Dystrophin involvement in peripheral circadian SRF signalling.

Absence of dystrophin, an essential sarcolemmal protein required for muscle contraction, leads to the devastating muscle-wasting disease Duchenne muscular dystrophy. Dystrophin has an actin-binding domain, which binds and stabilises filamentous-(F)-actin, an integral component of the RhoA-actin-serum-response-factor-(SRF) pathway. This pathway plays a crucial role in circadian signalling, whereby the suprachiasmatic nucleus (SCN) transmits cues to peripheral tissues, activating SRF and transcription of clock-target genes. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised dystrophin loss causes circadian deficits. We show for the first time alterations in the RhoA-actin-SRF-signalling pathway, in dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios, altered MRTF levels, dysregulated core-clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from Duchenne patients harbouring an array of mutations. Furthermore, we show dystrophin is absent in the SCN of dystrophic mice which display disrupted circadian locomotor behaviour, indicative of disrupted SCN signalling. Therefore, dystrophin is an important component of the RhoA-actin-SRF pathway and novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.

Reducing radiation exposure in early-onset scoliosis surgery patients: novel use of ultrasonography to measure lengthening in magnetically-controlled growing rods.

BACKGROUND CONTEXT: Magnetically-controlled growing rod (MCGR) technology has been reported for the treatment of early-onset scoliosis (EOS). Such technology allows for regular and frequent outpatient rod distractions without the need for additional surgery. However, pre- and postdistraction spine radiographs are required to verify the amount of lengthening. This increased exposure to ionizing radiation in developing children significantly increases their risk profile for radiation-induced cancer and noncancerous morbidity. PURPOSE: This study addressed the first and novel application and reliability of the use of ultrasonography, that has no ionizing radiation exposure, as an alternative to plain radiographs in the visualizing and confirming of rod distractions. STUDY DESIGN: A prospective study. PATIENT SAMPLE: Six EOS patients who underwent surgical treatment with MCGRs were prospectively recruited. OUTCOME MEASURES: Imaging measurements based on ultrasound and plain radiographs. METHODS: All patients were imaged via ultrasound, ease of rod identification was established, and the reliability and reproducibility of optimal reference point selection assessed blindly by three individuals. The clinical algorithm, using ultrasound, was subsequently implemented. Plain radiographs served as controls. RESULTS: Assessment of the rod's neck distance on ultrasound demonstrated a high degree of interrater reliability (a=0.99; p<.001). Intrarater reliability remained high on repeat measurements at different time intervals (a=1.00; p<.001). Satisfactory interrater reliability was noted when measuring the rod's neck (a=0.73; p=.010) and high reliability was noted in assessing the housing of the rod (a=0.85; p=.01) on plain radiographs. Under blinded conditions, 2 mm rod distraction measured on radiographs corresponded to 1.7 mm distraction on the ultrasound (standard deviation: 0.24 mm; p<.001). Subsequently, the clinical algorithm using ultrasound, instead of radiographs, has been successfully implemented. CONCLUSIONS: This is the first study to report the use of a novel technique using noninvasive, nonionizing ultrasound to reliably document rod distractions in EOS patients. A high level of inter- and intrarater reliabilities were noted. More importantly, the use of ultrasonography may result in fewer whole spine radiographs from being taken in patients who have had MCGRs implanted for EOS; thereby decreasing their exposure to ionizing radiation and the potential risk of future radiation-induced diseases.