Basal Ganglia Damage in Experimental Subarachnoid Hemorrhage.

Research suggests that early brain injury following subarachnoid hemorrhage (SAH) is a primary therapeutic target, and early SAH-induced basal ganglia injury is not well studied. The present study examined basal ganglia injury in a rat model of SAH. Adult male Sprague-Dawley rats (n = 78) weighing 275-300 g underwent endovascular perforation to mimic aneurysmal SAH. Sham rats (n = 12) underwent the same procedure but without perforation. Magnetic resonance imaging (T2 MRI) was performed at 24 h after SAH to measure ventricle volumes and brain T2 lesion. Hydrocephalus in SAH rats was defined as a ventricular volume greater than three standard deviations above that in shams. Western blotting and immunochemistry were utilized to assess basal ganglia damage. Sixty rats survived the SAH and 40 % of those animals had T2 lesions in the basal ganglia. Twenty-six SAH rats had hydrocephalus. Rats with hydrocephalus had higher incidence of basal ganglia lesion (69 vs. 18 % in rats without hydrocephalus; p < 0.01). Basal ganglia neuronal injury was also determined by examining the levels of dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32). We found that rats with hydrocephalus had more severe basal ganglia injury with greater DARPP-32 depletion (DARPP-32/beta-actin: 0.38 ± 0.32 vs. 0.86 ± 0.45 in rats without hydrocephalus and 1.10 ± 0.28 in sham, p < 0.05). In conclusion, SAH resulted in severe basal ganglia damage, which is associated with hydrocephalus development.

The Effect of Gender on Acute Hydrocephalus after Experimental Subarachnoid Hemorrhage.

Acute hydrocephalus is a common complication of subarachnoid hemorrhage (SAH). We investigated the effect of gender on acute hydrocephalus development in a rat SAH model. SAH was induced in adult male and female Sprague-Dawley rats using endovascular perforation. Sham rats underwent the same procedure without perforation. Magnetic resonance imaging (MRI) was performed 24 h after SAH to determine ventricular volume. Hydrocephalus was defined as a ventricular volume that was more than 3 standard deviations from the mean value in sham-operated animals. After MRI, animals were euthanized and the extent of SAH was assessed using a modified grading system. No sham animals died. Mortality rates after SAH induction in male and female animals were 27 and 22 %, respectively. SAH induced significant ventricular enlargement compared with sham-operated rats (p < 0.01). The T2* hypointensity volume in the ventricle (used to assess intraventricular blood) was correlated with ventricular volume after SAH (r = 0.33, p < 0.05). The incidence of acute hydrocephalus 24 h after SAH was greater in female (75 %) than in male animals (47 %, p < 0.05) and the relative changes in ventricular volume were significantly larger in female than in male rats (292 ± 150 % vs 216 ± 127 % of sham-operated animals, respectively, p < 0.05). The increased hydrocephalus occurred even though SAH severity grade and ventricular T2* hypointensity volumes were not significantly different between male and female animals. Our data demonstrate that gender influences acute hydrocephalus development in a rat SAH model. Future studies should determine the role of estrogen in SAH-induced hydrocephalus.

[A Patient with Advanced Gastric Cancer who Underwent Emergency Stenting for Carotid Artery Stenosis].

We report the case of a patient with advanced gastric cancer who underwent emergency stenting for carotid artery stenosis that was causing fluctuating symptoms of cerebral ischemic stroke. A 66-year-old man presented with transient dysarthria and right hemifacial palsy. Examination revealed left internal carotid artery stenosis, as well as anemia caused by advanced gastric cancer. The man was treated on an outpatient basis using antiplatelet medication and anti-cancer therapy. Two months later, he developed recurrent ischemic stroke;because of this progression, a stent was placed in the carotid artery. After surgery, the cerebral ischemia resolved and did not recur before his death 6 months later. In conclusion, surgical intervention is a viable treatment option for internal carotid artery stenosis in cancer patients whose general health status is good.

Subarachnoid hemorrhage-induced hydrocephalus in rats.

