Tranilast inhibits the proliferation of human coronary smooth muscle cell through the activation of p21waf1.

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) occurs due to vascular smooth muscle cell proliferation and migration. Recently, tranilast, an anti-allergic drug, has been used for the prevention of restenosis after PTCA. To determine the molecular mechanism involved, the effect of tranilast on the proliferation of human coronary smooth muscle cells (SMCs) was investigated. Tranilast arrested the proliferation of human coronary SMCs at the G0/G1 phase of the cell cycle. In association with this inhibitory effect, tranilast increased p21waf1 and p53 tumor suppressor factor, and decreased cyclin-dependent kinase 2 (CDK2) activity. These results suggest that tranilast inhibits the proliferation of human coronary SMCs during restenosis after PTCA via an induction of p21waf1 and p53. Tranilast may thus allow us to prevent restenosis after PTCA by interfering with this mechanism.

A novel reaction for annulation onto alpha,beta-unsaturated ketones: W(CO)(5).L promoted exo- and endo-selective cyclizations of omega-acetylenic silyl enol ethers prepared by 1,4-addition of propargyl malonate to enones.

A highly useful method for five- and six-membered ring annulation onto alpha,beta-unsaturated ketones is described. 1,4-Addition of propargylmalonate to alpha,beta-unsaturated ketones in the presence of silyl triflate gives 7-siloxy-6-en-1-yne derivatives in good yield. W(CO)(5).L-catalyzed cyclization of these substrates can be induced to give preferentially either exo- or endo-cyclized products in good yield simply by changing the reaction solvent. [reaction: see text]

Psychiatric status of intrafamilial child sexual abuse victims.

The initial psychiatric profile of a large sample of sexually abused children who presented at an outpatient child psychiatry clinic was assessed. The results identified a wide diversity in victim responses to incest. The older the victim, the closer the relationship of the offender to the child, the greater the frequency of abuse incidents, the longer the duration of the abuse, the offender having a history of alcohol abuse, and the victim being a victim of physical abuse as well as sexual abuse were all related to the presence of a DSM-III axis I clinical disorder.

Effect of a thromboxane A2 synthetase inhibitor (OKY-046.HCl) on airway hyperresponsiveness in guinea pigs.

We studied the effect of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046.HCl), a specific thromboxane (TX) A2 synthetase inhibitor, on airway hyperresponsiveness of guinea pigs. OKY-046.HCl (30-100 mg/kg, intraduodenally (i.d.) or orally (p.o.)) suppressed dose dependently the airway hyperresponsiveness to acetylcholine (ACh) induced by formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF) and repetitive antigen. OKY-046.HCl (100 mg/kg) also inhibited the increase in TXB2 in bronchoalveolar lavage fluid (BALF) induced by FMLP, PAF and antigen. Aspirin 10 or 30 mg/kg i.d. or p.o.) suppressed the airway hyperresponsiveness induced by FMLP and PAF but not by antigen. Azelastine (10 mg/kg i.d.) was ineffective on PAF- and antigen-induced airway hyperresponsiveness. TXA2 mimetic drugs caused airway hyperresponsiveness that was not inhibited by OKY-046.HCl (30 mg/kg i.v.). Furthermore, OKY-046.HCl showed no effect on propranolol- and physostigmine-induced airway hyperresponsiveness which did not accompany TXB2 generation in BALF. The number of eosinophils in BALF increased after FMLP exposure, an effect which was not inhibited by OKY-046.HCl. These results suggest that OKY-046.HCl inhibits airway hyperresponsiveness by suppressing TXA2 generation. We suggest that OKY-046.HCl will be a new antiasthmatic drug.

The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide.

Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells. However, its selectivity for the various K(ATP) channels is not known. In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 microM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.

Absence of exacerbation of myocardial stunning in anesthetized dogs treated with KAD-1229, a novel hypoglycemic agent.

