Zystische Adventitiadegeneration (CAD) als Ursache einer invalidisierenden Claudicatio intermittens

Zusammenfassung: Bei einem 45-jährigen Patienten mit wechselhaften Ischämiebeschwerden und initial limitierter Gehstrecke rechts von höchstens 50m führten die duplexsonographischen und angiographischen Abklärungen zur Verdachtsdiagnose einer zystischen Adventitiadegeneration. Intraoperativ zeigte sich ein zystisch aufgetriebenes Poplitealsegment mit Entleerung von gallertiger Flüssigkeit. Aufgrund der langstreckigen Veränderung erfolgte die Segmentresektion der A.poplitea und Rekonstruktion mittels eines autologen Veneninterponats. Die CAD ist ein seltenes Krankheitsbild, an das gerade bei jungen Patienten ohne systemische Arteriosklerose gedacht werden sollte. Die Therapie ist je nach Fall chirurgisch erhaltend durch Zystenresektion mittels "Exarterektomie" oder gefäßresezierend, insbesondere bei langstreckigen Veränderungen bzw. vollständiger Okklusion mittels Ersatz durch ein Veneninterpona

Iterative in Situ Click Chemistry Assembles a Branched Capture Agent and Allosteric Inhibitor for Akt1

We describe the use of iterative in situ click chemistry to design an Akt-specific branched peptide triligand that is a drop-in replacement for monoclonal antibodies in multiple biochemical assays. Each peptide module in the branched structure makes unique contributions to affinity and/or specificity resulting in a 200 nM affinity ligand that efficiently immunoprecipitates Akt from cancer cell lysates and labels Akt in fixed cells. Our use of a small molecule to preinhibit Akt prior to screening resulted in low micromolar inhibitory potency and an allosteric mode of inhibition, which is evidenced through a series of competitive enzyme kinetic assays. To demonstrate the efficiency and selectivity of the protein-templated in situ click reaction, we developed a novel QPCR-based methodology that enabled a quantitative assessment of its yield. These results point to the potential for iterative in situ click chemistry to generate potent, synthetically accessible antibody replacements with novel inhibitory properties

Epitope Targeting of Tertiary Protein Structure Enables Target-Guided Synthesis of a Potent In-Cell Inhibitor of Botulinum Neurotoxin

Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second in situ click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an in vitro inhibition constant of 165 pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model

A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH domain of Akt1

Ligands that can bind selectively to proteins with single amino-acid point mutations offer the potential to detect or treat an abnormal protein in the presence of the wild type (WT). However, it is difficult to develop a selective ligand if the point mutation is not associated with an addressable location, such as a binding pocket. Here we report an all-chemical synthetic epitope-targeting strategy that we used to discover a 5-mer peptide with selectivity for the E17K-transforming point mutation in the pleckstrin homology domain of the Akt1 oncoprotein. A fragment of Akt1 that contained the E17K mutation and an I19[propargylglycine] substitution was synthesized to form an addressable synthetic epitope. Azide-presenting peptides that clicked covalently onto this alkyne-presenting epitope were selected from a library using in situ screening. One peptide exhibits a 10:1 in vitro selectivity for the oncoprotein relative to the WT, with a similar selectivity in cells. This 5-mer peptide was expanded into a larger ligand that selectively blocks the E17K Akt1 interaction with its PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) substrate

Kearney Area Map

Kearney area map. Highlights local businesses and provides information on local services such as schools.https://openspaces.unk.edu/kc-kearney/1001/thumbnail.jp

Is keep/refer decision making an integral part of national guidelines for the physiotherapy profession within Europe? A review

Background Keep/refer decision as the ability to independently determine whether a patient’s condition is suitable for physiotherapy management (keep) or not (refer), is regarded as an core element in the World Confederation of Physical Therapists‘ (WCPT) Guideline for Standards of Physical Therapy Practice. However, it is currently unknown how individual European countries have implemented this in their national guidelines. Objectives To determine if keep/refer decision making abilities are an integral part of national guidelines for the physiotherapy profession of member countries of the European Network of Physiotherapy in Higher Education (ENPHE). Data Sources A review was performed including medical databases, the grey literature and personal correspondence with professional ENPHE member associations. To gain the information of interest, all eligible documents were reviewed. Results 11 national guidelines for the physiotherapy profession could be obtained. Two additional member associations use European guidelines as their national ones. Despite the fact that in the WCPT guidelines keep/refer decision making abilities are clearly described as a core element, there exists huge inconsistency as to how various European (with direct and non direct access systems) countries have included them in their national guidelines. Conclusion Despite the fact that most ENPHE member countries deem a close collaboration between health care professionals important and that physiotherapists should know the limitation of their expertise, keep/refer decision making abilities as explicitly stated in the WCPT guidelines were not included in the majority of guidelines that were reviewed