Mitoxantrone-Induced Cardiotoxicity in Acute Myeloid Leukemia-A Velocity Vector Imaging Analysis.

BACKGROUND: The purpose of this investigation was to: (1) determine incidence and predictors of mitoxantrone-induced early cardiotoxicity and (2) study left ventricular mechanics before and after receiving mitoxantrone. METHOD AND RESULTS: We retrospectively analyzed 80 subjects diagnosed with acute myeloid leukemia (AML) who underwent chemotherapy with bolus high-dose mitoxantrone. Echocardiographic measurements were taken at baseline and at a median interval of 55 days after receiving mitoxantrone. Thirty-five (44%) of the patients developed clinically defined early cardiotoxicity, 29 (36%) of which developed heart failure. There was a significant decrease in the ejection fraction (EF) not only in the cardiotoxicity group (17.6 ± 14.8%, P < 0.001) but also in the noncardiotoxicity group (5.3 ± 8.4%, P < 0.001). Decrease in global longitudinal strain (GLS) (-3.7 ± 4.5, P < 0.001 vs. -2.4 ± 4.3, P = 0.01) and global circumferential strain (GCS) (-5.6 ± 9, P = 0.003 vs. -5.3 ± 8.7, P < 0.001) was significant in both the cardiotoxicity and noncardiotoxicity group, respectively. A multivariate model including baseline left ventricular end-systolic diameter, baseline pre-E/A ratio, and baseline pre-E/e' ratio was found to be the best-fitted model for prediction of mitoxantrone-induced early clinical cardiotoxicity. CONCLUSION: High-dose mitoxantrone therapy is associated with an excellent remission rate but with a significantly increased risk of clinical and subclinical early cardiotoxicity and heart failure. Mitoxantrone-induced systolic dysfunction is evident from reduction in EF, increase in Tei index, and significant reduction in GLS and GCS. Baseline impaired ventricular relaxation evident from higher E/e' ratio and lower E/A ratio independently predicts increased risk of mitoxantrone-induced early cardiotoxicity.

Functional assessment after sciatic nerve injury in a rat model.

The aim of this study is to evaluate the effectiveness of Sciatic Function Index (SFI) and Basso, Beattie, and Bresnahan (BBB) Locomotor Rating in assessing peripheral nerve injuries. SFI is a standard method for evaluating crush and transected peripheral nerve injuries, likewise BBB for spinal cord injury. Models of chronic nerve compression (CNC), crush, and transection injury were created on Sprague-Dawley rats and functional outcomes were measured using BBB and SFI at 1-week interval for 6 weeks. All injury models showed high correlation between SFI and BBB scores. With crush injury, the SFI showed near complete recovery while BBB showed residual deficits 6 weeks after injury. Both the BBB and SFI were unable to detect motor deficits in 6-week CNC animals. The BBB score should be considered as an adjunct in evaluating peripheral nerve recovery and may be more sensitive in detecting residual deficits than SFI after crush-type injuries.

Transplantation of preconditioned schwann cells in peripheral nerve grafts after contusion in the adult spinal cord. Improvement of recovery in a rat model.

BACKGROUND: Recovery after injury to the peripheral nervous system is based on the pro-regenerative relationship between axons and the extracellular matrix, a relationship established by Schwann cells. As mechanical conditioning of Schwann cells has been shown to stimulate their regenerative behavior, we sought to determine whether transplantation of these cells to the central nervous system (i.e., the spinal cord), with its limited regenerative capacity after injury, would improve axonal regeneration and functional recovery. METHODS: A moderate contusion injury of the spinal cord was created with a force-directed impactor in forty-eight adult Sprague-Dawley rats, and, at one week postinjury, the spinal cords were reexposed in all animals. In twenty-four of these animals, peripheral nerve grafts with Schwann cells that had been obtained from the sciatic nerves of donor animals, and had been either untreated or subjected to mechanical conditioning, were transplanted to the contused area of the cords following resection of the glial scar. Another group of animals was treated with glial scar excision only, and a fourth group had the contusion injury but neither glial excision nor transplantation. Scores according to the Basso, Beattie, Bresnahan (BBB) Locomotor Rating Scale were assigned preoperatively and weekly thereafter. Tract tracing of descending and ascending spinal cord tracts was performed at six weeks postoperatively for quantitative histological evaluation of axonal regeneration. RESULTS: While the recovery following glial scar excision without peripheral nerve transplantation was significantly worse than the recovery in the other groups, both transplantation groups had significantly higher BBB scores than the controls (no transplantation) in the early postoperative period (p < 0.05). Moreover, histological analysis showed markedly increased axonal regeneration at the lesional sites in the animals treated with the mechanically conditioned grafts than in the other groups (p < 0.05). CONCLUSIONS: Functional recovery after spinal cord contusion improved following glial scar excision with transplantation of Schwann cells in peripheral nerve grafts to the contusion areas. Although recovery did not differ significantly between the transplantation groups, only the preconditioned grafts led to axonal regeneration at and past the lesional site. These grafts may further enhance functional recovery as the descending tracts eventually reach their target end-organs.

