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Biomedical subjects

E M Landaw

Publications and source records attributed to E M Landaw.

16 recordsLinked to original sources
PubMed1992

Hemolysis of transfused group O red blood cells in minor ABO-incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate.

Hemolysis most commonly occurs following bone marrow transplant when there is "minor" ABO blood group incompatibility between donor and recipient. The hemolysis has been attributed to destruction of the patient's incompatible erythrocytes by donor-derived anti-A and/or anti-B antibody produced from "passenger" immunocompetent donor lymphocytes. Extraordinary transfusion requirements of group O erythrocytes in a series of patients receiving unrelated minor ABO-incompatible marrow grafts led us to investigate whether this mechanism could account for the extent of hemolysis observed. In seven consecutive minor ABO-incompatible unrelated-donor bone marrow transplant recipients receiving cyclosporine without posttransplant methotrexate, we observed excessive hemolysis. For cases in this index group, a strongly reactive donor-derived ABO blood group antibody was identified coincident with development of hemolysis. Transfusion requirements in the first three patients (26 U of group O erythrocytes each) greatly exceeded the recipient's volume of incompatible erythrocytes, indicating that lysis of transfused group O erythrocytes was also occurring. Pretransplant erythrocyte exchange transfusion with group O erythrocytes performed in the four subsequent patients decreased the severity of hemolysis, but did not prevent it. Among minor ABO-incompatible marrow graft recipients, an analysis of variance demonstrated effects on transfusion requirements due to donor-recipient relationship being unrelated (P less than .002) and the use of posttransplant methotrexate (P = .0001), and there was interaction between these two factors (P less than .001). Bone marrow transplants from unrelated donors resulted in an exaggerated immune response to ABO blood group antigens, which was associated with hemolysis of transfused group O erythrocytes, as well as the patient's ABO-incompatible erythrocytes. This serious complication may be prevented by posttransplant immunosuppression with methotrexate.

ABO Blood-Group System↗
PubMed1992

Increase in bicarbonate stores with exercise.

We previously described bicarbonate exchange dynamics in humans at rest and during exercise using a three-compartment model. In the present study we tested the effect of certain assumptions of this model on the prediction of the change in exchangeable bicarbonate with the increased metabolic rate of exercise. We compared this prediction with a measurement of CO2 retention after exercise onset determined from gas exchange data. The change in tissue bicarbonate stores was estimated from differences in the kinetics of adjustment of VO2 and VCO2, and this was added to an estimate of the changes in venous blood gas stores to estimate the total change in bicarbonate. When the commonly held assumption that endogenous CO2 production, thought to occur in a rapidly equilibrating peripheral compartment at rest, was also applied to the exercise condition, the three-compartment bicarbonate model predicted an unphysiologically large increase in bicarbonate stores (700 mmol, or over 15 L). In contrast, the 'gas exchange' approach predicted a relatively small increase in bicarbonate (26 mmol), consistent with other reports. The incompatibility of these findings with the assumption about the source of endogenous CO2 production in the bicarbonate model requires that the underlying physiological correlates of the three compartments change from rest to exercise.

Bicarbonates↗
PubMed1992

DIMSUM: an expert system for multiexponential model discrimination.

DIMSUM is a highly automated, rule-based expert system designed to fit multiexponential models of increasing dimension to time series data, followed by selection of the best candidate model based on a user-modifiable and weighted decision tree of statistical criteria for model discrimination. The major features of DIMSUM are 1) an interactive and friendly user interface; 2) options for incorporating prior information about the parameters, the data, and/or the system from which the data were collected, in the form of equality and inequality constraints; 3) a built-in algorithm for automatically obtaining starting values for parameter estimation; 4) a robust weighted least-squares parameter estimation algorithm operating in an adaptive, user-adjustable search space; 5) comprehensive statistical results comparing different order candidate models fitted to the data; and 6) a novel, user-modifiable (learning) rule-based advisory subsystem providing an "expert's" interpretation of these statistical results and an explanation of all advice.

