Prevention of Acute Lung Allograft Rejection in Rat by CTLA4Ig

CTLA4 immunoglobulin (CTLA4Ig), which binds with a high affinity to B7-1 and B7-2, interrupts T-cell activation by inhibiting costimulatory signal. CTLA4Ig has been used in hopes of achieving antigen-specific tolerance induction in several solid organ transplants. In lung allograft rejection, however, its use has been controversial in terms of its effect on prevention of rejection. In the present study, the effect of murine CTLA4Ig on rat-lung allograft rejection was investigated. Rat left-lung transplantation was performed in an RT1 incompatible donor (Brown Norway; BN)-recipient (F344) combination. All allografts (n = 12) without any treatment were rejected within 7 days after transplantation. A single injection of murine form CTLA41g at a dose of 100 microg intraperitoneally (ip) or intravenously (iv) on day 1 post-transplantation achieved long-term graft survival (>90days) in 2/5 (40%) and 3/8 (38%), respectively. Moreover, 6/7 (86%) allografts in rats that received iv injection of 500 microg CTLA4Ig survived more than 90days. Allograft survival in the CTLA4Ig 500 microg iv recipient group was significantly longer than that in the no-treatment control or control immunoglobulin group (p <0.01). Four out of seven recipients bearing functional allografts for more than 90 days with the CTLA4Ig treatment accepted donor-specific skin grafts, whereas all third-party skin grafts (n=3) were rejected. Prevention of rat-lung allograft rejection could be achieved by intravenous administration of CTLA4Ig, resulting in long-term allograft survival with acceptance of donor-specific skin grafts.     

Effects of calcium in continuous cardioplegia on myocardial protection

The effects of calcium (Ca) on a hyperkalemic cardioplegic solution for continuous cardioplegia were examined in an isolated perfused working rat heart model. The coronary arteries were perfused with a modified Krebs-Henseleit bicarbonate buffer (K-H) solution, containing various concentrations of Ca(0.1, 0.6, 1.2, and 2.5 mmol/l) and a high concentration of potassium (20 mmol/l), for 180 min, after which cardiac arrest was induced at 37°C for 180 min. Cardiac function and creatine kinase (CK) were measured. In the control group, K-H solution was infused in place of the cardioplegic solution, and cardiac arrest was not induced. No significant differences were observed between the groups infused with the K-H solution containing Ca concentrations of 0.6, 1.2, and 2.5 mmol/l in the percent recovery of aortic flow (82.1±2.9%, 80.6±2.0%, and 71.5±3.7% (mean±SEM) respectively) or in the recovery of other indices of cardiac function, or in CK leakage. There were also no significant differences in the recovery of cardiac function and CK leakage between these groups and the control group. In the Ca 0.1 mmol/l group, however, the characteristic Ca paradox was observed. These findings suggest that if the Ca concentration in a cardioplegic solution is higher than 0.6 mmol/l during continuous cardioplegia, excellent cardioprotective effects will be achieved.     

Prognosis of pancreatic endocrine function in chronic pancreatitis: significance of surgical treatment

Of 100 cases of chronic pancreatitis, 20 received surgical treatment. The duration of illness before surgical treatment was less than 5 years in 75% of patients. Post-operatively, the persistent abdominal pain was relieved and serum pancreatic enzyme levels were normalized in all the patients except two who continued drinking alcohol. Exocrine and endocrine pancreatic function were unchanged or slightly improved post-operatively in most cases. In 9 of 10 patients who have been followed up post-operatively for over 4 years, pancreatic endocrine function has been maintained by diet control with no significant impairment of glucose tolerance. These results suggest that in patients with chronic pancreatitis surgical intervention is of greatest benefit in preservation of pancreatic functions when it is performed at an early stage in which these functions are relatively well maintained.     

