Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-ß, and/or bevacizumab for glioblastoma.

INTRODUCTION: We examined whether the amino acid PET tracers, trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) and (11)C-methyl-l-methionine ((11)C-Met), are suitable for detecting early responses to combination therapies including temozolomide (TMZ), interferon-ß (IFN), and bevacizumab (Bev) in glioblastoma. METHODS: Human glioblastoma U87MG (U87) cells were incubated with low dose TMZ to induce chemoresistance. Both trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) uptake were quantified using triple-label accumulation assays to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation) in vitro. U87 and U87R (TMZ-resistant subculture) cells were inoculated into the right and left basal ganglia, respectively, of F344/N-rnu rats. The efficacy of single-agent (TMZ, Bev) and combination therapy (TMZ/IFN, TMZ/Bev, TMZ/IFN/Bev) was examined in orthotopic gliomas using MRI, Evans blue extravasation, anti-(14)C-FACBC, and (3)H-Met autoradiography, and MIB-1 immunostaining. RESULTS: TMZ treatment decreased (3)H-TdR accumulation and the volume distribution of anti-(14)C-FACBC and (3)H-Met in U87 but not U87R cells. TMZ/IFN combination therapy significantly decreased these parameters in U87R cells; however, Bev had no additional effect in vitro. In vivo, U87R-derived gliomas were observed as equivocal tumors on MRI and T2-high intensity lesions. Bev treatment, either alone or in combination, markedly decreased U87 enhancing lesions. By contrast, autoradiographic images using anti-(14)C-FACBC and (3)H-Met clearly delineated tumor extent, which spread widely beyond T2-high intensity lesions and enhancing lesions. TMZ therapy significantly decreased tracer accumulation and proliferation of U87- but not U87R-derived tumors. TMZ/IFN combination treatment significantly decreased these parameters in U87R tumors, which were further reduced (in both tumor types) by Bev addition. Tracer uptake correlated with the MIB-1 proliferation index. However, MRI was unsuitable for tumor delineation and assessment of Bev treatment response. CONCLUSIONS: Triple-agent therapy (TMZ/IFN/Bev) was effective against even TMZ-resistant glioblastomas. PET with amino acid tracers provides useful information on the early response of glioblastomas to single-agent and combination therapy.

A novel screw guiding method with a screw guide template system for posterior C-2 fixation: clinical article.

OBJECT: Accurate insertion of C-2 cervical screws is imperative; however, the procedures for C-2 screw insertion are technically demanding and challenging, especially in cases of C-2 vertebral abnormality. The purpose of this study is to report the effectiveness of the tailor-made screw guide template (SGT) system for placement of C-2 screws, including in cases with abnormalities. METHODS: Twenty-three patients who underwent posterior spinal fusion surgery with C-2 cervical screw insertion using the SGT system were included. The preoperative bone image on CT was analyzed using multiplanar imaging software. The trajectory and depth of the screws were designed based on these images, and transparent templates with screw guiding cylinders were created for each lamina. During the operation, after templates were engaged directly to the laminae, drilling, tapping, and screwing were performed through the templates. The authors placed 26 pedicle screws, 12 pars screws, 6 laminar screws, and 4 C1-2 transarticular screws using the SGT system. To assess the accuracy of the screw track under this system, the deviation of the screw axis from the preplanned trajectory was evaluated on postoperative CT and was classified as follows: Class 1 (accurate), a screw axis deviation less than 2 mm from the planned trajectory; Class 2 (inaccurate), 2 mm or more but less than 4 mm; and Class 3 (deviated), 4 mm or more. In addition, to assess the safety of the screw insertion, malpositioning of the screws was also evaluated using the following grading system: Grade 0 (containing), a screw is completely within the wall of the bone structure; Grade 1 (exposure), a screw perforates the wall of the bone structure but more than 50% of the screw diameter remains within the bone; Grade 2 (perforation), a screw perforates the bone structures and more than 50% of the screw diameter is outside the pedicle; and Grade 3 (penetration), a screw perforates completely outside the bone structure. RESULTS: In total, 47 (97.9%) of 48 screws were classified into Class 1 and Grade 0, whereas 1 laminar screw was classified as Class 3 and Grade 2. Mean screw deviations were 0.36 mm in the axial plane (range 0.0-3.8 mm) and 0.30 mm in the sagittal plane (range 0.0-0.8 mm). CONCLUSIONS: This study demonstrates that the SGT system provided extremely accurate C-2 cervical screw insertion without configuration of reference points, high-dose radiation from intraoperative 3D navigation, or any registration or probing error evoked by changes in spinal alignment during surgery. A multistep screw placement technique and reliable screw guide cylinders were the key to accurate screw placement using the SGT system.

