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Biomedical subjects

R J Hansen

Publications and source records attributed to R J Hansen.

At least 19 recordsLinked to original sources
PubMed2001

Pharmacokinetics, pharmacodynamics, and platelet binding of an anti-glycoprotein IIb/IIIa monoclonal antibody (7E3) in the rat: a quantitative rat model of immune thrombocytopenic purpura.

The pharmacokinetics, pharmacodynamics, and platelet binding of 7E3, an anti-glycoprotein IIb/IIIa (GPIIb/IIIa) monoclonal antibody, were studied in the rat in an attempt to develop a quantitative animal model of immune thrombocytopenia (ITP). 7E3, a murine IgG1 antibody developed against human GPIIb/IIIa, demonstrated cross-reactivity with rat platelets by flow cytometry and via enzyme-linked immunosorbent assay. The apparent affinity (K(A)) of 7E3-rat platelet binding was 1.2 +/- 0.2 x 10(7) M(-1), with 3.3 +/- 0.3 x 10(4) binding sites per platelet. Following intravenous 7E3 administration (0.8, 4, and 8 mg/kg), plasma concentrations declined in a bi-exponential manner, with a terminal half-life of 61 +/- 5 h and a steady-state volume of distribution of 62 +/- 15 ml/kg. Clearance was dose-dependent, with values ranging from 0.64 +/- 0.08 ml/h/kg (8 mg/kg) to 1.01 +/- 0.08 ml/h/kg (0.8 mg/kg). 7E3 induced a reproducible, severe thrombocytopenia in rats and extended bleeding in a manner consistent with human ITP. Nadir platelet counts were 79 +/- 33, 25 +/- 6, and 17 +/- 2 x 10(6)/ml, for 7E3 doses of 0.8, 4, and 8 mg/kg, respectively. Bleeding times after a 10-mm tail incision ranged from 5 +/- 3 min in control animals to 15 +/- 0 min (the maximum allowed time in this study) in animals receiving 8 mg/kg. Blood volumes lost during bleeding experiments ranged from 30 +/- 24 microl (control) to 349 +/- 358 microl (8 mg/kg). A reproducible, quantitative rat model of ITP has been created; this model is expected to facilitate the evaluation of new treatments for this disease.

Abciximab↗
PubMed2000

Sensitivity of a S. cerevisiae RAD27 deletion mutant to DNA-damaging agents and in vivo complementation by the human FEN-1 gene.

We have investigated the sensitivity to DNA-damaging agents of a strain of Saccharomyces cerevisiae containing a deletion of the RAD27 gene. The mutant strain is sensitive to a number of alkylating agents that modify DNA at a variety of positions, including one that produces primarily phosphotriesters. In contrast, the mutant strain is not sensitive to the oxidizing agent hydrogen peroxide. The introduction of a plasmid containing the FEN-1 gene (the human ortholog of the RAD27 gene) can substantially complement the sensitivity to alkylating agents observed in the mutant strain.

Base Sequence↗
PubMed2000

Current and future trends in demographics of veterinary medicine in California.

OBJECTIVE: To evaluate the present and future supply of veterinarians in California, in light of changing trends in animal ownership. DESIGN: Database analysis. SAMPLE POPULATION: Human and animal populations, including populations of veterinarians, throughout the United States. PROCEDURES: Data on animal and human populations were compiled from a number of sources, including the US Census Bureau, American Veterinary Medical Association, State of California Department of Finance, and State of California Veterinary Medical Board. The distribution of veterinarians in California was contrasted with other health professionals in California and with that of veterinarians in other states. Recent changes in veterinary medical demographics in California were quantified and used to develop in-state projections about the supply of veterinarians for the next 20 years. RESULTS: Although California is the most populous of the 50 states, only 7 states had fewer veterinarians per capita. Furthermore, California ranked next to last among states in increase of number of veterinarians between 1990 and 1995. Los Angeles County had the smallest per-capita number of veterinarians among 9 populous California counties. During that period, California had a net gain of only 6 veterinarians who were exclusively or predominantly large-animal or mixed-animal practitioners. CONCLUSIONS AND CLINICAL RELEVANCE: If current trends continue, the per-capita number of veterinarians will continue to decrease in California. To maintain the current ratio of 17.8 veterinarians/100,000 people in California in the future, we estimate that an additional 50 veterinarians above the currently predicted increase will be required annually.

