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L T White

Publications and source records attributed to L T White.

At least 19 recordsLinked to original sources
PubMed2000

Postnatal expression and activity of the mitochondrial 2-oxoglutarate-malate carrier in intact hearts.

This study examines the functional implications of postnatal changes in the expression of the mitochondrial transporter protein, 2-oxoglutarate-malate carrier (OMC). Online (13)C nuclear magnetic resonance ((13)C NMR) measurements of isotope kinetics in hearts from neonate (3-4 days) and adult rabbits provided tricarboxylic acid cycle flux rates and flux rates through OMC. Neonate and adult hearts oxidizing 2.5 mM [2,4-(13)C(2)]butyrate were subjected to either normal or high cytosolic redox state (2.5 mM lactate) conditions to evaluate the recruitment of malate-aspartate activity and the resulting OMC flux. During development from neonate (3-4 days) to adult, mitochondrial protein density in the heart increased from 19 +/- 3% to 31 +/- 2%, whereas OMC expression decreased by 65% per mitochondrial protein content (P < 0.05). Correspondingly, OMC flux was lower in adults hearts than in neonates by 73% (neonate = 7. 4 +/- 0.4, adult = 2.0 +/- 0.1 micromol/min per 100 mg mitochondrial protein; P < 0.05). Despite clear changes in OMC content and flux, the responsiveness of the malate-aspartate shuttle to increased cytosolic NADH was similar in both adults and neonates with an approximate threefold increase in OMC flux (in densitometric units/100 mg mitochondrial protein: neonate = 25.8 +/- 2.5, adult = 6.0 +/- 0.2; P < 0.05). The (13)C NMR data demonstrate that OMC activity is a principal component of the rate of labeling of glutamate.

Age Factors↗
PubMed2000

Substrate-dependent proton load and recovery of stunned hearts during pyruvate dehydrogenase stimulation.

Stimulation of pyruvate dehydrogenase (PDH) improves functional recovery of postischemic hearts. This study examined the potential for a mechanism mediated by substrate-dependent proton production and intracellular pH. After 20 min of ischemia, isolated rabbit hearts were reperfused with or without 5 mM dichloroacetate (DCA) in the presence of either 5 mM glucose, 5 mM glucose + 2.5 mM lactate, or 5 mM glucose + 2.5 mM pyruvate. DCA inhibits PDH kinase, increasing the proportion of dephosphorylated, active PDH. Unlike pyruvate or glucose alone, lactate + glucose did not support the effects of DCA on the recovery of rate-pressure product (RPP) (without DCA, RPP = 14,000 +/- 1,200, n = 6; with DCA, RPP = 13,700 +/- 1,800, n = 9). Intracellular pH, from (31)P nuclear magnetic resonance spectra, returned to normal within 2.1 min of reperfusion with all substrates except for lactate + glucose + DCA or lactate + DCA, which delayed pH recovery for up to 12 min (at 2.1 min pH = 6. 00 +/- 0.08, lactate + glucose + DCA; pH = 6.27 +/- 0.34, for lactate + DCA). Hearts were also reperfused after 10 min of ischemia with 0.5 mM palmitate + 5 mM DCA and either 2.5 mM pyruvate or 2.5 mM lactate. Again, intracellular pH recovery was delayed in the presence of lactate. PDH activation in the presence of lactate also decreased coupling of oxidative metabolism to mechanical work. These findings have implications for therapeutic use of stimulated carbohydrate oxidation in stunned hearts.

Animals↗
PubMed1999

Cytosolic redox state mediates postischemic response to pyruvate dehydrogenase stimulation.

Augmented pyruvate oxidation via pharmacological stimulation of pyruvate dehydrogenase (PDH) during reperfusion has been related to improved recovery of postischemic hearts independent of glycolytic activity. This study examined recovery of postischemic rabbit hearts during activation of PDH with dichloroacetate (DCA) in the presence of lactate, as a source of pyruvate, to determine the response to substrate-dependent changes in cytosolic redox state. After 10 min of ischemia, isolated hearts were reperfused with either 2.5 mM or 0. 5 mM pyruvate (Pyr) or 2.5 mM lactate (Lac), with or without 5 mM DCA. (13)C-enriched substrates allowed NMR assessment of metabolic perturbations. During normal perfusion, Pyr and Lac supported similar mechanical work. Increasing Pyr oxidation restored postischemic rate-pressure product to 82 +/- 4 and 88 +/- 6% of preischemic values during reperfusion with 2.5 and 0.5 mM Pyr, respectively, vs. 61 +/- 6 and 45 +/- 14% for untreated 2.5 and 0.5 mM Pyr, respectively (P < 0.05). In contrast, increasing Lac oxidation did not benefit recovery of RPP in untreated (44 +/- 7%) vs. DCA-treated 36 +/- 4% hearts. Thus the benefit of PDH activation for contractile recovery of postischemic hearts is mediated by the source of pyruvate, which also influences cytosolic redox state.

