Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506.

BACKGROUND: Recently, specific immunonutrients were found to increase experimental allograft survival when combined with cyclosporine A (CsA). This study compared the effect on rat cardiac allograft survival when nutritional immunomodulation was used with CsA, rapamycin (Rapa), or tacrolimus (FK506). METHODS: Intra-abdominal ACI to Lewis cardiac allografts were performed and assessed daily by palpation. Study groups included untreated controls and those receiving CsA, Rapa, or FK506. Rats were fed ad libitum with Impact diet (fortified with fish oil, arginine, and RNA) or standard rat food. Further study groups were transplanted that received a donor-specific transfusion in addition to immunosuppression and diet. RESULTS: Allograft survival was extended by combining Impact with CsA (45.3+/-19 days) and Rapa (165.3+/-52 days), but not FK506 (12.4+/-3.2 days). Mean graft survival in the Rapa/Impact group met criteria for functional tolerance. The addition of a donor-specific transfusion did not lead to graft survival advantages over similar groups not receiving a donor-specific transfusion. CONCLUSIONS: The use of immunonutrients improves transplant outcome in animals treated with short courses of CsA and Rapa, but not FK506. These findings highlight the potential differences in the effects of nutritional immunomodulation with different immunosuppressive drugs in the treatment of transplant patients.

The effect of nutritional immunomodulation on cardiac allograft survival in rats receiving mycophenolate mofetil, cyclosporine A, and donor-specific transfusion.

BACKGROUND: Immunosuppressive drugs continue to pose significant risks such as infection, toxicity, or neoplasia when used in long-term therapy. The investigation of newer and safer combined treatment strategies that decrease the need for these drugs is becoming increasingly important. Immunonutrients are known to have significant modulating effects on the immune system. Feeding with Impact, a commercially available diet enriched with arginine, omega-3 fatty acids, and RNA, recently has been shown to extend rat cardiac allograft survival when combined with a donor-specific transfusion (DST) and cyclosporine A (CsA). Because mycophenolate mofetil (MMF) is now commonly used in the clinical setting, the current study was designed to examine the effect on rat cardiac allograft survival when MMF was added to this immunosuppressive regimen. METHODS: Intra-abdominal ACI to Lewis heterotopic cardiac allografts were performed. Study groups included untreated controls and recipients receiving varying combinations of a DST (1 mL) on the day prior to engraftment, MMF 45 mg/kg/day from the day of transplant through postoperative day six, and CsA 10 mg/kg on the day prior to operation and 2.5 mg/kg from the day of transplant through postoperative day 6. Animals were fed ad libitum with Impact diet or standard lab chow. Graft survival was determined by cessation of a palpable heartbeat. RESULTS: Treatment with MMF led to a prolonged allograft survival over historical untreated controls. The combination of MMF with a donor-specific transfusion, Impact, or CsA was associated with an increase in graft survival over MMF alone. The addition of Impact to the combination of MMF and CsA resulted in further improvement. The most pronounced graft survival advantage was seen when Impact was combined with a DST and both of the immunosuppressive agents. One quarter of the animals in this group had a palpable donor heart beat at greater than 150 days, indicating functional tolerance in those animals. CONCLUSIONS: The administration of Impact diet to treatment groups in this study was associated with graft survival advantages when compared to most of the other study groups receiving a similar drug regimen and standard chow. These findings support the importance of nutritional influences on allograft survival, and highlight the potential of diet therapy when used with short courses of clinically relevant immunosuppressive drugs.

Prospective, randomized comparison of epidural versus parenteral opioid analgesia in thoracic trauma.

