggered by somatic mutations plays a central role in the pathogenesis of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs). After the discovery of JAK2 and MPL mutations, continual technological advances have led to the identification of increasing numbers of genetic defects in MPN patients, most of them chromosomal aberrations such as deletions and acquired uniparental disomies. Although efforts to map the genetic lesions to single genes resulted in the discovery of defects in the TET2 and CBL genes, most of the target genes comprised in the chromosomal lesions still remain to be identified. In this review, the different genetic defects found in MPN and their relationships to each other and to disease pathogenesis are critically evaluated. At present, most of the evidence points to a random acquisition of phenotypic and non phenotypic mutations contributing to clonal heterogeneity in MPN. The origin of genetic instability in context of hereditary factors and the common JAK2 haplotype predisposing for the disease are discussed. Furthermore, we address how the choice of therapeutic approaches could be influenced by the genetic complexity.

We derive a new model for the established concept of the molecular free energy surface density (MolFESD) yielding a more rigorous representation of local surface contributions to the overall hydrophobicity of a molecule. The model parametrization makes efficient use of both local and global information about solvation thermodynamics, as formulated earlier for the problem of predicting free energies of hydration. The free energy of transfer is separated into an interaction contribution and a term related to the cavity formation. Interaction and cavity components are obtained from the statistical three-dimensional (3D) free energy density and a linear combination of surface and volume terms, respectively. An appropriate molecular interaction field generated by the program Grid is used as an approximate representation of the interaction part of the 3D free energy density. We further compress the 3D density by means of a linear combination of localized surface functions allowing for the derivation of local hydrophobic contributions in the form of a free energy surface density. For a set of 400 compounds our model yields significant correlation (R² = 0.95, σ = 0.57) between experimental and calculated log P values. The final model is applied to establish a correlation between partial free energies of transfer for a series of sucrose derivatives and their relative sweetness, as studied earlier in the group of the authors. We find considerable improvement regarding the rms error of the regression thus validating the presented approach.

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting>diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokineticpharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily ×5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.

Die elektrochemischen Eigenschaften von 2-Formylpyridin-thiosemicarbazon wurden mit Hilfe der Gleichstrom-, Wechselstrom- und Differentialpuls-Polarographie sowie der cyclischen Voltammetrie an der Hg-Elektrode untersucht. Die neue cytostatische Substanz wird in einer irreversiblen Zweielektronen-Stufe an der Stickstoff-Kohlenstoff-Doppelbindung der Seitenkette reduziert (pH-Bereich 0,212). In neutralen und alkalischem Medium entwickelt sich eine anodische Doppelstufe dicht bei der Oxidationsstufe des Quecksilbers, entsprechend der Bildung einer quecksilberorganischen Verbindung. Diese elektrochemischen Reaktionen werden durch Adsorptionsvorgange verkompliziert. In alkalischem Medium nimmt der Reduktionsstrom der Kohlenstoff-Stickstoff-Doppelbindung mit zunehmendem pH ab, was der Bildung einer elektrochemisch inaktiven Substanz zugeschrieben wird. In neutraler Lösung wird eine katalytische protonische Reduktionsstufe gebildet. Die quantitative Bestimmung war im Bereich von 1·10-7 bis 1·10-3 M möglich, wobei die diffusionskontrollierte Reduktionsstufe bei pH 7 benutzt wurde. Die qualitative Nachweisgrenze liegt bei 2·10-8 M (4 ng/ml).

In this article the role of defuzzification methods in the application of fuzzy controllers is adressed. In most applications described in literature the concepts of the fuzzy controllers used are presented without motivation. The defuzzifier of a fuzzy controller can deteriorate a great deal of the results achieved by the inference of fuzzy rules. Therefor a closer look at the influence of this specific part of the fuzzy controller is worthwile. It appears that the application of a specific defuzzification method can reduce completely the fuzziness of the controller. Otherwise, it is possible to use crisp representations of fuzzy sets and still being able to realize a fuzzy character of the controller. Examples are given which show the (dis)advantages of several defuzzification methods.

In this paper research the DICE toolbox is described. This toolbox has been developed for real-time AI issues. DICE offers progressive reasoning as a way to handle time critical situations. DICE is a multitasking environment developed for a VAX/VMS environment. It offers both boolean and multivalued logic implementations. Some examples concerning the syntax are given.

In this paper research into the application of 'expert system'-like inference mechanisms in the field of fuzzy control is adressed. Using techniques from the area of rule-based expert systems, a more flexible way of design and modification is presented of new and existing fuzzy systems for modelling and control. In comparison with 'normal' applications of fuzzy inference, the 'compositional rule of inference' is replaced by a fuzzy inference engine. General applicability of the fuzzy inference engine is made possible by its general character as a fuzzy expert system shell. Succesful implementations in simulation and realtime control environments show the flexibility and usefullness of the described fuzzy inference engine.

In this paper the concepts and models for intelligent control in real-time are given. The application of intelligent components in a (real-time) control scheme leads to a hierarchical system architecture, applying various AI-related techniques at different levels. The method to be applied depends on the required precizion and quantization and the knowledge available. Such an intelligent control scheme has to be embedded in a real-time environment, requiring specific features which should be apparant in a real-time expert system. Those specific requirements to apply AI related techniques in real-time led to the development of a testbed environment: DICE. This environment offers a blackboard solution using several knowledge sources attached to this blackboard. The knowledge sources operate in real time, using blackboard communication and progressive reasoning. Rule compilation is used for fast inferencing. The knowledge description includes the use of multivalued logic at the rule level. Two examples of real-time knowledge-based control using fuzzy logic are given

This article presents the development of a real-time intelligent control environment: DICE. Main emphasis is given to the requirements of knowledge-based systems to be realized in a real-time system. This results in a multi-task environment with several expert system kernels running in parallel. A blackboard mechanism is used for intertask communication. A kernel of the system uses demons to control other expert system kernels.

A new HPLC method for the determination of Cefoperazone in serum is described.

A sensitive and simple method for the 63Ni determination in plant material is needed to investigate the Ni uptake by plants and legume nodules, respectively. It could be shown that the liquid scintillation counting after a wet oxidation of the dry matter and resolving the residue in diluted HCl is suitable for this purpose. The method developed is demonstrated using two different 63Ni labelled plant materials. The detection limit amounts to 80 Bq. g-1 dry matter assuming a counting time of 10 min and a standard deviation of ±3% (95 confidence level).

We report the discovery of hard X-rays from the region of the supernova SN1987A in the Large Magellanic Cloud. The observations were made from the Mir-Kvant observatory 'Röntgen'. Hard X-rays were first observed on 10 August 1987 and SN1987A then became the main target of the observatory. Up to 15 September 1987, a total of 115 pointings on 21 days were made. The flux showed little variation during the observation period. The measured spectrum extends from 20 keV to 300 keV and is extremely hard, having a photon power law index of ˜1.4. At low energies the spectrum becomes even flatter and there is indication of a cutoff between 10 and 25keV. The luminosity over the energy range 20–300 keV is ˜2x1038erg s–1(assuming a distance of 55 kpc). The error box for the hard source has a (2σ) radius of 10 arc min and contains SN1987A. The results have important implications for current models of SN1987A.

Presents a memoir of life on a farm with a pond. Seasonal changes; Learning to swim.

Discusses replacing the broken handle of an ordinary garden tool. Difficulties; Tips.