Animals↗
PubMed1999

Mitochondrial transporter responsiveness and metabolic flux homeostasis in postischemic hearts.

The transport of metabolites between mitochondria and cytosol via the alpha-ketoglutarate-malate carrier serves to balance flux between the two spans of the tricarboxylic acid (TCA) cycle but is reduced in stunned myocardium. To examine the mechanism for reduced transporter activity, we followed the postischemic response of metabolite influx/efflux from mitochondria to stimulation of the malate-aspartate (MA) shuttle. Isolated rabbit hearts were either perfused with 2.5 mM [2-13C]acetate (n = 7) or similarly reperfused (n = 5) after 10-min ischemia. In other hearts, the MA shuttle was stimulated with a high cytosolic redox state (NADH) induced by 2.5 mM lactate in normal (n = 6) or reperfused hearts (n = 7). In normal hearts, the MA shuttle response accelerated transport from 8.3 +/- 3.4 to 16.2 +/- 5.0 micromol. min(-1). g dry wt(-1). Although transport was reduced in stunned hearts, the MA shuttle was responsive to cytosolic NADH load, increasing transport from 3.4 +/- 1.0 to 9.8 +/- 3.7 micromol. min(-1). g dry wt(-1). Therefore, metabolite exchange remains intact in stunned myocardium but responds to changes in TCA cycle flux regulation.

Animals↗
PubMed1998

Dehydrogenase regulation of metabolite oxidation and efflux from mitochondria in intact hearts.

To test how alpha-ketoglutarate dehydrogenase (alpha-KGDH) activity influences the balance between oxidative flux and transmitochondrial metabolite exchange, we monitored these rates in isolated mitochondria and in perfused rabbit hearts at an altered kinetics (Km) of alpha-KGDH for alpha-ketoglutarate (alpha-KG). In isolated mitochondria, relative Km dropped from 0.23 mM at pH = 7.2 to 0.10 mM at pH 6.8 (P < 0.05), and alpha-KG efflux decreased from 126 to 95 nmol.min-1.mg-1. In intact hearts, Km was reduced with low intracellular pH, while matching control workload and respiratory rate with increased Ca2+ (pHi = 7.20, perfusate CaCl2 = 1.5 mM; pHi = 6.89, perfusate CaCl2 = 3 +/- 1 mM). Sequential 13C nuclear magnetic resonance spectra from hearts oxidizing [2-13C]acetate provided tricarboxylic acid cycle flux and the exchange rate between alpha-KG and cytosolic glutamate (F1). Tricarboxylic acid cycle flux was 10 mumol.min-1.g-1 in both groups, but F1 fell from a control of 9.3 +/- 0.6 to 2.8 +/- 0.4 mumol.min-1.g-1 at low Km. The results indicate that increased activity of alpha-KGDH occurs at the expense of alpha-KG efflux during support of normal workloads.

Acetates↗
PubMed1997

Altered metabolite exchange between subcellular compartments in intact postischemic rabbit hearts.