BACKGROUND AND PURPOSE: Hydrocephalus is an important complication of subarachnoid hemorrhage (SAH). We investigated the occurrence of acute hydrocephalus in a rat SAH model. METHODS: SAH was induced by endovascular perforation in adult male Sprague-Dawley rats (n=36). Sham rats (n=8) underwent the same procedure without perforation. MRI was performed 24 hours after SAH and the volume of the ventricular system and extent of T2* hypointensity lesions were measured. We defined hydrocephalus as ventricular volume > +3 SDs above the mean in sham animals. SAH grade was determined and brains were used for histology, immunohistochemistry, Perls staining, and Western blot analysis. Ventricular wall damage was defined as percentage of ependymal surface disruption. RESULTS: All surviving rats (n=27) after SAH had ventricular enlargement (33.6 ± 4.7 versus 13.5 ± 1.4 mm(3) in sham animals, P<0.01). Ventricular volume correlated with SAH severity (r=0.48; P<0.05). Out of 27 SAH rats, 12 demonstrated hydrocephalus and all had intraventricular blood accumulation. Rats with hydrocephalus had more severe ventricular wall damage (7.4 ± 1.2%) than the sham animals (0.6 ± 0.2%; P<0.01) and rats without hydrocephalus (1.1 ± 0.2%; P<0.01). Periventricular iron deposition was observed and heme oxygenase-1 and Iba-1 expression were markedly increased in hydrocephalus rats. CONCLUSIONS: SAH causes ventricular enlargement in a rat endovascular perforation model, with hydrocephalus occurring in 44% of animals at 24 hours. Rats with hydrocephalus had more severe SAH, intraventricular hemorrhage, and greater ventricular wall damage.

Natural products reveal cancer cell dependence on oxysterol-binding proteins.

Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.

Cerebral hemorrhage, brain edema, and heme oxygenase-1 expression after experimental traumatic brain injury.

Intracranial bleeding is a common and serious consequence of traumatic brain injury (TBI). In the present study, we investigated cerebral hematoma occurrence, brain edema formation, blood-brain barrier (BBB) disruption, and heme oxygenase-1 (HO-1) expression after TBI. Moderate severity (1.8-2.2 atmospheres [ATM]) TBI was induced by lateral fluid percussion in male adult Sprague-Dawley rats. Sham rats underwent only a craniotomy. Rats were euthanized 24 h later for brain histology and immunoblotting analysis. We found TBI-induced cerebral hematomas and iron deposition in the ipsilateral hemisphere in all rats. TBI also caused marked BBB disruption (p < 0.05) and brain swelling (p < 0.05). HO-1, a key enzyme for heme degradation, was upregulated significantly after TBI (419 ± 89 vs 194 ± 59 pixels in the sham, p < 0.05). These results suggest that cerebral hematomas might play a role in brain injury after TBI. Future studies should determine the role of iron released from the cerebral hematoma in TBI.

Relation of LAT1/4F2hc expression with pathological grade, proliferation and angiogenesis in human gliomas.

BACKGROUND: LAT1/4F2hc heterodimeric complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Although it has been shown that LAT1/4F2hc is highly expressed in a variety of human tumors including gliomas, and LAT1 over-expression is associated with glioma grade and poor prognosis of glioma patients, the precise tissue location of LAT1/4F2hc in gliomas and the precise role of LAT1/4F2hc in glioma biological features remain unclear. METHODS: In the current study, the expressions of LAT1, 4F2hc, CD34 and Ki-67 were investigated by immunohistochemistry in 62 cases of human brain glioma; LAT1/4F2hc expression level, Ki-67 labeling index (Ki-67 LI) and microvessel density (MVD) were measured semi-quantitatively; and the correlation of LAT1/4F2hc expression with histopathological features, Ki-67 LI and MVD in gliomas was further analyzed. RESULTS: The results showed that both LAT1 and 4F2hc were expressed in all examined specimens. LAT1 but 4F2hc expression levels significantly correlated with the pathological grade and both expression levels significantly correlated with Ki-67 LI of gliomas. We also demonstrated that both LAT1 and 4F2hc immunoreactivity were observed in tumor cells as well as vascular endothelia; furthermore, the LAT1 expression level was markedly associated with glioma MVD as well. CONCLUSION: LAT1/4F2hc over-expression is closely correlates with the malignant phenotype and proliferation of gliomas, and LAT1 was associates with glioma angiogenesis. LAT1/4F2hc, especially LAT1, may become a novel potential molecular target for glioma biological therapy.

