[Foramen magunum meningioma presented as subarachnoid haemorrhage].

A 59-year-old woman was admitted with to our hospital with a sudden severe headache that had lasted for 5 days. Neck stiffness was present, but no other neurological deficits were present. Subarachnoid hemorrhage and intra-tumor hemorrhage were not noted on a head computed tomography (HCT). The patient's cerebrospinal fluid was xanthochromic. Magnetic resonance imaging (MRI) demonstrated a gadolinium-enhanced tumor with hemorrhagic changes around the foramen magnum. After conservative therapy, MRI showed a decrease in tumor size and a dural tail sign. This tumor was diagnosed as a hemorrhagic meningioma, and was resected with a posterior suboccipital approach. Histology confirmed that this tumor was a benign transitional meningioma with hemorrhagic change. This is a rare case involving benign meningioma onset by hemorrhagic change. Postoperative tumor recurrence was not present.

[Case of spontaneous cervical internal carotid artery dissection with embolic stroke after a job-change].

A 51 year old male was admitted to our hospital with sudden consciousness disturbance, global aphagia and right hemiparesis. Magnetic resonance imaging (MRI) revealed fresh infarctions in the territory of the left middle cerebral artery, and MR angiography (MRA) showed occlusion of the left carotid artery and the left middle cerebral artery. We started conservative therapy, including antiplatelet drug and blood pressure control. Three days later, cervical MRA revealed hematoma in the intracranial carotid wall of the petrous portion, leading to a diagnosis of spontaneous intracranial carotid artery dissection of the petrous portion. Two weeks after admission, MRA and angiography showed recanalization and pearl and string sign in the left petrous internal carotid artery. After that, the patient's neurological deficit improved, and the dissection also improved. Four months later, MR-angiography revealed an almost normalized condition.

[Pitfall in conservative therapy for working patients with brain ischemia].

A 59-year-old employed man was recommended to have surgical treatment for symptomatic left middle cerebral arterial stenosis. He refused surgical treatment for social reasons but was given conservative therapy for the prevention of the recurrence of cerebral infarction. Immediately after he retired, he had severe recurrent cerebral infarction with severe anemia and low blood pressure due to gastroduodenal ulcer bleeding. It was inferred from MRI findings that this recurrent cerebral infarction was related to a hemodynamic mechanism and mental stress due to the gastroduodenal ulcer. The influence of occupational mental stress has been reported to be a risk factor of gastroduodenal ulcer. The occupational situation of a patient should be an important factor in consideration of the prevention of cerebral apoplexy.

Mandibular Ewing sarcoma with chromosomal translocation t(21;22)(q22;q12).

Ewing sarcoma (ES) is a primary bone malignant neoplasm and is the second most common primary malignancy of the bone found in childhood and adolescence after osteosarcoma. ES has an annual frequency in the population younger than 20 years of approximately 2.9 per million. ES occurs most frequently in the long bones of the extremities and pelvis and very rarely in the jaw. Recently, it was revealed that chromosomal translocation t(11;22)(q24;q12), which fuses the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11, occurs in most cases of ES. We report here a rare case of mandibular ES in a 10-year-old child with chromosomal translocation t(21;22)(q22;q12) in which the EWS gene is fused with the ERG gene on chromosome 21.

Pre-radiation enhances the cytotoxicity of docetaxel in head and neck squamous cell carcinoma cells.

This study was designed to determine the effect of the treatment schedule on the interaction between docetaxel and irradiation. Human head and neck squamous cell carcinoma (HNSCC) cells with different p53 status, and HSC4 (p53 wild-type) and CAL27 (p53 mutant type) cells were treated with docetaxel and irradiation using three schedules: i) concurrent treatment, ii) docetaxel pretreatment and iii) pre-radiation. Docetaxel and radiation inhibited the proliferation of HSC4 and CAL27 cells in a dose-dependent manner. However, irradiation pretreatment was more effective than the other treatment regimens in all cells. Our data suggest that pre-radiation in HNSCC cells significantly enhances docetaxel cytotoxity by arresting S-phase, and this provides the most effective treatment sequence of docetaxel and radiation combination therapy. Therefore, radiation followed by docetaxel may be the most effective sequence for head and neck cancer therapy.