Animals↗
PubMed1999

Plasma lipoprotein changes in hens (Gallus domesticus) during an induced molt.

Blood plasma lipoproteins were studied during food and light deprivation or prolactin injection-induced involution of ovarian follicles (molt) of laying hens. Egg laying stopped 3 days after initiation of either treatment. Food and light-deprived hens lost 29% of initial body weight during the 10-day experiment (P < 0.05), whereas prolactin-treated hens lost 9% of body weight. Yolk-directed very low density lipoprotein (VLDLy) concentration in plasma decreased in both groups, but declined more rapidly in food and light-deprived hens. Very low density lipoprotein triacylglycerol decreased 40% in food and light-deprived hens by day 2 compared with a 13% decrease in the prolactin-treated hens. By day 5, a lipoprotein particle 21-22 nm in diameter appeared in the d = 1.019-1.046 g/ml density fraction of plasma in both groups. A similar lipoprotein particle, termed HDLR, developed in overfed hens with involuting ovarian follicles. In conclusion, hens undergoing ovarian regression due to food and light deprivation, prolactin treatment or overfeeding display marked decreases in plasma yolk-directed very low density lipoproteins and the appearance of HDLR. Other lipoprotein populations varied depending on whether the hens continued to feed or not.

Animals↗
PubMed1999

An ELISA for quantification of murine IgG in rat plasma: application to the pharmacokinetic characterization of AP-3, a murine anti-glycoprotein IIIa monoclonal antibody, in the rat.

An enzyme-linked immunosorbent assay (ELISA) has been developed to determine concentrations of murine IgG in rat plasma. Specifically, the assay was developed to measure a murine anti-glycoprotein IIIa antibody (AP-3) in rat plasma to facilitate future investigations of AP-3 pharmacokinetics and pharmacodynamics in the rat. The working range of the assay is 15-100 ng ml(-1), corresponding to a limit of quantification of 1.5 microg ml(-1) in rat plasma. The assay was validated with respect to accuracy, precision, and cross-reactivity with both pooled rat and mouse IgG. Intra-assay recoveries of AP-3 in rat plasma ranged from 93 to 103%, with CV% values ranging from 5.2 to 8.5%. Inter-assay recoveries of the plasma AP-3 samples ranged from 107 to 119% with CV% values ranging from 17.7 to 25.1%. The assay has no appreciable cross reactivity with pooled rat IgG and full cross reactivity with pooled mouse IgG, making this an ideal assay to determine plasma pharmacokinetics of mouse antibodies in the rat. The assay was used to determine the pharmacokinetics of AP-3 in a Sprague-Dawley rat.

Animals↗
PubMed1999

Estrogen induction of VLDLy assembly in egg-laying hens.

The yolk of a 60-g chicken egg contains 6 g of triacylglycerols transported to the oocyte from the liver of the laying hen in apolipoprotein (apo) B-containing particles. With the onset of egg production, estrogen shifts hepatocytic lipoprotein production from generic VLDL to VLDLy (yolk targeted). These VLDLy are triacylglycerol-rich particles; they are reduced in size by one half, are resistant to lipoprotein lipase and are taken up intact by oocyte receptors. The VLDLy pathway for apoB provides sufficient energy for the caloric requirements of chick development. VLDLy size reduction occurs in spite of surplus liver triacylglycerols and is necessary for VLDL particles to pass through the granulosa basal lamina and reach the receptors located on the oocyte surface. New ultrastructural data show that some proximal tubule cells of bird kidney secrete generic VLDL, perhaps providing energy and other VLDL-associated nutrients to tissues bypassed by VLDLy. Birds are an apoB100-only species, providing a natural in vivo model with which to investigate mechanisms of apoB100 VLDL assembly. Preliminary studies of liver lipoprotein assembly intermediates isolated from the biosynthetic membranes (endoplasmic reticulum) of the laying hen are consistent with the presence of both putative first- and second-step precursor particles of VLDLy. These findings suggest that the two-step mechanism of apoB core lipidation is an ancient development in apoB biology, handed down to mammals from oviparous ancestors.