OBJECTIVE: To evaluate systemic versus epidural opioid administration for analgesia in patients sustaining thoracic trauma. SUMMARY BACKGROUND DATA: The authors have previously shown that epidural analgesia significantly reduces the pain associated with significant chest wall injury. Recent studies report that epidural analgesia is associated with a lower catecholamine and cytokine response in patients undergoing elective thoracotomy compared with patient-controlled analgesia (PCA). This study compares the effect of epidural analgesia and PCA on pain relief, pulmonary function, cathechol release, and immune response in patients sustaining significant thoracic trauma. METHODS: Patients (ages 18 to 60 years) sustaining thoracic injury were prospectively randomized to receive epidural analgesia or PCA during an 18-month period. Levels of serum interleukin (IL)-1beta, IL-2, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were measured every 12 hours for 3 days by enzyme-linked immunosorbent assay. Urinary catecholamine levels were measured every 24 hours. Independent observers assessed pulmonary function using standard techniques and analgesia using a verbal rating score. RESULTS: Twenty-four patients of the 34 enrolled completed the study. Age, injury severity score, thoracic abbreviated injury score, and length of hospital stay did not differ between the two groups. There was no significant difference in plasma levels of IL-1beta, IL-2, IL-6, or TNF-alpha or urinary catecholamines between the two groups at any time point. Epidural analgesia was associated with significantly reduced plasma levels of IL-8 at days 2 and 3, verbal rating score of pain on days 1 and 3, and maximal inspiratory force and tidal volume on day 3 versus PCA. CONCLUSIONS: Epidural analgesia significantly reduced pain with chest wall excursion compared with PCA. The route of analgesia did not affect the catecholamine response. However, serum levels of IL-8, a proinflammatory chemoattractant that has been implicated in acute lung injury, were significantly reduced in patients receiving epidural analgesia on days 2 and 3. This may have important clinical implications because lower levels of IL-8 may reduce infectious or inflammatory complications in the trauma patient. Also, tidal volume and maximal inspiratory force were improved with epidural analgesia by day 3. These results demonstrate that epidural analgesia is superior to PCA in providing analgesia, improving pulmonary function, and modifying the immune response in patients with severe chest injury.

Dietary omega-3 and omega-9 fatty acids uniquely enhance allograft survival in cyclosporine-treated and donor-specific transfusion-treated rats.

BACKGROUND: Both laboratory and clinical studies have shown that dietary lipids may affect immunologic responses. This study was conducted to compare different classes of long-chain unsaturated fatty acids for their effect on allograft survival in animals receiving a donor-specific transfusion and a short course of low-dose cyclosporine (CsA). METHODS: Heterotopic ACI strain cardiac allografts were transplanted to Lewis strain rat recipients given diets with different lipid composition. In experiment 1, animals received CsA for 14 days and different diets were enriched with lipids with high concentrations of omega-3, omega-6, or omega-9 fatty acids. In experiment 2, animals received CsA for only 8 days and different diets were enriched with corn oil (omega-6), canola oil (omega-3 and omega-9), fish oil (omega-3) or a mixture of sunflower oil and fish oil (omega-3 and omega-9). RESULTS: In experiment 1, animals receiving the diet with 30% sunflower oil had the best allograft survival (200+/-42 days vs. 53+/-8 days for regular chow plus donor-specific transfusion and CsA, P<0.05). In experiment 2, diets containing canola oil (a mixture of omega-3 and omega-9 fatty acids) were associated with the best survival (P=0.0011 vs. regular chow). CONCLUSION: Dietary omega-3 and omega-9 fatty acids both enhanced cardiac allograft survival in a stringent rat strain combination. Canola oil is a convenient oil for administering both alpha-linoleic acid (omega-3) and oleic acid (omega-9) in a palatable form for human consumption. Further investigation of the potential usefulness of lipids in transplant therapy is warranted.

Withdrawal of zinc oxide-containing diets from mature, female domestic fowl: effects on selected tissue mineral contents.

1. Two hundred and sixteen laying hens of two strains were given diets containing ZnO to provide 0, 0.5, 0.75, 1.00, 1.25, 1.50, 2.00, 3.00 or 4.00 g added Zn/kg. These diets were offered ad libitum for 5 consecutive 28-d periods. All hens were subsequently offered the control diet with no added ZnO for 5 weeks. 2. Four hens from each treatment were killed 0, 1 and 5 weeks after substitution of the ZnO-supplemented diets by the control diet. 3. Dietary addition of ZnO significantly increased liver, kidneys, pancreas and gizzard Zn contents but this effect was rapidly reversed on removal of the ZnO-containing diets. 4. Hepatic and renal Fe contents were significantly depressed by dietary ZnO but after substitution of these diets by the control diet the values were comparable to that of the controls. 5. Liver Cu content declined significantly as dietary ZnO concentration increased but there was a return towards normal after ZnO withdrawal. Renal, pancreatic and gizzard Cu contents showed quadratic responses to added ZnO. 6. After ZnO withdrawal for 5 weeks, pancreas Cu contents declined linearly, whereas renal and gizzard Cu values were similar for all treatments. 7. Overall the long-term feeding of ZnO-supplemented diets followed by a period of withdrawal of the ZnO supplement had no detrimental effects on tissue mineral contents.

