Structure−Activity Relationships of Cinnamate Ester Analogues as Potent Antiprotozoal Agents

Protozoal infections are still a global health problem, threatening the lives of millions of people around the world, mainly in impoverished tropical and sub-tropical regions. Thus, in view of the lack of efficient therapies and increasing resistances against existing drugs, this study describes the antiprotozoal potential of synthetic cinnamate ester analogues and their structure-activity relationships. In general, Leishmania donovani and Trypanosoma brucei were quite susceptible to the compounds in a structure-dependent manner. Detailed analysis revealed a key role of the substitution pattern on the aromatic ring and a marked effect of the side chain on the activity against these two parasites. The high antileishmanial potency and remarkable selectivity of the nitro-aromatic derivatives suggested them as promising candidates for further studies. On the other hand, the high in vitro potency of catechol-type compounds against T. brucei could not be extrapolated to an in vivo mouse model.     

Finite constants: characterizations of a new decidable set of constants

Constant propagation, the replacement of program terms which represent a unique value at run time by their values, is a classical program optimization method. In spite of being treated for years, constant propagation still has been in the unsatisfactory phase of heuristics. We enhance the known constant propagation techniques to obtain an algorithm which is optimal for programs without loops. Fundamental is the introduction of a new decidable set of constants, the finite constants. This set has two different characterizations: a denotational one, which directly specifies our iterative algorithm and an operational one, which delivers the completeness or optimality of this algorithm for programs without loops. The algorithm is implemented in a commercial compiler project.     

Modellqualität als Indikator für Softwarequalität: eine Taxonomie

Zusammenfassung  Komplexit?t, Anforderungsmanagement und Variantenvielfalt sind zentrale Herausforderungen bei der Entwicklung und Evolution heutiger softwaregesteuerter Systeme. Diesen wird zunehmend durch den Einsatz modellbasierter Entwicklungsmethoden begegnet. Dadurch wird das Modell zum zentralen Artefakt und die Erstellung und Nutzung von Modellen zu einer zentralen T?tigkeit in der Softwareentwicklung. Mit der Bedeutung der Modelle steigen auch die Ansprüche an ihre Qualit?t. Dieser Beitrag untersucht die Implikationen, die daraus entstehen, insbesondere werden sinnvolle Qualit?tsmerkmale für softwarebeschreibende Modelle identifiziert und diskutiert.     

What do we learn from binding features? Evidence for multilevel feature integration.

Four experiments were conducted to investigate the relationship between the binding of visual features (as measured by their aftereffects on subsequent binding) and the learning of feature-conjunction probabilities. Both binding and learning effects were obtained, but they did not interact. Interestingly, (shape-color) binding effects disappeared with increasing practice, presumably because of the fact that only 1 of the features involved was relevant to the task. However, this instability was only observed for arbitrary, not highly overlearned combinations of simple geometric features and not for real objects (colored pictures of a banana and strawberry), where binding effects were strong and resistant to practice. These findings suggest that learning has no direct impact on the strength or resistance of bindings or on speed with which features are bound; however, learning does affect the amount of attention particular feature dimensions attract, which again can influence which features are considered in binding. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Unfavorable mechanical effects of heat and moisture exchangers in ventilated patients

OBJECTIVE: To investigate the mechanical effects of artificial noses. SETTING: A general intensive care unit of a university hospital. PATIENTS: 10 patients in pressure support ventilation for acute respiratory failure. INTERVENTIONS: The following three conditions were randomly tested on each patient: the use of a heated humidifier (control condition), the use of a heat and moisture exchanger without filtering function (HME), and the use of a combined heat and moisture exchanger and mechanical filter (HMEF). The pressure support level was automatically adapted by means of a closed-loop control in order to obtain constancy, throughout the study, of patient inspiratory effort as evaluated from airway occlusion pressure at 0.1 s (P0.1). Patient's ventilatory pattern, P0.1, work of breathing, and blood gases were recorded. MEASUREMENTS AND MAIN RESULTS: The artificial noses increased different components of the inspiratory load: inspiratory resistance, ventilation requirements (due to increased dead space ventilation), and dynamic intrinsic positive end-expiratory pressure (PEEP). The additional load imposed by the artificial noses was entirely undertaken by the ventilator, being the closed-loop control of P0.1 effective to maintain constancy of patient inspiratory work by means of adequate increases in pressure support level. CONCLUSIONS: The artificial noses cause unfavorable mechanical effects by increasing inspiratory resistance, ventilation requirements, and dynamic intrinsic PEEP. Clinicians should consider these effects when setting mechanical ventilation and when assessing patients' ability to breathe spontaneously.     

Evidence for disturbed S-adenosylmethionine : S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions?

