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To improve the data accuracy of the neutron emission spectra of the natLi(d,xn) reaction that will be used as the neutron source in the International Fusion Materials Irradiation Facility, the auth...

Neutron emission spectra and production rates of radioactive nuclide 7Be in the (d, n) reactions on thick lithium and 9Be targets have been measured for 25 MeV deuterons at the Tohoku University AVF cyclotron (K=110) facility to provide basic data for the design of the intense neutron source, International Fusion Reactor Material Irradiation Test Facility (IFMIF). Neutron spectra were measured with the time-of-flight method at ten laboratory angles between 0° and 90° by using a beam swinger system. Data were obtained down to ~1 MeV from the highest energy, using a two-gain NE213 detector system. Induced radioactivity of 7Be was measured by detecting the 478 keV γ-rays from 7Be with a pure Ge detector. The experimental results of neutron spectra revealed clearly the entire shape of the neutron emission spectrum and the angular dependence including so called “high energy tail” extending up to ~40 MeV. The present data at 0° are in reasonable agreement with corresponding value by Lone et al. at 23 MeV above ...

Energy-angular differential thick-target neutron yields were measured at 50 MeV for the C, Al, Ta, W(p,n) reactions with a time-of-flight (TOF) method using the Tohoku University K = 110-MeV cyclot...

To improve the data accuracy of the neutron emission spectrum of the 7 Li(d,n) reaction and the radioactivity ( 7 Be, 3 H, etc.) accumulated in the 7 Li target in IFMIF, we have measured the neutron emission spectrum and the radioactivity of Be induced in the lithium target for 25 MeV deuterons at the Tohoku University AVF cyclotron (K = 110) facility. Neutron spectra were measured with the time-of-flight (TOF) method at four laboratory angles by using a beam swinger system and a well collimated TOF channel. Induced radioactivity was measured by detecting the gamma-rays from Be with a pure Ge detector. Experimental results are compared with other experimental data. The present result of neutron emission spectra are in qualitative agreement with other experimental data but that of 7 Be production was much larger than expected by the recent codes. Measurement will be extended to several incident energies up to 40 MeV.

A position-sensitive proton recoil telescope (PSPRT) has been developed as a new-type neutron spectrometer to achieve high sensitivity and high energy resolution concurrently. The PSPRT consists of a radiator-detector and a proton detector, which employs a set of a position-sensitive photomultiplier (PS-PMT) and a scintillator. Neutron energy spectrum is derived by using only ‘‘good events’’ which are events for forward angles around 01; and correcting for the proton energy loss in the radiator detector. The expected performance of PSPRT was proved experimentally. r 2002 Elsevier Science B.V. All rights reserved.

Double differential (n,xp), (n,xd), (n,xt) and (n,xα) cross sections of oxygen and nitrogen were measured for 75 MeV incident neutrons at 25°, 65° and 125° angles using a specially designed spectrometer. The spectrometer has three counter telescope consisting of a low pressure gas proportional counter, a thin SSD and a BaF2 scintillator. The energy dependence of the BaF2 was calibrated with direct proton, deuteron and helium beams. The results were compared with the LA-150 data library. The library represents the experimental results of proton, triton and α-particle generally well, but shows the marked difference in the high energy part of deuteron one.

A brief review on recently developed non-invasive techniques for gas–liquid and gas–liquid–solid systems is presented first. The ultrasonic computed tomography (UCT) developed for measuring the time-averaged cross-sectional distributions of gas and solid holdups in a slurry bubble column is then described. The ultrasonic tomography is a coupling of the earlier developed transmission-mode ultrasonic technique with two-parameter sensing (the energy attenuation and the velocity change) and a tomographic reconstruction technique using a filtered back-projection algorithm. The ultrasonic tomographic technique provides a method capable of measuring the cross-sectional distributions of the gas and the solid concentrations simultaneously in a gas–liquid–solid system. The technique has been applied to a slurry bubble column to get the general structures of the distributions of gas bubbles and solid particles in the column. The macroscopic flow scheme of the slurry bubble column is illustrated based on the structure of the gas holdup distribution. And the solid particle concentrating mechanism in the slurry bubble column along with the effects of gas velocity, solid loading and particle diameter is discussed.

The problem of aging in a large population of coupled oscillators has been put forth recently, which means to study how its behavior changes by increasing the ratio of inactivated elements, i.e. damped oscillators. So far a number of interesting results such as aging transition have been found for some idealized systems chosen as a first step. Here we briefly describe our recent results about more general systems which have either nonscalar diffusive coupling or frequency distribution.