Treatment outcomes in glioblastoma patients aged 76 years or older: a multicenter retrospective cohort study.

Age is one of the most important prognostic factors in glioblastoma patients, but no standard treatment has been established for elderly patients with this condition. We therefore conducted a retrospective cohort study to evaluate treatment regimens and outcomes in elderly glioblastoma patients. The study population consisted of 79 glioblastoma patients aged ≥ 76 years (median age 78.0 years; 34 men and 45 women). The median preoperative Karnofsky performance status (KPS) score was 60. Surgical procedures were classified as biopsy (31 patients, 39.2 %), <95 % resection of the tumor (21 patients, 26.9 %), and ≥ 95 % resection of the tumor (26 patients, 33.3 %). Sixty-seven patients (81.0 %) received radiotherapy and 45 patients (57.0 %) received chemotherapy. The median overall progression-free survival time was 6.8 months, and the median overall survival time was 9.8 months. Patients aged ≥ 78 years were significantly less likely to receive radiotherapy (p = 0.004). Patients with a postoperative KPS score of ≥ 60 were significantly more likely to receive maintenance chemotherapy (p = 0.008). Multivariate analyses identified two independent prognostic factors: postoperative KPS score ≥ 60 (hazard ratio [HR] = 0.531, 95 % confidence interval [CI] 0.315-0.894, p = 0.017) and temozolomide therapy (HR = 0.442, 95 % CI 0.25-0.784, p < 0.001).The findings of this study suggest that postoperative KPS score is an important prognostic factor for glioblastoma patients aged ≥ 76 years, and that these patients may benefit from temozolomide therapy.

Aberrant increase in cytochrome c oxidase subunit I precedes neuronal death after cerebral ischemia.

Cerebral ischemia is known to produce excessive reactive oxygen species in mitochondria, and these radicals initiate radical chain reactions, causing cellular macromolecule damage, and also promote the mitochondrial apoptosis pathway, ultimately leading to cell death. However, little is known about the mitochondrial functional alterations after ischemia. The authors examined the expression of cytochrome c oxidase (COX), a terminal, rate-limiting enzyme of the electron transport chain to generate ATP, after global cerebral ischemia in rats. Immunofluorescent staining and western blot were performed to investigate the spatial and temporal changes in two important COX subunits: mitochondrion-encoded COX subunit I (COX I) and nucleus-encoded COX subunit IV (COX IV). Under the normal condition, these subunits have to be regulated precisely in a 1 : 1 stoichiometry to assemble the functional COX holoenzyme. In this study, a huge increase in COX I, which is disproportionate to COX IV, was observed in the early stage after lethal ischemia, preceding delayed neuronal death. In contrast, mild sublethal ischemia did not induce obvious changes in COX I and IV. This aberrant increase in COX I may be an early sign of delayed neuronal death or may predict later electron transport chain dysfunction to generate ATP.

Trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid (anti-18F-FACBC) is a feasible alternative to 11C-methyl-L-methionine and magnetic resonance imaging for monitoring treatment response in gliomas.

