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PubMed1984

Locus of control and treatment outcome in alcoholics.

Alcoholism is no longer regarded as a unitary disorder, but conventional measures of cognition and personality have yet to be shown capable of consistently predicting clinical outcomes. The present study evaluated the ability of two measures of locus of control--a generalized measure (IE) and a drinking-related one (DRIE)--to predict therapy involvement during, and treatment outcome following, an abstinence-oriented inpatient program for alcoholics. Both measures were administered to 106 patients (32 women) once near the beginning and once near the end of treatment. A range of other sociodemographic and psychological data was also recorded. Significant and independent shifts in the internal direction were found on both measures from the first to second testing. Relationship between locus of control and treatment participation was weak. DRIE fared better than IE in predicting treatment outcome. Ability to predict outcome was enhanced when interactions between locus of control and cognitive dysfunction were considered and when analyses included nonlinear relationships between these measures and treatment outcome.

Adult↗
PubMed2001

Response of potato tuber yield to stem injury by European corn borer (Lepidoptera: Crambidae) in the Mid-Atlantic United States.

The response of potato, Solanum tuberosum L., tuber yield to stem injury by European corn borer, Ostrinia nubilalis (Hübner), larvae was investigated in the Mid-Atlantic region of the United States for 3 yr. This response was described for 'Superior', 'Atlantic', and 'Snowden' potato, which are early-season, midseason, and late-season maturing cultivars, respectively. To model the yield/injury relationship, a range of corn borer injury levels was established in the field by augmenting the natural infestation with varying densities of laboratory-reared larvae. Linear and nonlinear regression analyses (plateau and second-order polynomial models) were used to describe the relationship between yield of U.S. No. 1 grade tubers and the percentage of stems injured by corn borer larvae. The maturity of the cultivar did not affect the response of potato yield to stem injury. In nine of 14 experiments, potato tolerated high levels of corn borer injury (55-90% of stems injured) without yield loss, suggesting that control of corn borer may not be necessary. Yet, in one of five Superior tests, in two of four Atlantic tests and in two of five Snowden tests, corn borer injury significantly reduced yield. Of the five data sets in which corn borer injury reduced yield, the plateau model fit two data sets and the quadratic model fit one data set. In two of the three cases, these models accounted for nearly identical amounts of total variation in yield as that accounted for by the linear model. The linear model fit four of the five data sets, but the R2 values were low for three of the four tests (0.10, 0.18, and 0.31). The parameter or parameters that interact with corn borer injury to cause tuber yield reduction should be identified before economic injury levels and thresholds are developed.

Animals↗
PubMed2004

Modelling ciclosporin double-peak absorption profiles in the early post-transplantation period.

OBJECTIVE: To apply a recent double-peak absorption model to ciclosporin. METHODS: Pharmacokinetic evaluation was performed in 20 patients who had undergone de novo renal transplantation and were receiving immunosuppressive therapy with corticosteroids, mycophenolate mofetil and ciclosporin Neoral. Data were analysed by nonlinear mixed-effects modelling using individual and population approaches. RESULTS: Six patients presented pharmacokinetic profiles with two peaks, whereas 14 curves apparently had a single, sometimes delayed and wide, peak. A one-compartment model with first-order elimination in association with the double-peak absorption model best fitted the data. This model reliably described the pharmacokinetics of ciclosporin, whether or not a double peak was present on the concentration-time profiles. CONCLUSIONS: The double-peak absorption model could be useful to optimise ciclosporin exposure in the early post-transplantation period.

Absorption↗
PubMed2005

Population pharmacokinetics of mycophenolic acid in renal transplant recipients.

BACKGROUND: Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics. OBJECTIVE: The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters. PATIENTS AND METHODS: Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling. RESULTS: The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (k(a)) 4.1h(-1), central volume of distribution (V1) 91 L, peripheral volume of distribution (V2) 237 L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21 h. The interpatient variability for k(a), V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for k(a), V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001). CONCLUSION: The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated.

Administration, Oral↗
PubMed2005

Age effects in perception of time.

Despite the widespread belief that the subjective speed of the passage of time increases with age, empirical results are controversial. In this study, a combination of questionnaires was employed to assess subjective time perception by 499 subjects, ages 14 to 94 years. Pearson correlations and nonlinear regression analyses on a variety of questionnaires and the age of the participants show that the momentary perception of the passage of time and the retrospective judgment of past periods of time are a function of chronological age; however, small-to-moderate effects accounted for at most 10% of the variance. Results generally support the widespread perception that the passage of time speeds up with age. These results are discussed in the context of models of prospective and retrospective time judgment, but interpretations have to be treated with caution given methodological limitations.

