Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood

The purpose of this study was to investigate the mechanisms of action of pituitary adenylate cyclase-activating polypeptide (PACAP) in stimulating aldosterone production in two different models: bovine adrenal zona glomerulosa (ZG) cells in primary culture and the human adrenocortical carcinoma cell line H295R. PACAP binds to two major groups of receptors: type I, which prefers PACAP38 and PACAP27 over vasoactive intestinal peptide (VIP); and type II, which has approximately equal affinity for PACAP38, PACAP27, and VIP. The type I subclass comprises multiple splice variants that can be distinguished by their specificity to PACAP38 and PACAP27 in their activation of adenylate cyclase and phospholipase C. Type II PACAP/ VIP receptors couple only to AC. In bovine ZG cells, PACAP38 and PACAP27 stimulated aldosterone production in a dose-dependent manner, whereas VIP was ineffective. In H295R cells, PACAP38, PACAP27, and VIP dose-dependently stimulated aldosterone production with roughly the same ED50. In bovine ZG cells, PACAP38 and PACAP27 stimulated cAMP production with similar efficacy, whereas VIP had no effect. In H295R cells, all three peptides stimulated cAMP accumulation. PACAP38 and PACAP27 also activated PLC in bovine ZG cells as they induced an increase in Ins(1,4,5)Ps production. In H295R cells, neither of these peptides was able to stimulate IP turnover. These results indicate that PACAP stimulation of aldosterone production is mediated by the PVR1s or the PVR1hop splice variants of the type I PACAP-specific receptor subtype in bovine ZG cells, whereas only type II PACAP/VIP receptors seemed to occur in the human H295R cell line. In addition, PACAP-stimulated aldosterone production was inhibited by atrial natriuretic peptide in bovine and human adrenocortical cells, however not by the same mechanism. This further supports species-specific and/or cell type-specific signaling pathways for PACAP in the regulation of aldosterone production.     

Implementing the directive for VDU work- the EU-state of the art

In order to improve occupational health and safety conditions in the workplace, several national directives and international standards have been defined. In 1990 the European Union (EU) defined such a directive, i.e. a minimal set of ergonomic requirements that should be met at workplaces equipped with Visual Display Units (VDUs). In order to put the directive to work, existing measurements have been reviewed to evaluate how far they support the implementation of the directive. The instrument that should be used finally for checking VDU-workplaces should not hinder the work flow and the organizational development of a company. The instrument should rather support the effective evaluation of all VDU-workplaces according to the directive. The investigations in this paper focus on the analysis of 18 techniques for measurement stemming from different disciplines. The directive addresses several different perspectives including human cognition, organization of work and technical features. However, an absence of comprehensive measurements has been identified. Most of the existing techniques for measurement focus either on users, user interfaces or on organizational issues. In order to support the development of a comprehensive instrument to check the minimal requirements of the EUdirective EU-CON, a technique for evaluation and re-design of VDU-work has been developed.     

PRT1 of Arabidopsis thaliana encodes a component of the plant N-end rule pathway

Mutants in the PRT1 gene of Arabidopsis thaliana are impaired in the degradation of a normally short-lived intracellular protein that contains a destabilizing N-terminal residue. Proteins bearing such residues are the substrates of an ubiquitin-dependent proteolytic system called the N-end rule pathway. The chromosomal position of PRT1 was determined, and the PRT1 gene was isolated by map-based cloning. The 45-kDa PRT1 protein contains two RING finger domains and one ZZ domain. No other proteins in databases match these characteristics of PRT1. There is, however, a weak similarity to Rad18p of Saccharomyces cerevisiae. The RING finger domains have been found in a number of other proteins that are involved in ubiquitin conjugation, consistent with the proposed role of PRT1 in the plant N-end rule pathway.     