To examine metabolic regulation in postischemic hearts, we examined oxidative recycling of 13C within the glutamate pool (GLU) of intact rabbit hearts. Isolated hearts oxidized 2.5 mmol/L [2-13C]acetate during normal conditions (n = 6) or during reperfusion after 10 minutes of ischemia (n = 5). 13C-Nuclear magnetic resonance spectra were acquired every 1 minute. Kinetic analysis of 13C incorporation into GLU provided both tricarboxylic acid (TCA) cycle flux and the interconversion rate (F1) between the TCA cycle intermediate, alpha-ketoglutarate (alpha-KG), and the largely cytosolic GLU. The rate-pressure product in postischemic hearts was 46% of normal (P < .05). No difference in substrate utilization occurred between groups, with acetate accounting for 92% of the carbon units entering the TCA cycle at the citrate synthase step. TCA cycle flux in postischemic hearts was normal (normal hearts, 10.7 mumol.min-1.g-1; postischemic hearts, 9.4 mumol.min-1.g-1), whereas F1 was 72% lower at 2.9 +/- 0.4 versus 10.2 +/- 2.5 mumol.min-1.g-1 (mean +/- SE) in normal hearts (P < .05). From additional hearts perfused with 2.5 mmol/L [2-13C]acetate plus supplemental 5 mmol/L glucose, any potential differences in endogenous carbohydrate availability were proved not to account for the reduced rate alpha-KG and GLU exchange, which remained depressed in postischemic hearts. However, specific activities of the transaminase enzyme, catalyzing chemical exchange of alpha-KG and GLU, were the same, and transaminase flux was 100 mumol.min-1.g-1 in postischemic hearts versus 68 mumol.min-1.g-1 in normal hearts. Normal transaminase activity and the increased flux in postischemic hearts are contrary to the reduced F1. The findings indicate reduced metabolite transport rates across the mitochondrial membranes of stunned myocardium, particularly through the reversible alpha-KG-malate carrier.

Animals↗
PubMed1996

Subcellular metabolite transport and carbon isotope kinetics in the intramyocardial glutamate pool.

The pathophysiological state of the cell must be translated into the mitochondria to meet the demands for oxidative energy production. Metabolite exchange across the mitochondrial membrane provides this communication and was observed with 13C NMR spectroscopy of hearts oxidizing [2-13C]-butyrate at normal or high cytosolic redox state. Previous NMR observations of 13C turnover within the glutamate pool of intact tissues have indicated its relationship with metabolic flux through the tricarboxylic acid (TCA) cycle, but the direct influence of isotope exchange between the TCA cycle intermediates in the mitochondria and the cytosolic glutamate pool has been much less considered. This current study was designed to determine whether the physical transport of metabolites across the mitochondrial membrane of intact heart tissues could be discerned as a rate determinant for isotope turnover in the NMR-detectable glutamate pool. 13C entry into glutamate provided measures of TCA cycle flux and the interconversion between mitochondrial intermediates and cytosolic glutamate. The influence of the malate-aspartate shuttle activity was examined by comparing two groups of hearts: one group oxidizing 2.5 mM [2-13C]-butyrate (n = 5) and the other oxidizing 2.5 mM [2-13C]butyrate in the presence of a lactate (2.5 mM)-induced elevation in the cytosolic redox to stimulate shuttle activity (n = 5). High redox state did not affect TCA cycle flux but increased the rate of interconversion between alpha-ketoglutarate and glutamate from 3.1 +/- 0.2 mumol min-1 (g dry)-1 to 14.3 +/- 2.0. High resolution 13C NMR spectra of tissue extracts confirmed that the exogenous lactate did not contribute as a carbon source for the formation of either the TCA cycle intermediates or glutamate. In both groups, over 95% of the acetyl-CoA was derived from the short-chain fatty acid butyrate, irrespective of the presence of lactate. Additional hearts perfused with unlabeled butyrate and [3-13C]lactate showed no label entry into glutamate, but rather the formation of [3-13C]alanine, indicating the net reverse flux through lactate dehydrogenase to increase NADH production. Thus, the addition of lactate served only to augment cytosolic redox state to drive the malate-aspartate shuttle. The dynamic-mode acquisition of 13C NMR data from intact hearts, oxidizing [2-13C]-butyrate with or without additional lactate, demonstrated the influence of malate-aspartate shuttle activity on the 13C enrichment rates within glutamate. These data indicate metabolic communication between the mitochondria and cytosol in response to the physiological state of intact tissues.

ATP-Binding Cassette Transporters↗
PubMed1996

Multiplet structure of 13C NMR signal from glutamate and direct detection of tricarboxylic acid (TCA) cycle intermediates.