Endosalpingiosis of nonmetastatic lymph nodes along the stomach in a patient with early gastric cancer: Report of a case

We report herein the case of a 32-year-old woman who underwent distal gastrectomy with D2 lymph node dissection for gastric cancer. Microscopic examination of the resected specimen revealed signet-ring cell carcinoma of the stomach with lymph node metastases, and endosalpingiosis in the normal lymph nodes. There was no evidence of malignancy in the peritoneal cavity. To our knowledge, no other case of endosalpingiosis in the lymph nodes along the stomach has ever been reported. The possible significance of endosalpingiosis is discussed following this case report.     

Demonstration of donor specific unresponsiveness in rat islet allografts: importance of transplant site for induction by cyclosporin A and maintenance

Summary The purpose of the present study was to evaluate the effects of transplant site (the liver via the portal vein vs the renal subcapsular space) on islet allograft survival using cyclosporin A and also to determine whether or not the unresponsiveness obtained is donor specific and how the site selected is related to the maintenance of unresponsiveness. Prolongation of islet allograft survival (WKA/Qdj:RT1^u Lewis:RT1¹) was obtained by using hand-picked clean fresh islets as donors and by s. c. administration of cyclosporin A (30 mg/kg, day 0, 1, 2) when the islets were transplanted into the liver. Eleven out of 15 recipients were normoglycaemic for more than 90 days after transplantation (control mean survival time: 4.4±1.1 days, n=5). However, all the renal subcapsular grafts were rejected within 18 days after transplantation. Two normoglycaemic recipients bearing intrahepatic grafts were challenged with full-thickness donor-strain (WKA/Qdj) skin grafts at 120 days after the islet transplantation. Both recipients became diabetic and the skin grafts rejected within 16 days. The nine normoglycaemic recipients were made diabetic again with streptozotocin (40 mg/kg) between 90 and 120 days after the initial islet transplantation. Re-transplants of fresh donor-strain (WKA/Qdj) islets into the liver (n=3) in the absence of cyclosporin A maintained normoglycaemia in the recipients for more than 60 days, whereas re-transplants of donor-strain islets beneath the kidney capsule were rejected within 20 days. Intrahepatic re-transplants of third party grafts (PVG/c: RT1^c:) (n=3) were rejected after seven days. These findings clearly demonstrate that the donor specific unresponsiveness in rat islet allografts was not only induced but also maintained only when the liver was the site used for implantation of the islets.     

Interaction of Interleukin-1 and Interferon-γ on Fibroblast Growth Factor-induced Angiogenesis

The interaction of interleukin-1 (IL-1) and interferon-γ (IFN-γ) actions on several aspects of angiogenesis in vitro and in vivo was studied. The proliferation and migration of human umbilical vein endothelial cells cultured with basic fibroblast growth factor (bFGF) were synergistically inhibited by cotreatment with IL-1 and IFN-γ. Endothelial cell adhesion to collagen was suppressed by IL-1 and the effect was slightly enhanced by the combination of IL-1 and IFN-γ. Local administration of IL-1 (10,000 U) and IFN-γ (1,000 U) inhibited bFGF-induced angiogenesis in the skin of mice, and synergistic inhibitory activity of the combination was demonstrated. Expression of FGF receptors was strongly downregulated by the combination, whereas expressions of epidermal growth factor (EGF) receptors, integrin β₁ and integrin β₃ were not. EGF partially abrogated the growth-inhibitory effects of IL-1 and IFN-γ. These findings indicate that IL-1 and IFN-γ are each able to act an angiogenesis inhibitor in a situation where FGF plays a major role in angiogenesis, and the activity is synergistically enhanced when they are used in combination.     