Algorithms↗
PubMed1991

13CO2 washout kinetics in acute hypercapnia.

The redistribution of CO2 and bicarbonate throughout the body following perturbations of normal respiration is not well described. We used tracer techniques to examine CO2-bicarbonate dynamics in an animal model in which acute hypercapnia was induced by hypoventilation. Eleven rabbits were anesthetized, tracheostomized, paralyzed and ventilated. In five animals PaCO2 was kept between 30 and 35 mmHg (control, C) while in six PaCO2 was held between 65 and 70 mmHg (acute hypercapnia, AH). A bolus of [13C]bicarbonate was given intravenously. Breath samples were obtained for 13CO2 by isotope ratio mass spectrometry and CO2 output (VCO2) was measured breath-by-breath for 240 min. There was no difference in the VCO2 between C [5.6 +/- 1.8 (SD) ml/min per kg] and AH (5.3 +/- 0.8). The 13CO2 washout for both C and AH was well fit by the sum of three exponentials. Only the time constant of the third (slowest) exponential was significantly longer in AH (103 +/- 11 min) compared with C (75 +/- 15, P less than 0.01). The mean residence time in AH (82 +/- 9 min) was significantly lower than in C (57 +/- 10, P less than 0.001). The estimated mass of exchangeable CO2 and bicarbonate was significantly greater in AH (443 +/- 37 ml per kg) compared with C (312 +/- 63, P less than 0.005). Compartmental analysis indicated that the increase in CO2-bicarbonate occurred primarily in the slowly exchanging pool. The data suggest that acute hypercapnia may be accompanied by a redistribution of exchangeable CO2 and bicarbonate in the body.

Acute Disease↗
PubMed1990

Influence of increased metabolic rate on [13C]bicarbonate washout kinetics.

The effect of changes in metabolic rate on the dynamics of CO2 exchange among its various compartments in the human body is not well understood. We examined CO2 dynamics in six healthy male subjects using an intravenous bolus of [13C]bicarbonate. Subjects were studied while resting, during light exercise [50% of the lactate threshold (LT), 3-4 times resting O2 uptake (VO2)], and during moderate exercise (95% of the LT, 6 times resting VO2). The sum of three exponential terms well described the washout of 13CO2 in exhaled breath both at rest and during each exercise level despite substantial increases in metabolic rate accompanying the exercise studies. Average recovery of 13C label rose from 67% during rest to 80% during light and moderate exercise (P less than 0.01). The estimate of CO2 elimination (VCO2) calculated from the washout parameters and corrected for recovery was in very good agreement with the VCO2 directly measured simultaneously breath by breath (r = 0.993, SE for VCO2 = 0.079 l/min). By use of a three-compartment mammillary model, the quantity of CO2 in the central pool (Q1) doubled from rest to light exercise (233 +/- 60 to 479 +/- 76 mmol, P less than 0.01) but did not change further with moderate exercise (458 +/- 74 mmol). Rate constants for exchange between pools and for irreversible loss from the system tended to increase with metabolic rate, but there was large variation in the responses. We conclude that the compartmental dynamics of CO2 transport and storage are very sensitive to changes in metabolic rate induced by exercise.

Adult↗
PubMed1988

Tegumental glucose permeability in male and female Schistosoma mansoni.

Tegumental hexose transporters have been kinetically characterized in mated and separated male and female Schistosoma mansoni 8-12 wk postinfection. Significant gender-specific differences in Km and Vmax were observed. In mated males, the estimated constants (mean +/- SE) were: Km = 0.63 +/- 0.31 mM, Vmax = 0.93 +/- 0.44 nmol/mg worm water/min, and the Kd = 0.25 +/- 0.09 microliter/mg worm water/min. In mated females the kinetics were: Km = 0.99 +/- 0.40 mM, Vmax = 1.22 +/- 0.42 nmol/mg worm water/min, and Kd = 0.60 +/- 0.14 microliter/mg worm water/min. The influx of 2-deoxy-D-glucose and 3-O-methylglucose has been similarly characterized; these analogs share the same glucose transporter in male and female schistosomes. 2-Deoxy-D-glucose has a higher affinity, and 3-O-methylglucose a lower affinity, than does glucose. Because mated male schistosomes supply glucose to female partners, similarities between the free glucose concentration of the male and the affinity of the transporter determined for mated female schistosomes suggest that male-to-female transfer may be a potentially rate-limiting step in glucose utilization by the female. Permeability x surface are (PS) products and Vmax/Km ratios were significantly elevated in mated schistosomes, suggesting that the transporter is primarily localized to the dorsal surface of the male. Gender- and mating-specific analyses of PS products indicate that tegumental permeability to glucose is significantly increased in mated schistosomes, and compares very favorably to that of the host liver.