For the first time, 13C NMR signals are shown from 13C-enriched, low-level tricarboxylic acid (TCA) cycle intermediates from extracts of normal cardiac tissue. As the low tissue content of the key intermediates alpha-ketoglutarate (alpha-KG) and succinate (SUC) in normal, well perfused tissues has until now precluded direct NMR detection from intact tissues and tissue extracts, 13C NMR signal from glutamate has generally been used to infer the isotopomer patterns of intermediates that are in chemical exchange with glutamate. However, the required assumptions regarding intracellular compartmentation for such indirect analysis have not been previously tested, as glutamate is largely cytosolic while the TCA cycle enzymes are located in the mitochondria. Chromatographic isolation of alpha-KG and SUC from heart tissue extracts allowed isotopomer analysis to be performed for comparison with that of glutamate. At steady state, a direct relationship between glutamate and alpha-ketoglutarate isotopomers was found, but succinate isotopomers matched those of glutamate only in hearts that displayed negligible contributions from the oxidation of unlabeled endogenous carbon sources.

Animals↗
PubMed1996

Chemical versus isotopic equilibrium and the metabolic fate of glycolytic end products in the heart.

Recent studies of isotope exchange across lactate dehydrogenase (LDH) and alanine aminotransferase (AAT) in hearts call into question whether both reactions are in equilibrium. To compare the oxidative and non-oxidative fates of glycolytic end products, isolated rabbit hearts were perfused with 5 mM [2-13C] glucose and 2.5 mM [3-13C] pyruvate: with (n = 6) and without (n = 7) stimulation of pyruvate oxidation using dichloroacetate (DCA), and during normal perfusion or hypoxia (n = 7/n = 6, +/- DCA). 13C NMR spectroscopy of intact hearts confirmed a steady-state enrichment level in both alanine and lactate. 1H- and 13C-NMR spectroscopy of tissue extracts identified the fractions of lactate, alanine and glutamate pools formed from each exogenous substrate. Glycolysis from glucose accounted for 22 +/- 7% of lactate formed and 10 +/- 2% of alanine formed in control hearts, and 16 +/- 2% lactate and 15 +/- 2% alanine in hypoxic hearts (mean +/- S.E.M.). In contrast, exogenous pyruvate formed 36 +/- 5% of the lactate pool, and 86 +/- 3% of the alanine pool in controls and 47 +/- 3% of lactate and of 67 +/- 3% alanine during hypoxia. [2(-13)C] glucose did not contribute to oxidative energy production via the TCA cycle as determined from low 13C enrichment of glutamate C5 from glucose (< 2%), while [3-13C] pyruvate accounted for 84 +/- 7% of labeled glutamate C4. Thus, exogenous pyruvate out-competed the metabolism of glucose, indicating low glycolytic activity. At 40 min, 96 +/- 2% of the total alanine was labeled from either glucose or pyruvate, confirming equilibrium at AAT. However, only 55 +/- 10% of total lactate was labeled, suggesting that the LDH reaction is not in rapid equilibrium within the myocardium.

Animals↗
PubMed1995

Pyruvate dehydrogenase influences postischemic heart function.

