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Biomedical subjects

G A Helm

Publications and source records attributed to G A Helm.

At least 37 records · Page 2Linked to original sources
PubMed1999

Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy.

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 beta-galactosidase (beta-gal) gene (Ad-beta-gal) was used as a control. In three groups (four rats each) 7.5 microl of virus (5x10(8) particles/microl) 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-beta-gal on the left; and Group 3 received Ad-beta-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.

Adenoviridae↗
PubMed1998

Bone morphogenetic protein gene therapy for the induction of spinal arthrodesis.

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 beta-galactosidase (beta-gal) gene (Ad-beta-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-beta-gal on the left, and 3) Ad-beta-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.

Journal Article↗
PubMed1998

In vitro proliferation and adhesion of basic fibroblast growth factor-producing fibroblasts on platinum coils.

PURPOSE: To evaluate the growth and adhesion characteristics in vitro of genetically modified, basic fibroblast growth factor-producing fibroblasts on platinum detachable coils. MATERIALS AND METHODS: Coils of two sizes were coated with laminin, poly-L-lysine, fibronectin, and type I and type IV collagen and were cultured with basic fibroblast growth factor-secreting fibroblasts. Type I collagen strands were inserted in the lumen of some coils. Cellular proliferation and adherence during passage of coils through microcatheters were studied with both light and scanning electron microscopy. Growth factor concentration in the culture medium was measured. RESULTS: Rapid cellular proliferation was noted on all coated coils except those coated with type IV collagen. Proliferation on uncoated coils was slightly slower than on most coated coils, although confluent cell layers were present on uncoated larger-diameter coils within 48 hours. Cells had a marked propensity to grow between the primary coil windings into the coil lumen, except in coils that contained collagen filaments. Passage through microcatheters caused widespread stripping of cells from the outer surface of coils, especially the uncoated samples. Viable cells remained in the coil lumen. Supernatant contained high concentrations of growth factor. CONCLUSION: Platinum embolic coils are a promising mechanism of cell delivery for stimulation of scar formation or other desirable biologic effects.

3T3 Cells↗
PubMed1998

Platinum coil-mediated implantation of growth factor-secreting endovascular tissue grafts: an in vivo study.

PURPOSE: To demonstrate in vivo that platinum embolic coils can be used to deliver genetically modified, growth factor-secreting fibroblast grafts into the endovascular space with the long-term goal of improving fibrosis within coil-embolized cerebral aneurysms. MATERIALS AND METHODS: Murine fibroblasts that contained multiple inserts of the DNA for human basic fibroblast growth factor were grown in culture onto 10-mm-long segments of Guglielmi detachable coils. Control (n = 4) and fibroblast-bearing (n = 4) coils were implanted into the common carotid artery in nude rats. The arterial segments that contained the coil were harvested after 14 or 35 days. Cellular content and collagen formation in the treated vessels were assessed histologically. RESULTS: At both 14 and 35 days, samples with control coils showed primarily involuting blood elements with minimal fibroblast proliferation or collagen formation. At 14 days, samples with fibroblast-bearing coils showed extensive fibroblast proliferation. At 35 days, samples with fibroblast-bearing coils showed marked interval fibroblast proliferation and collagen formation. CONCLUSION: Platinum coils can be used as a cell delivery device. Direct intravascular implantation of growth factor-secreting fibroblast grafts leads to improved intravascular scar formation, therefore theoretically reducing the potential for aneurysm regrowth or coil compaction.

Animals↗
PubMed1998

Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm.

OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.

Animals↗
PubMed1997

Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage.

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ET(A) receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH. Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters. The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm2 in the control group to 0.106 mm2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm2 (78.1% of control) compared with the placebo BID value of 0.134 mm2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups. These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.

Journal Article↗
PubMed1997

Acquired lumbar stenosis: topic review and a case series.

