Traumatic persistent trigeminal artery--cavernous sinus fistula treated by transcatheter arterial embolization. A case report.

We describe a rare case of traumatic persistent trigeminal artery (PTA) - cavernous sinus fistula. Cerebral angiography showed direct communication between the right PTA and the cavernous sinus which was treated by transcathether arterial embolization. Although previous reports have indicated the use of more coils to treat this condition, we successfully treated the patient with only two coils placed near the orifice of the fistula after sufficient anatomical evaluation.

Gene expression profiling in rat liver treated with compounds inducing elevation of bilirubin.

We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for the diagnosis of elevated total bilirubin (TBIL) and direct bilirubin (DBIL), we extracted 59 probe sets of rat hepatic genes from the data for seven typical drugs, gemfibrozil, phalloidin, colchicine, bendazac, rifampicin, cyclosporine A, and chlorpromazine, which induced this phenotype from 3 to 28 days of repeated administration in the present study. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters in the treated groups from their controls. Eighteen more drugs in the database, reported to elevate TBIL and DBIL, were estimated by PCA using these probe sets. Of these, 12 drugs, that is methapyrilene, thioacetamide, ticlopidine, ethinyl estradiol, alpha-naphthylisothiocyanate, indomethacin, methyltestosterone, penicillamine, allyl alcohol, aspirin, iproniazid, and isoniazid were also separated from the control clusters, as were the seven typical drugs causing elevation of TBIL and DBIL. The principal component 1 (PC1) value showed high correlation with TBIL and DBIL. In the cases of colchicine, bendazac, chlorpromazine, gemfibrozil, and phalloidin, the possible elevation of TBIL and DBIL could be predicted by expression of these genes 24 h after single administration. We conclude that these identified 59 probe sets could be useful to diagnose the cause of elevation of TBIL and DBIL, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.

Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans.

One expected result from toxicogenomics technology is to overcome the barrier because of species-specific differences in prediction of clinical toxicity using animals. The present study serves as a model case to test if the well-known species-specific difference in the toxicity of coumarin could be elucidated using comprehensive gene expression data from rat in-vivo, rat in-vitro, and human in-vitro systems. Coumarin 150 mg/kg produced obvious pathological changes in the liver of rats after repeated administration for 7 days or more. Moreover, 24 h after a single dose, we observed minor and transient morphological changes, suggesting that some early events leading to hepatic injury occur soon after coumarin is administered to rats. Comprehensive gene expression changes were analyzed using an Affymetrix GeneChip approach, and differentially expressed probe sets were statistically extracted. The changes in expression of the selected probe sets were further examined in primary cultured rat hepatocytes exposed to coumarin, and differentially expressed probe sets common to the in-vivo and in-vitro datasets were selected for further study. These contained many genes related to glutathione metabolism and the oxidative stress response. To incorporate human data, human hepatocyte cultured cells were exposed to coumarin and changes in expression of the bridging gene set were examined. In total, we identified 14 up-regulated and 11 down-regulated probe sets representing rat-human bridging genes. The overall responsiveness of these genes to coumarin was much higher in rats than humans, consistent with the reported species difference in coumarin toxicity. Next, we examined changes in expression of the rat-human bridging genes in cultured rat and human hepatocytes treated with another hepatotoxicant, diclofenac sodium, for which hepatotoxicity does not differ between the species. Both rat and human hepatocytes responded to the marker genes to the same extent when the same concentrations of diclofenac sodium were exposed. We conclude that toxicogenomics-based approaches show promise for overcoming species-specific differences that create a bottleneck in analysis of the toxicity of potential therapeutic treatments.

Calcified vestibular schwannoma with unusual histological characteristics - positive immunoreactivity for CD-34 antigen.

Calcification in vestibular schwannoma is extremely rare. A 36-year-old man presented with a history of decreased hearing on the left since childhood. Computed tomography showed a left cerebellopontine angle lesion protruding into the porus acousticus and enlarging the internal auditory meatus, with significant deposits of calcification. Histological and immunohistochemical examination, including staining for CD-34, a myeloid progenitor cell antigen, found highly degenerated schwannoma with collagen-rich tissue, calcification, formation of bone, abnormal vessels of various sizes, and old haemorrhage with marked haemosiderin-laden macrophages. Most of the surgical specimen was sclerotic collagenous tissue containing sparse spindle-shaped cells which formed approximately 90% of the total specimen. However, the spindle-shaped cells were partly concentrated into islands forming the cellular part (approximately 10% of the total). The spindle-shaped cells in both parts showed almost typical immunohistochemical characteristics of schwannoma. However, many spindle-shaped cells in only the sclerotic part were positive for CD-34, which is widely used for the diagnosis of solitary fibrous tumours. Cerebellopontine angle tumour showing fibromatous tissue, including calcification, may contain foci of typical schwannoma. Careful histological examination with detailed immunohistochemical staining is required for the correct diagnosis. In particular, spindle-shaped cells occasionally show positive immunoreactivity for CD-34 antigen in the areas of degenerated and calcified schwannoma characteristic of our case.

