Prevalence of Helicobacter pylori in NSAID users with gastric ulcer.

OBJECTIVE: Regarding the interaction of Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs), we cannot accept unanimous conclusions in inducing gastric ulcer. We therefore evaluated the role of Helicobacter pylori and NSAIDs in inducing gastric ulcer. METHODS: Dyspeptic patients receiving NSAIDs underwent endoscopic examination. Gastric ulcer formation and H. pylori status were investigated. Biopsy specimens from the antrum and lower body of the stomach were prepared for the rapid urease test and pathological evaluation. Anti-H. pylori antibody was measured by enzyme-linked immunosorbent assay. RESULTS: Two hundred and twenty-six patients receiving NSAIDs (220 chronic and six on-demand users) underwent gastrofibrescopic examination. There were 110 patients with gastric ulcer and 111 non-ulcer patients with gastritis. The remaining five patients had neither. NSAID users with gastric ulcer showed a low prevalence of H. pylori compared with those without them [55/110 (50.0%) vs 79/111 (71.2%), P < 0.01]. The same tendency was seen when patients receiving low-dose aspirin and those with rheumatoid arthritis were analysed separately [13/29 (44.8%) vs 50/62 (80.6%), P < 0.01, and 11/33 (33.3%) vs 16/26 (61.5%), P < 0.06 with Yates' correction, respectively]. CONCLUSION: Helicobacter pylori infection appeared to be a risk factor for developing gastritis, but we found no evidence that it increases gastric ulcer formation in NSAID users with dyspepsia.

Temperature dependency of radiation damage in inorganic materials by 300 keV electrons.

Temperature dependency of radiation damage in albite and natrolite was studied quantitatively by measuring the diffraction intensity with imaging plates. Radiation damage was reduced at low temperature in albite but was enhanced in natrolite. A damage process model, in which creation and annihilation of localized defects were considered, was proposed. According to this model, Boltzmann factor in temperature dependency is dominated by a difference between energy for diffusion of the localized defects and energy for breakdown of a crystal framework. When the diffusion energy is larger than breakdown energy, the activation energy in Boltzmann factor seems to be effectively negative.

Peroxisome proliferator-activated receptor-gamma activation inhibits interleukin-1beta -mediated platelet-derived growth factor-alpha receptor gene expression via CCAAT/enhancer-binding protein-delta in vascular smooth muscle cells.

CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-alpha, and platelet-derived growth factor-alpha receptor (PDGFalphaR). Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs). In the present study, we clarified a functional relationship between C/EBPs and PPARgamma in the regulation of IL-1beta-induced PDGFalphaR expression in VSMCs. PPARgamma activators, troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), inhibited IL-1beta-induced PDGFalphaR expression and suppressed PDGF-induced proliferation activity of VSMCs. Electromobility shift and supershift assays for a C/EBP motif in the PDGFalphaR promoter region revealed that PPARgamma activators suppressed IL-1beta-induced DNA binding activity of C/EBPdelta and beta. PPARgamma activators also suppressed IL-1beta-induced C/EBPdelta expression. In contrast, overexpression of C/EBPdelta reversed the suppressive effect of PPARgamma activators on PDGFalphaR expression almost completely. From these results, we conclude that the inhibitory effect of PPARgamma activators on PDGFalphaR expression is mainly mediated by C/EBPdelta suppression. Regulation of C/EBPdelta by PPARgamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.

Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells.

