Biomedical subjects

L J Hoffer

Publications and source records attributed to L J Hoffer.

17 recordsLinked to original sources

PubMed1992

Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics.

Diminished gating of the P50 auditory evoked response to repeated stimuli is a psychophysiological feature of schizophrenia, that is also present in many relatives of patients. Animal models of auditory sensory gating indicate that nicotinic cholinergic neurotransmission is a critical neuronal substrate. The aim of this experiment was to determine if the deficit in sensory gating could be reversed by nicotine administration. Nonsmoking relatives of schizophrenics with abnormal sensory gating were selected as subjects for this initial double-blind trial, to avoid effects of psychotropic medications that might complicate trials in schizophrenic patients themselves. Nicotine-containing gum increased P50 sensory gating to near normal levels within 30 min of administration. The effect was transient; the gating of P50 returned to baseline levels within 1 hr. There was no change observed after placebo administration. In one of the subjects, the anticholinesterase inhibitor physostigmine similarly normalized P50 gating. The results are consistent with the hypothesis that nicotinic cholinergic neurotransmission may mediate a familial psychophysiological deficit in schizophrenia.

Adult↗

PubMed1992

Protein metabolism in obese subjects during a very-low-energy diet.

We postulated that the return to nitrogen equilibrium after 3 wk of a negative balance during a very-low-calorie diet (VLCD) providing low-quality protein in obese subjects was due to availability of endogenously originating amino acids from a "pool" that, when depleted, would result in worsening balance. This should be reflected in altered kinetics of protein metabolism with the requirement for increased breakdown to maintain synthesis constant. Seven female obese subjects [body mass index (BMI) = 34.4 +/- 1.8 kg/m2] were given a 1.7-MJ/d all-protein diet (16.8 g N) derived from hydrolyzed gelatin (supplemented with tryptophan and methionine) that provides 18% of its amino acids as essential, a multivitamin-mineral supplement, and 16 mmol KCl for 42 d. At baseline (7-d isocaloric diet), and weeks 4 and 6 of VLCD, amino nitrogen flux rate was calculated from the 15N abundance in urinary urea using the oral 15N-glycine method and rates of synthesis (S) and breakdown (B) inferred from N flux. Whole-body N flux did not change from baseline to weeks 4 and 6 (39.5 +/- 2.0 vs 37.4 +/- 2.0 vs 39.2 +/- 1.9 g N/d). By contrast, S and B decreased at weeks 4 and 6 with S decreasing more so that net protein synthesis (S-B) was less positive at week 4 than at baseline (2.2 +/- 0.2 and 0.9 +/- 0.3 g N/d; P less than 0.05) and became negative at week 6 (-0.9 +/- 0.2 g N/d; P less than 0.05). Concurrently, N equilibrium was achieved by week 4 but returned to negative balance by week 6.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗

PubMed1992

Varied protein intake alters glutathione metabolism in rats.

We tested the possibility that protein consumption greater than needed for optimum growth of young adult rats might increase either their hepatic glutathione (GSH) content or plasma GSH turnover. Additional aims were to characterize the relationship between hepatic GSH content and plasma turnover under physiologic conditions and to evaluate the ability of values obtained by noninvasive blood sampling to accurately predict hepatic GSH content. Male Sprague-Dawley rats (300 g) were adapted to purified diets containing 0, 5, 10, 20 or 40% casein. Plasma GSH and amino acid concentrations, hepatic GSH content and [35S]GSH-determined plasma GSH turnover were measured in the anesthetized, intact animals. As dietary protein increased from 0 to 20% casein, liver weight and liver GSH concentration (mumol/g wet wt) both increased. In rats fed the 40% casein diet, liver weight increased even further while liver GSH concentration decreased, with the net result that total liver GSH content of the 40% casein-fed group was not significantly different from that of the 20% casein-fed group. Plasma urea, cysteine, methionine and GSH concentrations increased with increasing protein intake, but with the exception of plasma urea, which increased by 60%, there was no further increase at the 40% casein level. Plasma GSH turnover also increased as dietary casein increased from 0 to 20% but was not significantly increased further by the 40% casein diet. A sigmoid function best described the relationship between plasma GSH turnover and hepatic GSH content (r = 0.80, P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Plasma leucine kinetics and urinary nitrogen excretion in intensively treated diabetes mellitus.

