Transbrachial Mechanical Thrombectomy for Acute Ischemic Stroke in Marfan's Syndrome: A Case Report.

Objective: Marfan's syndrome (MFS) is a systemic connective tissue disorder with autosomal dominant inheritance. Cardiovascular complications of MFS such as aortic root or valve disease and aortic aneurysm or dissection are potential cause of access route problems of mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Here, we report a case of a patient with MFS who underwent MT for AIS. Case Presentation: A 58-year-old woman with MFS presented with a sudden onset of consciousness disturbance and right hemiparesis, and was referred to our hospital. After the infusion of tissue plasminogen activator, CTA showed a type III arch in the aortic arch and severe tortuosity of the thoracoabdominal aorta; thus, angiography was performed using the transbrachial approach. Left common carotid angiogram showed complete recanalization of the left middle cerebral artery. On the sixth day, the patient presented a sudden consciousness disturbance and left hemiparesis. MRA showed right internal carotid artery occlusion. MT was performed by the transbrachial approach, and complete recanalization was achieved on the first pass. Conclusion: MT via the transbrachial approach is a treatment option that should be considered, especially in MFS, where the transfemoral approach is difficult due to anatomical problems.

DNA methylation-mediated silencing of nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) in glioma cell lines.

Nonsteroidal anti-inflammatory drug-activated gene, NAG-1, a transforming growth factor-ß member, is involved in tumor progression and development. The association between NAG-1 expression and development and progression of glioma has not been well defined. Glioblastoma cell lines have lower basal expression of NAG-1 than other gliomas and normal astrocytes. Most primary human gliomas have very low levels of NAG-1 expression. NAG-1 basal expression appeared to inversely correlate with tumor grade in glioma. Aberrant promoter hypermethylation is a common mechanism for silencing of tumor suppressor genes in cancer cells. In glioblastoma cell lines, NAG-1 expression was increased by the demethylating agent, 5-aza-2'-deoxycytidine. To investigate whether the NAG-1 gene was silenced by hypermethylation in glioblastoma, we examined DNA methylation status using genomic bisulfite sequencing. The NAG-1 promoter was densely methylated in several glioblastoma cell lines as well as in primary oligodendroglioma tumor samples, which have low basal expression of NAG-1. DNA methylation at two specific sites (-53 and +55 CpG sites) in the NAG-1 promoter was strongly associated with low NAG-1 expression. The methylation of the NAG-1 promoter at the -53 site blocks Egr-1 binding and thereby suppresses Nag-1 induction. Treatment of cells with low basal NAG-1 expression with NAG-1 inducer also did not increase NAG-1. Incubation with a demethylation chemical increased Nag-1 basal expression and subsequent incubation with a NAG-1 inducer increased NAG-1 expression. We concluded from these data that methylation of specific promoter sequences causes transcriptional silencing of the NAG-1 locus in glioma and may ultimately contribute to tumor progression.

Usefulness of non-contrast MRI three dimensional brain surface imaging using a T(2) weighted image.

MR brain surface imaging using a 3D T(1) fast spoiled gradient recalled acquisition in the steady state (FSPGR) sequence with contrast medium is useful for surgical planning. However, this method has several problems such as use of the contrast medium. In this paper we evaluated the usefulness of MR 3D brain surface imaging using a non-contrast enhanced 3D T(2) fast recovery fast spin echo (FRFSE) sequence as a new alternative method. This study includes 5 volunteers who underwent 3D volume rendering (VR) imaging using both a non-contrast enhanced 3D T(1)-SPGR sequence and a non-contrast enhanced 3D T(2)-FRFSE sequence, and 10 patients with brain tumors, who underwent preoperative 3D VR imaging using both a contrast enhanced 3D T(1)-SPGR sequence and a non-contrast enhanced 3D T(2)-FRFSE sequence. Four neurosurgeons assessed the visibility of sulci, gyri, and brain surface veins using a 4-point confidence scale on each VR image. 3D VR imaging using a 3D T(2)-FRFSE sequence was significantly superior to that using a 3D T(1)-SPGR sequence in the visualization of the sulci and gyri (p<0.05). In contrast, there was no significant difference between both sequences in the visualization of the brain surface veins. MR brain surface imaging using a non-contrast 3D T(2)-FRFSE sequence is at least equal or superior to 3D imaging using a contrast enhanced 3D T(1)-SPGR sequence in the preoperative planning.