Thiazolidinediones, activators of peroxisome proliferator-activated receptor (PPAR)gamma, have been reported to induce apoptosis in many types of cells. In the present study, we investigated the effects of thiazolidinediones, troglitazone, and pioglitazone on the cell growth of vascular smooth muscle cells, and identified a specific effect of troglitazone in addition to PPARgamma activation. Subconfluent rat culture vascular smooth muscle cells were treated with or without PPARgamma activators, troglitazone (1-30 microM), or pioglitazone (1-30 microM) for 72 h. After treatment, cell viability was significantly reduced by troglitazone in concentrations of 5-30 microM but not by pioglitazone. Vascular smooth muscle cells appeared to float and shrink 48 h after treatment with 20 microM of troglitazone. In situ DNA labeling showed that the nuclei of these cells were positively stained, and genomic DNA extracted from the cells showed nucleosomal laddering. Messenger RNA expression levels of c-myc, p21, bax, bcl-2, and bcl-x were not changed by the treatment with troglitazone. In contrast, along with the induction of vascular smooth muscle cell apoptosis, both the mRNA and protein expression levels of p53 and Gadd45 markedly increased in response to troglitazone. These results strongly suggest that troglitazone can induce vascular smooth muscle cell apoptosis and that this effect is caused primarily by activation of the p53 and Gadd45 pathway but not by PPARgamma activation.

Giant unruptured aneurysm of the thoracic aorta--a case report.

An asymptomatic 88-year-old woman underwent a screening medical examination. The chest x-ray film showed a large mediastinal mass with calcification. Both chest computed tomography and nuclear magnetic resonance imaging revealed an unruptured aortic aneurysm, predominantly affecting the ascending aorta and the proximal part of the aortic arch. Its maximum diameter was 10.5 cm. An ascending aortic aneurysm more than 10 cm in diameter is very rare. She died of acute pulmonary embolism unrelated to the aneurysm, and autopsy indicated that the etiology of the aneurysm was atherosclerotic degeneration. Retrospectively, the natural progression of the aneurysm was able to be followed on a series of chest x-ray films obtained over 18 years.

Apoptosis and Bcl-xs in the intimal thickening of balloon-injured carotid arteries.

We performed balloon injury in the rat carotid artery and identified intimal thickening after injury. Balloon-injured carotid arteries showed maximum thickness of the neointima on the 14th day before complete endothelial cell regeneration. In this lesion we identified apoptosis of vascular smooth muscle cells (VSMCs) by in situ DNA labelling and electron microscopy in the neointima on the 14th day after injury. mRNA expression levels of bcl-2, bax, bcl-x, p53 and caspase-1 were determined by the reverse transcriptase-polymerase chain reaction method both in injured and uninjured carotid arteries. Neither bcl-2 nor bcl-xl mRNA expression was detected in either injured or uninjured arteries, whereas bax and p53 mRNA expression was identified and their mRNA levels were not altered after balloon injury. In contrast, both bcl-xs and caspase-1 mRNA was detected and was markedly induced only in the injured carotid artery. Positive staining for immunoreactive Bcl-x was observed specifically in the injured arterial wall and co-localized with positive staining of nuclei identified by in situ DNA labelling. We conclude that two opposite cellular responses, VSMC proliferation and apoptosis, exist together in the neointima of the rat carotid artery after balloon injury, and selective induction of Bcl-xs expression is a key regulator of VSMC apoptosis in the process of vascular remodelling.

Novel cis element for tissue-specific transcription of rat platelet-derived growth factor beta-receptor gene.

Platelet-derived growth factor (PDGF) and its receptors are widely expressed in several tissues in the stage of cellular growth and development. In adulthood, PDGF beta-receptor (PDGFbetaR) is mainly detected in pathological conditions such as atherosclerotic lesions and injured vascular wall. The purpose of the present study was to elucidate the underlying mechanism of PDGFbetaR gene expression under pathological conditions in vascular smooth muscle cells (VSMC) and to identify the important cis elements responsible for tissue-specific gene transcription. Gel mobility shift assay and supershift assay indicated that the CCAAT motif located at -67 (C67) was mainly interacted with NF-YC, and this element drove the basal promoter activity of the gene as a putative promoter. On the other hand, another important sequence essential for the basal transcription was found at a 30-bp region (R30) spanning -150 to -121. To test whether R30 actually regulates the tissue-specific transcription of PDGFbetaR gene, electromobility shift pattern was compared between VSMC and hepatoma cell line (HTC). We obtained the result that DNA-protein complex seen only in nuclear extracts from HTC suppressed the promoter activity in HTC in a tissue-specific manner. Furthermore, cis element decoy transfection experiments for C67 and R30 also revealed that both elements were functionally important in mRNA expression of PDGFbetaR in VSMC. From these results, we concluded that the basal activity of PDGFbetaR gene expression was transactivated by the interaction or coordination of both C67 and R30, and the latter one mainly controlled the tissue-specific gene expression in VSMC.

