Peristent tissue proliferation of multilink stents is dependent on preprocedural plaque area: a serial intravascular ultrasound analysis.

It is not known whether any factors are related to tissue proliferation within and surrounding stents in humans. The authors used serial intravascular ultrasound (IVUS) to evaluate the relationship between IVUS parameters and tissue proliferation within and surrounding Multilink stents. They were able to analyze preinterventional and postinterventional and follow-up IVUS studies in 33 native vessel lesions in 33 patients with stable angina pectoris. Quantitative coronary angiography and IVUS measurements were performed before and after intervention and at follow-up. IVUS imaging using an automatic transducer pullback device allowed follow-up analysis of the same lesion site. The vessel area at the lesion site increased from 17.1 +/- 4.5 mm2 after intervention to 18.5 +/- 5.9 mm2 at follow-up (p<0.01). The in-stent tissue growth (after intervention to follow-up) in-stent plaque area (PA) was 1.6 +/- 1.1 mm2, and the peristent tissue growth (after intervention to follow-up) peristent PA was 0.8 +/- 2.3 mm2. In multivariate analysis, the preprocedural PA at the lesion site was the best predictor of the peristent tissue growth, whereas no factors predicted the in-stent tissue growth. Risk factors, clinical characteristics, and quantitative coronary angiographic parameters showed no relation to the peristent tissue growth or the in-stent tissue growth. The peristent tissue growth was closely related to the preprocedural plaque size, while the factors that affect the in-stent tissue growth were not identified.

[Role of new devices for angioplasty in the unprotected left main coronary artery].

OBJECTIVES: Angioplasty for the unprotected left main trunk remains controversial, but new procedures and devices such as directional coronary atherectomy and stenting have improved the results. We compared the results of angioplasty with the inflexible balloon and new devices. METHODS: The procedures were performed in 239 consecutive lesions in 160 patients between April 1986 and March 2000. This study excluded emergency cases and repeat angioplasty cases, and included 120 initial and elective cases. Initial and long-term results were compared between the balloon group (n = 29) and the new device group (n = 91). RESULTS: Lesion success rate was lower in the balloon group (90% vs 100%, p < 0.05), but there were no significant differences in in-hospital results including cardiac death (0% vs 0%), noncardiac death (0% vs 3.3%), Q-wave myocardial infarction (0% vs 2.2%), non-Q wave myocardial infarction (3.4% vs 6.6%), bypass surgery (0% vs 0%) and repeat angioplasty (6.9% vs 1.1%). Quantitative angiography showed significant improvements in minimal lumen diameter (mean 2.17 vs 3.16 mm, p < 0.001) and percentage diameter stenosis (mean 31% vs 13%, p < 0.001) in the new device group after the procedures. The minimum lumen diameter remained larger at 3 (p < 0.001) and 6 months (p < 0.05) in the new device group. Therefore, angiographic restenosis rate was higher in the balloon group (55% vs 21%, p < 0.005). Five-year survival rate showed no significant difference between the groups (75.0% vs 83.8%). CONCLUSIONS: New devices significantly improved the minimal lumen diameter after angioplasty for unprotected left main trunk disease, and lead to significant improvement of restenosis rate at follow-up.

Prevention of the development of preneoplastic lesions, aberrant crypt foci, by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male F344 rats.

The modifying effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (MAK) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for three weeks to induce ACF and fed on diets containing 0, 1.25, 2.5 and 5.0% MAK for five weeks, starting one week before the first dose of carcinogen. MAK significantly and dose-dependently prevented the development of ACF, decreasing the total number of AC and inhibiting cyst formation. MAK (2.5 and 5.0%) also significantly reduced the longitudinal-cross section areas of colon epithelium. MAK in all doses significantly reduced the PCNA positive index, area of the germinal region and number of cells per half crypt. In an additional in vitro experiment, MAK inhibited anchorage-independent growth of several colon carcinoma cell lines. The present results thus indicate that dietary MAK could act as a preventive agent for colon carcinogenesis.