Coke formation and ageing have been studied in the conversion of light naphtha into aromatics over galloalumino-silicate (ZSM-5 type zeolite), the acid density of which was controlled by changing the pretreatment temperature. It was found that the catalyst life depended on the pre-treatment temperature of the zeolite and had its maximum at 1053 K. Furthermore, it was found that the acid density of the zeolite decreased, and non-framework gallium species increased, with increasing pretreatment temperature. Thus, it is suggested that the trends in catalyst life result from: (1) the appropriate combination of the dehydrogenation activity and the acidic activity, (2) the rapid decrease of coke formation with increasing pretreatment temperature, and (3) pore blockage by coke formation inside the crystals.

A 63-year-old man was diagnosed as having grade IV mitral regurgitation (MR). Intraoperative examination revealed perforation (13x7 mm) of the anterior mitral leaflet (AML) and prolapse of the posterior mitral leaflet (PML). The prolapsing part of the PML was resected as a rectangle and the AML perforation was covered with this resected PML patch. A Carpentier-Edwards rigid ring (30 mm) was used to secure the mitral valve annulus after suturing the PML. The patient had an uneventful course after surgery and postoperative echocardiography showed no regurgitation.

Differential thick target neutron yields (TTY) for natFe, natCu(p,xn) reactions were measured for 35, 50 and 70 MeV incident energy at several laboratory angles between 0‐ and 110‐deg. using the time‐of‐flight method with the Tohoku Univ. AVF cyclotron and a beam‐swinger system. We determined neutron energy spectra from ∼ 0.6 MeV to the highest secondary neutron energy. The experimental results were compared with the LA150 data library.

1. The consecutive pre- and post-1994 eras have demonstrated improved survival for all age groups. This is linked to improved preservation methods, surgical technique and immunosuppression agents. 2. The use of marginal donor hearts for Status I and alternate elderly patients has followed the model of matching donor and recipient risk without affecting patient outcome and minimized the use of implantable assist devices. 3. A donor history of systemic gram-negative infection, hypertension, or traumatic intracranial bleeds was an important marker for risk. Younger age and shorter ischemia time could compensate for other hazards. 4. Heart transplantation in carefully selected elderly recipients yielded clinical results similar to those of younger patients with less rejection. 5. An adult alternate recipient list proved useful to prevent diversion of standard donors away from younger recipients. 6. Retransplantation for TCAD is acceptable but much less satisfactory for acute graft failure. 7. Trends show an increase in the use of implantable devices; refinement in technology for mechanical assist and replacement is forthcoming.

A rare case of pulmonary Nocardia otitidiscaviarum (N. otitidiscaviarum) was encountered in an immunocompetent host. A 74-year-old man was admitted to our hospital with a high fever and a productive cough. His chest radiograph and CT scan revealed infiltrative shadows in the right middle and lower lung fields. Although several antibiotics (third-generation cephalosporin, minocycline, imipenem) were administered, the fever and cough persisted, and C-reactive protein remained elevated. Repeated sputum cultures showed normal flora, so a transbronchial lung biopsy and bronchoalveolar lavage (BAL) were performed bronchoscopically at the right S5. The BAL fluid contained acid-fast, branching filamentous structures. The microorganism was identified as N. otitidiscaviarum by the Research Center for Pathogenic Fungi and Microbial Toxicoses (Chiba University). Trimethoprim-sulfamethoxazole was therefore administered, but the fever continued to rise daily, and C-reactive protein remained elevated. This isolated N. otitidiscaviarum showed resistance to multiple antimicrobial agents in vitro when examined by the disk diffusion method, and so, on the basis of the antibiogram, the patient was treated with clarithromycin (oral, 600 mg/day) plus amikacin (400 mg/day), which proved successful. Testing for pulmonary nocardiosis should be added to the differential diagnosis procedures for refractory pneumonia as an opportunistic infection and for community-acquired pneumonia.

To investigate the causes of hepatic dysfunction after extensive resection of the liver together with pancreatectomy, rats were subjected to sham operation, to 68% hepatectomy alone, to 90% pancreatectomy alone, or to 68% hepatectomy combined with 90% pancreatectomy (hepatopancreatectomy). Solutions of 5% or 20% glucose were infused post-operatively for 48 h at a constant rate (250 ml/kg body weight/day) under fasting conditions. To improve the survival rates of pancreatectomized and hepatopancreatectomized rats given 20% glucose, it was necessary to use insulin. In hepatopancreatectomized rats, infusion of 20% glucose with insulin (1 U/5 g glucose) induced prominent hepatocyte vacuolar degeneration and mitochondrial swelling, associated with reduced hepatic protein content. The severity of histological changes was proportional to the insulin dose and the activity of hepatic glucokinase, a key glycolytic enzyme. These histological changes were observed in pancreatectomized rats albeit in a milder form, but not in sham-operated or hepatectomized rats given 20% glucose nor in any rats given 5% glucose. Our results suggest that hepatopancreatectomy followed post-operatively by a high glucose load and exogenously administered insulin enhances the development of hepatocyte swelling.