INTRODUCTION: Amino acid PET tracers are promising for visualizing gliomas and evaluating radiochemotherapeutic effects. We compared the glioma detection and early response assessment utility between trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) by simultaneously analyzing their uptake by rat gliomas treated with and without temozolomide (TMZ) in vitro and in vivo. METHODS: C6 rat gliomas were incubated with low-dose TMZ to induce chemoresistance. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated a significantly greater surviving fraction in the TMZ-resistant subline (C6R) than in drug-naive cells (C6). The anti-(14)C-FACBC and (3)H-Met uptakes were quantified using a triple-label accumulation assay to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation rate) in tumor cells. C6 and C6R cells were inoculated into the right and left basal ganglia, respectively, of rats. Efficacy of TMZ against the orthotopic gliomas was analyzed by MRI, Evans blue extravasation, anti-(14)C-FACBC and (3)H-Met autoradiography, and MIB-5 proliferation index. RESULTS: The (3)H-TdR accumulation rate and amino acid tracer (anti-(14)C-FACBC and (3)H-Met) uptake significantly decreased 48 and 72 h, respectively, after TMZ treatment in C6 but not C6R cells. Anti-(14)C-FACBC uptake correlated significantly with (3)H-Met uptake and the (3)H-TdR accumulation rate. In the intracerebral glioma model, anti-(14)C-FACBC and (3)H-Met autoradiography clearly delineated the tumor extent, which spread well beyond the high-T2-intensity and enhancing lesions visible on MRI and Evans blue extravasation. TMZ significantly decreased anti-(14)C-FACBC and (3)H-Met uptake and the MIB-5 index of C6 but not C6R tumors. TMZ inhibited tracer uptake and tumor proliferation before morphological changes on MRI. CONCLUSIONS: Anti-(14)C-FACBC, like (3)H-Met, was more sensitive than post-contrast T1-weighted MRI for detecting tumor extent and early tumor response to TMZ treatment. Anti-(18)F-FACBC should be a sensitive and precise imaging biomarker for tumor extent visualization and response assessment in glioma patients.

Multistep pedicle screw insertion procedure with patient-specific lamina fit-and-lock templates for the thoracic spine: clinical article.

OBJECT: Pedicle screw fixation is a standard procedure of spinal instrumentation, but accurate screw placement is essential to avoid injury to the adjacent structures, such as the vessels, nerves, and viscera. The authors recently developed an intraoperative screw guiding method in which patient-specific laminar templates were used, and verified the accuracy of the multistep procedure in the thoracic spine. METHODS: Preoperative bone images of the CT scans were analyzed using 3D/multiplanar imaging software and the trajectories of the screws were planned. Plastic templates with screw guiding structures were created for each lamina by using 3D design and printing technology. Three types of templates were made for precise multistep guidance, and all templates were specially designed to fit and lock on the lamina during the procedure. Plastic vertebra models were also generated and preoperative screw insertion simulation was performed. Surgery was performed using this patient-specific screw guide template system, and the placement of screws was postoperatively evaluated using CT scanning. RESULTS: Ten patients with thoracic or cervicothoracic pathological entities were selected to verify this novel procedure. Fifty-eight pedicle screws were placed using the screw guide template system. Preoperatively, each template was found to fit exactly and to lock on the lamina of the vertebra models, and screw insertion simulation was successfully performed. Intraoperatively the templates also fit and locked on the patient lamina, and screw insertion was completed successfully. Postoperative CT scans confirmed that no screws violated the cortex of the pedicles, and the mean deviation of the screws from the planned trajectories was 0.87 ± 0.34 mm at the coronal midpoint section of the pedicles. CONCLUSIONS: The multistep, patient-specific screw guide template system is useful for intraoperative pedicle screw navigation in the thoracic spine. This simple and economical method can improve the accuracy of pedicle screw insertion and reduce the operating time and radiation exposure of spinal fixation surgery.

Cilostazol for the prevention of acute progressing stroke: a multicenter, randomized controlled trial.