Immunomodulatory effects of aged garlic extract.

Using various kinds of models, we examined the effects of aged garlic extract (AGE) on immune functions. In the immunoglobulin (Ig)E-mediated allergic mouse model, AGE significantly decreased the antigen-specific ear swelling induced by picryl chloride ointment to the ear and intravenous administration of antitrinitrophenyl antibody. In the transplanted carcinoma cell model, AGE significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in natural killer (NK) and killer activities of spleen cells were observed in Sarcoma-180--bearing mice administered AGE. In the psychological stress model, AGE significantly prevented the decrease in spleen weight and restored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress. These studies strongly suggest that AGE could be a promising candidate as an immune modifier, which maintains the homeostasis of immune functions; further studies are warranted to determine when it is most beneficial.

Pharmacologic activities of aged garlic extract in comparison with other garlic preparations.

We investigated the pharmacologic activities of four garlic preparations, raw garlic juice (RGJ), heated garlic juice (HGJ), dehydrated garlic powder (DGP) and aged garlic extract (AGE). The study used three animal models, i.e., testicular hypogonadism (hypospermatogensis and impotence) induced by warm water treatment, intoxication of acetaldehyde and growth of inoculated tumor cells. RGJ was found to be effective only in recovery of testicular function. The efficacy of HGJ was observed in three models; however, it did not improve impotence. DGP was effective in recovery of spermatogenesis and stimulated acetaldehyde detoxification. Significant beneficial effects of AGE were found in all three models. Although all four garlic preparations significantly enhanced natural killer (NK) and killer cell activities of the spleen cells of tumor-bearing mice, only AGE and HGJ inhibited the growth of inoculated tumor cells. These results suggest that different types of garlic preparations have different pharmacologic properties, and among the four garlic preparations studied, AGE could be the most useful garlic preparation.

Initial and long-term results of directional coronary atherectomy in unprotected left main coronary artery.

Angioplasty in the unprotected left main coronary artery (LMCA) has been controversial. Recently, several studies have suggested that new procedures and devices such as directional coronary atherectomy (DCA) and stents may change this situation. Although there are many reports of unprotected LMCA stenting, there are few reports of DCA of this lesion. Therefore, initial and long-term results were evaluated in 101 patients who underwent DCA for unprotected LMCA in our hospital. Emergency procedures were performed in 15 patients and electively in 86 patients. Scheduled angiographic follow-up was routinely performed, and all patients were clinically followed for >4 months after DCA. Technical success was achieved in 99%, and in-hospital outcomes were cardiac death (2%), noncardiac death (4%), Q-wave myocardial infarction (1%), non-Q-wave myocardial infarction (8.9%), coronary artery bypass grafting (0%), and repeat angioplasty (4%). In-hospital results varied considerably, depending on presentation. In-hospital mortality was significantly higher in the emergency, left ventricular ejection fraction < or =35%, and high-risk surgical subgroups. The angiographic restenosis rate was 20.4% at follow-up, and its predictor was postminimal lumen diameter by multivariate analysis. Mean clinical follow-up was 2.8 years; estimated 1- and 3-year survival rates were 87% and 80.7%, respectively. The cardiac survival rate of the low-risk surgical subgroup was significantly higher than that of the high-risk surgical subgroup (p <0.05). Thus, our data show that DCA can be performed safely and effectively in unprotected LMCA with an acceptable low restenosis rate and high survival rate.

[Predictors of prognosis after angioplasty in the unprotected left main coronary artery].