Allogenic transplantation of hematopoietic stem cells in the treatment of children with high-risk acute leukemia

BACKGROUND: Most children with acute lymphoblastic leukemia (ALL) and increasing number of children with acute myelogenous leukemia (AML) are currently cured with conventional chemotherapy. Despite of this success there is a subset of patients with high-risk features at diagnosis who are predisposed to a very high risk of relapse. Relapse of AML and early bone marrow relapse of ALL can not be cured by conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is therapeutic option in these children with very high-risk acute leukemia. METHODS AND RESULTS: Between XI/1989-XII/1996 33 children with acute leukemia (ALL: 22, AML: 11) underwent an allogeneic HSCT from HLA identical related donors (HLA-identical sibling: 30, twin: 1, other HLA-identical relative: 2) at the 2nd Dept. of Pediatrics, University Hospital Motol. Median age of our group was 9 years (1.5-19 y.), boys (n = 23) clearly dominated over the girls (n = 10). The resource of stem cells was bone marrow in 31 children, bone marrow and peripheral blood progenitor cells (PBPC) and PBPC in one child respectively. Myeloablative conditioning regimen varied, consisting of total body irradiation and chemotherapy in 21 children and chemotherapy in 12 children. HSCT was performed in first complete remission of acute leukemia in 9 children (AML: 7, ALL: 2), in second remission in 14 children (AML: 2, ALL: 12), in third remission in 4 children (ALL: 4). Six children underwent HSCT in first partial remission (n = 1) and in second (n = 4) or third (n = 1) chemoresistant relapse. Seven (21%) children died due to post-transplant complications. Nine (28%) children suffered from clinically significant acute graft-versus-host reaction (GVH) and 15% (4/27) children who survived 100 days post-transplant suffered from chronic GVH disease. Relapse of leukemia was diagnosed in 39% (12/31) children. Fourteen (42%) children are alive and well in continuous remission with median follow-up 42 months. CONCLUSIONS: Allogeneic HSCT can cure children with very high-risk acute leukemia in the situations where conventional chemotherapy fails. Relapse of leukemia and GVH reaction are most important causes of post-transplant morbidity and mortality.     

Representation still matters: cognitive engineering and user interface design

With the increased utilization of cognitive models for designing user interfaces several disciplines started to contribute to acquiring and representing knowledge about users, artifacts, and tasks. Although a wealth of studies already exists on modeling mental processes, and although the goals of cognitive engineering have become quite clear over the last decade, essential epistemological and methodological issues in the context of developing user interfaces have remained untouched. However, recent challenging tasks, namely designing information spaces for distributed user communities, have led to a revival of well known problems concerning the representation of knowledge and related issues, such as abstraction, navigation through information spaces, and visualization of abstract knowledge. All of these issues are associated with mental processes and thus, might become part of cognitive models. In this paper we reveal epistemological and methodological assumptions in the field of cognitive modeling as well as their implications for user interface design. It turns out that in order to achieve the goal of developing human-oriented (in contrast to technology-driven) human-computer interfaces developers have to develop knowledge of the structure and the representational dynamics of the cognitive systems which are interacting with the computer. We show that in a first step it is necessary to study and investigate the different levels and forms of representation that are involved in the interaction processes between computers and human cognitive systems. We propose a hybrid user modeling approach as part of the task-based development procedure in TADEUS (Task Analysis/Design/End User Systems). The hybrid approach does not only enable the representation of functional roles end users have to perform, but also how end users perform these roles, i.e. the representation and reflection, if not prediction of their behavior. This way, holistic system development that equally takes into account the organizational requirements and the end user reality at work places is facilitated.     

A Network Flow Solution to a Rectilinear Distance Facility Location Problem

The problem of locating new facilities is considered with respect to existing facilities so as to minimize a sum of costs which consists of costs proportional to the rectilinear distances between new and existing facilities, and costs proportional to the rectilinear distances among new facilities. The location problem decomposes into two independent sub-problems, each of which is equivalent to a linear programming problem which is essentially the dual of a minimal cost network flow problem. Fulkerson's out-of-kilter algorithm provides an efficient means of solving each of the network flow problems as well as the location problem. The dual variables in each of the optimum tableaus to the two flow problems give the x and y coordinates respectively of the optimum locations of the new facilities. Several alternative approaches to solving the equivalent linear programming problems are also discussed, and some research questions are identified.     

CFD-Simulation einer generischen Reaktion in einem gerührten Behälter

Stirred tanks are widely used in chemical engineering, which is why there is a large variety of different designs. Numerical fluid dynamics is therefore often used in stirred tank studies that focus on flow behavior. In this work, a generic reaction in a stirred tank is simulated using computational fluid dynamics and the temperature control of the reactor is investigated. Design-critical aspects are derived from the simulation. In addition, the simulation approach is very well suited for a reaction-specific optimization of a stirred tank.     

Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL,Transformed Follicular Lymphoma,Richter’s Trans-Formed DLBCL and Germinal Center B-Cells

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.