BACKGROUND: Progressing stroke is one of the major determinants of outcome after acute ischemic stroke. A pilot randomized controlled trial was conducted to investigate the effect of cilostazol on progressing stroke. METHODS: Adult patients with noncardioembolic ischemic stroke within 24 hours after onset were randomized to receive cilostazol 200 mg/day (cilostazol group) or no medication (control group) in addition to the optimum medical treatments (a free radical scavenger plus an antiplatelet agent or an antithrombin agent). The primary endpoints were the rate of progressing stroke, defined as aggravation of the National Institutes of Health Stroke Scale (NIHSS) score by ≥ 4 points on days 3 and/or 5 and a modified Rankin Scale score of 0 to 1 at 3 months after enrollment. Aggravation caused by systemic complications, edema, hemorrhagic infarction, or recurrent stroke was not considered as progressing stroke. This trial was registered as UMIN000001630. RESULTS: A total of 510 patients were enrolled from 55 institutions in Japan between February 2009 and July 2010. The rate of progressing stroke was 3.2% and 6.3% in the cilostazol and control groups, respectively (P = .143). The modified Rankin Scale score of 0 to 1 at 3 months did not differ between the groups. CONCLUSIONS: Cilostazol failed to show a preventive effect against acute progressing stroke. However, the tendency to reduce progressing stroke and the results of stratified analyses may encourage additional studies to clarify the effect of cilostazol in the treatment of acute ischemic stroke.

[Cerebellar hemangioblastoma with marked pleomorphism: a case report].

We reported an extremely rare case of cerebellar hemangioblastoma with marked pleomorphism and reviewed the literature. A 68-year-old male presented with a one-month history of headache and vomiting. Neurological examination revealed right-sided dysmetria and truncal ataxia. Contrast-enhanced T1-weighted MR imaging revealed a heterogeneously enhancing tumor with solid and cystic components in the right cerebellum. The solid portion of the tumor was low intensity on diffusion-weighted imaging and low intensity on susceptibility-weighted imaging. 18F-fluorodeoxyglucose PET showed low uptake in the cerebellar tumor and the whole body examination was negative for malignancy. Vertebral angiogram demonstrated moderate tumor staining and no early filling veins. The patient underwent total removal of the tumor through suboccipital craniotomy. Microscopically, the solid tumor contained a cellular rich component consisting of stromal cells and a markedly pleomorphic component including atypical and multinucleated giant cells. The MIB-1 positive rate was 8.2%, which was slightly higher compared to that of hemangioblastomas. We observed strong staining for inhibin-α, aquaporin 1 and neuron specific enolase (NSE) in the tumor cells. PAX-2, cytokeratin and epithelial membrane antigen (EMA) were completely negative in the tumor cells, whereas the tumor cells demonstrated focal staining for CD10. The histological diagnosis was hemangioblastoma. Follow-up MR images showed no evidence of recurrent tumor 14 months after the resection. The study using a combination of immunohistochemical markers (e.g. inhibin-α, aquaporin 1 and PAX-2) is useful for differential diagnosis of hemangioblastoma from metastatic renal cell carcinoma.

ß-Tricalcium phosphate promotes bony fusion after anterior cervical discectomy and fusion using titanium cages.

STUDY DESIGN: Retrospective consecutive cohort study. OBJECTIVE: To study the effectiveness of ß-tricalcium phosphate (ß-TCP) granules as a packing material in the titanium cages for anterior cervical discectomy and fusion (ACDF), compared with the conventional hydroxyapatite (HA) granules. SUMMARY OF BACKGROUND DATA: ACDF using titanium cages is a standard procedure for the treatment of cervical spinal degenerative diseases. Synthetic bone substitutes are widely used to pack the titanium cage to augment intervertebral bony fusion, but the efficacy has not been confirmed. METHODS: Fusion condition was evaluated on lateral radiographs and computed tomography. Complete fusion of the treated segments was defined by three criteria: movement of the spinous process at flexion and extension positions of less than 3 mm, bony bridging between vertebral bodies, and absence of the halo around the titanium cage. The evaluation was performed at 6 months, 1 year, and 2 years after surgery. RESULTS: Intervertebral fusion was studied in patients who underwent ACDF using ß-TCP (93 segments of 57 patients) or HA (72 segments of 48 patients) packing of cylindrical titanium cages. Complete fusion rate at 6 months and 1 year was significantly better in the ß-TCP group (46% at 6 months and 69% at 1 year) than in the HA group (24% at 6 months and 49% at 1 year), but the rate was similar at 2 years in the ß-TCP group (94%) and the HA group (90%). There were no material-related adverse effects. CONCLUSION: Satisfactory final fusion rates were obtained after ACDF using both ß-TCP- and HA-packed titanium cages. ß-TCP showed higher fusion rate in the early stage after surgery and can be recommended as a bone substitute for ACDF with titanium cages.

