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Biomedical subjects

Q R Rogers

Publications and source records attributed to Q R Rogers.

At least 19 recordsLinked to original sources
PubMed2000

Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer.

Previous studies have revealed that adenovirus-mediated ectopic liver expression of human LPL (huLPL) can efficiently mediate plasma triacylglycerol (TG) catabolism in mice despite its native expression in adipose and muscle tissue. We aimed to explore the feasibility of liver-directed gene transfer and enzyme replacement for human LPL deficiency in a larger, naturally occurring feline animal model of complete LPL deficiency that is remarkably similar in phenotype to the human disorder. A cohort of LPL-deficient (LPL -/-) cats was given an intravenous injection of 8 x 10(9) PFU/kg of a CMV promoter/enhancer-driven, E1/E3-deleted adenoviral (Ad) vector containing a 1.36-kb huLPL cDNA (Ad-LPL) or reporter alkaline phosphatase gene (Ad-AP). After Ad-LPL administration, active, heparin-releasable huLPL was readily detected along with a 10-fold reduction in plasma TGs, disappearance of plasma TG-rich lipoproteins up to day 14, and enhanced clearance of an excess intravenous fat load on day 9. However, antibody against the huLPL protein was detected on day 14 in cats receiving Ad-LPL and adenovirus-specific neutralizing antibody was present 7 days after gene transfer in both cat cohorts. Tissue-specific expression of the huLPL transgene relative to controls was confirmed by RT-PCR. While huLPL expression was evident in the liver, other tissues including spleen and lung expressed huLPL message, in direct correlation with histological evidence of increased Oil red O (ORO)-positive neutral lipid influx. In contrast, intravenous LPL enzyme replacement therapy (ERT) led to rapid disappearance of 9000 mU/kg of active bovine LPL enzyme from the circulation, with t1/2 occurring at <10 min in two LPL-/- cats. Heparin injection 1 hr later released <10% of the original bovine LPL, further indicating its rapid systemic clearance, inactivation, or degradation as well as its ineffectiveness as a viable therapeutic alternative for complete LPL deficiency. Although LPL gene transfer and expression via this first-generation Ad vector was limited by the immune response against both the human LPL protein and adenovirus our results clearly provide a key advance supporting further development of LPL gene therapy as a viable therapeutic option for clinical LPL deficiency.

Adenoviridae↗
PubMed1999

Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin.

OBJECTIVE: To determine the effectiveness and safety of asparaginase administered s.c. versus i.m. for treatment of multicentric lymphoma in dogs receiving doxorubicin. DESIGN: Prospective study. ANIMALS: 49 dogs with multicentric lymphoma. PROCEDURE: Dogs were treated with doxorubicin every 3 weeks, for a total of 5 treatments, and were given 3 weekly treatments of asparaginase, s.c. or i.m. Using high-performance liquid chromatography, mean plasma asparagine, aspartic acid, glutamine, and glutamic acid concentrations were determined in dogs before and during treatment with asparaginase (10,000 U/m2 of body surface area, once a week for 3 weeks). Asparaginase was administered s.c. in 23 dogs and i.m. in 26 dogs. Variables evaluated included time to response to chemotherapy, remission and survival times, and clinical and serum biochemical indicators of toxicoses. RESULTS: Using the World Health Organization's staging system for lymphoma, 30 dogs were in clinical stage III and 19 were in clinical stage IV. One week after asparaginase treatment, plasma asparagine concentrations were low and plasma aspartic acid, glutamine, and glutamic acid concentrations were high. Differences in plasma amino acid concentrations were not found between s.c. and i.m. groups. For dogs in clinical stage IV, i.m. administration of asparaginase significantly decreased the number of days to complete remission, compared with s.c. administration (8 vs 17 days, respectively). For dogs in clinical stage III, i.m. administration favorably increased the duration of first remission (191 vs 103 days) and survival time (289 vs 209 days). Overall, dogs treated i.m. had a faster response to chemotherapy (9 vs 15 days), a longer remission (191 vs 109 days), and a longer survival time (286 vs 198 days), compared with all dogs treated s.c. Asparaginase toxicoses were not observed regardless of the route of administration. CLINICAL IMPLICATIONS: For dogs with multicentric lymphoma that are receiving doxorubicin, i.m. treatment with asparaginase is more effective than s.c. treatment.

