The role of device closure of patent foramen ovale in patients with cryptogenic stroke.

One of the most frequent causes of cardiac embolism in cryptogenic stroke is a paradoxical embolus, which originate from systemic venous source though an unidentified patent foramen ovale (PFO). PFO is a common finding in the general population with a prevalence of 25% to 30%. Transcatheter PFO device closure is known to be feasible and safety treatment for such patients. In recent years, several randomized controlled trials (RCTs) have been conducted to address the superiority of PFO closure over medical therapy alone in the prevention of stroke recurrence in patients with PFO. In contrast to findings from early 3 RCTs, recent 4 RCTs could successfully show the benefits of PFO device closure compared with medical therapy, with less peri- and postprocedural complication. Based on these data, PFO device closure is recommended to carefully select cryptogenic stroke patients aged from 18 to 65 years, with a high probability of a causal role of the PFO in stroke events. However, it is still uncertain whether PFO closure is superior to oral anticoagulants therapy in these patients. Therefore, further prospective randomized trials are needed to address the efficacy of PFO device closure to oral anticoagulants therapy.

A possible role of VEGF in osteolytic bone metastasis of hepatocellular carcinoma.

The incidence of bone metastasis was around 13% in 404 patients with hepatocellular carcinoma (HCC) who underwent treatment at the National Kyushu Cancer Center between 1988-97, which is a high value among various cancers. This is, in part, due to the prolonged survival time of HCC patients in recent years. Serum vascular endothelial growth factor (VEGF) levels were significantly elevated in HCC patients with bone metastases as compared to those in patients with liver cirrhosis/chronic hepatitis and HCC patients without bone metastasis. VEGF was positively stained in both the primary lesion and bone metastasis of HCC by immunohistochemistry. In the process of bone metastasis, an increase in bone resorption is a crucial step prior to invasion of the bone. VEGF, the most important angiogenic factor, has been shown to stimulate bone resorption through its effects on osteoclasts. Thus, HCC cells reach the bone marrow space, and then secrete VEGF which facilitates osteolytic bone metastasis. VEGF may also facilitate tumor growth in the bone by acting as an angiogenic factor once invasion of the bone is complete. This might be another reason for the high incidence of bone metastasis in HCC.

[The change process of sex-role attitudes in female high school students].

The present study examined how changes would occur in sex-role attitudes of female high school students. Six hundred (600) randomly sampled female high school students from a metropolitan area completed a questionnaire. Partial Order Scalogram Analysis (POSA) was conducted for three variables: complaint against sex discrimination, interest in women's independence, and attitude toward women's achievement in the public arena. POSA found two separate change routes for sex-role attitudes. In the first, the complaint process, increasing complaint against sex discrimination led to positive attitude toward women's achievement in the public arena, which in turn to heightened interest in women's independence. For the second, the interest process, heightened interest in women's independence was followed by positive attitude toward women's achievement, and then by more complaint against sex discrimination. Results also suggested not only that the complaint process was facilitated by external factors like discrimination, and that the interest process by increasing interest in self. But students in the last stage of both processes experience sex-role conflict.

Increased incidence of bone metastases in hepatocellular carcinoma.

