(1/1045) The sodium concentration of enteral diets does not influence absorption of nutrients but induces intestinal secretion of water in miniature pigs.
Contradictory opinions exist as to whether the sodium concentration of enteral diets influences absorption of macronutrients and transepithelial movement of sodium and water. Therefore, we investigated the effects of various sodium concentrations of enteral diets on absorption of macronutrients and on net fluxes of sodium and water. In unanesthetized miniature pigs, a 150-cm jejunal segment was perfused with an oligopeptide (Peptisorb), an oligomeric and a polymeric diet. The polymeric diet was supplemented with pancreatic enzymes. The sodium concentrations varied between 30 and 150 mmol/L. The energy density was 3.4 MJ/L. The sodium concentration of the diets did not influence absorption of macronutrients and of total energy. However, increasing sodium concentrations of the diets were associated with increasing osmolality of the solutions, resulting in a linear increase in net secretion of water and flow rate of chyme. With all diets and sodium concentrations net secretion of sodium occurred. The sodium secretion was independent of the initial sodium concentration of the diets. It was linearly correlated with net flux of water and was largest in miniature pigs infused with the oligomeric diet. The sodium concentration of the jejunal effluent did not correspond to the initial sodium concentration of the diets. The present results indicate that enteral feeding of diets with high energy density inevitably increases net secretion of water and sodium as sodium concentration increases. Therefore, the sodium concentration of diets should be as low as possible to meet only the minimal daily requirement of sodium. Low sodium concentrations of diets have no negative effects on absorption of macronutrients. (+info)
(2/1045) Composition of enteral diets and meals providing optimal absorption rates of nutrients in mini pigs.
BACKGROUND: Commercial enteral diets differ widely in nutrient composition. It is unknown whether the nutrient composition of the diets influences intestinal absorption. OBJECTIVE: The objective of this study was to investigate the effects of different enteral diets providing 60% of energy as carbohydrate, protein, or fat or 33.3% of energy from each nutrient on intestinal absorption in mini pigs. DESIGN: Kinetics of nutrient absorption were determined by perfusing a 150-cm jejunal segment. The kinetics of absorption were used to determine optimal relations between the absorption and recovery of each nutrient. From these data, the optimal nutrient composition of the diets providing complete absorption of the macronutrients in the shortest intestinal length was evaluated. Absorption of nutrients was further determined after oral administration of 4 corresponding meals. RESULTS: With all enteral diets, the absorption of nutrients displayed saturation kinetics. Absorption rates of carbohydrate were significantly larger than those of fat and protein. Consequently, the amounts of nutrients remaining unabsorbed per unit length of jejunum differed among the macronutrients. After administration of various test meals, the length of the small intestine required for complete absorption of the nutrients depended on the composition of the meals. The shortest intestinal length for complete absorption was needed for a diet providing 48% of energy as carbohydrate, 23% as protein, and 29% as fat. This composition closely matched the nutritional requirements. CONCLUSION: The nutrient composition of diets can optimize intestinal absorption. This may be especially important in patients with malabsorption or short-bowel syndrome. (+info)
(3/1045) In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement.
OBJECTIVES: The purpose of this study was to target acoustically reflective liposomes to atherosclerotic plaques in vivo for ultrasound image enhancement. BACKGROUND: We have previously demonstrated the development of acoustically reflective liposomes that can be conjugated for site-specific acoustic enhancement. This study evaluates the ability of liposomes coupled to antibodies specific for different components of atherosclerotic plaques and thrombi to target and enhance ultrasonic images in vivo. METHODS: Liposomes were prepared with phospholipids and cholesterol using a dehydration/ rehydration method. Antibodies were thiolated for liposome conjugation with N-succinimidyl 3-(2-pyridyldithio) propionate resulting in a thioether linkage between the protein and the phospholipid. Liposomes were conjugated to antifibrinogen or anti-intercellular adhesion molecule-1 (anti-ICAM-1). In a Yucatan miniswine model, atherosclerosis was developed by crush injury of one carotid and one femoral artery and ingestion of a hypercholesterolemic diet. After full plaque development the arteries were imaged (20-MHz intravascular ultrasound catheter and 7.5-MHz transvascular linear probe) after injection of saline, unconjugated liposomes and antibody conjugated liposomes. RESULTS: Conjugated liposomes retained their acoustically reflective properties and provided ultrasonic image enhancement of their targeted structures. Liposomes conjugated to antifibrinogen attached to thrombi and fibrous portions of the atheroma, whereas liposomes conjugated to anti-ICAM-1 attached to early atheroma. CONCLUSIONS: Our data demonstrate that this novel acoustic agent can provide varying targeting with different antibodies with retention of intravascular and transvascular acoustic properties. (+info)
(4/1045) Functional arteries grown in vitro.
