Combination treatment with statins and bezafibrate induces myotoxicity via inhibition of geranylgeranyl pyrophosphate biosynthesis and Rho activation in L6 myoblasts and myotube cells.

Statins and fibrates are frequently used to treat hyperlipidemia; however, these drugs may have adverse effects such as rhabdomyolysis. The incidence of rhabdomyolysis due to fibrates and statins is low (0.0028-0.0096%) when administered as monotherapy, however it increases to 0.015-0.021% when the drugs are used in combination. The mechanism underlying myotoxicity induced by the combination of statins and fibrates is yet unclear. Here, we investigated the mechanisms underlying induced myotoxicity in rat myoblasts L6 and differentiated L6 cells (myotubes) using a combination of statins and fibrates. We found that cell death induced by a combination of fluvastatin or simvastatin with bezafibrate or fenofibrate in L6 myoblasts and myotubes was mediated by inhibition of geranylgeranyl pyrophosphate (GGPP) production. Additionally, the drug combination inhibited Rho activation in L6 myoblasts and myotube cells. In L6 myoblasts, the combination of statins and bezafibrate enhanced p27 expression and induced G1 arrest and apoptosis. Furthermore, combined treatment suppressed Akt activation and enhanced Bim expression in L6 myotubes but did not affect extracellular regulated protein kinase 1/2 activation. These results suggested that combined administration of statins and fibrates induced death of L6 myoblasts and myotube cells by inhibiting GGPP biosynthesis and Rho pathway activation. Supplementation with GGPP may be therapeutically beneficial for preventing myotoxicity associated with combined statin and fibrates treatment.

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region.

An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1alpha m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1alpha protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF-1alpha-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

Diffusion anisotropy and diffusivity of white matter tracts within the temporal stem in Alzheimer disease: evaluation of the "tract of interest" by diffusion tensor tractography.

PURPOSE: Our aim was to determine whether diffusion anisotropy and diffusivity of white matter tracts of the temporal stem in patients with Alzheimer (AD) can be evaluated independently by using diffusion tensor tractography. MATERIALS AND METHODS: Subjects included 15 patients with AD (11 women and 4 men; mean age, 74 years) and 15 age-matched control subjects (11 women and 4 men; mean age, 72 years). Diffusion tensor images were acquired by using echo-planar imaging. We drew tractographies of the uncinate fasciculus, inferior occipitofrontal fasciculus, and Meyer's loop, with diffusion tensor analysis software. We measured diffusion anisotropy, diffusivity, and the number of voxels along the "tracts of interest" and used the Student t test to compare results between patients with AD and controls. RESULTS: Values of diffusion anisotropy of the bilateral uncinate fasciculus and left inferior occipitofrontal fasciculus were significantly lower for patients with AD than for controls. Also, values of diffusivity in the bilateral uncinate fasciculus were significantly greater for patients with AD than for controls. There was no significant difference in diffusion anisotropy or diffusivity along Meyer's loop between the 2 groups. There was no significant difference in the number of voxels included in all constructed tracts between patients with AD and controls. CONCLUSION: White matter tracts of the temporal stem can be evaluated independently by using diffusion tensor tractography, which appears to be a promising technique for determining changes in white matter in degenerative diseases.

Evaluating the effect of superficial temporal artery to middle cerebral artery bypass on pure motor function using motor activation single photon emission computed tomography.

OBJECTIVE: We evaluated and analyzed the effect of superficial temporal artery to middle cerebral artery bypass for internal carotid artery occlusion on pure motor function using motor activation single photon emission computed tomography. METHODS: Motor activation single photon emission computed tomographic (SPECT) images were obtained for nine patients who had undergone superficial temporal artery to middle cerebral artery anastomosis for symptomatic internal carotid artery occlusion. All motor activation SPECT images using the finger opposition task on the affected side were obtained before bypass surgery and at 1 week, 1 month, and 3 months after bypass surgery. The results of motor activation single photon emission computed tomography were expressed as negative or positive. RESULTS: Before bypass surgery, the resting SPECT images revealed reduction of cerebral blood flow (CBF) on the affected side in all nine patients. The results of motor activation single photon emission computed tomography in three patients were positive. One week after bypass surgery, the results of the resting and motor activation CBF studies did not demonstrate any marked changes. One month after bypass surgery, the resting CBF increased in four patients. The results obtained for two of the patients revealed preoperative positive motor activation. The results of motor activation single photon emission computed tomography obtained for five patients were positive. Three months after bypass surgery, eight patients experienced improvement in the resting CBF, and the results of motor activation single photon emission computed tomography obtained for seven patients were positive. Among these, the results of preoperative motor activation single photon emission tomography obtained for four patients were negative. CONCLUSION: Superficial temporal artery to middle cerebral artery bypass is useful not only for resting CBF but also for pure motor function based on motor activation SPECT images. From the preoperative motor activation study, it was concluded that patients with preoperative positive motor activation could attain the effect of bypass earlier than patients with preoperative negative motor activation.

