Correlations of milk and serum element concentrations with production and management traits in dairy cows.

The present study investigated the potential consequences, positive or negative, that selection for favorable production-related traits may have on concentrations of vitamin B12 and key chemical elements in dairy cow milk and serum and the possible impact on milk healthiness, and associated benefits, for the dairy product consumer. Milk and serum samples (950 and 755, respectively) were collected from Holstein-Friesian dairy cows (n = 479) on 19 occasions over a 59-mo period, generating 34,258 individual records, and analyzed for concentrations of key trace and quantity elements, heavy metals, and milk vitamin B12. These data were then matched to economically important production data (milk, fat, and protein yield) and management data (dry matter intake, liveweight, and body condition score). Multivariate animal models, including full pedigree information, were used to analyze data and investigate relationships between traits of interest. Results highlighted negative genetic correlations between many quantity and trace elements in both milk and serum with production and management traits. Milk yield was strongly negatively correlated with the milk quantity elements Mg and Ca (genetic correlation between traits, ra = -0.58 and -0.63, respectively) as well as the trace elements Mn, Fe, Ni, Cu, Zn, and Mo (ra = -0.32, -0.58, -0.52, -0.40, -0.34, and -0.96, respectively); and in serum, Mg, Ca, Co, Fe, and Zn (ra = -0.50, -0.36, -0.68, -0.54, and -0.90, respectively). Strong genetic correlations were noted between dry matter intake with V (ra = 0.97), Fe (ra = -0.69), Ni (ra = -0.81), and Zn (ra = -0.75), and in serum, strong negative genetic correlations were observed between dry matter intake with Ca and Se (ra = -0.95 and -0.88, respectively). Body condition score was negatively correlated with serum P, Cu, Se, and Pb (ra = -0.45, -0.35, -0.51, and -0.64, respectively) and positively correlated with Mn, Fe, and Zn (ra = 0.40, 0.71, and 0.55, respectively). Our results suggest that breeding strategies aimed at improving economically important production-related traits would most likely result in a negative impact on levels of beneficial nutrients within milk for human consumption (such as Mg, Ca, Fe, Zn, and Se).

Cephalosporin-induced alteration in hepatic glutathione redox state. A potential mechanism for inhibition of hepatic reduction of vitamin K1,2,3-epoxide in the rat.

Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second- and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal gamma-carboxylation of a synthetic pentapeptide. Since MTT is a thiocarbamide, a type of compound that can increase oxidation of glutathione, the present studies were carried out to determine whether alterations in hepatic glutathione redox state might interfere with vitamin K metabolism. Dose-related increases in biliary efflux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MTT or MTT-containing antibiotics to rats. This finding suggested that these compounds could alter the hepatic glutathione redox state in vivo. Microsomal reduction of vitamin K epoxide occurred in the presence of 100 microM dithiothreitol (DTT), but was inhibited by preincubation with GSSG at concentrations as low as 10 microM. At higher concentrations of DTT (1.0 mM) inhibition by GSSG persisted, but higher concentrations were required, suggesting that the thiol/disulfide ratio, rather than the absolute concentration of GSSG was important. By contrast, GSSG did not effect microsomal gamma-carboxylation of a pentapeptide, using either vitamin K1 or its hydroquinone as a cofactor. These findings suggest a novel mechanism for the hypoprothrombinemia occurring after administration of MTT-containing antibiotics.

Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man.

Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine has been shown to inhibit the hepatic oxidation of a number of drugs and to protect rats from acetaminophen-induced hepatic necrosis. The aim of this study was to define the mechanism by which cimetidine reduced acetaminophen-induced hepatic necrosis and to determine whether inhibition of formation of the reactive metabolite(s) of acetaminophen occurred also in man. In vivo cimetidine pretreatment decreased covalent binding of [3H]acetaminophen to the liver from 552 +/- 23.8 to 170 +/- 31.6 nmol/g protein 2 h after a toxic dose of acetaminophen in 3-methylcholanthrene pretreated rats (P less than 0.05). Cimetidine pretreatment also significantly reduced the rate of hepatic glutathione depletion. Both cimetidine and metiamide produced dose-dependent inhibition of acetaminophen oxidation in vitro, whereas inhibition by ranitidine and cimetidine sulfoxide was quantitatively less. Inhibition of acetaminophen oxidation by cimetidine and metiamide was primarily competitive with an inhibition constant (Ki) of 130 +/- 16 and 200 +/- 50 microM, respectively. By contrast, cimetidine inhibited acetaminophen glucuronidation minimally with a Ki of 1.39 +/- 0.23 mM. Similar results were obtained using human liver microsomes as a source of enzymes. In a dose-related fashion, cimetidine also reduced acetaminophen-induced toxicity to human lymphocytes when incubated with microsomes and NADPH. Pharmacokinetics of acetaminophen elimination were studied in normal volunteers with and without co-administration of cimetidine 300 mg every 6 h. In normal volunteers, cimetidine decreased the fractional clearance of the oxidized (potentially toxic) metabolites of acetaminophen more than the conjugated metabolites. This finding confirmed the hypothesis that cimetidine is a relatively selective inhibitor of the oxidation of acetaminophen to reactive metabolites in man as well as in animals. When considered together with the results of previous studies showing improved survival and decreased hepatoxicity in acetaminophen-poisoned animals, the present results provide a rational basis for assessing possible benefits of cimetidine treatment of acetaminophen overdoses in man.

Effects of oral contraceptive steroids on acetaminophen metabolism and elimination.

Plasma acetaminophen elimination was examined in women taking low-dose estrogen oral contraceptive (OC) steroids and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +/- 13 ml/min to 470 +/- 51 ml/min in women taking OC steroids, whereas elimination t1/2 decreased from 2.40 +/- 0.14 hr to 1.67 +/- 0.16 hr. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OC steroids, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OC steroids results from increased glucuronidation of the drug, although the mechanism is not known.

PIP: Plasma acetaminophen elimination was examined in women taking low-dose oral contraceptives (OCs) and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +or- 13 ml/minute to 470 +or- 51 ml/minute in women taking OCs, whereas elimination t1/2 decreased from 2.40 +or- 0.14 hours to 1.67 +or- 0.16 hours. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OCs, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OCs results from increased glucuronidation of the drug, although the mechanism is not known.

Changes in plasma amino acids during sobriety in alcoholic patients with and without liver disease.

Plasma amino acid profiles of alcoholic subjects without clinically apparent liver disease, alcoholic patients with biopsy-proven alcoholic hepatitis, and nonalcoholic controls were compared. Differences in the plasma aminograms of alcoholic subjects with and without liver disease appear to be due predominantly to differences in liver function whereas differences in plasma amino acid levels between the alcoholic subjects and nonalcoholic controls may be related to inadequate dietary-protein intake and pyridoxine deficiency in the alcoholic groups.

Alcohol and dietary intake in the development of chronic pancreatitis and liver disease in alcoholism.

Alcohol and dietary intake were determined in alcoholic patients with chronic pancreatitis and alcoholic liver disease. Patients with chronic pancreatitis, alcoholic hepatitis, and cirrhosis ingested approximately 50% of their calories as alcohol, and all had low mean intakes of protein, carbohydrate, and fat as compared with control subjects. Patients with severe alcoholic hepatitis had the lowest intake of nonalcohol calories and protein. Women with chronic pancreatitis had ingested alcohol for a shorter period of time than men whereas women with alcoholic hepatitis and cirrhosis had ingested less alcohol per kilogram body weight per day as compared with men. This study does not support the hypothesis that consumption of a high-protein and high-fat diet is a factor in the development of chronic pancreatitis in the alcoholic patient. The increased susceptibility of women as compared with men to alcoholic liver disease is established.

Increased hepatic efflux of glutathione after chronic ethanol feeding.

