Small angle X-ray scattering as a high-throughput method to classify antimicrobial modes of action.

Multi-drug resistant bacteria are currently undermining our health care system worldwide. While novel antimicrobial drugs, such as antimicrobial peptides, are urgently needed, identification of new modes of action is money and time consuming, and in addition current approaches are not available in a high throughput manner. Here we explore how small angle X-ray scattering (SAXS) as high throughput method can contribute to classify the mode of action for novel antimicrobials and therefore supports fast decision making in drug development. Using data bases for natural occurring antimicrobial peptides or predicting novel artificial peptides, many candidates can be discovered that will kill a selected target bacterium. However, in order to narrow down the selection it is important to know if these peptides follow all the same mode of action. In addition, the mode of action should be different from conventional antibiotics, in consequence peptide candidates can be developed further into drugs against multi-drug resistant bacteria. Here we used one short antimicrobial peptide with unknown mode of action and compared the ultrastructural changes of Escherichia coli cells after treatment with the peptide to cells treated with classic antibiotics. The key finding is that SAXS as a structure sensitive tool provides a rapid feedback on drug induced ultrastructural alterations in whole E. coli cells. We could demonstrate that ultrastructural changes depend on the used antibiotics and their specific mode of action. This is demonstrated using several well characterized antimicrobial compounds and the analysis of resulting SAXS curves by principal component analysis. To understand the result of the PCA analysis, the data is correlated with TEM images. In contrast to real space imaging techniques, SAXS allows to obtain nanoscale information averaged over approximately one million cells. The measurement takes only seconds, while conventional tests to identify a mode of action require days or weeks per single substance. The antimicrobial peptide showed a different mode of action as all tested antibiotics including polymyxin B and is therefore a good candidate for further drug development. We envision SAXS to become a useful tool within the high-throughput screening pipeline of modern drug discovery. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

Comparison of PD-L1 expression between paired cytologic and histologic specimens from non-small cell lung cancer patients.

Expression of programmed death ligand 1 assessed on histologic samples is a confirmed predictive biomarker for anti-PD-1 immunotherapy, but its evaluation is not approved for immunocytochemistry. We investigated if PD-L1 expression shows comparable results on paired cytologic and histologic tumor specimens and interobserver variability. Percentage of PD-L1-positive tumor cells of 247 paired samples of non-small cell lung cancer was evaluated by three independent investigators. Samples were compared on the basis of the continuous values and also categorized with the tumor proportion score (TPS). Concordance was defined if continuous values were both within a deviation of 10% and if categorized values were identically grouped. Interobserver variability was assessed by the standard deviation of the mean. Based on continuous values between paired samples, perfect concordance rate was approximately 53%. With categorization of PD-L1 expression based on TPS, category was identical in 74.1%. However, defining the continuous values of PD-L1 expression between paired samples within a deviation of 10% as concordant, concordance rate was 82%. Interobserver variability was significantly higher in evaluation of cytologic specimens. Evaluation of PD-L1 expression in paired histologic and cytologic tumor specimens shows comparable results if a deviation of 10% between the values is tolerated. Interobserver variability demonstrates a much more challenging interpretation of PD-L1 expression for cytologic samples.

[A new adaptive hand prosthesis]. / Eine neue adaptive Handprothese.

In the paper, a new adaptive hand prosthesis developed in the Institute of Applied Computer Sciences of the Forschungszentrum Karlsruhe is described. Starting from the state-of-the-art, the requirements of the hand prosthesis are derived and the realisation of the new prosthesis is shown. Finally the results obtained are discussed.

Steer by ear: Myoelectric auricular control of powered wheelchairs for individuals with spinal cord injury.

PURPOSE: Providing mobility solutions for individuals with tetraplegia remains challenging. Existing control devices have shortcomings such as varying or poor signal quality or interference with communication. To overcome these limitations, we present a novel myoelectric auricular control system (ACS) based on bilateral activation of the posterior auricular muscles (PAMs). METHODS: Ten able-bodied subjects and two individuals with tetraplegia practiced PAM activation over 4 days using visual feedback and software-based training for 1 h/day. Initially, half of these subjects were not able to voluntarily activate their PAMs. This ability was tested with regard to 8 parameters such as contraction rate, lateralized activation, wheelchair speed and path length in a virtual obstacle course. In session 5, all subjects steered an electric wheelchair with the ACS. RESULTS: Performance of all subjects in controlling their PAMs improved steadily over the training period. By day 5, all subjects successfully generated basic steering commands using the ACS in a powered wheelchair, and subjects with tetraplegia completed a complex real-world obstacle course. This study demonstrates that the ability to activate PAM on both sides together or unilaterally can be learned and used intuitively to steer a wheelchair. CONCLUSIONS: With the ACS we can exploit the untapped potential of the PAMs by assigning them a new, complex function. The inherent advantages of the ACS, such as not interfering with oral communication, robustness, stability over time and proportional and continuous signal generation, meet the specific needs of wheelchair users and render it a realistic alternative to currently available assistive technologies.

[Isolated complete duodenal avulsion at the pylorus after blunt abdominal trauma]. / Isolierter kompletter Duodenalabriss am Pylorus nach stumpfem Bauchtrauma.

We would like to place on record a case of an isolated complete duodenal avulsion distal to the pylorus after blunt abdominal trauma, in a 78-year-old patient. From all relevant literature, this is the first case known to us of duodenal rupture, around its complete circumference, in close proximity to the pylorus, which did not result in the injury of any further organs, in the absence of chronically infectious alterations. A duodenal injury in the case of blunt abdominal trauma is rare and amongst injuries to hollow organs is of no great importance. In isolated cases of duodenal injuries, it is normally the second or third section that is affected, both of which are fairly rigidly anchored to the retroperitoneum. If the first section is injured this is normally accompanied by considerable injury to the liver or head of the pancreas.

[Expanding control possibilities of myoelectric hand prostheses]. / Erweiterung der Ansteuerungsmöglichkeiten Myoelektrischer Handprothesen.

Raising control possibilities of myoelectric prostheses--The control of hand prostheses is based on the surface scan of myoelectric voltage caused by muscle contractions in an amputees arm stump. So far available prostheses only perform up to two different grip types. This paper introduces a control scheme that is able to execute a variety of grip types dependent on the patient's control signals. Therefore a platform is presented to adapt control parameters especially to the patients anatomy. Developed algorithms are flashed on a microcontroller, processing data online and controlling a new generation of prostheses (FZK-prosthesis, Forschungszentrum Karlsruhe).