To prevent the development of liver failure after simultaneous massive resection of the liver and pancreas, we examined whether fat emulsion could be used as an energy source during postoperative transfusion. Using rats, the following four groups were prepared: the simple laparotomy group (S group), 68% hepatectomy group (H group), 90% pancreatectomy group (P group) and 68% hepatectomy + 90% pancreatectomy group (HP group). A constant total calorie level and transfusion dose were used. Three kinds of transfusions with different glucose-to-fat emulsion caloric ratios, that is: 75% fat emulsion (of the total calorie level) + 25% glucose (75L), 50% fat emulsion + 50% glucose (50L) and 25% fat emulsion + 75% glucose + 1 unit/5 g glucose of insulin (25L), were continuously administered for 48 hours, and the effects of these transfusions on the survival rate and liver were examined. After 75L administration, survival rates in the H group and HP group were significantly lower than those in the S group and P group. After administration of 50L, survival rates did not significantly differ among the four groups. After 25L administration, the survival rate in the HP group was significantly lower than that in other groups. In the HP group, the survival rate after 50L administration was the highest. However, necrosis was observed in a portion of the hepatic lobule, while the blood aspartate aminotransferase (AST) level was increased. After 25L administration, hepatocellular mitochondrial swelling and degeneration were noted in the HP group; furthermore, the blood total protein level was decreased. These results showed that the post-operative administration of fat emulsion at a percentage of 50% of the total calorie level caused partial hepatocellular necrosis in the HP group, but improved the survival rate.

We describe a patient who experienced a recurrence of idiopathic iridocyclitis on day 12 after autologous peripheral blood stem-cell transplantation (auto-PBSCT) followed by G-CSF administration for acute lymphoblastic leukemia (ALL). Autologous SCT has been reported to be effective and safe in achieving dose intensification of chemotherapeutic drugs for the treatment of hematopoietic malignancies, but its therapeutic effect on autoimmune diseases is not definite. The findings from the present case suggest that auto-PBSCT followed by G-CSF administration for patients with a history of some kind of autoimmune disorders may induce exacerbation or recurrence of its symptoms after hematopoietic recovery.

In the last decade, the number of patients undergoing heart transplant has steadily increased as a result of expanding indications for this procedure. The limitation on the number of transplants performed has been the number of donor organs available. At UCLA, 900 heart transplant procedures have been performed from 1984-1998. Since 1991, the percent of patients free from rejection and infection in the first year after transplant was 70% and 73%, respectively. Actuarial one-, 3-, and 5-year survival rates are 84%, 76%, and 72%, respectively. Survival of patients aged 60 years and over (n = 105) was comparable to that of patients under age 60. We have been pursuing corticosteroid-free immunosuppression, which has led to a decrease in infection complications. Our work with pravastatin early after transplantation has led to a decrease in clinically severe rejection episodes, which has translated into improved survival. Pravastatin also appears to decrease the development of transplant coronary artery disease and appears to have an adjunct immunosuppressive effect in our heart transplant patients on CsA-based immunosuppression. We have also demonstrated benefit of cardiac rehabilitation early after transplant which should therefore be considered as standard postoperative care. Finally, we have participated and led the multicenter mycophenolate study in demonstrating this drug's effectiveness in improved outcomes in primary heart transplant recipients. Future studies include the use of Rapamycin and interleukin-2 receptor blockers which have been demonstrated in kidney transplantation to significantly reduce rejection. Our program is committed to seek better ways to improve outcome and the quality of life of our heart transplant patients.

We examined the relationship between the expression of mutant p53 and Ki-67 antigens in urinary bladder transitional cell carcinoma and the pathological and clinical findings. Tissues were obtained from 28 patients with bladder carcinoma who underwent total or partial cystectomy. An ABC immunostaining method and two primary antibodies (DO-7 and MIB-1 antibodies) were used. The percentages of p53 and Ki-67 antigen-positive cells to the total number of cells were regarded as the p53 and Ki-67 labeling indices (LI) respectively. There were no statistically significant correlations between p53 LI and the histological grade or stage, although p53 LI increased slightly in the high grade and high stage group. There was a statistically significant correlation between Ki-67 LI and the histological grade and stage (p0.05). The correlation between p53 LI and Ki-67 LI was linear. Some cases had a p53 LI below the mean even though the Ki-67 LI was higher. The clinical course was characteristic of superficial bladder carcinoma initially, but progressed to invasive bladder carcinoma over the next several years. These results suggest that even cases initially diagnosed as superficial bladder carcinoma with a low p53 LI may progress to invasive bladder carcinoma in subsequent years. Therefore, it is important that the patient be followed-up.