OBJECTIVES: Recently, we often encounter hepatocellular carcinoma patients with bone metastases. We therefore examined the changes in the incidence of bone metastases in hepatocellular carcinoma from 1978 to 1997 and tried to identify the characteristic clinical features. We also discuss the reasons for the increased incidence of bone metastasis in hepatocellular carcinoma. METHODS: A total of 673 patients with hepatocellular carcinoma during the period 1978-1997 were studied. Bone metastasis was screened by bone scintigraphy, and bone lesions were confirmed by plain radiography, computed tomography and/or magnetic resonance imaging. The serum levels of the C-terminal telopeptide of type 1 collagen, which represent osteoclastic bone resorption, were also measured. RESULTS: The incidence of bone metastasis during the decade 1988-1997 was significantly higher than that during the period 1978-1987. The median survival time of patients with hepatocellular carcinoma during 1988-1997 was also significantly longer than that during 1978-1987. Portal thrombus was found in about half of the patients with bone metastases. The most common site of bone metastases was the vertebra followed by the pelvis, rib and skull in that order. All bone lesions depicted by plain radiograph, computed tomography and/or magnetic resonance imaging were of the osteolytic type, and the serum levels of C-terminal telopeptide of type 1 collagen were significantly elevated in the patients with bone metastases. CONCLUSIONS: The increased incidence of bone metastasis in hepatocellular carcinoma in the decade 1988-1997 is first attributed to the prolonged survival rate of hepatocellular carcinoma patients due to recent progress in both the diagnosis and treatment of the disease. Dissemination of hepatocellular carcinoma cells to the vertebra through the portal vein-vertebral vein plexuses due to the presence of portal thrombus and/or portal hypertension may be related to a higher incidence of bone metastasis in hepatocellular carcinoma. Both an early diagnosis and timely treatment of bone metastases are thus called for in the follow-up of hepatocellular carcinoma patients.

Telomerase activity is repressed during differentiation along the hepatocytic and biliary epithelial lineages: verification on immortal cell lines from the same origin.

Recent investigations indicate that telomerase activity regulates the life span of cells by compensating for telomere shortening during DNA replication. In addition, as differentiation progresses, telomerase activity is reduced in several different cell lineages. These findings lend support to the theory that more immature cells have greater remaining proliferative capacity and longer life span. However, it has not been directly demonstrated that the differentiation along a hepatocytic or a bile ductal lineage is accompanied by reduction of telomerase activity. In this study, we present direct evidence that telomerase activity is reduced during hepatocytic and biliary epithelial differentiation by using our unique cell lines including a stem-like cell line, ETK-1. When hepatocytic differentiation was induced in ETK-1 by 5-azacytidine, telomerase activity decreased significantly. Similarly, when we compared the telomerase activity on SSP-25 and RBE cell lines from the same origin but representing different maturation stages of cholangiocarcinoma, more mature cells were found to possess significantly lower activity. These results indicate that the generally accepted relationship between telomerase activity and differentiation stage also applies in the hepatocytic and biliary epithelial lineages.

Decline of hepatitis C virus load in serum during the first 24 h after administration of interferon-beta as a predictor of the efficacy of therapy.

BACKGROUND/AIMS: Hepatitis C virus (HCV) kinetics during interferon (IFN)-alpha treatment have been evaluated recently, however, little is known about the resultant viral kinetics in IFN-beta treatment. In this study, we evaluated HCV kinetics during the first 24 h of IFN-beta treatment, and also assessed their relationship to therapeutic outcomes. METHODS: We measured HCV RNA levels at 0 and 24 h after the initiation of IFN-beta treatment, and we calculated the decay slope, viral half-life, and viral production and clearance. Then we analyzed these factors as they related to therapeutic responses with IFN-beta as well as to clinical variables, i.e. genotype, diversity of hyper variable region, and histological findings. RESULTS: Patients with sustained responses (SR) displayed steeper decay slopes of the viral load than those without SR (2.87 +/- 1.41 vs. 1.82 +/- 1.66, P = 0.031). On the other hand, the decay slope was not affected by the clinical variables. The values of viral half-life and viral production and clearance showed no significant correlation to the response and the clinical variables. CONCLUSION: This study demonstrated that the decay slope of the viral load during the first 24 h is related to the virological response to IFN-beta treatment.

Prevalence of hepatitis B or C virus infections in patients with non-Hodgkin's lymphoma.

BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) are not only hepatotropic, but also lymphotropic viruses. Recently, some reports suggested that these viruses may participate in the development of malignant lymphoproliferative disorders. METHODS: We investigated the prevalence of HCV or HBV infection in 348 patients with non-Hodgkin's lymphoma (NHL). We also compared these prevalences with those in blood donors as a control group representing the general population in our area (n= 1,513,358). Next, we evaluated the clinical and pathologic characteristics of HCV- or HBV-infected NHL cases. Non-Hodgkin's lymphoma was classified according to the Working Formulation classification. RESULTS: Thirty-seven cases (14.9%) were found to be infected with HCV or HBV; of these, 20 (8.1%) were infected with HCV, and 17 (6.9%) with HBV. In male NHL patients, the rate of HCV infection was significantly higher than in an age- and sex-matched population in the same area (P < 0.001, Mantel-Haenszel test). The rate of HBV infection also tended to be higher in the population (P = 0.0551). In contrast, in female NHL patients, the rate of HCV or HBV infection was not higher than in the general population. In HCV-infected cases, 15 cases (75%) had B-cell NHL and 16 cases (80%) were classified as being in the intermediate grade; B-cell NHL comprised 83% of all NHL cases. In HBV-infected NHL cases, 11 (65%) were of B-cell type and 10 (58%) were classified as being in the intermediate grade. CONCLUSIONS: The high prevalence of HCV or HBV infections in our study population provides epidemiologic evidence suggesting that HCV and HBV infections may be involved in the development of a subgroup of NHL in males. Our investigation also revealed that both HCV- and HBV-infected NHL patients showed certain similarities in clinical and pathologic manifestations.

Predictors of the efficacy of intravenous natural interferon-beta treatment in chronic hepatitis C.

INTRODUCTION: Several pretreatment factors have been reported to be useful in predicting patients with a high probability for a sustained response to IFN-alpha treatment, however, predictors of the efficacy of interferon-beta treatment in chronic hepatitis C have not been fully assessed. MATERIAL AND METHODS: To clarify this issue, a prospective study of 52 patients with chronic hepatitis C was conducted. Patients were treated with human natural interferon-beta by drip infusion at doses of 6 MU/day for 8 weeks. The following characteristics were compared between patients with sustained response (SR) and no response (NR): gender, age, source of HCV infection, mean pretreatment serum ALT levels, liver histology, pretreatment serum HCV-RNA levels and HCV genotype. RESULTS: Seventeen of 52 patients (32.7%) demonstrated SR. The proportion of patients with undetectable HCV-RNA levels determined by branched DNA assay (< 0.5 x 10(6) eq/ml) was higher in patients with SR than in those with NR (88.2% vs. 22.9%; p = 0.0001). Pretreatment HCV RNA levels determined by multicyclic reverse transcriptase polymerase chain reaction were lower in patients with SR than in those with NR (10(5.1 +/- 1.5) vs. 10(7.1 +/- 1.3) copies/ml; p = 0.0001). The rate of SR was higher in patients with genotype 2a or 2b than in genotype 1b (43.8% vs. 15.0%; p = 0.0382). Multivariate stepwise logistic regression analysis showed that a younger age and low pretreatment serum levels of HCV RNA were independent predictors of SR to treatment. This prospective study demonstrated that a younger age, low pretreatment viral load and HCV genotype 2a or 2b were factors influencing the SR to interferon-beta treatment, but a younger age and low pretreatment viral load were most important predictors of the efficacy of the treatment.

Changes in platelet, granulocyte, and complement activation during cardiopulmonary bypass using heparin-coated equipment.

