Cell type-specific localization of optineurin in the striatal neurons of mice: implications for neuronal vulnerability in Huntington's disease.

Striatal neuropathology of Huntington's disease (HD) involves primary and progressive degeneration of the medium-sized projection neurons, with relative sparing of the local circuit interneurons. The mechanism for such a patterned cell loss in the HD striatum continues to remain unclear. Optineurin (OPTN) is one of the proteins interacting with huntingtin and plays a protective role in several neurodegenerative disorders. To determine the cellular localization pattern of OPTN in the mouse striatum, we employed a highly sensitive immunohistochemistry with the tyramide signal amplification system. In this study, we show that OPTN appeared as a cytoplasmic protein within the subsets of the striatal neurons. Of particular interest was that OPTN was abundantly expressed in the interneurons, whereas low levels of OPTN were observed in the medium projection neurons. This cell type-specific distribution of OPTN in the striatum is strikingly complementary to the pattern of neuronal loss typically observed in the striatum of patients with HD. We suggest that OPTN abundance is an important cellular factor in considering the cell type-specific vulnerability of striatal neurons in HD.

Cyclin-dependent kinase 5 with phosphorylation of tyrosine 15 residue is enriched in striatal matrix compartment in adult mice.

Accumulating evidence suggests that the striosome-matrix systems have a tight link with motor and behavioral brain functions and their disorders. Cyclin-dependent kinase 5 (Cdk5) is a versatile protein kinase that plays a role in synaptic functions and cell survival in adult brain, and its kinase activity is stimulated by phosphorylation at tyrosine 15 residue (pY15). In this study, we used an immunohistochemical method to show differential localization of Cdk5-pY15 in the striatal compartments of adult mice, with a heightened density of Cdk5-pY15 labeling in the matrix relative to the striosomes. Our findings indicate that Cdk5-pY15 can be a new marker for the striatal matrix compartment, and suggest a possible involvement of Cdk5-mediated signaling in compartment-specific neurotransmission and disease pathology in the striatum.

Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia.

The neuron-specific isoform of the TAF1 gene (N-TAF1) is thought to be involved in the pathogenesis of DYT3 dystonia, which leads to progressive neurodegeneration in the striatum. To determine the expression pattern of N-TAF1 transcripts, we developed a specific monoclonal antibody against the N-TAF1 protein. Here we show that in the rat brain, N-TAF1 protein appears as a nuclear protein within subsets of neurons in multiple brain regions. Of particular interest is that in the striatum, the nuclei possessing N-TAF1 protein are largely within medium spiny neurons, and they are distributed preferentially, though not exclusively, in the striosome compartment. The compartmental preference and cell type-selective distribution of N-TAF1 protein in the striatum are strikingly similar to the patterns of neuronal loss in the striatum of DYT3 patients. Our findings suggest that the distribution of N-TAF1 protein could represent a key molecular characteristic contributing to the pattern of striatal degeneration in DYT3 dystonia.

[A case of convexity meningioma en plaque].

We present a case of convexity meningioma en plaque (MEP). A 51-year-old male occasionally suffering from right parietalgia and numbness of left upper limb. An intracranial abnormal mass was pointed out incidentally by the brain check up. Computed tomographic (CT) scans demonstrated a hyperostosis and an enhanced abnormal mass at the right front-parietal region. Magnetic resonant images (MRI) revealed a carpet like tumor extended along the dura mater. Cerebral angiography disclosed feedings from parietal branches of right middle meningeal artery and superficial temporal artery. The tumor was removed subtotally with adjacent dura mater, leaving the portion of close adhesion to the brain parenchyma. Histologic diagnosis was transitional meningioma. Immunohistological stainings showed a high staining index (6.9%) of MIB-1 (Ki-69 antigen) and high expression of metalloproteinase-9 (MMP-9), especially along the dura mater. Convexity MEP is so rare that we review previous reported cases of convexity MEP, and discuss the clinicopathologic features on that.

A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas.

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.

Genetic aberrations detected by comparative genomic hybridization in biliary tract cancers.

