AOA Critical Issues Symposium: So, You Want to Be a Department Leader: Essentials for Success.

ABSTRACT: Most health systems are vertically integrated, and the leaders of orthopaedic surgery departments or service lines must have a comprehensive understanding of their role in the strategic plan of the health system. Orthopaedic surgery departments must be profitable while supporting the tripartite mission of excellence in clinical care, research, and education. This symposium had 4 specific objectives: to discuss how to (1) create synergy between the department or service line and the health system, (2) develop a strategy to enhance financial stability and revenue growth, (3) develop a comprehensive plan to enhance recruitment and retention of a diverse faculty, and (4) consider alternative strategies to foster education and research, even when the health system may be more focused on revenue generation.

Increased expression of tissue plasminogen activator messenger ribonucleic acid is an immediate response to parathyroid hormone in neonatal rat osteoblasts.

Osteoblasts have been reported to produce tissue-type (t) plasminogen activator (PA), which may be involved in the initiation of bone resorption via plasmin-metalloproteinase degradation of adjacent extracellular matrix. To investigate this cAMP-activated gene, we characterized the PTH regulation of tPA messenger RNA (mRNA) in neonatal rat osteoblast cultures before and after differentiation in vitro. RNA was purified from cultures at confluence or after treatment with glucocorticoid for 1 week and BGJ/ascorbic acid/beta-glycerophosphate for a second week. Northern blots of total or poly(A)+ RNA were hybridized simultaneously with an oligonucleotide or complementary RNA probe for rat tPA and an oligomeric DNA probe for cyclophilin (CYP), an abundant control gene. Differentiation was monitored by expression of rat osteocalcin mRNA and protein. Both bovine PTH1-34 and forskolin caused an increase in tPA/CYP ratio in the presence of phosphodiesterase inhibitor (IBMX) and cycloheximide (CHX). The effect was maximal (16- to 21-fold increase in tPA mRNA and 6- to 8-fold increase in tPA/CYP ratio) with 25 nM hormone for 6 h and was half-maximally stimulated by 0.75-2.5 nM PTH. The tPA response to PTH was present in first passage osteoblast cultures at confluence and after 1 to 2 weeks of glucocorticoid treatment. Exposure of the differentiated cultures of 1,25-dihydroxyvitamin D (10 nM) for 2 days markedly stimulated osteocalcin mRNA while having no effect on tPA. In Northern blots of poly(A)+ RNA from cultures not treated with CHX, IBMX and PTH (2.5 h) independently stimulated tPA mRNA with no significant effect on CYP mRNA levels. The tPA/CYP ratio increased in five consecutive experiments and the effect of IBMX and PTH were additive. These data indicate that PTH acts via cAMP to stimulate tPA expression by a mechanism that is independent of protein synthesis. The enhancement of PTH action by CHX is compatible with feedback inhibition of tPA transcription by a hormone-activated repressor (which has been proposed to occur in granulosa cells) but effects of CHX on tPA mRNA stability may also occur. Expression of tPA mRNA before and after differentiation may indicate that the enzyme has more than one function.

Glucocorticoid-induced differentiation of fetal rat calvarial osteoblasts is mediated by bone morphogenetic protein-6.

Glucocorticoids (GCs) at physiological concentrations promote osteoblast differentiation from fetal calvarial cells, calvarial organ cultures, and bone marrow stromal cells; however, the cellular pathways involved are not known. Bone morphogenetic proteins (BMPs) are recognized as important mediators of osteoblast differentiation. Specific roles for individual BMPs during postembryonic membranous bone formation have yet to be determined. We recently reported that GC potentiated the osteoblast differentiation effects of BMP-2 and BMP-4, but not of BMP-6, which, by itself, was the most potent of the three. In the present study, we used fetal rat secondary calvarial cultures to study the role of BMP-6 during early osteoblast differentiation. Treatment with the GC triamcinolone (10(-9) M) resulted in a 5- to 8-fold increase in BMP-6 steady-state messenger RNA levels, peaking at 12 h. In contrast, BMPs -2, -4, -5, -7, and transforming growth factor (TGF)-beta1 messenger RNA levels increased by less than 2-fold, after GC treatment, compared with untreated control cultures at 24 h. BMP-6 protein secretion increased 6- to 7-fold by 12 h and 12-fold (from 7.5 to 90 ng/ml) by 24 h, as measured by quantitative Western analysis. Treatment of cells with oligodeoxynucleotides antisense to BMP-6 diminished secretion of BMP-6 protein and significantly inhibited the GC-induced differentiation, as determined by a 10-fold decrease in the number of mineralized bone nodules, compared with controls that were treated with sense oligonucleotides or no oligonucleotides (ANOVA, P < 0.05). The antisense oligonucleotide inhibition of differentiation was rescued by treatment with exogenous recombinant human BMP-6. We conclude that GC-induced differentiation of osteoblasts from the pluripotent precursors is mediated, in part, by BMP-6. These results suggest that BMP-6 has an important and unique role during early osteoblast differentiation.