Evaluation of postoperative status after clipping surgery in patients with cerebral aneurysm on 3-dimensional-CT angiography with elimination of clips.

BACKGROUND AND PURPOSE: the use of 3-dimensional computed tomography angiography (3D-CTA) for clipped aneurysms is limited. Usefulness of 3D-CTA with elimination of bone and clips was evaluated in patients with clipped cerebral aneurysms. METHODS: forty-three clipped cerebral aneurysms were included. As review of digital subtraction angiography after surgery is the current gold standard, the presence or absence of remnant necks on 3D-CTA with elimination of bone and clips was compared with that on conventional CTA, using receiver operating characteristic analysis (5, definitely absent; 1, definitely present). RESULTS: in the ROC analysis, the Az (.949) in CTA with clip elimination significantly (P < .05) differed from that (.751) of conventional 3D-CTA. If a score of 1 or 2 is considered to represent positive detection of remnant necks, then the sensitivity of 3D-CTA with clip elimination and of conventional 3D-CTA is 73% and 36%, respectively. If a score of 5 or 4 is considered to represent negative detection of remnant necks, then the specificity of 3D-CTA with clip elimination and of conventional 3D-CTA is 88% and 78%, respectively. CONCLUSIONS: 3D-CTA with elimination of bone and clips can improve the accuracy of detection of remnant necks after clipping surgery for cerebral aneurysms.

Association of stem cell marker CD133 expression with dissemination of glioblastomas.

Dissemination of glioblastoma was once considered rare but is now increasingly encountered with longer survival of glioblastoma patients. Despite the potential negative impact of dissemination on clinical outcome, however, molecular markers useful for prediction of dissemination risk still remains ill defined. We tested in this study for an association between the expression of stem cell marker CD133 and the risk of dissemination in 26 cases of glioblastoma (16 with dissemination and 10 without dissemination). The protein expression of CD133 was examined by western blot analysis of tumor specimens, and the CD133 expression levels were quantified by densitometry and normalized to beta-actin. The results indicated that CD133 expression levels are significantly higher in glioblastomas with dissemination (mean 10.3, range 0.20-27.8) than in those without (mean 1.18, range 0.07-3.58). The results suggest that CD133 could be a molecular predictor of glioblastoma dissemination, and also give rise to an intriguing idea that CD133-positive cancer stem cells may be implicated in the initiation of disseminated lesions.

Long term outcome and adjacent disc degeneration after anterior cervical discectomy and fusion with titanium cylindrical cages.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is widely performed for the treatment of cervical spinal degenerative disease. Autogenic or allogenic bone grafts are used for interbody fusion with satisfactory long term outcomes. However, harvest of the autograft causes donor site complications and allograft is associated with low fusion rate. Threaded titanium cages (TC) have recently been introduced to cope with these disadvantages, but there is little evidence of long term results. METHODS: The long term outcome was studied after ACDF using TC. Clinical and imaging follow up was performed in 41 patients for at least 5 years (range 5-8.3 years). New computer-assisted measurement methods for radiographs are proposed. FINDINGS: ACDF with TC achieved 80% excellent or good outcome by Odom's criteria, 95% fusion rate, and few minor complications. Asymptomatic adjacent disc degeneration was detected in 50% of the patients by our measurement methods. However, symptomatic adjacent disc degeneration occurred in 5% of the patients and only 2% required additional surgery. CONCLUSIONS: These results are comparable or better than those after ACDF with autograft or allograft. ACDF with TC can achieve rigid fixation and provide good long term results.

Limaprost alfadex improves myelopathy symptoms in patients with cervical spinal canal stenosis.