It is well known that inadequate insulin therapy stimulates body protein loss in insulin-dependent diabetes mellitus (IDDM). It is less well known, however, that accelerated body protein loss (as indicated by increased leucine oxidation) occurs in IDDM even during conventional glycemic control. It is not known whether intensified insulin therapy fully normalizes protein oxidation or, more importantly, whether such therapy is sufficient to allow the adaptive decrease of protein oxidation that normally occurs when protein intake is restricted below the customary surfeit level. We used two measures of protein oxidation [daily urinary nitrogen (N) excretion over several days of intensive insulin therapy and plasma [1-13C]leucine oxidation during short-term strict euglycemia] to assess the response of 7 men with IDDM and 12 normal men after adaptation first to a control diet providing maintenance energy and conventional (surfeit) protein then to an isoenergetic protein-free diet. After adaptation to the protein-free diet and during short-term strict euglycemia achieved using intravenous insulin, leucine turnover and oxidation decreased equivalently in normal and diabetic subjects. However, daily urinary obligatory N excretion, which indicated the effect of the low-protein diet and intensive subcutaneous insulin therapy over several days, was increased by 18% in the diabetic group (P less than 0.05). Even mildly elevated average blood glucose values well within the guidelines for intensive therapy were strongly correlated with high rates of urinary N excretion (r = 0.97, P = 0.0002). Thus insulin therapy of IDDM that imposes strict euglycemia is compatible with a normal ability to diminish body protein oxidation in response to protein restriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗

PubMed1991

Reappraisal of the resting metabolic rate of normal young men.

The Harris-Benedict (HB) equation, widely used to estimate the resting metabolic rate (RMR), has been disputed by Owen et al who reported that it overestimates the RMR of men aged less than 50 y by approximately 9%. We measured the RMR of 29 healthy, nonsmoking men aged 18-33 y by direct oxygen consumption with a closed-circuit technique similar to that used by Harris and Benedict (respirometer), as well as by a ventilated-hood technique. RMR determined by the ventilated-hood technique was 5.6% lower than when determined by the respirometer (1643 +/- 148 vs 1721 +/- 145 kcal/d, respectively, means +/- SD; P less than 0.001). RMRs by both these methods were lower than the value of 1813 +/- 164 kcal/d predicted by the HB equation; the 95% confidence intervals (CIs) for RMR were 92.4-98.1% (respirometer) and 88.5-91.1% (ventilated hood) of the value predicted by the HB equation. The 95% CI for RMR determined by ventilated hood was 98.4-103.5% of the value predicted by using a new equation proposed by Owen et al. We conclude that the HB equation overestimates RMR by 9.2% in normal young men. This could be due in part to the inherent discomfort experienced by subjects when the original technique was used.

Adolescent↗

PubMed1991

Plasma glutathione turnover in the rat: effect of fasting and buthionine sulfoximine.

Hepatic glutathione (GSH) plays an important role in the detoxification of reactive molecular intermediates. Because of evidence that the intrahepatic turnover of glutathione in the rat may be largely accounted for by efflux from hepatocytes into the general circulation, the quantitation of plasma GSH turnover in vivo could provide a noninvasive index of hepatic glutathione metabolism. We developed a method to estimate plasma glutathione turnover and clearance in the intact, anesthetized rat using a 30-min unprimed, continuous infusion of 35S-labelled GSH. A steady state of free plasma glutathione specific radioactivity was achieved within 10 min, as determined by high-pressure liquid chromatography with fluorometric detection after precolumn derivatization of the plasma samples with monobromobimane. The method was tested after two treatments known to alter hepatic GSH metabolism: 90 min after intraperitoneal injection of 4 mmol/kg buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, and after a 48-h fast. Liver glutathione concentration (mean +/- SEM) was 5.00 +/- 0.53 mumol/g wet weight in control rats. It decreased to 3.10 +/- 0.35 mumol/g wet weight after BSO injection and to 3.36 +/- 0.14 mumol/g wet weight after fasting (both p less than 0.05). Plasma glutathione turnover was 63.0 +/- 7.46 nmol.min-1.100 g-1 body weight in control rats, 35.0 +/- 2.92 nmol.min-1.g-1 body weight in BSO-treated rats, and 41.7 +/- 2.28 nmol.min-1.g-1 body weight after fasting (both p less than 0.05), thus reflecting the hepatic alterations. This approach might prove useful in the noninvasive assessment of liver glutathione status.