Alterations of p16 and p14ARF genes and their 9p21 locus in oral squamous cell carcinoma.

The p16 gene encodes a 16-kDa cyclin kinase inhibitor, and the p14ARF gene a 14-kDa protein, which acts as a cell cycle regulator or tumor suppressor in human cancer cells. Both genes are mapped on chromosome 9p21. Previous studies have suggested that the p16 gene has important roles in head and neck squamous cell carcinoma. To clarify carcinogenesis in oral squamous cell carcinoma (OSCC), we examined 44 primary OSCCs for alterations of p16 and p14ARF mRNA expression, the methylation status of the p16 gene promoter, the loss of heterozygosity (LOH) at the 9p21 locus, and p16 and p14ARF gene mutations. Alterations of p16 and p14ARF mRNA expression were seen in 27 (61.4%) of 44 and 10 (22.7%) of 44 of OSCC samples, respectively. Methylation of the p16 gene promoter region was detected in 28 (63.6%) of 44 samples, and LOH at 9p21 locus was found in 30 (68.2%) of 44. p16 and p14ARF gene mutations were observed in 4 (9.0%) of 44 and 2 (4.5%) of 44 samples, respectively. Suspected homozygous deletion (HD) was seen in 9 (20.5%) of 44. All cases except one (97.7%) showed alterations in p16, p14ARF, and their locus. These data indicate that the status of p16 and p14ARF genes in OSCC is frequently influenced by methylation, gene mutation, and allelic deletions. Furthermore, these genes and their 9p21 locus have various roles in the pathogenesis of OSCC.

Antitumour effect of electrochemotherapy with bleomycin on human prostate cancer xenograft.

OBJECTIVE: To investigate the antitumour effect of electroporation (EP), a drug delivery system that has been shown to be effective synergistically with antitumour drugs, with bleomycin on the growth of prostate cancer xenografts in nude mice. MATERIALS AND METHODS: PC-3 cells were implanted subcutaneously into nude mice. After determination of the optimal conditions of electric pulse voltage and bleomycin dose, tumour growth in mice treated with EP plus bleomycin was compared with that in mice receiving EP alone, bleomycin alone or no treatment. In all four groups, apoptosis in the tumours was assessed. RESULTS: There was a significant reduction in tumour growth in mice that received EP with bleomycin. Apoptotic cells in tumours at 24 h after treatment with EP plus bleomycin showed a significant difference compared with the other three groups, but not at 12 h after treatment. CONCLUSIONS: These results indicate the possibility that EP with bleomycin could be effective as an ablation therapy for prostate cancer, especially androgen-independent cancer.

[Ruptured true posterior communicating artery fusiform aneurysm: case report].

A 32-year-old female complained of a headache persisting for approximately one week. She was emergently brought to the hospital for sudden consciousness disorder early in the morning. Her neurological state was JCS 200 and WFNS Grade V. CT scan demonstrated a subarachnoid hemorrhage. 3D-CTA and DSA showed a right true posterior communicating artery fusiform aneurysm. We performed open surgery the same day, and found that the aneurysmal wall had thinned markedly. The aneurysm ruptured, and trapping was performed. A perforating artery from the aneurysm was sacrificed, but there was no apparent neurological deficit. The patient was ambulatory when discharged after a VP shunt was implanted, and she has returned to normal daily life. True posterior communicating artery fusiform aneurysm is very rare, and has been reported in detail in only 6 cases to date. A brief clinical review of the literature is presented. Since this type of aneurysm enlarges rapidly in some patients, and the possibility of re-rupture in the acute period is high, prompt trapping after onset is recommended.

