Biomedical subjects
C E Day
Publications and source records attributed to C E Day.
Erosion of veterinary influence.
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Silent allelic variants of a T-cell receptor V beta 12 gene are present in diverse human populations.
Amino acid substitutions in variable regions of the T-cell receptor (TCR) can alter T-cell reactivity; however, relatively little is known about the extent of allelic variation in human TCR coding sequences. In the present studies, coding region variation in the human TCR V beta 12.2 gene was examined in detail. Virtually the entire V beta 12.2 coding region was screened for nucleotide substitutions by single-stranded conformational polymorphism analysis. Four alleles were identified in a sample population of 90 unrelated people from diverse genetic backgrounds. Three of the alleles were common, with estimated frequencies of 0.32, 0.47, and 0.20. Sequence analyses revealed that variation between the alleles was confined to three single-base differences in codons 24, 31, and 45; none of these changes altered the amino acid sequence. No evidence for other coding region differences in this gene were found. This analysis suggests that coding region variation in V beta 12.2 is limited, and amino acid sequence is highly conserved.
Increased serum catalase activity in septic patients with the adult respiratory distress syndrome.
Excessive hydrogen peroxide (H2O2) generation appears to contribute to the development of the adult respiratory distress syndrome (ARDS), but H2O2-combatting antioxidant defenses have not been evaluated. We found that serum from septic patients with ARDS scavenged more (p less than 0.05) H2O2 in vitro (82.7 +/- 3.8%) than did serum from septic patients without ARDS (56.9 +/- 3.1%) or control subjects (20.2 +/- 2.4%). Serum from septic patients with ARDS also had more (p less than 0.05) catalase activity (54.9 +/- 10.9 U/ml) than did serum from septic patients without ARDS (28.6 +/- 3.4 U/ml) or control subjects (7.3 +/- 0.8 U/ml). In contrast, serum from septic patients with or without ARDS and control subjects had the same glutathione peroxidase (GPX) activity. Serum H2O2 scavenging activity correlated with serum catalase (r = 0.77) but not GPX (r = 0.33) activity and was inhibitable (greater than 90%) by sodium azide, a catalase inhibitor. Increases in serum catalase activity did not appear to be derived from erythrocytes (RBC) because septic patients with or without ARDS and control subjects had similar RBC hemolysis in response to osmotic stress in vitro and serum haptoglobin concentrations. Serum from septic patients with ARDS also protected endothelial cells against H2O2-mediated damage (34.5 +/- 2.2% 51Cr release) better (p less than 0.05) than serum from septic patients without ARDS (47.3 +/- 7.4%) or control subjects (82.1 +/- 10.2%), but killing of bacteria by neutrophils in vitro was the same in serum from patients and control subjects. Our findings indicate that patients with sepsis and/or ARDS have increased serum catalase activity, which may alter H2O2-dependent processes.
Dimethyl sulfoxide decreases lung neutrophil sequestration and lung leak.
To investigate basic mechanisms of acute edematous lung injury (adult respiratory distress syndrome), the formylated tripeptide formyl-norleucyl-leucyl-phenylalanine (FNLP) was instilled intratracheally into hamsters. Intratracheal FNLP produced time-dependent and dose-dependent increases in neutrophils recoverable by lung lavage (neutrophil alveolitis) and leak of intravenously injected albumin into the extravascular lung space (lung leak). Treatment with dimethyl sulfoxide (DMSO) decreased (p less than 0.05) neutrophil alveolitis and lung leak in hamsters given FNLP intratracheally. The effect of DMSO on various neutrophil functions was also studied in vitro. Addition of DMSO at concentrations (about 0.20%) measured in plasma of hamsters given DMSO decreased (p less than 0.05) neutrophil chemotaxis but not neutrophil superoxide anion generation or adherence to cultured endothelial cell monolayers or nylon fiber in vitro. We conclude that intratracheal FNLP causes neutrophil alveolitis and lung leak and that DMSO treatment ameliorates these processes, possibly by inhibiting neutrophil chemotaxis.
Guar gum reduces serum cholesterol in sea quail fed a cholesterol diet.
Guar gum at 6% and 12% in the diet reduces total serum cholesterol by 31% and 51%, respectively, in male SEA quail fed a diet containing 0.5% cholesterol for a period of one week. Although the potency of hypocholesterolemic action of guar gum in cholesterol fed SEA quail is much less than that in cholesterol fed chickens, SEA quail are a reasonable alternative to chickens for evaluation of guar and similar products, based on other considerations such as smaller size and compound requirements and shorter duration of testing.
Activity of psyllium hydrophilic colloid for reducing serum cholesterol in sea quail fed a diet supplemented with cholesterol.
Groups of six SEA quail were fed a 0.5% cholesterol supplemented diet to which was added 3, 6, and 10% microcrystalline cellulose (controls) or the same concentrations of psyllium hydrophilic colloid for a period of 14 days. Total serum cholesterol was measured enzymically on each animal at the end of the treatment period. Cellulose control cholesterol values averaged approximately 1500 mg/dl overall. Psyllium hydrophilic colloid had no significant effect on total serum cholesterol at either 3% or 6% in the diet but did reduce cholesterol significantly by 52% at the 10% dietary level. These results demonstrate that SEA quail appear to be less sensitive to the hypocholesterolemic action of psyllium than are chickens.