Differential effects and glucocorticoid potentiation of bone morphogenetic protein action during rat osteoblast differentiation in vitro.

Bone morphogenetic proteins (BMPs) induce cartilage and bone differentiation in vivo and promote osteoblast differentiation from calvarial and marrow stromal cell preparations. Functional differences between BMP-2, -4, and -6 are not well understood. Recent investigations find that these three closely related osteoinductive proteins may exert different effects in primary rat calvarial cell cultures, suggesting the possibility of unique functions in vivo. In this study, we use a fetal rat secondary calvarial cell culture system to examine the differential effects of BMP-2, -4, and -6 on early osteoblast differentiation. These cells do not spontaneously differentiate into osteoblasts, as do cells in primary calvarial cultures, but rather require exposure to a differentiation initiator such as glucocorticoid or BMP. We determined that BMP-6 is a 2- to 2.5-fold more potent inducer of osteoblast differentiation than BMP-2 or -4. BMP-6 induced the formation of more and larger bone nodules as well as increased osteocalcin secretion. The effects of all three of these BMPs were potentiated up to 10-fold by cotreatment or pretreatment with the glucocorticoid triamcinolone (Trm). The Trm effects were synergistic with those of BMP-2 or -4, suggesting that this glucocorticoid may increase the cell responsiveness to these BMPs. Finally, BMP-6 did not require either cotreatment or pretreatment with Trm to achieve greater amounts of osteoblast differentiation than seen with BMP-2 or BMP-4 treatment, suggesting that BMP-6 may act at an earlier stage of cell differentiation.

LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation.

Glucocorticoids can promote osteoblast differentiation from fetal calvarial cells and bone marrow stromal cells. We recently reported that glucocorticoid specifically induced bone morphogenetic protein-6 (BMP-6), a glycoprotein signaling molecule that is a multifunctional regulator of vertebrate development. In the present study, we used fetal rat secondary calvarial cultures to determine genes induced during early osteoblast differentiation as initiated by glucocorticoid treatment. Glucocorticoid, and subsequently BMP-6, was found to induce a novel rat intracellular protein, LIM mineralization protein-1 (LMP-1), that in turn resulted in synthesis of one or more soluble factors that could induce de novo bone formation. Blocking expression of LMP-1 using antisense oligonucleotide prevented osteoblast differentiation in vitro. Overexpression of LMP-1 using a mammalian expression vector was sufficient to initiate de novo bone nodule formation in vitro and in sc implants in vivo. These data demonstrate that LMP-1 is an essential positive regulator of the osteoblast differentiation program as well as an important intermediate step in the BMP-6 signaling pathway.

Biology of lumbar spine fusion and use of bone graft substitutes: present, future, and next generation.

Posterolateral lumbar spine arthrodesis is a commonly performed procedure, yet the biology of healing is poorly understood. Nonunion, or failure to achieve a solid bony fusion, occurs in up to 40% of patients. We first developed and validated a rabbit model to characterize the healing process by measuring macroscopic parameters, microscopic parameters, and gene expression. We found that presently available osteoconductive and weakly osteoinductive materials were insufficient to replace autografts, but could in some cases serve as bone graft extenders. In contrast, two osteoinductive growth factors currently in development could replace autograft in non-human primates and in humans, but may be limited by the high dose required, carrier variability, and high cost. We identified, cloned, and sequenced a novel complementary DNA (cDNA) encoding for an intracellular protein LMP-1, which is expressed during the first few hours of osteoblast differentiation. LMP-1 expression is able to induce many BMPs, their receptors, and other bone growth factors. Local implantation of bone marrow cells transfected with LMP-1 cDNA induced spine fusion in 100% of sites tested; no bone formed at the control sites without LMP-1. This strategy of local gene therapy may provide a basis for the next generation of bone graft substitutes.