BACKGROUND: The pyruvate dehydrogenase (PDH) enzyme complex determines the extent of carbohydrate oxidation in the myocardium. PDH is in a largely inactive state during early reperfusion of postischemic myocardium. The resultant decrease in pyruvate oxidation in postischemic hearts has been documented with 13C nuclear magnetic resonance (NMR) spectroscopy. This study demonstrates that counteracting depressed pyruvate oxidation can enhance contractile recovery in the absence of increases in either glycolytic activity or glucose oxidation. The findings indicate that increased incorporation of carbon units from pyruvate into the intermediates of the oxidative pathways by PDH influences the metabolic efficiency and mechanical work of postischemic hearts. METHODS AND RESULTS: Isolated rabbit hearts were situated in an NMR magnet and perfused or reperfused (10 minutes of ischemia) with 2.5 mmol/L [3-13C]pyruvate as sole substrate to target PDH directly and bypass the glycolytic pathway. Hearts were observed with or without activation of PDH with dichloroacetate. Mechanical function and oxygen consumption (MVO2) were monitored. 13C and 31P NMR spectroscopy allowed observations of pyruvate oxidation and bioenergetic state in intact, functioning hearts. Metabolite content and 13C enrichment levels were then determined with in vitro NMR spectroscopy and biochemical assay. PDH activation did not affect performance of normal hearts. Postischemic hearts with augmented pyruvate oxidation (dichloroacetate-treated) sustained improved mechanical function throughout 40 minutes of reperfusion. Rate-pressure-product (RPP) increased from 8300 +/- 1800 (mean +/- SEM) in untreated postischemic hearts to 21,300 +/- 2400 in hearts treated with dichloroacetate (P < .05). Oxygen use per unit work [MVO2 multiplied by 10(4) divided by RPP] was improved from 1.50 +/- 0.13 to 1.14 +/- 0.11 (P < .05) without differences in high-energy phosphate content between treated and untreated hearts. Values of dP/dt were also consistently higher, by as much as 185%, during reperfusion with dichloroacetate. Postischemic hearts displayed reduced pyruvate oxidation from the incorporation of 13C into the tissue glutamate pool. With the tissue alanine level as a marker of 13C-enriched pyruvate availability in the cell, the ratio of labeled glutamate to alanine was only 58% of the control value during early reperfusion. With dichloroacetate, that ratio was 167% greater than that of untreated hearts (P < .05). By the end of the reperfusion period, the 13C enrichment of the tissue glutamate pool by pyruvate oxidation was elevated from dichloroacetate treatment (untreated, 62 +/- 7%; DCA-treated, 81 +/- 6%; P < .05), but glycogen content was similar in both groups and 13C enrichment of tissue alanine remained unchanged, near 60%, indicating no increases in glycolytic end-product formation. CONCLUSIONS: Metabolic reversal of contractile dysfunction was achieved in isolated hearts by counteracting depressed PDH activity in the postischemic myocardium. Improved cardiac performance did not result from, nor require, increased glycolysis secondary to the activation of PDH. Rather, restoring carbon flux through PDH alone was sufficient to improve mechanical work by postischemic hearts.

Adenosine Triphosphate↗
PubMed1995

Kinetic analysis of dynamic 13C NMR spectra: metabolic flux, regulation, and compartmentation in hearts.

Control of oxidative metabolism was studied using 13C NMR spectroscopy to detect rate-limiting steps in 13C labeling of glutamate. 13C NMR spectra were acquired every 1 or 2 min from isolated rabbit hearts perfused with either 2.5 mM [2-13C]acetate or 2.5 mM [2-13C]butyrate with or without KCl arrest. Tricarboxylic acid cycle flux (VTCA) and the exchange rate between alpha-ketoglutarate and glutamate (F1) were determined by least-square fitting of a kinetic model to NMR data. Rates were compared to measured kinetics of the cardiac glutamate-oxaloacetate transaminase (GOT). Despite similar oxygen use, hearts oxidizing butyrate instead of acetate showed delayed incorporation of 13C label into glutamate and lower VTCA, because of the influence of beta-oxidation: butyrate = 7.1 +/- 0.2 mumol/min/g dry wt; acetate = 10.1 +/- 0.2; butyrate + KCl = 1.8 +/- 0.1; acetate + KCl = 3.1 +/- 0.1 (mean +/- SD). F1 ranged from a low of 4.4 +/- 1.0 mumol/min/g (butyrate + KCl) to 9.3 +/- 0.6 (acetate), at least 20-fold slower than GOT flux, and proved to be rate limiting for isotope turnover in the glutamate pool. Therefore, dynamic 13C NMR observations were sensitive not only to TCA cycle flux but also to the interconversion between TCA cycle intermediates and glutamate.

Acetates↗
PubMed1995

Cardiac responses to induced lactate oxidation: NMR analysis of metabolic equilibria.