[Refractory idiopathic cold agglutinin disease successfully treated with intermittent high-dose cyclophosphamide].

A 56-year-old woman, who had been suffering from idiopathic cold agglutinin disease and treated unsuccessfully with prednisolone and cyclosporine A for 6 months, was referred to our hospital in November 1998. She was given methylprednisolone pulse therapy followed by low-dose cyclophosphamide, but her anemia did not improve. We then began administration of intermittent high-dose cyclophosphamide (1,200 mg/day, every 4 weeks), and this resulted in a dramatic increase of her hemoglobin level and improvement of her symptoms. She is currently receiving 500 mg of cyclophosphamide every 2 months and showing a good response. Intermittent high-dose cyclophosphamide therapy can be an effective treatment for refractory cold agglutinin disease.

Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection and CYP2C19 genetic polymorphism.

BACKGROUND: Rabeprazole is a new, potent, proton pump inhibitor. The metabolism of rabeprazole is less dependent on CYP2C19 genetic polymorphism. METHODS: A total of 102 Helicobacter pylori-positive patients with gastric ulcer were randomly allocated to three groups: rabeprazole 10 mg (RAC10), rabeprazole 20 mg (RAC20) or rabeprazole 40 mg (RAC40) plus amoxicillin 750 mg and clarithromycin 200 mg twice daily for 7 days. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: All-patients-treated-based eradication rates in patients treated with RAC10, RAC20 and RAC40 were 83%, 77% and 90%, respectively, and per protocol-based eradication rates were 83%, 80% and 90%, respectively. The eradication rates in the three groups were not significantly different. There was also no significant difference between the all-patients-treated-based eradication rate in CYP2C19 extensive metabolizers and that in poor metabolizers (86% vs. 77%). Adverse events were 12% in extensive metabolizers and 23% in poor metabolizers, and the difference in these incidence rates was also not statistically significant. CONCLUSIONS: Triple therapy with 10 mg of rabeprazole combined with amoxicillin/clarithromycin is effective for Japanese patients with H. pylori infection, and the H. pylori eradication rate is not affected by CYP2C19 genetic polymorphism.

Primary lymphoma of spermatic cord.

Primary lymphomas of spermatic cord are extremely rare. In a review of the world medical literature, until now, only fourteen cases of spermatic cord lymphoma have been reported, and, furthermore, they have a poor prognosis even in patients with stage I disease. Herein, we report a new case of primary non-Hodgkin's lymphoma of the spermatic cord. In August, 1993, 76-year-old man visited an urological hospital with a compaint of a right intrascoral mass, and underwent orchiectomy. Macroscopically no invasive lesion in the testis was observed, and the tumorous lesion was restricted to the epididymis. The histopathological study indicated that he suffered from primary malignant lymphoma of the spermatic cord (B-cell, diffuse medium-sized cell type). As radiographic investigations showed no other invasive lesion, the patient was diagnosed to be in stage IE. He was followed only with clinical observation, and, in August, 1996, relapsed with extensive disease in the abdoninal cavity, and was transferred to our hospital. Fourty months after the orchiectomy, he died of progression of disease irrespective of the salvage radio-chemotherapies given to him.

[Occurrence of angioimmunoblastic T-cell lymphoma six months after onset of Lyme disease].

A 68-year-old man, who had suffered a tick bite one week previously, consulted his home doctor because of fever and an erythematous rash around the bite scar. He underwent a skin biopsy, and Borrelia garinii was detected, from which Lyme disease was diagnosed. He received amoxicillin for two weeks and his symptoms disappeared. After 6 months he noticed swelling of his cervical, axillary and inguinal lymph nodes. A biopsy sample was taken from a left cervical lymph node, and this revealed angioimmunoblastic T-cell lymphoma. The patient achieved a complete remission after chemotherapy. The relationship between Lyme disease and lymphoma is discussed.

[Non-Hodgkin's lymphoma associated with polymyositis].