The effect of (+)-momocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate]dihydrate (KAD-1229), a novel hypoglycemic agent with a chemical structure different from that of the sulfonylureas, on myocardial stunning was assessed in anesthetized dogs by comparison with that of glibenclamide, a sulfonylurea. Even though their hypoglycemic effects were of similar magnitude, glibenclamide (1 mg/kg, i.v.), but not KAD-1229, exacerbated the myocardial stunning induced by occlusion/reperfusion of the descending coronary artery. In a receptor-binding experiment, unlabeled glibenclamide completely inhibited [(3)H]glibenclamide binding to the myocardium, but KAD-1229 did not. These results suggest that the difference in binding properties of KAD-1229 and glibenclamide toward cardiac sulfonylurea receptors is one of the causes of their different effects on myocardial stunning. It is likely that KAD-1229 is highly specific for pancreatic sulfonylurea receptors and is speculated to be a safer hypoglycemic agent than, at least, glibenclamide.

Pyoderma gangrenosum following cytosine arabinoside, aclarubicin and granulocyte colony-stimulating factor combination therapy in myelodysplastic syndrome.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis, which may be associated with systemic conditions such as hematologic disorders. We present a patient who had been diagnosed as having myelodysplastic syndrome associated with PG at onset, in whom a febrile ulcerative skin lesion developed following cytosine arabinoside, aclarubicin and granulocyte colony-stimulating factor (G-CSF) combination chemotherapy in the course of the disease. Skin biopsy revealed dense neutrophilic infiltrate in the dermis with central epidermal ulceration, consistent with the diagnosis of PG. Oral prednisolone was effective for the skin lesion. In this case, G-CSF application may participate in the recurrence of PG.

Ki-1 (CD30)-positive anaplastic large cell lymphoma, sarcomatoid variant accompanied by spontaneously regressing lymphadenopathy.

Although it has been reported that primary Ki-1 (CD30)-positive anaplastic large cell lymphoma (ALCL) of the skin may undergo spontaneous regression, it is rare for ALCL without cutaneous involvement to have spontaneously regressing lymphadenopathy. We report a case of sarcomatoid variant of ALCL accompanied by spontaneously regressing lymphadenopathy. The patient had gastric and pulmonary involvement of ALCL in addition to systemic lymphadenopathy, but with no cutaneous involvement. The lymphadenopathy spontaneously improved gradually during a period of one month without any treatment. At the same time, multiple small nodules in both lung fields decreased on chest computed tomography and multiple elevated gastric tumors with dimples were endoscopically recognized to have improved. He has since been treated with combination chemotherapy because of recurrence of the lymphadenopathy.

Sudden cardiac death from hypertrophic cardiomyopathy and acute idiopathic (Fiedler's) myocarditis: autopsy report.

A 45-year-old man with a rapidly deteriorating heart condition died suddenly, two hours after admission, after resistance to attempts of cardiac pacing. At autopsy, the heart weighed 600g with asymmetric septal hypertrophy. Histological examination revealed an extensive and diffuse disarray of myocardial fibers in the ventricular septum and in the free wall of both ventricles. Pronounced mononuclear cell infiltrations and interstitial edema were distributed widely in both ventricles. There were few abnormal findings in the other organs. The diagnosis was hypertrophic cardiomyopathy accompanied by Fiedler's myocarditis. Such a case appears to be rare.

Malignant solitary fibrous tumor arising in the right buttock associated with metastatic parietal pleural and intrapulmonary tumors in addition to pleural effusion.

A malignant solitary fibrous tumor arising in the right buttock associated with metastatic parietal pleural and intrapulmonary tumors and pleural effusion was found in a 59-year-old man. A chest computed tomogram revealed three tumors attached to the parietal pleura with rib destruction, and a tumor in the left lower lung field. Histologically, the tumors of the buttock and parietal pleura were characterized by proliferation of bundles of spindle-shaped or oval cells separated by wavy hyalinized collagen tissue with no expression of cytokeratin, S-100 protein, muscle actin or epithelial membrane antigen, but these cells weakly expressed CD34 and strongly expressed vimentin.

Ultrastructural observation of epithelioid sarcoma.

Epithelioid sarcoma located in the right hip-to-thigh region of a 58-year-old female was studied by light microscopy, immunohistochemistry, and electron microscopy. Light microscopy revealed both light and dark cells among the tumor cells. Round, homogeneous, eosinophilic bodies were noted extracellularly and intracellularly. Extracellular bodies were similar in size to tumor cells and were not stained by PAS or Congo red. In contrast, intercellular bodies were PAS positive and diastase resistant. Tumor cells were positive for vimentin, keratin, and, partially, for epithelial membrane antigen. Ultrastructurally, tumor cells had numerous microfilaments with tonofibril-like arrangement, lipid droplets, and reticulogranular structure in their cytoplasm. The reticulogranular structure was similar to the tonofilaments recognized in degenerative tumor cells. Oval filamentous bodies were recognized in the stroma. They appeared to be very similar to colloid bodies derived from tonofilaments of keratinocytes. It was considered that the filamentous bodies corresponded to extracellular eosinophilic bodies and showed signs of fibrous necrosis of tumor cells. Intracellular eosinophilic bodies were considered to be lipid droplets.