Regulation of EP4 expression via the Sp-1 transcription factor: inhibition of expression by anti-cancer agents.

For glioblastomas, COX-2 expression is linked to poor survival. COX-2 effects are mediated by the receptors EP2 and EP4, whose regulation is poorly understood. The expression of EP4, and activation or inhibition of EP4 activity in human glioblastoma T98G cells, was found to correlate with growth on soft agar. Chemoprevention drugs, troglitazone (TGZ) and some COX inhibitors, significantly suppressed EP4 expression in T98G cells in a dose dependant manner. Specificity protein 1 (Sp-1) binding sites, located within region -197 to -160 of the human EP4 promoter, are important for the transcription initiation of the human EP4 gene and are responsible for the EP4 suppression by TGZ. Mutation in the Sp-1 sites altered the promoter activity of luciferase constructs and TGZ effects on the promoter. The inhibitory effect of TGZ on EP4 expression was reversed by PD98059, a MEK-1/Erk inhibitor. Immunoprecipitation-Western blot analysis detected Sp-1 phosphorylation that was dependent on TGZ-induced Erks activation. ChIP assay confirmed that Sp-1 phosphorylation decreases its binding to DNA and as a result, leads to the suppression of EP4 expression. Thus, we propose that the expression of EP4 is regulated by Sp-1, but phosphorylation of Sp-1 induced by TGZ suppresses this expression. This represents a new and unique mechanism for the regulation of the EP4 receptor expression.

A rat glioblastoma model with diffuse leptomeningeal gliomatosis induced by intracarotid injection of C6 glioma cells.

OBJECTIVE: A reproducible brain tumor model using experimental animals is required to study biological behavior and develop more potent antineoplastic drugs and effective therapeutic modalities. In this work, we attempted to establish diffuse leptomeningeal gliomatosis in the rat by intracarotid injection of C6 glioma cells. METHODS: Intracarotid injection of 1 x 10(7) C6 glioma cells in Wistar rats was performed to establish a primary diffuse leptomeningeal gliomatosis model. Ki-67 and matrix metalloproteinases (MMPs) immunohistochemistry staining were used to study the biological behavior of the developed tumor. Methodology, physical findings and histopathological features were also discussed. RESULTS: Leptomeningeal gliomas grew in all Wistar rats after the administration of 1 x 10(7) C6 glioma cells. Intracranial hypertension, weight loss and cachexia developed, and the median survival time was 18.0 +/- 2.9 days. The glioma mass distributed throughout the ventricles, the leptomeningeal regions in the brain and the brainstem, with typical pathological features of glioblastoma. The immunohistochemistry stainings showed high Ki-67 labeling index (42.1 +/- 10.3%), and concomitant overexpression of MMP-2 and MMP-9 suggested proliferation, invasion and angiogenesis potential. DISCUSSION: The advantage of the intracarotid injection route is the absence of an operative scar in the cranium. This established animal model is a novel model of primary diffuse leptomeningeal gliomatosis. This model probably can be used for pre-clinical testing in the progression of glioblastoma.

Aberrant promoter methylation and expression of the imprinted PEG3 gene in glioma.

Glioma includes astrocytoma, oligodendroglioma, ependymoma and glioblastoma. We previously reported the epigenetic silencing of paternally expressed gene 3 (PEG3) in glioma cell lines. In this study, we investigated methylation of an exonic CpG island in the promoter region and the expression of PEG3 gene in 20 glioma and 5 non-tumor tissue samples. We found wide variations in the methylation level. Hypomethylaiton and hypermethylation was found in 3 and 4 glioma tissue samples, respectively. Monoallelic expression, which is an evidence of an imprinted gene, was maintained in eight out of nine informative cases which have T/C polymorphisms in PEG3. The lower gene expression, which suggested epigenetic silencing of PEG3, was confirmed statistically in glioblastoma using quantitative reverse-transcription polymerase chain reaction. Interestingly, we found higher expression of PEG3 in two out of three oligodendrogliomas. A negative correlation between the methylation level and gene expression was shown by regression analysis. These results suggest that the abnormal regulation of PEG3 is associated with several glioma subtypes and that it plays an important role in tumorigenesis.

