Effect of anticomplement agent K-76 COOH in hamster-to-rat and guinea pig- to-rat xenotransplantation

In normal rats, the xenobiotic K76 inhibited the C5 and probably the C2 and C3 steps of complement and effectively depressed classical complement pathway activity, alternative complement pathway activity, and the C3 complement component during and well beyond the drug's 3-hr half-life. It was tested alone and with intramuscular tacrolimus (TAC) and/or intragastric cyclophosphamide (CP) in rat recipients of heterotopic hearts from guinea pig (discordant) and hamster (concordant) donors. Single prevascularization doses of 100 and 200 mg/kg increased the median survival time of guinea pig hearts from 0.17 hr in untreated controls to 1.7 hr and 10.2 hr, respectively; with repeated injections of the 200-mg dose every 9-12 hr, graft survival time was increased to 18.1 hr. Pretreatment of guinea pig heart recipients for 10 days with TAC and CP, with or without perioperative splenectomy or infusion of donor bone marrow, further increased median graft survival time to 24 hr. Among the guinea pig recipients, the majority of treated animals died with a beating heart from respiratory failure that was ascribed to anaphylatoxins. Hamster heart survival also was increased with monotherapy using 200 mg/kg b.i.d.i.v. K76 (limited by protocol to 6 days), but only from 3 to 4 days. Survival was prolonged to 7 days with the addition to K76 of intragastric CP at 5 mg/kg per day begun 1 day before operation (to a limit of 9 days); it was prolonged to 4.5 days with the addition of intramuscular TAC at 2 mg/kg per day beginning on the day of transplantation and continued indefinitely. In contrast to the limited efficacy of the single drugs, or any two drugs in combination, the three drugs together (K76, CP, and TAC) in the same dose schedules increased median graft survival time to 61 days. Antihamster antibodies rapidly increased during the first 5 days after transplantation, and plateaued at an abnormal level in animals with long graft survival times without immediate humoral rejection. However, rejection could not be reliably prevented, and was present even in most of the xenografts recovered from most of the animals dying (usually from infection) with a beating heart. Thus, although effective complement inhibition with K76 was achieved in both guinea pig- and hamster-to-rat heart transplant models, the results suggest that effective interruption of the complement cascade will have a limited role, if any, in the induction of xenograft acceptance

Price differentials among brands in retail distribution: product quality and service quality

We develop a theoretical model of retail competition that include two sources of quality, one inherently linked to brand characteristics and the other linked to the retailer level of service. We then measure their contribution in explaining the observed price differentials for a sample of U.K. grocery retailer prices in the south of Coventry during the period November 1995 to March 1997. We find that retailers that offer a higher quality service sell same quality brands at higher prices. These price premia are explained solely by differences in service quality levels. We find econometric evidence that they amount to 6 percent for national brands and to a range between 9 percent and 15 percent for low-quality store brands. Besides, at a given store, the price premia paid for the national brand is positive. These differentials are very large: around 150 percent between national brands and low-quality store brands, around 40 percent between national brands and high-quality store brands. Also, the price differential between the national brand and the low-quality store brand does not increase with its service quality. Besides, the price of the high-quality store brand approaches the price of the national brand when service quality increases. Thus suggesting that stores that offer high quality service uses the level of service as a strategic tool to target the leading national brand consumers

Divergence of the Response Induced by Xenogenic Immunization in the Sepsis Survival of Rats

