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Biomedical subjects

O A Levander

Publications and source records attributed to O A Levander.

At least 55 records · Page 3Linked to original sources
PubMed1995

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates.

Previous work from our laboratory demonstrated that selenium deficiency in the mouse allows a normally benign (amyocarditic) cloned and sequenced Coxackievirus to cause significant heart damage. Furthermore, Coxsackievirus recovered from the hearts of selenium-deficient mice inoculated into selenium-adequate mice still induced significant heart damage, suggesting that the amyocarditic Coxsackievirus had mutated to a virulent phenotype. Here we report that sequence analysis revealed six nucleotide changes between the virulent virus recovered from the selenium-deficient host and the avirulent input virus. These nucleotide changes are consistent with known differences in base composition between virulent and avirulent strains of Coxsackievirus. To the best of our knowledge, this is the first report of a specific nutritional deficiency driving changes in a viral genome, permitting an avirulent virus to acquire virulence due to genetic mutation.

Animals↗
PubMed1995

Lower levels of urinary 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) in humans with higher CYP1A2 activity.

Heterocyclic aromatics amines (HAAs), such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), are metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2). We examined the relationship between CYP1A2 and NAT2 activity and the excretion of total unconjugated MeIQx in 66 healthy subjects. The subjects ate a control diet for 7 days containing lean ground beef cooked at low temperature. On day 8, they were tested for CYP1A2 and NAT2 activity by caffeine phenotyping. On the evening of day 8, subjects consumed lean ground beef cooked at high temperature containing 9.0 ng of MeIQx/g of meat. The subjects ate 3.1-4.0 g meat/kg body wt. Twelve-hour urine samples were collected and MeIQx was measured by gas chromatography-mass spectrometry. Using linear regression analyses, we found that higher CYP1A2 activity was associated with lower levels of total unconjugated MeIQx in the urine (P = 0.008) when adjusted for amount of meat eaten, while NAT2 activity showed no relationship with the latter. This suggest that a greater percentage of MeIQx is converted to metabolites such as the N-hydroxy derivative when CYP1A2 activity is higher. This finding supports the concept that inter-individual variation is CYP1A2 activity may be relevant for cancers associated with exposure to HAAs.

Adult↗
PubMed1995

Protection against murine cerebral malaria by dietary-induced oxidative stress.

Feeding 20% (w/w) menhaden-fish oil in a standard laboratory chow diet for 4 wk partially protected CBA/CaJ mice from the central nervous system consequences of infection with Plasmodium berghei (ANKA). Full protection (complete survival for 14 days postinfection) could be obtained by feeding a purified pro-oxidant vitamin E-deficient diet containing 4% (w/w) menhaden oil (MO - VE diet). The purified pro-oxidant MO - VE diet also exerted a pronounced suppressive effect against the parasite (depressed 6-day parasitemias). The anitmalarial effect of the MO - VE diet could be prevented by supplementing the diet with vitamin E or with either of 2 synthetic antioxidants, N,N'-diphenyl-p-phenylenediamine or probucol. These results suggest that the fish oil exerts its antimalarial effect by imposing a dietary-induced oxidative stress on the infected host erythrocyte, the parasite, or both. Nutritional manipulation of host oxidative stress status may be a useful adjunct therapy in patients undergoing treatment with pro-oxidant antimalarials such as drugs of the qinghaosu family.

Animal Feed↗
PubMed1994

Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans.