The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extracellular signal-regulated kinase 5 and PPARgamma1 transcriptional activation: involvement in flow-induced PPARgamma activation in endothelial cells.

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. Since both flow and PPARgamma have atheroprotective effects and extracellular signal-regulated kinase 5 (ERK5) kinase activity is significantly increased by flow, we investigated whether ERK5 kinase regulates PPARgamma activity. We found that activation of ERK5 induced PPARgamma1 activation in endothelial cells (ECs). However, we could not detect PPARgamma phosphorylation by incubation with activated ERK5 in vitro, in contrast to ERK1/2 and JNK, suggesting a role for ERK5 as a scaffold. Endogenous PPARgamma1 was coimmunoprecipitated with endogenous ERK5 in ECs. By mammalian two-hybrid analysis, we found that PPARgamma1 associated with ERK5a at the hinge-helix 1 region of PPARgamma1. Expressing a hinge-helix 1 region PPARgamma1 fragment disrupted the ERK5a-PPARgamma1 interaction, suggesting a critical role for hinge-helix 1 region of PPARgamma in the ERK5-PPARgamma interaction. Flow increased ERK5 and PPARgamma1 activation, and the hinge-helix 1 region of the PPARgamma1 fragment and dominant negative MEK5beta significantly reduced flow-induced PPARgamma activation. The dominant negative MEK5beta also prevented flow-mediated inhibition of tumor necrosis factor alpha-mediated NF-kappaB activation and adhesion molecule expression, including vascular cellular adhesion molecule 1 and E-selectin, indicating a physiological role for ERK5 and PPARgamma activation in flow-mediated antiinflammatory effects. We also found that ERK5 kinase activation was required, likely by inducing a conformational change in the NH(2)-terminal region of ERK5 that prevented association of ERK5 and PPARgamma1. Furthermore, association of ERK5a and PPARgamma1 disrupted the interaction of SMRT and PPARgamma1, thereby inducing PPARgamma activation. These data suggest that ERK5 mediates flow- and ligand-induced PPARgamma activation via the interaction of ERK5 with the hinge-helix 1 region of PPARgamma.

Activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion.

Big MAP kinase 1 (BMK1/ERK5) plays a critical role in pre-natal development of the cardiovascular system and post-natal eccentric hypertrophy of the heart. Of the two isoforms upstream of MAPK-kinase 5 (MEK5) known to exist, only the longer MEK5alpha isoform potently activates BMK1. We generated cardiac-specific constitutively active form of the MEK5alpha (CA-MEK5alpha transgenic (Tg) mice), and observed a 3 to 4-fold increase in endogenous BMK1 activation and hyperphosphorylation of connexin 43 in the ventricles of the Tg compared to wild-type mice. The CA-MEK5alpha-Tg-mice demonstrated a profoundly accelerated recovery of left ventricular developed pressure after ischemia/reperfusion. We propose a novel role for BMK1 in protecting the heart from ischemia/reperfusion-induced cardiac injury.

ERK1/2 associates with the c-Met-binding domain of growth factor receptor-bound protein 2 (Grb2)-associated binder-1 (Gab1): role in ERK1/2 and early growth response factor-1 (Egr-1) nuclear accumulation.