Withdrawal of zinc oxide-containing diets from mature, female domestic fowl: effects on laying performance and the weights of selected tissues.

1. Two hundred and sixteen laying hens of two strains were given diets containing ZnO to provide 0, 0.5, 0.75, 1.00, 1.25, 1.50, 2.00, 3.00 or 4.00 g added Zn/kg. These diets were given ad libitum for 5 consecutive 28-d periods. All hens subsequently received the control diet with no added ZnO for 5 weeks. 2. Four hens from each treatment were killed 0, 1 and 5 weeks after substitution of the ZnO-supplemented diets by the control diet. 3. The adverse effects of the ZnO-containing diets on body weight, food intake, egg production, pancreas, gizzard, oviduct and ovary weights/kg body weight were reversed by removal of the ZnO from the diets. 4. Five weeks after withdrawal egg production of the group which had received the diet with the highest concentration of added ZnO was only 50% of that of the control birds. 5. The beneficial effect of the added ZnO on internal egg quality was not maintained after withdrawal of the ZnO-containing diets.

Plasma concentrations of corticosterone and thyroid hormones in laying fowls from different housing systems.

Plasma concentrations of corticosterone, thyroxine (T4) and triiodothyronine (T3) were measured in representative mature female domestic fowls from three housing systems: cages, covered strawyard and range. There were no between-system differences for T4 but T3 was lower in birds from range than in those from cages. Corticosterone concentrations were lower in birds from strawyards than in those from range and cages. In the strawyards there were no differences in corticosterone concentrations between normal and low-ranking hens. The latter were selected on the basis that they remained apart from the flock, were under-weight, poorly feathered and unable to feed at will. Low-ranking hens had significantly higher plasma concentrations of T3 and T4 than normal birds. This was attributed mainly to the poor feather covering of most low-ranking birds. It was concluded that, in the assessment of different housing systems, plasma corticosterone and thyroid hormones were not useful measures of long-term stress or welfare. Different factors relevant to welfare may have contrary effects on the plasma concentrations of these hormones.

Comparison of the effects of feeding diets supplemented with zinc oxide or zinc acetate on the performance and tissue mineral content of mature female fowls.

An experiment is reported in which zinc, as acetate or oxide, was fed to laying hens for 10 weeks at concentrations equivalent to 1, 2, 3, 4 and 5 g added Zn/kg diet. Both concentration and form of Zn additive significantly reduced food, water and Zn intakes, egg production and body weight, the acetate having a greater detrimental effect than the oxide at equivalent added Zn inclusion. Zinc acetate depressed the fresh weight/kg body weight of the kidneys, ovary and oviduct to a greater extent than the corresponding oxide treatments. Concentration, but not form of additive, significantly reduced liver and pancreas weights and liver lipid concentration, while spleen and gizzard weights showed increases. Overall, the additives significantly increased the Zn and Fe concentrations of the liver, kidneys, pancreas and gizzard. Zinc concentrations of liver, pancreas and gizzard and Fe concentrations of liver were consistently higher for the acetate-fed birds. Liver, pancreas and gizzard Cu concentrations significantly declined as inclusion rate of Zn increased.

Effects of short- and long-term feeding of zinc oxide-supplemented diets on the mature, female domestic fowl with special reference to tissue mineral content.

1. In Expt 1, the effects on laying hens of diets supplemented with zinc oxide providing up to 20 g added zinc/kg were compared. In Expt 2 the diets contained up to 6 g added Zn/kg. 2. In both experiments, food intake, body-weight, egg number, and liver, oviduct and ovary weights/kg body-weight were significantly reduced by added ZnO; gizzard weight/kg body-weight was significantly increased. In Expt 2, pancreas weight was significantly reduced by added ZnO. 3. Liver, kidney and pancreatic Zn and iron concentrations were significantly elevated in both experiments. 4. In both experiments, liver, kidneys and pancreatic copper concentrations gave quadratic responses to added ZnO.