In patients who have received a cardiac transplant, the denervated donor heart responds abnormally to exercise and exercise tolerance is reduced. The role of physical exercise in the treatment of patients who have undergone cardiac transplantation has not been determined. We assessed the effects of training on the capacity for exercise early after cardiac transplantation.Twenty-seven patients who were discharged within two weeks after receiving a heart transplant were randomly assigned to participate in a six-month structured cardiac-rehabilitation program (exercise group, 14 patients) or to undergo unstructured therapy at home (control group, 13 patients). Each patient in the exercise group underwent an individualized program of muscular-strength and aerobic training under the guidance of a physical therapist, whereas control patients received no formal exercise training. Cardiopulmonary stress testing was performed at base line (within one month after heart transplantation) and six months later.As compared with the control group, the exercise group had significantly greater increases in peak oxygen consumption (mean increase, 4.4 ml per kilogram of body weight per minute [49 percent] vs. 1.9 ml per kilogram per minute [18 percent]; P=0.01) and workload (mean increase, 35 W [59 percent] vs. 12 W [18 percent]; P=0.01) and a greater reduction in the ventilatory equivalent for carbon dioxide (mean decrease, 13 [20 percent] vs. 6 [11 percent]; P=0.02). The mean dose of prednisone, the number of patients taking antihypertensive medications, the average number of episodes of rejection and of infection during the study period, and weight gain did not differ significantly between the groups.When initiated early after cardiac transplantation, exercise training increases the capacity for physical work.

Previously, we reported a case of complete response (CR) of metastatic renal cell carcinoma with inhalant interferon-gamma. This inhalant therapy was considered effective against metastatic lung hilar tumors. On the other hand, metastatic tumors of the peripheral lung field tumor did not respond to the inhalation therapy. We report, a case of metastatic renal cell carcinoma in peripheral lungs showing complete response to continuous subcutaneous administration of interferon alpha and gamma. A 53-year-old woman was admitted to our hospital because of a large palpable mass in the left upper quadrant in March, 1994. Computerized tomographic (CT) scan disclosed a huge renal tumor. To reduce the tumor size, transarterial embolization, and subcutaneous administration of interferon-gamma were performed. In April 1994, the tumor was completely excised. In the post-operative course, multiple metastases were recognized in the lower peripheral lung field, subcutaneous administration of IFN-gamma and inhalation of IFN-gamma were begun, but the tumor size increased in October 1994. She underwent continuous subcutaneous administration of IFN-alpha and gamma. Three months later, the lung tumor disappeared. She has remained tumor-free as of October 1995. We concluded that this therapy may be effective against metastatic renal cell carcinoma in the lungs.

We studied the relationship between clinical stage and tumor infiltrating lymphocytes (TIL) in 26 cases of renal cell carcinoma. In 10 patients, interferon-gamma (IFN-gamma) was administered preoperatively (administration group); 5 patients had low stage (Robsonor = I), and the remaining 5 patients had high stage (Robsonor = II) tumors. The other 16 patients underwent nephrectomy alone without preoperative IFN administration (control group); 11 patients had low stage, and the remaining 5 patients had high stage tumors. Immunohistochemical studies of tumor infiltrating lymphocytes in renal cell carcinoma showed a significantly high incidence of CD3, CD8, CD11b and ICAM-1 in the administration group, while CD4, LFA-1 and Ber-MAC3 were increased without significance (p0.05). Concerning clinical stage (Robson), a significant increase in CD3, CD8, CD11b and ICAM-1 was observed in the patients with high-stage tumors in the administration group compared to those in the control group (p0.05). This suggested that TIL could be changed by preoperative administration of IFN-gamma.

We reviewed 17 cases of patients with interrupted hepatic arterial blood flow to determine the effect of such an interruption.In 17 patients undergoing radical resection of pancreaticobiliary carcinoma with simultaneous hepatic artery excision (n=15) or intraoperative hepatic artery obstruction (n=2), morbidity and mortality were reviewed. Nine hepatic artery anastomoses were performed in 7 of these patients, and postoperative patency was obtained for 5 anastomoses. The patients were classified into the following groups: group I was 6 patients with complete interruption of hepatic arterial flow to the whole liver or the remnant liver, group II was 6 patients with interruption of hepatic arterial flow to a lobe of the liver, and group III was 5 patients with preservation of hepatic arterial flow.Disruption of the bilioenteric anastomosis occurred in all 6 patients from group I versus none of those in groups II and III (p0.05). Liver abscess and liver failure developed in 1 patient each from group I, but the mortality rate in this group was not high.Hepatic artery reconstruction in patients with complete interruption of hepatic arterial blood flow appears to be necessary to avoid ischemic breakdown of the bilioenteric anastomosis.