A method for accurate temperature measurement using infrared thermal camera.

The temperature distribution on a centre-holed thin foil of molybdenum, used as a sample and heated using a sample-heating holder for electron microscopy, was measured using an infrared thermal camera. The temperature on the heated foil area located near the heating stage of the heating holder is almost equal to the temperature on the heating stage. However, during the measurement of the temperature at the edge of the hole of the foil located farthest from the heating stage, a drop in temperature should be taken into consideration; however, so far, no method has been developed to locally measure the temperature distribution on the heated sample. In this study, a method for the accurate measurement of temperature distribution on heated samples for electron microscopy is discussed.

Correlation of L-methyl-11C-methionine (MET) uptake with L-type amino acid transporter 1 in human gliomas.

L-type amino acid transporter 1 (LAT1) is a neutral amino acid transport system and is a major route for the transport of large neutral amino acids, including methionine, through the plasma membrane. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional expression. Positron emission tomography (PET) with L-[methyl-(11)C] methionine (MET) provides information about amino acid metabolism in brain tumors. We conducted a clinicopathologic study to elucidate the correlation of LAT1 and 4F2hc expression with MET uptake in patients with newly diagnosed human gliomas. Thirty-three newly diagnosed glioma patients were enrolled in this study. Uptake of MET in the tumor was evaluated with the maximum standardized uptake value (SUVmax). Expression of the LAT1, 4F2hc, and CD34, and Ki-67 labeling index of the tumor were analyzed by immunohistochemical staining, and the correlation with the SUVmax in the tumors was examined. Expression of LAT1 and 4F2hc was higher in high-grade gliomas than in low-grade gliomas. The grade of LAT1 immunostaining increased with glioma grade. LAT1 was mainly expressed in the tumor cytoplasm and vascular endothelium and 4F2hc was mainly expressed in the tumor cytoplasm and plasma membrane. Expression of LAT1 but not 4F2hc was significantly correlated with MET SUVmax. Expression of LAT1 in the tumor vascular endothelium is significantly correlated with CD34 positive microvessel density. In conclusion, MET SUVmax correlates with LAT1 expression in the tumor in newly diagnosed gliomas. MET transport may be increased by an increased number of microvessels combined with a higher density or activity of LAT1 in the tumor endothelial cells in high-grade gliomas. Use of MET-PET as a molecular target combined with anti-angiogenesis in glioma therapy should be addressed in future studies.

Radiation Response of Negative Gate Biased SiC MOSFETs.

Silicon carbide (SiC) metal-oxide-semiconductor field effect transistors (MOSFETs) are expected as power electronic devices for high radiative conditions, including nuclear plants and space. Radiation response of commercial-grade prototype SiC MOSFETs with applying the gate bias is of interest, in terms of installation of the device in robots or sensors working under such radioactive circumstances. Due to gamma-rays irradiation, the threshold voltages (Vth) of samples with un- and negative-biased up to -4.5 V slightly shift toward the negative voltage side. In contrast, the positive bias of 2.25 V shifts Vth more negatively. Positive charge densities trapped in the gate oxide of un- and positive-biased samples increased with increasing dose. However, no significant increase was observed for negative-biased samples of -2.25 and -4.5 V. We calculated characteristic parameters for the accumulation of holes in the gate oxide, σpJp which is defined as the product of current density due to holes generated by irradiation and capture cross section for a hole in a trap, and it is lower for these negative biased samples compared with the unbiased case. Application of appropriate negative gate biases to SiC MOSFETs during irradiation suppresses accumulation of positive charges in the gate oxide and negative shift of Vth, due to irradiation.

The Importance of Recognizing Diffuse Idiopathic Skeletal Hyperostosis for Neurosurgeons: A Review.