Basal ganglia germinoma: diagnostic value of MR spectroscopy and (11)C-methionine positron emission tomography.

We herein report a 12-year-old girl with a basal ganglia germinoma who presented with right-sided hemiparesis after a minor head trauma. Magnetic resonance (MR) imaging revealed a minimally enhanced lesion involving the left putamen, thalamus, and corona radiata. The lesion showed low-signal intensity on T1-, and high intensity on T2- and diffusion-weighted imaging. The MR signal in the adjacent globus pallidum was also low on T2-weighted imaging. MR spectroscopy on the lesion showed a large lactate/lipid/macromolecule peak with a decreased NAA/Cr ratio, but no increase in the Cho/Cr ratio. However, posttraumatic infarction at the territory of lateral lenticulostriate artery was ruled out 1 month later. This was based on progression of the hemiparesis and neuroimaging results, including an increased Cho/Cr ratio and weak uptake on (11)C-methionine positron emission tomography of the basal ganglia lesion. Stereotaxic brain biopsy confirmed the diagnosis of germinoma.

Metastasis of carcinoid to the arch of the axis in a multiple endocrine neoplasia patient: a case report.

BACKGROUND CONTEXT: Carcinoid tumors eventually metastasize to the spine, and epidural spinal cord compression is a relatively frequent neurologic complication of carcinoid. However, a case of multiple endocrine neoplasia type 1 (MEN1) presenting with spinal cord compression as a result of a metastatic carcinoid tumor has not been reported previously. PURPOSE: To report an extremely rare case of MEN1 presenting with spinal cord compression by metastatic carcinoid tumor. STUDY DESIGN: Case report. METHODS: A 51-year-old man, with a past history of thymoma, insulinoma, and gastric carcinoid presented with neck pain. Neuroradiological examination revealed that a tumor around the arch of the axis compressed the spinal cord with osteoblastic changes. RESULTS: After hemilaminectomy of the axis and removal of the tumor followed by irradiation, the patient returned to his previous job. Histological examination confirmed metastatic carcinoid tumor. CONCLUSIONS: Spinal metastasis of carcinoid tumor occurred in a multiple endocrine neoplasia patient, and it is significant to note that carcinoid metastasis is one of differential diagnoses for osteoblastic lesions.

Establishment of experimental glioma models at the intrinsic brainstem region of the rats.

OBJECTIVES: As the treatment of human intrinsic brainstem gliomas remains challenging, experimental glioma models are needed. METHODS: We developed a rat model of intrinsic brain stem glioma that uses a stereotactic frame to fix the head for the delivery of C6 glioma cells to target sites via a permanently implanted cannula. We inoculated the rat midbrain, pons or cerebral cortex with 5 x 10(4) cells suspended in 1 microl culture medium over the course of 2 minutes. RESULTS: Three days post-implantation, tumor formation was visible in the periaqueductal gray matter in the midbrain and the tegmentum of the pons. On the tenth day, the tumor diameter exceeded over 2 mm; there was no tumor cell seeding into the cerebrospinal fluid space. The tumor manifested the histological features typical of glioblastoma; Ki-67 labeling index was 32%. DISCUSSION: Because in our model the cannula is permanently implanted, additional inocula can be delivered. Here we detail our rat brainstem glioma model and discuss its usefulness for the investigation of these tumor in humans.

Mixed germ cell tumors with abundant sarcomatous component in the temporal lobe after radiochemotherapy of neurohypophyseal germinoma: a case report.