Animals↗
PubMed1999

Lipid and lipoprotein analysis of cats with lipoprotein lipase deficiency.

BACKGROUND: We have previously described a colony of domestic cats with a naturally occurring mutation in the lipoprotein lipase (LPL) gene. We have now further characterized cats homozygous for LPL deficiency (LPL -/-, homozygotes), and have contrasted these with heterozygotes (LPL +/-) and normal cats (LPL +/+). MATERIALS AND METHODS: Density gradient ultracentrifugation with subsequent lipid analysis, agarose and polyacrylamide gel electrophoresis was used to examine detailed liproprotein differences between the genotypes. Oral fat loading studies and breast milk fatty acid analysis were also performed to further characterize the phenotypic expression of LPL deficiency in this model system. RESULTS: Several lipid abnormalities associated with homozygosity for LPL deficiency were evident. Triglyceride-rich lipoprotein-triglycerides (TRL-TG) and cholesterol (TRL-C) were higher (TRL-TG 2.09 +/- 1.14 vs. 0.15 +/- 0.04 mmol L-1, P < 0.001; TRL-C 0.42 +/- 0.30 vs. 0.11 +/- 0.16 mmol L-1, P < 0.05) in male -/- than in male +/+ cats, as was HDL-cholesterol (HDL-C, 1.75 +/- 0.24 vs. 1.41 +/- 0.14 mmol L-1, P < 0.05). LDL-C levels were lower in homozygous cats than in control cats, similar to what is seen in human LPL deficiency. Oral fat loading studies revealed that homozygous cats have a marked reduced ability to clear plasma TGs in terms of peak time (7 h vs. 3 h), peak height (9.36 vs. 1.1 mmol L-1), area under the TG clearance curve (AUC, 280.3 vs. 2.2 h mmol L-1) and time to return to baseline. Fasting lipid and lipoprotein levels were not significantly different between heterozygous and normal cats. However, oral fat loading in heterozygotes revealed an intermediate phenotype (peak of 2.35 mmol L-1 at 5 h, AUC 13.1 h mmol L-1), highlighting the impaired TG clearance in these animals. CONCLUSION: Thus, LPL deficiency in the cat results in a lipid and lipoprotein phenotype that predominantly parallels human LPL deficiency, further validating the use of these animals in studies on the pathobiology of LPL.

Animals↗
PubMed1999

High dietary protein and taurine increase cysteine desulfhydration in kittens.

The objective of this study was to determine the effect of dietary protein and taurine on cysteine desulfhydration in various kitten tissues. Cysteine desulfhydration was assessed in liver, kidney, skeletal muscle, heart, spleen, brain and jejunum of kittens fed one of the following diets for 5 wk: 20% protein, 0% taurine diet (LP0T); 20% protein, 0.15% taurine diet (LPNT); 60% protein, 0% taurine diet (HP0T); and 60% protein, 0.15% taurine diet (HPNT). Cats fed LP0T and HP0T had been fed a taurine-free diet for 10 wk before the 5-wk experiment. The activity of cysteine desulfhydration was determined by measuring the production of H(2)(35)S from (35)S-cysteine in the presence and absence of alpha-ketoglutarate (alphaKG) in the incubation medium. Liver and kidney had the highest total activities among the tissues tested (P < 0.01). Total hepatic desulfhydration activities [micromol H(2)S/(min. kg body wt)] in cats fed LP0T, LPNT, HP0T and HPNT were (mean +/- SEM) 117 +/- 6, 135 +/- 10, 137 +/- 10 and 190 +/- 9, respectively. Dietary taurine had a significant effect on activity when expressed per gram liver (P < 0.01), per gram protein (P < 0.05) and per kilogram body weight (P < 0.001). Dietary protein had a significant effect (P < 0.001) only when activity was expressed relative to body weight because of the significant effect of protein on relative liver weight. The direct pathway via cysteine desulfhydrase appears to be the major route of cysteine desulfhydration in kitten liver because the values obtained in the absence of alphaKG were 81-88% of those obtained in the presence of alphaKG.

Animals↗
PubMed1999

Lysine deficiency alters diet selection without depressing food intake in rats.