Adolescent↗
PubMed1992

Growth patterns of two lines of Angus cattle selected using predicted growth parameters.

Linear functions of body weight and condition score at weaning and 18 mo of age were used to predict the mature weight (A) and maturing rate (k) parameters of an asymptotic growth model of Angus cows at the Subtropical Agricultural Research Station, Brooksville, FL. From 1981 through 1988 a heavy-mature-weight line (Line A) and a rapid-maturing line (Line K) were selected based on predicted A and k values. Linear contrasts (A-K) of least squares means for weight at fixed ages indicated that the weight difference between lines increased from birth to maturity during the period of the study. Animals from Line A were heavier (P less than .01) at all ages. A negative response in maternal ability, relative to increased growth potential of their calves, seems to have occurred in the cows of Line A. Mature weight was reached at approximately 4.5 yr of age in Line K and at approximately 5.5 yr in Line A. Brody's three-parameter and Richards' four-parameter functions were fitted to 2,855 quarterly weights of cows, from birth to 6.5 yr of age, to estimate the average growth curve for each line. Brody's model gave better estimates of weights from 18 mo to maturity, but the asymptotic residual mean squares were slightly higher because early weights were overestimated. Linear and nonlinear regression analyses of weight-age data and comparisons of degree of maturity at different premature ages showed differences in the growth patterns of the two lines selected for early predicted values of A and k.

Animals↗
PubMed1997

[A comprehensive system for detecting ventricular fibrillation using various signal descriptors].

A novel comprehensive system based on artificial neural networks (ANN) for detecting ventricular fibrillation (VF) using various signal descriptors is proposed. First, by using time-, frequency-domain, and nonlinear dynamics analyses, different kinds of descriptors with different meanings are extracted from cardiac rhythmic signals, and then incorporated into the detection system and make decision automatically via the comprehensive ability of ANN. The detection performance of the system is tested by actual ECG database. Finally, its feasibility in clinical application is discussed.

Decision Making, Computer-Assisted↗
PubMed1992

Membrane permeation characteristics of 5'-modified thymidine analogs.

The membrane permeation characteristics of 5'-deoxythymidine (5'-ddThd) and 5'-azido-5'-deoxythymidine (5'-N3-5'-ddThd) were investigated in human erythrocytes, with an inhibitor-stop assay, at 20 degrees. Uptake of both nucleoside analogs occurred without metabolism, was nonconcentrative, and was partially inhibited by nucleosides or inhibitors of nucleoside transport at micromolar permeant concentrations. At higher permeant concentrations (greater than 1.0 mM), the influx rate of each analog was linearly dependent on concentration and insensitive to inhibition by nucleosides, inhibitors of nucleoside transport, and nucleobases. Kinetic analyses using nonlinear regression revealed that a saturable component of 5'-ddThd influx (Km = 200 microM) was competitively inhibited by thymidine (dThd) (Ki = 86 microM) or 5-iodo-2'-deoxyuridine (Ki = 84 microM). Similarly, a saturable component of 5'-N3-5'-ddThd influx (Km = 220 microM) was competitively inhibited by 2-chloroadenosine (Ki = 18 microM). The Ki values for these nucleoside inhibitors were similar to their reported Km values as permeants of the nucleoside transporter. Both 5'-ddThd and 5'-N3-5'-ddThd competitively inhibited the influx of dThd (Km = 60 microM), with similar Ki values (150 and 200 microM, respectively). We conclude that these two 5'-modified dThd analogs enter human erythrocytes both by nonfacilitated diffusion and by the nucleoside transporter. The absence of the 5'-hydroxyl group of dThd (5'-ddThd) resulted in a large increase in the octanol/buffer partition coefficient, in an ability to permeate human erythrocytes by nonfacilitated diffusion, and in a 3-fold diminished binding to the nucleoside transporter. The 5'-azido group (5'-N3-5'-ddThd) resulted in an additional 1.4-fold increase in the octanol/buffer partition coefficient and in a 2-fold increase in the rate of nonfacilitated diffusion.

Antiviral Agents↗
PubMed1990

Stopped flow and steady state kinetic studies of the effects of metabolites on the soluble form of NADP+:isocitrate dehydrogenase.

