Cerebral ischemia-reperfusion injury: a novel therapeutic approach with TAK-218.

The goal of the present study was to evaluate the potential neuroprotective effect of TAK-218 in an in vivo rat focal cerebral ischemia/reperfusion model. TAK-218 is a novel compound with multiple antiischemic properties, including suppression of aberrant dopamine release, modulation of sodium channels, and inhibition of lipid peroxidation. The study was a blinded, randomized, placebo-controlled study of TAK-218 in a three-vessel focal ischemic rat model. A total of 22 rats were randomly assigned to the treatment or placebo group. Animals were injected intrapertoneally with either a 2 mg/kg dose of drug or saline at 2 hours after reperfusion. Infarction volume was measured with use of 2,3,5-triphenyltetrazolium chloride. Total adjusted infarction volume in treated animals decreased by 10%. With use of a statistical analysis requiring 80% power with a 20% reduction desired effect, there was no statistically significant difference in the end-point of infarction volume between drug and placebo treatment groups. In light of the proven efficacy of thrombolytic therapy for acute stroke, it is now desirable to test neuroprotective agents during the 3-hour therapeutic window after ischemia. Further research is necessary to discern if a therapeutic agent with multiple antiischemic properties may provide a more robust neuroprotective effect than an agent with a single neuroprotective action.

Human RhoA/RhoGDI complex expressed in yeast: GTP exchange is sufficient for translocation of RhoA to liposomes.

The human small GTPase, RhoA, expressed in Saccharomyces cerevisiae is post-translationally processed and, when co-expressed with its cytosolic inhibitory protein, RhoGDI, spontaneously forms a heterodimer in vivo. The RhoA/RhoGDI complex, purified to greater than 98% at high yield from the yeast cytosolic fraction, could be stoichiometrically ADP-ribosylated by Clostridium botulinum C3 exoenzyme, contained stoichiometric GDP, and could be nucleotide exchanged fully with [3H]GDP or partially with GTP in the presence of submicromolar Mg2+. The GTP-RhoA/RhoGDI complex hydrolyzed GTP with a rate constant of 4.5 X 10(-5) s(-1), considerably slower than free RhoA. Hydrolysis followed pseudo-first-order kinetics indicating that the RhoA hydrolyzing GTP was RhoGDI associated. The constitutively active G14V-RhoA mutant expressed as a complex with RhoGDI and purified without added nucleotide also bound stoichiometric guanine nucleotide: 95% contained GDP and 5% GTP. Microinjection of the GTP-bound G14V-RhoA/RhoGDI complex (but not the GDP form) into serum-starved Swiss 3T3 cells elicited formation of stress fibers and focal adhesions. In vitro, GTP-bound-RhoA spontaneously translocated from its complex with RhoGDI to liposomes, whereas GDP-RhoA did not. These results show that GTP-triggered translocation of RhoA from RhoGDI to a membrane, where it carries out its signaling function, is an intrinsic property of the RhoA/RhoGDI complex that does not require other protein factors or membrane receptors.

Optimizing accuracy in magnetic resonance imaging-guided stereotaxis: a technique with validation based on the anterior commissure-posterior commissure line.

OBJECT: Some of the earliest successful frame-based stereotactic interventions directed toward the thalamus and basal ganglia depended on identifying the anterior commissure (AC) and posterior commissure (PC) in a sagittal ventriculogram and defining the intercommissural line that connects them in the midsagittal plane. The AC-PC line became the essential landmark for the localization of neuroanatomical targets in the basal ganglia and diencephalon and for relating them to stereotactic atlases. Stereotactic/functional neurosurgery has come to rely increasingly on magnetic resonance (MR) imaging guidance, and methods for accurately determining the AC-PC line on MR imaging are being developed. The goal of the present article is to present the authors' technique. METHODS: The technique described uses MR sequences that minimize geometric distortion and registration error, thereby maximizing accuracy in AC-PC line determinations from axially displayed MR data. The technique is based on the authors' experience with the Leksell G-frame but can be generalized to other MR imaging-based stereotactic systems. This methodology has been used in a series of 62 stereotactic procedures in 47 adults (55 pallidotomies and seven thalamotomies) with preliminary results that compare favorably with results reported when using microelectrode recordings. The measurements of the AC-PC line reported here also compare favorably with those based on ventriculography and computerized tomography scanning. CONCLUSIONS: The methodology reported here is critical in maintaining the accuracy and utility of MR imaging as its role in modern stereotaxy expands. Accurate parameters such as these aid in ensuring the safety, efficacy, and reproducibility of MR-guided stereotactic procedures.