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by calcification and ossification of the soft tissues, mainly ligaments and entheses. The spines of patients with DISH generally become increasingly rigid and osteoporotic, and fractures may occur after even a relatively minor traumatic event such as a ground-level fall. Moreover, the prevalence of DISH may be rapidly increasing in affluent societies. Thus, awareness of this condition is becoming more important for neurosurgeons when assessing trauma patients. For the present article, a literature review was conducted to summarize the current clinical, pathogenetic, and therapeutic knowledge of this disease. Furthermore, current treatment strategies for DISH-related spine injuries are also reviewed. Although the recommended treatment for spinal injuries in DISH patients is surgical, mainly through long-segment posterior fusion, rather than conservative options, stable fractures without any associated neurologic deficits have often been successfully managed with immobilization alone. Percutaneous instrumentation and the use of teriparatide may be useful depending on the surgical risks and patient neurological status.

Brain abscess caused by Nocardia asiatica.

BACKGROUND: Nocardia infection of the central nervous system leading to brain abscess is a rare condition but has a high mortality rate. Among the species of Nocardia, only three cases of brain abscess due to Nocardia asiatica infection have been reported. CASE DESCRIPTION: A 65-year-old man with a history of autoimmune hemolytic anemia treated with prednisolone presented to our hospital because of occipital headache. Brain magnetic resonance imaging showed bilateral occipital lesions. The patient underwent craniotomy and resection of the left occipital lobe lesion. N. asiatica was identified by 16S rRNA sequencing of the resected specimen. Treatment with trimethoprim/sulfamethoxazole led to a complete resolution of the brain lesion. CONCLUSION: Because of the different antimicrobial sensitivity patterns among Nocardia species, both appropriate subtyping and susceptibility testing of uncommon species such as N. asiatica are required for the successful treatment of nocardial infections.

Neurofibromatosis Type 1-Associated Extracranial Vertebral Artery Aneurysm Complicated by Vertebral Arteriovenous Fistula After Rupture: Case Report and Literature Review.

BACKGROUND: Extracranial vertebral artery aneurysm related to neurofibromatosis type 1 (NF1) is rare. Aneurysmal rupture typically induces such symptoms as cervical hematoma, hemothorax, and hypotension. Here we report a case of ruptured extracranial vertebral artery aneurysm in a patient with NF1 who, rather than cervical hematoma, hemothorax, or hypotension, developed a vertebral arteriovenous fistula (AVF) after aneurysm rupture. CASE DESCRIPTION: A 35-year-old woman with a family history of NF1 presented with sudden-onset right neck and shoulder pain. Computed tomography angiography showed a right extracranial vertebral artery aneurysm. She had neither a cervical hematoma nor hypotension; however, angiography showed an AVF secondary to aneurysmal rupture. The patient was treated with endovascular coil embolization to prevent re-rupture. Postoperatively, her right neck and shoulder pain improved, and she was discharged without further neurologic deficits. CONCLUSIONS: This patient's clinical course suggests that if there is minimal bleeding from an NF1-associated ruptured extracranial vertebral artery aneurysm, then typical symptoms, such as cervical hematoma, hemothorax, and hypotension, may be absent. Thus, ruptured extracranial vertebral artery aneurysm should be considered in the differential diagnosis of patients with NF1 with sudden-onset radiculopathy, even in the absence of typical symptoms. The detection of a vertebral AVF provides a useful clue to the diagnosis of aneurysm rupture in such cases.

A magnetic resonance imaging grading system for subarachnoid hemorrhage severity in a rat model.