Heterocyclic aromatic amines (HAAs) are formed when meat juices are pyrolyzed. In humans HAAs are activated in vivo by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2) to mutagens or carcinogens. While activity of NAT2 is noninducible, exposure to cigarettes, polycyclic aromatic hydrocarbons, and cruciferous vegetables has been shown to induce CYP1A2 activity in humans. To date, it is unknown if pan-fried meat, which is consumed at high levels in the United States, is capable of inducing CYP1A2. In order to address this issue, we measured CYP1A2 and NAT2 activities in 66 healthy nonsmokers (33 males and 33 females) in a controlled metabolic feeding study. The study was designed to minimize the influence of known inducers of CYP1A2. Subjects consumed meat pan-fried at a low temperature (100 degrees C) for 7 days followed by 7 days of meat pan-fried at a high temperature (250 degrees C). The low temperature-cooked meat had undetectable levels of HAAs while the high temperature-cooked meat contained high amounts of HAAs [9.0 ng/g of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2.1 ng/g of 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 32.8 ng/g of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)]. In contrast, total polycyclic aromatic hydrocarbon content was similar in both meat samples (10.7 ng/g in low temperature-cooked meat and 10.1 ng/g in high temperature-cooked meat). At the end of each period, subjects were tested for CYP1A2 and NAT2 enzyme activity by caffeine metabolism phenotyping. NAT2 activity remained unchanged throughout the study while CYP1A2 activity increased in 47 of 65 (72%) of the subjects after consuming high temperature-cooked meat (P < 0.0002), suggesting induction by some compound(s) formed during high temperature cooking. If HAAs are shown to be human carcinogens in epidemiological studies, then meat cooked at high temperatures may pose an increased cancer risk because it contains both inducers of CYP1A2 and procarcinogens MeIQx, DiMeIQx, and PhIP known to be activated by this enzyme.

Carcinogens↗
PubMed1994

Benign human enterovirus becomes virulent in selenium-deficient mice.

Coxsackieviruses have been implicated as possible co-factors in the etiology of the selenium (Se)-responsive cardiomyopathy known as Keshan disease. Here we report that a cloned and sequenced amyocarditic coxsackievirus B3 (CVB3/0), which causes no pathology in the hearts of Se-adequate mice, induces extensive cardiac pathology in Se-deficient mice. CVB3/0 recovered from the hearts of Se-deficient mice inoculated into Se-adequate mice induced significant heart damage, suggesting mutation of the virus to a virulent genotype. We demonstrate the important role of host nutritional status in determining the severity of a viral infection.

Animals↗
PubMed1994

Increased virulence of a human enterovirus (coxsackievirus B3) in selenium-deficient mice.

Coxsackievirus B3 (CVB3/20)-induced myocarditic lesions occurred more quickly and were more severe and virus titers in heart and liver were higher in selenium (Se)-deficient than Se-adequate mice. NK cell activity and serum neutralizing antibody titers were similar in both Se-adequate and -deficient CVB3/20-infected mice; however, lymphocyte proliferation to both mitogen and antigen was decreased in Se-deficient mice. CVB3/20 isolated from Se-deficient donor mice and inoculated into Se-adequate recipient mice induced severe myocarditis. In contrast, CVB3/20 isolated from Se-adequate donor mice and inoculated into Se-adequate recipient mice induced only moderate myocarditis, similar to that caused by the original virus stock. Thus, the general population of CVB3/20 virions, as a consequence of replicating in an Se-deficient host, underwent a phenotypic change to increased virulence. These results have important implications for the emergence of virulent viruses.

Animals↗
PubMed1994

Vitamin E deficiency intensifies the myocardial injury of coxsackievirus B3 infection of mice.