OBJECTIVES: The short-term and long-term predictors of outcome after coronary angioplasty in the unprotected left main coronary artery were investigated. METHODS: The procedure was performed in 122 consecutive patients for de novo lesions without myocardial infarction in our hospital between April 1986 and October 1998, including 16 emergency cases. Procedures were directional coronary atherectomy (73 patients), balloon angioplasty (31 patients), and stent implantation (18 patients). There were 101 males and mean age was 68 +/- 10 years. Follow-up angiography was performed in 98% of discharged patients, and all patients were clinically followed up for more than 1 year. Clinical and angiographic predictors of in-hospital and long-term outcome were evaluated. RESULTS: The in-hospital mortality was 5.7% (7 of 122 patients). Multivariate analysis revealed that more patients were admitted as emergency cases (57% vs 10%, p = 0.0088), with left ventricular ejection fraction < or = 35% (57% vs 22%, p = 0.029) and renal failure (43% vs 3%, p = 0.0004) finally died. Mean follow-up period was 3.5 years. Estimated survival rate was 77.1%, and cardiac-death free survival rate was 81.0% at 5 years by the Kaplan-Meier method. Univariate analysis showed that the predictors of cardiac death were emergency angioplasty, renal failure, decreased left ventricular ejection fraction, multivessel disease and unstable angina and/or congestive heart failure. Cox's regression model showed that renal failure (p = 0.0004) and multivessel disease (p = 0.0075) were significant predictors of long-term prognosis. CONCLUSIONS: Renal failure was the strongest predictor of outcome after unprotected left main coronary artery angioplasty.

Initial and 6-month results of biodegradable poly-l-lactic acid coronary stents in humans.

BACKGROUND: Although metallic stents are effective in preventing acute occlusion and reducing late restenosis after coronary angioplasty, many concerns still remain. Compared with metallic stents, poly-l-lactic acid (PLLA) stents are biodegradable and can deliver drugs locally. The aim of this study was to evaluate the feasibility, safety, and efficacy of the PLLA stent. METHODS AND RESULTS: Fifteen patients electively underwent PLLA Igaki-Tamai stent implantation for coronary artery stenoses. The Igaki-Tamai stent is made of a PLLA monopolymer, has a thickness of 0.17 mm, and has a zigzag helical coil pattern. A balloon-expandable covered sheath system was used, and the stent expanded by itself to its original size with an adequate temperature. A total of 25 stents were successfully implanted in 19 lesions in 15 patients, and angiographic success was achieved in all procedures. No stent thrombosis and no major cardiac event occurred within 30 days. Coronary angiography and intravascular ultrasound were serially performed 1 day, 3 months, and 6 months after the procedure. Angiographically, both the restenosis rate and target lesion revascularization rate per lesion were 10.5%; the rates per patient were 6.7% at 6 months. Intravascular ultrasound findings revealed no significant stent recoil at 1 day, and they revealed stent expansion at follow-up. No major cardiac event, except for repeat angioplasty, developed within 6 months. CONCLUSIONS: Our preliminary experience suggests that coronary PLLA biodegradable stents are feasible, safe, and effective in humans. Long-term follow-up with more patients will be required to validate the long-term efficacy of PLLA stents.

Angiographic and clinical outcome of a new self-expanding intracoronary stent (RADIUS): results from multicenter experience in Japan.

The RADIUS coronary stent featuring a multisegmented slotted tube design and self-expanding nitinol delivery system has a high radial force and flexibility, uniform expansion, and contours to the shape of the vessel. Successful stent deployment was achieved in 104 stable angina patients (106 lesions; 44% LAD, 19% circumflex, and 37% RCA). Mean minimal lumen diameter (MLD) increased from 0.77 +/- 0.46 mm to 2.88 +/- 0.61 mm and mean percent diameter stenosis (% DS) decreased from 73 +/- 14% to 6 +/- 13% immediately after the procedure. At 6-month follow-up, two patients (2%) underwent urgent target revascularization, and cerebral bleeding occurred in one patient (1%). Angiographic follow-up was performed in 94 lesions (89%) and mean MLD and mean % DS were 2.08 +/- 0.92 mm and 30% +/- 24%, respectively. Stent restenosis (>50% diameter stenosis at follow-up) was observed in 16 (17%) of all lesions. The high success rate for stent deployment, low incidence of major adverse cardiac event, and lower restenosis rate after stent implantation indicate that the RADIUS stent is useful for coronary intervention.