Animals↗
PubMed1999

Catechin is present as metabolites in human plasma after consumption of red wine.

Flavonoids are components of fruits, vegetables and wines. An abundance of flavonoids in the diet is correlated with reduced heart disease mortality, suggesting that they act as protective nutrients. However, little is known about the absorption and metabolism of flavonoids after normal foods are consumed. This study measured the levels of one abundant flavonoid, (+)-catechin, and its metabolites in plasma after five male and four female volunteers consumed 120 mL of red wine (RW) one day and de-alcoholized red wine (DRW) on a separate day. Each wine sample contained 35 +/- 1 mg catechin (mean +/- SEM). Plasma levels of catechin and its metabolite 3'-O-methylcatechin (3'MC) were determined by gas chromatography-mass spectrometry (GC-MS) of the trimethylsilylated (TMS) derivatives. Glucuronide and sulfate conjugates were determined after enzymatic hydrolysis. Before RW or DRW consumption, plasma levels of catechin, 3'MC and all conjugates were <2 nmol/L. After 1 h, average levels of catechin, 3'MC and all conjugates increased to 91 +/- 14 nmol/L (RW) and 81 +/- 11 nmol/L (DRW). At 1 h, 21 +/- 1% of the metabolites were methylated and <2% of catechin and 3'MC were unconjugated. Catechin was present as both a sulfate conjugate and a conjugate containing both glucuronide and sulfate residues. 3'MC was present primarily as a glucuronide conjugate. At every time point, catechin was present almost exclusively as metabolites, and these levels were independent of ethanol. Therefore, if flavonoids are protective nutrients, the active forms are likely to be metabolites, which are far more abundant in plasma than the forms that exist in foods.

Adult↗
PubMed1999

Effect of divergent selection for total plasma phosphorus on plasma and yolk very low density lipoproteins and plasma concentrations of selected hormones in laying Japanese quail.

Japanese quail lines were divergently selected over 32 generations for laying hen plasma yolk precursor, as measured by total plasma phosphorus (TPP). The high (HP) and low (LP) lines were developed from a randombred control population (R1) that was maintained without conscious selection. The purpose of the present study was to characterize the composition of very low density lipoproteins (VLDL) in laying Japanese quail hens (VLDLy) and the concentration of selected hormones in laying hens from the HP, LP, and R1 lines. The changes in TPP because of genetic selection in the Japanese quail lines were associated with large alterations in plasma VLDLy concentration (HP > R1 > LP), but only minor changes in lipid composition and size (HP > LP = R1; P< or =0.01) of plasma VLDLy particles. Basal plasma levels of hormones associated with reproduction and lipid metabolism were also different among lines, with luteinizing hormone (LH) ranking HP >R1 = LP and triiodothyronine (T3), thyroxine (T4), and 17beta-estradiol ranking HP > R1 > LP (P< or =0.05). The results suggest possible increased rates of hepatic lipogenesis, hepatic VLDLy assembly and secretion, and plasma VLDLy concentration in association with increases in concentrations of plasma LH, T3, T4, and 17beta-estradiol. Concentrations of total lipids in yolk VLDL were not different among lines, and only minor line differences in the concentration of different classes of yolk VLDL neutral lipids were detected. The data indicate a preferential uptake of a specific plasma VLDLy subpopulation into rapidly growing ovarian follicles, resulting in a constant composition of yolk VLDL of laid eggs among lines of Japanese quail with large differences in plasma VLDLy concentration.