Animals↗

PubMed1990

Nutritional status affects renal 3-methylhistidine handling in humans.

The plasma concentration of 3-methylhistidine (3MH) has been used in the assessment of nutritional status. Because urinary excretion is the sole route of elimination, and hence a potential determinant of the plasma concentration, 3MH renal handling was examined under different nutritional conditions. Ten obese women consumed a meat-free maintenance energy diet for 4 days before undergoing a 21-day total fast, after which they were assigned into two groups (n = 5) that received 7 days of hypocaloric feeding with 80 g of either milk protein or carbohydrate. 3MH excretion and plasma levels decreased in parallel during fasting and protein refeeding, suggesting that the plasma concentration accurately reflected a decrease of myofibrillar protein turnover, but carbohydrate refeeding was associated with a 31% increase in plasma 3MH (P less than .05) despite a concurrent 28% decrease in its excretion (P less than .05). This was due to a 41% decrease in 3MH renal clearance (P less than .05). Creatinine and urea clearances changed insignificantly in all diet periods. Plasma histidine (HIS) concentrations decreased with fasting and carbohydrate refeeding (P less than .05). 3MH clearance was found to be related to the plasma HIS/3MH concentration ratio (r = .60, P less than .001). Under some circumstances, an altered plasma HIS concentration appears to influence renal 3MH clearance and hence its plasma concentration.

3-Hydroxybutyric Acid↗

PubMed1990

Prolonged fasting as conditioned by prior protein depletion: effect on urinary nitrogen excretion and whole-body protein turnover.

To study the influence of previous dietary protein depletion on nitrogen (N) loss and protein turnover during a total fast, we measured plasma leucine kinetics and urinary N and 3-methylhistidine (3MH) excretion in obese and normal subjects. In one study, 10 moderately obese women fasted for 2 weeks after adaptation either to a normal maintenance intake of 80 g protein and 150% of estimated resting energy expenditure (control group), or to 10 days of a 950-kcal, 200-g carbohydrate, 4-g protein diet (depletion group), with measurement of postabsorptive (or fasting) plasma leucine turnover on the maintenance diet and after 3 and 10 days of fasting. As measured after 10 days of fasting, body N loss was blunted by 17% when preceded by the protein-deficient diet. Plasma leucine flux and oxidation of the control group increased in early fasting and decreased by 10 days, in accordance with previous reports. Results for the depletion group were similar in absolute magnitude, despite the preceding protein-deficient diet. In a second study of five normal men, leucine kinetics were measured on a maintenance diet, after 10 days of a protein-free diet, and after 3 days of fasting. After protein depletion, leucine flux decreased by 19% (P less than .05). After 3 days fasting, leucine flux was 16% higher than on the maintenance diet (P less than .05), but 44% higher than the value on the protein-free diet 3 days earlier (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Fasting↗

PubMed1990

Protein metabolic effects of a prolonged fast and hypocaloric refeeding.

In a study of the mechanism of adaptation to protein deficiency, 10 moderately obese women underwent a 3-wk fast followed by random allocation to a 1-wk refeeding regimen providing 80 g carbohydrate or protein. Protein metabolism was studied by means of nitrogen (N) balance, urinary 3-methylhistidine excretion, and postabsorptive plasma leucine flux using L-[1-13C]leucine infusions. After the 3-wk fast, plasma leucine flux and 3-methylhistidine excretion both decreased by 31% from control diet values (P less than 0.01), and N balance was -5.9 g/day. After protein refeeding, N balance was positive (+1.7 g/day, P less than 0.05) whereas leucine flux was unchanged from prolonged fasting values. After carbohydrate refeeding, N balance improved to -3.1 g N/day, whereas leucine flux decreased by a further 18% (P less than 0.05). Protein and carbohydrate refeeding were associated with further 23 and 31% reductions of 3-methylhistidine excretion compared with prolonged fasting (P less than 0.05). The results support the hypothesis that improved efficiency of protein retention in starvation is intimately associated with a decreased rate of protein turnover.