Lumbar intertransverse-process spinal arthrodesis with use of a bovine bone-derived osteoinductive protein. A preliminary report.

The use of a bovine bone-derived osteoinductive protein extract as a bone-graft substitute was evaluated in a rabbit model of intertransverse process arthrodesis of the lumbar spine. Forty-five adult New Zealand White rabbits had arthrodesis between the fifth and sixth lumbar vertebrae with use of one of three graft materials: autogenous iliac-crest bone, osteoinductive protein delivered in an allogeneic demineralized bone matrix/collagen carrier, or demineralized bone matrix/collagen carrier or demineralized bone matrix/collagen carrier without osteoinductive protein. Fusion was assessed by manual palpation, radiography, biomechanical testing, and light microscopy at two and five weeks after the operation. At two weeks, light microscopic analysis of the arthrodesis site in which osteoinductive protein had been used showed that most of the demineralized bone matrix was still present, with small amounts of membranous and endochondral bone formation at the peripheral margins of the implant. Light microscopic analysis of the five-week specimens showed increased new-bone formation and a more homogeneous and mature fusion mass with the osteoinductive bone protein than with the autogenous bone graft. At five weeks, the fusions with the osteoinductive protein extract were characterized by more secondary spongiosa, with formation of bone marrow centrally and a cortical rim peripherally. Of the thirty-five rabbits that were examined at five weeks, all ten in the group that had received osteoinductive bone protein had a solid fusion, but the rate of fusion was significantly less in the other two groups: eight of thirteen rabbits (p = 0.05) in the group that had received autogenous bone graft and two of twelve rabbits (p = 0.0001) in the group that had received demineralized bone matrix/collagen carrier without osteoinductive bone protein. The use of osteoinductive bone protein resulted in stronger (p = 0.02) and stiffer (p = 0.005) fusions compared with those obtained with the use of autogenous iliac-crest graft.

Orientation of the lumbar facet joints: association with degenerative disc disease.

The orientation of the lumbar facet joints was studied with magnetic resonance imaging in 140 subjects to determine if there is an association between facet tropism and intervertebral disc disease or between the orientation of the facet joints and degenerative spondylolisthesis. The 140 subjects were divided into four groups: sixty-seven asymptomatic volunteers, forty-six of whom did not have a herniated disc on magnetic resonance scans (Group I) and twenty-one who did (Group II); forty-six symptomatic patients who had a herniated disc confirmed operatively (Group III); and twenty-seven patients who had degenerative spondylolisthesis at the interspace between the fourth and fifth lumbar vertebrae (Group IV). Axial scans were made at each lumbar level and digitized, and the facet joint angle was measured by two independent observers with use of image analysis software in a personal computer. The technique of measurement of the facet angles on magnetic resonance scans was validated with a subset of subjects who also had computed tomography scans made. Similar values were obtained with the two methods (r = 0.92; p = 0.00001). For the forty-six asymptomatic volunteers who did not have a herniated disc on the magnetic resonance scans (Group I), the median facet tropism was 5 to 6 degrees and was more than 10 degrees in 24 per cent (eleven) of the subjects. There was no association between increased facet tropism and disc degeneration. At the level of the fourth and fifth lumbar vertebrae, the median facet tropism was 10.3 degrees in the symptomatic patients who had a herniated disc at the same level and 5.4 degrees in the asymptomatic volunteers (Group I) (p = 0.05). The mean orientation of the lumbar facet angles relative to the coronal plane was more sagittal at all levels in the patients who had degenerative spondylolisthesis. The greatest difference was at the level of the fourth and fifth lumbar vertebrae (p = 0.000001). The mean facet angle was 41 degrees (95 per cent confidence interval, 37.6 to 44.6 degrees) in the asymptomatic volunteers and 60 degrees (95 per cent confidence interval, 52.7 to 67.1 degrees) in the patients who had degenerative spondylolisthesis. Furthermore, both the left and the right facet joints were more sagittally oriented in the patients who had degenerative spondylolisthesis. An individual in who both facet-joint angles at the level of the fourth and fifth lumbar vertebrae were more than 45 degrees relative to the coronal plane was twenty-five times more likely to have degenerative spondylolisthesis (95 per cent confidence interval, seven to ninety-eight times). The increase in facet angles at levels other than that of the spondylolisthesis suggests that increased facet angles represent variations in anatomy rather than a secondary result of spondylolisthesis.