Under states of protein deficiency, the dietary limiting amino acid, rather than protein content, can act as the dietary stimulus to control diet selection. If fact, threonine-deficient rats will alter their diet selection patterns solely on the basis of very small changes (0.009 g/100 g) in the dietary threonine concentration. In these studies, we assessed whether lysine-deficient rats will also alter their diet selection patterns on the basis of small changes in dietary Lys concentration. In all experiments, growing rats were adapted to diets in which the protein fraction (purified amino acids or wheat gluten) was limiting in Lys. They were then given a choice between the adaptation diet (AD) diet and a slightly more deficient diet. Rats that were adapted to a Lys-deficient diet (0.25 g Lys/100 g) selected their AD over diets containing as little as 0.01% less Lys (P < 0.01) within 5 d. To determine how deficient rats must be before they alter their selection patterns, rats were adapted to diets containing various levels of Lys, i.e., 2 levels below the requirement for growth and 2 levels above the requirement for growth, but below the requirement for maximal nitrogen retention. Only rats adapted to diets containing Lys below their requirement for growth selected their AD over a diet containing 0.05% less Lys (P < 0.005). Finally, to determine whether rats will alter their selection to whole protein-based diets, rats were adapted to 25% wheat gluten diets supplemented with 0.03-0.21% Lys. Rats selected the AD over a diet containing as little as 0.09% less supplemental Lys by d 4 of the trial (P < 0.05). We conclude that rats are sensitive to changes as small as 0.01% in dietary Lys concentration, but that sensitivity requires prior adaptation to Lys-deficient diets.

Adaptation, Physiological↗
PubMed1999

Effects of glutamine supplementation of an amino acid-based purified diet on intestinal mucosal integrity in cats with methotrexate-induced enteritis.

OBJECTIVE: To determine effects of glutamine-supplemented and glutamine-free amino acid-based purified diets, compared with a dry expanded diet, on intestinal structure and function in a model that used cats with methotrexate-induced enteritis. ANIMALS: 18 adult specific-pathogen-free cats. PROCEDURE: 12 cats were given intragastric feedings of an amino acid-based purified diet supplemented with glutamine (7% [wt:wt]) or an isonitrogenous amount of glycine and alanine; 6 cats consumed a dry expanded diet. After 21 days, cats received methotrexate (MTX; 11 mg/kg of body weight, IV). Intestinal permeability testing was performed immediately before and 66 hours after MTX administration. Celiotomy was performed 72 hours after MTX administration for aseptic removal of mesenteric lymph nodes, collection of full-thickness intestinal biopsy specimens, determination of intestinal cellular proliferation, and collection of aortic and portal venous blood samples for determination of arteriovenous amino acid concentrations across the intestine. RESULTS: Administration of MTX was associated with severe enterotoxicosis manifested as diarrhea (8/12 cats), vomiting (12/12), and positive results for bacterial culture of mesenteric lymph nodes (12/12) in cats receiving the purified diets, independent of glutamine supplementation. Diet did not affect villus tip length and villus surface area in the small intestine or cellular proliferation. Administration of MTX was associated with significantly increased intestinal permeability, which was not attenuated by glutamine supplementation. CONCLUSIONS: Feeding of a glutamine-supplemented amino acid-based purified diet was unable to preserve intestinal function in cats with MTX-induced enteritis. CLINICAL RELEVANCE: Intestinal morphologic alterations correlate poorly with intestinal function as measured by means of bacterial translocation and intestinal permeability.

Amino Acids↗
PubMed1999

Plasma amino acid profiles in cats with naturally acquired chronic renal failure.