3-Hydroxybutyric Acid↗

PubMed1989

Generalized decrease in brain glucose metabolism during fasting in humans studied by PET.

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylation fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.

Adult↗

PubMed1989

A comparison of enflurane with alfentanil anaesthesia for gynaecological surgery.

Forty patients undergoing gynaecological surgery were randomly assigned to receive either alfentanil and thiopentone for induction of anaesthesia, followed by alfentanil-N2O/O2 (60%/40%) for maintenance of anaesthesia, or low-dose fentanyl and thiopentone, followed by enflurane-N2O/O2 (60%/40%). More patients given enflurane developed a tachycardia (P less than 0.03) and 20% decreases in systolic and diastolic blood pressure. Times to recovery were significantly shorter after alfentanil than after enflurane. Plasma concentrations of alfentanil during induction suggested that haemodynamic and catecholamine responses were either less than, or did not differ from, baseline levels when the plasma concentration of the drug exceeded 150 ng ml-1. At extubation and the beginning of spontaneous breathing, the plasma concentration was 278 +/- 129 ng ml-1. Values for pharmacokinetic parameters of alfentanil were as follows: clearance, 5.2 +/- 2.0 ml kg-1 min-1; volume of distribution, 0.63 +/- 0.20 1 kg-1; and elimination half-life, 96.9 +/- 52.5 min. Two patients who had extended surgery had significantly lower plasma clearance of alfentanil and increased half-life. The authors conclude that the alfentanil technique was preferable to maintenance with enflurane.

Adult↗

PubMed1988

Alanine flux in obese and healthy humans as evaluated by 15N- and 2H3-labeled alanines.

Estimates of plasma alanine flux as measured in humans using L-[15N]-alanine or L-[3,3,3-2H3]alanine were compared by simultaneous intravenous infusion of both tracers. Plasma isotope enrichments were measured by chemical ionization gas chromatography-mass spectrometry. In 16 obese women before and during a hypocaloric diet and in 4 normal men in the postabsorptive and fed states, the fluxes were highly correlated (r2 = 0.93) although plasma alanine flux with the 2H tracer was two to three times greater than that obtained with [15N]alanine. The fluxes decreased with the hypocaloric diet in obese subjects and increased during the fed state in healthy adults. Thus, although the estimates of alanine flux differed according to the tracer used, both appear to give equivalent information about changes in alanine kinetics induced by the nutritional conditions examined.

Adult↗

PubMed1988

Measurement of branched chain amino acids in blood plasma by high performance liquid chromatography.

A simple and rapid high performance liquid chromatographic technique is described for the separation and quantitation of plasma branched chain amino acids. After addition of a norleucine internal standard, plasma samples are acidified with acetic acid, and amino acids are separated from proteins and other plasma components by passage of the acidified plasma through an ion exchange resin. The ammonium hydroxide eluate from the resin is dried, phenylisothiocyanate derivatives are prepared, and the amino acids are separated on a Waters reverse-phase "Pico-Tag" column with an ultraviolet detector set at 254 nm. In addition to the branched chain amino acids (leucine, valine, and isoleucine), aspartate, glutamate, serine, threonine, alanine, and methionine are quantitated with high precision and accuracy, as verified by quantitative recovery and comparison with an automatic amino acid analyzer. The advantages of the method are its simplicity, speed, stability of derivatives, high reproducibility, low per-sample cost, and the use of a simple fixed-wavelength ultraviolet detector.

Amino Acids, Branched-Chain↗

PubMed1986

Effects of adenosine and adenosine analogues on glycogen metabolism in isolated rat hepatocytes.

