Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine.

In rats, FK significantly prolonged heterotopic heart graft survival over a wide dose range when given for 2 weeks starting on the day of the operation. Brief courses of FK for one to four days preoperatively, and especially beginning four days postoperatively, allowed long subsequent survival of heart grafts in otherwise untreated recipients. The seeming acceptance of the grafts with postoperative FK treatment was largely but not exclusively donor specific when tested eight days after the last FK dose by second grafts from the same donor v third-party donor grafts. FK in minimally therapeutic doses was synergistic with suboptimal doses of CyA

FK 506 pre-treatment is associated with reduced levels of tumor necrosis factor and interleukin 6 following hepatic ischemia/reperfusion

Using a rat model, the effect of pre-treatment with FK 506 on hepatic ischemia/reperfusion injury was investigated. All control animals died within 72 h of the ischemia/reperfusion injury. Pre-treatment of the animals with FK 506 (0.3 mg/kg in 0.5 ml saline) administered intravenously improved survival. The most striking protection against fatal ischemia/reperfusion injury was achieved in rats that were given FK 506 6 and 24 h prior to the induction of the hepatic ischemic insult (70% and 80% 10-day survival rates, respectively). The hepatoprotective effect of FK 506 was assessed further in a second experiment in which the serum levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were measured. These results suggest that a 60-min period of hepatic ischemia and subsequent reperfusion triggers the release of both TNF and IL-6, and that FK 506 pre-treatment (6 h before the ischemic episode) significantly inhibits the production and/or release of these two cytokines compared to untreated controls. These data provide additional information concerning the immunosuppressive and hepatoprotective activities of FK 506. Based upon these data, it is probable that FK 506 attenuates hepatic ischemia/reperfusion injury, at least in part, by reducing TNF and IL-6 levels. © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved

Cytomegalovirus infection of the upper gastrointestinal tract following liver transplantation—incidence, location, and severity in cyclosporine- and FK506-treated patients

One hundred and forty randomly selected liver transplant recipients were studied before and after primary orthotopic liver transplantation for the presence or absence of CMV enteritis. Following OLTx, 65 patients were treated with cyclosporine A and 75 were treated with FK506. The two groups were similar with regard to the incidence, location, and outcome of their upper gastrointestinal CMV infection. Prior to OLTx, only one patient had evidence of enteric CMV infection. The incidence of CMV enteritis post-OLTx was 27.7% in the CsA-treated group and 20% in the FK-treated group. During the first posttransplant month, no patient in the FK-treated group developed CMV enteritis, compared with 11.5% of the patients who were treated with CsA (P<0.05). Gastric CMV was found in over 80% of those positive for any organ in either group. In addition to CMV infection of the upper gastrointestinal tract, clinically evident CMV disease involved more nonenteric organs in the CsA-treated group than in the FK-treated group. In the CsA-treated group, CMV-negative patients had a statistically higher 1-year survival rate (100%) than CMV-positive patients (77.8%) (P<0.05). In the FK-treated group, no difference in survival was observed between CMV-positive or CMV-negative cases at 1 year. Of the patients on CsA, 20% received OKT3 for persistent rejection, as compared with 13% in the FK-treated group. The patients receiving both CsA and OKT3 had a higher rate of upper gastrointestinal CMV infection than did FK-treated patients who also received OKT3 therapy (38.5% versus 20%, respectively). Based upon these data, it can be concluded that (1) patients receiving FK have a lower incidence of enteric CMV infection; (2) following OLTx, upper gastrointestinal CMV infection presents later in FK-treated patients; (3) the stomach is the most frequently involved organ in the UGIT; (4) FK-treated liver recipients have less severe enteric CMV infection than do CsA-treated patients; (5) enteric CMV is not a major cause of mortality in liver trans lant recipients; and (6) in patients receiving FK, those who require OKT3 therapy do not appear to be at a greater risk for the development of CMV enteritis than those who do not. © 1992 by Williams & Wilkins

A prospective randomized trial of fk506 versus cyclosporine after human pulmonary transplantation

