[Combined simulation training: a new concept and workshop is useful for crisis management in gastrointestinal endoscopy]. / Kombiniertes Simulationstraining: Ein neues Kurskonzept trainiert und verbessert das Krisenmanagement der gastroenterologischen Endoskopie.

INTRODUCTION: Crisis management as well as realistic emergency situations can be trained in the new developed simulation workshop "Gastrointestinal Endoscopy and Crisis Resource Management" by combining a full-scale simulator and the Erlanger Endoscopy Trainer. The aim of the current study was to evaluate the efficiency of the newly developed simulation workshop. METHODS: Endoscopists with more than 12 months experience can train their endoscopic skills and crisis resource management with the help of different simulators. In addition, two different scenarios (GI bleeding with significant blood loss and sedation overdoses) embedded in a realistic surrounding (emergency room) have to be managed by the participants. Vital parameters, endoscopic skills, as well as personal interactions were recorded and graded. RESULTS: 100 participants took part in the newly developed workshop (between June and December 2003). The participants showed a significantly better endoscopic performance and a significantly better crisis management after the standardized training program. CONCLUSIONS: Simulation training plays an essential role in aviation and minimizes the risk for human errors. In the current study it is clearly shown that simulation training is also useful in gastrointestinal endoscopy. The newly developed workshop may thus be of crucial importance to improve personal crisis management. Simulation also leads to an improvement of endoscopic and emergency skills. Accordingly, simulation training should be recommended or offered as an education option in gastrointestinal endoscopy.

Coarse-grained entropy and information dimension of dynamical systems: The driven Lorentz gas.

We study the resolution dependence of the steady-state saturation values of coarse-grained entropies characterizing general dynamical systems. For dissipative maps they are proportional to the information codimension of the chaotic attractor. Thus, they provide a highly accurate method for determining the information dimension and related characteristics of the dynamical system. This general result is demonstrated for the field-driven Lorentz gas. In the discussion, we take the results on the resolution dependence of the entropy as the starting point to revisit different approaches to define thermodynamic entropy production for transport processes in dynamical systems, and discuss the role of local equilibrium in this enterprise.

Functional expression and analysis of a human HLA-DQ restricted, nickel-reactive T cell receptor in mouse hybridoma cells.

Nickel-induced contact dermatitis represents a T cell mediated delayed type hyperreactivity. The elucidation of the molecular basis of T cell activation by Ni2+ ions may serve as a model for the understanding of other metal allergies. We describe here the expression of hybrid T cell antigen receptor (TCR) alpha- and beta-genes, containing rearranged human Ni-reactive variable and mouse constant regions, together with human CD4 in a mouse T cell hybridoma. The resulting hybridoma specifically responds to IL-2 secretion to Ni, but not to other metal ions in the presence of HLA-matched antigen-presenting cells. Loss of CD4 decreases, but does not completely abrogate this reactivity. The restricting HLA-DQ element is identified as consisting of DQA1*0101 and DQB1*0501; however, only some of the B cell lines homozygous for these molecules effectively present Ni to the hybridoma. We interpret these data to show that (i) Ni-reactivity is definitely mediated by alpha beta TCR variable regions; (ii) as for peptide-specific TCR, the CD4 co-receptor enhances Ni-reactivity, but is not absolutely essential; (iii) Ni2+ ions like nominal peptide antigens require HLA (here class II) molecules of the APC for presentation; (iv) the restricting molecule may require a special conformation or the association with a particular type of peptide or an as yet unidentified other surface structure on the antigen-presenting cell for effective Ni-presentation.

TCR reactivity in human nickel allergy indicates contacts with complementarity-determining region 3 but excludes superantigen-like recognition.

Nickel is the most common inducer of contact sensitivity in humans. We previously found that overrepresentation of the TCRBV17 element in Ni-induced CD4+ T cell lines of Ni-allergic patients relates to the severity of the disease. Amino acid sequences of these beta-chains suggested hypothetical contact points for Ni2+ ions in complementarity-determining region (CDR) 1 and CDR3. To specifically address the molecular requirements for Ni recognition by TCR, human TCR alpha- and beta-chains of VB17+ Ni-reactive T cell clones were functionally expressed together with the human CD4 coreceptor in a mouse T cell hybridoma. Loss of CD4 revealed complete CD4 independence for one of the TCR studied. Putative TCR/Ni contact points were tested by pairing of TCR chains from different clones, also with different specificity. TCRBV17 chains with different J regions, but similar CDR3 regions, could be functionally exchanged. Larger differences in the CDR3 region were not tolerated. Specific combinations of alpha- and beta-chains were required, excluding a superantigen-like activation by Ni. Mutation of amino acids in CDR1 of TCRBV17 did not affect Ag recognition, superantigen activation, or HLA restriction. In contrast, mutation of Arg95 or Asp96, conserved in many CDR3B sequences of Ni-specific, VB17+ TCR, abrogated Ni recognition. These results define specific amino acids in the CDR3B region of a VB17+ TCR to be crucial for human nickel recognition. CD4 independence implies a high affinity of such receptor types for the Ni/MHC complex. This may point to a dominant role of T cells bearing such receptors in the pathology of contact dermatitis.

Dominance of the BV17 element in nickel-specific human T cell receptors relates to severity of contact sensitivity.