Hypocholesterolemic activity of beta-sitosterol in cholesterol fed sea quail.
Male SEA quail were fed a 0.5% cholesterol supplemented diet, to which was added 0%, 1%, and 2% beta-sitosterol, for a period of seven days. Dietarily administered beta-sitosterol reduced total serum cholesterol levels by 62% and 72% at the 1% and 2% treatment doses, respectively. This hypocholesterolemic activity of sitosterol in cholesterol fed SEA quail was anticipated on the basis of the numerous earlier studies demonstrating similar activity in cholesterol fed chickens. Beta-sitosterol was tested in SEA quail to experimentally confirm its expected serum cholesterol lowering effects and to expand further the utility of the SEA quail model in cholesterol and atherosclerosis research.
Non-specific pruritus in dogs.
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Anti-atherosclerotic activity of colestipol hydrochloride in SEA quail.
Young, male, SEA (Susceptible to Experimental Atherosclerosis) Japanese quail (Coturnix coturnix japonica) were fed an atherogenic diet consisting of yellow corn meal and soybean meal supplemented with 2% cholesterol and 1% cholic acid. A control group of ten animals was fed the atherogenic diet for eight weeks, and another group was fed the same diet containing 2% colestipol hydrochloride for the same length of time. At the end of the treatment period serum and arterial total cholesterols were measured and extent of macroscopic atherosclerotic lesions assessed. Colestipol hydrochloride treatment significantly reduced both serum and arterial total cholesterol levels by 50 and 59%, respectively. Grossly visible atherosclerosis was significantly reduced by 64%. These data further demonstrate that male SEA quail are an appropriate and relevant small animal model for examining the cardiovascular effects of bile acid sequestrants.
Comparison of hypocholesterolemic activities of the bile acid sequestrants cholestyramine and colestipol hydrochloride in cholesterol fed SEA quail.
The pharmacopolymer bile acid sequestrants cholestyramine and colestipol hydrochloride were mixed with a diet supplemented with 0.5% cholesterol at levels of 0.25%, 0.5%, and 1.0% for cholestyramine and 0.5% and 1.0% for colestipol and fed to young, male, SEA (Susceptible to Experimental Atherosclerosis) Japanese quail (Coturnix coturnix japonica) for a period of seven days. After treatment blood was obtained by venipuncture from non-fasted animals and analyzed for serum total cholesterol concentration. Cholestyramine significantly reduced total cholesterol concentrations at all doses in a dose dependent manner. Colestipol significantly reduced total cholesterol only at the 1.0% dose. Based on these observations, cholestyramine is significantly more potent for reducing serum cholesterol in hypercholesterolemic male SEA quail than is colestipol hydrochloride.
Hypocholesterolemic activity of colestipol hydrochloride in SEA quail.
Male SEA (Susceptible to Experimental Atherosclerosis) quail were fed a semi-purified diet containing 0.5% cholesterol for a period of one week. Colestipol hydrochloride was mixed with the diet at levels of 0.5% and 1.0%. In control animals total serum cholesterol increased from a basal level of 241 mg/dl to 820 mg/dl after one week on the cholesterol supplemented diet. At 0.5% colestipol hydrochloride treated animals experienced a change in serum cholesterol from 223 mg/dl to 528 mg/dl after one week of cholesterol feeding. Colestipol hydrochloride at 1.0% in the diet completely prevented any increase in serum cholesterol in response to the hypercholesterolemic diet. Total serum cholesterols in this treatment group were 258 and 222 mg/dl initially and after the one week treatment, respectively. These data demonstrate that the bile acid sequestrant colestipol hydrochloride clearly prevents the hypercholesterolemia produced by feeding male SEA quail a cholesterol supplemented diet. Based on this activity cholesterol fed SEA quail may be a convenient and practical model for the preclinical evaluation of new cholesterol lowering drugs which act via a mechanism of bile acid sequestration.
Molecular basis for the defective expression of the mouse Ew17 beta gene.
Four of the eleven independent H-2 haplotypes of inbred mouse strains and approximately 15% of wild mouse chromosomes 17 fail to express the E alpha E beta class II histocompatibility (Ia) Ag. These E- haplotypes are defective in the expression of the E alpha and/or the E beta chain. None of the E beta defects has previously been described at the molecular level. In this study, we report the molecular basis for the defective expression of the E beta gene from the w17 haplotype of the H-2 congenic strain B10.CAS2, derived from wild Mus musculus castaneus. Comparison of the Ew17 beta genomic sequence to those of the functional Eb beta and Ed beta genes reveals a single base insertion in the RNA donor splice site of the first intron. By DNA shuffling, we have corrected the single base mutation, and we show by FACS analysis and 2-D PAGE of immunoprecipitates that the corrected Ew17 beta is expressed in L cells when co-transfected with an Ed alpha gene. Conversely, an Eb beta gene construct containing the mutant RNA splice site from Ew17 beta is not expressed. We conclude that the single base insertion in the first RNA splice donor site is the sole molecular defect in the Ew17 beta gene.
