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S Todo

Publications and source records attributed to S Todo.

At least 91 records · Page 5Linked to original sources
PubMed1998

Analogs of cyclic nucleotides in rat liver preservation.

BACKGROUND: Cyclic nucleotides mediate intracellular signal transduction of several vasodilators. In addition to its vascular relaxant effects, cAMP is known to protect endothelial cells and to suppress Kupffer cell activation. On the other hand, cGMP potently ameliorates adhesion of leukocytes and platelets. We tested the effects of two analogs of cyclic nucleotides (8bromo cyclic adenosine monophosphate [8br-cAMP] and 8bromo cyclic guanosine monophosphate [8br-cGMP]) in rat liver preservation. METHODS: In experiment 1, either analog (0.1-1.0 mM) alone was added to University of Wisconsin (UW) solution in a survival study. In experiment 2, donors and recipients were also treated with 8br-cAMP or 8br-cGMP, with the following three groups tested: group 1=control; group 2=administration of 8br-cAMP to donors, UW solution, and recipients; group 3=administration of 8br-cGMP to donors, UW solution, and recipients. Experiment 3 tested combined treatments: group 4=administration of 8br-cGMP to donors and UW solution, and cAMP to recipients; group 5=administration of 8br-cAMP to donors and UW solution, and 8br-cGMP to recipients. To elucidate the roles of each nucleotide, two further groups were tested: group 6=administration of 8br-cAMP to donors and UW solution; group 7=administration of 8br-cGMP to recipients. In experiment 4, rats in groups 1, 5, 6, and 7 were killed at several time points after reperfusion, and percent graft blood flow (%BF), number of accumulated neutrophils, plasma levels of tumor necrosis factor-alpha and interleukin-1, and serum alanine aminotransferase levels were examined. RESULTS: In experiments 1 and 2, no significant effect was observed on animal survival. In experiment 3, a significant increase in animal survival was observed only in group 5 (100%, 7/7, P=0.0004 vs. group 1: 16.7%, 2/12). In group 5, no improvement of %BF was observed during the early phase of reperfusion (15 and 30 min) compared with that in group 1. On the other hand, the %BF of group 5 was significantly higher in the later phase (6 hr), consistent with the decrease in accumulation of neutrophils observed then. Production of tumor necrosis factor-alpha and serum alanine aminotransferase levels were also reduced with this treatment. Histologically, the bleeding and segmental necrosis, observed in group 1, were completely prevented in group 5. CONCLUSIONS: We conclude that restoration of grafts with cAMP and administration of cGMP to recipients led to successful transplantation, and that the two analogs acted synergistically in opposing preservation and reperfusion injury without improvement of graft blood flow during the early phase of reperfusion. The effect was due to their regulation of neutrophil activation and sequestration.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1998

Current status of intestinal transplantation in children.

PURPOSE: A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). METHODS: Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n=33), and multivisceral (MV) (n=8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n=14), volvulus (n=13), necrotizing enterocolitis (n=6), intestinal atresia (n=8), chronic intestinal pseudoobstruction (n=5), Hirschsprung's disease (n=4), microvillus inclusion disease (n=3), multiple polyposis (n=1), and trauma [n=1). RESULTS: Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n=18), intestinal allograft rejection (n=52), posttransplant lymphoproliferative disease (n=16), cytomegalovirus (n=16) and graft-versus-host disease (n=4). A combination of associated complications included intestinal perforation (n=4), biliary leak (n=3), bile duct stenosis (n=1), intestinal leak (n=6), dehiscence with evisceration (n=4), hepatic artery thrombosis (n=3), bleeding (n=9), portal vein stenosis (n=1), intraabdominal abscess (n=11), and chylous ascites (n=4). Graft loss occurred as a result of rejection (n=8), infection (n=12), technical complications (n=8), and complications of TPN after graft removal (n=3). There were four retransplants (SB, n=1; LSB n=3). CONCLUSIONS: Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation.

Child, Preschool↗
PubMed1998

Clinical intestinal transplantation: new perspectives and immunologic considerations.

BACKGROUND: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high-dose treatment has inhibited the widespread use of these procedures. We have examined our 1990-1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. STUDY DESIGN: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. RESULTS: With a mean followup of 32 +/- 26 months (range, 1-86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. CONCLUSIONS: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol.

Actuarial Analysis↗
PubMed1998

Attenuation of ischemic liver injury by prostaglandin E1 analogue, misoprostol, and prostaglandin I2 analogue, OP-41483.