The role of lactate as a source of pyruvate oxidation in supporting cardiac work, energetics, and formation of oxidative metabolites was examined in normal myocardium. 13C- and 31P-nuclear magnetic resonance (NMR) spectra were acquired from isolated rabbit hearts supplied 2.5 mM [3-13C]lactate or [3-13C]pyruvate with or without stimulation of pyruvate dehydrogenase (PDH) by dichloroacetate (DCA). Similar workloads determined by rate-pressure products were noted with pyruvate (21,700 +/- 2,400; mean +/- SE) and lactate (18,970 +/- 1,510). Oxygen consumption was similar in all four groups with means between 19.0 and 22.2 mumol.min-1.g dry weight-1 (SE = 1.6-2.0) as was the ratio of phosphocreatine to ATP with means between 1.8 and 2.1 (SE = 0.1-0.6). Intracellular pH, determined from 31P-NMR spectra, was essentially the same with pyruvate (7.06 +/- 0.02) and lactate (7.05 +/- 0.04). 13C enrichment of glutamate was higher with lactate (92%) than with pyruvate (70%). Pyruvate plus DCA induced no change in glutamate content at 9-10 mumol/g, but 13C enrichment increased to 83%, while lactate plus DCA maintained enrichment at 90%. Levels of alpha-ketoglutarate were lower with lactate (1.81 mumol/g) than with pyruvate (2.36 mumol/g). Lactate plus DCA elevated glutamate by 60% with a proportional increase in alpha-ketoglutarate. Thus the balance between glutamate and alpha-ketoglutarate was affected by substrate supply only and not by PDH activation. The results suggest that the equilibrium between alpha-ketoglutarate and glutamate is sensitive to cytosolic redox state, an important consideration for 13C-NMR analyses that rely on glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The influence of HLA matching on cytomegalovirus hepatitis and chronic rejection after liver transplantation.

Previous findings in liver transplantation patients have raised the concept that HLA plays a dualistic role. HLA matching will reduce rejection but may augment MHC restricted cellular immune mechanisms of liver allograft injury. To evaluate this concept, we studied CMV hepatitis in 399 FK506-treated liver transplant patients, including 355 cases for which complete HLA-A,B,DR,DQ typing information was available. CMV hepatitis developed in 25 patients, and 17 of them (or 68%) showed a one or two HLA-DR antigen match with the donor. In contrast, HLA-DR matches were found in only 35% of 330 patients without CMV hepatitis (P = 0.005). No significant associations were seen for HLA-A, HLA-B, and HLA-DQ antigens. In pretransplant CMV-seronegative patients with seropositive grafts (n = 39), the frequency of CMV hepatitis was 44% for HLA-DR-matched livers but 14% for HLA-DR-unmatched livers. In seropositive recipients (n = 187), these frequencies were 12% and 2% for HLA-DR-matched and unmatched liver grafts. Chronic rejection developed in 29 patients (or 8%) during a follow-up between 10 and 24 months after transplantation. Its incidence was higher in the CMV hepatitis group (24% vs. 6%) (P = 0.007). Although no associations were found between HLA matching and the incidence of chronic rejection, there was an earlier onset of chronic rejection of HLA-DR-matched livers irrespective of CMV hepatitis. These findings suggest that an HLA-DR match between donor and recipient increases the incidence of CMV hepatitis in both primary and secondary CMV infections. Although HLA compatibility leads to less acute cellular rejection, it is suggested that DR matching may accelerate chronic rejection of liver transplants, perhaps through HLA-DR-restricted immunological mechanisms toward viral antigens, including CMV.

Chronic Disease↗
PubMed1991

Influence of diet and calorie restriction on the initiation and promotion of skin carcinogenesis in the SENCAR mouse model.

Diets were restricted to 60% of the intake of the control mice by feeding less diet (total diet restriction, TDR) or by feeding fewer calories from fat and carbohydrate (calorie restriction, CR) during the initiation or promotion phases of skin tumorigenesis in female SENCAR mice. Skin cancer was initiated by topical treatment with 10 nmol of 7,12-dimethylbenzanthracene in acetone and promoted by twice weekly treatments with 12-O-tetradecanoylphorbol-13-acetate in acetone for 20 wk. Dietary restriction preceding and during 7,12-dimethylbenzanthracene treatment did not influence skin papilloma or carcinoma yield. Papilloma incidence and the number of papillomas per effective mouse were reduced in mice restricted by both TDR and CR protocols during and following promotion with 12-O-tetradecanoylphorbol-13-acetate. Papilloma size was reduced at experimental wk 16 and 20 in both TDR and CR groups fed these diet regimens during promotion. However, by wk 28 and 32, papilloma sizes were similar in the control and TDR groups, and smaller papillomas were observed only in the CR group. The average carcinoma latency was extended by 26% in the groups restricted during promotion, and incidence was reduced in both groups. The reduction, however, was statistically significant only in the CR group. Body weight gain was reduced during the times when dietary restriction was enforced, and in a short-term study, both restricted diet treatments reduced the percentage of carcass protein.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Comparison of the effects of dietary beef tallow and corn oil on pancreatic carcinogenesis in the hamster model.