Endothelial cell (EC) migration contributes to reendothelialization after angioplasty or rupture of atherosclerotic plaques. Extracellular signal-regulated kinase (ERK)1/2 translocates to the nucleus and activates transcription factors such as Ets-like transcription factor-1 and early growth response factor-1 (Egr-1) during reendothelialization. Because ERK1/2 does not possess a nuclear localization signal (NLS), its mechanism of translocation and accumulation in the nucleus remains unclear. Because Gab1 has a putative NLS in its N-terminal region, and Gab1 associates with phosphorylated ERK1/2, we hypothesized that Gab1 participates in ERK1/2 and Egr-1 nuclear accumulation. Using regenerating EC as a model system, we found that endogenous growth factor receptor-bound protein 2-associated binder-1 (Gab1) translocates into the nucleus in migrating EC. Wild-type red fluorescent protein-tagged Gab1 could be observed in both nucleus and cytoplasm, whereas the putative NLS deletion mutant (deltaNLS-Gab1) specifically localized in the cytoplasm. In addition, reduction of Gab1 expression by antisense Gab1 oligos or overexpression of deltaNLS-Gab1 inhibited serum-induced ERK1/2 and Egr-1 nuclear accumulation, suggesting a functional role for the NLS of Gab1 and a role for Gab1-ERK1/2 interactions in ERK1/2-Egr-1 nuclear accumulation. To investigate whether Gab1-ERK1/2 interaction is critical for ERK1/2 and Egr-1 nuclear accumulation, we created a dominant-negative Gab1 construct that consisted of the c-Met binding domain (amino acids 442-536) of Gab1. We found that overexpression of the c-Met binding domain of Gab1 disrupted serum-induced Gab1-ERK1 interaction and inhibited ERK1 and Egr-1 nuclear accumulation. These data suggest that Gab1-ERK1/2 binding and their nuclear translocation play a crucial role in Egr-1 nuclear accumulation.

[Delayed facial palsy after microvascular decompression for hemifacial spasm due to reactivation of varicella-zoster virus].

We report a patient suffering from delayed facial palsy after microvascular decompression (MVD) for hemifacial spasm, in whom the pathogenesis was proved. A 56-year-old man with a left hemifacial spasm was admitted to our hospital. Preoperative MR imaging showed that the left anterior inferior cerebellar artery (AICA) was compressing the left facial nerve. The causative vessel was defined as AICA during surgery, and MVD was performed successfully. Seven days later, the patient showed severe left facial palsy. Serum antibody of varicella-zoster virus (VZV) was increased, and Gd enhanced MR imaging demonstrated an enhancement of a geniculate ganglion of the left facial nerve, indicating inflammation. These findings suggested that delayed facial palsy after MVD was caused by a re-activation of VZV. The facial palsy disappeared completely over a period of nine months.

Importance of neuropsychological evaluation after surgery in patients with unruptured cerebral aneurysms.

BACKGROUND: We evaluated neuropsychological function before and after surgery in patients with unruptured cerebral aneurysms. METHODS: Neuropsychological functions in 43 patients with unruptured cerebral aneurysms were evaluated before and 1 month after surgery. The neuropsychological examination included the Mini-Mental State examination, "Kana-hiroi" test, Kohs Block Design test, and Miyake's Memory test. Then, if scores of even a single test were decreased 1 month after surgery, the tests were performed again 5 months later. In 24 of the 43 subjects, cerebral blood flow (CBF) was measured before and 1 month after surgery by single-photon emission tomography. RESULTS: The outcome in all patients was evaluated as good according to the Glasgow Outcome Score (GOS). In 17 (40%) of the 43 patients, neuropsychological function had deteriorated 1 month after surgery. The most sensitive test applied was the Miyake's Memory test. Of 14 patients with neuropsychological deterioration 1 month after surgery, 6 showed complete recovery, 5 showed partial recovery, and 3 still showed cognitive deterioration 6 months after surgery. Patients over 65 years old, those with anterior communicating artery aneurysms, those operated by interhemispheric approach, or those with systemic diseases showed a greater tendency toward a decline in postoperative neuropsychological function than the other patients. The postoperative CBF and vascular response in the frontal lobe of affected-side was decreased in cases showing cognitive deterioration. CONCLUSIONS: These results suggested that the neuropsychological outcomes after surgery for unruptured cerebral aneurysms were not satisfactory.

55 kDa nuclear matrix protein (nmt55) mRNA is expressed in human prostate cancer tissue and is associated with the androgen receptor.