Chronic ethanol feeding increases hepatotoxicity of drugs, such as acetaminophen, which form electrophilic metabolites. Availability of glutathione (GSH) is important in preventing liver damage from reactive metabolites. Chronic ethanol feeding has been reported to increase turnover of hepatic GSH in rats. The results of the present study show that the total hepatic efflux of GSH was increased from 5.95 +/- 0.42 nmoles/min/g liver (control) to 9.96 +/- 0.57 nmoles/min/g (P less than 0.001) in isolated perfused livers from rats 24 hr after withdrawal from chronic ethanol feeding. The increase in total efflux of GSH was due to a significant increase in sinusoidal GSH efflux from 4.76 +/- 0.49 nmoles/min/g liver in control rats to 9.07 +/- 0.47 nmoles/min/g (P less than 0.001) in ethanol-fed rats, while biliary efflux decreased slightly, 1.20 +/- 0.11 (control) vs 0.89 +/- 0.31 (ethanol). The increase in cellular efflux of GSH was similar in magnitude to the increase in hepatic GSH turnover that we reported previously. Biliary GSSG was similar in both groups of animals. Hepatic GGT activity was increased slightly, but not significantly, whereas renal GGT activity was similar in ethanol-fed rats. Hepatic GSH and GSSG levels were also similar. The increase in turnover of hepatic GSH in rats withdrawn from chronic ethanol feeding was most likely due to increased cellular efflux of GSH. This finding suggests that chronic ethanol feeding may increase cellular requirements for GSH, although the mechanism remains unknown. This alteration in GSH turnover may have important consequences for detoxification of xenobiotics or their metabolites by the liver.

Effects of chronic ethanol feeding on glutathione turnover in the rat.

Glutathione (GSH) is important in protection of cells against electrophilic drug injury and against reactive oxygen species. Both steady-state concentrations and turnover of GSH are important determinants of susceptibility of the hepatocyte to injury. Chronic ethanol administration is known to enhance susceptibility to electrophilic drug injury. We have examined the effects of chronic ethanol feeding on GSH turnover and the hepatic activities of GSH peroxidase and enzymes of the gamma-glutamyl cycle in the rat. Turnover of GSH was measured in individual animals by measuring the decrease in specific activity of GSH in bile over time after i.v. administration of [35S]cysteine. Rats fed ethanol had significantly increased rates of GSH turnover, 0.287 +/- 0.050 hr-1 vs 0.131 +/- 0.041 hr-1 (P less than 0.001), as well as steady-state GSH levels, 6.59 +/- 1.55 vs 4.30 +/- 1.28 mumoles/g liver (P less than 0.01). The activities of gamma-glutamyltransferase (GGT) and GSH-synthesizing enzymes were correspondingly increased significantly. By contrast, GSH peroxidase activity was decreased in ethanol-fed rats, 194 +/- 20.8 vs 311 +/- 89.9 nmoles NADPH oxidized/min/mg protein (P less than 0.001). Biliary output and concentrations of GSH and GSSG were similar in both groups. The increase in turnover of GSH was not due to an increase in oxidation of GSH. There was, however, an association between GSH turnover and the activity of hepatic GGT in ethanol-fed but not in control rats.

Differential effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism in the rat.

The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P less than 0.05) whereas in vivo N-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-Demethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P less than 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants, Km, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P less than 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448 mediated drug metabolism, with a greater effect on the former microsomal system.

Progressive hemochromatotic cardiomyopathy despite reversal of iron deposition after liver transplantation.

Dilated cardiomyopathy is a frequent and serious complication of idiopathic hemochromatosis. The mechanism by which disordered iron metabolism induces heart failure is not entirely understood, but myocardial dysfunction appears to be intimately related to the deposition of iron in myocytes. Cardiac function characteristically worsens or improves in proportion to the degree of iron accumulation in cardiac myocytes. The authors report the case of a 47-year-old man with idiopathic hemochromatosis and cirrhosis who developed symptoms of congestive heart failure and was found to have dilated cardiomyopathy 7 months after receiving a liver transplant. An initial endomyocardial heart biopsy demonstrated severe iron deposition in myocytes. The patient's heart failure worsened in the next 3 years and he eventually required a heart transplant. Examination of the explanted heart revealed dilated cardiomyopathy, but the previously demonstrated iron deposits in the cardiac myocytes were depleted. This "uncoupling" of cardiac function and cardiac iron load suggests that a threshold may be reached at which point the metabolic and ultrastructural derangements of iron deposition are no longer reversible, even with the removal of the inciting agent. Furthermore, displacement of myocyte iron stores after liver transplantation implicates altered hepatic iron metabolism as a primary or contributing mechanism in the pathophysiology of idiopathic hemochromatosis.

Energy state and vasomotor tone in hypoxic pig lungs.