BACKGROUND: Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage. STUDY DESIGN: Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5 microg/kg/min). Animals were divided into five groups: untreated control group (n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5); middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed. RESULTS: Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension. CONCLUSIONS: These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects.

Analysis of Variance↗
PubMed1998

Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation.

BACKGROUND: Because of the rarity of hilar cholangiocarcinoma, its prognostic risk factors have not been sufficiently analyzed. This retrospective study was undertaken to evaluate various pathologic risk factors which influenced survival after curative hepatic resection or transplantation. METHODS: Between 1981 and 1996, 72 patients (43 males and 29 females) with hilar cholangiocarcinoma underwent hepatic resection (34 patients) or transplantation (38 patients) with curative intent. Medical records and pathologic specimens were reviewed to examine the various prognostic risk factors. Survival was calculated by the method of Kaplan-Meier using the log rank test with adjustment for the type of operation. Survival statistics were calculated first for each kind of treatment separately, and then combined for the calculation of the final significance value. RESULTS: Survival rates for 1, 3, and 5 years after hepatic resection were 74%, 34%, and 9%, respectively, and those after transplantation were 60%, 32%, and 25%, respectively. Univariate analysis revealed that T-3, positive lymph nodes, positive surgical margins, and pTNM stage III and IV were statistically significant poor prognostic factors. Multivariate analysis revealed that pTNM stage 0, I, and II, negative lymph node, and negative surgical margins were statistically significant good prognostic factors. For the patients in pTNM stage 0-II with negative surgical margins, 1-, 3-, and 5-year survivals were 80%, 73%, and 73%, respectively. For patients in pTNM stage IV-A with negative lymph nodes and surgical margins, 1-, 3-, and 5-year survivals were 66%, 37%, and 37%, respectively. CONCLUSIONS: Satisfactory longterm survivals can be obtained by curative surgery for hilar cholangiocarcinoma either with hepatic resection or liver transplantation. Redefining pTNM stage III and IV-A is proposed to better define prognosis.

Adult↗
PubMed1998

Donor lymphocyte infusion at unstable mixed chimerism in an allogeneic BMT recipient for chronic granulomatous disease.

We report a 14-year-old boy who had successfully received allogeneic BMT for chronic granulomatous disease and 3 years later was treated with donor lymphocyte infusion (DLI, 3.3 x 10(8) cells/kg) at unstable mixed chimerism in association with reduced neutrophil function. Following DLI, the patient developed transient acute hepatic GVHD, which was confirmed by liver biopsy and was manageable with cyclosporin A and prednisolone. The patient eventually attained complete chimerism with improved neutrophil function. At the time of writing (2.5 years from the DLI), the patient is doing well, free from infectious episodes and chronic GVHD. Our experience suggests that DLI could be a safe and effective strategy for dissolution of unstable mixed chimerism in BMT recipients for inherited disorders.

Adolescent↗
PubMed1998

Effect of high concentrations of bile acids on cultured hepatocytes.

High concentrations of bile acids have been reported as injurious to hepatocytes. We report the influence of various combinations of bile acids on the liver-specific function of cultured rat hepatocytes. Using 4 bile acids (glycocholate [GC], taurocholate [TC], glycohenodeoxycholate [GCDC], and taurochenodeoxycholate [TCDC]), we obtained 6 bile-acid mixtures, each containing equal amounts of 2 bile acids (total bile acids [TBA], 2 mM). Changes in gluconeogenesis, ureagenesis, DNA contents, medium alanine aminotransferase, and morphologies were compared among the paired bile acid compositions by measuring the C/CDC ratio ([GC + TC]/[GCDC + TCDC]) of each. In terms of their relative impairments of ureagenesis from greatest to least, the acids were GCDC, TCDC, and GC, which was almost the same as TC. When the C/CDC ratio was 0, the values of all parameters measured deteriorated. When the C/CDC ratio was 1 in the presence of 1 mM GCDC, only the rate of ureagenesis was diminished. When the C/CDC ratio was infinite, no hepatocellular injury was observed. GCDC and TCDC, together or separately, showed significant hepatocellular injury when the TBA concentration was 2 mM.

Alanine Transaminase↗
PubMed1998

Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet.

