Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning

Caveolae are an abundant feature of many animal cells. However, the exact function of caveolae remains unclear. We have used the zebrafish, Danio rerio, as a system to understand caveolae function focusing on the muscle-specific caveolar protein, caveolin-3 (Cav3). We have identified caveolin-1 (alpha and beta), caveolin-2 and Cav3 in the zebrafish. Zebrafish Cav3 has 72% identity to human CAV3, and the amino acids altered in human muscle diseases are conserved in the zebrafish protein. During embryonic development, cav3 expression is apparent by early segmentation stages in the first differentiating muscle precursors, the adaxial cells and slightly later in the notochord. cav3 expression appears in the somites during mid-segmentation stages and then later in the pectoral fins and facial muscles. Cav3 and caveolae are located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan is restricted to the muscle fiber ends. Down-regulation of Cav3 expression causes gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers reveals defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3P104L, causes severe disruption of muscle differentiation. In addition, knockdown of Cav3 resulted in a dramatic up-regulation of eng1a expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. These studies provide new insights into the role of Cav3 in muscle development and demonstrate its requirement for correct intracellular organization and myoblast fusion.

PRN Sedation-patterns of prescribing and administration in a child and adolescent mental health inpatient service

Objective: To identify utilisation rates of prn (pro re nata) sedation in children and adolescents receiving inpatient psychiatric treatment, and to compare correlates of prn prescribing and administration. Method A retrospective chart review examined 122 medical charts from a child and youth mental health inpatient service. Results 71.3% of patients were prescribed prn sedation and 50.8% were administered prn sedation. Patients received an average of 8.0 doses of prn sedation, with 9.8% receiving 10 or more doses. Chlorpromazine and diazepam were the most commonly utilised agents. Prescribing of prn sedation was only related to use of regular medications (p < 0.01), and non-parent carers (p < 0.01). In contrast, administration of prn sedation was associated with multiple diagnoses (p < 0.01), pervasive development disorder (p < 0.01), mental retardation (p < 0.01) ADHD (p < 0.01), longer hospital admission (p < 0.01), use of atypical antipsychotics (p < 0.01) and polypharmacy (p < 0.01). Conclusions Despite lack of data to inform practice, prn sedation is widely utilised, especially in complex patients. Future research in this area needs to incorporate nurses and examine whether patients benefit from prn sedation, which drugs and dosing patterns optimise safety and efficacy, and what is the role of prn sedation in the context of other medication.