Dysembryoplastic neuroepithelial tumor of the cerebellum and brainstem. Case report.

The authors present a case in which dysembryoplastic neuroepithelial tumors (DNETs) occurred in the cerebellum and brainstem of a 44-year-old woman. A magnetic resonance image of the brain revealed multiple cystic lesions in the right cerebellar hemisphere, vermis, tonsil, and brainstem. Partial removal of the tumors was performed. There were gray multinodular gelatinous lesions on the cerebellar hemisphere. Histologically, the tumors exhibited areas of multiple microcystic nodules in the cerebellar white matter, which were composed of oligodendroglia-like cells (OLCs), astrocytes, and neurons. There were multiple, variable nodules in the lesions, lined by OLCs. The adjacent cerebellar cortex displayed dysplastic features. Reduction of granule neurons and dislocation of Purkinje cells into the molecular layer were observed. The pathological profile of this patient agrees with that described by Daumas-Duport, et al., as a "dysembryoplastic neuroepithelial tumor."

Radiosurgery-induced brain tumor. Case report.

The authors describe a case of glioblastoma multiforme (GBM) associated with previous gamma knife radiosurgery for a cerebral arteriovenous malformation (AVM). A 14-year-old boy had undergone radiosurgery for an AVM, which was performed using a 201-source 60Co gamma knife system at another institution. The maximum and margin radiation doses used in the procedure were 40 and 20 Gy, respectively. One year after radiosurgery, the patient noticed onset of mild left hemiparesis due to radiation necrosis. Six and one-half years after radiosurgery, at the age of 20 years, the patient experienced an attack of generalized tonic-clonic seizure. Magnetic resonance (MR) imaging revealed the existence of a brain tumor in the right parietal lobe. The patient underwent an operation and the histological diagnosis of the lesion was GBM. Ten months following the operation, that is, 99 months postradiosurgery, this patient died. To the best of the authors' knowledge, this is the first reported case of a neoplasm induced by radiosurgery for an AVM and the second case in which it occurred following radiosurgery for intracranial disease.

Effect of stimulation of the dorsal aspect of the cervical spinal cord on local cerebral blood flow and EEG in the cat.

Currently there is considerable interest in electrical stimulation of the dorsal aspect of the cervical spinal cord as a potentially effective therapy for persistent vegetative patients. The authors assessed change in the local cerebral blood flow (LCBF) and electroencephalogram (EEG) in the cat following spinal cord stimulation (SCS). In 31 adult cats under isoflurane anesthesia, an electrode for SCS was introduced epidurally to the midline of the C2-C3 segment. Stimulation was performed at 25 Hz and 0.1 msec for 30 min. These animals were divided into five groups by the voltage: (1) 2V (n = 7), (2) 4V (n = 7), (3) 6V (n = 7), (4) 4V with intravenous injection of muscarinic cholinergic agents--atropine sulfate (n = 5), and (5) sham-operated control (n = 5) without stimulation. LCBF was measured by laser Doppler flowmetry through bilateral small burr holes at the parietal area during and 60 min after stimulation. At 2V, LCBF increased only during SCS, then returned to the pre-stimulated level, while the increase continued until the end of the experiment at 4V and 6V. The increase in LCBF was not affected by atropine sulfate. EEG showed spike and wave or polyspikes after SCS in two animals of the 6V group, but not in the 2V and 4V groups, and moreover a moderate increase of the background activity at only 4V. The present data suggested that SCS at 4V can provide the appropriate microcirculatory enhancement with less harmful influence which continues to increase 30 min after SCS, although the exact mechanism should be elucidated continuously. Within the limitation of animal experiments, this study could provide the logical basis for determining the condition of SCS.