[A case of lung cancer with Mallory bodies].

This paper is a report of a large cell carcinoma (solid carcinoma with mucus formation-WHO) which developed in the right upper lobe of a 71-year-old woman and in which cytoplasmic Mallory body-like inclusions (MBL) similar to Mallory bodies (MB) often found in alcoholic liver disease and hepatocellular carcinoma were noted in the tumor cells. MBL was an eosinophilic massive or reticular hyalin, and showed staining properties similar to those of MB in general stainings. Electron microscopically, it was made up mainly of a fine granular amorphous substance with high electron density and was not surrounded by a membrane. A part of the margin was in close contact with filaments approximately 10 nm in diameter, with tonofibril-like structures around it, which suggested a relationship with cytokeratin. On immunoperoxidase staining using a couple of cytokeratin antibodies, definitely positive findings were not obtained with MBL themselves. MBL of this case basically has the same character as that of MBL which appears in fibrous lesions in the lung and MB in liver disease. It was concluded that it is necessary to preoperatively distinguish this entity cytologically or histologically from pulmonary metastasis of hepatocellular carcinoma.

[A case of intrascrotal neurilemmoma].

The case was in a 65-year-old male who complained of right scrotal painless swelling. Surgical excision was performed. The tumor was placed in tunica dartos but did not connect with the testis, epididymis and spermatic cord. The tumor was 2.8 x 2.0 x 1.5 cm and 10 gr. in weight. Histological diagnosis was neurilemmoma. To our knowledge, this is the first report about intrascrotal neurilemmoma in Japan.

[A case of endocrinologically active retroperitoneal ganglioneuroma].

A 27-year-old female complained of right upper abdominal pain. Computed tomography revealed a retroperitoneal tumor located between the right kidney and the vena cava. The preoperative value of noradrenaline in urine was high, 221.1 micrograms/day. She underwent surgery and the resected tumor was 330 g in weight and 8 x 6 x 4 cm in size. Histopathological diagnosis was ganglioneuroma. Retroperitoneal ganglioneuroma is rare and only 82 cases including our case have been reported in Japan, in recent years, adult cases are increasing in number. Endocrinological abnormalities were observed in 9 cases. Although six of the 9 patients were younger than 5 years old, the others were adults. These adult patients had no endocrinological symptoms.

[Bladder carcinoma producing granulocyte colony stimulating factor (G-CSF). A case report].

A 69-year-old woman was admitted to the hospital complaining of general fatigue and lower abdominal pain. She had undergone total cystectomy because of invasive recurrent bladder carcinoma three months ago. Histopathological diagnosis was transitional cell carcinoma (TCC) grade 3 and squamous cell carcinoma (SCC), pT3a. A goose egg-sized painful mass was noticed at the lower abdominal region. A CT scan revealed an intrapelvic fist-sized mass and suggested tumor recurrence with ileus caused by intestinal invasion. The laboratory examination showed remarkable leukocytosis of 79,700/mm3 in the peripheral blood and serum analysis revealed high value of granulocyte colony stimulating factor (G-CSF), 240 pg/ml (normal: less than 30 pg/ml). In spite of active treatment, the patient died of cachexia about a month after detection of the leukocytosis. The autopsy showed that the recurrent tumor had positive immunohistochemical staining for G-CSF, and the bone marrow had reactive proliferation mainly by granulocytes. From these findings, this case was diagnosed as bladder carcinoma producting G-CSF. G-CSF producting tumor of the bladder is very rare. This was the 8th case in Japanese literatures. The previous reports were reviewed and discussed.

[A case report of ileovesical fistula in radiation enteritis].