Increase of motion between lumbar vertebrae after excision of the capsule and cartilage of the facets. A cadaver study.

Seventeen fresh segments of cadaveric lumbar spines were tested in flexion, extension, and axial rotation. The resulting angular rotations were measured with the use of a goniometer and a three-dimensional system of video analysis. Measurements of flexibility were made, in order, in the intact spine; after decompression (bilateral total laminectomies, partial medial facetectomies, and foraminotomies); after excision of the capsule and cartilage of the facets; and after cancellous bone had been packed into the facet defects. Decompression resulted in a slight increase in the sagittal and axial ranges of motion. Subsequent excision of the capsule and cartilage of the facets, as in preparation for an arthrodesis of the facets, resulted in a significant increase in both the sagittal (5.7 +/- 2.9 degrees, mean and standard deviation) (p < 0.001) and the axial (1.4 +/- 0.9 degrees) (p < 0.01) ranges of motion compared with the motion in the intact specimen and with the motion in the specimen after only decompression had been done (p < 0.01 and p < 0.05, respectively). Packing of bone in the facets did not significantly reduce motion. It was calculated that the increase in the sagittal range of motion after excision of the capsule and cartilage of the facets would increase the tensile strain in a graft between the transverse processes of the fourth and fifth lumbar vertebrae (18 +/- 1 per cent tensile strain [mean and 95 per cent confidence interval] for the intact vertebrae and 25 +/- 1 per cent for the vertebrae in which the facets had been excised).

Mechanical considerations for the syndesmosis screw. A cadaver study.

The purpose of this study was to examine the mechanical necessity of using a syndesmosis screw to supplement rigid internal fixation of the fibula and medial malleolus in the treatment of pronation-external rotation fractures. The legs of thirty embalmed and five fresh cadavera were dissected and mounted through the tibia to a frame so that multiple radiographs could be made with a constant relationship between the specimen and the x-ray apparatus. A standardized pronation-external rotation load was applied to the foot, and widening of the syndesmosis was studied on mortise radiographs that were made after each experimental step. On the basis of previous investigations, we developed a model for pronation-external rotation injuries that included disruption of the syndesmosis and interosseous membrane up to the level of the fibular fracture. Accordingly, multiple repaired fibular fractures could be simulated at several levels in the same specimen by incremental proximal division of the interosseous membrane. Specimens were separated into two groups. Group I consisted of thirteen specimens in which the deltoid ligament, syndesmosis, and interosseous membrane were serially sectioned in 1.5-centimeter increments. Group II (ten sections) was subjected to the same protocol, except that the deltoid ligament was kept intact until the final step. The five fresh specimens were sectioned in the same way as those in Group I. In Group I, since the simulated pronation-external rotation injury included a deltoid tear, rigid medial fixation was not possible; accordingly, there was rigid fibular fixation only.(ABSTRACT TRUNCATED AT 250 WORDS)

Rheumatoid arthritis of the cervical spine. A long-term analysis with predictors of paralysis and recovery.