BACKGROUND: Elevated homocysteine concentrations have been associated with premature arteriosclerosis and with impairment of key methylation reactions through accumulation of the homocysteine metabolite S-adenosylhomocysteine. In end-stage renal failure high homocysteine concentrations are commonly found but thus far the concentrations of related adenosylated metabolites in plasma have not been assessed. METHODS: In this prospective study we determined plasma homocysteine and related metabolites in 25 patients on regular haemodialysis, and in 40 healthy volunteers. Blood samples from patients were drawn immediately before and in 10 patients additionally after the dialysis session. RESULTS: Folic acid and vitamin B12 in plasma were similar in patients (mean +/- SEM 25+/-2 nmol/l and 400+/-41 pmol/l respectively) and controls (24+/-3 and 324+/-23 respectively). In patients plasma homocysteine, S-adenosylmethionine and S-adenosylhomocysteine were markedly elevated (36.6+/-3.6 micromol/l, 381+/-32nmol/l and 1074+/-55 nmol/l respectively) compared to the control values (6.8+/-0.4 micromol/l, 60+/-3 nmol/l and 24.4+/-1.1 nmol/l respectively) whereas the molar ratio of plasma S-adenosylmethionine and S-adenosylhomocysteine was significantly decreased (0.36+/-0.02 and 2.7+/-0.2 in patients and controls respectively). Haemodialysis failed to normalize the abnormal levels of these metabolites. CONCLUSION: Since the ratio of S-adenosylmethionine : S-adenosylhomocysteine is closely linked to the activity of numerous enzymatic methylation reactions, these results suggest that methylation may be impaired in these patients.     

The protease-protected 30 kDa domain of SecA is largely inaccessible to the membrane lipid phase

SecA binds to the inner membrane of Escherichia coli through low affinity lipid interactions or with high affinity at SecYEG, the integral domain of preprotein translocase. Upon addition of preprotein and nucleotide, a 30 kDa domain of SecYEG-bound SecA is protected from proteolysis via membrane insertion. Such protection could result from some combination of insertion into the lipid phase, into a proteinaceous environment or across the membrane. To assess the exposure of SecYEG-bound SecA to membrane lipids, a radiolabeled, photoactivatable and lipid-partitioning crosslinker, 3-trifluoromethyl-3-(m[125I]iodophenyl) diazirine benzoic acid ester, was incorporated into inner membrane vesicles. The 30 kDa domain of SecYEG-bound SecA, inserted into the membrane in response to translocation ligands, is 18-fold less labeled than SecY, which is labeled effectively. In contrast, incorporation of the purified 30 kDa SecA fragment into crosslinker-containing detergent micelles or addition of detergent to crosslinker-containing membranes bearing the protease-protected SecA domain readily allows for labeling of this domain. We propose that the protease-inaccessible 30 kDa SecA domain is shielded from the fatty acyl membrane phase by membrane-spanning SecYEG helices and/or is largely exposed to the periplasm.     

Generation of chromosome fragment specific bovine DNA sequences by microdissection and DOP-PCR

Trends in causative organisms and sources of infection were studied in a series of 288 episodes of bacteremia in neutropenic cancer patients observed in a single institution from 1986 to 1993. The incidence of bacteremia increased significantly from 20 episodes per 1000 admissions in 1986 to 50 episodes per 1000 admissions in 1993 (p = 0.00001). Over the study period, a continuous increment in gram-positive bacteremia, which reached 81% of episodes in 1993 (p = 0.000001), was observed. Conversely, the incidence of gram-negative bacteremia remained stable. Coagulase-negative staphylococci and viridans group streptococci were the most commonly isolated pathogens. Bacteremia caused by coagulase-negative staphylococci increased from 3 episodes per 1000 admissions to 19 episodes per 1000 admissions (p = 0.0001), and viridans group streptococci bacteremia increased from 0 episodes per 1000 admissions to 19 episodes per 1000 admissions (p = 0.000001). The upward trend in gram-positive bacteremia appeared to be related to a significant increase in both intravascular catheters (p = 0.003) and oral mucositis (p = 0.003) as sources of infection. Specific strategies to prevent chemotherapy-induced mucositis and catheter-related bacteremia merit further investigations.     

Zur Frage der Elastizität,der Beanspruchung und der Festigkeit warmbetriebener Rohrleitungen

Zusammenfassung Die Entwicklung der Dampfkraftanlagen zu immer h?heren Temperaturen, Drücken und Leistungen zwingt den Rohrleitungsbauer, sich noch eingehender als bisher mit den Fragen der Elastizit?t, der Beanspruchung und der Festigkeit der Rohrleitung zu besch?ftigen. Zu einigen der wesentlichen Fragen werden im folgenden rechnerische und experimentelle Beitr?ge mitgeteilt. VDI     

Symbolic control of visual attention: The role of working memory and attentional control settings.

This study examined how 1 symbol is selected to control the allocation of attention when several symbols appear in the visual field. In Experiments 1-3, the critical target feature was color, and it was found that uninformative central arrows that matched the color of the target were selected and produced unintentional shifts of attention (i.e., involuntary, initiated slowly, producing long-lasting facilitatory effects). Experiment 4 tested whether such selection is the result of an attentional filter or of a competition bias due to a match of incoming information against integrated object representations stored in working memory. Here, the critical feature was shape and color was irrelevant, but matching color arrows were still selected. Thus, features of objects in working memory will bias the selection of symbols in the visual field, and such selected symbols are capable of producing unintentional shifts of attention. (PsycINFO Database Record (c) 2010 APA, all rights reserved)