We report a case of intracranial germ cell tumor that showed pathological changes from neurohypophyseal germinoma to mixed germ cell tumors consisting exclusively of undifferentiated sarcomatous component after radiochemotherapy. Three surgical specimens and autopsied brain from the patient were histologically examined. An initial specimen from the neurohypophyseal tumor was diagnosed as germinoma with a two-cell pattern. Five years later, after repeated radiochemotherapy, the second specimen resected from the right temporal lobe showed mixed germ cell tumors consisting of the three components of germinoma, choriocarcinoma, and immature teratoma. Six months later after intensive radiotherapy, the right temporal tumor recurred and was surgically removed. The histological diagnosis was mixed germ cell tumors with abundant immature teratoma component. The patient died of uncontrollable tumor growth with repeated intratumoral hemorrhages. The autopsied brain showed sarcoma with angionecrosis. This pathological alteration indicated an increase in the sarcomatous component after undergoing various treatments. We discuss the histological changes of intracranial germ cell tumor modified by treatment.

Relationship of hypotension and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Changes in systemic arterial blood pressure and the degree of cerebral vasospasm were investigated in 125 patients with aneurysmal subarachnoid hemorrhage. METHODS: Systemic arterial blood pressure was measured every 2 hours in each patient for a period of more than 2 weeks, and a fall in systemic blood pressure (FBP) was defined as a decrease of >40 mmHg of systolic blood pressure between two consecutive measurements. RESULTS: A total of 91 FBPs occurred in 52 (41.6%) of 125 patients despite specific post-operative management to prevent hypovolemia. Five (5.5%) of the 91 FBPs occurred just before the onset of symptomatic vasospasm. Symptomatic vasospasm was observed in 36 (69.2%) of 52 patients with FBP and in 32 (43.8%) of 73 patients without FBP (p<0.01, chi-squared test). A hypodense area on computed tomographic scans in association with cerebral vasospasm was observed in 25 (48.1%) of 52 patients with FBP and in 21 (28.8%) of 73 patients without FBP (p<0.05). DISCUSSION: We conclude that FBP might result from delayed cerebral vasospasm and/or brain dysfunction owing to subarachnoid hemorrhage itself.

A case of Tolosa-Hunt syndrome affecting both the cavernous sinuses and the hypophysis, and associated with C3 and C4 aneurysms.

BACKGROUND: We describe the first case of Tolosa-Hunt syndrome that is associated with C3 and C4 aneurysms. CASE DESCRIPTION: The patient, a female aged 58 years, had diplopia and right retroorbital pain. Magnetic resonance imaging revealed an enlargement of the hypophysis and bilateral cavernous sinuses, particularly on the right side. Cerebral angiography demonstrated ICA aneurysms of the left C3 and right C4 portions. These symptoms were immediately alleviated after initiation of prednisolone therapy, but recurred after the dose was tapered off. Radiological examination revealed an enlargement of the hypophysis whereas the right C4 aneurysm had decreased in size and no blood flow was apparent in the ipsilateral ophthalmic artery. A biopsy was performed and the results showed a focal inflammatory change. Steroid therapy was represcribed, and after a follow-up period of 10 months without therapy, the patient has been free of symptoms. CONCLUSION: We conclude that bilateral ICA aneurysms might be directly induced by inflammatory infiltration into intracavernous ICAs.

Surgical treatment of arteriovenous malformation in a patient with human immunodeficiency virus infection and hemophilia a: case report.

This case illustrates surgical treatment of an arteriovenous malformation (AVM) in a patient with hemophilia A also infected with human immunodeficiency virus (HIV). A 31-year-old man was admitted to our hospital with right parietal intracerebral hemorrhage. He had previously been diagnosed with hemophilia A and HIV. Carotid angiography revealed an AVM. As the hematoma enlarged and clinical symptoms progressed, we resected the hematoma and the AVM while providing supplemental infusion of Factor VIII before, during, and after the operation. The patient did not experience abnormal postoperative bleeding, and he was discharged with mild motor weakness of the left lower extremity. We discuss the surgical indications, risk, and patient management in relation to hemophilia and HIV infection.

Cerebral venous sinus thrombosis associated with iron deficiency: two case reports.

