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Background-Failing human myocardium is characterized by an attenuated contractile response to ␤-adrenergic receptor (␤AR) stimulation due to changes in this signaling cascade, including increased expression and activity of the ␤-adrenergic receptor kinase (␤ARK1). This leads to desensitization and downregulation of ␤ARs. Previously, expression of a peptide inhibitor of ␤ARK1 (␤ARKct) has proven beneficial in several animal models of heart failure (HF). Methods and Results-To test the hypothesis that inhibition of ␤ARK1 could improve ␤-adrenergic signaling and contractile function in failing human myocytes, the ␤ARKct was expressed via adenovirus-mediated (Ad␤ARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. Ad␤ARKct also contained the marker gene, green fluorescent protein, and successful gene transfer was confirmed via fluorescence and immunoblotting. Compared with uninfected failing myocytes (control), the velocities of both contraction and relaxation in the Ad␤ARKct-treated cells were increased in response to the ␤-agonist isoproterenol Key Words: myocytes Ⅲ heart failure Ⅲ gene therapy F ailing human myocardium is characterized by a decreased responsiveness to ␤-adrenergic stimulation. 1 This is attributed to a reduction in the myocardial density of ␤-adrenergic receptors (␤ARs) and functional uncoupling of the ␤AR pathway. 2 ␤ARs, like other G-protein-coupled receptors (GPCRs), undergo desensitization and downregulation in response to ongoing stimulation. GPCR kinases (GRKs) phosphorylate activated receptors, which leads to an incapacity for further G-protein stimulation. 3 For ␤ARs, the most important GRK appears to be GRK2, or ␤ARK1, which desensitizes ␤ARs and other GPCRs via membrane translocation dependent on direct binding to dissociated ␤␥-subunits of G proteins (G ␤␥ ). 4 In human heart failure (HF), the expression and activity of ␤ARK1 are elevated, which contributes to the lack of ␤-adrenergic reserve. 5 This is probably the result of enhanced sympathetic nervous system activity and excessive catecholamine stimulation of ␤ARs associated with the failing heart. 6It has been demonstrated in numerous animal models that inhibition of ␤ARK1 translocation with a peptide containing the G ␤␥ -binding site (␤ARKct) can lead to in vivo ␤ARK1 inhibition and rescue of HF. 3,4 Cardiac expression of the ␤ARKct, whether in transgenic mice or after intracoronary gene delivery to larger animal models of HF, can improve myocardial function and lead to enhanced responsiveness to catecholamines through preservation of ␤AR density and G-protein coupling. [7][8][9][10][11][12] Currently, it is unknown whether expression of the ␤ARKct peptide will lead to improvement of function in the failing human heart. Because myocytes from failing human hearts are characterized by an attenuated response to ␤AR stimulation and contractile dysfunction, 13,14 we sought to determine, as an ultimate "proof of concept" for ␤ARK1 inhibition fo...

No difference in player performance after concussion was found whether the player did or did not miss games before return. Return without missing games may be associated with experience and timing of injury within a season and less likely after newer guidelines.

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The spine has several important functions including load transmission, permission of limited motion, and protection of the spinal cord. The vertebrae form functional spinal units, which represent the smallest segment that has characteristics of the entire spinal column. Discs and paired facet joints within each functional unit form a three-joint complex between which loads are transmitted. Surrounding the spinal motion segment are ligaments, composed of elastin and collagen, and joint capsules which restrict motion to within normal limits. Ligaments have variable strengths and act via different lever arm lengths to contribute to spinal stability. As a consequence of the longer moment arm from the spinous process to the instantaneous axis of rotation, inherently weaker ligaments (interspinous and supraspinous) are able to provide resistance to excessive flexion. Degenerative processes of the spine are a normal result of aging and occur on a spectrum. During the second decade of life, the intervertebral disc demonstrates histologic evidence of nucleus pulposus degradation caused by reduced end plate blood supply. As disc height decreases, the functional unit is capable of an increased range of axial rotation which subjects the posterior facet capsules to greater mechanical loads. A concurrent change in load transmission across the end plates and translation of the instantaneous axis of rotation further increase the degenerative processes at adjacent structures. The behavior of the functional unit is impacted by these processes and is reflected by changes in the stress-strain relationship. Back pain and other clinical symptoms may occur as a result of the biomechanical alterations of degeneration.

Tibial tubercle avulsion fractures most commonly occur in adolescent boys and usually result from pushing off or landing while jumping. These fractures are relatively uncommon but can have a significant functional effect. The purpose of this study was to determine the long-term outcome with return to play in 8 adolescent basketball players with at least 4 years of postoperative reconditioning. Results with return to play at the preinjury level are favorable after treatment of acute tibial avulsion fractures in adolescent basketball players. Long-term outcome was excellent in all patients regardless of fracture type. Open reduction and internal fixation using 1 or 2 cancellous bone screws achieved union in all cases.