A 49-year-old female was admitted with chief complaint of fecaluria on March 4th 1993. A radiation therapy had been performed for uterocervical cancer 18 years ago. The small intestine and bladder was detected by DIP- and cystogram simultaneously. It was diagnosed as an ileovesical fistula. A segmental resection of the ileum with partial cystectomy was performed on March 23rd. Histopathologically, the ileum showed a radiation enteritis. Eventually, we diagnosed that this ileovesical fistula was caused by radiation. After operation, an incompletion of suture occurred. So we made an ileostomy secondarily and performed hyperbaric oxygen therapy. The patient was getting well temporarily but died of gastric hemorrhage on May 1st.

[Increased neuron-specific enolase levels in patients with long-standing pyothorax-associated lymphoma].

A 78-year-old man was admitted for the evaluation of chest pain and a subcutaneous giant mass in the left chest, which had been growing for 3 months. A computed tomogram of the chest revealed a giant tumor attached to the parietal pleura with calcification of long-standing pyothorax. Pathological findings of a specimen obtained from this tumor showed diffuse proliferation of large atypical lymphocytes with 1-2 nucleoli and abundant cytoplasm. In immunohistochemical studies, tumor cells stained positive for CD20 but not for CD45 RO. The diagnosis was long-standing pyothorax-associated lymphoma (diffuse large-cell lymphoma, B-cell type). The patient's serum neuron-specific enolase (NSE) level was 101 ng/ml on admission, and declined in tandem with a chemotherapy-induced decrease in tumor size. In addition, immunohistochemical studies showed staining of tumor cells by anti-NSE polyclonal antibody. Although rarely observed in patients with malignant lymphoma, increased serum NSE levels may serve as an index of chemotherapeutic effectiveness.

[Subacute cor pulmonale due to microscopic pulmonary tumor embolism].

We report a case of subacute pulmonary hypertension caused by microscopic pulmonary tumor embolism due to the dissemination of gastric cancer cells. The patient, a 61-year-old man with no history of malignant diseases, was admitted to our hospital on October 14 in 1998 because of cough and dyspnea on effort, that had developed since the previous month. On admission, chest radiography including CT scans showed slight cardiomegaly and disseminated reticulonodular shadows predominating in the lower lung fields of both lungs, and arterial blood gas analysis disclosed severe hypoxemia. Lung perfusion scintigraphy revealed multiple irregular defects in both lungs. Echocardiography indicated right ventricular overload, and the pulmonary artery systolic pressure was estimated to be higher than 80 mmHg. Disseminated intravascular coagulation (DIC) developed on the 6th day of hospitalization. Multiple pulmonary embolism with DIC of unknown cause was diagnosed, and the patient was given anticoagulant therapy with heparin. However, he died of respiratory failure on the 7th day of hospitalization. At autopsy, an invasive cancer was found in the stomach, resembling type IIc early gastric cancer. The lumens of the pulmonary arterioles were significantly narrowed by fibrocellular proliferation and thrombi accompanying tumor cell clusters, and some of the microvessels were completely occluded. Disseminated microscopic pulmonary metastasis of malignant tumors should be included in the differential diagnosis of subacute pulmonary hypertension due to multiple pulmonary embolism of unknown cause.

[Chronic thromboembolic pulmonary hypertension associated with initial pulmonary involvement in Takayasu arteritis].

A 37-year-old non-smoking woman was admitted to our hospital because of nocturnal coughing and exertional dyspnea after using an ultrasonic humidifier. Chest roentgenograms and computed tomography showed many ground-glass opacities in the right upper lobe and left upper lung field. Her symptoms were alleviated and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels returned to normal following the administration of prednisolone (40 mg/day). The same symptoms subsequently recurred, and ESR and CRP levels increased proportionately to a decreased dosage of prednisolone. In addition, chest computed tomography showed new opacities in the left lower lobe. Transbronchial lung biopsy specimens revealed multiple stenotic or obstructive changes in the small pulmonary arteries by organizing thromboemboli, with no vasculitis. The diagnosis of chronic thromboembolic pulmonary hypertension was made on the basis of multiple defects from lung perfusion scintigraphy, irregular or tapering of the pulmonary arteries detected by pulmonary arteriograms, and increased pulmonary pressure measured by echocardiography. We propose that the pulmonary thromboembolism observed in this case was related to the initial pulmonary involvement of Takayasu arteritis, since the patient's symptoms, ESR and CRP levels all improved markedly following the administration of prednisolone.