Aberrant production of gliostatin/platelet-derived endothelial cell growth factor in rheumatoid synovium

Objective. To purify a protein inhibitor from rheumatoid arthritis (RA) synovial fluids which suppresses the apparent incorporation of ³H-thymidine into fibroblasts and synovial cells, and to define its biochemical features that have clinical relevance to the pathogenesis of RA. Methods. Several standard chromatographic techniques were employed for the purification of the protein. Immunochemical methods with monoclonal antibody were used to quantify and visualize the protein in sera, synovial fluids, and tissues from RA patients. Results. The chemical properties of purified inhibitor from RA synovial fluids confirmed its identity as gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF), a potent angiogenic factor. The gliostatin/ PD-ECGF level in synovial fluid and serum was higher in RA patients than in osteoarthritis controls. Conclusion. These findings strongly suggest that gliostatin/PD-ECGF might play an important role in the aberrant neovascularization of rheumatoid synovium.     

High performance liquid chromatographic procedure for quantitative determination of urinary delta-aminolevulinic acid as indices of lead exposure

Summary A high performance liquid chromatographic method for the determination of delta-aminolevulinic acids (ALA) in urine, is described. 2-Methyl-3 carbmethoxy-4-(3-propionic acid) pyrrole was produced by the condensation of ALA with methylacetoacetate (MAA) while heating. The methylacetoacetate could be replaced by ethylacetoacetate. The ALA pyrrole thus obtained was injected into high performance liquid chromatography (HPLC). A stainless-steel column packed with octadecyl silanized silica gel was used. The mixed solution of acetonitrile/50mM KH₂PO₄ (adjusted to pH 2.5 with 0.001 volumes of 85 g/dl H₃PO₄)(20/80) was a favorable mobile phase for the separation of ALA. Amino acetone pyrrole was produced by the condensation of amino acetone with methyl acetoacetate. The amino acetone pyrrole appeared later than ALA pyrrole on HPLC. The method is simple and specific. It has a lower detection limit of 0.2 ng on column. The analysis and quantitative determination of one specimen can be performed within 20 min. Mean ALA concentration of normal urine by HPLC was 1.18mg/g creatinine.     

The role of cathepsin B and cystatin C in the mechanisms of invasion by ovarian cancer

OBJECTIVE: The aim of this study was to investigate the contribution of cathepsin B and cystatin C to the mechanisms of invasion by ovarian cancer. MATERIALS AND METHODS: Using surgical materials from patients with ovarian cancer, immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis were performed using antibodies against cathepsin B or cystatin C. Serum levels of cathepsin B and cystatin C in patients with benign and malignant ovarian lesions were determined by enzyme-linked immunosorbent assay (ELISA). An invasion assay using an ovarian cancer cell line was performed by addition of cystatin C or specific inhibitors of cathepsin B. RESULTS: While immunohistochemical staining of cathepsin B and cystatin C was evident in cancer cells and associated stromal tissue, this was not the case in benign tumors. The malignancies were also found to be positive for cathepsin B and cystatin C by SDS-PAGE and Western blotting analysis. No significant difference in serum cathepsin B levels was observed between patients with benign and malignant disease. However, the concentration of cystatin C in cases with ovarian cancer was significantly higher in benign cases (P<0.0001) and in healthy controls (P<0.0001). Invasion by cancer cells was dose-dependently suppressed by cystatin C and cathepsin B inhibitors. CONCLUSION: The results provided convincing evidence that cathepsin B and cystatin C may contribute to the mechanisms of invasion of ovarian cancer.     

Malignant solitary fibrous tumor of the meninges

Increasing numbers of solitary fibrous tumors (SFTs) in the meninges have been reported since this entity was first recognized. While most cases previously reported were considered to be benign, the malignant potential of extrathoracic SFTs has not been excluded. The authors report a rare case of a meningeal SFT with malignant behavior occurring in a Japanese female patient, initially resected when she was 44 years old and recurring in the same place four times during a 26-year follow-up period. A metastatic tumor to the right lung arose 25 years after the resection of the first meningeal tumor and focal invasion into the cerebellum was also observed with her last (5th) meningeal tumor. Immunohistochemical analysis showed all tumors to be diffusely positive for CD34 and negative for EMA, with a so-called patternless histological pattern, featuring thin collagen fibers between tumor cells. A focal staghorn vascular pattern was also observed. Ki67 (MIB-1) labeling indices and mitosis rates were 3.1±1.2% and less than 1/10 high power fields (HPF) in the first meningeal tumor and 16.1±6.4% and 6/10HPF in the last (5th) one, respectively. Thus, the present case suggests that meningeal SFTs possess malignant potential so that careful long-term follow up is required.     

Timed-release formulation to avoid drug-drug interaction between diltiazem and midazolam

The purpose of this study was to investigate whether the use of a timed-release (TR) drug formulation can avoid unfavorable pharmacokinetic drug-drug interactions in vivo. First, the effects of the time interval between administration of midazolam and diltiazem on the known drug-drug interaction between these drugs were investigated in dogs. When dogs were given midazolam orally at the same time they were orally given an aqueous diltiazem solution, the area under the plasma concentration-time curves of midazolam increased significantly compared with that of midazolam given orally in the absence of diltiazem. However, there was no significant difference in pharmacokinetics of midazolam when the diltiazem solution was administered 1-2 h after midazolam. Tests on a TR formulation containing diltiazem demonstrated that the first appearance of diltiazem in plasma occurs at 2.6 +/- 0.5 h in dogs. Subsequent tests showed that the plasma concentration-time profile of midazolam after concurrent oral administration of the diltiazem TR formulation was almost the same as that of midazolam administered alone. These results demonstrate that a TR formulation of diltiazem can avoid the interaction between diltiazem and midazolam by creating a time interval between absorption of drugs in vivo, without the need for closely controlling the time of drug administration.     