Prevention of psychological stress-induced immune suppression by aged garlic extract.

We determined the effect of Aged Garlic Extract (AGE) on damage caused to immune function by a psychological stress using a communication box. After four days of a psychological stress, a decrease in spleen weight and spleen cells was observed in the psychological stress-exposed mice as compared normal mice (non-stress). AGE significantly prevented the decreases in spleen weight and cells. Additionally, AGE significantly prevented the reduction of hemolytic plaque-forming-cells in spleen cells and anti-SRBC antibody titer in serum caused by this psychological stress. Moreover, a reduction in NK activities was observed in the psychological stress-exposed mice as compared with normal mice (non-stress), whereas NK activities in the AGE administered mice were almost the same as normal mice (non-stress). These results indicate that psychological stress qualitatively and quantitatively impairs immune function, and that AGE is extremely useful for preventing psychologically-induced damage.

Immunomodulation and antitumor activities of Aged Garlic Extract.

We found that Aged Garlic Extract (AGE) could be a significant immuno-potentiator, and could exhibit anti-tumor activities through immune modulation. Consequently, AGE stimulated the proliferation of mouse spleen cells and the release of cytokines, such as IL-2, TNF-alpha and IFN-gamma, increased NK activities, and enhanced phagocytosis of peritoneal macrophages. AGE treatment also stimulated the reactivity of lymphocytes in response to cytokines or mitogens. AGE was far superior to PSK in IL-2 induction, but slightly inferior to PSK in nitric oxide induction. AGE, as effectively as PSK (Krestin), significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in NK and killer activities of spleen cells were observed in Sarcoma-180 bearing mice treated with AGE. These results strongly suggest that AGE is as effective as PSK, and could serve as a potent biological response modifier on NK cells and T lymphocytes, and subsequently inhibit the growth of transplanted tumors.

Anti-allergic effects of aged garlic extract.

To examine the effect of Aged Garlic Extract (AGE) on the function of mast cells and activated T lymphocytes, we adopted the in vitro histamine release system, the in vivo IgE mediated skin reaction system and the in vivo late phase reaction system. Consequently, at 1.25, 2.5, and 5.0% (v/v), AGE dose-dependantly inhibited the antigen specific histamine release by mouse anti-TNP monoclonal antibody and TNP-BSA hapten carrier complex against rat basophil cell line RBL-2H3 by 50, 80, and 90 percent, respectively. In the IgE mediated skin reaction system, repeated or single intragastric administration of AGE (10 ml/kg), decreased by 25-45% the antigen specific ear swelling which was induced by a picryl chloride ointment applied to the ear of mice also given an intravenous administration of anti-TNP antibody IgE ascites. In the late phase reaction system, repeated or single intragastric administration of AGE (10 ml/kg) suppressed by 45-55% the antigen specific ear swelling induced by a secondary challenge to the ear of mice given a picryl chloride ointment seven days prior. These results suggest that AGE application could modify, directly or indirectly, the function of mast cells, basophils and activated T lymphocytes which play a leading role in allergic cascade reactions including inflammation.

Interleukin 1 alpha acts as an autocrine growth stimulator for human gastric carcinoma cells.

The expression and effect of interleukin 1 alpha (IL-1 alpha) were examined in human gastric carcinoma cell lines to determine if IL-1 alpha acts as a growth stimulator for these cells. Six of 8 gastric carcinoma cell lines expressed IL-1 alpha mRNA at various levels. Among them, TMK-1 and MKN-7 cells secreted IL-1 alpha into the culture fluid, in an especially large amount by MKN-7 cells. Scatchard plot analysis of IL-1 alpha binding revealed that TMK-1 cells had only one type of high-affinity receptors, whereas MKN-7 cells had high- and low-affinity receptors. Cell growth and DNA synthesis of TMK-1 and MKN-7 cells were stimulated by IL-1 alpha, and those of MKN-7 were inhibited by addition of anti-IL-1 alpha antibody or IL-1 receptor antagonist. The expression of IL-1 alpha mRNA by these cell lines was induced by either IL-1 alpha, epidermal growth factor, or transforming growth factor alpha. On the other hand, IL-1 alpha increased the mRNA expression for transforming growth factor alpha and epidermal growth factor receptor. These findings indicate that IL-1 alpha is an autocrine growth stimulator for gastric carcinoma cells and the interaction with epidermal growth factor/transforming growth factor alpha/receptor system should be involved in the growth modulation by IL-1 alpha.