<div><p>We have previously described that boosted natural xenoantibodies in rats cross-react to bacteria by targeting carbohydrate antigens. This type of immunization is associated with reduced survival after cecal ligation and puncture (CLP). In the present study, we investigated further this phenomenon by immunizing Lewis rats with three intraperitoneal injections, every other day, of hamster blood compared to saline-injected control animals. One day after the last injection, CLP was performed to produce a low-grade sepsis. Induction of xenoantibodies was associated with a reduction in animal survival after CLP relative to controls (45% vs. 90%, p<0.01). No bacterial blood load was observed after CLP in this model either with or without xenoantibody enhancement, indicating that the augmented mortality was not mediated by a direct effect of boosted xenoantibodies over blood bacteria. Nevertheless, the xenoimmunization produced a systemic inflammatory response in all rats. Additionally, a lack of weight gain at the time of CLP was present in animals that died after the procedure, which was not observed in surviving rats and controls. The cytokine profile at the time of CLP in animals that died after the procedure was characterized by an increase in the serum level of several cytokines, particularly adipokines. In contrast, the cytokine profile at CLP of xenoimmunized rats that survived the procedure was characterized by a reduction in the level of cytokines. In conclusion, this study failed to show a direct effect of boosted xenoantibodies over blood bacterial isolates as cause for the decreased survival after CLP. However, it evidenced that non-infectious systemic inflammation may lead to a pattern of augmented cytokines, particularly adipokines, which impairs survival after subsequent CLP. Therefore, the profile of cytokines existing before the infectious insult appears more crucial than that resulting from the condition for the outcome of sepsis.</p></div

Generation of rat anti-hamster xenoantibodies and their impact on sepsis survival after CLP.

<p>(<b><i>A</i></b>) Levels of anti-hamster IgM and IgG xenoantibodies in Lewis after three injections of hamster blood, with one injection administered every other day. Mean ± SEM of 5 animals per group. MFI: Mean fluorescence intensity. (<b><i>B</i></b>) Percent survival of Lewis rats with and without enhanced anti-hamster xenoantibodies submitted to CLP (n = 20 per group; *p<0.01). (<b><i>C</i></b>) Level of anti-hamster IgM and IgG xenoantibodies at baseline (day—5) and before CLP (day 0) in Lewis rats immunized with hamster blood and subsequently submitted to CLP that survived (Xeno-A; n = 9) or died (Xeno-D; n = 11) after the procedure. Values are the mean ± SEM.</p

Cytokine concentrations.

<p>Fold changes of 33 cytokines on days -5 (baseline), 0 (before CLP; black column) and 2 (two days after CLP; white column). (<b><i>A</i></b>) Control; (<b><i>B</i></b>) animals with increased anti-hamster xenoantibodies that survived CLP (Xeno-A); (<b><i>C</i></b>) animals with boosted anti-hamster xenoantibodies that died after CLP (Xeno-D). Mean ± SEM of 3 animals per group. (*p<0.05 compared to day -5;#p<0.05 compared to days -5 and 0).</p

Change in body weight.

<p>(<b><i>A</i></b>) Body weight before and after CLP (day 0) with or without enhancement of anti-hamster xenoantibodies (n = 20 per group from day -5 to 0, n = 18 in control from day 3 to 10, and n = 9 in Xeno group from day 6 to 10). (<b><i>B</i></b>) Body weight before CLP in animals with boosted anti-hamster xenoantibodies that survived (Xeno-A; n = 9) or died (Xeno-D; n = 11) after CLP. (*p<0.05 compared to control; #p<0.05 compared to Xeno-A).</p

Absolute leukocyte counts present in peripheral blood.

<p>Total leukocytes (<b><i>A</i></b>), neutrophils (<b><i>B</i></b>), lymphocytes (<b><i>C</i></b>) and monocytes (<b><i>D</i></b>), on days -5, 0 and 2 of CLP in animals with and without enhancement of anti-hamster xenoantibodies (n = 20 per group) and on days -5 and 0 in rats with boosted anti-hamster xenoantibodies that survived (Xeno-A; n = 9) or died (Xeno-D; n = 11) after CLP. (*p<0.05).</p

Clinical chemistry determinations in peripheral blood.

<p>ALT (<b><i>A</i></b>), AST (<b><i>B</i></b>), urea (<b><i>C</i></b>) and triglycerides (<b><i>D</i></b>), on days -5, 0 and 2 of CLP in animals with and without enhancement of anti-hamster xenoantibodies (n = 20 per group) and on days -5 and 0 in rats with boosted anti-hamster xenoantibodies that survived (Xeno-A; n = 9) or died (Xeno-D; n = 11) after CLP. (*p<0.05).</p