Delayed Rupture of a Pseudoaneurysm Following Pancreatoduodenectomy: Report of a Case

We report herein the case of a 63-year-old man in whom delayed rupture of a pseudoaneurysm occurred 120 days following pancreatoduodenectomy. Color Doppler examination indicated a pseudoaneurysm originating from the ligated gastroduodenal artery. Transcatheter arterial embolization was done at the common hepatic artery, proximal and distal to the pseudoaneurysm, with microcoils. The patient had a minor elevation of liver enzymes, which subsequently returned to normal. Due to the absence of any postoperative complications such as pancreatic anastomotic leakage, we assumed that the pseudoaneurysm formation had been caused by a weakness in the arterial wall according to skeletonization resulting from lymphadenectomy and intraoperative radiation therapy. To our knowledge, this case represents the longest interval between pancreatoduodenectomy and rupture of a pseudoaneurysm ever to be reported in the literature. Received: November 6, 2000 / Accepted: May 15, 2001     

Role of interleukin-18 and T-helper type 1 cytokines in the development of Mycoplasma pneumoniae pneumonia in adults

STUDY OBJECTIVE: Interleukin (IL)-18 is a proinflammatory cytokine, originally termed interferon (IFN)-gamma-inducing factor, which promotes T-helper type 1 (Th1) cytokine responses. We recently reported that serum IL-18 levels were elevated in children with Mycoplasma pneumoniae pneumonia (MP). In this study, we investigated the contribution of IL-18 to the infection and assessed the Th1 cytokine response to pulmonary involvement in adults. METHODS: We investigated the clinical course, pulmonary involvement, and serum levels of IL-18, IFN-gamma, IL-12p40, and soluble IL-2 receptor (sIL-2R) in 21 patients with acute-stage MP and in 21 age- and sex-matched control subjects. RESULTS: Significantly (p < 0.001) increased serum IL-18 (median, 248 pg/mL [range, 89 to 441 pg/mL] vs. median, 126 pg/mL [range, 47 to 217 pg/mL]) and sIL-2R (median, 617 U/mL [range, 410 to 1,032 U/mL] vs. median, 425 U/mL [range, 268 to 601 U/mL]) were found in patients with MP as compared with healthy control subjects, and there was a tendency toward increased serum IFN-gamma and IL-12p40. Circulating IL-18 values had a positive correlation with serum sIL-2R levels (r = 0.62, p = 0.028) and the number of affected pulmonary lobes (sigma = 0.61, p = 0.024), but not with the serum levels of antibodies to M pneumoniae, IFN-gamma, or IL-12p40. Serum IL-18 and sIL-2R values in severe cases were significantly higher (p < 0.03) than those in mild cases. IFN-gamma and sIL-2R levels in four patients with pleural effusion were significantly (p < 0.05) higher than those in the other 17 subjects. CONCLUSIONS: Serum levels of IL-18 were raised during the acute phase of MP. We suggest IL-18 and Th1 cytokines may play a significant role in the immunopathologic responses in MP.     

Pulmonary hemorrhage induced by epileptic seizure

We report a 35-year-old man who presented with pulmonary hemorrhage induced by an epileptic seizure. He had experienced recurrent episodes of massive hemoptysis after epileptic seizures since the age of 28 years. He was admitted to Kyoto University Hospital with massive hemoptysis and hypoxia after an epileptic seizure of a few minutes' duration. Radiographic signs of infiltrations and hemorrhagic bronchoalveolar lavage fluid were observed. He was intubated and successfully treated with anti-epilepsy drugs and corticosteroids. Epileptic seizures may have induced increased pulmonary vascular permeability and structural damage to the blood-gas barrier, which may have caused pulmonary hemorrhage. Pulmonary hemorrhage could be in the list of differential diagnoses of hemoptysis in patients with epilepsy.     

Different Keratin Profilesin Craniopharyngioma Subtypes and Ameloblastomas

Craniopharyngiomas are generally considered to arise from the remnants of Rathke's pouch or a misplaced enamel organ. We tried to refine these hypotheses, comparing the subtypes of craniopharyngioma with Rathke's cleft cyst, a known Rathke's pouch derivative, and with ameloblastoma, an enamel organ derivative. Nineteen craniopharyngiomas (14 adamantinomatous and 5 papillary type tumors) and 17 ameloblastomas were immunostained for cytokeratin (CK) 7, CK 8, CK 14, and human hair keratin (HHK). All cases of adamantinomatous craniopharyngioma were CK 7+/CK 8+/CK 14+. Two cases (40%) of papillary craniopharyngioma were CK 7+/CK 8+/CK 14+, whereas the remaining three cases (60%) were CK 7+/CK 8-/CK 14+. Fifteen cases (88%) of ameloblastoma were CK 7-/CK 8+/CK 14+. Only the shadow cells present in adamantinomatous craniopharyngiomas were positive for HHK, which may indicate their follicular differentiation. In Rathke's cleft cyst, ciliated cuboidal cells were CK 7+/CK 8+/CK 14- and metaplastic squamous cells were CK 7+/CK 8/CK 14+. These findings suggest that both subtypes of craniopharyngioma may differ from ameloblastoma in histogenesis, although cytokeratin expression patterns may change during tumor development. Adamantinomatous craniopharyngioma may be related to a heterotopic ectodermal tissue which can differentiate into hair follicles, while papillary craniopharyngioma may arise from Rathke's cleft cyst.