Two patients presented with cerebral venous sinus thrombosis (CVST) associated with iron deficiency. A 14-year-old man had thrombosis extending from the end of the superior sagittal sinus to the left transverse sinus. Severe dehydration after competitive sport had induced CVST. The laboratory findings showed severe iron deficiency anemia which persisted for 1 year. A 47-year-old man had thrombosis in the entire superior sagittal sinus. Dehydration caused by poor nutrition had induced CVST. The laboratory findings showed transient iron deficiency in the acute phase. Both patients received conservative treatment for dehydration and iron supplementation. These two cases indicate that iron deficiency is a risk factor for CVST.

Spatial resolution of calpain-catalyzed proteolysis in focal cerebral ischemia.

Transient forebrain ischemia induces calpain-mediated degradation of the neuronal cytoskeleton, alpha-fodrin, and this results in ischemic neuronal death. In this study, we investigated the spatial distribution and temporal changes of calpain-catalyzed alpha-fodrin proteolysis in focal cerebral ischemia and examined the effects of a calpain inhibitor. Ischemia was induced in gerbils by 3-h middle cerebral artery occlusion followed by reperfusion. Animals were divided into four groups: a sham-operated group, an ischemic group, a vehicle-treated group, and a calpain inhibitor-treated group. Intravenous injections of vehicle or calpain inhibitor I were administered 30 min before ischemia. Infarct volumes were measured 1 day after reperfusion and the spatial distribution of calpain-catalyzed alpha-fodrin proteolysis was investigated by immunohistochemistry 15 min, 1 h, 4 h, and 1 day after reperfusion. Infarct volume (mean +/- SD) in the ischemic group and the vehicle-treated group was 204.6 +/- 19.1 mm3 and 212.4 +/- 16.3 mm3, respectively, and the calpain inhibitor I reduced the infarct volume [149.4 +/- 25.2 mm3 (P < 0.05)]. Immunoblot analysis demonstrated that calpain inhibitor reduced proteolysis. Ischemia induced fodrin proteolysis in the ischemic core and the peri-infarct zone within 15 min after reperfusion, with proteolysis developing quickly in the ischemic core and more slowly in the peri-infarct zone. Proteolysis preceded neuronal death in the peri-infarct zone. Calpain inhibitor I ameliorated neuronal death in the peri-infarct zone but not in the ischemic core. Thus, calpain plays a pivotal role on focal ischemia as well as in global ischemia.

A non-enzymatic derived arachidonyl peroxide, 8-iso-prostaglandin F2 alpha, in cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage participates in the pathogenesis of delayed cerebral vasospasm.

We performed serial measurements of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a non-enzymatic derived arachidonyl peroxide, in the cerebrospinal fluid (CSF) of 34 patients with subarachnoid hemorrhage (SAH). Patients were treated with open or endovascular surgery within 48 h of onset. Delayed cerebral vasospasm was verified by the presence of a low-density area on CT scan indicating focal cerebral infarction occurring after symptomatic delayed vasospasm. Concentrations of 8-iso-PGF2alpha in the CSF of 15 patients exhibiting delayed cerebral vasospasm were compared with those of 19 patients who did not exhibit vasospasm. The concentrations of 8-iso-PGF2alpha in the CSF of patients showing vasospasm were 42.4+/-37.1 pg/ml (mean+/-S.D., n=12) on Days 0-2, 66.4+/-41.0 pg/ml (n=14) on Days 3-5, 118.5+/-89.9 pg/ml (n=15) on Days 6-8, 86.2+/-70.2 pg/ml (n=11) on Days 9-11, 48.8+/-31.8 pg/ml (n=10) on Days 12-14, 27.8+/-20.1 pg/ml (n=7) after Day 20, while the concentrations in patients not showing vasospasm were 24.8+/-12.0 pg/ml (n=18) on Days 0-2, 25.7+/-15.2 pg/ml (n=19) on Days 3-5, 47.5+/-52.3 pg/ml (n=18) on Days 6-8, 56.7+/-72.0 pg/ml (n=13) on Days 9-11, 34.2+/-53.1 pg/ml (n=15) on Days 12-14, 20.1+/-18.2 pg/ml (n=10) after Day 20. CSF concentrations of 8-iso-PGF2alpha on Days 3-5 and Days 6-8 were significantly higher in patients showing vasospasm as compared to patients not showing vasospasm. CSF levels of 8-iso-PGF2alpha in patients showing vasospasm gradually increased in the days after onset of SAH and peaked on Days 6-8. Levels returned to normal after Day 20. These values on Days 3-5, Days 6-8, and Days 9-11 were significantly higher than the value after Day 20. Considering these data and the biological activities of 8-iso-PGF2alpha, such as development of inflammation, membrane perturbation and vasoconstriction, we conclude that 8-iso-PGF2alpha may play a role in delayed cerebral vasospasm after SAH.