To avoid the long-term side effects of corticosteroids, corticosteroid-free immunosuppression has been introduced immediately or late (more than 6 months) after heart transplantation. Late corticosteroid weaning may have a higher success rate as patients are selected on the basis of rejection history. Previous reports of HLA-DR mismatching and the long-term metabolic benefits with respect to corticosteroid weaning have been equivocal.One hundred and one eligible heart transplant recipients receiving triple-drug immunosuppression 6 months from heart transplantation were weaned from prednisone by decreasing the daily prednisone dose by 1 mg each month. Moderate rejection episodes were recorded and after conclusion of the study, HLA-DR mismatching of recipient and donor was reviewed. Serum cholesterol level, body weight, and number of patients receiving blood pressure medications were recorded before and 1 year after corticosteroid weaning.Successful weaning from corticosteroids was achieved in 82% of patients. Of 31 patients with zero or one HLA-DR mismatch, 30 (97%) were successfully weaned. For those patients more than 1 year after discontinuation of corticosteroids, 67 had more weight loss and a lower serum cholesterol level than 15 patients who were unsuccessful at corticosteroid weaning and dependent on corticosteroids.Heart transplant recipients can safely be weaned from corticosteroids late after heart transplantation with zero or one HLA-DR mismatch conferring a higher success rate. The long-term metabolic benefits of corticosteroid weaning include a reduction in weight and serum cholesterol.

In the last decade, the number of patients undergoing heart transplantation has steadily increased as a result of expanding indications for cardiac transplantation. The limitation on the number of transplants performed has been the number of donor organs available. At UCLA, 511 heart transplant procedures were performed from 1984-1994. The mean number of rejection episodes and infections per patient in the first year after transplant was 1.1+/-1.3 and 1.0+/-1.2, respectively. Actuarial one-, 3-, and 5-year survival rates were 84%, 77% and 73%, respectively. Survival of patients age 60 years and over (n=105) was comparable to that of patients under age 60. Despite transplanting more critically ill patients (Status 1) and having longer cold ischemic times, outcomes have been improving. We have been pursuing corticosteroid-free immunosuppression, which no doubt has led to the decrease in infection complications. Furthermore, our work with pravastatin early after transplantation has led to a decrease in clinically severe rejection episodes which has translated into improved survival. Pravastatin also appeared to decrease the development of transplant coronary artery disease and appeared to have an adjunct immunosuppressive effect in our heart transplant patients on CsA-based immunosuppression. Future studies will include the use of mycophenolate mofetil which has properties against B-lymphocytes in addition to T-lymphocytes to block both humoral and cellular rejection. Our program continues to seek better ways to improve survival and the quality of life of our patient population.

Immunological effect of recombinant interferon gamma (IFN-gamma) was studied in 18 cases of renal cell carcinoma. Sixteen of them were administered IFN-gamma as post-operative adjuvant therapy. Two of them were administered IFN-gamma for metastatic renal cell carcinoma. All of them were followed for at least 1 year. We divided the patients into two groups. One group subcutaneously received IFN-gamma every other day for 16 days, then 4 weeks later every week for one year (group A), and the other group, received alternate subcutaneous IFN-gamma every other day for 16 days and every week for 4 weeks (group B). For immunological testing, peripheral blood lymphocytes were obtained before treatment on day 1, 2 weeks later, 6 months later and 12 months later. The cells were tested for natural killer activity (NK), antibody dependent cellular cytotoxicity (ADCC), positive lymphocytes of CD3, CD4, CD8 and CD11b. Both ADCC and NK activity were increased after therapy, especially in group B. CD3, CD4 and CD8 positive lymphocytes were increased by means of IFN-gamma. On the other hand, CD11b-positive lymphocytes could not be elicited in group B. Tumor regression was observed in 2 cases of metastatic renal cell carcinomas. When clinical responses were observed, both ADCC and NK were elicited as compared with the pretreatment values. Our findings indicated that ADCC and NK could be elicited in group B.

Recently, we applied inhalation of recombinant interferon (IFN)-gamma, to 4 patients with pulmonary metastatic tumor (3 with renal cell carcinoma and 1 with renal pelvic tumor). Of the patients with renal cell carcinoma 2 had received previous nephrectomy, 1 patient had received embolization alone, 1 subcutaneous IFN-gamma in 1, and 1 systematic chemotherapy. All 4 patients inhaled 1 x 10(6) JR U-2 x 10(6) JR U recombinant IFN-gamma 3 times per day. Additionally, all metastatic renal cell carcinomas received subcutaneous injection of IFN-gamma. One patient with renal cell carcinoma achieved a complete response after inhalation therapy and 2 patients did not respond (NC: 1, PD: 1). A case of metastatic renal pelvic tumor did not respond. Immunohistochemical staining with antibody to Ber-MAC3 (stimulated macrophage) of this case revealed positive cells within the transitional cell carcinoma. According to these results, inhalation of IFN-gamma appears to be applicable as one treatment for pulmonary metastatic tumor of renal cell carcinoma.