Resection of glial scar following spinal cord injury.

While many studies have focused on modulating the immune response and enhancing axonal regeneration after spinal cord injury (SCI), there is limited work being performed on evaluating the role of glial scar in SCI. We sought to evaluate the effects of glial scar resection in contusion models and dorsal hemisection models of SCI. At 1-week postinjury, 2 mm of glial scar was excised from specimens in one of the two groups from each injury model. Functional outcome was measured weekly using the Basso, Beattie, Bresnahan (BBB) Locomotor Rating Scale along with histologic evaluation of spinal cord tracts to determine axonal regeneration. Within the dorsal hemisection model, there was no significant difference in recovery for animals that underwent glial scar excision versus animals that did not have scar excision (p = 0.61). Animals subjected to the contusion model, however, demonstrated lower BBB scores in the glial resection group during the earlier postoperative periods (< 4 weeks; p < 0.05). Histological analysis revealed no axons within the glial resection contusion model, and moderate axonal growth within the nonresection contusion group and both hemisection groups (p > 0.05 for differences among the three groups). While glial scar may serve to stabilize the preserved axonal tracts and thereby permit modest recovery in a contusion model of SCI, it may be of less importance with a dorsal hemisection model. These experiments highlight that basic biologic processes following SCI may vary tremendously based on the injury mechanism and that the role of glial scar in spinal cord regeneration must be elucidated.

Transplantation of preconditioned Schwann cells following hemisection spinal cord injury.

STUDY DESIGN: Chronically compressed sciatic nerve segments were transplanted to hemisected spinal cord injured rats. Histologic evaluation and behavior functional outcomes were tested after 6 weeks following surgery. OBJECTIVE: To evaluate the outcome of preconditioned peripheral nerves as a permissive environment in axonal regeneration of the injured spinal cord. SUMMARY OF BACKGROUND DATA: Schwann cells have been used to facilitate a permissive environment for the injured spinal cord to regenerate. Previous experiments have shown compressive mechanical stress to be important in stimulating the regenerative behavior of Schwann cells. Transplantation of highly permissive Schwann cell-enriched peripheral nerve grafts may enhance regeneration in spinal cord injury. METHODS: Adult Sprague-Dawley rats (n = 24) were used to create a hemisection injury of the spinal cord. At 1-week postinjury creation, the spinal cords were reexposed for all animals. Peripheral nerve grafts were obtained from rat sciatic nerve, either untreated or subjected to mechanical compression for 2 weeks with nonconstrictive tubing. Transplantation of grafts was performed after a resection of the glial scar. Functional outcome was measured using the Basso, Beattie, Bresnahan Locomotor Rating Score and footprint analysis. Tract tracing of descending and ascending spinal cord tracts was performed at 6 weeks after surgery for histologic evaluation of axonal regeneration. RESULTS: Preconditioned transplants had significantly higher Basso, Beattie, Bresnahan Scores versus hemisection alone in the late postoperative period (P < 0.05). They also had significantly less foot exorotation and base of support when compared to nonconditioned transplants. Histologic analysis showed increased regeneration at lesional sites for preconditioned transplants versus control group (P < 0.05). CONCLUSIONS: Functional recovery after hemisection injury improved significantly in the late postoperative period with transplantation of preconditioned peripheral nerve. Preconditioned grafts also exhibit sustained axonal regeneration at and past the lesional site in histologic analysis. Further investigation with later time points is warranted.