Platelet-derived growth factor induces apoptosis in vascular smooth muscle cells: roles of the Bcl-2 family.

Apoptosis (programmed cell death) is observed in vascular smooth muscle cells (VSMC) in atherosclerotic lesions and stenotic lesions after injury, and modulates the cellularity of these lesions. It is recognized that cell growth and apoptosis are two linked processes. Platelet-derived growth factor (PDGF) induces VSMC proliferation and migration in vitro. We studied the effect of PDGF on apoptosis in VSMC. Cultured rat VSMC were treated with PDGF-AA or PDGF-BB. PDGF-BB induced cell death in cultured VSMC in a time- and dose-dependent manner, but PDGF-AA did not. Gel electrophoresis of genomic DNA and in situ DNA labeling confirmed that the cell death induced by PDGF-BB is apoptosis. PDGF-BB treatment reduced bcl-2 mRNA and bcl-xl mRNA expression, in contrast, induced bcl-xs mRNA expression, linked with the induction of apoptosis in cultured VSMC.

[An elderly patient with bleeding from the alimentary tract caused by aberrant pancreas of the small intestine].

A 71-year-old woman was admitted to hospital because of malaise and bloody stool. Laboratory findings consistently showed anemia (Hb 9.2 g/dl) and occult blood in the stool. Although barium series and endoscopy of the upper and lower intestinal tructs were carried out, there was no evidence of bleeding from the gastrointestinal tract 99mTcO4- scintigraphy, which was performed to exclude bleeding from Meckel's diverticulum, also did not locate a significant lesion. Angiographic imaging of the superior mesenteric arteries (SMA) was performed to exclude lesions such as small intestine tumors with extraluminal growth and vascular abnormalities such as A-V malformation and it revealed the round encasement of arteries in the peripheral SMA region, strongly suggestive of a small intestine tumor. Surgery was performed and an extraluminally protruding tumor was found in the small intestine. The excised tumor was 4 x 3 x 3.5 cm in size, are was diagnosed histologically as aberrant pancreas. The postoperative laboratory findings showed that the anemia had improved and occult blood was not detected in the stools. Although aberrant pancreas of the small intestine is a common benign tumor, it is a very unusual cause of bleeding from the alimentary tract.

Efficacy of lansoprazole against peptic ulcers induced by non-steroidal anti-inflammatory drugs: endoscopic evaluation of ulcer healing.

Beyond the obvious step of limiting use of non-steroidal anti-inflammatory drugs (NSAIDs), the treatment of ulcers induced by NSAIDs remains controversial. We evaluated the efficacy of the proton-pump inhibitor lansoprazole on NSAID-induced ulcers. Ulcers were endoscopically diagnosed in 47 NSAID users. These patients received 30 mg/day lansoprazole, orally, for 6 or 8 weeks (6 weeks for duodenal ulcers and 8 weeks for other ulcers). Ulcer healing was assessed using an established classification system. The presence of immunoglobulin G antibody against Helicobacter pylori was also evaluated. The antibody was present in the sera of 51% of patients (24/47). Most of the ulcers reached scarring stages S1 (healing) or S2 (good healing), and the S2 healing rate was 35%. Two H. pylori seropositive patients did not reach these stages; their ulcers were improved by H. pylori eradication therapy, followed, in one case, by medication with misoprostol. Lansoprazole seemed to be useful for most patients with NSAID-induced ulcers, but a few needed additional treatments.