Feeding a vitamin E-deficient diet increases pathology in hearts of mice infected with a myocarditic coxsackievirus B3 (CVB3/20). Hearts from infected mice fed a vitamin E-deficient diet rich in highly unsaturated fat (menhaden oil) exhibited more severe pathology than hearts from infected mice fed a vitamin E-deficient diet based largely on saturated fat (lard). Furthermore, a cloned and sequenced amyocarditic coxsackievirus B3 (CVB3/0), which caused little or no pathology in the hearts of vitamin E-supplemented mice, induced extensive cardiac pathology in vitamin E-deficient mice. In infected mice, both mitogen and antigen responses were depressed by vitamin E deficiency, although neutralizing antibody responses were unaffected. Natural killer cell responses were comparable in infected mice fed a lard-based diet with or without supplemented vitamin E. However, a menhaden oil-based diet, whether supplemented with vitamin E or not, significantly depressed natural killer cell activity in infected mice compared with mice fed the lard-based diet. Coxsackievirus B3/0 recovered from the heart of a vitamin E-deficient donor mouse, passaged one time onto HeLa cells, caused significant heart damage when passed back into vitamin E-supplemented recipient mice, demonstrating that the amyocarditic CVB3/0 had changed to a virulent phenotype. Enhanced virulence was also seen with CVB3/20 virus similarly passaged in a vitamin E-deficient donor. Our work demonstrates the important role of host nutritional antioxidant status in determining the severity of certain viral infections.

Animals↗
PubMed1993

Malarial parasites and antioxidant nutrients.

Susceptibility to oxidative stress is a well-established feature of the malarial parasite. Pharmacologists have taken advantage of this property to design highly effective pro-oxidant antimalarial drugs. Less well appreciated is the fact that nutritional manipulation of host oxidative stress status by dietary means can have a profound effect on the growth of the parasite. In particular, rapid induction of vitamin E deficiency in mice by feeding highly unsaturated fatty acids (fish oil) strongly suppresses plasmodial growth. Likewise, the status of other antioxidant nutrients (e.g., riboflavin or vitamin C) may also influence the course of malarial infection under certain conditions. A combined nutritional pharmacology approach may offer some promise in controlling malaria.

Animals↗
PubMed1993

The bioavailability to humans of ascorbic acid from oranges, orange juice and cooked broccoli is similar to that of synthetic ascorbic acid.

The relative bioavailability of ascorbic acid from several sources was compared in 68 male non-smokers. Subjects underwent two 8-wk ascorbic acid depletion-repletion cycles. In repletion, subjects were randomized to receive 108 mg/d ascorbic acid as tablets with or without iron, as orange segments or juice, or as raw or cooked broccoli with a crossover within each major treatment group (e.g., cooked to raw broccoli) for the second repletion. Relative ascorbic acid bioavailability was estimated based on the slope obtained from linear regression of plasma ascorbic acid on time during each repletion. In the first repletion, slopes for all groups were similar except for the group consuming raw broccoli (20% lower response, P < 0.01). Second repletion responses were attenuated, but were similar to the first repletion. Ascorbic acid ingested as cooked broccoli, orange juice or fruit, or in synthetic form seems to be equally bioavailable. The lower relative bioavailability of ascorbic acid from raw broccoli is unlikely to be of practical importance in mixed diets.

Adult↗
PubMed1992

Selenium and sulfur in antioxidant protective systems: relationships with vitamin E and malaria.

The metabolic relationships among the antioxidant nutrients selenium, sulfur, and vitamin E are particularly close. Selenium and vitamin E have long been known to spare one another in certain nutritional diseases of animals, and selenium has been considered to have a key antioxidant defense function as a component of glutathione peroxidase. However, the antioxidant role of glutathione peroxidase has been questioned and new proteins containing selenium have been identified: phospholipid hydroperoxide glutathione peroxidase, selenoprotein P, and iodothyronine deiodinase. Glutathione peroxidase activity independent of selenium resides in the glutathione S-transferases. Glutathione participates in both enzymatic and nonenzymatic antioxidant defense systems. Some low-molecular weight selenium compounds (e.g., ebselen) exhibit glutathione peroxidase-like action. Certain low molecular weight thiols decompose peroxides nonenzymatically (e.g., the ovothiols). Murine malaria appears to be a useful experimental model for investigating interrelationships of selenium and vitamin E. Vitamin E deficiency protects against the parasite, especially when the mice are concurrently fed peroxidizable fat such as fish or linseed oils. Selenium deficiency, on the other hand, has little or no protective effect against the parasite. Any practical utility of pro-oxidant diets in combating human malaria remains to be determined.