The pivotal issue of transplant rejection diagnosis and management is design, conduct, and analysis of clinical trials. The historical experience with clinical trials of major immunosuppressive drugs (cyclosporine and especially tacrolimus) is examined in this article. Cyclosporine was a turning point in transplantation, providing an extraordinary improvement over previous therapies. Additionally, early investigational experience with tacrolimus was shown to be important in rescue from cyclosporine failure. Experience with tacrolimus in liver recipients for primary therapy led to understanding that the side effect profile was similar to cyclosporine and that the important side effects of tacrolimus (toxicity and diabetes) could be lessened by altering the drug dose. Early dosing regimens were determined by attempts to balance the toxicities (representing a dose ceiling) against rejection (for minimum dosing). Drug levels became understandable and trough levels could be used to guide therapy. However, when the multicenter liver trial was implemented, high starting doses were included in the protocol design, ignoring information obtained with drug level monitoring. Disregard for this information led to a distortion of the potential value of tacrolimus. Historical controls from the Pittsburgh experience suggested that tacrolimus was a critical immunosuppressant, and the randomized trial against cyclosporine confirmed the drug's ability to compete. The multicenter liver trial, however, was not balanced across treatment arms for other immunosuppressive agents (ie, higher doses of prednisone from center to center, additional induction protocols at various centers). Additionally, analysis of study results differed across continents, and the role of tacrolimus in cyclosporine rescue was not examined thoroughly. When tacrolimus was proposed for use in extrahepatic organ transplantation, again the Pittsburgh experience, as well as experience from other single centers, was determined inadequate evidence of efficacy, and randomized trials were required by the FDA. The fact that multicenter trials in transplantation have historically been poorly designed or analyzed weighed against the dramatic improvements shown from historically controlled studies or single-center trials should lead to question of the regulatory requirement for multicenter randomized trials for all organ types.

Cyclosporine↗
PubMed1998

Acute invasive sinusitis due to Trichoderma longibrachiatum in a liver and small bowel transplant recipient.

We describe a case of acute invasive sinusitis due to an unusual moniliaceous fungus, Trichoderma longibrachiatum Rifai 1969 (a member of the class Hyphomycetes), in a small bowel and liver transplant recipient treated with tacrolimus (FK-506) and prednisone. The patient was successfully treated with surgical debridements and amphotericin B followed by oral itraconazole.

Acute Disease↗
PubMed1998

Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases.

OBJECTIVE: To analyze a single center's 14-year experience with 62 consecutive patients with hilar (HCCA) and peripheral (PCCA) cholangiocarcinomas. SUMMARY BACKGROUND DATA: Long-term survival after surgical treatment of HCCA and PCCA has been poor. METHODS: From March 1981 until December 1994, 62 consecutive patients with HCCA (n = 28) and PCCA (n = 34) underwent surgical treatment. The operations were individualized and included local excision of the tumor and suprapancreatic bile duct, lymph node dissection, vascular reconstruction, and subtotal hepatectomy. Clinical and pathologic risk factors were examined for prognostic influence. RESULTS: Patients were followed for a median of 25 months (12-102 months). Postoperative morbidity and mortality (at 30 days) were 32% and 14%, respectively, for HCCA and 24% and 6% for PCCA. The survival rates for HCCA and PCCA were 79% (+/-8%) and 67% (+/-8%) at 1 year; 39% (+/-10%) and 40% (+/-9%) at 3 years; and 8% (+/-7%) and 35% (+/-10%) at 5 years, respectively. The median survival was 24 (+/-4) months for HCCA and 19 (+/-8) months for PCCA. The disease-free survival rates for HCCA and PCCA were 85% (+/-10%) and 77% (+/-9%) at 1 year; 18% (+/-11%) and 41% (+/-12%) at 3 years; and 18% (+/-11%) and 41% (+/-12%) at 5 years, respectively. Nearly 80% of these patients had TNM stage IV tumors. With HCCA, no risk factors were associated with patient survival. For PCCA, multiple tumors (relative risk [RR] = 3.5; 95% confidence interval [CI] = 1.2-10.5) and incomplete resection (RR = 8.3; 95% CI = 2.3-29.6) were independently associated with a worse prognosis. For HCCA, there was a trend for lower disease-free survival in females (p = 0.056; log rank test). For PCCA, tumor size >5 cm was the only factor associated with disease recurrence (p = 0.024; log rank test). CONCLUSIONS: Even though rare, 5-year survival by resection can be achieved in both HCCA and PCCA, but new adjuvant treatments are clearly needed.

Aged↗