Animals↗
PubMed1997

Transfection of avian LMH-2A hepatoma cells with cationic lipids.

LMH-2A is an estrogen-responsive avian hepatoma cell line whose susceptibility to cationic-lipid-mediated transfection is poorly described. 3 beta[N-N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DCC) requires a one-step synthesis, and can be used to formulate transfection-grade liposomes when combined with dioleoylphosphatidyl-ethanolamine (DOPE) 1/1 (wt/wt). Luciferase activities in LMH-2A cells were 8.5-fold and 87.5-fold greater than those in HepG2 and FTO2B cells, respectively, following DCC-liposome-mediated transfection with a reporter consisting of the human cytomegalovirus immediate-early promoter (CMV), joined to Photinus pyralis luciferase (L) cDNA, designated pCMVL. Using pCMVL, N-(2-bromoethyl)-N,N-dimethyl-2,3-bis(9-octadecenyloxy)-propana minimun bromide) (BMOP)/DOPE 1/1 (wt/wt), at a 7.5:1 ratio with DNA, produced luciferase activities that were 2.9-fold higher than those of DCC-liposomes, at an optimal 10:1 lipid:DNA ratio. At optimal lipid:DNA ratios, commercially available liposomes, Transfectam, Lipofectamine, and Lipofectin, produced luciferase activities that were 1.39, 1.03, and 0.47-fold those of DCC-liposomes. The effect of 0, 10, 100, or 500 nM/L 17 beta-estradiol on the expression of pCMVL and a second luciferase reporter containing the -593/+48 promoter region of the estrogen-responsive avian apo VLDL-II gene, designated pApoL, was tested in cells cultured in the presence or absence of 10% chicken serum. The CMV promoter supported a high level of expression in LMH-2A cells that was unaffected by serum alone, but was weakly responsive to estrogen. Estrogen responses of both reporters reached a plateau at 10 nM/L. Estrogen increased the expression of pApoL 24-fold and 79-fold in the absence and presence of serum, respectively. The -593/+48 region of the apo VLDL-II promoter may not contain previously reported negative insulin response elements, but chicken serum contains factors that enhance estrogen responsiveness of this region.

Analysis of Variance↗
PubMed1996

Effects of short-term use of nicotine gum in pregnant smokers.

OBJECTIVES: To compare blood concentrations of nicotine and cotinine and maternal and fetal hemodynamic effects resulting from use of nicotine gum versus cigarette smoking in pregnant smokers. METHODS: Pregnant women (24 to 36 weeks' gestation) who smoked chronically were randomly assigned with a 1:2 randomization scheme to either a group that smoked cigarettes (n = 10) or to a group that stopped smoking and chewed at least six pieces of nicotine gum (2 mg nicotine per piece) per day (n = 19). Blood nicotine and cotinine concentrations, maternal heart rate and blood pressure, uterine resistance index, and fetal heart rate and umbilical artery resistance index were obtained before and after one cigarette was smoked at baseline and after 5 continuous days of either chewing gum or smoking. RESULTS: A significant reduction from baseline in nicotine (p < 0.0001) and cotinine (p < 0.0025) concentrations was observed in those who chewed nicotine gum compared with those who smoked cigarettes. No significant differences in the changes in maternal or fetal hemodynamic parameters from baseline to estimated time of peak nicotine exposure were observed between those who smoked cigarettes and those who chewed nicotine gum. CONCLUSION: Short-term use of nicotine gum delivers less nicotine than usual cigarette smoking in pregnant women.

Adult↗
PubMed1995

Older plasma lipoproteins are more susceptible to oxidation: a linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease.