We analyzed the cases of seventy-three patients who were managed over a twenty-year period for rheumatoid involvement of the cervical spine and were followed for a minimum of two years, with an average follow-up of seven years. A neurological deficit did not develop in thirty-one patients (Ranawat et al. Class I) and paralysis developed in the remaining forty-two patients: Class II in eleven and Class III in thirty-one. Of the forty-two patients in whom paralysis developed, thirty-five had operative stabilization. Seven patients were managed with a soft cervical collar because they refused or were medically unable to have the operation; all of the had an increase in the severity of the paralysis. The posterior atlanto-odontoid interval and the diameter of the subaxial sagittal canal measured on the cervical radiographs demonstrated statistically significant correlations with the presence and severity of paralysis. All of the patients who had a Class-III neurological deficit had a posterior atlanto-odontoid interval or diameter of the subaxial canal that was less than fourteen millimeters. In contrast, the anterior atlanto-odontoid interval, which has traditionally been reported, did not correlate with paralysis. The prognosis for neurological recovery following the operation was not affected by the duration of the paralysis but was influenced by the severity of the paralysis at the time of the operation. The most important predictor of the potential for neurological recovery after the operation was the preoperative posterior atlanto-odontoid interval. In patients who had paralysis due to atlanto-axial subluxation, no recovery occurred if the posterior atlanto-odontoid interval was less than ten millimeters, whereas recovery of at least one neurological class always occurred when the posterior atlanto-odontoid interval was at least ten millimeters. If basilar invagination was superimposed, clinically important neurological recovery occurred only when the posterior atlanto-odontoid interval was at least thirteen millimeters. All patients who had paralysis and a posterior atlanto-odontoid interval or diameter of the subaxial canal of fourteen millimeters had complete motor recovery after the operation. In this series, although only patients who had a neurological deficit were operated on, we observed the range of the posterior atlanto-odontoid interval that was associated with poor or no recovery after the operation, and we identified the safe range on the basis of the patients in whom paralysis did not develop.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation.

We performed magnetic resonance imaging on sixty-seven individuals who had never had low-back pain, sciatica, or neurogenic claudication. The scans were interpreted independently by three neuro-radiologists who had no knowledge about the presence or absence of clinical symptoms in the subjects. About one-third of the subjects were found to have a substantial abnormality. Of those who were less than sixty years old, 20 per cent had a herniated nucleus pulposus and one had spinal stenosis. In the group that was sixty years old or older, the findings were abnormal on about 57 per cent of the scans: 36 per cent of the subjects had a herniated nucleus pulposus and 21 per cent had spinal stenosis. There was degeneration or bulging of a disc at at least one lumbar level in 35 per cent of the subjects between twenty and thirty-nine years old and in all but one of the sixty to eighty-year-old subjects. In view of these findings in asymptomatic subjects, we concluded that abnormalities on magnetic resonance images must be strictly correlated with age and any clinical signs and symptoms before operative treatment is contemplated.

Proximal femoral focal deficiency. Evidence for a defect in proliferation and maturation of chondrocytes.

Proximal femoral focal deficiency is a rare congenital malformation, characterized by a failure of normal development of the proximal part of the femur. To our knowledge, there have been no reports on the histology of fetal growth plates that are affected by this disorder. To characterize this focal developmental anomaly further, we studied the histopathology of the growth plates and epiphyses from a twenty-one-week fetus with unilateral proximal femoral focal deficiency. Although the shape of the cartilaginous anlage of the fetus appeared normal, the growth plate of the proximal part of the involved femur was markedly abnormal. The major findings were: (1) striking failure of the proximal growth plate to migrate proximally, away from the central part of the diaphysis, and failure of formation of a normal growth plate; (2) failure of organization of proliferative and hypertrophic chondrocytes into longitudinal columns; (3) truncation of an immature hypertrophic zone that had abnormal septal architecture; and (4) disorganized vascular invasion with a honeycomb rather than a columnar pattern of primary trabeculae. In contrast, the histological characteristics of the growth plates from the distal part of the femur and from all other long bones were normal.

Metatropic dwarfism. Uncoupling of endochondral and perichondral growth.

Metatropic dwarfism is a rare heritable skeletal dysplasia that is thought to result from a defect in endochondral ossification. Histological studies have been few and have yielded inconsistent findings. In addition, no investigator has commented on the structure and function of the perichondral portion of the growth plate in patients who have metatropic dysplasia. To further characterize this disturbance, histological studies were carried out on autopsy specimens from the proximal part of the femur and the iliac crest of a patient who had this disorder. The major findings were: the absence of formation of normal primary spongiosa in the metaphysis; the presence of a thin seal of bone at the chondro-osseous junction, with abnormal metaphyseal vascular invasion and arrest of endochondral growth; and normal-appearing perichondral ring structures with persistence of circumferential growth. These findings suggest an uncoupling of endochondral and perichondral growth and offer an explanation for the dumbbell-shaped morphological structure of the osseous metaphysis that is seen in patients who have metatropic dysplasia. Other observations included prominence of the cartilaginous canals and vascular channels in the reserve zone; clumping of chondrocytes with enhanced staining of the pericellular matrix in the proliferative zone; a decreased ratio of cells to matrix in the hypertrophic zone, with intracellular metachromatic granules and incomplete evolution of chondrocytes; complete absence of an alcian-blue-positive zone of provisional calcification; and, finally, islands of dysplastic chondrocytes in the metaphysis. These abnormalities suggest that metatropic dysplasia is not simply a disorder of endochondral ossification. There appear to be associated defects in the longitudinal proliferation and maturation of chondrocytes and in the production of normal matrix.

Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation.

Previous investigations with plain radiography, myelography, and computed tomography have shown that degenerative disease of the cervical spine frequently occurs in the absence of clinical symptoms. We studied the magnetic resonance-imaging scans of sixty-three volunteers who had no history of symptoms indicative of cervical disease. The scans were mixed randomly with thirty-seven scans of patients who had a symptomatic lesion of the cervical spine, and all of the scans were interpreted independently by three neuroradiologists. The scans were interpreted as demonstrating an abnormality in 19 per cent of the asymptomatic subjects: 14 per cent of those who were less than forty years old and 28 per cent of those who were older than forty. Of the subjects who were less than forty, 10 per cent had a herniated nucleus pulposus and 4 per cent had foraminal stenosis. Of the subjects who were older than forty, 5 per cent had a herniated nucleus pulposus; 3 per cent, bulging of the disc; and 20 per cent, foraminal stenosis. Narrowing of a disc space, degeneration of a disc, spurs, or compression of the cord were also recorded. The disc was degenerated or narrowed at one level or more in 25 per cent of the subjects who were less than forty years old and in almost 60 per cent of those who were older than forty. The prevalence of abnormal magnetic-resonance images of the cervical spine as related to age in asymptomatic individuals emphasizes the dangers of predicating operative decisions on diagnostic tests without precisely matching those findings with clinical signs and symptoms.

The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study.

BACKGROUND: In 1989, a group of sixty-seven asymptomatic individuals with no history of back pain underwent magnetic resonance imaging of the lumbar spine. Twenty-one subjects (31%) had an identifiable abnormality of a disc or of the spinal canal. In the current study, we investigated whether the findings on the scans of the lumbar spine that had been made in 1989 predicted the development of low-back pain in these asymptomatic subjects. METHODS: A questionnaire concerning the development and duration of low-back pain over a seven-year period was sent to the sixty-seven asymptomatic individuals from the 1989 study. A total of fifty subjects completed and returned the questionnaire. A repeat magnetic resonance scan was made for thirty-one of these subjects. Two neuroradiologists and one orthopaedic spine surgeon interpreted the original and repeat scans in a blinded fashion, independent of clinical information. At each disc level, any radiographic abnormality, including bulging or degeneration of the disc, was identified. Radiographic progression was defined as increasing severity of an abnormality at a specific disc level or the involvement of additional levels. RESULTS: Of the fifty subjects who returned the questionnaire, twenty-nine (58%) had no back pain. Low-back pain developed in twenty-one subjects during the seven-year study period. The 1989 scans of these subjects demonstrated normal findings in twelve, a herniated disc in five, stenosis in three, and moderate disc degeneration in one. Eight individuals had radiating leg pain; four of them had had normal findings on the original scans, two had had spinal stenosis, one had had a disc protrusion, and one had had a disc extrusion. In general, repeat magnetic resonance imaging scans revealed a greater frequency of disc herniation, bulging, degeneration, and spinal stenosis than did the original scans. CONCLUSIONS: The findings on magnetic resonance scans were not predictive of the development or duration of low-back pain. Individuals with the longest duration of low-back pain did not have the greatest degree of anatomical abnormality on the original, 1989 scans. Clinical correlation is essential to determine the importance of abnormalities on magnetic resonance images.

Adenoviral delivery of LIM mineralization protein-1 induces new-bone formation in vitro and in vivo.