Stenosis of the central and lateral lumbar vertebral canal can be congenital or acquired; the latter is most often caused by a degenerative process. The associated neurogenic claudication and/or radiculopathic symptom complexes are thought to result from compression of the cauda equina and lumbosacral nerve roots by hypertrophy of or encroachment by any combination of the following: canal walls, ligamenta flava, intervertebral discs, posterior longitudinal ligament, or epidural fat. The authors' technique for the treatment of lumbar stenosis involves extensive unilateral decompression with undercutting of the spinous process and obviates the need for instrumentation by using a contralateral autologous bone fusion. The results in a series of 29 patients in whom the procedure was performed suggest that this decompression method safely and successfully treats not only the radicular symptoms caused by lateral stenosis but also the neurogenic claudication symptoms associated with central stenosis. In addition, the procedure can preserve spinal stability without instrumentation by using contralateral autologous bone fusion along the laminae and spinous processes.

Journal Article↗
PubMed1997

MPP+ induced apoptotic cell death in SH-SY5Y neuroblastoma cells: an electron microscope study.

PD is a common, late-onset neurodegenerative disorder that results in part from the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The neurotoxin MPTP can induce PD-like clinical symptomatology and neuropathological destruction and, thus, has been used as a PD model. The human neuroblastoma cell line SH-SY5Y possesses many of the qualities of human neurons and, as such, has served as a model for them. Apoptosis is the mode of cell death induced in SH-SY5Y cells by MPTP, and this was confirmed with nick end labeling and bisbenzimide staining. Transmission electron microscopic analysis of the ultrastructural changes occurring in neurotoxin exposed SH-SY5Ys revealed many morphological characteristics consistent with apoptosis. These changes included plasmalemmal blebbing, altered cytosolic density, nuclear condensation and fragmentation, pronounced vacuole formation, ribosomal dispersion, and the disappearance of the golgi complex, microtubules, and smooth endoplasmic reticulum. Limited amounts of rough endoplasmic reticulum and mitochondria exhibited normal morphology throughout the apoptotic changes but then were disrupted during secondary necrotic changes. The in vitro induction of apoptosis by a parkinsonism neurotoxin might be reflective of the mechanisms of in vivo nigral degeneration occurring during PD.

1-Methyl-4-phenylpyridinium↗
PubMed1997

Partial pediculectomy in the treatment of lumbar spinal stenosis: technical note.

OBJECTIVE: We note an additional pathological condition associated with lumbar spinal stenosis that may be responsible for significant postoperative pain. Recognizing that nerve roots are stretched around hypertrophic pedicles in some cases of spinal stenosis, we have altered our surgical management of these cases to address what may be a previously unrecognized but significant anatomic pathological finding. SURGICAL TECHNIQUE: After ipsilateral posterior bony decompression of the spinal canal, the nerve root is examined as it courses around the pedicle. If the root appears stretched, the medial part of the pedicle is removed using first a diamond bit and then a curet. The nerve root is retracted and protected during this procedure. RESULTS: Inspection of the root after partial pediculectomy frequently reveals lateral movement of the root into space previously occupied by the pedicle. Anatomically, the nerve is better decompressed and free of obstruction. This technique adds little time to the overall duration of the operation. CONCLUSION: Anatomic evidence obtained through intraoperative examination and preoperative imaging techniques indicates that partial pediculectomy may play a role in the treatment of some cases of lumbar stenosis.

Decompression, Surgical↗
PubMed1997

Routine angiography after surgery for ruptured intracranial aneurysms: a cost versus benefit analysis.