Increases in plasma cholesterol are associated with progressive increases in the risk of atherosclerotic cardiovascular disease. In humans plasma cholesterol is contained primarily in apolipoprotein B-based low density lipoprotein (LDL). Cells stop making the high-affinity receptor responsible for LDL removal as they become cholesterol replete; this slows removal of LDL from plasma and elevates plasma LDL. As a result of this delayed uptake, hypercholesterolemic individuals not only have more LDL but have significantly older LDL. Oxidative modification of LDL enhances their atherogenicity. This study sought to determine whether increased time spent in circulation, or aging, by lipoprotein particles altered their susceptibility to oxidative modification. Controlled synchronous production of distinctive apolipoprotein B lipoproteins (yolk-specific very low density lipoproteins; VLDLy) with a single estrogen injection into young turkeys was used to model LDL aging in vivo. VLDLy remained in circulation for at least 10 days. Susceptibility to oxidation in vitro was highly dependent on lipoprotein age in vivo. Oxidation, measured as hexanal release from n-6 fatty acids in VLDLy, increased from 13.3 +/- 5.5 nmol of 2-day-old VLDLy per ml, to 108 +/- 17 nmol of 7-day-old VLDLy per ml. Oxidative instability was not due to tocopherol depletion or conversion to a more unsaturated fatty acid composition. These findings establish mathematically describable linkages between the variables of LDL concentration and LDL oxidation. The proposed mathematical models suggest a unified investigative approach to determine the mechanisms for acceleration of atherosclerotic cardiovascular disease risk as plasma cholesterol rises.

Aging↗
PubMed1994

Overfeeding increases very low density lipoprotein diameter and causes the appearance of a unique lipoprotein particle in association with failed yolk deposition.

Structurally specific very low density lipoprotein (VLDL) particles are presumed to redirect VLDL uptake during yolk deposition. Egg production is an energy intensive process, but energy excess negatively affects egg production. This study sought to determine whether overfeeding changed hen lipoprotein profiles, and if so, whether changes were related to egg production. Overfeeding caused 33% of hens to stop yolk deposition and reabsorb unovulated follicles (involute). VLDL of control hens possessed characteristic small particle size (30 nm) and composition indicative of limited intravascular metabolism. Overfeeding generally increased VLDL diameter, the effect being slight (+6.6 nm) in overfed laying hens when compared to overfed-involuted hens (+51.2 nm). Changes in composition indicated that increased intravascular metabolism of VLDL parallelled increases in particle diameter. Overfed-involuted hens showed significant elevations of plasma low density lipoprotein, VLDL cholesteryl ester, and high density lipoprotein (HDL) triacylglycerol content. Overfeeding increased plasma HDL, and in association with involution, caused redistribution of HDL particle sizes, including the appearance of novel HDL approximately 20 nm in diameter, termed HDLR, and a 97 kDa protein within the HDL fraction. The overfed hen model may provide new insight into the role of lipoprotein physical properties in determining the metabolism of triacylglycerol-rich lipoprotein, and the process of reverse lipid transport. Overfeeding generally increases VLDL size and plasma HDL levels suggesting that increased peripheral metabolism, and perhaps mechanical exclusion of enlarged VLDL by the granulosa basal lamina, contribute to the obesity and impaired yolk deposition observed in hens with excessive energy intakes. Temporal definition of massive VLDL enlargement relative to follicular collapse remains to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Feed↗
PubMed1993

Fatty liver hemorrhagic syndrome in hens overfed a purified diet. Selected enzyme activities and liver histology in relation to liver hemorrhage and reproductive performance.