GC factor represses transcription of several growth factor/receptor genes and causes growth inhibition of human gastric carcinoma cell lines.

The GC factor (GCF) binds to specific GC-rich sequences in the epidermal growth factor receptor (EGFR) gene promoter and represses its transcription. In this study, by the use of GCF transfection, we examined whether GCF represses the gene expression of several other growth factors and receptors and causes growth inhibition of cancer cells. The transfection of GCF expression vector into gastric carcinoma cell lines (TMK-1 and MKN-28) decreased the mRNA levels of transforming growth factor (TGF) alpha, insulin-like growth factor II, and c-met. The reduction of TGF-alpha expression was confirmed at the protein level by enzyme-linked immunosorbent assay. Transfection of GCF expression vector interfered with the mRNA accumulation for EGFR and TGF-beta induced by epidermal growth factor in gastric carcinoma cell lines. The carcinoma cells transfected with GCF expression vector did not grow in a serum-free medium, whereas the control cells did grow under serum-free conditions. When the growth of the gastric carcinoma cell lines was studied in nude mice, GCF-transfected carcinoma cells showed a significantly slower growth compared to the control tumor. Transient cotransfection analysis with NIH3T3 cells revealed that GCF repressed the promoter activity of TGF-alpha in addition to EGFR. These findings indicate that GCF negatively regulates gene expression of not only the EGFR but also several other growth factor and receptor genes and can inhibit the growth of gastric carcinomas in immunodeficient mice.

Biologic effect of human hepatocyte growth-factor on human gastric-carcinoma cell-lines.

Biologic effect of human hepatocyte growth factor (hHGF), which is now known to be the same protein of scatter factor and tumor cytotoxic factor, on gastric cancer cell lines were examined. hHGF messenger RNA expression was undetectable in human gastric cancer cell lines TMK-1 (poorly differentiated adenocarcinoma) and MKN-28 (well differentiated adenocarcinoma). Human fetal lung fibroblast cell line MRC-5 and human stomach derived fibroblast ST-Fib expressed high levels of hHGF mRNA. hHGF production was also confirmed in the culture media of the fibroblast cell lines by enzyme linked immunosorbent assay. Interestingly, TMK-1, having weak expression of E-cadherin, showed marked scattering on 0.1% collagen gel with hHGF (10 ng/ml). The same scattering activity was also observed with fibroblast conditioned medium or with stomach derived fibroblast ST-Fib co-culture. Contrarily, well differentiated adenocarcinoma cell line MKN-28 maintaining strong E-cadherin expression did not show this morphologic change. The expression of c-met proto-oncogene, which encodes the receptor for hHGF, and the biochemical character of hHGF receptor did not differ significantly between TMK-1 and MKN-28. On the other hand, Western blot analysis using specific antibody to phosphotyrosine revealed a difference in phosphoprotein pattern between the two cell lines. These results indicate that hHGF produced by the stromal fibroblasts has a histologic type-specific morphogenic activity on gastric cancer cells with different expression of E-cadherin in a paracrine manner in vivo and a different post-receptor signal transduction mechanism.

Reduced tumorigenicity and cell motility of a gastric-carcinoma cell-line by introduction of wild-type p53 gene.