To evaluate the role of energy state in pulmonary vascular responses to hypoxia, we exposed isolated pig lungs to decreases in inspired PO2 or increases in perfusate NaCN concentration. Lung energy state was assessed by 31P nuclear magnetic resonance spectroscopy or measurement of adenine nucleotides by high-pressure liquid chromatography in freeze-clamped biopsies. In ventilated lungs, inspired PO2 of 200 (normoxia), 50 (hypoxia), and 0 Torr (anoxia) did not change adenine nucleotides but resulted in steady-state pulmonary arterial pressure (Ppa) values of 15.5 +/- 1.4, 30.3 +/- 1.8, and 17.2 +/- 1.9 mmHg, respectively, indicating vasoconstriction during hypoxia and reversal of vasoconstriction during anoxia. In degassed lungs, similar changes in Ppa were observed; however, energy state deteriorated during anoxia. An increase in perfusate NaCN concentration from 0 to 0.1 mM progressively increased Ppa and did not alter adenine nucleotides, whereas 1 mM reversed this vasoconstriction and caused deterioration of energy state. These results suggest that 1) pulmonary vasoconstrictor responses to hypoxia or cyanide occurred independently of whole lung energy state, 2) the inability of the pulmonary vasculature to sustain hypoxic vasoconstriction during anoxia might be associated with decreased energy state in some lung compartment, and 3) atelectasis was detrimental to whole lung energy state.

Comparison of determinants of frame size in older adults.

Accurate designations of body frame size can enhance the interpretation of height-weight tables. Determinants of frame size should be quantifiable, reflective of skeletal dimensions, and not influenced by adiposity. Visual assessment, the height:wrist circumference ratio, elbow breadth by 1983 and 1984 standards, and Frame Index 2 were studied in 300 healthy adults over 64 years of age. Distribution of frame size across small, medium, and large categories revealed that visual assessment and height:wrist circumference ratio agreed with designations of elbow breadth measurements for less than 50% of the population. Highest levels of agreement occurred between elbow breadth (1984) and Frame Index 2. For men, high partial correlations between height:wrist circumference ratio and subscapular fatfold measurements corrected for age and arm muscle area indicated that measurement may be affected by body fat. Lowest correlations with subscapular fatfolds were for wrist and ankle breadths for women and ankle breadth for men. Elbow breadth and Frame Index 2 had low negative correlations with subscapular skinfold for men but much higher values for women. Elbow breadth measurements are widely used as frame size determinants, but for women, at least, ankle and wrist breadths meet the criterion of low associations with body fatness.

Weight gain and pregnancy outcome in underweight and normal weight women.

The relationship of antenatal weight gain to pregnancy outcome was studied in 362 pairs of underweight women (less than 90% Metropolitan Relative Weight) and normal weight (90% to 110%) women who were matched for age, occupation, height, parity, race, and smoking habits. The mothers, selected from a study of pregnancy outcome in 1,080 middle-class women, had early and regular prenatal care. Regression analyses within each initial weight category revealed that there was no relationship between initial weight of mothers and birth weight of their infants, but birth weight increased significantly with antenatal weight gain (p less than .0001). A 1-kg maternal increase in weight was associated with a 12.85-gm increase in birth weight in offspring of underweight women and an 8.59-gm increase in offspring of normal weight women. Underweight women had significantly larger prenatal weight gains (9.3 vs. 8.5 kg), but there were no statistically significant differences in mean birth weight, gestational age, or Apgar scores between infants of women in the two weight groups. Very underweight women (less than 80% MRW) had lower-birth-weight infants, more preterm infants, and more infants with medical complications. Antenatal weight gain accounted for the greatest variation in birth weight among infants of underweight and normal weight women. When underweight mothers gained less than 9 kg, their infants had mean birth weights 361 gm less than the mean birth weights of infants of underweight women who gained more weight.

Factors that influence the outcome of pregnancy in middle-class women.

A retrospective analysis was made of 1,080 singleton pregnancies of middle-class women to identify factors that influence outcome as measured by birth weight, gestational age, Apgar scores, and the incidence of complications. Increased birth weight was associated with increases in weight gain, maternal age, gestational age, maternal initial body weight, maternal hemoglobin and hematocrit values at 3 months, hemoglobin levels at 7 months, and socioeconomic status. For women whose initial weights were 90% to 135% of the standard, highest birth weights occurred when weight gains exceeded 29 lb. A 1 lb gain in maternal weight was associated with a 6 gm increase in birth weight. Birth weight was negatively correlated with a complicated obstetrical history and maternal cigarette smoking. Infants of heavy smokers weighed an average of 156 gm less than infants of nonsmokers. One-minute Apgar scores were significantly lower for infants of mothers who consumed alcohol and those who had had a complicated obstetrical history. Initial maternal weight and the husband's occupation positively influenced gestational age. There was no relationship between the incidence of maternal or infant complications and independent variables.