Preoperative embolization of the right portal vein branch before extended right hepatectomy for hepatocellular carcinoma or hilar cholangiocarcinoma has been recommended for the prevention of postoperative liver failure. Percutaneous transhepatic insertion into the intrahepatic portal vein and insertion into the ileocolic vein at open laparotomy are used for inserting a catheter introducer into the portal vein. We devised a new technique for the laparoscopic insertion of a catheter introducer into the ileocolic vein and used it for right portal embolization in three patients. Measurement of hepatic volume by computed tomography 3 weeks after right portal embolization showed a 28.6 to 66.0% increase in the volume of the predicted remnant liver. This minimally invasive procedure has three advantages: reduction of postoperative pain, avoidance of hepatic injury, and the opportunity for a laparoscopic observation of the liver and the intra-abdominal organs before right portal embolization and hepatectomy.

The immunological effect of interferon-gamma (IFN-gamma) was investigated in 18 cases of renal cell carcinoma before and after the operation. In 6 patients, IFN-gamma was administered preoperatively for 21 days (administration group), while 12 patients underwent nephrectomy alone without preoperative treatment (control group). The peripheral immunological effects were measured at before and 12 days after the operation in the administration group and at 11 days in the control group. In the administration group, a marked increase was noted in the test of antibody dependent cell-mediated cytotoxicity (ADCC) activity and natural killer (NK) activity, and slight increase in CD4/8 and CD11b. In low stage cases, no appreciable effect was obtained by the administration of IFN-gamma. However, in high stage cases, IFN-gamma tended to increase the value of ADCC activity and NK activity. Immunohistochemical studies of tumor infiltrating lymphocytes in renal cell carcinoma showed a high incidence of CD8 and CD11b in the administration group. Moreover, the presence of CD8 was higher than that of CD4 in the administration group in contrast to the results of the peripheral blood analysis.

OKT3 is often used routinely for induction immunotherapy or selectively to avoid acute cyclosporine nephrotoxicity in heart transplant recipients at high risk for immediate postoperative kidney failure. It has not been shown in a randomized trial to be useful in patients at low risk for early kidney failure. We randomized 30 patients with a serum creatinine level of less than 1.4 mg/dl before heart transplantation to be treated with triple-drug immunotherapy with cyclosporine, which was started before surgery, (group 1) or to be treated with OKT3 for 4 to 6 days after surgery with oral cyclosporine, which was started between days 2 and 4, after renal function had stabilized (group 2). Follow-up for 6 months revealed no significant differences in the total number of rejection episodes, total number of infections, or in the serum creatinine level. Four patients in group 1 and five patients in group 2 have had no rejection. OKT3 showed a trend to delay time to first rejection (p = 0.10), as has been reported for the 14-day induction course of OKT3. A short course of OKT3 induction in heart transplant recipients at low risk for immediate postoperative kidney failure prolongs the time to first rejection for most patients but does not appear to reduce the total incidence of rejection in the first 6 months after heart transplantation.

Steroid-free maintenance immunosuppression is frequently initiated early after transplantation. There is concern that later steroid withdrawal, particularly after previous rejection, may cause more serious rejection. To determine the safety of gradual weaning from steroid maintenance, 68 patients (more than 6 months from transplantation) were weaned from 5 mg/day by decreasing the daily dose by 1 mg each month, with monthly biopsies. Asymptomatic moderate rejection occurred in 13 compliant patients. Rejection with hemodynamic compromise occurred in two patients with documented medication noncompliance, who were excluded from further analysis. Successful weaning without rejection was possible in 53 of 66 (80%) compliant patients. Compared with the rejection group, there were no differences in the number of women, previous rejection episodes, or time from transplantation. All moderate rejection episodes responded to oral steroid pulse therapy. The two serious rejections after noncompliance responded to OKT3. There were no symptoms from steroid withdrawal that required taper alteration. We conclude that regardless of previous rejection episodes, weaning from maintenance steroids can be attempted safely if guided by frequent biopsy procedures, but compliance is critical.

We have studied about the treatment of aggregated galloalumino-silicate (ZSM-5 type zeolite) with KOH solution. The suitable KOH treatment of TPA-Si-Al-Ga is found to be a very valid preparation to disperse the aggregated zeolites into small particles and expose the external surface of unit crystals without changing other properties. Furthermore, the suitable KOH teratment of TPA-Si-Al-Ga increased the catalyst life in aromatization of n-hexane.

