Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Since drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogs of 1, which provided an excellent starting point for optimization of the chemotype. We report our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU621, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new tool for studying regulation of the trypanosome cell cycle.

The AR approach that reduced the length of time spent ambulating on crutches resulted in improved general physical function and quality of life and an earlier attainment of full active knee extension when compared with the CR approach. There were no graft complications ascertained through MRI. This regimen appears safe and may potentially speed up the recovery of normal gait function. A larger patient cohort and follow-up are required to observe long-term graft outcomes.

IV.

Patients in the AR group who reduced the length of time spent ambulating on crutches produced comparable outcomes up to 24 months, without compromising graft integrity.

Study Design Systematic review. Background Electromyography (EMG) has previously been used to guide postoperative rehabilitation progression following rotator cuff repair to prevent deleterious loading of early surgical repair. Objective To review the current literature investigating EMG during rehabilitation exercises in normal shoulders, and to identify exercises that meet a cut point of 15% maximal voluntary isometric contraction (MVIC) or less and are unlikely to result in excessive loading in the early postoperative stages. Methods An electronic search of MEDLINE via Ovid, Embase, CINAHL, SPORTDiscus, PubMed, and the Cochrane Library for all years up to June 2016 was performed. Studies were selected in relation to predefined selection criteria. Pooled mean MVICs were reported and classified as low (0%-15% MVIC), low to moderate (16%-20% MVIC), moderate (21%-40% MVIC), high (41%-60% MVIC), and very high (greater than 60% MVIC). Results A search identified 2159 studies. After applying the selection criteria, 20 studies were included for quality assessment, data extraction, and data synthesis. In total, 43 exercises spanning passive range of motion, active-assisted range of motion, and strengthening exercises were evaluated. Out of 13 active-assisted exercises, 9 were identified as suitable (15% MVIC or less) to load the supraspinatus and 10 as suitable to load the infraspinatus early after surgery. All exercises were placed in a theoretical-continuum model, by which general recommendations could be made for prescription in patients post rotator cuff repair. Conclusion This review identified passive and active-assisted exercises that may be appropriate in the early stages after rotator cuff repair. J Orthop Sports Phys Ther 2017;47(12):931-944. Epub 13 Jul 2017. doi:10.2519/jospt.2017.7271.