The effects of heparin-coated cardiopulmonary bypass (CPB) systems on platelet, granulocyte, and complement activation were investigated during cardiopulmonary bypass. Thirty patients underwent coronary artery bypass surgery with a heparin-coated (Carmeda Bio-Active Surface, CBAS, Medtronic, U.S.A.) CPB system (HC group, n = 10), a heparin-coated oxygenator and uncoated CPB circuit (HO group, n = 10), or an uncoated system (UC group, n = 10). In the HO group, plasma C3a (1667 +/- 632 ng/ml) and C4a (1088 +/- 319 ng/ml) concentrations were significantly (p < 0.05) lower than in the UC group (2846 +/- 1045 ng/ml and 1494 +/- 480 ng/ml, respectively) 10 min after the administration of protamine, but there were no significant differences in the platelet or granulocyte counts. In the HC group, granulocyte elastase concentrations 120 min after the onset of CPB (365 +/- 177 micrograms/L) and 10 min after the administration of protamine (676 +/- 314 micrograms/L) were significantly (p < 0.05) lower than in the other 2 groups (820 +/- 341 and 893 +/- 303 micrograms/L and 1365 +/- 595 and 1,258 +/- 622 micrograms/L). In addition, the increase in the plasma C3a concentration in the HC group 60 (p < 0.05) and 120 min after the onset of CPB (p < 0.05) was significantly less than in the other 2 groups. The C3a and C4a concentrations 10 min after the administration of protamine were significantly (p < 0.005 and p < 0.05) less in the HC group than in the UC group. Platelet counts 10 min after the administration of protamine were significantly higher (p < 0.05) and plasma beta-thromboglobulin concentrations during CPB were significantly lower in the HC group than in the other 2 groups 5 (p < 0.05), 60, and 120 min (p < 0.005) after the onset of CPB. Postoperative blood loss during the first 12 h in the HC group was significantly (p < 0.05) less than that in the UC group. The heparin-coated oxygenator and uncoated CPB circuit reduced complement activation but demonstrated no significant effects on the platelet and granulocyte systems. However, the heparin-coated CPB circuit (with all components making blood contact) reduced platelet, granulocyte, and complement activation and significantly reduced postoperative blood loss. Therefore, heparin coating of CPB systems improves biocompatibility.

Efficacy and limitation of a left ventricular assist system in a patient with dilated cardiomyopathy accompanying multi-organ dysfunction.

A left ventricular assist system (LVAS, Toyobo CO., LTD., Japan) was used to provide life support for 190 days in a 44-year-old male patient with end-stage dilated cardiomyopathy. Before LVAS implantation, heart failure and cardiogenic shock with multi-organ dysfunction progressed despite the use of intra-aortic balloon pumping (18 days), mechanical ventilatory support (15 days), continuous veno-venous hemofiltration (two days) and intravenous administration of catecholamines. Before LVAS implantation, the patient had marked hepatic and renal dysfunction (total bilirubin 6.1, BUN 73 and serum creatinine 3.1 mg/dl). Those functions returned to normal (total bilirubin 1.2, BUN 11 and serum creatinine 0.6 mg/dl) one month after implantation. He was complicated by multiple cerebral embolisms occurring on the 9th, 57th and 175th postoperative days and died 190 days after surgery. Autopsy showed thrombi attaching to the diaphragm of the blood pump and multiple embolisms in the kidney and the spleen. By scanning electron microscopic examination, initial thrombi with attached erythrocytes were seen on the diaphragm surface without intimal lining formation. In conclusion, LVAS support can be useful for patients with end-stage heart disease complicated by multi-organ dysfunction. However, the LVAS may cause thromboembolic complications over the prolonged use.

[Surgical repair of bilateral atrioventricular valves in corrected transposition of the great arteries].

The patient was a 50-year-old man who had an SLL-type corrected transposition of the great arteries (C-TGA) accompanied by significant regurgitation of the bilateral atrioventricular valves, atrial septal defect (ASD), persistent left superior vena cava, atrial fibrillation, and ventricular extrasystoles. The systemic tricuspid valve was repaired with a 28 mm Carpentier-Edwards ring (C-E ring) for the mitral valve, while the systemic mitral valve was repaired with a 32 mm C-E ring for the tricuspid valve. Simultaneously, the associated ASD was closed. Although mild tricuspid valve regurgitation persisted postoperatively, his general condition greatly improved. The report of valve repair for both atrioventricular valves in C-TGA is rare, and only 6 such cases have been reported in the Japanese literature.

Size-reduced cryopreserved pulmonary valve allograft for an RV-PA conduit: technical modification and functional evaluation.

Cryopreserved pulmonary allografts harvested from adults at the time of kidney donation were size reduced and used in two children with pulmonary atresia and ventricular septal defect. A technical modification for the creation of size-reduced pulmonary allograft conduits is described. Postoperative ultrasonic and cineangiographic assessments revealed excellent function of the pulmonary bicuspid valved conduit with a minimal pressure gradient and essentially no regurgitation. Although the long-term fate of cryopreserved bicuspid pulmonary valve and conduit is unknown, this conduit provides excellent handling characteristics that render allograft conduits preferable to synthetic conduits. In addition, the remodeled bicuspid pulmonary allograft conduits have exhibited excellent hemodynamic characteristics and are a reasonable alternative to other types of conduits when an appropriate size allograft is not available.