Wild-type or mutant human p53 gene was transfected into a human gastric carcinoma cell line MKN-1 which shares a mutant p53 allele. Transfected wild-type p53 reduced the colony forming efficiency and tumorigenicity of MKN-1 cells. However, no difference in expression of cell adhesion molecule, oncogenes and growth factors was observed among parent, wild-type p53 and mutant p53 transfectants. In motility assay, the wild-type p53 transfectants relative to the parental or mutant p53 transfectants exhibited a decreased motility, and HGF had a greater effect on the motility of the mutant p53 transfectants, but very little effect on the motility of either the parental or wild-type transfectants. In invasion assay, mutant p53 transfectants revealed the increased invasion ability into collagen gel. These results suggest that allele loss and point mutation of p53 gene may play a critical role not only in growth but also in invasion of gastric carcinoma cells.

Systemic atrioventricular valve replacement in an infant with corrected transposition of the great arteries.

A 3-month-old infant with corrected transposition of the great arteries and severe systemic atrioventricular valve regurgitation due to "Ebstein-like anomaly" is reported. Through a right thoracotomy and longitudinal left atrial incision, a 19-mm St. Jude Medical valve was implanted into the annulus without removing the native valve. He is doing well 7 months after operation.

A monoclonal antibody capable of detecting new differentiation antigen of the stomach.

A monoclonal antibody (MAb) was raised against a gastric adenocarcinoma cell line TMK-1 that shows parietal cell differentiation. This MAb, an IgMK, named 20DII, reacted immunohistochemically with the intracytoplasmic secretory canalicular membranes of normal parietal cells of the stomach. In the fetal stomach at 4 months of gestation, the luminal surface of fundic epithelia and developing parietal cells had MAb20DII immunoreactivity, but at 6 months of gestation only parietal cells showed immunoreaction. Out of 133 gastric carcinomas, 98 (74%) had MAb20DII immunoreactivity. In the well-differentiated type, immunoreactivity was localized at the luminal surface of tumor cells and, in the poorly differentiated type, in the intracytoplasmic tubulovesicles of tumor cells. In Western-blot analysis, the antigenic molecule had a molecular weight exceeding 300 kDa in the tumor tissues, but only a 62-kDa immunoblot band was seen in the corresponding non-cancerous gastric mucosa. However, there was no correlation between the expression of high-molecular-weight antigens and the histological types of gastric carcinoma. These results suggest that 20DII antigen may be involved in differentiation of parietal cells in the fetal stomach and in stomach cancer.

Growth inhibition of transforming growth factor beta on human gastric carcinoma cells: receptor and postreceptor signaling.

The effect of transforming growth factor beta (TGF-beta) on human gastric carcinoma cell lines was examined. Cell growth and DNA synthesis of TMK-1 were inhibited by TGF-beta, whereas MKN-28 presented no response to TGF-beta. Scatchard plot analysis of TGF-beta binding showed that TMK-1 had a relatively small number of high-affinity receptors, whereas MKN-28 had a large number of low-affinity receptors. By affinity labeling, only the type I receptor (Mr 65,000) for TGF-beta was detected in TMK-1, while three types of receptors, type I, type II (Mr 85,000-95,000), and type III (Mr 250,000-350,000), for TGF-beta were present in MKN-28. TGF-beta treatment reduced p34cdc-2 kinase activity and the level of phosphorylation of retinoblastoma protein in TMK-1, whereas it did not affect them in MKN-28. mRNAs for MYC and platelet-derived growth factor B chain were increased by treatment of TGF-beta on TMK-1. cAMP-responsive element binding activity was decreased by TGF-beta treatment in MKN-28 but not in TMK-1. This was closely correlated with protein kinase C activity. These results suggest that the type I receptor for TGF-beta in human gastric carcinoma cells may be mainly linked with the growth inhibition of TGF-beta by a decrease in retinoblastoma protein phosphorylation by p34cdc-2 without suppression of MYC expression. Conversely, TGF-beta may reduce protein kinase C activity and cAMP-responsive element binding activity in TGF-beta-resistant gastric carcinoma cells.