A 67-year-old man was admitted to with severe nasal congestion. One year previously, he had been suffered from polymyositis (PM) and had been treated with prednisolone. Physical examination and computed tomography revealed a mass in the upper pharynx. Biopsy revealed non-Hodgkin's lymphoma (diffuse medium, B-cell type). Bone marrow aspiration also revealed the infiltration by lymphoma cells. The patient achieved a complete remission after combination chemotherapy (cyclophosphamide, adriamycin, vincristine, prednisolone). However, one month later, he suffered from central nervous system involvement of lymphoma cells, and he died of an aspiration pneumonia. Polymyositis/dermatomyositis associated with non-Hodgkin's lymphoma is extremely rare.

Intraluminal tumor of the common bile duct as a metastasis of renal cell carcinoma.

A 57-year-old woman was admitted for evaluation of liver dysfunction. A physical examination revealed jaundice and a left abdominal mass, which was diagnosed as being a large renal tumor. Cholangiography showed a smooth filling defect 1 cm in diameter at the common bile duct. Left nephrectomy, and resection of the common bile duct were performed. The pathological diagnosis was metastasis of the common bile duct wall resulting from renal cell carcinoma. Metastatic common bile duct tumors are extremely rare. However, it is important to consider that this is one of the causes of obstructive jaundice.

[Non-Hodgkin's lymphoma presenting as a soft tissue tumor in the connective tissue at the thigh].

A 62-year-old man visited our hospital in July 1993, because of a right thigh mass which had grown gradually since two years previously. Physical examination revealed that the mass at the right thigh region, was elastic soft and about 15 x 10 cm in diameter, without regional lymph node swelling. An ultrasound study showed a hypoechogenic and mesh patterned mass. MRI revealed that the tumor was well defined from subcutaneous adipose tissue and skeletal muscle, indicating that it arose in connective tissue. Angiography demonstrated diffuse hypervascularization of the tumor, and Gallium scintigraphy showed remarkable accumulation at the tumor. Serum IgM was increased, which was proven to be an monoclonal hypergammopathy (IgM, lambda). Histological examination of a biopsied specimen obtained from the thigh mass revealed B cell lymphoma, lymphoplasmacytic cell type. The patient achieved a complete remission after surgical treatment following radiation and combination chemotherapy.

Effect of herbimycin A, an inhibitor of tyrosine kinase, on protein tyrosine kinase activity and phosphotyrosyl proteins of Ph1-positive leukemia cells.

Herbimycin A, a benzoquinonoid anasamycin antibiotic, preferentially inhibited the in vitro growth of Ph1-positive leukemia cell lines. On the other hand, genistein, which was developed as an inhibitor of receptor-type tyrosine kinase, and other protein kinase inhibitors showed no selective inhibition of Ph1-positive leukemia cell growth. Herbimycin A also displayed an abrogative effect on the transformation of murine hematopoietic cells by transfection with a bcr/abl oncoprotein-expressing retroviral vector. The antitumor action of herbimycin A on Ph1-positive leukemia cells is related to an inhibition of activity of bcr/abl protein tyrosine kinase and a subsequent reduction of the constitutive phosphotyrosyl proteins, however, the antibiotic has no effect on the expression of bcr/abl mRNA and oncoprotein. Therefore, herbimycin A may provide an important insight into the oncogenic action of bcr/abl oncoprotein and the future development of oncoprotein-targeted therapeutic agents.

Expression, purification and binding to the receptor of human insulin-like growth factor II.

Human insulin-like growth factor II (IGF-II) was expressed as a fused protein with 14 additive amino acids in Escherichia coli with a high yield by an expression system using T7 RNA polymerase. Purification of the expressed protein was simply performed using only differential ultrafiltrations, giving a homogeneous preparation upon polyacrylamide gel electrophoresis and high-performance liquid chromatography. The expressed peptide was reacted with a monoclonal antibody raised against native IGF-II on a blotted membrane. Furthermore, the peptide was bound to IGF-II receptor in solubilized rat fetus membrane, though the affinity was slightly inferior to that of native IGF-II. In addition, fusion IGF-II immobilized on a gel matrix was useful for one-step purification of the IGF-II receptor with a high yield from solubilized rat fetus membranes.

BCR/ABL oncoprotein-targeted antitumor activity of antisense oligodeoxynucleotides complementary to bcr/abl mRNA and herbimycin A, an antagonist of protein tyrosine kinase: inhibitory effects on in vitro growth of Ph1-positive leukemia cells and BCR/ABL oncoprotein-associated transformed cells.