Left atrial plication combined with mitral valve surgery in patients with a giant left atrium.

The benefits of performing left atrial plication during mitral valve surgery for patients with a giant left atrium were evaluated by analyzing the short- and long-term surgical results and changes in the left atrial dimension (LAD) and respiratory function of 30 patients. Of the 30 patients, 2 (7%) died of multiple organ failure on postoperative days 26 and 117, but no other deaths occurred during the mean follow-up of 5.9 +/- 2.1 years. Valve thrombosis was observed in one patient and cerebral complications with no residual deficit were observed in two patients, with a 9-year event-free rate of 87 +/- 7%. The LAD decreased significantly from 69.0 +/- 8.5 mm to 53.7 +/- 9.1 mm (P < 0.01) shortly after surgery, and this decreased was maintained even 5 years after surgery (53.3 +/- 11.4 mm). The cardiothoracic ratio decreased from 74.8 +/- 8.3% to 62.8 +/- 9.0% (P < 0.01) and the vital capacity of the lungs increased from 71.1 +/- 18.0% to 82.9 +/- 22.2% (P < 0.01). Thus, we conclude that performing left atrial plication during mitral valve surgery is safe and effective for patients with giant left atrium.

Intravenous leiomyomatosis extending into the right atrium.

Intravenous leiomyomatosis, also called benign leiomyoma, is a rare tumour that originates from a uterine myoma and spreads intravenously. A 54-year-old woman who had experienced faintness after a hysterectomy for uterine myoma 10 years earlier presented with this lesion. Ultrasonographic, computed tomographic and angiographic examination revealed a long tumour that originated in the uterus and extended into the right atrium through the right internal iliac vein and inferior vena cava. On the basis of a diagnosis of intravenous leiomyomatosis the neoplasm was extirpated by a one-stage cardiotomy and laparotomy with the aid of cardiopulmonary bypass. Retrospective histological analysis of the excised uterus revealed tumorous thrombosis in the venous cavity of the tunica muscularis. Some 26 cases in which open-heart surgery has been undertaken for intracardiac tumour thrombosis have been reported. These and the case described here are reviewed and analysed. In the present case, a full view of the tumour was obtained before surgery, and the lesion removed by a one-stage procedure using median sternotomy (cardiotomy) and laparotomy. Reports of one-stage procedures are few; only eight (30%) of 27 cases.

[Coronary artery bypass surgery-redo operation particularly in patients with a functioning ITA graft or with a patent atheromatous vein graft].

An experience with redo-CABG in 20 patients is described. The incidence of reoperation in patients undergoing primary CABG in our hospital was 1.4%, relatively low even in Japanese population. The low incidence of redo-CABG in our hospital depends on the relatively short period of follow-up of 14 years, the prevalence of interventional cardiology and the early routine use of ITA grafts. The main cause of reoperation was the failure of a SVG to the LAD in 70 to 80% of the cases. The most important and difficult decision-making in redo-CABG is the selection of surgical approaches and cardioprotective methods in patients with a patent functioning ITA graft, and the management of an atherosclerotic patent SVG. Surgical strategies in these situations are discussed.

[Allograft (homograft) valve surgery: current status in Japan].

The advance of cryopreservation techniques has dramatically increased the durability of human allograft valves, resulting in the wide-spread use of allograft valves in many western countries except Japan. The superiority of the allograft valve to other prosthetic valves has become apparent in some specific situations such as active endocarditis, small aortic root and hemorrhagic conditions. In this manuscript, we described the setting-up of the cryopreservation laboratory, quality control and the clinical use of allograft valves in our institute. The authors believe that surgeons should have an option of utilizing allograft valves in selected patients in Japan.

[Efficacy of GRF (gelatin-resorcin-formalin) glue on surgery for type A aortic dissection].