The effect of lesionectomy and the perilesional GABAergic neuronal changes in alumina cream-induced focal motor epilepsy in cats.

The effect of lesionectomy depends on the reversibility of the epileptogenic changes in the perilesional cortex. We studied how the perilesional GABAergic neuronal changes are related to the effect of lesionectomy in the alumina cream-induced focal epilepsy model in cats. Sequential changes of GABAergic neurons and spike activities were measured after the micro-injections of alumina cream (AC). Alumina granulomas were excised 15 days and 40 days after the injections. At day 20 following the AC injection, GABAergic neurons were decreased 25 to 40% compared with those in the contralateral intact cortex. At day 40, a significant increase of spike activities occurred. GABA positive cells were decreased more than 50% compared with those in the contralateral cortex. At day 80, significant cell loss in perilesional cortex was demonstrated. The effect of lesionectomy was greater in the early excised group than in the late excised group. Decrease of GABAergic neuron was more severe in the late excised group compared to the early excised group. Our results indicate that more than 50% reduction of perilesional GABA neurons may be a critical point in epileptogenesis in this model. Lesionectomy alone prior to a 50% reduction in perilesional GABAergic neurons may be sufficient for seizure control. With these data it is still unclear whether these findings contribute to the choice between lesionectomy alone and lesionectomy with resection of the perilesional cortex. Further study is needed to understand the difference between the AC epilepsy model and human chronic epilepsy.

A case of early-onset benign occipital seizure susceptibility syndrome: decreased cerebral blood flow in the occipital region detected by interictal single photon emission computed tomography, corresponding to the epileptogenic focus.

Early-onset benign childhood occipital seizure susceptibility syndrome (EBOSS) recently described by Panayiotopoulos, is an early-onset variant of benign childhood epilepsy with occipital paroxysms. EBOSS is characterized by partial seizures that are predominantly manifested at night and associated with deviation of the eyes, vomiting and impairment of consciousness, but without ictal visual symptoms or postictal headache. The clinical features of our case were consistent with those of EBOSS, and we therefore diagnosed the patient as having a typical form of EBOSS. Neuroimaging by CT, MRI and MR angiography did not reveal a focal lesion. Interictal single photon emission computed tomography (SPECT) revealed decreased cerebral blood flow in the right occipital region corresponding to the epileptogenic focus shown on EEG. It remains unclear whether our finding on SPECT reflects secondary hypoperfusion due to minor morphological abnormality or immediate functional hypoperfusion. No reference to SPECT in a case of EBOSS has appeared in the literature to date. This report provides a better understanding of benign childhood epileptic syndromes with occipital spikes.

Secretory meningioma with elevated serum carcinoembryonic antigen level.

We recently encountered a 68-year-old woman with right sphenoid wing meningioma of the secretory type accompanied by an elevated serum carcinoembryonic antigen level. This case was neuroradiologically characterized by marked brain edema. Histologically, the lesion was rated as having meningothelial components and was rich in blood vessels and pseudopsammoma bodies. Carcinoembryonic antigen, epithelial membrane antigen, keratin, and cytokeratin were immunohistochemically detected in the pseudopsammoma bodies and the cells producing these bodies.

Surgery for dural arteriovenous fistula in superior sagittal sinus and transverse sigmoid sinus.

The aim of this study was to evaluate the outcome of surgically treated dural arteriovenous fistula (DAVF). The authors performed surgical removal of DAVF in 12 patients. The locations of DAVF were the transverse sigmoid sinus in seven patients and superior sagittal sinus in five patients. These 12 patients had undergone endovascular embolisation prior to removal. Among them, six patients were completely cured, according to angiography immediately after embolisation, but these six patients showed the recurrence of DAVF within 1 year. The other six patients showed a decrease of feeding vessels. Therefore, all 12 patients underwent surgical removal of DAVF. The surgical strategies were as follows. The feeding vessels and the cortical veins with retrograde filling were occluded and cut. The affected sinus was skeletonised, and if it was occluded or almost occluded, the sinus was removed. Postoperatively, transient aphasia was seen in one patient. There was no surgical morbidity or mortality. During the follow-up period (mean 2.9 years), no recurrence of DAVF was seen. Surgical treatment is a safe and effective treatment manoeuvre for DAVF around the transverse sigmoid sinus and superior sagittal sinus.