Total replacement of urethral mucosa with oral mucosa in dogs.

PURPOSE: If the urethral mucosa is replaced by another mucosa, urethral recurrence might decrease in patients who undergo neobladder construction for bladder cancer. We determined whether such replacement is possible. MATERIALS AND METHODS: Six dogs underwent an operation consisting of a longitudinal urethral incision at its full length and immediate closure. In 6 other dogs, after the urethral mucosa was totally removed, a tubularized sublingual mucosa was closely set inside the urethral lumen. Postoperatively, the urinary stream and external meatus were observed every day. To measure urine leakage, a 10-minute pad test was performed once a month. All dogs were sacrificed 3 to 12 weeks after the operation for histological examination of the urethra. The excised urethras were examined with a 12F catheter for urethral patency. RESULTS: All dogs were continent postoperatively. The results of the 10-minute pad test showed no significant difference in the weight increase of the pad among the control, sham-operated and mucosa-replaced dogs. Urethral stricture developed in 1 mucosa-replaced dog. Histological examination revealed that all of the grafted oral mucosa survived in the urethra. CONCLUSION: These results indicate that the urethral mucosa can be replaced by oral mucosa without damaging the continence mechanism in female dogs.

Increase in lectin binding sites on epithelial cells by chronic bladder infection in rats.

Using lectin histochemistry we assessed whether chronic bladder infection modifies carbohydrate residues of glycoconjugates on uroepithelial cells in rats. The bladder infection was produced by implanting a knotted silk thread with Escherichia coli into the bladder. One or 4 weeks after the implantation the bladder was excised, incubated with sixteen biotinylated lectins and stained. The bladder epithelia as a whole stained more strongly positive for eight lectins in the infected rats than in the control rats having a sterile silk thread in the bladder. In the infected rats, the superficial epithelial layer that stained negative for Arachis hypogaea (PNA) in the controls became strongly positive for PNA, whereas the middle and deep epithelial layers increased in staining for Canavalia ensiformis and six other lectins. These results indicate that chronic bladder infection increases carbohydrate residues on uroepithelial cells and may facilitate bacterial adherence to uroepithelial cells.

Differences in signal transduction between platelet-derived growth factor (PDGF) alpha and beta receptors in vascular smooth muscle cells. PDGF-BB is a potent mitogen, but PDGF-AA promotes only protein synthesis without activation of DNA synthesis.

Cultured vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats express both alpha and beta isoforms of the platelet-derived growth factor (PDGF) receptors at high levels (100,000 and 240,000 sites/cell, respectively). In this cell type, PDGF-BB elicited a mitogenic response; however, PDGF-AA increased only protein synthesis without activating DNA synthesis. Protein kinase C (PKC) was activated by PDGF-AA as well as PDGF-BB with concomitant translocation from cytosol to membrane fractions. However, the hypertrophic effect of PDGF-AA was not affected by depletion of cellular PKC, whereas the mitogenic action of PDGF-BB was partially attenuated by the depletion. Following incubation with PDGF-AA or -BB, phospholipase C-gamma 1 (PLC-gamma 1) and phosphatidylinositol 3-kinase were tyrosine phosphorylated; however, the phosphorylation of Ras-GTPase-activating protein was induced only by PDGF-BB. Both PDGF isoforms resulted in a prompt and transient increase in the level of 1,2-diacylglycerol (DAG), presumably through the action of PLC-gamma 1. After returning to basal levels, the rate of DAG synthesis steadily increased for at least 15 min due to activation of phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC). Incubation with PDGF-BB-activated phospholipase D (PLD) in a PKC-dependent manner resulting in the formation of phosphatidic acid (PA). PA was also formed by the sequential reactions of PC-PLC and DAG kinase in the PDGF-BB-stimulated VSMC, and these sequential reactions were not affected by PKC depletion. In contrast, PDGF-AA stimulation did not result in increased PA synthesis as neither PLD nor DAG kinase activities were affected. PA may be a significant second messenger in the activation of DNA synthesis by PDGF-BB. These results indicate that signaling mechanisms of the PDGF-alpha and -beta receptors in VSMC are distinctly different in signal transduction in VSMC and that the alpha receptor promotes cellular hypertrophy (but not hyperplasia), whereas a mitogenic response is mediated only through the beta receptor.

