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.

Correlation between diffusion tensor tractography and proton MR spectroscopy in normal controls.

Tractography is a procedure that can track and demonstrate the 3D neural tracts of the white matter of the brain. The images of the brain are obtained by analyzing the diffusion tensor, identification of which can provide the anatomical connections of the brain. Studying these connections is integral to the understanding of the brain function. Specifically, the uncinate fasciculus and fornix, which are the white matter in the human brain, are said to be related to cognitive function. The tractography is calculated using diffusion tensor imaging (DTI) parameter. Studies have shown that the DTI parameter of dementia patients is lower than that of healthy individuals. It is also suggested that the DTI parameter of healthy individuals decreases with age. In addition, Proton MR Spectroscopy ((1)H-MRS) is indicative of neuronal damage and has been used for decades as a noninvasive technique for assessing the biochemistry of the human brain. This is reflected by the increasing number of clinical MRS investigations of neurological disorders. Thus, MRS and DTI can provide complementary images on white matter in brain and it is important to investigate the white matter brain changes by simultaneously acquiring DTI and MRS in health control subjects. In this research, we have calculated the correlation coefficient between the DTI parameter of uncinate fasciculus, fornix and (1)H-MRS. Our result shows that the correlation coefficient of DTI parameter and (1)H-MRS of a left fornix is 0.65 at the maximum. Correlation between DTI measurement and (1)H-MRS suggests the relationships between the uncinate fasciculus, fornix and cognitive neuronal function. Our finding matches previous reports on the correlation between DTI parameters and (1)H-MRS.

Correlation between uncinate fasciculus and memory tasks in healthy individual using diffusion tensor tractography.

Tractography is a procedure that can track and demonstrate the 3D neural tracts of the white matter of the brain. The images of the brain are obtained by analyzing the diffusion tensor, identification of which can provide the anatomical connections of the brain. Studying these connections is integral to the understanding of the brain function. Specifically, the uncinate fasciculus (UF), which is the white matter in the human brain, is said to be related to cognitive function. The UF tractography is calculated using diffusion tensor imaging (DTI) parameter. Studies have shown that the DTI parameter of dementia patients is lower than that of healthy individuals. It is also suggested that the DTI parameter of healthy individuals decreases with age. In addition, the WMS-R score, which is indicative of general memory, verbal memory and other cognitive functions, of the elderly are lower than of the young. However, there is no report yet that has holistically investigated DTI parameter and the memory functions. Thus, in this research, we have calculated the correlation coefficient between the DTI parameter of UF and WMS-R score. Our result shows that the correlation coefficient of diffusivity of the fiber direction and visual memory of a left UF is -0.226 at the maximum. Correlation between DTI measurement and memory performance suggests the relationships between the UF and function in memory tasks lateralization. Our finding matches previous reports on the correlation between FA in the left, or L1 in the right UF, and performance on visual memory.

Diffusion tensor tractography of the Meyer loop in cases of temporal lobe resection for temporal lobe epilepsy: correlation between postsurgical visual field defect and anterior limit of Meyer loop on tractography.

BACKGROUND AND PURPOSE: Visual field defects sometimes occur after temporal resection surgery. Our purpose was to evaluate the correlation between visual field defects caused by temporal lobe resection and the degree of resection of the Meyer loop, as assessed by diffusion tensor tractography. MATERIALS AND METHODS: We examined 14 patients who underwent temporal resection for temporal lobe epilepsy. We obtained presurgical tractographies and then measured the distance between the temporal tip and the anterior limit of the Meyer loop (T-M distance). The degree of resection of the Meyer loop was defined as the distance from the anterior limit of the Meyer loop to the posterior limit of the temporal lobe resection (M-R distance). This was calculated by subtracting the T-M distance from the measured distance between the temporal tip and the posterior limit of the resection (T-R distance). RESULTS: The mean T-M distance was 36.6 mm. The interindividual variation of the distance ranged from 30.0 to 43.2 mm. Although there was no statistically significant correlation between the extent of the visual field defect and the T-R distance, there was a statistically significant correlation between the degree of the visual field defect and the M-R distance. CONCLUSION: The range of interindividual variation for the position of the Meyer loop was rather large, indicating that this variation is the key factor in visual field defects after temporal lobectomy, and the visual field defect appears to be predicted by presurgical tractography. Evaluation of the Meyer loop through the use of tractography seems to be a feasible method, which can be used to predict the visual field defect after temporal lobe resection.

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.

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.

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.

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.

[Surgery for intractable epilepsy in children: pre- and perioperative evaluations with special reference to dipole tracing method estimated from interictal spike].

Methods of preoperative and perioperative evaluation methods for surgical treatment of intractable epilepsy in children are described. Among non-invasive diagnostic methods, EEG-video monitoring is the most fundamental. Amygdalohippocampal volume measurement by MR was useful for the differential diagnosis of mesial temporal lobe epilepsy (TLE) from lateral TLE and generalized epilepsy. The dipole tracing method with a realistic head model was useful for identification of epileptic foci from the interictal spikes of scalp EEG, when an abnormal electric source was estimated as an equivalent current dipole (ECD) in the brain of patients with organic lesion and TLE. ECD concentration ratio ranged from 70 to 90% within 20 mm around the lesion. After lesionectomy seizures disappeared in every patient. The mean distance between the centers of the ECD and epileptic focus (identified by subdural electrode recording) was 14 mm (range: 8 to 18 mm). ECDs of mesial TLE were located in the temporal base rather than mesial temporal lobe, whereas those of lateral TLE in the lateral cortex precisely. In unilateral, intermediate and bilateral TLE, 76%, 52% and 36% of ECDs were localized in the ictal onset zone respectively (p = 0.007). Electrical cortical stimulation with chronically placed intracranial electrodes was used to accurately identify eloquent areas to avoid postsurgical complications. Immediately after operation, 10 to 20% of patients showed better or deteriorated results in neuropsychological examinations, which recovered in all patients after one year. Postoperative seizures were absent in three fourths of patients. Further efforts are needed to obtain better seizure control in future.