Hypercholesterolemia occurs in many cardiac transplant patients and may aggravate graft coronary arteriopathy as well as contributing to peripheral vascular disease. Lovastatin, which inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase, in doses of 40-80 mg/day effectively lowers cholesterol in the general cardiac population but has been associated with rhabdomyolysis in cardiac transplant recipients. To determine whether lower doses of lovastatin would be effective and safe for lowering cholesterol after cardiac transplantation, 44 patients with blood cholesterol greater than 200 mg/dl at least 6 months after cardiac transplantation received 10-20 mg lovastatin daily. In addition, lovastatin enzyme inhibitor level was assayed in six patients to determine whether metabolism of the drug was abnormal. Lovastatin decreased total cholesterol by 28% from 282 +/- 54 to 208 +/- 62 mg/dl (p less than 0.005), primarily because of reduction in the low-density lipoprotein fractions, and was well-tolerated without any symptoms or abnormal creatine phosphokinase levels in 43 of 44 patients. One patient developed rhabdomyolysis and reversible renal failure when lovastatin was increased to 40 mg daily. Enzyme inhibitor levels in the six transplant patients were 4.2-7.8 times higher than those measured in normal volunteers. Low-dose lovastatin effectively lowers cholesterol in patients after transplantation, but metabolism is altered, perhaps by cyclosporine. Monitoring of enzyme inhibitor levels may be required to allow safe administration of this drug to cardiac transplant recipients.

The international experience has documented the therapeutic value of cardiac transplantation in the management of carefully selected patients with endstage heart disease. The UCLA program's experience over the years 1984 to 1990 mirrors these results, establishing heart transplantation as an accepted form of therapy that offers extended survival and improved quality of life compared to alternative means of treatment. Criteria of eligibility for recipient candidates have become less restrictive, most notably the expansion of age limits to include increasingly older patients. Seventy-three patients over 55 years of age underwent heart transplantation in this series, with actuarial survival results comparable to that achieved in adult patients 55 years of age and under (68.5% vs 74.7% at 4 years, respectively). Twenty-one children between the ages of 7 months and 17 years have undergone cardiac transplantation at UCLA with survival results comparable to that of our adult population (74.3% vs 76.5% actuarial survival at 3 years, respectively). Continued efforts aimed at the development of improved means of immunosuppression as well as better methods for the detection of rejection are needed if these results are to be significantly improved.

Embryonic stem cells (ESCs) of nonhuman primates are important for research into human gametogenesis, because of similarities between the embryos and fetuses of nonhuman primates and those of humans. Recently, the formation of germ cells from mouse ESCs in vitro has been reported. In this study, we established cynomolgus monkey ES (cyES) cell lines and attempted to induce their differentiation into germ cells in order to obtain further information on the development of primate germ cells by observing the transcripts of some markers reported as specific for germ cells. CyES cell lines were established using blastocysts produced by intracytoplasmic sperm injection (ICSI). For inducing superovulation, females were treated with 25 IU kg-1 pregnant mare serum gonadotropin once a day for 9 days, followed by 400 IU kg-1 hCG. Oocytes were collected at 40 h after injection of hCG. After sperm injection, embryos were cultured in mCMRL medium to the blastocyst stage. For cyES cell establishment, inner cell masses (ICMs) were isolated by immunosurgery. The ESC colonies developed at about 10 days after ICM plating, and 3 cell lines were successfully established (3/11; 27.3%). All cell lines expressed Oct3/4, SSEA-4, and ALP activity. These ESCs formed teratomas containing 3 different embryonic layers when injected into SCID mice. And the cells could be passaged over 50 times without losing their original properties. To observe in vitro gametogenesis, we attempted to induce differentiation by non-adherent conditions. When cyES cells differentiated spontaneously, the aggregated structures (i.e. embryoid bodies; EBs) accumulated vasa, the expression of which is restricted to germ cells, and some meiotic markers such as dmc1 and sycp1 that exist only in synaptonemal complexes in meiosis. The existence of these markers was also confirmed by immunocytochemistry on cryosections. Interestingly, these products expressed oct4 and nanog again at Day 16, though the expression of both genes diminished at once with onset of differentiation. In vivo, it is reported that vasa, oct4, and nanog are expressed in migrating PGCs, posibly throughout the development of germ cells into spermatocytes/oocytes. Given the results obtained with the meiotic markers, it is possible that developing germ cells such as PGCs or gonocytes could be formed in cynomolgus EBs as in previous cases with mouse or human EBs. These results demonstrate that cyES cells might contribute to putative germ cells in vitro by differentiating into EBs and could be used as a model for studying mechanisms of germ cell development. This study was supported by a Grant-in-Aid for the 21st Century COE Program of the Japan Mext and by a grant for the Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technology Excellence of the JST.