In order to elucidate cytogenetic changes characteristic of biliary tract cancer, we examined the genetic imbalances in 18 biliary tract cancers using comparative genomic hybridization (CGH). The most common sites of increases in copy number, in order of frequency, were 17q (33% of the cases), 5p (28%), 3q (22%), 7p (22%), 8q (22%), and 12p (22%), whereas copy number decreases of 6q (28%), 18q (28%), 4q (22%), 5q (22%), and 9p (22%) were frequent. The average number of chromosomal aberrations was significantly greater in stage IV than in stage III tumors (7.9 vs. 2.2/tumor, p < 0.05). The frequent aberrations detected in this study may be related to the development and/or progression of biliary tract cancers. This is the first report on CGH of biliary tract cancers.

Detection of K-ras and p53 gene mutations in pancreatic juice for the diagnosis of intraductal papillary mucinous tumors.

The aim of this study was to investigate mutations of the K-ras oncogene and the p53 tumor suppressor gene in pancreatic juice and to evaluate our method for the diagnosis of intraductal papillary mucinous tumors (IPMT). Pancreatic juice was collected endoscopically from 12 patients with IPMT who underwent surgical resection (eight carcinomas and four adenomas) and eight cases without evident pancreatic diseases. DNA was extracted and both genes were examined by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. In addition, surgically resected specimens were analyzed for both genes by the same methods, and p53 overexpression was investigated immunohistochemically. K-ras point mutations were detected in pancreatic juice from all 12 patients (100%) and p53 mutations were detected in five of 12 (42%). They were detected not only in carcinoma but also in adenoma and there was no difference between the mutations detected in pancreatic juice and surgical specimens. No mutations were found in any cases without pancreatic diseases. These findings suggest that alterations of K-ras and p53 gene are common events in the development of IPMT and that genetic analysis of them in pancreatic juice can be a useful tool for the clinical diagnosis of IPMT before surgery.

Detection of Ki-ras and p53 gene mutations in tissue and pancreatic juice from pancreatic adenocarcinomas.

Pancreatic carcinomas have a high incidence of Ki-ras mutations, and the genetic change is thought to occur at an early stage in the carcinogenesis. The aim of this study was to evaluate the usefulness of detecting genetic mutations in pure pancreatic juice (PPJ). DNA was extracted from tissue specimens of pancreatic carcinomas and from cells in PPJ, and subjected to polymerase chain reaction-single-strand conformation polymorphism analysis. Two types of mobility shifts that indicate Ki-ras mutations were observed in 13 of the 20 (65%) tissue specimens obtained by operation or autopsy. Ten of 15 specimens (67%) of PPJ collected from patients with pancreatic carcinomas showed two types of mobility shifts. Conventional imaging techniques did not show two in 10 of these patients. PPJ from patients with non-cancerous pancreatic diseases showed no Ki-ras mutations. The p53 tumor suppressor gene, examined by PCR-SSCP analysis, was mutated in 8 of the 20 tissue specimens obtained by operation or autopsy (40%). The detection of Ki-ras and p53 mutations in PPJ could be useful for the early diagnosis of pancreatic carcinomas, especially for neoplastic lesions of the intraductal type.

Expression of vascular endothelial growth factor correlates with tumor progression in gallbladder cancer.

Angiogenesis must occur for malignant tumors to proliferate and vascular endothelial growth factor (VEGF) is now believed to be central to this process. Immunohistochemical staining for VEGF was performed on surgical resection specimens from 50 patients with gallbladder cancer. VEGF-positive rate was 38%. Comparison of clinicopathologic parameters between the groups with and without VEGF expression showed significant differences in tumor size, lymphatic invasion and disease stage. Survival rate was worse in the patients whose tumors demonstrated VEGF expression. It is suggested that VEGF is correlated with tumor progression and may be used as a prognostic indicator.

Large sixth nerve neuroma involving the prepontine region: case report.

OBJECTIVE AND IMPORTANCE: Tumors originating from the cranial nerves are uncommon, except for the acoustic and trigeminal neuromas. The sixth nerve, however, has the potential to generate neuromas with characteristic clinical features. CLINICAL PRESENTATION: A 54-year-old woman presented with diplopia and increased intracranial pressure. Magnetic resonance imaging showed a large mass in the prepontine region. Surgery was performed via a condylar approach and demonstrated a tumor originating from the prepontine portion of the sixth nerve. CONCLUSION: The sixth nerve neuroma at the pontomedullary junction showed characteristic clinical features and could be successfully removed via a condylar approach.

p53 mutations in two patients with intraductal papillary adenoma of the pancreas.