Evaluation of timefurone, a new anti-atherosclerotic drug, for its effects on lipoprotein cholesterol in male cynomolgus monkeys fed an atherogenic diet for 18 months.
Forty male cynomolgus monkeys were fed a nutritionally complete diet containing butter and 0.5% cholesterol for 18 months to ensure development of atherosclerosis. Timefurone was administered daily at 10 mg/kg/day. Lipoprotein cholesterol parameters were measured every 4 weeks and clinical chemistries were done at approximately 8-week intervals. Low density lipoprotein cholesterol [LDL-C] was significantly reduced 24-45% at all time periods and total-C was lowered 17-23% at weeks 12, 16, and 24-40 in the timefurone group. Very low density lipoprotein cholesterol [VLDL-C] was increased 68-156% from weeks 40-78 and triglycerides [TG] were significantly elevated 52-220% on weeks 4-16, 24, 28, and 36-78 by timefurone. Timefurone caused small but significant changes in several clinical chemistry parameters including: creatinine, total bilirubin, albumin, glucose, serum glutamic-oxalacetic transaminase, and serum glutamic-pyruvic transaminase during the test. Significant reductions in arterial cholesterol were observed in thoracic aorta (-24%) and carotid arteries (-29%) in treated monkeys when compared to placebo. Arterial cholesterol in treated monkeys was positively correlated to LDL-C (R = 0.54, p less than or equal to 0.05). Timefurone, therefore, appears to have a significant beneficial effect against the development of atherosclerosis in cholesterol-fed male monkeys and possesses excellent potential for clinical experimentation.
Evaluation of timefurone, a new anti-atherosclerotic drug, for its effects on lipoprotein cholesterol in male SEA Japanese quail and rats.
Timefurone was evaluated in several animal models for cholesterol-lowering and anti-atherosclerotic activity. In normal male rats, a dose-response study with timefurone (3, 10, 30, 50 and 100 mg/kg/day) was conducted for 7 days. Significant activity was observed only at 50 and 100 mg/kg/day, where very low and low density lipoprotein cholesterol [(VLDL + LDL)-C] and total-C levels were reduced (mean 27 and 20%). High density lipoprotein cholesterol (HDL-C) was lowered 24% by the high timefurone dose. Timefurone (10, 20, 50 and 100 mg/kg/day in the diet) was then examined in normocholesterolemic SEA japanese quail. beta-lipoprotein cholesterol (VLDL + LDL)-C was reduced at all doses (mean 58%), while alpha-lipoprotein cholesterol (HDL-C) was elevated by all doses of timefurone (mean 45%). Male weanling rats made moderately hypercholesterolemic represented a 3rd phase of timefurone (2.5, 5, 10, 20, 50, 100 mg/kg/day) testing. After 4 days of drug treatment, marked hypocholesterolemic activity was observed for (VLDL + LDL)-C (mean decrease 49%) and total-C (mean 33%). HDL-C levels were increased with 10 and 100 mg/kg/day doses. Timefurone (25 and 100 mg/kg/day in the diet) also caused a significant reduction in atherosclerotic development in hypercholesterolemic SEA japanese quail. Atherosclerotic involvement (determined by visual assessment of plaque), arterial weight, and arterial cholesterol (total and mg/g artery) were clearly lowered by both doses of timefurone. There was no evidence of significant drug toxicity in any of these experiments. On the basis of these data, timefurone has excellent therapeutic potential and additional study of the drug's hypocholesterolemic and anti-atherosclerotic properties appears warranted.
Hypocholesterolemic effect of khellin and khelloside in female cynomolgus monkeys.
Khellin and khelloside (khellol glucoside) were examined in female cynomolgus monkeys to substantiate their ability to favorably modify serum lipoprotein cholesterol. Clinical chemistry parameters were also measured to obtain information indicative of possible drug toxicity. Both drugs were evaluated in two week multiple-dose studies and after a single oral dose. After two weeks at 20 mg/kg per day, khellin and khelloside significantly lowered low density lipoprotein cholesterol (LDL-C) by 87% and 73%, high density lipoprotein cholesterol (HDL-C) by 41% and 23%, and total-C by 55% and 44%, respectively. Very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) were not changed. No apparent toxicity was observed as clinical chemistry parameters and body weights were not different compared to control values. Similar results were observed with lower doses of khellin and khelloside. Khellin at 5 mg/kg per day reduced LDL-C by 50%, HDL-C by 15%, and total-C by 30%, while khellol glucoside at 10 mg/kg per day lowered LDL-C by 46%, HDL-C by 20%, and total-C by 31%. Neither drug produced significant changes in VLDL-C, TG, body weights, or clinical chemistry variables. A 2 mg/kg per day dose of khellin also had no observable effect in this study. Single oral doses (20 mg/kg) of khellin and khelloside caused modulation of LDL-C (-32% and -30%) and total-C (-18% and -15%). Visual observation of the monkeys during this study revealed that khellin caused emesis in 9/9 animals, while khelloside and control had no emetic effect.(ABSTRACT TRUNCATED AT 250 WORDS)