We previously reported an enhancement of pancreatic carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters fed diets containing high levels of corn oil. The research presented here compared diets high in corn oil with those high in beef tallow in the enhancement of pancreatic carcinogenesis. Pancreatic cancer was induced with 20 mg BOP/kg body wt, s.c. administered at 8 weeks of age. One week later, hamsters were assigned to one of five diet treatments: (i) 4.3% corn oil (control); (ii) 20.5% corn oil (high corn oil); (iii) 0.5% corn oil + 3.8% beef tallow (low beef tallow); (iv) 0.6% corn oil + 19.9% beef tallow (high beef tallow); and (v) 5.1% corn oil + 15.4% beef tallow (high fat mixture). These diets were fed until the study ended 84 weeks after BOP treatment. Hamsters were trained through pair feeding to consume the same calorie allotment as the control corn oil group. By the end of the experiment, BOP-treated hamsters that were fed diets containing beef tallow were consistently heavier than those fed corn oil. Survival was longer in hamsters fed the high-beef tallow and high-fat mixture compared with the other diet groups. Tumor data were age adjusted to correct for survival differences. Pancreatic adenoma incidence and multiplicity (no./effective animal) were higher in hamsters fed beef tallow than those fed corn oil diets. Carcinoma in situ multiplicity was elevated in hamsters fed high-fat diets irrespective of the nature of fat fed. Pancreatic adenocarcinoma multiplicity was elevated in hamsters fed the low- or high-beef tallow diets compared with the low- or high-corn oil diets. The mixture of fat resulted in an intermediate yield.

Adenocarcinoma↗
PubMed1990

Multiscreen serum analysis of highly sensitized renal dialysis patients for antibodies toward public and private class I HLA determinants. Implications for computer-predicted acceptable and unacceptable donor mismatches in kidney transplantation.

A multiscreen serum analysis program has been developed that permits a determination of antibody specificity for the vast majority of highly sensitized patients awaiting transplantation. This program is based on a 2 x 2 table analysis of correlations between serum reactivity with an HLA-typed cell panel and incorporates two modifications. One implements the concept of public HLA determinants based on the serologic crossreactivity among class I HLA antigens. The other modification derives from the premise that most highly sensitized patients maintain the same PRA and antibody profiles over many months and even years. Monthly screening results for patients with persistent PRA values can therefore be combined for analysis. For 132 of 150 highly sensitized patients with greater than 50% PRA, this multiscreen serum analysis program yielded information about antibody specificity toward public and private class I HLA determinants. The vast majority of patients (108 of 112) with PRA values between 50 and 89% showed antibody specificity generally toward one, two, or three public markers and/or the more common private HLA-A,B antigens. For 24 of 38 patients with greater than 90% PRA, it was possible to define one or few HLA-specific antibodies. The primary objective of the multiscreen program was to develop an algorithm about computer-predicted acceptable and unacceptable donor HLA-A,B antigens for patients with preformed antibodies. A retrospective analysis of kidney transplants into 89 highly sensitized patients has demonstrated that allografts with unacceptable HLA-A,B mismatches had significantly lower actuarial survival rates than those with acceptable mismatches (P = 0.01). This was shown for both groups of 32 primary transplants (44% vs. 67% after 1 year) and 60 retransplants (50% vs. 68%). Also, serum creatinine levels were significantly higher in patients with unacceptable class I mismatches (3.0 vs. 8.4 mg% [P = 0.007] after 2 weeks; 3.9 vs. 9.1 mg% [P = 0.014] after 4 weeks). Histopathologic analysis of allograft tissue specimens from 47 transplant recipients revealed a significantly higher incidence of humoral rejection (P = 0.02), but not cellular rejection, in the unacceptable mismatch group. These results suggest that the multiscreen program can establish which donor HLA-A,B mismatches must be avoided in kidney transplantation for most highly sensitized patients. For 18 of 150 high PRA renal dialysis patients, the multiscreen program could not define HLA-specific antibody. Most patients had greater than 90% PRA, and many of their sera appeared to contain IgM type nonspecific lymphocytotoxins that could be inactivated by dithioerythreitol (DTE).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