Bacteria isolated from surgical infections and their susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2000 and March 2001

Tendency of isolated bacteria from infections in general surgery and their antimicrobial susceptibilities during the period from April 2000 to March 2001 were investigated in a multicenter study in Japan, and the following results were obtained. The number of cases investigated as objectives was 234 for one year. A total of 388 strains (136 strains from primary infections and 252 strains from postoperative infections) were isolated from 165 cases (70.5% of total cases). In primary infections, anaerobic Gram-positive bacteria were predominant, while from postoperative infections, aerobic Gram-positive bacteria were predominant. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus faecalis was the highest, followed by that of Staphylococcus aureus from postoperative infections. Among anaerobic Gram-positive bacteria, the isolation rate of Peptostreptococcus spp. was the highest from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae and Pseudomonas aeruginosa in this order, and from postoperative infections, P. aeruginosa was the most predominantly isolated, followed by Enterobacter spp. and Klebsiella spp. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both types of infections. There was no vancomycin-resistant S. aureus nor Enterococcus spp. Among anaerobic bacteria, there were many resistant strains against penicillins and cephems with MICs higher than 100 micrograms/ml, and the same trend was observed among other Bacteroides spp. and Prevotella spp.     

The start of an islet transplantation program in Japan

In Japan, pancreas donation had become possible from cadaveric donor sources, both heart-beating or non-heart-beating (NHB). Pancreas allografts have been distributed in the organ allocation system of the Japan Organ Transplant Network. Meanwhile, islet transplantation has been categorized as a tissue transplantation; it is free from legal restraints. Thus, pancreata for islet isolation must be obtained from NHB donors. Herein we report the starting program and preliminary results of islet transplantation in Japan. Selection and listing criteria for transplantation include regional priority, ABO blood type, previous islet transplant status with insulin independence, and a longer waiting time. Five institutes in Japan (Fukushima, Chiba, Kyoto, Kobe, and Fukuoka) are prepared to start programs. A two-layer cold storage method using perfluorocarbons and UW solution is recommended for pancreas preservation. Islet isolation and purification procedures are performed according to institute-specific protocol. Immunosuppression is based on sirolimus/tacrolimus combined with basiliximab induction. Two or three consecutive infusions of >5000 IE/kg are planned for each recipient until achieving insulin independence. Twenty-seven isolations and 14 transplants were performed in eight non-insulin-dependent diabetes mellitus (IDDM) recipients. Almost all (26 of 27) were NHB donors. All recipients are free from hypoglycemic episode after transplantation. One of these recipients is insulin independent; the others are currently on minimal doses of exogenous insulin. The feasibility of islet transplantation using NHB donors was confirmed using a two-layer cold storage method and a steroid-free immunosuppressive protocol, with a high rate of graft function.     

Amino- and carboxyl-terminal mutants of presenilin 1 cause neuronal cell death through distinct toxic mechanisms: Study of 27 different presenilin 1 mutants

Presenilin (PS)1 and its mutants, which consist of the N-terminal and C-terminal fragments, cause certain familial forms of Alzheimer's disease (FAD). Our earlier studies found that FAD-linked M146L-PS1 causes neuronal cell death through nitrogen oxide synthase (NOS) and that FAD-linked N141I-PS2, another member of the PS family, causes neuronal cell death through NADPH oxidase. In this study, we examined 27 different FAD-linked mutants of PS1, and found that PS1 mutants with mutations in the N-terminal fragment caused NOS inhibitor (NOSI)-sensitive neuronal cell death; in contrast, the PS1 mutants with mutations in the C-terminal fragment caused NOSI-resistant neuronal cell death. The former toxicity was resistant to the specific NADPH oxidase inhibitor apocynin and was inhibited by Humanin (HN), a newly identified neuroprotective factor against Alzheimer's disease (AD)-relevant insults, but not by insulin-like growth factor-I (IGF-I). In contrast, the latter toxicity was sensitive to apocynin and inhibited by both IGF-I and HN. This study indicates for the first time that N- and C-terminal fragment PS1 mutants can generate distinct neurotoxic signals, which will provide an important clue to the understanding of the entire array of neurotoxic signals generated by FAD-causative mutations of PS1.