The tissue biological adhesive GRF glue has been used in our department to have dissected aortic layers adhered and to reinforce the dissected aortic stumps during surgery for aortic dissection. From May 1992 to August 1993, 12 patients were operated for type A aortic dissection; 4 patients with acute dissection and 8 patients with chronic dissection. There were 5 men and 7 women whose ages ranged from 51 to 69 years with an average of 60.6 years. Replacement of the ascending aorta alone was performed for 6 patients. Replacement of both the ascending aorta and transverse arch was carried out for 4 patients, and replacement of the ascending aorta, transverse arch and the descending aorta was accomplished in 1 patient. Primary repair was performed for 1 patient with intraoperative acute dissection that occurred during surgery for mitral valve. There were no operative or hospital deaths. Preoperative aortic regurgitation was present in 5 patients. Following gluing the aortic root dissection, aortic regurgitation disappeared in all patients confirmed by postoperative aortograms. The use of GRF glue significantly reduced the average amount of intraoperative bleeding from 2893 ml to 1169 ml and also significantly reduced the use of Teflon felt strips for the proximal anastomosis. We believe that use of GRF glue can improve the surgical outcome for acute and chronic aortic dissection.

[Myocardial protection during multiple coronary artery bypass grafting--a comparison of antegrade and combined antegrade-retrograde cardioplegia].

We compared the effectiveness of antegrade cardioplegia (A group, 100 cases) and combined antegrade-retrograde cardioplegia (A + R group, 66 cases) on myocardial protection in patients undergoing coronary artery bypass grafting for more than 3 vessels. The two groups were similar in patients' age, the extent of coronary artery diseases and preoperative risk factors, cardiac output and ejection fractions. The mean number of grafts was 3.3 in A group and 3.6 in A + R group (p < 0.05). The mean number of ITA grafts used was 1.2 in A group and 1.4 in A + R group (p < 0.05). Aortic cross-clamp time was 114 minutes in A group and 138 minutes in A + group (p < 0.01). The serum CK-MB concentration on postoperative day 1 was 38 IU/L in A group and 25 IU/L in A + R group (p < 0.05). The left ventricular stroke work index 3 hours after reperfusion was 33 gm min/m2 in A group and 43 gm min/m2 in A + R group (p < 0.05). The maximum dose of catecholamine required was similar in two groups. Intra-aortic balloon pump was used in 11 patients (11%) in A group and in 2 patients (3.6%) in A + R group (p < 0.05). We conclude that the combined method of intermittent antegrade and continuous retrograde perfusion of cardioplegic solution provides better myocardial protection than intermittent antegrade cardioplegia alone for multivessel coronary artery bypass surgery.

[Reoperative coronary artery bypass grafting in patients with patent internal thoracic artery grafts].

The incidence of reoperative coronary artery bypass grafting (reCABG) is recently increasing. However, there has been no report of reCABG in patients with patent internal thoracic artery (ITA) grafts in Japan. We performed reCABG in three such patients with patent ITA grafts. The first patient was a 49-year-old male who had undergone a 2 CABG (left ITA-LAD, SVG-DX 1), 8 years and 7 months prior to the 2nd operation, he received a re 2 CABG (GEA-RCA, RITA-SVG-DX 1) with a patent prior LITA-LAD graft. The second patient was a 65-year-old female who had undergone CABG in which the LITA had been erroneously anastomosed to the DX 2 in place of the LAD. Three year later, the reCABG (RITA-LAD) was performed with a patent prior LITA-DX 2 graft. The third patient was a 51-year-old male who had undergone 3-CABG (RITA-LAD, LITA-DX, SVG-RCA). The RITA was closed most probably due to technical errors and his angina recurred. Tree year after the first operation, he received a re 3-CABG (GEA-LAD, SVG-RCA, SVG-OM) with a patent prior LITA-DX graft. In each patient, PTCA had been tried twice, twice and once prior to redo operations. Their post-redo courses were uneventful, and they were discharged free from angina. In such cases it is important to manage with care the patent ITA grafts at reoperation. Biplane ITA angiograms are quite helpful to evaluate the course of grafts in relation to the sternum. To cover the ITA graft with a GORE-TEX membrane may also be useful for easy identification of the graft at redo operations.