Sutureless repair of major intracranial vessels with the Sundt clip-graft: technical note.

Major intracranial vessels can be damaged during tumor resection. With the availability of refined microvascular techniques, direct repair or by-pass of the damaged segment is possible. These methods, however, often require temporary occlusion of the offending vessel, can result in a less than optimal angiographic result, and are difficult to perform in a deep field. Additionally, in some patients direct repair or by-pass is not feasible because of the friability of the vessel or as a result of the large size of the tear. In these cases the Sundt clip-graft represents a valid adjunct to the armamentarium of the surgeon. Over the years, it has been used by the senior author in five patients where vascular injury occurred during the removal of brain tumors (3 meningiomas, one pituitary adenoma, and one low-grade glioma). In this report we illustrate our most recent experience with this ingenious tool. A 22-year-old man underwent resection of a recurrent left temporal lobe low-grade glioma. During resection of the tumor, a tear occurred in a branch of the middle cerebral artery. The tear was repaired using a Sundt clip-graft. A post-operative angiogram, performed five days later, showed patency of the vessel with no evidence of wall irregularities. Described 30 years age to be used primarily in aneurysm surgery, the Sundt clip-graft provides an excellent, too often forgotten, sutureless method of repairing intracranial vessels damaged during tumor removal.

Recovery of useful hearing after posterior fossa surgery: the role of otoacoustic emissions: case report.

OBJECTIVE AND IMPORTANCE: Hearing preservation has become an important issue in surgical procedures involving the cerebellopontine angle (CPA). Although several prognostic factors for hearing preservation in patients with "useful" preoperative hearing have been described, it is difficult to predict which patients have the potential for hearing preservation or recovery. Otoacoustic emission measurement is a new technique that allows recording of sounds produced by the cochlear outer hair cells as a normal byproduct of the receptor process and can be used to assess cochlear involvement in patients with hearing loss. CLINICAL PRESENTATION: We present the case of a 53-year-old patient with a recurrent arachnoid cyst of the CPA. She had noticed progressive severe hearing loss ipsilateral to the cyst that was confirmed by preoperative audiogram. TECHNIQUE: Otoacoustic emissions were obtained and were within normal limits on the involved side, suggesting that the cochlear outer hair cells were still intact and that the patient had the potential for hearing recovery. The CPA was decompressed by marsupialization of the cyst. Postoperative audiogram demonstrated a dramatic recovery of hearing to a normal level. CONCLUSION: Otoacoustic emissions clearly provide valuable information about the potential for hearing preservation/recovery after CPA surgery and have significant implications for the current neurosurgical management of these lesions.

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.

One century after the description of the "sign": Joseph Babinski and his contribution to neurosurgery.

One hundred years ago, in 1896, Joseph Babinski published a preliminary report on "réflexe cutané plantaire" (cutaneous plantar reflex), which became widely known as the Babinski sign. However, Babinski did not view the description of the sign as his major achievement. Instead, he considered his greatest contribution to medicine to be his having "... indiqué la voie à Martel et à Vincent" (pointed the way to Thierry de Martel and Clovis Vincent, founders of French neurosurgery). Several of Babinski's manuscripts deal with neurosurgical problems. In 1900, 1 year before Alfred Fröhlich's description, Babinski gave the first account of the adiposogenital syndrome and its relation to pituitary-hypothalamic disorder. Many other original contributions ensued. These include a report on the relief of papilledema by surgical decompression in 1901, the successful removal (in collaboration with de Martel) of an intracranial meningioma in 1909, the description (again with de Martel) of a cerebellopontine angle tumor treated by surgical excision with good result in 1925, and several manuscripts concerning diagnosis and treatment of compressive spinal cord lesions. Babinski's dream to establish a department of neurosurgery became a reality shortly after his death. The Hôpital de la Pitie in Paris, where Babinski did most of his work, established the first French department of neurosurgery chaired by Babinski's pupil, Vincent.

