QSAR of ecotoxicological data on the basis of data-driven if-then-rules

A rather small data matrix of seven chemicals and 17 different ecotoxicological end points is examined by methods of Discrete Mathematics. Especially, the lattice theory and its variant, the Formal Concept Analysis may be an attractive tool to analyze Quantitative Structure Activity Relationships, when a numerical functional approach is not at hand. The central item is the so called concept, which is a pair of subsets: A subset of molecules and a subset of properties which correspond to each other. The concepts are partially ordered due to a subset relation. From this subset relation, if–then-rules are derived, which aim to relate the structure of molecules with their ecotoxicological properties. For example, the following chemical rule is found: Cl (2A,2C,2M). That means, all substances considered here having a –Cl as structural code have a medium ecotoxicological effect on Daphnia magna , Orconectes immunisare (Crustacea) and on Photobacterium phosphoreum , at least within the training set.     

The heat shock protein Gp96 binds to human neutrophils and monocytes and stimulates effector functions

The endoplasmic reticulum (ER)-resident heat shock protein Gp96 is involved in protein folding and is released into the extracellular space after necrotic cell death. In this context, Gp96 has immunostimulatory properties: it activates dendritic cells or macrophages and delivers associated peptides into the antigen presentation pathway, resulting in the induction of specific T-cell responses. The inflammatory response after necrotic tissue damage leads to the recruitment of polymorphonuclear neutrophils (PMNs) and monocytes, allowing them to make their first encounter with Gp96. We therefore investigated whether PMNs and monocytes interact with Gp96. We were able to show that PMNs and monocytes specifically bind fluorescein isothiocyanate (FITC)-conjugated Gp96. The binding of Gp96-FITC was competed by lipopolysaccharide (LPS) or fucoidan, a known inhibitor of scavenger receptors. Interestingly, the binding of LPS-FITC was also competed not only by fucoidan, but by Gp96, suggesting that LPS and Gp96 share a common receptor on PMNs. One important effector function of PMNs is the clearance of an inflammatory site by phagocytosis. We therefore assessed the influence of Gp96 on phagocytic activity using fluorochrome-labeled polystyrene beads. We found a marked enhancement of phagocytosis in the presence of Gp96 and concluded that PMNs not only bind Gp96, but are also activated by it. Additionally, Gp96-stimulated PMNs and especially monocytes release large amounts of interleukin-8, a potent neutrophil-attracting chemokine. In conclusion, we demonstrate that Gp96 specifically binds to and activates PMNs and monocytes, extending the function of Gp96 as a danger signal to additional members of the innate immune system.     

Down-regulation of retroviral transgene expression during differentiation of progenitor-derived dendritic cells

OBJECTIVE: Hematopoietic progenitor cells are a promising source for generation of genetically modified dendritic cells. A prerequisite for using these cells in therapeutic approaches is stable vector-mediated transgene expression during and after cell maturation. We investigated the expression of enhanced green fluorescence protein (EGFP) mediated by retroviral vectors in dendritic cells and other hematopoietic cells differentiated in vitro. MATERIAL AND METHODS: CD34(+) cells were efficiently transduced with retroviral vector constructs known to mediate different expression levels due to distinct cis-acting elements. EGFP(+) cells were purified by cell sorting and differentiated to monocytes, granulocytes, dendritic cells, and erythrocytes. Coexpression of EGFP and cell type-specific markers was analyzed by flow cytometry. RESULTS: Transgene expression from various retroviral vectors was silenced exclusively in dendritic cells, but not in other mature myeloid cells. Loss of EGFP was most pronounced in cells initially displaying low expression levels. This was confirmed by using a retroviral vector coding for a variant of EGFP with significantly reduced half-life. In contrast, a majority of dendritic cells showed stable expression when a self-inactivating retroviral construct using an internal cytomegalovirus promotor was used. CONCLUSIONS: We suggest that expression from the retroviral long terminal repeat is silenced during dendritic cell differentiation in vitro. High levels of stable transgene product in progenitor cells may mask a loss of expression. An improvement of retroviral vectors mediating stable transgenic expression is necessary for therapeutic approaches using gene-modified dendritic cells.     