C-terminus of p47(phox) is required for interaction with leukocyte type rat 12-lipoxygenase.

In yeast two-hybrid system, rat 12-lipoxygenase (12-LO) bound to complete (390 amino acids) or the N-terminus truncated form of human p47 (phox), but not to the C-terminus truncated form (residues 1-286). When glutathione S-transferase fused human p47(phox) was added to an in vitro 12-LO enzyme activity assay, formation of 12-hydroperoxyeicosatetraenoic acid was reduced significantly compared to the C-terminus truncated form. These results indicate that C-terminus of p47(phox) is important for its interaction to rat 12-LO.

A non-NF2 case of schwannomas of vestibular and trigeminal nerves with different genetic alterations of NF2 gene: case report.

BACKGROUND: We report a patient with 2 separate schwannomas, a vestibular schwannoma and a trigeminal schwannoma, that were attached to each other and appeared to be a single tumor on imaging studies. CASE DESCRIPTION: The patient, without any family history of neurofibromatosis, presented with a progressive hearing loss and mild left facial nerve palsy. Magnetic resonance imaging showed a snowman-like tumor in the left cerebellopontine angle. Surgical exposure revealed that the tumor consisted of 2 "kissing" schwannomas, a trigeminal and vestibular schwannoma. Molecular genetic analysis detected a 1-base pair deletion at exon 10 of the neurofibromatosis type 2 (NF2) gene in the trigeminal schwannoma, but not in the acoustic schwannoma. However, loss of heterozygosity at chromosome 22q (D22S282 and D22S929) was detected in both tumors, losing the same allele. CONCLUSION: Multiple schwannomas in non-NF2 patients are extremely rare, and possible causes include simple coincidence or germline genetic alteration of adjacent gene on chromosome 22q, similar to the cause recently suggested in familial schwannomatosis. Although not always possible, molecular genetic examination may help to understand the underlying mechanism and would be warranted in such cases.

Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines.

The human paternally expressed gene 3 (PEG3) on chromosome 19q13.4 is one of the candidate tumor suppressor genes for glioma. We have previously reported that the epigenetic silencing of PEG3 expression in glioma cell lines is dependent on aberrant DNA methylation of an exonic CpG island. Here, we have identified three expressed sequence tags (ESTs), H80201, H78825 and AW197312, that exhibit paternal allele-specific expression, using human monochromosomal hybrids containing the paternal or maternal origin of PEG3 locus. The EST H80201 was shown to be expressed only from the paternal allele in normal human lymphoblasts by utilizing a single nucleotide polymorphism (SNP). Monoallelic expression of EST H80201 was also detected in non-tumor adult human brain tissues of gliomas. These ESTs were located directly adjacent to PEG3 in a head-to-head orientation. We have named this new transcript, imprinted transcript 1, which is located upstream but oppositely oriented to PEG3 (ITUP1). The ITUP1 showed a similar expression profile with PEG3 in glioma cell lines. Bisulfite genomic sequencing and reverse transcription (RT)-PCR analysis indicated that hypermethylation of the promoter region correlated with the absence of these transcripts. This suggests that ITUP1 and PEG3 are coordinately regulated, and that downregulation of the both genes may be important in the development of glioma.