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.

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.

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.

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.

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.

Carotid artery revascularization following Crutchfield clamp placement. Report of two cases.

Several types of adjustable clamp have been widely utilized to gradually occlude the carotid artery for the treatment of various intracranial vascular lesions. A fairly large number of patients, many of whom have not been adequately followed, have these clamps still in place. The authors report two patients, initially treated with a Crutchfield clamp for an intracranial aneurysm, in whom carotid artery system revascularization occurred through the clamp many years later, leading to continued filling of the aneurysm. Recommendations are given on monitoring patients with Crutchfield clamps in order to minimize long-term complications.

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.

A method for utilizing biocytin to study retinofugal pathways at the light and electron microscopic levels.

Numerous methods have been utilized in the past to study the retinofugal pathway at both the light and electron microscopic levels. However, many of these techniques have technical drawbacks that make them difficult to use in electron microscopic studies. We present herein a method for utilizing the anterograde tracer biocytin to study the retinal pathways at both the light and electron microscopic levels. Biocytin is an especially useful tracer since it clearly labels very small axons and boutons in addition to the larger fibers. In addition, the synaptic ultrastructure is left intact and the technique can be utilized in numerous double-labeling neuroanatomical studies.

Descriptive morphology of developing fetal neostriatal allografts in the rhesus monkey: a correlated light and electron microscopic Golgi study.

Primate fetal striatal neurons were transplanted into the ibotenic acid lesioned rhesus monkey striatum. Ten weeks after transplantation the monkeys were transcardially perfused and graft tissue was histologically stained. Golgi impregnated, and processed for electron microscopy. The monkeys received magnetic resonance imaging (MRI) scans before lesioning, after lesioning, and ten weeks after transplantation to noninvasively study the striatal grafts. The study demonstrated that fetal striatal grafts, measuring up to 0.4 x 0.8 cm, can survive for extended periods of time in the non-human primate. Hematoxylin-eosin stained sections of the transplant demonstrated that neuronal, glial, vascular, and lymphocytic cells were present in the graft. The majority of the neurons had somatic diameters between 8 and 20 microns and were characterized by nuclei containing multiple nucleoli. A few neurons within the graft had somatic diameters up to 40 microns. These larger neurons exhibited more mature cytoplasm containing a moderate amount of Nissl substance. Some of the blood vessels within the graft were surrounded by a large number of plasma cells, but there was no evidence of hemorrhage or necrosis. Bielschowsky staining and Golgi impregnation of the transplanted tissue demonstrated that there were neurons at various degrees of differentiation. Some of the neurons had varicose dendrites, growth cones, and filopodia, which are all characteristics of immature neurons, while others had a much more mature appearance, including a moderate number of dendritic spines. Some of these neurons had an appearance typical of differentiating "medium spiny" neurons of the normal striatum. Electron microscopic analysis of the transplanted tissue and individual Golgi-impregnated neurons within the transplant confirmed that there were developing neurons within the graft. These neurons had an increased nuclear-to-cytoplasmic ratio and had nuclei containing multiple nucleoli. The neuropil surrounding these neurons was loosely organized and contained large areas of extracellular space. The neuropil exhibited developing dendrites, numerous growth cones, and mature synapses. In summary, the study demonstrated that fetal striatal allografts can survive for up to three months in the rhesus monkey and undergo normal differentiation as assessed by Golgi impregnation and electron microscopy.