A tissue engineering approach was developed to produce arbitrary lengths of vascular graft material from smooth muscle and endothelial cells that were derived from a biopsy of vascular tissue. Bovine vessels cultured under pulsatile conditions had rupture strengths greater than 2000 millimeters of mercury, suture retention strengths of up to 90 grams, and collagen contents of up to 50 percent. Cultured vessels also showed contractile responses to pharmacological agents and contained smooth muscle cells that displayed markers of differentiation such as calponin and myosin heavy chains. Tissue-engineered arteries were implanted in miniature swine, with patency documented up to 24 days by digital angiography. (+info)
(5/1045) Recovery of 15N-lactoferrin is higher than that of 15N-casein in the small intestine of suckling, but not adult miniature pigs.
Performance of biological functions of lactoferrin in the small intestine requires at least some resistance to degradation. Therefore, we studied prececal digestibility of lactoferrin in comparison to casein both in suckling and adult miniature pigs, applying 15N-labeled proteins. In study 1, 43 piglets (10-d-old), deprived of food for 12 h received 10 mL of sow's milk supplemented with 120 mg of 15N-labeled protein (porcine or bovine lactoferrin or bovine casein). Piglets were anesthetized 150 min later, after which the small intestine was excised, cut into three sections, and chyme was collected. In study 2, nine food-deprived boars fitted with T-canulae at the terminal ileum were given two semisynthetic experimental meals (204 g) in a cross-over design, 2 wk apart. One contained 7.5% (g/100 g) 15N-labeled bovine casein, the other 1.25% 15N-labeled bovine lactoferrin. Both were adjusted to 15% total protein with nonlabeled casein. Ileal chyme was collected from the canula over 33 h postprandially. All diets contained the indigestible marker chromic oxide. 15N-digestibility of lactoferrin, both porcine (84.4 +/- 3.2%) and bovine (82.3 +/- 4.8%), was significantly lower than casein digestibility (97.6 +/- 0.5%) in the distal small intestine of suckling piglets (P < 0.05). Based on immunoblotting after acrylamide electrophoresis, 4.5% of non- and partially digested lactoferrin was found in the last third of the small intestine of piglets. In adult miniature pigs there was no difference in 15N-digestibility of bovine lactoferrin compared to bovine casein (90.7 +/- 1.9% vs. 93.9 +/- 1.0%, P > 0.05). In suckling miniature pigs, the reduced digestibility of lactoferrin may provide the prerequisite for biological actions along the whole intestinal tract. The source of lactoferrin, porcine or bovine, made no difference in this respect. (+info)
(6/1045) Human CD4+ T cells mediate rejection of porcine xenografts.
It has previously been demonstrated that xenograft rejection in rodents is dependent on CD4+ T cells. However, because of the lack of an appropriate in vivo model, little is known about the cellular basis of human T cell-mediated rejection of xenografts. In this study, we have evaluated the ability of human T cells to mediate rejection of porcine skin grafts in a novel in vivo experimental system using immunodeficient mice as recipients. Recombinase-activating gene-1-deficient mice (R-) lacking mature B and T cells were grafted with porcine skin and received human lymphocytes stimulated in vitro with irradiated porcine PBMC. Skin grafts on mice given either unseparated, activated human lymphocytes, or NK cell-depleted lymphocyte populations were rejected within 18 days after adoptive cell transfer. In contrast, skin grafts on mice given T cell-depleted human lymphocytes or saline showed no gross or histologic evidence of rejection up to 100 days after adoptive transfer. Purified CD4+ T cells were also able to mediate rejection of porcine skin grafts. These data suggest that human CD4+ T cells are sufficient to induce rejection of porcine xenografts. Thus, strategies directed toward CD4+ T cells may effectively prevent cellular rejection of porcine xenografts in humans. (+info)
(7/1045) Human anti-porcine T cell response: blocking with anti-class I antibody leads to hyporesponsiveness and a switch in cytokine production.