OBJECTIVE: To characterize potential changes in preprandial plasma amino acid concentrations in cats with naturally acquired chronic renal failure (CRF), compared with healthy cats, and to assess potential effects of the severity of renal failure on plasma amino acid concentrations in these cats. ANIMALS: 62 adult cats. PROCEDURE: Preprandial plasma amino acid concentrations were evaluated in 38 cats with mild, moderate, or severe CRF and in 24 apparently healthy cats. Effects of severity of renal failure, amount of dietary protein, degree of weight loss, appetite, and body condition on plasma amino acid profiles were evaluated. RESULTS: Cats with various stages of CRF had significantly (P< 0.05) decreased plasma concentrations of o-hydroxyproline, glutamate, proline, glycine, alanine, tyrosine, tryptophan, and arginine, and significantly increased plasma concentrations of asparagine, citrulline, ornithine, 1-methylhistidine, and 3-methylhistidine. Significant (P < 0.05) alterations in amino acid concentrations also were identified when cats with CRF were grouped by appetite or severity of renal disease. Amount of dietary protein, body condition, or degree of weight loss had no significant effect on plasma amino acid concentrations. CONCLUSIONS: Compared with those in healthy cats, preprandial plasma amino acid profiles in cats with mild, moderate, or severe CRF are abnormal. CLINICAL RELEVANCE: Despite frequency of altered plasma amino acid concentrations in cats with CRF, the magnitude of these changes is mild and of little clinical relevance. Short-term use of a commercial protein-restricted diet has no deleterious effects on plasma amino acid concentrations.

Amino Acids↗
PubMed1998

Heinz body formation in cats fed baby food containing onion powder.

OBJECTIVE: To determine whether cats fed baby food with onion powder develop Heinz bodies and anemia and to establish a dose-response relation between dietary onion powder content and Heinz body formation. DESIGN: Prospective study. ANIMALS: 42 healthy, adult, specific-pathogen-free cats. PROCEDURE: Commercial baby food with and without onion powder was fed to 2 groups of 6 cats for 5 weeks. Heinz body percentage, PCV, reticulocyte percentage, turbidity index, and methemoglobin and reduced glutathione concentrations were determined twice weekly and then weekly for 4 weeks following removal of the diet. For the dose-response study, 5 groups of 6 cats were fed a canned diet for 2 months that contained 0, 0.3, 0.75, 1.5, or 2.5% onion powder. Heinz body percentage, PCV, and reticulocyte percentage were determined twice weekly. RESULTS: Compared with cats fed baby food without onion powder, cats ingesting baby food with onion powder had significantly higher Heinz body percentages that peaked at 33 to 53%. Methemoglobin concentration also significantly increased but did not exceed 1.2%. Glutathione concentration, PCV, and food intake did not differ between the 2 groups. Rate and degree of Heinz body formation differed significantly between various onion powder concentrations fed. Compared with 0% onion powder, the diet with 2.5% onion powder caused a significant decrease in PCV and an increased punctate reticulocyte percentage. CLINICAL IMPLICATIONS: Baby food or other foods containing similar amounts of onion powder should be avoided for use in cats because of Heinz body formation and the potential for development of anemia, particularly with high food intake. Cats with diseases associated with oxidative stress may develop additive hemoglobin damage when fed baby food containing onion powder.

Anemia, Hemolytic↗
PubMed1998

Maximal growth occurs at a broad range of essential amino acids to total nitrogen ratios in kittens.

Kittens fed diets containing 2.0 and 3.0 times (x) the NRC (1986) essential amino acid (EAA) requirement (EAArq) and 210 to 560 g crude protein (CP)/kg diet had growth rates and plasma amino acid patterns that were not significantly different than kittens fed a control diet (CD) containing 1.5 x EAArq and 350 g CP/kg diet. Growth rates of kittens fed diets containing only EAA (with nontoxic levels of arginine and methionine) and 280 to 460 g CP/kg diet were equivalent to those of kittens fed CD. Kittens fed only EAA and 140 and 210 g CP/kg diet had growth rates that were significantly lower than kittens fed CD. Since the growth rate of kittens fed 1.5 x EAArq and 210 g CP/kg diet in a previous experiment was equivalent to kittens fed CD (Taylor et al., 1997), it is suggested that the requirement for CP is higher (up to 280 g CP/kg diet) when only EAA are fed. The higher crude protein requirement appears to be primarily a consequence of the high obligatory nitrogen loss as urea (especially from arginine) incurred in the conversion of nitrogen from EAA to dispensable amino acids in the liver and secondarily because of a slow rate of catabolism of the EAA. A 3-dimensional plot of weight gains vs. CP levels and EAA to total nitrogen (E:T) ratios of kittens shows a broad range of CP levels and E:T ratios that support optimal growth in the kitten. It is suggested that similar patterns would occur in the chick, rat and other species if adverse effects caused by excesses of specific amino acids are avoided.

