Interfascicular matrix-mediated transverse deformation and sliding of discontinuous tendon subcomponents control the viscoelasticity and failure of tendons.

In the present article, we investigated the sliding of discontinuous tendon subcomponents and the variation of nonhomogeneous deformation in the human Achilles tendon (AT) over time using uniaxial tensile and relaxation tests. The deformation and the resulting strain distribution under uniaxial tension are examined using a vision-based 3-D digital image correlation (DIC) system, which allows estimation of the strain field in the axial and lateral directions. Relaxation test under B-mode ultrasound imaging with the use of DIC method provides information about the local strain variation over time in the axial and anteroposterior directions. The observed nonhomogeneous deformation, a result from the twisted structure of the tendon, shows both compressive and tensile transverse strains that can generate interfascicular matrix (IFM) failure and initiate water accumulation in the course of tendinopathy. Moreover, using B-mode elastography with the DIC method, we have observed areas of low stiffness when the strain values exceed the strength limits, and this could correspond to IFM carrying the load between discontinuous tendon subcomponents. Thus, IFM carrying complex multiscale stresses may be responsible for the strength and viscoelastic properties of the AT. The results presented here reveal a new pathomechanism of AT failure. This could be useful in further studies on tendinopathy as well as effective planning of the AT therapy.

Effect of cellular cholesterol changes on insulin secretion by tumor cell lines.

UNLABELLED: Glucose and cell swelling induce insulin secretion by alternative signaling pathways. Swelling-induced secretion is in most systems independent of calcium and various mediators of glucose stimulation. Comparison of two insulinoma tumor cell lines revealed surprising difference; INS-1E cells in contrast to INS-1 cells and isolated rat pancreatic islets do not respond to hypotonicity in the presence of calcium. To delineate the role of cholesterol the effect of its extraction or addition on the insulin secretion in response to glucose and cell swelling was compared. INS-1E cells have significantly higher cholesterol content than INS-1 cells (58.5 ± 2.9 and 46.3 ± 2.5 mg chol/mg prot respectively). After cholesterol desorption by 1.0, 5.0 and 10.0 mM of carboxymethyl-ß-cyclodextrin, methyl-ß-cyclodextrin, or 2-hydroxypropyl-ß- cyclodextrin the response to hypotonicity in INS-1E cells emerged. On the contrary, supplementation of INS-1 cells with cholesterol inhibited their response to cell swelling. Cyclodextrin pretreatment inhibited glucose-induced insulin secretion from INS-1 cells while INS-1E cells were more resistant to their effect. CONCLUSION: Cellular cholesterol content substantially affects secretory process; both high and low levels could be inhibitory. Absence of swelling-induced insulin secretion in INS-1E cells despite adequate response to glucose is related to their high cholesterol content. Optimal cholesterol concentration is different for either type of stimulation; swelling-induced mechanism is more sensitive to higher cholesterol content. The difference is likely to reflect involvement of sequential type exocytosis after cell swelling. Sensitivity of secretory processes suggests that either hypercholesterolemia or excessive effort to decrease plasma cholesterol in patients could have adverse effect on insulin secretion.

Two mutants selectively resistant to polyenes reveal distinct mechanisms of antifungal activity by nystatin and amphotericin B.

Polyene macrolides nystatin and amphotericin B are widely used in the treatment of fungal infections. In order to characterize factors affecting polyene activity, we have isolated Saccharomyces cerevisiae mutants showing selective resistance to nystatin and amphotericin B. Characterization of two of these mutants (nystatin-resistant mutant X1/16 and amphotericin B-resistant mutant X3/33) is presented. Genetic analysis revealed that resistance in each of these mutants is caused by a mutation in one gene with a different mode of inheritance. Nystatin resistance in mutant X1/16 is caused by changes in sterol spectrum while amphotericin B resistance in mutant X3/33 is probably related to modification of the cell wall. Our results suggest that, in spite of their structural similarity, nystatin and amphotericin B differ significantly in mechanisms of their antifungal activity.