Intervention in the molecular interactions that lead to an immune response is possible at various stages of Ag recognition and T cell activation. Perturbation of the interaction of the TCR with the MHC/peptide ligand complex is one approach that has shown promise for autoimmunity and graft rejection in blocking T cell-activated responses. In this study, we investigated the effect of altering the target MHC class I molecule by blocking with Abs. We established a system that analyzed the human T cell response against MHC class I+/class II- porcine stimulatory cell targets. The primary human response against porcine smooth muscle cells was CD8+ T cell dependent. In the presence of F(ab')2 fragments of the MHC class I-reactive Ab, PT-85, the proliferative response was inhibited and production of IL-2 and IFN-gamma was blocked. Moreover, in a secondary response, proliferation was reduced and type 1 cytokine levels were inhibited. In contrast, levels of IL-10 and IL-4 were sustained or slightly increased. These findings indicate that Ab against MHC class I blocked the recognition of porcine cells by the human CD8+ T cells and altered the cytokine secretion profile. Thus, a single treatment with PT-85 F(ab')2 directed against the MHC class I molecule provides an attractive approach to the induction of T cell tolerance that may provide long-term graft survival in porcine-to-human cell transplantation. (+info)
(8/1045) Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species.
The pharmacokinetics of moxifloxacin was investigated in NMRI mice, Wistar rats, rhesus monkeys, beagle dogs, Gottingen minipigs and healthy human volunteers after i.v. and oral administration of moxifloxacin-HCl (single doses of moxifloxacin 9.2 mg/kg bodyweight) in animals and 100 mg moxifloxacin (1.4 mg/kg bodyweight p.o. and 1.2 mg/kg bodyweight i.v.) in humans. The plasma concentration vs time courses of the unchanged compound (determined by HPLC) and the derived pharmacokinetic parameters were used to evaluate the absorption process, to compare the pharmacokinetics in these species and to perform an interspecies scaling. The results of the pharmacokinetic investigations indicate a clear dependence on the species. Moxifloxacin is absorbed quickly (rats, dogs, humans > monkeys): the major portion of the dose reached the systemic circulation within the first 2 h. In the minipig absorption was slower. Bioavailability was high to moderate (91-52%) in all species. Protein binding (f(u)) was low (55-71%) in all species. The volume of distribution at steady state (Vss) was medium to large (2.0-4.9 L/kg) in all species. There were considerable differences in maximum concentrations (C(max,norm), 0.430-0.070 kg/L) and in AUCnorm values (oral, 6.18-0.184 kg x h/L; i.v., 7.51-0.237 kg x h/L). Total body clearance (CL) decreased with increasing bodyweight (4.21-0.132 L/(h x kg)). The mean residence time (MRT) decreased with decreasing bodyweight (15-0.88 h). The half-life (t(1/2)) decreased with decreasing bodyweight (oral, 12-1.3 h, i.v., 13-0.93 h). There was moderate to low renal excretion (i.v., 20-6.2%), the renal clearance, (CL(R)) was in the range 0.615-0.0222 L/(h x kg). Regarding the pharmacokinetic parameters determined after oral administration, the dog was most similar to the human in terms of Cmax, AUC and t(1/2). There was good correlation between bodyweight and CL (coefficient of correlation (r) = 0.959), Vss (r = 0.990) and MRT (r = 0.943). On the basis of preclinical studies a terminal half-life appropriate for once-daily dosing in humans was predicted and confirmed by Phase I data. (+info)