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  • Author or Editor: David F. Kallmes x
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Jennifer S. McDonald, Michelle J. Clarke, Gregory A. Helm and David F. Kallmes

Object

The presence of a “July effect,” where the influx of new residents and fellows at teaching hospitals every July may negatively affect patient care and outcomes, is widely debated. The authors used the Nationwide Inpatient Sample (NIS) to identify all cases of spinal surgery and examine outcomes among patients who underwent surgery in July compared with those who underwent surgery in other months.

Methods

Spinal surgery hospitalizations from 2001 to 2008 were identified in the NIS by extracting relevant ICD-9 codes. Rates of in-hospital mortality, discharge to a long-term care facility, and postoperative complications were compared between admission months and between teaching and nonteaching hospitals using the Wilcoxon rank-sum test, Fisher exact test, and multivariate regression analysis.

Results

Compared with patients admitted in other months, patients who were admitted to teaching hospitals in July for spinal surgery showed a similar likelihood of in-hospital mortality (OR 0.94 [95% CI 0.78–1.11], p = 0.46), reaction to implanted device/instrumentation (OR 0.88 [95% CI 0.77–1.02], p = 0.09), and postoperative wound dehiscence (OR 1.12 [95% CI 0.94–1.33], p = 0.25). A significantly higher likelihood of discharge to a long-term care facility (OR 1.03 [95% CI 1.00–1.07], p = 0.0467) and postoperative infection (OR 1.11 [95% CI 1.05–1.17], p = 0.0341) was observed in teaching hospitals in July compared with other months; however, incidence rates were similar regardless of admission month. Higher-risk patients (Charlson score ≥ 2) admitted to teaching hospitals in July had a similar likelihood of all outcomes regardless of admission month.

Conclusions

This study of nationwide hospitalizations demonstrates that the influx of new residents and fellows in July has a negligible effect on periprocedural outcomes following spinal surgery.

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Tord D. Alden, Gerald R. Hankins, Elisa J. Beres, David F. Kallmes and Gregory A. Helm

Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion. Twelve athymic nude rats were used in this study. Recombinant, replication-defective type-5 adenovirus with a universal promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with a universal promoter and ß-galactosidase (ß-gal) gene (Ad-ß-gal) was used as a control. Seven and one-half microliters of virus was injected percutaneously and paraspinally at the lumbosacral junction in three groups (four animals each): 1) Ad-BMP-2 bilaterally, 2) Ad-BMP-2 on the right, Ad-ß-gal on the left, and 3) Ad-ß-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, and 12 weeks. At 12 weeks, the animals were killed for histological inspection. Ectopic bone formation was seen both on three-dimensional CT reconstruction and histologically in all rats at sites treated with Ad-BMP-2. Histological analysis revealed bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes. This study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.

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Tord D. Alden, Debra D. Pittman, Elisa J. Beres, Gerald R. Hankins, David F. Kallmes, Benjamin M. Wisotsky, Kelvin M. Kerns and Gregory A. Helm

Object. Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion.

Methods. Twelve athymic nude rats were used in this study. Recombinant, replication-defective type 5 adenovirus with the cytomegalovirus (CMV) promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with the CMV promoter and β-galactosidase (β-gal) gene (Ad-β-gal) was used as a control. In three groups (four rats each) 7.5 µl of virus (5 × 108 particles/µl) was injected percutaneously and paraspinally at the lumbosacral junction: Group 1 received Ad-BMP-2 bilaterally; Group 2 received Ad-BMP-2 on the right, Ad-β-gal on the left; and Group 3 received Ad-β-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, 8, and 12 weeks. At 12 weeks, the animals were killed and underwent histological inspection. Ectopic bone formation was observed both on three-dimensionally reconstructed CT scans and histological examination in all rats at sites treated with Ad-BMP-2. Histological analysis demonstrated bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes.

Conclusions. Results of this study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.