The cytosolic form of NADP+:isocitrate dehydrogenase, a primary source of the NADPH required for de novo fatty acid synthesis in lactating bovine mammary gland, was studied to determine possible mechanisms of regulation by metabolites. Stopped flow kinetics showed a distinct lag time, followed by attainment of an apparently linear final velocity. Direct nonlinear regression analyses of the reaction progress curves allowed for the calculation of the rate constant (kappa) for the transition of the enzyme from an inactive to an active form; this transition is best catalyzed by its metal-substrate complex. Preincubation with metal-substrate or metal-citrate nearly abolished the lag by increasing kappa 10-fold. In steady state experiments, analyses of velocity versus metal-citrate complex as a binding isotherm, following the assumptions of Wyman's theory of thermodynamic linkage, showed that binding of metal-citrate complex could both activate and inhibit the enzyme. This analysis suggested: (a) activation by binding to sites with an average dissociation constant of 0.25 mM; (b) inhibition by binding to sites with an average dissociation constant of 3.83 mM; and (c) modulation (reactivation) by binding to sites with an average dissociation constant of 1.54 mM. Concentration ranges observed for these transitions are compatible with physiological conditions, suggesting that complexes of metal-citrate and metal-isocitrate serve to modulate the activity of NADP+:isocitrate dehydrogenase.

Animals↗
PubMed1984

Kinetic evidence for differential agonist and antagonist binding to bovine hippocampal synaptic membrane opioid receptors.

To examine the kinetics of opioid receptor binding, the agonists [D-Ala2-D-Leu5]enkephalin (DADL) and [D-Ala2-MePhe4-Gly-ol5]enkephalin (DAGO) and the antagonists diprenorphine and naltrexone were used with bovine hippocampal synaptic plasma membranes. By computer modeling of equilibrium binding displacement curves utilizing the LIGAND program, we found opioid peptides bind with high affinity to single populations of synaptic plasma membranes receptors, whereas opiate alkaloids bind to multiple sites. Initial kinetic experiments revealed that agonist rates of association were radioligand concentration-independent. Pseudo first-order rate constants for DADL, DAGO, diprenorphine, and naltrexone association were estimated to be 5.63 X 10(5), 5.08 X 10(5), 4.60 X 10(6), and 2.3 X 10(6) mol-1 X s-1, respectively. After preincubation of 0.2-1 nM radioligand for variable time intervals, dissociation was initiated by addition of 1 microM unlabeled ligand. If saturation binding was achieved before dissociation was initiated, then nearly monophasic dissociation of DADL, DAGO, and diprenorphine and a biphasic off-rate for naltrexone were observed. When association times were reduced to pre-equilibrium intervals, the kinetics of dissociation of agonists became biphasic and association time-dependent, but that for antagonists did not change significantly. Comparisons by both graphical methods and computerized nonlinear regression analyses of rate constants revealed that the fraction of the rapid component of agonist dissociation decreases and that of the slow component is elevated with increasing receptor occupancy. In the presence of 100 mM NaCl, DADL dissociation became association time-independent. These data are consistent with the idea that the Na+ effect is brought about by a change of receptor to an antagonist-like conformation. On the basis of both association and dissociation kinetic data, opioid agonists appear to interact in a multistep process in which a rapid, reversible association is followed by the formation of a more tightly bound complex.

Animals↗
PubMed1983

In vivo quantification of receptor-mediated uptake of asialoglycoproteins by rat liver.