Staphylocidal action of thrombin-induced platelet microbicidal protein is not solely dependent on transmembrane potential.

Thrombin-induced platelet microbicidal protein (tPMP) is a small, cationic, antimicrobial peptide released from rabbit platelets when stimulated with thrombin. We studied the relationship between staphylococcal transmembrane potential (delta psi) and tPMP staphylocidal activity. A genetically related pair of Staphylococcus aureus strains, 6850 and JB1, which differ in delta psi generation (-143 and -97 mV, respectively) were used. Mutant JB-1 was substantially less susceptible to tPMP than the parental strain, 6850. Menadione supplementation, which normalized the delta psi of strain JB-1, did not restore JB-1 tPMP susceptibility. These findings suggest that the staphylocidal activities of tPMP require factors other than or in addition to an intact delta psi.     

Evaluation of invasiveness and efficacy of 2 different keyhole approaches to large basal ganglia hematomas

BACKGROUND: The aim of this study was to evaluate the invasiveness and efficacy of 2 different keyhole approaches to large basal ganglia hematomas (LBGHs). METHODS: The invasiveness and efficacy of the temporal (15 cases) and the frontal (15 cases) microsurgical keyhole approach were retrospectively evaluated in 30 early-operated patients with LBGH, using recorded neuronavigation data. Invasiveness was assessed calculating the angles of brain retraction and the volume of brain exposed to surgery. Reduced invasiveness was related to a fall of these values. Efficacy was evaluated by comparing the volume of microscopically visualized clot and the largest hemorrhage diameter exposed with the 2 different keyhole approaches. Increased efficacy was related to a rise in these parameters. All estimations were correlated to the volume of residual clot detected on postoperative computed tomography scan. RESULTS: The comparison between both approaches revealed a significant reduction of invasiveness (smaller angles of brain retraction [P<.001] and reduced brain exposition [P<.001]), as well as a raised efficacy (increased volume of visualized clot [P<.001] and largest hemorrhage diameter exposed to surgery [P<.001]) for frontally approached LBGH. These patients showed less postoperative residual hematomas (P<.05). Residual clots were correlated to the evaluated brain retraction (P<.001) and volume of brain (P<.001), as well as volume of clot surgically exposed (P<.05). CONCLUSION: We conclude that the frontal approach to LBGH leads to less invasiveness and higher efficacy as evaluated by using neuronavigation data. This approach shows a reduced number of patients with residual postoperative clots.     

Semi-automatic blood lactate assay: experiences from an exercise laboratory

A semi-automatic system based on flow injection analysis (FIA) for the transportation of small sample aliquots has been combined with fluorometric, enzymatic methods for blood lactate determination and has been described earlier. In the present study duplicate blood samples were obtained from exercising subjects to enable a comparison of lactate concentrations between neutralized and non-neutralized samples. Duplicate samples were also obtained to enable FIA lactate values to be compared to those obtained with a manual enzymatic method, and with a colorimetric method. No significant change was observed if the sample was not neutralized, enabling a more rapid sample turnover. The FIA method was reliable, with a coefficient of variation of 4.9% between duplicate blood samples. FIA lactate values were valid when compared to two other manual assays. FIA has been shown to be a rapid (60 samples x h-1) means of accurately determining blood lactate concentrations with 25 microliter blood samples and is of particular relevance to the exercise laboratory.     

Non-word repetition and non-word discrimination in Swedish preschool children

By looking at data on expressive phonology, non-word repetition, non-word discrimination and phonological sensitivity in two groups of Swedish children, the common basis for tasks tapping into different levels of phonological processing is discussed. Two studies were performed, one including children with language impairment (LI) and one including children with normal language development (NL). A discrimination task consisting of non-word pairs differing in one phoneme was developed. In both groups there was a significant correlation between non-word repetition and phoneme identification. In children with LI phoneme identification was significantly correlated with expressive phonology. In children with NL non-word repetition correlated significantly with non-word discrimination, which was linked both to rhyme recognition and phoneme identification. Non-word discrimination might be equally useful as non-word repetition as an early screening tool and would circumvent the confounding factor of an expressive phonological impairment as well as decrease the amount of complicating factors involved in scoring procedures.