We have conducted a unique prospective randomized study to compare the effect of PK506 and cyclosporine (CsA) as the principal immunosuppressive agents after pulmonary transplantation. Between October 1991 and March 1993, 74 lung transplants (35 single lung transplants [SLT], 39 bilateral lung transplant [BLT]) were performed on 74 recipients who were randomly assigned to receive either FK or CsA. Thirty-eight recipients (19 SLT, 19 BLT) received FK and 36 recipients (16 SLT, 20 BLT) received CsA. Recipients receiving FK or CsA were similar in age, gender, preoperative New York Heart Association functional class, and underlying disease. Acute rejection (ACR) was assessed by clinical, radiographic, and histologic criteria. ACR was treated with methylprednisolone, 1 g i.v./day, for three days or rabbit antithymocyte globulin if steroid-resistant.During the first 30 days after transplant, one patient in the FK group died of cerebral edema, while two recipients treated with CsA died of bacterial pneumonia (1) and cardiac arrest (1) (P=NS). Although one-year survival was similar between the groups, the number of recipients free from ACR in the FK group was significantly higher as compared with the CsA group (P<0.05). Bacterial and viral pneumonias were the major causes of late graft failure in both groups. The mean number of episodes of ACR/ 100 patient days was significantly fewer in the FK group (1.2) as compared with the CsA group (2.0) (P<0.05). While only one recipient (1/36=3%) in the group treated with CsA remained free from ACR within 120 days of transplantation, 13% (5/38) of the group treated with FK remained free from ACR during this interval (P<0.05). The prevalence of bacterial infection in the CsA group was 1.5 episodes/100 patient days and 0.6 episodes/100 patient days in the FK group. The prevalence of cytomegaloviral and fungal infection was similar in both groups.Although the presence of bacterial, fungal, and viral infections was similar in the two groups, ACR occurred less frequently in the FK-treated group as compared with the CsA-treated group in the early postoperative period (<90 days). Early graft survival at 30 days was similar in the two groups, but intermediate graft survival at 6 months was better in the FK group as compared with the CsA group. © 1994 by Williams and Wilkins

Effects of combined administration of FK 506 and the purine biosynthesis inhibitors mizoribine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures

Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the purine biosynthesis inhibitors mycophenolic acid (MPA; the active moiety of RS61443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six-day human mixed lymphocyte cultures (MLC), FK 506, MPA or MZB exhibited dose-dependent inhibition of T-lymphocyte DNA synthesis. FK 506, however, was 100-fold more potent than MPA, and 10000-fold more potent than MZB. Combination of FK 506 with either MPA or MZB, each at suboptional concentrations, produced no more than additive inhibitory effects on 3H thymidine incorporation. Two-colour flow cytometric analysis of lymphocytes revealed that none of the drugs affected cell surface activation molecule expression (CD25 = IL-2R 55 kD α-chain, HLA-DR or CD71 = transferrin receptor [TR]) on allostimulated CD4+ or CD8+ cells harvested at three days of culture. By day six, however, all three agents, at levels which markedly inhibited proliferation, suppressed the expression of activation markers on both CD4+ and CD8+ cells. Also at day six, inhibition of activation molecule expression on CD4+ cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which, on their own, were ineffective. These data provide new, additional information on the in vitro antilymphocytic action of FK 506, MPA and MZB when used alone and in combination. © 1993

Total orthotopic small bowel transplantation in swine under FK 506

Previous experimental studies in rodents and in dogs have established the efficacy of FK 506 in controlling the immunologic events following small bowel or multivisceral transplantation.1–5 To complete the assessment of FK 506 in experimental small bowel transplantation, we present here our experience with the frequently used swine model

Stable Frank-Kasper phases of self-assembled, soft matter spheres

Single molecular species can self-assemble into Frank Kasper (FK) phases, finite approximants of dodecagonal quasicrystals, defying intuitive notions that thermodynamic ground states are maximally symmetric. FK phases are speculated to emerge as the minimal-distortional packings of space-filling spherical domains, but a precise quantitation of this distortion and how it affects assembly thermodynamics remains ambiguous. We use two complementary approaches to demonstrate that the principles driving FK lattice formation in diblock copolymers emerge directly from the strong-stretching theory of spherical domains, in which minimal inter-block area competes with minimal stretching of space-filling chains. The relative stability of FK lattices is studied first using a diblock foam model with unconstrained particle volumes and shapes, which correctly predicts not only the equilibrium {\sigma} lattice, but also the unequal volumes of the equilibrium domains. We then provide a molecular interpretation for these results via self-consistent field theory, illuminating how molecular stiffness regulates the coupling between intra-domain chain configurations and the asymmetry of local packing. These findings shed new light on the role of volume exchange on the formation of distinct FK phases in copolymers, and suggest a paradigm for formation of FK phases in soft matter systems in which unequal domain volumes are selected by the thermodynamic competition between distinct measures of shape asymmetry.Comment: 40 pages, 22 figure

Cluster Percolation and First Order Phase Transitions in the Potts Model

The q-state Potts model can be formulated in geometric terms, with Fortuin-Kasteleyn (FK) clusters as fundamental objects. If the phase transition of the model is second order, it can be equivalently described as a percolation transition of FK clusters. In this work, we study the percolation structure when the model undergoes a first order phase transition. In particular, we investigate numerically the percolation behaviour along the line of first order phase transitions of the 3d 3-state Potts model in an external field and find that the percolation strength exhibits a discontinuity along the entire line. The endpoint is also a percolation point for the FK clusters, but the corresponding critical exponents are neither in the Ising nor in the random percolation universality class.Comment: 11 pages, 6 figure