The in vivo kinetics of hepatic clearance of 125I-asialo-orosomucoid and 125I-asialofetuin was determined with a portal vein injection technique in barbiturate-anesthetized rats. Nonlinear regression analyses of saturation data gave the following parameters for asialo-orosomucoid, Km = 0.26 +/- 0.06 mg/ml, Vmax = 320 +/- 70 micrograms/min/g, and for asialofetuin, Km = 0.32 +/- 0.07 mg/ml, Vmax = 240 +/- 40 micrograms/min/g. Unlabeled asialofetuin inhibited the clearance of 125I-asialo-orosomucoid with a Ki = 0.25 +/- 0.04 mg/ml. Based on a model assuming that in vivo receptor concentration much greater than receptor KD, then the maximal binding capacity of the external surface of liver cells in vivo for asialo-orosomucoid is 2Km or 520 micrograms/ml or 52 micrograms/g of liver, assuming the liver interstitial space is 0.1 ml/g. Our estimate of in vivo binding capacity approximates in vitro estimates of total hepatic binding capacity, but is 10-fold greater than in vitro estimates of binding capacity on the external surface of liver cells. These results suggest the large majority of asialoglycoprotein receptors are located on the external surface of liver cells. The saturability of 125I-asialo-orosomucoid clearance was also demonstrated with a portal vein double bolus technique, wherein the portal injection of 20-1000 micrograms of unlabeled asialo-orosomucoid was followed 30 s later by the portal injection of tracer. Maximal inhibition of uptake was obtained with a portal vein injection of greater than or equal to 500 micrograms of asialo-orosomucoid. The specific extraction of the 125I-asialo-orosomucoid, which was near zero shortly after a 400-micrograms loading dose, gradually increased toward normal levels with a t1/2 of 21 min. This t1/2 may represent the in vivo rate of receptor recycling, since the gradual increase in unoccupied receptor sites is consistent with the model of receptor binding, internalization, and recycling.

Acetylgalactosamine↗
PubMed1980

Characterization of fibronectin interactions with glycosaminoglycans and identification of active proteolytic fragments.

Fibronectin is a major cell-surface glycoprotein which has been reported to interact with glycosaminoglycans. A nitrocellulose filter-binding assay was developed to quantitate these interactions at physiological pH and ionic strength. Fibronectin isolated from chick embryo fibroblasts binds both hyaluronic acid and heparin; heparan sulfate is bound less efficiently, and chondroitin sulfate and glycopeptides are bound minimally. The binding of hyaluronic acid and heparin to fibronectin is saturable and reversible and occurs at separate binding sites. The binding of both molecules to fibronectin is not blocked by EDTA or by other glycosaminoglycans, and is only moderately inhibited by elevated ionic strength. Scatchard analyses revealed nonlinear, high affinity binding to fibronectin with a KD of approximately 10(-7) to 10(-8) M for these glycosaminoglycans. The affinity for heparin was utilized for the isolation of heparin-binding domains of fibronectin on heparin-agarose affinity columns. Heparin-binding proteolytic fragments with apparent molecular weights of 160,000 and 50,000 were isolated following hydrolysis of fibronectin by chymotrypsin or pronase, respectively. The possible involvement of such high affinity binding sites of fibronectin in the binding of glycosaminoglycans to the cell surface or in the organization of extracellular matrices is discussed.

Animals↗
PubMed1993

High-affinity substance P binding sites of neurokinin-1 receptor type autoradiographically associated with vascular sinuses and high endothelial venules of human lymphoid tissues.

BACKGROUND: Factors that affect leukocyte-endothelial cell interaction in high endothelial postcapillary venules and vascular sinuses of lymphatic tissues indirectly regulate immune function. Studies in sheep demonstrated that acute infusion of substance P (SP) into cannulated popliteal lymph node afferent lymphathics produced a marked and prolonged increase in the output of lymphocytes into nodal efferent lymph. The proposed mechanism is an influence of SP on lymph vascular systems. Such functional importance of the immunoregulatory properties of SP in man is unknown. EXPERIMENTAL DESIGN: The expression and distribution of SP receptors in human lymphoid tissue was investigated using slide-mounted fresh-frozen sections of lymph node, hyperplastic tonsillitis, and spleen for ligand binding and autoradiographic studies. RESULTS: Specific binding of radiolabeled SP to lymph node and tonsils reached a plateau within approximately 40 minutes, being half-maximal at 20 minutes. The specific binding was between 65 and 75% of total binding. In contrast, iodinated neurokinin A under identical incubation conditions, did not significantly associate with the tissues. Neither the SP nor the neurokinin A tracer specifically associated with spleen. Binding specificity of radiolabeled SP was analyzed in binding competition experiments. Synthetic SP, SP (3-11), a selective neurokinin-1 agonist and a neurokinin-1 antagonist competed with the specific binding of SP to lymph node and tonsil sections. The half-maximal inhibition of binding was obtained at a concentration of about 0.5 nmol/liter of SP. The fragment SP (1-4) and selective neurokinin-2 ligands did not compete with the specific binding of SP. Scatchard and nonlinear algorithm analyses revealed two binding sites for SP. For lymph node and tonsil, one site showed a high affinity of about 0.4 nmol/liter and 0.7 nmol/liter and a low capacity for SP, respectively. The second site exhibited a lower affinity of 100 nmol/liter and 50 nmol/liter and a higher capacity for SP in lymph node and tonsil, respectively. Autoradiographic localization of the binding sites shows a very high concentration of silver grains when compared with controls. The reaction occurred mainly over vascular sinuses and high endothelial venules with heterogenous density. Silver grain accumulation was also noticed over the marginal sinuses of the B cell follicles. CONCLUSIONS: The biochemical results indicate the presence of neurokinin-1 receptors in human lymph node and tonsil. We suggest that the neurokinin-1 receptors localized to vascular tissues of lymph node and tonsil mediate the affects of SP on lymphocyte traffic, and we propose that SP plays a regulatory role in lymphocyte homing in man.