We investigated whether antisense oligodeoxynucleotides complementary to bcr/abl mRNA or protein kinase antagonists display antitumor activity on Ph1-positive leukemia cell lines. bcr/abl antisense oligomers showed inhibitory effects on the in vitro growth of Ph1-positive leukemia cell lines in liquid culture, and further displayed an inhibitory effect on transformed murine hematopoietic cells using transfection with a retroviral vector expressing P210bcr/abl oncoprotein. However, in vitro treatment with a bcr/abl antisense oligomer did not completely abolish the expression of bcr/abl mRNA and did not display the desired "killing effect" on Ph1-positive leukemia cells. On the other hand, investigation of the effect on Ph1-positive leukemia cells by various types of protein kinase antagonists revealed that herbimycin A, a protein tyrosine kinase antagonist, displays preferential and remarkable suppression of the growth of Ph1-positive leukemia cells and P210bcr/abl associated transformed cells by virtue of suppressing bcr/abl protein tyrosine kinase activity. These results may provide important future insights in developing a new category of antitumor therapy by targeting oncogene products.

Selective beta 1-adrenoceptor agonist activity of denopamine and its derivatives in dogs.

Cardiovascular effects of intravenously administered denopamine and its derivatives were investigated in anesthetized dogs and their positive inotropic and hypotensive effects were compared. Structure-activity relationships were examined by modifying the methoxy group in ring B and the hydroxy group in ring A in structure II, a ring-fissioned product of trimetoquinol. Almost all test compounds demonstrated positive inotropic and chronotropic effects as well as hypotensive effects which were mediated by beta-adrenoceptors. With modification of the methoxy group in ring B, only 3,4-dimethoxy, 2,3,4-trimethoxy and 3,4,5-trimethoxy derivatives exhibited beta 1-adrenoceptor selectivity. The 3,4-dimethoxy derivative showed the most potent positive inotropic effect and the highest selectivity to beta 1-adrenoceptor. By structural modification of the hydroxyl group in ring A of the 3,4-dimethoxy derivatives, the potency of positive inotropic effect was affected, while beta 1-adrenoceptor selectivity of the derivatives with 3,5-dihydroxy, 3- and 4-monohydroxy groups were essentially maintained. Among beta 1-adrenoceptor selective compounds, the dose ratios between intravenous and intraduodenal administrations of catechol derivatives like isoproterenol were higher than those of non-catechol derivatives. The 4-monohydroxy derivative (racemic denopamine) exhibited the smallest dose ratio with a long-lasting action. Thus, we could identify selective beta 1-adrenoceptor agonists by the structural modification of a selective beta 2-adrenoceptor agonist, trimetoquinol. In this group of compounds, beta-hydroxy moiety was suggested to be requisite to potent beta-adrenoceptor stimulating action and 3,4-dimethoxyphenethyl structure was important for manifestation of beta 1-adrenoceptor selectivity.

[Insulin-like growth factor II/mannose-6 phosphate receptors in a rat fibrosarcoma cell line].

Insulin-like growth factor II (IGF II)/mannose 6-phosphate (Man-6-P) receptor, which has two binding sites, was efficiently purified using a phospho-pentamannan affinity column. The molecular mass of the receptor purified from rat fibrosarcoma cells (KMT-17) was 240,000 (240K), whereas that of the receptor from normal rat liver and fibroblasts (NRK-49F) was 250K. However, when the receptor was subjected to deglycosylation by treatment with tunicamycin, the receptors of the KMT-17 and MRK-49F cells gave the same molecular mass of 225K, indicating that the difference in molecular mass between two cell lines resulted from the different oligosaccharide sizes. Analysis of the number of receptor site and binding affinity with IGF II on cell surface showed that KMT-17 cells expressed about 10 times more sites than in NRK-49F cells, whereas the binding affinity of KMT cells was lower than that of NRK-49F cells. Since it is known that asparagine-linked oligosaccharides in the IGF II/Man-6-P receptor are essential for IGF II binding, the types of oligosaccharides in the receptor were investigated by concanavalin A affinity chromatography. It was revealed that a ratio (38%) of tetra- and triantennary (multiantennary) complex-type oligosaccharides in the receptor of KMT-17 cells was lower than that (61%) in NRK-49F cells. These results indicate that the receptor of KMT-17 cells possesses predominantly less branched complex-type oligosaccharides and that multiantennary complex-type oligosaccharides of the receptor are most likely to contribute to higher affinity binding of IGF II. To determine whether IGF II activates phosphatidyl inositol-specific phospholipase C (PLC) in KMT-17 cells, the production of inositol trisphosphate (IP3) was measured. Treatment with IGF II increased the level of IP3 in a concentration-dependent manner. The level of IP3 reached the maximum after 15 seconds of incubation. When the cells were pretreated with anti-receptor antibody, no activation of the PLC was observed. These findings suggest that IGF II stimulates PLC through binding to the IGF II/Man-6-P receptor.