Most prostate cancer grows in a hormone-dependent manner. Most patients, however, show hormone-independent growth after several years of hormone therapy. The mechanism of hormone-refractory prostate cancer remains unknown. It is important, therefore, to identify gene(s) related to prostate cancer that are up- or downregulated. We studied differences in gene expression in pairs of prostate cancer and normal prostate tissue utilizing the differential display method. Expression of the identified gene was examined by RT-PCR and real time quantitative PCR (TaqMan-PCR) using 26 pairs of human prostate cancer and normal tissues. We identified a specific upregulated gene encoding a 55 kDa nuclear matrix protein (nmt55) in human prostate cancer. nmt55 gene expression in human prostate cancer tissue was higher (20/26 cases) than that in normal prostate tissue. Moreover, the relationship between nmt55 and androgen receptor (AR) expression showed a positive correlation. In another experiment, transcriptional activity of the prostate specific antigen (PSA) promoter was upregulated by nmt55 in 293 cells. nmt55 showed high expression in prostate cancer compared to normal tissue and its expression showed a positive correlation with AR expression. The PSA promoter was activated by nmt55 expression. These results suggest the possibility that nmt55 expression is related to hormone-dependency or -independence associated with the AR.

Hippocampal CA1 neuron survival and cytosolic FKBP12, the 12 kDa FK506-binding protein, after ischemia and tacrolimus treatment in gerbils.

To assess the neuroprotective effect of tacrolimus (FK506) in transient forebrain ischemia models in gerbils, 10.0 mg/kg of FK506 was injected intraperitoneally immediately following reperfusion and at intervals of 1, 3, 6, 9, and 12 h after reperfusion. FK506 produced a significant neuroprotective effect for up to 6 h after 5 min of ischemia. Immunoblot and immunohistochemistry revealed that the amount of FKBP12, the 12-kDa FK506-binding protein, in the cytosol remained unchanged until 12 h after reperfusion. Translocation of FKBP12 from the nucleus to the cytosol was not observed until 24 h after reperfusion. Administration of FK506 did not appear to induce the cytosolic increase in FKBP12. In this study, no correlation was apparent between the post-ischemic therapeutic efficacy of FK506 and the post-ischemic changes in the cytosolic FKBP12.

[Early recurrent meningioma with malignant transformation: case report].

It has been reported that the incidence of malignant transformation of meningioma is 10 to 38%. However, it is rare for a benign meningioma to recur with malignant transformation shortly after surgery. We reported a case of recurrent meningioma with malignant transformation 4 months after the initial surgery. A 64-year-old female was admitted for meningioma in the right parietal convexity on July 1, 1999. The tumor was totally resected on August 31st. There were no surgically nor histologically detected malignancies. The tumor was diagnosed as a psammomatous meningioma, but there was a co-exsisting transitional meningioma-like area. There were no postoperative neurological deficits, but, left hemiparesis and numbness on the left side of the body appeared around the end of December, and the patient was re-hospitalized on January 11, 2000. The CT scan and MRI showed that a cystic tumor had formed at the site of the previous tumor. Using Gd-DTPA, this new tumor showed ring enhancement. The tumor was extirpated again on February 3, 2000. It was histologically diagnosed as a malignant transformation of the meningioma. The Patient died of tumor recurrence on December 17, 2000. We speculated that the mechanism of recurrence as follows: Tumor cells with the possibility of becoming malignant, remained in the brain after the initial surgery. Postoperatively, these cells underwent malignant transformation and the tumor recurred.

Inhibition of growth of human prostate cancer xenograft by transfection of p53 gene: gene transfer by electroporation.