3-O-Methylglucose↗
PubMed1987

A minimax approach to the single-point method of drug dosing.

The single-point dose prediction method is based on the observation that for drugs obeying single compartment elimination kinetics there is a nearly constant reciprocal relation between the plasma level at a fixed time following a single loading dose and the dose that is required to maintain the desired steady state plasma level of the drug. This paper describes an improved method for choosing a plasma sampling time and a proportionality constant. It applies to either drugs administered intravenously or to drugs whose rates of absorption from the site of administration are very rapid compared to their rates of elimination from the body. The sampling time and proportionality constant chosen are those that minimize the maximum relative deviation of the maintenance dose estimated by the single-point method from the dose that would be estimated if the individual's true elimination rate constant were known. The paper also supplies a method to determine the maximum error that may be introduced into the estimation of the maintenance dose by using the single-point method.

Mathematics↗
PubMed1987

Steady state model of 3,5,3'-triiodothyronine transport in liver predicts high cellular exchangeable hormone concentration relative to in vitro free hormone concentration.

The hepatic nuclear receptor for T3 is known to be approximately 50% saturated in vivo. Since the receptor dissociation constant (Kd) is 1 nM, and since 50% receptor occupancy occurs when the concentration of free ligand in the nucleus is 1 nM, the concentration of free T3 in the hepatic nucleus is also approximately 1 nM or about 200-fold greater than the concentration of free T3 in human serum, as measured in vitro by equilibrium dialysis. However, previous tracer kinetic studies have shown that T3 is available for transport from both the circulating albumin- and thyroid hormone-binding globulin-bound pools in plasma. Since the plasma proteins per se do not significantly exit the hepatic microcirculation on a single pass, the protein-bound hormone is operationally available for transport into liver via a proposed mechanism of enhanced dissociation caused by interactions between the plasma proteins and the hepatic microcirculation. These considerations raise the question as to whether the dissociation of T3 from serum proteins is sufficiently enhanced to allow for enrichment in the hepatic pools of exchangeable hormone that can generate 50% receptor occupancy. The present studies present a physiologically based steady state model of T3 transport and distribution in liver. All parameters of the model pertain to physiologically discrete pathways of hormone, plasma protein, or plasma flux through the liver. The rate constants were estimated from previously reported tracer kinetic transport data in rat liver in vivo using rat and human serum proteins. A computer program in BASIC for steady state analysis is presented. The results of the stimulation studies are as follows. The concentration of cellular exchangeable T3 in liver is predicted to be approximately 2 log orders greater than the concentration of free T3 measured in vitro, but approximately equal to the concentration of free T3 predicted to exist in the hepatic nucleus; thus, the high degree of hepatic nuclear T3 receptor occupancy is compatible with the model that T3 is available for transport into liver from the circulating serum protein-bound pools. The concentration of cellular exchangeable T3 is governed primarily by the concentration of plasma exchangeable T3 (and membrane transport and cellular metabolism of T3) and is predicted to be independent of changes in the concentration of cytosolic T3-binding proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Hyperthyroidism in children treated with long term medical therapy: twenty-five percent remission every two years.