PURPOSE: To assess the cost versus the benefit of routine cerebral angiography after surgery for ruptured aneurysms. METHODS: Decision tree and Markov analyses that used cohort simulation were conducted to determine the incremental cost:benefit ratio of routine postsurgical angiography. Input data for unexpected partially clipped and unclipped cerebral aneurysms were estimated from the literature for the following variables: frequency; annual rate of subsequent hemorrhage; morbidity and mortality rates of subsequent hemorrhage; efficacy and morbidity and mortality rates of subsequent surgery; and costs of subsequent surgery, angiography, subsequent hemorrhage of aneurysm, and rehabilitation. RESULTS; Baseline input variables resulted in an acceptable cost:benefit ratio for routine postsurgical angiography. However, essentially all of the benefit was derived from intervening in cases of unexpected unclipped aneurysms rather than partially clipped aneurysms. Isolated instances of angiography and subsequent surgery for unexpected partially clipped aneurysms yielded unacceptable cost:benefit ratios. Surgical costs had minimal effect on the analysis. CONCLUSIONS: When routine postsurgical angiography was performed primarily to diagnose and to subsequently operate on unexpected partially clipped aneurysms, the cost:benefit ratio was unacceptable. However, even low frequencies of unexpected unclipped aneurysms resulted in favorable cost:benefit ratios.

Algorithms↗
PubMed1997

Utilization of type I collagen gel, demineralized bone matrix, and bone morphogenetic protein-2 to enhance autologous bone lumbar spinal fusion.

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.

Animals↗
PubMed1996

The accessory optic system in the frog, Rana Pipiens: an electron microscopic study of the retinal afferents utilizing the anterograde tracer biocytin.

The retinal afferents to the basal optic nucleus in the frog, Rana Pipiens, were labeled anterogradely with biocytin and subsequently studied at the electron microscopic level. Labeled synaptic terminals in the nucleus varied in size from 0.5 microns to 2.0 microns and made symmetric synaptic contacts with large and small dendrites, although very rare axospinous and axosomatic contacts were also demonstrated.

Animals↗
PubMed1996

Molecular methods of enhancing lumbar spine fusion.

OBJECTIVE: An optimal method for spinal fusion would induce rapid growth of bone via an osteoconductive and osteoinductive implant. This study examines the spinal fusion enhancement potential of some osteoconductive and osteoinductive biomaterials. METHODS: Four similar canines received unilateral posterolateral fusions on the left side at T13-L1 and L4-L5 and on the right side at L2-L3 and L6-L7. The experiments were grouped as follows: Group A, autogenous bone harvested from the iliac crest; Group B, autogenous bone and collagen; Group C, no implant; and Group D, autogenous bone, collagen, and recombinant human bone morphogenetic protein-2. Radiographic assessment, three-dimensional computed tomographic volumetric analysis, and biomechanical testing were performed at each level. RESULTS: For Groups A and B, the fusions demonstrated moderate bone formation at 6 and 12 weeks postoperatively. Group D fusions exhibited earlier and more dramatic increases in volume and radiodensity and eventually were comparable in size to the vertebral bodies. Average fusion volumes computed from three-dimensional computed tomographic analysis were: Group A = 1.243 cc, Group B = 0.900 cc, Group C = 0.000 cc, and Group D = 6.668 cc (P = 0.003 compared to Group A). Group D exhibited flexion and extension biomechanical properties much greater than controls. The addition of recombinant human bone morphogenetic protein-2 consistently yielded the strongest fused segments and, on average, enhanced extension stiffness by 626% and flexion stiffness by 1120% over controls. CONCLUSION: The most advantageous spinal fusion implant matrix consisted of recombinant human bone morphogenetic protein-2, autogenous bone, and collagen. Future investigators, however, need to examine the appropriate quantities of the individual components and clarify the efficacy of the matrix for the various types of spinal fusion approaches.

Animals↗
PubMed1996

Treatment of lumbar spinal stenosis by extensive unilateral decompression and contralateral autologous bone fusion: operative technique and results.