Amino Acids↗
PubMed1998

Dietary excess of vitamin B-6 affects the concentrations of amino acids in the caudate nucleus and serum and the binding properties of serotonin receptors in the brain cortex of rats.

Vitamin B-6 is a cofactor in many reactions of nitrogen metabolism. Deficiency alters tissue amino acid concentrations but effects of excess vitamin B-6 have not been well described. We fed female rats (218 g, 7 per group) 1 (control), 10, 100, 175 or 250x) the National Research Council recommended level of pyridoxine HCl (7 mg/kg) for 10 wk and measured serum amino acids, amino acids and neurotransmitters in brain regions and the binding properties of serotonin receptors in the cerebral cortex using a ketanserin binding assay. Rats were decapitated, and unheparinized blood was obtained. In the caudate nucleus, concentrations of glutamate, threonine, taurine, methionine, gamma-amino-butyric acid and the sum of the essential amino acids in groups 10X and 100X were approximately 130 to 180% of control levels (P < 0.05); groups 1X, 175X and 250X were not different. A similar pattern was seen in the serum for serine, glycine, aspartate and ornithine; the latter two amino acids increased to over 200% of control in group 100X. In the ketanserin binding assay, both the antagonist binding affinity and the maximal number of binding sites were higher for group 100X than for 1X, 175X and 250X, and were higher for 10X than for 1X. Norepinephrine in the raphe nucleus followed a similar biphasic pattern. Excess dietary pyridoxine affected brain and serum concentrations of some amino acids and binding properties of cortical serotonin receptors in a biphasic pattern over the range of concentrations fed in this study.

Amino Acids↗
PubMed1998

Vitamin B-6 deficiency and level of dietary protein affect hepatic tyrosine aminotransferase activity in cats.

Total activity [pyridoxal 5'-phosphate (PLP) added in the assay] of hepatic tyrosine aminotransferase (TAT) measured in cats at 0300, 0900, 1500 and 2100h was 10.3 +/-1.1, 14.0 +/- 0.7, 9.8 +/- 1.3 and 11.0 +/- 0.7 nkat/g liver, indicating little diurnal variation. Activity after 18 h of food deprivation was 10.0 +/- 0.3 nkat/g liver, also not different from cats that were eating ad libitum. These findings support the idea that cats have only limited changes in the activity of hepatic TAT compared with rats. Total TAT activity was measured in cats fed high protein (550 g/kg) and low protein (180 g/kg) diets for 4 wk. Cats fed a high protein diet had activities significantly higher (about twice) than cats fed the low protein diet. Hepatic TAT activity of vitamin B-6-deficient cats (diet without pyridoxine for 9 wk) was compared with cats given the same diet with 8 mg pyridoxine/kg. Total hepatic TAT activity in deficient cats was significantly (P < 0.05) lower per gram soluble or total protein (but not per gram liver) than control cats; holoenzyme activity and percentage of active enzyme in deficient cats were also significantly lower by 75 and 64%, respectively. The apparent Km of TAT from cats for tyrosine (2.1 mmol/L) was similar to that for rats (1.9 mmol/L), but higher for PLP in cats (0.16 micromol/L) than rats (0.034 micromol/L). Part of the reason for the higher plasma tyrosine in vitamin B-6-deficient cats than rats is the higher Km of TAT for PLP in cats than rats.

Animals↗
PubMed1998

Taurine status in cats is not maintained by dietary cysteinesulfinic acid.