Partial corpus callosotomy beneficial for Lennox-Gastaut syndrome--report of two cases.

Seizures in patients with Lennox-Gastaut syndrome are very resistant to drug therapy. Division of the anterior half of the corpus callosum was performed in two patients with Lennox-Gastaut syndrome incapacitated by frequent atonic seizures leading to sudden falls. Postoperatively, the atonic seizures were completely eliminated and their mental reactivities remarkably improved. It is clear that they have benefited from a lower frequency of seizures and reduced dosages of anticonvulsant medication, which outweight the acquired disabilities.

Spontaneous intracerebral hemorrhage in cases of severe angiospasm following ruptured aneurysm--a pathological study.

Eleven patients with a history of moderate or severe angiospasm following ruptured cerebral aneurysm developed spontaneous intracerebral hemorrhage between 31 and 111 months after aneurysm surgery. In all cases, hemorrhage occurred in the ipsilateral hemisphere to the original aneurysm. In nine patients, the hematoma was surgically evacuated and bleeding perforating arteries were resected for histological examination. Computed tomographic scans showed the hematomas to be unusually extended compared to those after hypertensive intracerebral hemorrhage. The histological examination showed various degenerative changes in the elastic lamina and media of the perforating arteries, even though most patients were young and normotensive. These findings suggest that patients who have suffered severe cerebral angiospasm may have a higher risk for subsequent development of intracerebral hemorrhage than those without prior angiospasm.

Immunohistochemical study of a newly defined oncofetal antigen (HGR-Ag) in tumors of the central nervous system.

The oncofetal antigen (HGR-Ag) in brain tumors was newly defined using the monoclonal antibody derived from tissue extracts of an anaplastic astrocytoma. The HGR-Ag was purified through sequential chromatography using diethylaminoethyl-Sephadex A-50 and Con-A Sepharose affinity columns. The latter method indicated that HGR-Ag is not a glycoprotein, and Western blot analysis indicated a molecular weight of 80-90 kd. Purified antigen was used to produce antibody. This new antibody, designated H1H2, was shown to be an immunoglobulin G1 by immunodiffusion assay. Histological/immunohistochemical studies using the H1H2 antibody on paraffin and frozen tissue sections showed HGR-Ag to be intracellular rather than membrane-associated. The immunoreactivity of H1H2 was highest in malignant astrocytomas, glioblastomas, and normal fetal brain tissue. Neurinomas and certain carcinomas of other organs showed lesser, variable reactivity to H1H2. The strength of the antigen-antibody binding was correlated with the degree of malignancy in human gliomas. H1H2 bound to fetal brain tissue and undifferentiated neural tumors, but not to normal adult brain tissue, so HGR-Ag is probably a fetal oncoantigen.

Pleomorphic adenoma of the lacrimal gland manifesting as exophthalmos in adolescence--case report.

A 16-year-old girl presented with a pleomorphic adenoma of the lacrimal gland manifesting as left painless exophthalmos which had persisted for 3 years. Computed tomography revealed a tumor about 15 mm in diameter in the superolateral site of the left orbit. The tumor was removed completely by combined orbitofrontal craniotomy through a transcranial approach. Histological examination demonstrated the growth of tumor cells as glandular cavities or sheets, with myxoid and partly chondroid connective tissue stroma. Pleomorphic adenoma of the lacrimal gland is unusual in adolescents.

Experimental study of the mechanism of seizure induction: changes in the concentrations of excitatory amino acids in the epileptic focus of the cat amygdaloid kindling model.

L-glutamate (Glu) and L-aspartate (Asp) are two major excitatory amino acids that may be involved in seizure susceptibility and seizure induction. The concentrations of Glu and Asp were measured by microdialysis in the epileptic focus in a cat amygdaloid kindling model. Sequential changes in Glu and Asp (before, during, and after seizure) were measured in the partial seizure (S4) and generalized seizure (S6) groups. By stimulation at and 50 microA below the partial seizure-triggering threshold in the S4 group and the generalized seizure-triggering threshold in the S6 group, Glu was released from the epileptic focus in the S4 group, and both Glu and Asp were released in the S6 group after seizure and stimulation (below threshold), and the amount of Glu and/or Asp release determined seizure induction. Excitatory amino acids may be the trigger of seizure induction in the cat amygdaloid kindling model.

Anaplastic astrocytoma of an oncocytic type occurring in the cerebellar vermis in Pierre Robin syndrome--case report.

