A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation.

Fibroblast activation protein (FAP) is a focus of interest as a potential cancer therapy target. This membrane bound protease possesses the unique catalytic activity of hydrolysis of the post-proline bond two or more residues from the N-terminus of substrates. FAP is highly expressed in activated fibroblastic cells in tumours, arthritis and fibrosis. A rare, novel, human polymorphism, C1088T, encoding Ser363 to Leu, occurring in the sixth blade of the ß propeller domain, was identified in a family. Both in primary human fibroblasts and in Ser363LeuFAP transfected cells, we showed that this single substitution ablates FAP dimerisation and causes loss of enzyme activity. Ser363LeuFAP was detectable only in endoplasmic reticulum (ER), in contrast to the distribution of wild-type FAP on the cell surface. The variant FAP showed decreased conformational antibody binding, consistent with an altered tertiary structure. Ser363LeuFAP expression was associated with upregulation of the ER chaperone BiP/GRP78, ER stress sensor ATF6, and the ER stress response target phospho-eIF2α, all indicators of ER stress. Proteasomal inhibition resulted in accumulation of Ser363LeuFAP, indicating the involvement of ER associated degradation (ERAD). Neither CHOP expression nor apoptosis was elevated, so ERAD is probably important for protecting Ser363LeuFAP expressing cells. These data on the first loss of function human FAP gene variant indicates that although the protein is vulnerable to an amino acid substitution in the ß-propeller domain, inactive, unfolded FAP can be tolerated by cells.

Mechanical performance of hybrid Ilizarov frames containing full-threaded Schanz screws.

Modification of circular Ilizarov frames is necessary to overcome the difficulties in pin positioning due to unfavorable anatomic site or local soft-tissue conditions. Hybrid frame configurations consisting of half pins or full-threaded schanz screws are widely used in clinical practice. This study compared the mechanical performance of hybrid frames and a standard system. One standard and five modified hybrid systems were tested under axial compression, four-point bending, and torsional forces. Systems modified with full-threaded schanz screws showed a higher stiffness than half pin modifications and exhibited a similar mechanical performance of a standard system.

Overgrowth after radial shortening for Kienböck's disease in a teenager: case report.

A 16-year-old boy was treated by a radial-shortening procedure for symptomatic stage IIIB Kienböck's disease with 4 mm negative ulnar variance. The osteotomy corrected the ulnar variance to negative 1 mm after surgery, but further negative ulnar variance of 9 mm occurred at follow-up evaluation as a result of radial overgrowth. The functional outcome was excellent with remodeling of the lunate. The possibility of overgrowth should be considered when contemplating a radial-shortening osteotomy for Kienböck's disease in skeletally immature patients.

Comparison of mechanical performance among different frame configurations of the Ilizarov external fixator: experimental study.

The circular frame of the Ilizarov fixator can be modified to reflect anatomic variations and treatment aims. However, these modifications in the frame system cannot always achieve the mechanical performance of the standard frame system. A standard system has two rings in each bone fragment connected by four longitudinal bars on each side of the ring. In this study, the mechanical performances of one standard and eight modified frame systems were compared. Each system was loaded on a material testing machine, with calculation of axial compression, four-point bending, and torsion. As a result, systems that were modified with drop wires and Schanz screws 45 degrees oblique to the wires on the proximal ring provided a mechanical performance closer to the standard system than systems with other modifications.

Clinical analysis of the trigger thumb of childhood.

Trigger thumb of childhood, termed congenital trigger thumb, is a pathology of the flexor pollicis longus tendon with an unknown etiology. In this study, treatment outcomes of 47 trigger thumbs of 36 children were evaluated. There were 18 males and 18 females with a mean age of 34 months (9 months-13 years). Average age of recognition of pathology by the family was 20.5 months (0-8 years). In seven of 11 bilateral cases pathology was recognized simultaneously while in the other four, diagnosis was made at different times. We used conservative treatment for all patients under three years of age, which was unsuccessful. Thus, surgical relase was performed in all cases. In the mean follow-up of seven years (range 5-15), contracture and palpable nodules disappeared. In conclusion, we believe trigger thumb in childhood should be treated surgically and that the term "congenital trigger thumb" should be changed to "developmental trigger thumb".