Hsp72 preserves muscle function and slows progression of severe muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.

Blood conservation techniques in spinal deformity surgery: a retrospective review of patients refusing blood transfusion.

STUDY DESIGN: A retrospective review. OBJECTIVE: To review the effectiveness of blood conservation techniques in the spinal fusion of patients that refuse blood transfusion; specifically the Jehovah's witnesses population. SUMMARY OF BACKGROUND: Spinal surgery can be challenging in patients refusing blood transfusion. There is paucity in the literature examining blood conservation techniques in spinal surgery. METHODS: The radiographic and medical records of 19 Jehovah's witnesses patients who underwent spinal deformity surgery at a single institution between 2000 and 2003 were reviewed. Patients were assessed for excessive blood loss (EBL), deformity correction, operative time, perioperative complications, and hospital stay. At latest follow-up (mean, 40 months; range, 8-76) the patients were examined for radiographic fusion, progression and complications. RESULTS: Spinal fusion was attempted in 19 patients, with a mean age of 17 years (range, 10-36 years). All 19 patients were identified through the "Bloodless Surgery Program." Hypotensive anesthesia, hemodilution, and cell saver was employed for all 19 cases. Erythropoietin with supplemental iron was used in 15 patients. Aprotinin was used in 3 patients. EBL and blood returned by cell saver averaged 855 and 341 mL, respectively. Operative times average 315 minutes. The average drop in hemoglobin from after surgery was 3.1 g/dL. There were 2 intraoperative complications: (i) transient loss of somatosensory evoked potential/motor evoked potential signals; and (ii) one surgery abandoned due to EBL. The average spinal deformity correction was 58%. There were 3 postoperative complications, none related to their refusal of a transfusion. 17 patients were available for radiographic and clinic follow-up of at least 24 months. All displayed radiographic fusion without progression. CONCLUSION: These blood conservation techniques allow satisfactory completion of deformity surgery on those patients not willing to be transfused and without major anesthetic or medical complications.