Interspecies nuclear transfer has been used as an invaluable tool for studying nucleus-cytoplasm interactions and it may also be used for rescuing endangered species whose oocytes are difficult to obtain. In this study, we investigated interaction of the cynomolgus monkey cell as a nuclear donor with the rabbit oocyte as a host cytoplasm. Whole cynomolgus fibroblast cells were injected into the rabbit enucleated oocytes (cynomolgus-rabbit cloned embryos) and cultured in TCM-199 and RPMI 1640 culture media. Rabbit-rabbit cloned embryos we used as control in this study. Karyotype analyses confirmed that genetic material of blastocysts was derived from the cynomolgus donor cells at blastocyst stage. Mitochondrial constitution analysis of the cynomolgus-rabbit cloned embryos indicated that mitochondria from both donor cells and enucleated oocytes coexisted. After culture for 168 h post-nuclear transfer, all cynomolgus-rabbit cloned embryos in TCM-199 were arrested at the 8-cell stage, but some of them developed to the blastocyst stage in RPMI 1640 (11/59, 18.6%). In this experiment, the nutrition requirement in vitro and the cleavage rate at each 24 h were examined. When TCM-199 was supplemented with lactate, some of these embryos developed to the blastocyst stage (15.3%, 2/13). This means that cynomolgus-rabbit cloned embryos might be controlled by the donor nucleus even in these early developmental stages. However, the timing of cleavage of cynomolgus-rabbit cloned embryos is very similar to that of the rabbit-rabbit cloned embryos. Time of cleavage may depend on the protein accumulated in the cytoplasm. In the prolonged culture of reconstructed embryos on feeder cells, adhesion cells were observed. These cells are also very similar to the cells derived from cynomolgus embryos by the same method. Our results suggest that: (1) a cynomolgus nucleus can co-ordinate with rabbit oocyte cytoplasm in early embryo development, (2) the 8- to 16-cell stage block in the cynomolgus-rabbit cloned embryos may due to the same reason as that in the cynomolgus embryos, and (3) ooplasmic factors that control time of cleavage are highly conservative between the species.

Embryonic stem cells (ESCs) of nonhuman primate are important tools for human gametogenesis research. Generally, ESCs, embryos, and fetuses of nonhuman primates are similar to these of human. Recently, germ cell formation of mouse ESCs in vitro has been reported. In this study, we established new cynomolgus monkey ES (cyES) lines and determined germinal competency by assessing expression of mRNA markers. CyES lines were established using blastocysts produced by intracytoplasmic sperm injection (ICSI). For inducing super-ovulation, females were treated with 25 IU/kg pregnant mare serum gonadotropin (PMSG) once a day for 9 days, followed by 400 IU/kg hCG. Oocytes were collected 40 h after injection of hCG. After sperm injection, embryos were cultured in mCMRL medium to the blastocyst stage. For ES line establishment, inner cell masses (ICMs) were isolated by immunosurgery. ESC colonies emerged at about 10 days after ICM plating; three cyES cell lines were successfully obtained (3/11; 27.3%). We characterized these lines by immunocytochemistry for Oct-3/4, SSEA-3, and SSEA-4, which are diagnostic markers for primate ESCs, and by assay for alkaline phosphatase (ALP) activity. All cell lines expressed Oct-3/4, SSEA-4 and ALP activity. The previously reported SSEA-3 weak expression in cyES cells was not observed. These lines differentiated spontaneously when they were replaced in non-adherent culture (embryoid body: EB) or injected into SCID mice subcutaneously. To assess germ cell competency in vitro, we analyzed for the presence of vasa mRNA which shows a restricted expression pattern to germ cell formation, and DMC1 and SYCP1 which show specific existence on synaptonema complex in meiosis. Detection of these germ cell markers was performed by RT-PCR with total cDNA from ESCs and EBs. Nanog mRNA was detected only in ESCs. Oct-4 was detected in gonadal tissue of both sexes, ESCs, and EBs. Vasa was expressed in testis, but not in ESCs or somatic cells. Interestingly, we recognized weak expression of Vasa in Day 12-16 EBs. DMC1 and SYCP1 as meiosis markers were not detected. Because Oct-4 and Vasa mRNA are transcribed simultaneously, similar to that in the early part of gametogenesis such as the latter period of primordial germ cell (PGC) migration, PGC formation in cynomolgus EBs could occurr as in some cases of mouse or human EBs previously reported. Although detailed properties such as the functions of these Vasa-positive cells have not been confirmed, these results demonstrate that cyES cells obtained in the current study might contribute to putative germ cells in vitro by differentiating to EBs. This study was supported by a Grant-in-Aid for the 21st Century COE Program of the Japan Mext and by a grant for the Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technology Excellence of the JST.