STUDY DESIGN: Myelopathy symptoms were prospectively studied in patients with cervical spinal canal stenosis (CSCS), using objective grading systems and stabilometry, to examine the effect of administration of prostaglandin E1 derivative limaprost alfadex (limaprost). OBJECTIVE: Myelopathy scores/grades and stabilometry parameters were evaluated before, and 1 and 3 months after starting the limaprost treatment. SUMMARY AND BACKGROUND DATA: Limaprost is a potent vasodilator and antiplatelet agent and has been used to treat the symptoms of lumbar spinal canal stenosis. The action presumably involves increased blood flow in the compressed cauda equina. Limaprost can also increase blood flow in the compressed spinal cord, but effects on myelopathy symptoms in patients with CSCS have not been established. METHODS: This study examined 21 patients with mild spondylotic CSCS based on neurologic findings and compression of the cervical spinal cord on magnetic resonance imaging. Japanese Orthopedic Association score, grip and release test, and finger escape sign were measured, and stabilometry was performed by independent examiners, before, and 1 and 3 months after starting the oral limaprost treatment. RESULTS: Most patients experienced amelioration of the symptoms at 1 month after starting the treatment. Mean Japanese Orthopedic Association score and grip and release count were significantly improved and finger escape sign grade was higher in some patients. Stabilometry area with eyes closed and Romberg rate were also significantly improved. These improvements were maintained at 3 months. CONCLUSION: The efficacy of oral limaprost administration for patients with CSCS was confirmed by objective scoring and quantitative data.

Model mice for mild-form glycine encephalopathy: behavioral and biochemical characterizations and efficacy of antagonists for the glycine binding site of N-methyl D-aspartate receptor.

Glycine encephalopathy (GE) is caused by an inherited deficiency of the glycine cleavage system (GCS) and characterized by accumulation of glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.

Negative pressure pulmonary edema following foramen magnum decompression for Chiari malformation type I.

A 57-year-old obese female presented with vagal and hypoglossal nerve pareses, and magnetic resonance imaging revealed Chiari malformation type I. Standard surgical treatment for Chiari malformation type I was successfully performed. However, immediately after the patient was extubated, she developed signs of upper airway obstruction and chest radiography revealed pulmonary edema. Her ventilation was assisted by maintaining positive end-expiratory pressure at 8 cmH2O. Intravenous furosemide and hydrocortisone were administered. Her respiratory status improved 12 hours later, and she was extubated 3 days after the operation. Postextubational course was uneventful, and the patient was discharged 2 weeks after extubation. The initial neurological deficits had mostly disappeared by 10 months after the operation. This unusual case of negative pressure pulmonary edema indicates that obesity and lower cranial nerve paresis are further risk factors for pulmonary edema as a postextubational complication of surgical treatment.

Reduced perfusion reserve in Leukoaraiosis demonstrated using acetazolamide challenge 123I-IMP SPECT.

OBJECTIVE: We examined the relationship between the perfusion reserve as measured by acetazolamide (ACZ)-challenge N-isopropyl-I-123-p-iodoamphetamine (IMP)-single-photon emission computed tomography (SPECT) and the degree of leukoaraiosis (LA) as estimated using magnetic resonance imaging. METHODS: In 51 patients receiving IMP-SPECT with the resting state and ACZ challenge, the unaffected cerebral hemispheres were included in the present study. Mean cerebral blood flow (CBF) in the resting state and ACZ reactivity were acquired. Absolute CBF value and ACZ reactivity were compared among patients with LA grades 0, 1, and 2. The relationship between mean age and LA grade was also assessed. RESULTS: No significant difference in the absolute CBF value in the resting state was observed among the 3 LA groups. Although vasoreactivity in LA grade 0 did not differ from that in grade 1, vasoreactivity in LA grade 2 was significantly lower (P < 0.05) than that in grades 0 or 1. CONCLUSIONS: The perfusion reserve is impaired in advanced LA.

(99m)Tc-MIBI imaging for prediction of therapeutic effects of second-generation MDR1 inhibitors in malignant brain tumors.