BACKGROUND: The endovascular perforation model of subarachnoid hemorrhage (SAH) has a large variation in outcomes. This may reflect differences in the SAH size. NEW METHOD: Magnetic resonance imaging (MRI) was performed 24h after endovascular perforation in adult male (n=58) and female (n=58) rats. Rats were divided into five grades according to MRI characteristics: grade 0: no SAH or intraventricular hemorrhage (IVH); grade 1: minimal or thin SAH without IVH; grade 2: minimal or thin SAH with IVH; grade 3: thick SAH without IVH; grade 4: thick SAH with IVH. We investigated whether MRI grading scale reflected severity of SAH (determined post mortem) and neurological score. RESULTS: There was a strong correlation between MRI grading scale and current SAH grading scale (P<0.01) and neurological score (P<0.01) in male rats. In female rats, there was also a strong correlation between MRI grading scale and SAH grading scale (P<0.01) but not with neurological score (P=0.24). COMPARISON WITH EXISTING METHODS: The current grading system is based on the amount of SAH and needs animal euthanasia to evaluate SAH severity. There is no useful grading system to classify severity of SAH without decapitating animals. CONCLUSIONS: We demonstrated a correlation between the MRI grading scale and the current SAH grading scale in an endovascular perforation rat model. The MRI grading scale allows evaluation of SAH severity without euthanizing animals.

Use of PET in the diagnosis of primary CNS lymphoma in patients with atypical MR findings.

OBJECTIVE: The diagnosis of primary central nervous system lymphoma (PCNSL) in immunocompetent patients with atypical magnetic resonance (MR) findings such as disseminated lesions or no (non-enhancing) lesion is sometimes difficult because of mimicking other tumorous and non-tumorous diseases. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) and (11)C-methionine (MET) can measure the glucose and amino acid metabolism in the lesions and may provide useful information for diagnosing PCNSL in patients with such subtle MR findings. METHODS: We performed PET studies with FDG and MET in 17 histologically proven PCNSL and compared the uptake of FDG and MET qualitatively and quantitatively in the tumors between 12 typical and 5 atypical MR findings. RESULTS: All typical PCNSL showed strong uptake of FDG and MET; however, visual analysis of FDG and MET uptake in atypical PCNSL was not very useful for finding lesions in the brain. Semiquantitative FDG and MET uptake values (SUVmax) and quantitative FDG influx rate constant (K ( i )) in the tumors are significantly lower in atypical PCNSL compared with those in typical PCNSL. These values obtained in the lesions with atypical MR findings were also not useful for differentiating PCNSL from other tumorous and non-tumorous diseases. The k (3) values evaluated by FDG kinetic analysis in atypical PCNSL were similar to those obtained in typical PCNSL. CONCLUSIONS: Visual analysis of FDG and MET uptake in atypical PCNSL was not useful for finding the lesions in the brain. Semiquantitative and quantitative values obtained in the lesions with atypical MR findings were also not useful for differentiating PCNSL from other tumorous and non-tumorous diseases. The k (3) values evaluated by FDG kinetic analysis in atypical PCNSL may provide valuable information in the diagnosis of PCNSL.

Structure-function analysis of NADE: identification of regions that mediate nerve growth factor-induced apoptosis.

Nerve growth factor (NGF) can induce apoptosis in neural cells via activation of the low affinity neurotrophin receptor p75NTR. NADE (p75NTR-associated cell death executor) is a p75NTR-associated protein that mediates apoptosis in response to NGF by interacting with the death domain of p75NTR in 293T, PC12, and nnr5 cells (Mukai, J., Hachiya, T., Shoji-Hoshino, S., Kimura, M. T., Nadano, D., Suvanto, P., Hanaoka, T., Li, Y., Irie, S., Greene, L. A., and Sato, T. A. (2000) J. Biol. Chem. 275, 17566-17570). We performed extensive mutational analysis on NADE, to better characterize its structural and functional features. Truncation of a minimal region, including amino acid residues 41-71 of NADE, was found to be sufficient to induce apoptosis. The designated regulatory region includes the C-terminal amino acid residues (72-112) and is essential for NGF-dependent regulation of NADE-induced apoptosis. Furthermore, the mutants with amino acid substitutions in the leucine-rich nuclear export signal (NES) sequence (residues 90-100) abolished the export of NADE from the nucleus to the cytoplasm. Mutation of the NES also abolished self-association of NADE, its interaction with p75NTR, and NGF-dependent apoptosis. Expression of a fragment of NADE (amino acid residues 81-124) blocked NGF-induced apoptosis in oligodendrocytes, suggesting that this region has a dominant negative effect on NGF/p75NTR-induced apoptosis. These studies identify distinct regions of NADE that are involved in regulating specific functions involved in p75NTR signal transduction.