Antioxidants↗
PubMed1991

Effect of aging and diet on proton NMR spectra of rat urine.

500 MHz 1H NMR studies of rat urine are used to assess metabolic changes resulting from aging (0.5-20 months) and changes in diet (casein versus chow). Aging rats fed chow diets decrease their excretion of citrate and 2-oxoglutarate, while the output of taurine and creatinine increases. Only young rats (1 month or less postweaning) excrete significant amounts of betaine and trimethylamine-N-oxide. Rats fed casein diets for 1 month postweaning do not excrete 2-oxoglutarate and excrete lower levels of hippurate, succinate, and citrate compared to rats fed chow diets. They also excrete N-methylnicotinamide. These high resolution proton NMR studies provide metabolic profiles which are not readily available by other techniques.

Aging↗
PubMed1991

Selenium in diet, blood, and toenails in relation to human health in a seleniferous area.

To determine whether high dietary selenium intake was associated with adverse effects, selenium in diet, blood, and toenails was studied in relation to human health in adults residing in western South Dakota and eastern Wyoming. Over a 2-y period 142 subjects were recruited from households selected at random and from ranches where unusually high selenium intakes were suspected. Subjects completed health questionnaires, underwent physical examinations, provided blood samples for clinical assessment, and provided blood, urine, toenails, and duplicate-plate food collections for selenium analysis. About half of the 142 free-living subjects had selenium intakes greater than 2.54 mumol/d (200 micrograms/d) (range 0.86-9.20 mumol/d, or 68-724 micrograms/d). Physical findings characteristic of selenium toxicity were not present nor were clinically significant changes in laboratory tests or frequency of symptoms related to selenium in the blood, toenails, or diet. We found no evidence of toxicity from selenium in subjects whose intake was as high as 9.20 mumol/d (724 micrograms/d).

Adult↗
PubMed1991

Human [74Se]selenomethionine metabolism: a kinetic model.

A study was undertaken to investigate the pharmacokinetics of an organically bound form of selenium. Six adults received a single oral 200-micrograms dose of 74Se as L-selenomethionine. A kinetic model was developed to simultaneously account for the appearance and disappearance of the tracer in plasma, urine, and feces. The model included absorption distributed along the gastrointestinal tract, uptake by the liver-pancreas subsystem, enterohepatic recirculation, distribution to two large tissue pools, and transport through four components of the plasma pool. Average turnover time of the plasma components varied from 0.01 to 1.1 d. The turnover time in the liver-pancreas subsystem ranged from 1.6 to 3.1 d. Turnover time ranged from 61 to 86 d in the peripheral tissues with the slowest turnover. The whole-body residence time was approximately five-fold greater than the turnover time of the tissue pool with the slowest turnover, reflecting substantial reutilization of labeled material.

Absorption↗
PubMed1991

Scientific rationale for the 1989 recommended dietary allowance for selenium.

During the past 15 years, our knowledge of human selenium requirements has improved greatly, primarily because of research conducted in the People's Republic of China. Dietary surveys demonstrated that Keshan disease, a juvenile cardiomyopathy, was absent in parts of China where the food supply provided at least 19 and 13 micrograms selenium per day for men and women, respectively. Such intakes can be regarded as minimum daily requirements for selenium. Chinese scientists also carried out a study in an area where Keshan disease was prevalent to determine the amount of dietary selenium needed to maximize the activity of the selenium-containing enzyme, glutathione peroxidase, in plasma. For a man weighing 60 kg, enzymatic activity reached a plateau at selenium intakes of about 40 micrograms per day. These data were used by the US National Research Council as the basis for its 1989 Recommended Dietary Allowance (RDA) for selenium. The RDA was calculated as 70 and 55 micrograms per day for adult men and women, respectively, after correcting for differences in body size and taking into consideration possible individual variations in requirements. This RDA is readily satisfied by typical diets in countries with relatively selenium-rich soils, such as the United States. In selenium-poor areas of the world (eg, China, New Zealand, Scandinavia), diets would not readily furnish such intakes.