A new surgical technique for the treatment of lumbar spinal stenosis features extensive unilateral decompression with undercutting of the spinous process and, to preserve stability, uses contralateral autologous bone fusion of the spinous processes, laminae, and facets. The operation was performed in 29 patients over a 19-month period ending in December of 1991. All individuals had been unresponsive to conservative treatment and presented with low-back pain in addition to signs and symptoms consistent with neurogenic claudication or radiculopathy. Nine had undergone previous lumbar decompressive surgery. The minimum and mean postoperative follow-up times were 2 and 2 1/2 years, respectively. The mean patient age was 64 years; only two patients were younger than 50 years of age. Of the patients with neurogenic claudication, 69% reported complete pain relief at follow-up review. Of those with radicular symptoms, 41% had complete relief and 23% had mild residual pain that was rated 3 or less on a pain-functionality scale of 0 to 10. For the entire sample, this surgery decreased pain from 9.2 to 3.3 (p < 0.0001) on the scale. Sixty-nine percent of patients were satisfied with surgery. Low-back pain was significantly relieved in 62% of all patients (p < 0.0001). Low-back pain relief correlated negatively with number of levels decompressed (p < 0.05). To assess fusion, follow-up flexion/extension radiographs were obtained, and no motion was detected at the surgically treated levels in any patient. The results suggest that this decompression procedure safely and successfully treats not only the radicular symptoms caused by lateral stenosis but also the neurogenic claudication symptoms associated with central stenosis. In addition, the procedure, by using contralateral autologous bone fusion along the laminae and spinous processes, can preserve stability without instrumentation.

Adult↗
PubMed1996

Acquired lumbar spinal stenosis.

Based on the individual clinical presentation and radiographic findings, an operation that completely decompresses the neural elements in the spinal canal and neural foramina followed by posterior, posterolateral, or interbody fusion, with or without instrumentation should be the procedure of choice in the future. The introduction of pharmacological agents to decrease scarring around the decompressed nerve roots will also increase the number of successful procedures. It must be stressed, however, that any new operative technique must be tested in a rigorous fashion, ideally with a prospective randomized clinical trial.

Humans↗
PubMed1994

Magnetic resonance imaging of neuronal grafts in the primate.

This preliminary study demonstrates the vital role that magnetic resonance imaging plays in the study of neuronal grafts in a nonhuman primate model of Huntington's disease. MRI scans were used to accurately locate and stereotactically lesion the anterior putamen of an adult rhesus monkey, thereby mimicking the anatomical and biochemical changes in Huntington's disease. Follow-up scans were utilized to confirm correct placement of the lesion and to stereotactically implant primate fetal neuronal tissue precisely into the lesion. Additionally, MRI appeared capable of imaging the fetal striatal grafts in rhesus monkeys. While the precise cellular composition of growing grafts was not identifiable on MRI scans, differentiation between normal, lesioned, and engrafted tissue was possible. Correlation of the magnetic resonance images of the grafted regions with actual graft tissue in perfused sections of the brain was shown. The use of magnetic resonance imaging, as indicated in these neuronal implantation studies, allows for a wide variety of future research possibilities where noninvasive and precise localization of the graft is mandated.

Animals↗
PubMed1993

Degeneration of long-term fetal neostriatal allografts in the rhesus monkey: an electron microscopic study.

Primate fetal neostriatal neurons were implanted into the ibotenic acid-lesioned primate striatum and the animals were allowed to survive for 8 months. Light microscopic examination of the transplanted tissue demonstrated that the grafts were between 1.0 and 1.5 mm in diameter. The transplants were highly gliotic, but contained both normal appearing and degenerating neurons. At the electron microscopic level, the transplanted neurons displayed ultrastructural features identical to those of medium spiny, medium aspiny, and large aspiny striatal neurons. However, the majority of the grafted neurons showed evidence of degeneration. The grafts' neuropil demonstrated numerous glial processes, as well as mature axodendritic and axospinous synapses. Although this study was limited to only two graft recipients, the degenerative changes seen in the long-term primate allografts suggest that extension of these techniques into the clinical setting may be premature at the present time.

Animals↗