Background and Purpose. The Functional Gait Assessment (FGA) is a 10-item gait assessment based on the Dynamic Gait Index. The purpose of this study was to evaluate the reliability, internal consistency, and validity of data obtained with the FGA when used with people with vestibular disorders. Subjects. Seven physical therapists from various practice settings, 3 physical therapist students, and 6 patients with vestibular disorders volunteered to participate. Methods. All raters were given 10 minutes to review the instructions, the test items, and the grading criteria for the FGA. The 10 raters concurrently rated the performance of the 6 patients on the FGA. Patients completed the FGA twice, with an hour's rest between sessions. Reliability of total FGA scores was assessed using intraclass correlation coefficients (2,1). Internal consistency of the FGA was assessed using the Cronbach alpha and confirmatory factor analysis. Concurrent validity was assessed using the correlation of the FGA scores with balance and gait measurements. Results. Intraclass correlation coefficients of .86 and .74 were found for interrater and intrarater reliability of the total FGA scores. Internal consistency of the FGA scores was .79. Spearman rank order correlation coefficients of the FGA scores with balance measurements ranged from .11 to .67. Discussion and Conclusion. The FGA demonstrates what we believe is acceptable reliability, internal consistency, and concurrent validity with other balance measures used for patients with vestibular disorders.
Bid, a pro-apoptosis "BH3-only" member of the Bcl-2 family, can be cleaved by caspase-8 after Fas/TNF-R1 engagement. The p15 form of truncated Bid (tBid) translocates to mitochondria and induces cytochrome c release, leading to the activation of downstream caspases and apoptosis. In the current study, we investigated the mechanism by which tBid regulated cytochrome c release in terms of its relationship to mitochondrial permeability transition and Bax, another Bcl-2 family protein. We employed an in vitro reconstitution system as well as cell cultures and an animal model to reflect the physiological environment where Bid could be functional. We found that induction of cytochrome c release by tBid was not accompanied by a permeability transition even at high doses. Indeed, inhibition of permeability transition did not suppress the activity of tBid in vitro nor could they block Fas activation-induced, Biddependent hepatocyte apoptosis in cultures. Furthermore, Mg 2؉ , although inhibiting permeability transition, actually enhanced the ability of tBid to induce cytochrome c release. We also found that tBid did not require Bax to induce cytochrome c release in vitro. In addition, mice deficient in bax were still highly susceptible to anti-Fas-induced hepatocyte apoptosis, in which cytochrome c release was unaffected. Moreover, although Bax-induced cytochrome c release was not dependent on tBid, the two proteins could function synergistically. We conclude that Bid possesses the biochemical activity to induce cytochrome c release through a mechanism independent of mitochondrial permeability transition pore and Bax.
The mitochondrial pathway is critical for the efficient execution of death receptor-initiated apoptosis in certain cell types. Questions remain as to why the mitochondria are required in that scenario. We investigated the molecular events that determined the need for the mitochondria by using an in vivo model of anti-Fas-induced hepatocyte apoptosis. In wild-type mice, Fas stimulation resulted in normal activation of caspase-3, with the generation of the active p19-p12 complex. In biddeficient mice, caspase-3 activation was arrested after the initial cleavage at Asp 175 . This allowed the generation of the p12 small subunit, but the p20 large subunit could not be further processed to the p19 subunit. The p20-p12 complex generated by Fas stimulation in biddeficient hepatocytes was inactive, arresting the death program. Failure of p20/p12 caspase-3 to mature and to exhibit activity was because of the inhibition by the inhibitor-of-apoptosis proteins (IAPs), such as XIAP, and also to a low caspase-8 activity. This block could be overcome in wild-type mice by two mechanisms. Smac was released from mitochondria early following Fas activation and was competitively bound to the IAPs to reverse their effects. XIAP could also be cleaved, and this occurred later and was likely mediated by enhanced caspase activities. Both mechanisms were dependent on Bid and thus were not operative in bid-deficient hepatocytes. In conclusion, mitochondrial activation by Bid is required for reversing the IAP inhibition through Smac release. It is also required for the alternative activation of caspases through cytochrome c release, as demonstrated previously. Together, these events ensure a successful progression of the death program initiated by the death receptor activation in the hepatocyte.
Tumor necrosis factor-␣ (TNF␣)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of prodeath Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNF␣-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNF␣ in the presence of Dgalactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the biddeficient mice. Additional genetic factor(s) could further modify the dependence of TNF␣ toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNF␣-mediated pathogenesis in vivo.
We have investigated the role of the BH3-only prodeath Bcl-2 family protein, Bid, in ischemic neuronal death in a murine focal cerebral ischemia model. Wildtype and bid-deficient mice of inbred C57BL/6 background were subjected to 90-min ischemia induced by left middle cerebral artery occlusion followed by 72-h reperfusion. The volume of ischemic infarct was significantly smaller in the bid-deficient brains than in the wild-type brains, suggesting that Bid participated in the ischemic neuronal death. Indeed, following the ischemic treatment there was a significant reduction of apoptosis in the ischemic areas, particularly in the inner infarct border zone (the penumbra), of the bid-deficient brains. In addition, activation of Bid in the wild-type brains could be readily detected at ϳ3 h after ischemia, as evidenced by its proteolytic cleavage and translocation to the mitochondria as determined using Western blot analysis and immunofluorescence staining. Correspondingly, mitochondrial release of cytochrome c could be detected around the same time Bid was cleaved in the wild-type brains. However, no significant cytochrome c release was detected in the bid-deficient brains until 24 h later. This suggests that, although the mitochondrial apoptosis pathway might be activated by multiple mechanisms during focal cerebral ischemia, Bid is critical to its early activation. This notion was further supported by the finding that caspase-3 activation was severely impaired in the bid-deficient brains, whereas activation of caspase-8 was much less affected. Taken together, these data suggest that Bid is activated early in neuronal ischemia in a caspase-8-dependent fashion and that Bid is perhaps one of the earliest and most potent activators of the mitochondrial apoptosis pathway. Thus, the role of Bid in the induction of ischemic neuronal death may render this molecule an attractive target for future therapeutic intervention.
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