Alcohol-induced impairment of central nervous system function: behavioral skills involved in driving.

Several points emerge from the large body of data on the effects of alcohol on CNS function. First, the degree of impairment is dose related, but not identical or strictly linear for all behaviors. Alcohol-related impairment of behavioral skills involved in driving is greatest for those tasks that require cognitive functioning; simple perception alone is least affected. Impairment of cognitive functioning, which includes information processing and decision making under conditions of divided attention, is evident at BALs above 50 mg/dl and is markedly affected above 100 mg/dl. Above a BAL of 100 mg/dl, almost all behavioral skills are impaired by alcohol. Most studies have employed only one or at most two doses of alcohol in testing for impairment. The limited range of BALs studied makes determination of the overall shape of the dose-response curve difficult. Second, alcohol-related impairment of CNS functions cannot be demonstrated at low BALs. There is no consistent evidence that BALs below 50 mg/dl impair any behavior in most individuals. Youth and the elderly, groups not typically studied in the laboratory, may represent exceptions to this general observation. Nonetheless, these findings are more consistent with a threshold effect for impairment than for impairment at all levels of BAL. Third, for most behavioral skills, the decrement in performance after alcohol is slight, rarely exceeding 35-50% of the control period. In many studies, changes of only 8-10% are reported to be statistically significant. Whether these small statistically significant decrements in performance are an explanation for increased crash risk remains uncertain.(ABSTRACT TRUNCATED AT 250 WORDS)

Midodrine treatment for patients with hemodialysis hypotension.

Hypotension is the principal complication of chronic hemodialysis. Autonomic insufficiency is thought to be a primary contributing cause of hemodialysis hypotension. We treated patients who experience hemodialysis hypotension with midodrine, a selective alpha-1 adrenergic pressor agent in an initial effort to assess potential efficacy. Twenty-one patients who experienced severe hypotension during hemodialysis participated in this study. To qualify, patients had to exhibit a fall of > or = 30 mmHg in systolic blood pressure with associated clinical symptoms during hemodialysis. The lowest intra- and post-dialysis blood pressures were monitored for five consecutive hemodialysis treatment periods before receiving midodrine, as a baseline. After the patients were titrated to a maintenance midodrine dose, the lowest intra- and post-dialysis blood pressure data were again collected for five consecutive dialysis treatments. Hemodialysis blood pressures on midodrine treatment were compared to baseline to evaluate the effect of midodrine. Midodrine given at a mean treatment dose of 8 mg (range 2.5-25) significantly increased the mean (+ or - SE) minimal systolic pressure from 93.1 "+ or - " 3.8 to 107.1 + or - 3.2 mmHg (p <0.01) and elevated the mean diastolic pressure from 52.3 + or - 2.9 to 57.9 + or - 2.3 mmHg during hemodialysis. Also, the post-dialysis blood pressures (systolic/diastolic) were significantly increased from 115.6 + or - 3.1/62.3 + or - 2.1 to 129.9 + or - 3.9/68.1 + or - 1.7 mmHg (p <0.01 and 0.05, respectively). No apparent clinical or laboratory abnormalities were observed. Oral midodrine appears to be a safe and effective therapy for the treatment of hemodialysis hypotension.

Titin content of beef in relation to tenderness.

Steaks obtained from the longissimus dorsi muscle of 24 crossbred steers were subjected to four treatments (unaged raw, aged raw, unaged cooked, aged cooked) and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Titin migrated primarily as a single protein band in unaged raw samples (48 h post mortem), as a doublet in aged (16 days) raw samples, and as a triplet in unaged and aged cooked samples. Total titin band density remained constant among steaks that varied widely in Warner-Bratzler shear value, suggesting that beef steaks varying in tenderness contain the same amount of titin. It is concluded that titin content, as determined by gel electrophoresis, does not distinguish 'tough' from 'tender' beef.