We use an antithyroid drug for the treatment of hyperthyroidism due to Graves' disease in children and adolescents for as long as the patients are willing to comply and/or tolerate the drug. In more than 60 patients treated since 1961, the remission rate was 25% in the first 2 yr. This report looks at these same patients again, followed for an additional 5 yr. Survival analysis methods applied to the follow-up data on 63 children confirm our original statistical findings and suggest a continuing remission rate of 25% every 2.1 +/- 0.4 (+/- SE) yr regardless of the duration of previous therapy. The median time to remission was 4.3 +/- 1.5 yr, and 75% of patients are predicted to be in remission in 10.9 +/- 2.3 yr. Of 36 patients who went into remission, defined by their being euthyroid for 1 yr after cessation of therapy, 1 relapsed, and 2 developed spontaneous hypothyroidism; the remainder are euthyroid 1-11.7 yr after therapy was discontinued. Of 14 who switched from medical therapy, 2 of 7 treated surgically and 4 of 7 treated with 131I are hypothyroid. Only 1 patient had a significant adverse reaction to both methimazole and propylthiouracil. While medical therapy may have some direct effect on the autoimmune response in hyperthyroidism, its role in affecting the time to ultimate remission is unknown. These data, however, describe the course of children so treated and allow us to present therapeutic options initially or during treatment based on statistically derived probabilities of outcome.

Child↗
PubMed1986

Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.

Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.

Adult↗
PubMed1985

Comments on mean residence time determination.

In a recent paper, D. O. Chanter challenged the applicability of the use of statistical moments in estimating mean residence time and proposed an alternative approach. Errors in that paper are pointed out which involve the improper equating of whole-body amount of drug with plasma amount of drug in a kinetic system. The theory for the two methods discussed by Chanter is presented in a pharmacokinetic context.

Body Burden↗
PubMed1985

Carotid artery injection technique: bounds for bolus mixing by plasma and by brain.

Estimation of Michaelis-Menten kinetic parameters (Km, Vmax) of blood-brain barrier (BBB) transport processes with the carotid artery single injection technique assumes that mixing of the bolus with unlabeled substrate either from (a) circulating plasma or (b) amino acid efflux from brain, is minimal. The maximum extent to which the bolus could mix by these two sources is quantified in the present studies by measuring 14C-phenylalanine extraction in pentobarbital-anesthetized and conscious rats after the addition of 0-80% rat serum to the arterial injection solution. An upper bound (+/- SE) of bolus mixing due to mixing from both sources, expressed in terms of percentage of rat plasma, is 8.8 +/- 1.9 and 7.0 +/- 2.1% for the anesthetized and conscious rat, respectively. The estimated contribution to bolus mixing due to amino acid efflux from brain is 3.3 and 2.1% for the anesthetized and conscious rat, respectively. Based on these estimates, the upper bound for bolus mixing with circulating rat plasma is only 5.5 and 4.9%, respectively, for the anesthetized and conscious catheterized rat. Thus, any bolus mixing after rapid carotid injection is relatively small and is comparable to the mixing effects observed with the carotid artery infusion technique. Mixing effects on the order of 5% are shown to have no significant effect on the estimation of kinetic parameters of BBB nutrient transport, except for neutral and basic amino acid transport, which are characterized by very low Km values relative to the usual amino acid plasma concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1985

Testosterone transport in brain: primary role of plasma protein-bound hormone.

Physiologically based mathematical modeling is used to predict the steady-state concentration of intracellular free and bound testosterone in brain. On the basis of previous in vivo tracer kinetic studies of blood-to-brain and brain-to-blood transport of testosterone in the rat, values are assigned to various physiological parameters (hormone association and dissociation reactions with plasma and cytosolic binding proteins, capillary transit time, and membrane transport). The model does not adhere to the restrictions of the free hormone hypothesis and allows for the enhanced transport of hormone from the plasma protein-bound pool into the tissue extravascular space. This process is believed to occur via an endothelial inhibition of ligand binding to the plasma protein without the protein crossing the endothelial wall. The model predicts that the steady-state concentration of intracellular free hormone changes in parallel more closely to changes in the concentration of plasma protein-bound hormone as measured in vitro and not the free hormone as measured in vitro.

Animals↗