Despite numerous publications and clinical trials, the results of treatment of recalcitrant chronic plantar fasciitis with extracorporeal shockwave therapy (ESWT) still remain equivocal as to whether or not this treatment provides relief from the pain associated with this condition. The objective of this study was to determine whether extracorporeal shock wave therapy can safely and effectively relieve the pain associated with chronic plantar fasciitis compared to placebo treatment, as demonstrated by pain with walking in the morning. This was set in a multicenter, randomized, placebo-controlled, double-blind, confirmatory clinical study undertaken in four outpatient orthopedic clinics. The patients, 114 adult subjects with chronic plantar fasciitis, recalcitrant to conservative therapies for at least 6 months, were randomized to two groups. Treatment consisted of approximately 3,800 total shock waves (AE10) reaching an approximated total energy delivery of 1,300 mJ/mm 2 (EDþ) in a single session versus placebo treatment. This study demonstrated a statistically significant difference between treatment groups in the change from baseline to 3 months in the primary efficacy outcome of pain during the first few minutes of walking measured by a visual analog scale. There was also a statistically significant difference between treatments in the number of participants whose changes in Visual Analog Scale scores met the study definition of success at both 6 weeks and 3 months posttreatment; and between treatment groups in the change from baseline to 3 months posttreatment in the Roles and Maudsley Score. The results of this study confirm that ESWT administered with the Dornier Epos Ultra is a safe and effective treatment for recalcitrant plantar fasciitis. ß
A high (HAHT) and a low (LAHT) affinity hexose transport system are present in undifferentiated rat L6 myoblasts; however, only the latter can be detected in multinucleated myotubes. This suggests that HAHT is either down-regulated or modified as a result of myogenesis. The present investigation examined the relationship between HAHT and myogenic differentiation. While myogenesis could be inhibited by the potent hexose transport inhibitor phloretin, it was not affected by phlorizin which had no effect on hexose transport. This relationship was further explored using six different HAHT-defective mutants. All six mutants, altered in either the HAHT transport affinity (Type I mutants) or capacity (Type II mutants), were impaired in myogenesis. Since these mutants were selected from both mutagenized and non-mutagenized cells with different reagents, or with different concentrations of the same reagent, the deficiency in myogenesis was likely due to changes in HAHT properties. This notion was confirmed by the observation that growth of Type I mutants in high D-glucose concentrations could rectify the defect in myogenesis. D-glucose was unlikely to rectify the defect in myogenesis, if this defect was due to a second unrelated mutation that may have arisen during isolation of the mutants. Since both types of mutants were not altered in LAHT, D-glucose should still be taken up into the cells. The fact that the glucose-mediated increase in fusion could not be observed in Type II mutants (deficient in the HAHT transporter) suggested that myogenesis was dependent on the presence of D-glucose or its metabolites in specific HAHT-accessible compartments. It is tempting to speculate that trans-acting regulators involved in myogenesis may be synthesized from the glucose metabolites in these specialized HAHT-accessible compartments.
Previous studies revealed an inverse relationship between GLUT 1 and GLUT 4 expression in rat myoblasts [L. Xia, Z. Lu, T.C.Y. Lo, J. Biol. Chem., 268 (1993) 23258-23266]. It was not clear whether these were coincidental or causal occurrences. To examine the regulatory roles of the GLUT 4 isoform, rat L6 myoblasts were transfected with full length GLUT 4 cDNAs (2.5 kb) in the sense or antisense orientation. L6 myoblasts transfected with the GLUT 4 sense cDNA (L6/G4S transfectants) possessed much elevated levels of both endogenous GLUT 4 transcripts (1.4 kb and 2.8 kb). Transport and immunofluorescence studies showed that this GLUT 4 sense cDNA was responsible for a functional GLUT 4 transporter. L6 cells transfected with the GLUT 4 antisense cDNA (L6/G4A transfectants) possessed only 6% of the L6 level in day 6 cultures. These antisense transfectants were essentially devoid of any functional GLUT 4 transporter. The activation of transcription of the endogenous GLUT 4 gene in L6/G4S myoblasts suggested auto-regulation of GLUT 4 expression. GLUT 3 expression and activity were not altered in both sense and antisense GLUT 4 transfectants. More interestingly, GLUT 1 expression was reduced in L6/G4S myoblasts, whereas it was elevated in L6/G4A myoblasts. This was the first direct evidence indicating GLUT 4 might play an important role in suppressing GLUT 1 expression.
We have recently demonstrated a close relationship between the GLUT 3 transporter and the myogenic ability of rat skeletal L6 myoblasts [1]. This investigation examined the effects of over‐and under‐expression of the GLUT 3 transporter on both biochemical and morphological differentiation. L6 transfectants expressing two to five times the normal L6 GLUT 3 transcript level were impaired in the expression of myogenesis‐associated genes, such as myogenin, MLC, MHC and TnT, and in myotube formation. Similar defects were also observed in myoblast mutants expressing less than 20% of the normal GLUT 3 level. Forced expression of an exogenous GLUT 3 cDNA could partially rescue the myogenic defect of these GLUT 3‐ mutants. However, such myogenic defects were not observed in L6 GLUT 3 antisense transfectants expressing 39% of the normal L6 GLUT 3 level. These data suggest that myogenic differentiation will proceed only within a critical level of the GLUT 3 transporter. The optimal GLUT 3 content for myogenesis ranges from around 2 × 105 to 5 × 105 molecules per cell in day 2 cultures; GLUT 3 levels outside this range have a negative effect on myogenesis. Our data suggest that GLUT 3 may regulate myogenesis by modulating the levels of signal transducers required for expression of myogenin and muscle‐specific contractile protein genes.
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