Hypersensitivity to nickel (Ni) represents the most common manifestation of contact allergy in humans. The role of metal-specific T cells in this disease is well established, but the molecular interactions involved in their activation are poorly understood. We examined the T cell receptor (TCR) repertoire in T cells activated with either NiSO4 or NiSO4-treated human serum albumin from six allergic patients. For the three most hyperreactive donors, we found a strong over-representation of the TCR BV17 element. TCR sequencing for one of these donors revealed an additional skewing for AV1 as well as a selection for an N region encoded argine at position 95 of the BV17 complementarity determining region (CDR)3. Since Arg is not known to participate in Ni complexing, we suppose that this selection is driven by contacts with peptide rather than nickel. However, the CDR1 of BV17 contains a unique combination of amino acids (HDA) that bears similarities to known motifs in Ni-binding proteins or peptides. We therefore propose that the severe hypersensitivity reactions found in BV17 over-expressors may be the result of Ni2+ ions bridging the germ-line-encoded BV17 CDR1 loop to corresponding sites in the major histocompatibility complex/peptide complex and thereby creating a superantigen-like enhancement of weak TCR-peptide contacts.

Characterization of processing requirements and metal cross-reactivities in T cell clones from patients with allergic contact dermatitis to nickel.

Metal ions such as nickel, cobalt, copper and palladium are known to be potent sensitizers in humans, but the antigenic determinants created by these metals as well as the mechanisms of recognition by specific T cell clones are still not elucidated. In this paper, nickel-specific T lymphocyte clones were isolated from four patients exhibiting contact dermatitis to this metal. A panel of 42 independent T cell clones was studied. They were shown to recognize nickel in the context of major histocompatibility complex (MHC) class II molecules and to belong to the CD4 subset. Using fixed autologous Epstein-Barr virus-transformed B cells as antigen-presenting cells (APC), we could distinguish two distinct groups of T cell clones on the basis of processing requirements: 40% of the T cell clones were strictly processing dependent, whereas the remaining 60% could proliferate in response to nickel even in the presence of glutaraldehyde-fixed APC. Furthermore, we present arguments indicating that individual Ni-specific T cell clones cross-react with some transition metals (e.g. Cu or Pd), but not with others (e.g. Co, Cr and Pt), presented by identical MHC class II molecules. These results thus provide an explanation for the multiple metal-reactivities observed in vivo in human patients: they indicate that for Cu and Pd, these co-reactivities in vivo might be due to cross-reactivity at the clonal level. Our findings also suggest that this is not the case for cobalt allergy, which might result from cosensitization of the patient to cobalt in addition to nickel.

Cross-reactive trinitrophenylated peptides as antigens for class II major histocompatibility complex-restricted T cells and inducers of contact sensitivity in mice. Limited T cell receptor repertoire.

The induction of contact sensitivity in mice by hapten reagents such as trinitrochlorobenzene (TNCB) involves the activation of class II major histocompatibility complex (MHC)-restricted, hapten-specific, CD4+ T cells. Reports from different laboratories have indicated that the relevant antigenic epitopes in such reactions might include hapten-conjugated, MHC class II-associated peptides. This study for the first time directly demonstrates that hapten-peptides account for the majority of determinants recognized by trinitrophenyl (TNP)-specific CD4+ T lymphocytes. The sequences of those TNP carrier peptides do not have to be related to mouse proteins. Thus, we show that TNP-modified peptides derived from mouse IgG, pigeon cytochrome c or staphylococcal nuclease known to bind to I-Ab or from lambda repressor with specificity to I-Ad as well as TNP-proteins such as bovine serum albumin, ovalbumin or keyhole limpet hemocyanin all create class II-restricted hapten determinants for a number of TNP-specific T cell clones and hybridomas. All of these cells were induced with cells modified by trinitrobenzene sulfonic acid (TNBS). In addition, we present arguments indicating that individual TNP-specific helper T cells may cross-react with different TNP-peptides bound to identical class II molecules. Chemical treatment of antigen-presenting cells with TNCB or TNBS may thus result in a limited number of particularly repetitive immunodominant hapten epitopes. Immunodominant epitopes were also indicated by an overrepresentation of the TCR elements V beta 2 and V alpha 10 in I-Ab/TNP-specific T cells. Most importantly, however, we demonstrate that TNP attached to lysine 97 in the staphylococcal nuclease peptide 93-105 (i.e. a clearly "non-self" sequence) is able to prime mice for subsequent elicitation of contact sensitivity by TNCB in the absence of foreign protein. We take this to indicate that those TNP-peptide determinants defined by us as immuno-dominant are responsible for the induction of contact sensitivity to haptens.

[Clinical course of paraneoplastic limbic encephalitis]. / Verlaufsbeobachtung bei paraneoplastischer limbischer Enzephalitis.

A 49-year-old woman presented with increasing memory loss without dementia. The EEG showed slow activity over the temporal lobe. MRT revealed temporal areas of increased signal intensity without gadolinium enhancement. The diagnosis of limbic encephalitis was made after detection of a bronchial carcinoma. A MRT control examination after chemotherapy showed resolution of the abnormalities. This observation may indicate that chemotherapy has modified that part of the immunological system responsible for induction of limbic encephalitis.

Toxicity of very high dose nitrosourea administration.

We report a case of inadvertent administration of over twice the usual dose of methyl-CCNU. The patient exhibited an early onset of bone marrow suppression. Profound pancytopenia, including lymphopenia, persisted for over seven weeks, Although early recovery started at about five weeks. Permanent marrow damage was indicated by persistent thrombocytopenia and abnormal megakaryocyte morphology at autopsy, some six months after the single exposure to methyl-CCNU. There was no discernible toxicity to lung, liver, or kidneys. The case suggests that the cummulative bone marrow toxicity seen with nitrosoureas is not dose-schedule sensitive. There is also evidence suggesting that high dose nitrosourea therapy affects a bone marrow target population other than the early stem cell target affected by usual doses of these drugs.