Autoradiography↗
PubMed1995

[Prediction of carboplatin clearance from morphological and biological patient characteristics].

Hematologic toxicity of carboplatin is largely dependent on its pharmacokinetics. Its seems likely that therapeutic efficacy is also related to plasma drug exposure. Dosage adjustments based on isotopic determination of glomerular filtration rate have been proposed but their ambulatory use is not conceivable. A population pharmacokinetic study was undertaken to determine a relationship between patient characteristics and carboplatin clearance. Plasma carboplatin pharmacokinetics were determined as ultrafilterable platinum in 70 patients (23 to 84 years old) treated with different combination regimens including carboplatin at doses ranging from 184 to 950 mg (1-hr i.v. infusion) for various tumor types. Data were analysed using Nonlinear Mixed Effects Model (NONMEM). The data from 34 patients (46 cycles) were used to obtain the most predictive formula for the carboplatin clearance (ml/min): [formula: see text] The obtained formula was prospectively evaluated with the data from 36 other patients (43 cycles) and compared to other methods available to predict carboplatin clearance. Prospectively this formula predicted the clearance with a good precision (median absolute percent error of 10% range 0-30%) and minimal bias (median percent error: 2% range--25-30%). This method of prediction was as accurate as the one which requires the glomerular filtration rate to be measured by 51Cr-EDTA injection. This formula should allow to individualize very easily the carboplatin dosage in adults by multiplying the calculated carboplatin clearance by the area under the curve desired for administration.

Adult↗
PubMed1997

An empirical study of economies of scope in home healthcare.

OBJECTIVE: To apply the economic theory of economies of scope to the home healthcare industry. DATA SOURCES: Data on 488 observations obtained from the Cost Report (HCFA Form 1728-86) of all Connecticut state-licensed, Medicare-certified home health agencies. STUDY DESIGN: The Cost Report was the primary source of data for this study. Information on total cost, scope, and other related factors was collected. Logarithmic and nonlinear regression analyses were used to identify factors related to scope and also to test for economies of scope. DATA COLLECTION METHOD: Data collected were both cross-sectional and time series (from 1988-1992). Data accuracy was verified using description of frequencies, measures of central tendency and variation, and a calculation package so that a computer calculation on the data could be compared with the agency's calculation. PRINCIPAL FINDINGS: It was determined that initially as scope increases, costs go down, thus proving economies of scope. For larger values of scope, it was determined that costs go up, proving diseconomies of scope. CONCLUSIONS: Many of the home health agencies included in this study provide more services than is cost effective given the economic theory of economies of scope.

Connecticut↗
PubMed2000

Nonlinear activity of identified Lymnaea neurons.

Two long-lasting discharges of action potentials were recorded from a buccal cell of the pond snail, respectively, before and after superfusing the preparation with low-calcium solution. The corresponding sequences of interspike intervals were then analysed by the nonlinear prediction methods. The results yield evidence of a small but clear nonlinearity only in the second of analysed tachograms. This finding is evaluated and discussed.

Action Potentials↗
PubMed2002

Multiple focused-waves production by parametric mixing in a layer with hysteretic quadratic nonlinearity.

Nonlinear scattering of a weak probe wave by a strong pump wave in a layer with nonlinearity hysteresis is analysed. It is demonstrated that a spherical probe wave from a point source after nonlinear process of difference frequency excitation is scattered in several foci. Different foci correspond to different frequencies of the transformed wave spectrum. In the case of a plane pump wave and under the condition that nonlinear scattering proceeds without acoustic mode conversion wave front reversal is possible. To achieve wave front reversal in a layer with hysteretic quadratic nonlinearity the pump wave should have a frequency equal to the frequency of the probe wave or to any of its subharmonics.

Journal Article↗