BACKGROUND: The LIM mineralization protein-1 (LMP-1) gene encodes for an intracellular protein that induces the expression of several bone growth factors. The purpose of the present study was to determine the feasibility and the optimal dose of adenoviral delivery of the LMP-1 cDNA to promote spinal fusion. METHODS: A replication-deficient human recombinant adenovirus was constructed with the LMP-1 cDNA driven by a cytomegalovirus promoter. In phase 1, an in vitro dose-response experiment was performed to determine the optimal adenovirus-LMP-1 (AdLMP-1) concentration and infection time. In phase 2, nine rabbits had a single-level posterolateral arthrodesis of the lumbar spine with implantation of a carrier matrix loaded with bone-marrow-derived buffy-coat cells that had been infected for ten minutes with adenovirus containing the cDNA for LMP-1 (AdLMP-1) or beta-galactosidase (AdBgal). In phase 3, posterolateral arthrodesis of the spine was performed with implantation of cells infected with AdLMP-1 (ten rabbits) or cells infected with an empty adenovirus that did not contain LMP-1 cDNA (ten rabbits) and the results were compared. In this phase, peripheral-blood-derived buffy-coat cells were used instead of bone-marrow-derived cells and a collagen-ceramic-composite sponge was used as the carrier. RESULTS: In phase 1, the in vitro dose-response experiment showed that a multiplicity of infection of 0.25 plaque-forming units per cell was the most efficient dose. In phase 2, the implants that had received cells infected with AdLMP-1 induced a solid, continuous spinal fusion mass at five weeks. In contrast, the implants that had received cells infected with AdBgal or a lower dose of AdLMP-1 induced little or no bone formation. In phase 3, a solid spinal fusion was observed at four weeks in all ten rabbits that had received cells infected with AdLMP-1 and in none of the ten rabbits that had received cells infected with the empty adenovirus. Biomechanical and histological testing of the AdLMP-1-treated specimens revealed findings that were consistent with a high-quality spinal fusion. CONCLUSIONS: Adenoviral delivery of LMP-1 cDNA promotes spinal fusion in immune-competent rabbits.

Rheumatoid arthritis of the cervical spine. Surgical decision making based on predictors of paralysis and recovery.

OBJECTIVE: This article reviews the current knowledge of predictors of paralysis and the potential for neurologic recovery in patients with rheumatoid arthritis involving the cervical spine. The primary goal is to prevent the onset of an irreversible neurologic deficit. SUMMARY OF BACKGROUND DATA: Use of the posterior atlantodental interval of less than 14 mm as measured from lateral cervical radiographs is a reliable screening tool for identifying high risk patients who require further evaluation with magnetic resonance or computed tomography/myelography. The primary technical objective of surgery in patients with impending neurologic deficit is stabilization of the diseased spine segments and relief of spinal cord compression via reduction of subluxation or direct decompression. Complications are not uncommon, but tend to occur less frequently in patients who have surgical intervention before the onset of severe myelopathy. Pain relief is good when a solid arthrodesis is achieved, and neurologic recovery is most favorable when severe cord compression is not present preoperatively. CONCLUSION: An improved understanding of the natural history, physical findings, and radiographic parameters will allow the construction of a management strategy for timely intervention in rheumatoid patients with progressive cervical disease.

Spine update. Animal use in spinal research.

Progress in biomedical research often has depended on the use of animals as a testing ground for both experimental and clinical hypotheses. Animal models have been widely used in all specialties of medicine and have been crucial for acquiring basic science and clinical knowledge pertaining to spinal surgery. In addition to overcoming the many ethical and societal restrictions normally encountered in human studies, the use of animal models permits certain methodologic approaches inapplicable in humans. The purpose of this article is to: 1) review the general concepts of models, 2) discuss recommendations and regulations regarding the use of animals in biomedical research, and 3) present guidelines for the selection of the most suitable model for a particular study. Animal data are only as applicable as the model from which it is derived. Thus, future animal models must be carefully chosen using rational guidelines and should overcome the deficiencies and limitations of previous models.

Biologic factors affecting spinal fusion and bone regeneration.

STUDY DESIGN: Literature review. OBJECTIVES: This article reviews the existing data on the multiplicity of local and systemic factors affecting lumbar spinal fusion and the general biology of bone regeneration. SUMMARY OF BACKGROUND DATA: Arthrodesis is one of the most commonly performed, yet incompletely understood, procedures in spinal surgery. There exists a paucity of knowledge about the basic biology involved in achieving a successful fusion. METHODS: Medline and manual search of all relevant articles were performed and summarized. RESULTS: The success or failure of spinal fusion may be influenced by a host of local and systemic factors. CONCLUSIONS: Future research should focus on expanding our existing knowledge pertaining to the basic biology of bone regeneration specific to spinal fusion.