Endogenous synthesis of taurine by cats is limited. Putative precursors of taurine, cysteinesulfinic acid and cysteic acid, were fed to cats to determine whether they were utilized. Groups of five cats were depleted of taurine by a resin (Colestipol(R)) diet, then given 6 dietary treatments containing (g/kg diet): 0.0, 0.4, or 0.8 taurine; or 0.98 or 1.96 cysteinesulfinic acid, or 0.4 taurine + 1.0 cysteic acid for 12 wk. Plasma and whole blood taurine concentrations and body weights were measured weekly. Concentration of taurine in semitendinosus muscle was measured initially, after 2 wk of taurine depletion (after resin-diet), and monthly thereafter. The resin diet decreased concentrations of taurine in plasma, whole blood, and muscle to 0.20, 0.49, and 0.37 of initial values, respectively. Cysteinesulfinic acid diets resulted in no significant (P > 0.05) increase in the concentration of taurine in plasma, whole blood, or muscle, and no increased excretion of cysteinesulfinate or taurine in urine or feces. Cats fed the diets containing 1.0 g cysteic acid + 0.4 g taurine, or 0.8 g taurine/kg diet had similar concentrations of taurine in plasma, whole blood, and muscle. Aminotransferase activity for cysteinesulfinic acid in the liver and intestinal mucosa of cats and rats was higher than that for aspartic or cysteic acids. Transamination of dietary cysteinesulfinic acid to beta-sulfinylpyruvate (which spontaneously decomposes), rather than decarboxylation is postulated as the basis for no detectable conversion to taurine. In contrast, cysteic acid is reversibly transaminated to beta-sulfopyruvate which is stable and thereby is a precursor for taurine in cats.

Animals↗
PubMed1998

Neurochemical changes after imbalanced diets suggest a brain circuit mediating anorectic responses to amino acid deficiency in rats.

Amino acid-imbalanced (IMB) diets induce an acute amino acid deficiency and hypophagic responses in most animals. The neural circuits underlying these responses are unknown. To ascertain potential neural circuits involved in the recognition of IMB, we measured the concentrations of norepinephrine, dopamine, serotonin, their metabolites and 20 amino acids in 14 rat brain areas in three studies. Rats were prefed a basal diet with L-amino acids as the protein source for at least 1 wk. For the experiments, either threonine or isoleucine IMB diet was offered for 2.5 or 3.5 h. Brains were taken before (using a mildly IMB diet) or after (using moderately or severely IMB diet) food intake was significantly (P < 0.05) depressed. Brain areas were dissected and analyzed for monoamines, metabolites and amino acids. Only in the anterior piriform cortex (APC), a brain area that may contain the amino acid chemosensor, was the limiting amino acid lower in IMB groups than in controls across all of the experiments. Before the onset of the anorectic response to the IMB diets, monoaminergic activity was affected in areas that have recognized monosynaptic connections with the APC. We propose a circuit for the neural responses in the initial recognition of acute amino acid deprivation that begins with activation of the APC and includes areas in the hindbrain and hypothalamus. After a significant hypophagic response, serotonergic indicators were altered in areas of the taste pathway and the limbic system. These results suggest that different circuits mediate the initial recognition and secondary conditioned responses to IMB diets.

Amino Acids↗
PubMed1997

The potency of dietary amino acids in elevating plasma cholecystokinin immunoreactivity in cats is related to amino acid hydrophobicity.

Incomplete agreement exists on the relative potency of amino acids in stimulating endocrine secretion of cholecystokinin (CCK). Species and methodological variations have been suggested to account for the apparent inconsistencies. In the present research, the CCK-releasing potency of dietary amino acids was evaluated in cats using plasma CCK-like immunoreactivity (CCK-LI) as an indicator of CCK secretion rather than pancreatic protein and enzyme secretion, as has been used in past research. Oral-gastric administrations of a casein-simulating amino acid mixture increased (P < 0.05) plasma CCK-LI but not to the extent of that observed for casein or sodium oleate. The response in plasma CCK-LI to administrations of 50 mM solutions of amino acids was significant (P < 0.05) for tryptophan, phenylalanine, leucine, and isoleucine and the response increased linearly (P < 0.01) with increasing amino side-chain hydrophobicity. Control administrations of water and saline also evoked elevation in plasma CCK-LI, but the responses were so transient that amino acid effects were not obscured. This was substantiated by the finding of a significant linear (P < 0.001) dose response to phenylalanine administration. Cholecystokinin-8, 33 and 58 were among the CCK molecular forms identified by HPLC in plasma after administrations of phenylalanine and water. The present findings indicate that lipophilic amino acids released during digestion account for at least part of the endocrine CCK response in cats to ingested protein. The greater CCK-releasing potency observed for intact protein relative to free amino acids may have been the result of a slow digestive release of amino acids, elaboration of peptide secretogogues or protection of protease-sensitive releasing factors.

Amino Acids↗