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Gregory A. Helm, Tord D. Alden, Elisa J. Beres, Sarah B. Hudson, Subinoy Das, Jonathan A. Engh, Debra D. Pittman, Kelvin M. Kerns and David F. Kallmes

Object. Bone morphogenetic proteins (BMPs) have been shown to have significant osteoinductive activity in numerous in vitro and in vivo assay systems, and BMP-2 and BMP-7 are currently being evaluated in human clinical studies. In the spinal region, BMPs have been shown to promote spinal arthrodesis at a higher rate than autologous bone alone. The delivery of BMPs via direct or ex vivo gene therapy techniques is also currently being evaluated and has shown promise in several mammalian models. The present study was designed to evaluate the efficacy of the use of direct, percutaneous BMP-9 adenoviral gene therapy to promote spinal fusion in the rodent.

Methods. Each animal was injected with 7.5 × 108 pfu of a BMP-9 adenoviral vector in the lumbar paraspinal musculature and allowed to survive 16 weeks. Computerized tomography studies and histological analysis demonstrated massive bone induction at the injection sites, clearly leading to solid spinal arthrodesis, without evidence of pseudarthroses, nerve root compression, or systemic side effects.

Conclusions. The results of this study strongly support the advancement of BMP gene therapy techniques toward clinical use.

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Gregory A. Helm, Jonas M. Sheehan, Jason P. Sheehan, John A. Jane Jr., Charles G. diPierro, Nathan E. Simmons, George T. Gillies, David F. Kallmes and Thomas M. Sweeney

✓ Autologous bone grafts are currently considered “gold standard” material for achieving long-term spinal arthrodesis. The present study was performed to determine whether demineralized bone matrix (DBM), type I collagen gels, or bone morphogenetic protein-2 (BMP-2) can improve autologous bone spinal fusions. Using a unilateral decompression—contralateral fusion technique in dogs, each of these materials was added to an autologous bone graft. Volumetric analysis, histological analysis, and biomechanical testing were performed to assess the effectiveness of each material. The DBM had an inhibitory effect on solid bone fusion of the spine, whereas the type I collagen gels improved the bony interface between the graft and the host spine. The BMP-2 strongly enhanced the amount of bone deposition at the fusion site and increased the number of intervertebral levels that were solidly fused. This study strongly supports the use of BMP-2 as an additive to autologous bone grafts in spine stabilization.

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Gregory A. Helm, Jin Zhong Li, Tord D. Alden, Sarah B. Hudson, Elisa J. Beres, Mary Cunningham, Mark M. Mikkelsen, Debra D. Pittman, Kelvin M. Kerns and David F. Kallmes

Object. Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that have attracted the greatest interest. Expression of the BMP-13 gene is predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/neoligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector.

Methods. Athymic nude rats were injected with 3.75 × 1010 plaque-forming units of adenovirus (Ad)-BMP-13 or Ad-β-galactosidase in the thigh musculature, and the region was examined using light and electron microscopy at various time points between 2 days and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the treated tissue displayed the histological and ultrastructural appearance of neotendon/neoligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the treated tissue. A short-term bromodeoxyuridine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection. At all time points, the control AD-β-gal injection sites were found to contain only normal muscle, without evidence of inflammation or mesenchymal cell proliferation.

Conclusions. The results of this study indicate that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.

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Gregory A. Helm, Jin Zhong Li, Tord D. Alden, Sarah A. Hudson, Elisa J. Beres, Mary Cunningham, Mark M. Mikkelsen, Debra D. Pittman, Kelvin M. Kerns and David F. Kallmes

Object

Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that has attracted the greatest interest. Expression of the BMP-13 gene has been shown to be predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/ligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector.

Methods

Athymic nude rats were injected with 3.75 × 1010 plaque-forming unit adenovirus (Ad)-BMP-13 or Ad-β-galactosidase in the thigh musculature, and the regions examined using light and electron microscopy at various time points between 2 and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the induced tissue had the histological and ultrastructural appearance of neotendon/ligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the induced tissue. A short-term bromodeoxyuri-dine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection.

Conclusions

The results of this study suggest that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.