A 44-year-old male with Pierre Robin syndrome and funnel chest was diagnosed with a tumor of the cerebellar vermis and spontaneous pneumothorax. He received tube thoracostomy for pneumothorax and ventriculoperitoneal shunt for hydrocephalus, followed by radiological examination, subtotal removal of the tumor, pneumonorrhaphy, and chemoradiotherapy. Light microscopy of the tumor sample revealed marked pleomorphism of the tumor cells and numerous giant cells, without mitotic figures. Microcystic changes due to vasogenic edema were also evident throughout the tumor. Electron microscopy showed more than 50% of all tumor cells to be oncocytes, with numerous mitochondria in the cytoplasm. The tumor was diagnosed as anaplastic astrocytoma of an oncocytic type.

Strategies to improve the outcome of carotid endarterectomy.

The outcomes of carotid endarterectomy (CEA) including long-term results in 121 patients (126 procedures) were retrospectively analyzed to identify the causes of operative morbidity. The angiographic internal carotid artery (ICA) stenosis was severe (> 70%) in 62 patients and moderate (50-70%) with ulceration in 64. The arterial wall was sutured primarily in 91 patients and with patch graft in 35. The outcomes 3 months after operation were good recovery in 86 patients, moderately disabled in 20, severely disabled in 11, and death in four. Three patients suffered operative morbidity (2.5%). During follow-up, three patients (2.6%) suffered transient ischemic attack on the operative side due to middle cerebral artery stenosis (50%) or ICA occlusion at the origin, and recurrent stenosis (40%) of the common carotid artery and ICA (1 each). In the latter two cases, the artery was primarily sutured. Improved therapeutic results require use of patch vein graft for the arterial wall suture, checking of the CEA patency, and prevention of intracranial ischemic events and hemorrhage due to associated lesions.

[A characteristic magnetic resonance image of a dissecting aneurysm in the vertebrobasilar system].

Recently several reports of dissecting aneurysm in the vertebrobasilar system have been published. We report the effectiveness of MRI for the detection of a dissecting aneurysm in the vertebrobasilar distribution system. A 47 year-old male [correction of female] was admitted to our hospital due to right occipitalgia and the right Wallenberg's syndrome. Computed tomography disclosed no abnormalities. Cerebral angiogram showed the pearl and string sign of the right vertebral artery, which suggested a dissecting aneurysm. MRI exhibited the infarct area at the right dorsolateral part of the medulla oblongata, which corresponded to right Wallenberg's syndrome. It disclosed high intensity ring-like findings circumscribing a low intensity spot of the lumen of the right vertebral artery. This high intensity was thought to be the hematoma between the intima and the media at the subacute stage. Its high intensity corresponded to the site of the dissecting aneurysm and of Wallenberg's syndrome. These findings are thought to be useful in the diagnosis of a dissecting aneurysm of the vertebral artery.

[Experimental study of acute spinal cord injury: a histopathological study].

The microscopic appearance of a rat spinal cord which was acutely compressed by aneurysmal clip for one minute, was investigated 15 minutes, 30 minutes, 1 hour, 3 hours and 6 hours after the injury. Although the resulting small hemorrhagic lesion involved primarily only the central gray matter of the injured portion 15 minutes after compression injury, hemorrhage, necrosis and edema in the central gray matter enlarged progressively until 3 hours after injury. Petechial hemorrhage, necrosis and edema were observed in the surrounding area one hour after spinal compression. Then these pathological changes extended rostrally and caudally, but their extension was more significantly remarkable in the rostral side than in the caudal side 3 hours after compression. It was observed that leukocytes begin to infiltrate into the injured capillary walls and plug up the capillary lumen 30 minutes after the injury. Three hours following the injury, leukocytes (lymphocyte, macrophage) extravasated into the surrounding spinal tissue. From these histopathological observations, we reached the following conclusions. A. Secondary injuries play an important role in grave impairment of neurological function of the spinal cord following acute trauma. B. Pathological findings (hemorrhage necrosis and edema) extend more prominently to the rostral side, because the direction of spinal blood flow may be rostral in the thoracic spinal cord. C. Severe disturbance of intraspinal capillary blood flow leading to grave spinal damage may be evoked, because leukocytes infiltrate into the capillary around the injured area and plug up the their lumen about 30 minutes after the injury.