Participation of diacylglycerol kinase in mitogenic signal transduction induced by platelet-derived growth factor in vascular smooth muscle cells.

In rat vascular smooth muscle cells, platelet-derived growth factor (PDGF), stimulated phosphatidic acid synthesis by activating both of the two alternative pathways, diacyglycerol kinase (DGK) and phospholipase D (PLD). Genistein, a tyrosine kinase inhibitor, inhibited PLD activation but not DGK activation, the latter was inhibited selectively by R 59022. PDGF-induced DNA synthesis was partially inhibited by genistein or R 59022, but these inhibitors had no effect on phorbol ester-induced DNA synthesis. Further, the specific effects of these inhibitors on PDGF-induced DNA synthesis were additive.

Molecular cloning and expression of the gene encoding human angiotensin II type 2 receptor.

The gene of human angiotensin II type 2 (AT2) receptor was isolated from a genomic DNA library prepared from human placenta. The coding region of the human AT2 receptor gene was contained in a single exon coding segment of the gene indicating an intronless structure of the coding region. The amino acid sequence of human AT2 receptor deduced from its nucleotide sequence has 363 amino acids and shows a high degree of sequence identity to rat and mouse receptor sequences. Specific binding of [125I]Sar1Ile8-angiotensin II was demonstrated in COS-7 cells transfected with a plasmid containing the human AT2 sequence. Scatchard analysis and ligand displacement profile were typical of the AT2 receptor. Reverse transcription-polymerase chain reaction analysis showed that AT2 receptor mRNA was expressed in adult uterus and pheochromocytoma.

[Massive skeletal invasion in Hodgkin's disease observed by MRI].

A 35-year-old female developed cervical adenopathy and mediastinal tumor in 1988. A lymph node biopsy specimen showed nodular sclerosing Hodgkin's disease. She received combination chemotherapy with cyclophosphamide, vincristine, adriamycin and prednisolone, and radiotherapy for mediastinal tumor. She had a complete remission (CR). In September 1990, she developed swelling of the left hip and felt pain in the left hip and thigh. She also noticed swelling of the left inguinal lymph nodes. MRI T2-weighted images showed enlargement and destruction of the fascia and hyperintense signal of the left iliac and gluteus muscle. A biopsy specimen of the inguinal lymph node showed recurrence of Hodgkin's disease of mixed cellularity. She received salvage therapy with ifosfamide, methotrexate, etoposide and procarbazine, and achieved a second CR. The clinical appearance of the skeletal muscle involvement by lymphoma is uncommon, especially in Hodgkin's disease.

Interstitial pneumonitis possibly due to mitoxantrone.

A 41-year-old patient with chronic myelogenous leukemia in the accelerated phase was treated with mitoxantrone. She developed pyrexia 7 days after receiving the third administration of mitoxantrone. After 3 more days, she experienced dry cough and dyspnea. Bilateral fine crackles were audible, but no signs of heart failure were found. A chest X-ray film revealed diffuse reticulogranular infiltrates bilaterally. An increase in the prednisolone dosage led to an improvement. Specimens of the bronchoalveolar lavage revealed an increase in CD4-/CD8- lymphocytes. The peripheral lymphocytes also expressed neither CD4 nor CD8. Specimens of a transbronchial lung biopsy disclosed thickening of the alveolar wall with infiltration of lymphoid cells.