The aim of this study was to explore whether (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second-generation MDR1 inhibitors (PSC833, MS-209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR-resistant sublines compared to those of drug-naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR-resistant cells than drug-naive cells in each line. Volume distribution (V(d)) of (99m)Tc-MIBI was negatively correlated with MDR1 mRNA expression among drug-naive and VCR-resistant cells. MDR1 inhibitors decreased surviving fractions and increased V(d) of (99m)Tc-MIBI significantly in VCR-resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that (99m)Tc-MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of (99m)Tc-MIBI revealed higher uptake in drug-naive cells at basal ganglia compared with VCR-resistant cells at the opposite basal ganglia of rats. Oral administration of the second-generation MDR1 inhibitors significantly increased (99m)Tc-MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using (14)C-methyl-L-methionine ((14)C-Met) and MIB-5 index. (14)C-Met uptake and MIB-5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of (99m)Tc-MIBI accumulation is considered informative for detecting MDR1-mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors.

Angiographically occult spinal dural arteriovenous fistula located using selective computed tomography angiography. Case report.

Spinal dural arteriovenous fistula (DAVF) is the most common type of spinal arteriovenous malformation and may cause progressive myelopathy but is usually treatable in the early stages by direct surgery or intravascular embolization. Selective spinal angiography has been the gold standard for diagnosis, but angiographically occult DAVF is not uncommon. A 67-year-old man presented with a 2-year history of progressive paraparesis. Magnetic resonance (MR) imaging demonstrated segmental atrophy of the spinal cord and dilated coronary veins on the dorsal surface of the spinal cord. A DAVF was suspected, but repeated selective angiography failed to demonstrate the fistula. Findings from spoiled gradient echo MR imaging suggested that the draining vein flowed into the dilated venous plexus at the T-9 level. Selective computed tomography (CT) angiography of the right T-9 intercostal artery confirmed the location of the fistula. The authors successfully occluded the draining vein through surgery, and they observed that the fistula was low flow. The patient exhibited improvement in his symptoms, and postoperative MR imaging confirmed closure of the fistula. Selective CT angiography is useful in locating the draining vein of angiographically occult DAVF and therefore minimizing the extent of the surgical procedure.

Direct correlation between ischemic injury and extracellular glycine concentration in mice with genetically altered activities of the glycine cleavage multienzyme system.

BACKGROUND AND PURPOSE: Ischemia elicits the rapid release of various amino acid neurotransmitters. A glutamate surge activates N-methyl-d-aspartate (NMDA) glutamate receptors, triggering deleterious processes in neurons. Although glycine is a coagonist of the NMDA receptor, the effect of extracellular glycine concentration on ischemic injury remains controversial. To approach this issue, we examined ischemic injury in mice with genetically altered activities of the glycine cleavage multienzyme system (GCS), which plays a fundamental role in maintaining extracellular glycine concentration. METHODS: A mouse line with increased GCS activity (340% of C57BL/6 control mice) was generated by transgenic expression of glycine decarboxylase, a key GCS component (high-GCS mice). Another mouse line with reduced GCS activity (29% of controls) was established by transgenic expression of a dominant-negative mutant of glycine decarboxylase (low-GCS mice). We examined neuronal injury after transient occlusion of the middle cerebral artery in these mice by measuring extracellular amino acid concentrations in microdialysates. RESULTS: High-GCS and low-GCS mice had significantly lower and higher basal concentrations of extracellular glycine than did controls, respectively. In low-GCS mice, the extracellular glycine concentration reached 2-fold of control levels during ischemia, and infarct volume was significantly increased by 69% with respect to controls. In contrast, high-GCS mice had a significantly smaller infarct volume (by 21%). No significant difference was observed in extracellular glutamate concentrations throughout the experiments. An antagonist for the NMDA glycine site, SM-31900, attenuated infarct size, suggesting that glycine operated via the NMDA receptor. CONCLUSIONS: There is a direct correlation between ischemic injury and extracellular glycine concentration maintained by the GCS.