Cyclosporin A has low potency as a calcineurin inhibitor in cells expressing high levels of P-glycoprotein

Cyclosporin A (CsA) is a widely-used immunosuppressant drug whose therapeutic and toxic actions are mediated through inhibition of calcineurin (CN), a calcium- and calmodulin-dependent phosphatase. Inhibition of CN by CsA requires drug binding to its protein cofactor in the inhibition, cyclophilin. Because cyclophilin is a high affinity target for CsA it is expected that this protein can act as a reservoir for the drug in the cell and may be able to inhibit cellular efflux of CsA. P-glycoprotein (P-gp) is known to increase the rate of CsA efflux from CsA loaded cells but it is not clear if the P-gp drug efflux pump can compete effectively with cyclophilin at therapeutically relevant concentrations of CsA. To test the hypothesis that increased expression of P-gp confers protection against CsA-dependent inhibition of CN phosphatase activity, KB-V cells expressing varying levels of P-gp were analyzed to determine the potency of CsA as a CN inhibitor. When intact cells were treated with CsA, a positive correlation was observed between P-gp expression and resistance to CsA-dependent inhibition of CN: the IC50 is approximately 20-fold higher in the multidrug resistant epidermal carcinoma cell line, KB-V, which expresses P-gp at a high level than in the parental, KB, cell line expressing very low levels of P-gp. The resistance displayed by KB-V cells is abrogated by co-administration of the P-gp inhibitor verapamil, whereas verapamil has no effect on CsA potency in control KB cells. In cell lysates from KB-V cells with different amounts of P-gp CsA exhibits equivalent potency, indicating that the difference in sensitivity to CsA among the cell types requires maintenance of cell integrity. These observations support the view that resistance to CN inhibition by CsA occurs in cells with moderately elevated P-gp activity. Therefore, P-gp activity appears to be an important determinant of CsA cellular specificity for both therapeutic and toxic effects.     

Influence of out‐of‐plane fiber orientation on reaction‐to‐fire properties of carbon fiber reinforced polymer matrix composites

This work investigates the influence of the out‐of‐plane orientation of carbon fibers on the reaction‐to‐fire characteristics of polymer matrix composites. A deep insight into combustion processes is gained, which is necessary to fully understand and assess advantages of composites with out‐of‐plane fiber angles. Epoxy‐based Hexply 8552/IM7 specimens with primarily low fiber angles between 0° and 15° are characterized by cone calorimetry. Heat release during fire is greatly affected by the out‐of‐plane fiber angle because of the thermal boundaries created by the fibers. The advancement of the pyrolysis front during fire was determined from peak heat release rates and validated by temperature measurements along the back surface of the panels, representing a novel method of determining position‐dependent pyrolysis migration velocity. These measurements show a transverse shift in pyrolysis front velocity for increasing out‐of‐plane fiber angles. Pyrolysis pathways between the fiber boundaries facilitate faster combustion through the composite thickness, especially for increasing angles from 0° to 15°. It was determined that under the chosen conditions, the pyrolysis front advances approximately 4 times faster when propagating parallel to the fibers than perpendicular.     

Glial progenitor cell recruitment drives aggressive glioma growth: mathematical and experimental modelling

Currently available glioma treatments remain unsuccessful at prolonging disease-free remission. Recent evidence suggests that tumour recruitment of glial progenitor cells by platelet-derived growth factor (PDGF) may play a role in the development and progression of these tumours. Building upon our recent experimental results and previous proliferation–invasion (PI) reaction–diffusion model, in this study, we created a proliferation–invasion–recruitment (PIR) model that includes a mechanism for progenitor cell recruitment, wherein paracrine PDGF signalling stimulates migration and proliferation of progenitors derived from the local brain environment. Parametrizing this mathematical model with data obtained from the PDGF-driven rat glioma model, we explored the consequences of recruitment, using the PIR model to compare the effects of high versus low PDGF secretion rates on tumour growth and invasion dynamics. The mathematical model predicts correlation between high levels of recruitment and both increased radial velocity of expansion on magnetic resonance imaging and less diffusely invasive edges. Thus, the PIR model predicts that PDGF levels correlate with tumour aggressiveness, and results are consistent with both human and experimental data, demonstrating that the effects of progenitor cell recruitment provide a novel mechanism to explain the variability in the rates of proliferation and dispersion observed in human gliomas.     

COMPUTATION OF THE FREE SURFACE FLOW OF A THIN LIQUID FILM AT ZERO AND NORMAL GRAVITY

The results of numerical computations are presented for the free surface flow of a thin liquid film in the presence or absence of a gravitational body force. Three different flow systems were studied: a falling film down a vertical wall, plane and radial film flows under zero gravity, and plane and radial film flows along a horizontal plate in the presence of gravity. Computations were performed using a boundary-fitted coordinate system where the irregular free surface conformed to one of the flow boundaries. The distributions of film height and friction coefficient were found to be strongly affected by the magnitude and orientation of the gravitational body force. Besides the Reynolds number, the Froude number of the film, which characterizes the flow regime (i.e., supercritical or subcritical), is found to be an important parameter for horizontal flow in the presence of gravity.     

Evaluation of specific stabilizing exercise in the treatment of chronic low back pain with radiologic diagnosis of spondylolysis or spondylolisthesis

STUDY DESIGN: A randomized, controlled trial, test--retest design, with a 3-, 6-, and 30-month postal questionnaire follow-up. OBJECTIVE: To determine the efficacy of a specific exercise intervention in the treatment of patients with chronic low back pain and a radiologic diagnosis of spondylolysis or spondylolisthesis. SUMMARY OF BACKGROUND DATA: A recent focus in the physiotherapy management of patients with back pain has been the specific training of muscles surrounding the spine (deep abdominal muscles and lumbar multifidus), considered to provide dynamic stability and fine control to the lumbar spine. In no study have researchers evaluated the efficacy of this intervention in a population with chronic low back pain where the anatomic stability of the spine was compromised. METHODS: Forty-four patients with this condition were assigned randomly to two treatment groups. The first group underwent a 10-week specific exercise treatment program involving the specific training of the deep abdominal muscles, with co-activation of the lumbar multifidus proximal to the pars defects. The activation of these muscles was incorporated into previously aggravating static postures and functional tasks. The control group underwent treatment as directed by their treating practitioner. RESULTS: After intervention, the specific exercise group showed a statistically significant reduction in pain intensity and functional disability levels, which was maintained at a 30-month follow-up. The control group showed no significant change in these parameters after intervention or at follow-up. SUMMARY: A "specific exercise" treatment approach appears more effective than other commonly prescribed conservative treatment programs in patients with chronically symptomatic spondylolysis or spondylolisthesis.