A nutritionally adequate, purified diet was developed and used in studies to characterize selected aspects of laying hens in which fatty liver hemorrhagic syndrome (FLHS) was induced by overfeeding. Hens consuming the diet ad libitum or intubated with the diet in quantities equivalent to usual daily energy intake maintained normal rates of lay, did not become obese, and did not develop liver hemorrhage. Overfed hens had a 33% incidence of FLHS, as indicated by the presence of severe liver hemorrhage score, and displayed the full range of symptoms associated with spontaneous outbreaks of FLHS, including definitive lesions of hepatic reticulin. Among four groups of hens clinically classified according to rates of liver hemorrhage and egg production, there were no differences noted in total liver fat, liver fat concentration, or final body weight. Liver hemorrhage was associated with the degree of induction of liver lipogenic accessory enzymes. Serum enzyme activities indicate that overfed hens, unlike the overfed goose, retain hepatocellular membrane integrity. Overfeeding caused altered reproductive performance in 72% of hens. Alterations included erratic laying, increased incidence of double ovulations, shell defects, follicular collapse, and oviduct involution. Pattern of lay preceding necropsy seemed to influence follicle weight at necropsy. The data presented re-emphasize the interdependence among liver, ovary, and oviduct function in the etiology of FLHS.

Animal Feed↗
PubMed1993

Avian fatty liver hemorrhagic syndrome: a comparative review.

Metabolic fatty liver syndromes occur in a variety of species including chickens, humans, cows, and cats. Both energy excess and deficit appear to initiate the accumulation of liver fat. Although the conditions preceding the onset of liver steatosis vary, all syndromes share a common basis in altered lipid utilization, lipoprotein assembly, and secretion. Laying hens and humans appear to develop fatty livers under similar metabolic conditions of energy excess. This similarity and the additional structural requirements inherent in yolk deposition make the laying hen an exciting model in which to study lipoprotein synthesis, assembly, and secretion. The overfed hen provides additional insights into the effects of nutrition and hormones on these same processes. Within this model it may be possible to distinguish the effects of altered gene expression versus altered physical properties (lipids) and postranslational processing (proteins) in mediating the observed responses.

Animals↗
PubMed1991

Relationship between growth and selected liver enzyme activities of individual rainbow trout.

Interpretation of enzymatic data requires consideration of the food intake of each animal studied. Food intake and body mass gain are closely correlated in rapidly growing animals. Direct measurement of food intake by individual fish within a school is nearly impossible. We examined the relationship between growth and liver enzyme activity as a means of inferring the food intake of individual fish within a school. Trout, identified by passive integrated transponder implants, were fed either 0, 0.3, 1, or 2% body mass/d to produce a wide range of growth rates. The activities of five enzymes, predominantly localized in liver, were measured. Results showed that, although the magnitude of response differed, increases in total liver activities of all five enzymes measured were linearly related to growth. Hexokinase (EC 2.7.1.1) increased at a rate below, and beta-D-glucose:NAD(P)+1-oxidoreductase (EC 1.1.1.47) increased at a rate equivalent to, observed increases in total liver mass. Malic enzyme (EC 1.1.1.40), glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) showed preferential increases in activity as food intake increased. Correlation of enzyme activities measured in fish fed restricted rations with either growth or nominal feeding rate showed that growth of individual fish was more closely related to liver enzyme activities than nominal feeding rate.

Animals↗
PubMed1988

Molecular diversity of glucose-6-phosphate dehydrogenase: rat enzyme structure identifies NH2-terminal segment, shows initiation from sites nonequivalent in different organisms, and establishes otherwise extensive sequence conservation.

The NH2-terminal region of rat liver glucose-6-phosphate dehydrogenase (EC 1.1.1.49) is shown to differ radically from a reported amino acid sequence for the fruit fly enzyme and from one for the human enzyme. The results indicate considerable differences in the translational start point. However, a close relationship with another reported sequence for the human enzyme is established, now showing agreement between an indirectly deduced and a directly analyzed NH2-terminal structure of this enzyme type. The results provide evidence of one structural motif common to mammalian species but also suggest that genetic inconstancy 5' to, or at the start of, the region coding for the enzyme protein could be a source of intra- and interspecies diversity. This is of interest in relation to the large number of genetic variants of human glucose-6-phosphate dehydrogenase.

Amino Acid Sequence↗