To date, there is no effective therapy for hormone-independent prostate cancer. Therefore, as a new strategy for refractory cancer, gene therapy is showing increasing promise. In this study, we attempted to use a nonviral gene transfer system, in vivo electroporation, in prostate cancer cell PC-3 xenografts with the wild-type p53 (wt-p53) gene, as gene therapy for hormone-independent prostate cancer. To evaluate this in vivo gene transfer method, the beta-galactosidase gene was transfected into xenografts by electroporation. Then, the efficiency of transfection of exogenous p53 gene by electroporation was confirmed by reverse transcription-PCR, which indicated that p53 mRNA was present in samples from xenografts. Next, to estimate the reduction of prostate cancer xenografts by this method, we measured the size of PC-3 xenografts in nude mice after electroporation with the wt-p53 gene. The growth of tumors was markedly suppressed by wt-p53 gene transfection by electroporation compared with transfection of mutated type p53 gene (P = 0.0027) or vector only (P = 0.0015). Furthermore, histological specimens revealed increased apoptotic cell death in p53-transfected tumors. These results suggest that it is possible to transfer wt-p53 into prostate cancer xenografts using electroporation and to suppress the growth of tumors; they, furthermore, suggest that this system might be used for local advanced hormone-independent prostate cancer.

[Bilateral carotid stenting for bilateral carotid artery stenosis improved vascular dementia].

We report a case of bilateral internal carotid artery (ICA) stenosis treated with stenting. A 78-year-old man suffered from vascular dementia and left hemiparesis, and, by magnetic resonance angiogram (MRA), was diagnosed as having bilateral ICA stenosis. Cerebral angiogram showed severe, bilateral ICA stenosis (right; 88%, left; 93%) and xenon single photon emission tomography (SPECT) showed severely decreased cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). We performed bilateral carotid angioplasty with self-expanding stents. Both CBF and CVR were improved bilaterally after the operation. The patient was discharged without neurological deficits. Carotid stenting may be an alternative treatment for severe ischemia caused by severe, bilateral ICA stenosis.

Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression.

Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-kappaB activation by tumor necrosis factor (TNF)-alpha and enhanced TNF-alpha-mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH(2)-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-kappaB activation by TNF-alpha, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-kappaB transcriptional activation by TNF-alpha. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-kappaB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.

The novel role of the C-terminal region of SHP-2. Involvement of Gab1 and SHP-2 phosphatase activity in Elk-1 activation.

SHP-2, a nontransmembrane-type protein-tyrosine phosphatase that contains two Src homology 2 (SH2) domains, is thought to participate in growth factor signal transduction pathways via SH2 domain interactions. To determine the role of each region of SHP-2 in platelet-derived growth factor signaling assayed by Elk-1 activation, we generated six deletion mutants of SHP-2. The large SH2 domain deletion SHP-2 mutant composed of amino acids 198-593 (SHP-2-(198-593)), but not the smaller SHP-2-(399-593), showed significantly higher SHP-2 phosphatase activity in vitro. In contrast, SHP-2-(198-593) mutant inhibited wild type SHP-2 phosphatase activity, whereas SHP-2-(399-593) mutant increased activity. To understand these functional changes, we focused on the docking protein Gab1 that assembles signaling complexes. Pull-down experiments with Gab1 suggested that the C-terminal region of SHP-2 as well as the SH2 domains (N-terminal region) associated with Gab1, but the SHP-2-(198-593) mutant did not associate with Gab1. SHP-2-(1-202) or SHP-2-(198-593) inhibited platelet-derived growth factorinduced Elk-1 activation, but SHP-2-(399-593) increased Elk-1 activation. Co-expression of SHP-2-(1-202) with SHP-2-(399-593) inhibited SHP-2-(399-593)/Gab1 interaction, and the SHP-2-(399-593) mutant induced SHP-2 phosphatase and Elk-1 activation, supporting the autoinhibitory effect of SH2 domains on the C-terminal region of SHP-2. These data suggest that both SHP-2/Gab1 interaction in the C-terminal region of SHP-2 and increased SHP-2 phosphatase activity are important for Elk-1 activation. Furthermore, we identified a novel sequence for SHP-2/Gab1 interactions in the C-terminal region of SHP-2.