Adenosine and adenosine analogues were incubated with isolated rat hepatocytes. Adenosine and 5'-deoxy-5'-chloroadenosine stimulated glucose release, glycogen loss, and the conversion of glycogen phosphorylase b to a. The effect was of short duration for adenosine, but of long duration for 5'-deoxy-5'-chloroadenosine. The effects on glucose release and phosphorylase were blocked by theophylline, an R-receptor blocking agent, but not by nitrobenzylthioinosine or dipyridamol which are nucleoside transport inhibitors. A dose-dependent rise in cyclic AMP concentration was observed in hepatocytes 1 min after adding adenosine. It is concluded that adenosine exerts these effects in liver by activating adenylcyclase. Adenosine may be involved in the short-term regulation of hepatic glycogen phosphorylase.

Adenosine↗

PubMed1986

Effects of severe dietary restriction on male reproductive hormones.

The reproductive hormone response to severe caloric restriction (600 Cal day-1) was studied in six men 33-67% over ideal body weight who completed a 32-day protocol consisting of three periods in the following order: control (4 days), maintenance protein and energy; diet A (14 days), 50 g lean beef protein plus 50 g casein; and diet B (14 days), 50 g lean beef protein plus 50 g carbohydrate. Weight loss (8.7-12.5 kg) was associated with a decrease in mean blood glucose [4.52 +/- 0.60 (+/- SEM), 3.49 +/- 0.29, and 3.80 +/- 0.30 mM] and an increase in beta-hydroxybutyrate (less than 0.10, 2.09 +/- 0.44, and 1.06 +/- 0.34 mM), as determined on the final morning of each period. On the same days, mean serum FSH and LH responses to LHRH infusion of 0.2 micrograms min-1 for 4 h (expressed as milliinternational units per ml area under the concentration-time curve) were: FSH, 1558 +/- 359, 1336 +/- 545, and 1337 +/- 321 (P = NS); and LH, 1730 +/- 545, 1612 +/- 481, and 1782 +/- 556 (P = NS), respectively. Basal serum FSH, LH, free testosterone (T), and total T changed, while 24-h urinary LH and FSH excretion increased on diet A only. Unlike 10 days of total fasting, during which the same amount of weight was lost, basal serum FSH and LHRH-stimulated serum FSH responses were both significantly diminished by 25%, and serum T was diminished by 19% (1), these same parameters were little changed by either low energy diet. The increased urinary excretion of FSH and LH during diet A suggests that greater ketosis increases renal gonadotropin clearance.

Adult↗

PubMed1985

Effects of meal consumption on whole body leucine and alanine kinetics in young adult men.

The effects of meal consumption on plasma leucine and alanine kinetics were studied using a simultaneous, primed, continuous infusion of L-[1-13C]leucine and L-[3,3,3-2H3]alanine in four healthy, young, adult male subjects. The study included an evaluation of the effect of sampling site on plasma amino acid kinetics, with blood being drawn simultaneously from an antecubital and dorsal heated hand vein. In comparison with the postabsorptive state, the ingestion of small hourly meals resulted in a 35% increase in plasma leucine flux and a 77% increase in leucine oxidation. Calculated entry of leucine into the plasma compartment from endogenous sources decreased by 65%. Plasma alanine flux more than doubled, indicating a significant enhancement in de novo alanine synthesis. 13C enrichment of leucine in venous and arterialized plasma did not differ significantly, but alanine flux calculated from isotopic measurement in venous plasma was substantially greater than that based on analysis of arterialized blood plasma.

Adult↗

PubMedDate not supplied

Cori cycle contribution to plasma glucose appearance in man.

The contribution of recycled glucose to gluconeogenesis and plasma glucose appearance (Cori cycle) has previously been calculated from liver balance studies and from infusions of labeled glucose. Both techniques resulted in the estimate that Cori cycle activity accounts for about 15% of plasma glucose appearance. However, it is now understood that the specific activity of gluconeogenic precursors, which is used to determine their contribution to glucose appearance in plasma, overestimates the true precursor specific activity. Using earlier published data on substrate utilization and glucose turnover kinetics in humans, an empiric correction factor of 2.7 is derived which may approximately account for label dilution in the precursor pool. Use of this factor confirms that the former estimate of the contribution of Cori cycle activity to glucose turnover should be revised substantially upwards.

Blood Glucose↗