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.

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."

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.

Accuracy and availability of the computed assisted neurosurgery navigation system during epilepsy surgery.

The magnetic-force-based Computed Assisted Neurosurgery System was used for epilepsy surgery to localize targets accurately in the operative field. The correlation between X components of target coordinates in the axial plane and the coronal plane for the same target was strong in all cases. Concerning Y components, there were statistically significant differences in 2 cases. There was a case that showed statistically significant differences only in the Z dimension. The interdisk distance by data sets of coordinates obtained from neuronavigation was calculated to quantify localization error, and the measuring error ranged from -5 to 13.3 mm (1.3 +/- 3.2 mm). The magnitude of the application errors in this study tended to be large in the frontal and vertex regions.

Usefulness of the dipole tracing method with a scalp-skull-brain head model: relationship between the epileptic focus and equivalent current dipole locations.

PURPOSE: We examined whether the dipole tracing (DT) method with a realistic three-shell head model and inhomogeneous electric conductivity is useful to estimate the epileptic focus from interictal spikes. METHOD: This study included 17 temporal lobe epilepsy (TLE) cases, classified into three types as type A (unilateral), type B (intermediate) and type C (bilateral) and 5 extratemporal epilepsy (XTLE) cases. The epileptic areas were determined by noninvasive and/or invasive examinations. Selected interictal spikes were analyzed and the calculated equivalent current dipoles (ECDs) of dipolarity greater than 0.98 were superimposed over the realistic head model in each patient. We evaluated the ECD concentration within and around the epileptic area. RESULTS: In TLE cases, types A showed better ECD concentration (87%) within the epileptic area than other types (type B: 68%; type C: 74%). XTLE exhibited variable ECD distribution within and around the epileptic area. CONCLUSION: The DT method with a realistic head model and inhomogeneous electric conductivity can be useful to estimate the epileptic area from interictal spikes, especially in unilateral TLE cases.

Rebleeding during transport of patients with a ruptured intracranial aneurysm.

Although many reports have described the rebleeding risk of the ruptured aneurysm in already hospitalized patients, there are only a few reports that have addressed the incidence of rebleeding in these patients before hospitalization. To improve the prognosis of patients with a ruptured intracranial aneurysm, it seems very important to know the incidence of rebleeding before hospitalization. We focused on changes in the computed tomographic (CT) scans and neurological findings at the primary hospital and our institution in 366 patients with ruptured aneurysms who were transferred on the day of the initial hemorrhage, and studied the rebleeding rates in these patients. In 73 (19.9%), we confirmed that rebleeding from the ruptured aneurysm had occurred during transport. The incidence of rebleeding in the prehospitalized patients with a ruptured aneurysm is supposed to by very high. Appropriate medical countermeasures for prevention of rebleeding in prehospitalized patients are crucial to decrease the overall mortality and morbidity rate of intracranial aneurysm.

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.

Giant true posterior communicating artery aneurysm.

The case of a giant posterior communicating artery (PCoA) aneurysm is reported in which the clinical presentation was Korsakoff's syndrome. Left carotid angiography revealed a partially thrombosed giant PCoA aneurysm. Three-dimensional computed tomography angiography showed the precise neck of aneurysm and surrounding structures from a multidirectional view. Hypoperfusion of the bilateral frontal, temporal, and medial inferior thalamus was seen on single-photon emission computed tomography. According to previous reports, giant true PCoA aneurysms are rare; in fact, there has been only one report of a giant true PCoA aneurysm. We discuss the radiological characteristics and the clinical presentation of giant true PCoA aneurysms.

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.

[Experimental study on hypertensive crises in epileptic seizures--changes in pial artery diameter, intracranial pressure and regional cerebral blood flow].

It is well known that severe hypertension occurs during epileptic seizures, but little information is available concerning these hypertensive crises. We therefore investigated them by monitoring regional cerebral blood flow (rCBF), intracranial pressure (ICP) and pial artery diameter (PAD) in paralyzed mechanically-ventilated cats with penicillin-induced seizures. The animals were assigned to two groups. In one (Group H), they were maintained in an untreated state. In the other (Group C), spinal cord injury was performed in advance to prevent the rise in arterial blood pressure during the seizures. In both groups, the values of the various parameters increased during seizure activity, but the increases in group H, were greater than in group C. In both groups, PAD, rCBF and ICP increased immediately at the onset of the seizures with no hypertension. In group H, further increases in PAD, rCBF, and ICP were found concurrent with the elevation of arterial blood pressure in the latter half of the seizure, while in group C, rCBF decreased concurrent with the increase in ICP in the latter half of the seizure, although PAD was found to be maximal. These findings suggest that hypertensive crises during epileptic seizures represent a protective mechanism to maintain perfusion pressure.