Animals↗
PubMed1990

Plasmodium yoelii: comparative antimalarial activities of dietary fish oils and fish oil concentrates in vitamin E-deficient mice.

Feeding vitamin E-deficient diets containing either fish oils such as menhaden, salmon, or anchovy oil or fish oil concentrates based on n-3 ethyl esters or free fatty acids protected mice against Plasmodium yoelii as indicated by decreased parasitemia and improved survival. The fish oil concentrates depressed plasma tocopherol levels more strongly in vitamin E-supplemented mice than the menhaden oil. The free fatty acid concentrate appeared to suppress parasitemia in vitamin E-deficient mice better than the menhaden oil, although ultimate survival was similar in both groups. Dietary manipulation of host antioxidant status offers promise as a possible means of malaria control.

Animals↗
PubMed1990

Nutritional status and growth in juvenile rheumatoid arthritis.

The specific cause of short stature in juvenile rheumatoid arthritis (JRA) is unknown. One hypothesis links altered growth to inadequate dietary intake. In this study, nutritional status was assessed in 34 children with JRA (8 with systemic JRA, 14 with polyarticular JRA, and 12 with pauciarticular JRA) and 9 healthy controls using 3-day diet records, anthropometrics, and biochemical analyses. Differences in growth were found among the three types of JRA. One third of all subjects were at or below the 10th percentile in height for age (these being predominantly among the systemic and polyarticular groups). With few exceptions, the mean dietary intake for calories and essential nutrients was found to be adequate for each of the three groups. However, more than half of those with systemic JRA reportedly consumed less than the recommended caloric intake for their age and weight. No significant correlations were found linking dietary intake to growth percentiles in any of the groups studied. Biochemical abnormalities were found among the systemic and polyarticular groups. These abnormalities included low plasma levels of vitamins A and C, proteins (albumin, prealbumin, and retinol binding protein) and zinc; and increased levels of copper and glutathione peroxidase activity. Plasma selenium and vitamin E levels were unchanged. The discrepancy between intake and certain circulating nutrient levels may reflect alterations in the requirements, absorption, or use of these nutrients in the presence of chronic inflammation.

Adolescent↗
PubMed1990

The effect of early caloric restriction on colonic cellular growth in rats.

Although the inhibitory effect of caloric restriction on tumorigenesis is substantial and well known, the pertinent mechanisms remain to be determined. We recently suggested that the risk of cancer may be directly related to the total number of dividing cells within an affected organ. This study evaluates the effects of early caloric restriction on the cellular growth of the colon. The experiment began one day postpartum and ended six weeks later with the killing of all animals. It consisted of two consecutive periods: a) three weeks of suckling and b) three weeks postweaning. Animals whose food was restricted only during the suckling period showed normal colons when killed at six weeks. Caloric restriction (40%) for three weeks postweaning resulted in colons of lower weight with fewer cells (less total DNA) and reduced total DNA synthesis [( 3H]thymidine uptake, dpm/colon) when compared with animals fed ad libitum postweaning. Conversely, only rats fed ad libitum from birth through the first three weeks after weaning demonstrated an increase (21%) in the rate of DNA synthesis (dpm/mg DNA) compared with other animals. In addition, the colonic crypts showed no differences in the number of cells or the number of dividing cells, as determined by autoradiography. By contrast, the total number of crypts (and/or the number of mucosal cells between crypts) are reduced, and hence the total number of colonic mucosal cells dividing at any given time are similarly decreased. The reduced number of dividing cells in the colons of these animals (i.e., those restricted postweaning) could explain previous data suggesting that they are resistant to the induction of colon cancer.

Animals↗