There has been no report on p53 gene mutation in benign human pancreatic intraductal tumors. We examined pancreatic juice and tissue specimens from two patients with intraductal papillary adenoma of the pancreas by polymerase chain reaction-single-strand conformation polymorphism analysis and direct sequencing and found point mutations of p53 gene resulting in amino acid substitutions in exons 6 and 8. Thus, p53 gene mutation may be an early event in the neoplastic process of some pancreatic intraductal tumors and may play an important role in tumorigenesis.

[Swyer-James syndrome with pneumomediastinum and subcutaneous emphysema due to bronchial asthma].

A 24-year-old woman was admitted to our hospital due to moderate asthmatic attacks. Dyspnea and hypoxemia progressed gradually despite medication. A chest roentgenogram revealed left unilateraly hyperlucency with pneumomediastiumn and subcutaneous emphysema. Swyer-James syndrome was diagnosed. Several cases of Swyer-James syndrome with bronchial asthma airway hyperresponsiveness have been reported, but we know of no reports of Swyer-James syndrome with pneumomediastinum and subcutaneous emphysema due to prolonged asthmatic attacks. Pneumomediastinum and subcutaneous emphysema may be caused by abnormally high pressures in the bronchial lumen and alveolar space during asthmatic attacks, because the emphysematous lesion may be structurally weak.

Infrequent somatic alteration of p16/MTS1 in human primary superficial bladder cancers.

Although superficial bladder cancer, usually presenting as low grade transitional cell carcinomas, are easily resected by transurethral intervention, their frequent recurrence and progression of satage or grade of the recurrent tumors in some cases is a major problem in urology. Deletion of chromosome 9, bands 9p21-22 in bladder cancers including the lowest grade and stage, suggest potential location of candidate tumor suppressor genes. Recently, p16/MTS1 was isolated from 9p21-22 as a multiple tumor suppressor gene, which regulates the cyclin dependent kinase 4 in the G1/S phase of the cell cycle. In the present study, somatic alterations of p16/MTS1 were examined concentrating on histologically defined superficial bladder carcinomas by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) technique using paraffin embedded materials. Infrequent alterations of p16/MTS1 in superficial bladder cancers, one deletion and one silent mutation in 15 cases, were detected. The results suggest that p16/MTS1 mutation is not involved in the development of superficial urinary bladder carcinomas.

Clinical findings in patients with recurrent intracerebral hemorrhage.

BACKGROUND: The use of computerized tomography has led to the detection of second intracerebral hemorrhage (ICH) in some patients. There have, however, only been a few clinical studies of second ICH. SUBJECTS AND METHODS: Thirty patients with a second ICH were analyzed according to clinical criteria. These patients comprised 5.9% of all patients admitted to Chugoku Rosai Hospital for ICH between 1984 and 1992. RESULTS: The mean interval between the first and second ICH was 27.7 months (range 1-144). The incidence of second hemorrhage was especially high within the first year after the initial ICH. Twelve patients bled bilaterally into the basal ganglia or thalamus during either the first or second attack. Most of these patients had poor outcomes and prognoses. The nine patients with good prognoses included patients with high activity of daily living (ADL) prior to the second attack, and those with neurologic grade 1 following the second attack. All of these patients were managed with conservative therapy. The 10 patients who underwent surgery had poor prognoses. CONCLUSIONS: The incidence of second ICHs is greater than that of initial ICHs. Many patients who experience a second ICH will have a poor prognosis, possibly worse than expected. Surgical therapy should not be recommended in such patients, since our data suggest that they will not do well even after surgery.

p53 mutation without allelic loss and absence of mdm-2 amplification in a transplantable hamster pancreatic ductal adenocarcinoma and derived cell lines but not primary ductal adenocarcinomas in hamsters.

An investigation of p53 gene mutation by single-stranded conformation polymorphism analysis of polymerase chain reaction products followed by direct sequencing and of murine double minute 2 (mdm-2) gene amplification by Southern blot analysis was performed, using a series of hamster pancreatic duct adenocarcinomas: 18 primary adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine, a transplantable adenocarcinoma (HPD), and three cell lines derived from HPD (HPD1NR, HPD2NR, and HPD3NR). A mutation in the p53 gene was detected at codon 197, resulting in an amino acid change from leucine to phenylalanine, in both HPD and the three cell lines but in none of the 18 primary adenocarcinomas. In the three HPD cell lines, which were confirmed to contain only cancer cells, a normal p53 gene allele was retained. Immunohistochemical investigation of p53 expression using polyclonal antibody Ab-7 revealed positive nuclear staining in the HPD and two back-transplanted tumors derived from HPD1NR and HPD2NR but not in the 18 primary adenocarcinomas. mdm-2 gene amplification was not detected in 18 primary adenocarcinomas or any of the tumor cell lines. The results suggest that a p53 gene mutation without allelic loss, together with overexpression of p53 protein, may be a genetic alteration involved in the progression stage of multistep pancreatic carcinogenesis in hamsters and that mdm-2 gene amplification is not important for this process.

Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl)amine in hamsters.

The effects of dehydroepiandrosterone sulfate (DHAS), a typical hydroxysteroid sulfotransferase (HSTase) inhibitor, and of 3'-phosphoadenosine 5'-phosphate (PAP), a nonspecific sulfation inhibitor on N-nitrosobis(2-oxopropyl)-amine (BOP)-induced initiation were examined in a rapid production model for pancreatic carcinomas in hamsters in order to elucidate the involvement of sulfotransferase in the metabolic activation of beta-oxypropylnitrosamines. While neither low nor high doses of DHAS and PAP exerted any significant influence on the incidence of ductal lesions including carcinomas, the high dose of DHAS (350 mg/kg body wt) and a both low (90 mg/kg) and high (180 mg/kg) doses of PAP reduced the mean numbers of pancreatic ductal adenocarcinomas. The high dose of PAP also reduced the number of all ductal lesions combined. The results thus suggest that metabolic activation with STase is involved in BOP-induced pancreatic ductal carcinogenesis in hamsters, and support the hypothesis that BOP is metabolized to beta-hydroxyalkylnitrosamines followed by activation to proximate sulfuric acid esters by HSTase.

High rates of Ki-ras point mutation in both intra- and extra-hepatic cholangiocarcinomas.

The presence of the Ki-ras gene mutations in 14 cases of intrahepatic cholangiocarcinoma (IHC) and nine cases of extrahepatic cholangiocarcinoma (EHC) were investigated by polymerase chain reaction-single strand conformation polymorphism analysis. To obtain enriched tumor cell DNA, the microdissection method was used on formalin-fixed paraffin-embedded tissue sections. Point mutations at codon 12 of the Ki-ras gene were detected in seven (50%) of the 14 cases of IHC and six (67%) of the nine EHC cases. In all but one of the ras gene mutation cases, G to A transitions in the second position of codon 12 were detected, the exception being a G to T transition in the same position in one IHC. No point mutations were detected at codon 13 or 61 in either IHC or EHC. Furthermore, there was no demonstrable correlation between Ki-ras mutation and patient age, tumor Stage, histological findings or prognosis. The present results demonstrated a higher participation of Ki-ras gene mutations in EHC than found in previous studies, and provided a confirmation and extension of the results earlier reported by Tada et al. and Tsuda et al. for IHC.

Primary pineal melanoma with long-term survival: case report.

A rare case of primary pineal melanoma is reported. The patient was a 53-year-old woman who complained of a severe headache. Computed tomography and magnetic resonance images revealed obstructive hydrocephalus caused by a mass lesion in the pineal region. A biopsy was performed through an occipital transtentorial approach. A black pigmented solitary tumor was seen without leptomeningeal dissemination. Histologic examination revealed melanoma. Chemotherapy consisting of dacarbazine, ACNU, vincristine, and interferon was used. Follow-up imaging studies showed dramatic reduction of the tumor without recurrence for 4 years. This report demonstrates that a solitary primary intracranial melanoma without leptomeningeal dissemination and with rare mitoses may yield a good result with chemotherapy.

Cavernous sinus cavernoma treated with radiation therapy--case report.

A 71-year-old female presented with a syncopal attack. She underwent surgery for what appeared to be a meningioma. However, a small incision in the dura mater caused severe bleeding. Histological examination of the biopsy specimen showed sinus cavernoma with an incomplete pseudocapsule. The dura mater encapsulated the cavernous sinus cavernoma, explaining the severe bleeding from the dural incision. She was treated with Linac irradiation (40 Gy) which resulted in a decrease in tumor size. Radiation therapy is indicated for the treatment of cavernous sinus cavernoma, especially if associated with severe intraoperative bleeding.