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PubMed1997

Isoelectric focusing in immobilized pH gradients: recent analytical and preparative developments.

Isoelectric focusing in immobilized pH gradients (IPG), covering both analytical and preparative aspects, is here reviewed. An extensive introduction covers the development of the technique from its inception in 1982 to present day methodology, with particular emphasis on the development of computer programs able to calculate and optimize linear and nonlinear pH gradients, spanning as much as 9 pH units, from a mixture of as many as 10 different buffering ions and titrants. The unique resolving power of IPGs is illustrated with the resolution of fetal globin chains differing by an Ala/Gly substitution in residue 75, this bringing about a minute difference in pI value of only 0.001 pH units. IPG runs, performed under denaturing conditions, allow an excellent correlation between experimental and theoretical protein pIs, to the extent that outliers were found to be polypeptide chains which had undergone post-synthetic modifications. The IPG methodology allows easy interfacing with mass spectrometry, due to the fact that proteins eluted from an IPG gel are isoionic as well as isoelectric, and thus are not contaminated by any buffer ion. The review ends with an excursus on preparative aspects of IPGs: a novel apparatus, based on the principle of isoelectric, buffering membranes, allows pilot-scale purification of r-DNA proteins to extreme purity, with recovery in a liquid vein. Isoelectric membranes have a selectivity based on a continuous titration process, and thus act as isoelectric traps for individual protein species. This same preparative apparatus can be used as a novel immobilized enzyme reactor, with superior performance compared to conventional types of reactors.

Amino Acid Sequence↗
PubMed1996

Aqueous and vitreous penetration of ciprofloxacin following different modes of systemic administration.

The overall importance of the peak or the mean serum concentrations as predictors of ocular drug penetration is unknown. To address this fundamental question with an agent which shows promise as adjunctive therapy in the treatment of endophthalmitis, we studied the penetration of ciprofloxacin into the aqueous and vitreous humors following three different modes of systemic administration. New Zealand white rabbits received either a single bolus dose (40 mg kg-1), three intermittent doses of 13.33 mg kg-1 evenly spaced over an 8 hr period, or a continuous infusion of 40 mg kg-1 over an 8 hr period. Pharmacokinetic analysis was performed using RSTRIP II, a non-linear, least square regression model analysis program. The serum area under the concentration-time curve (AUC) values for each mode of drug administration were similar: 32.9 micrograms hr ml-1 for single dose, 31.9 micrograms hr ml-1 for intermittent dose, and 33.8 micrograms hr ml-1 for continuous infusion modes. The percentage penetration into the aqueous and vitreous were also similar; 30.5% and 6.5% for a single dose, 31.6% and 7.4% for intermittent doses and 30.0% and 7.5% for continuous infusion. The penetration into the aqueous and vitreous humors was not influenced by mode of administration. As with other quinolones we have studied, elimination rates were similar for the central and peripheral compartments in the post-distributive phase. Vitreous humor ciprofloxacin concentrations achieved were below that which inhibits most Staphylococcus epidermidis, the most common isolate in patients with post-operative endophthalmitis.

Animals↗
PubMed1994

Quantitative structure-activity relationships by neural networks and inductive logic programming. I. The inhibition of dihydrofolate reductase by pyrimidines.

Neural networks and inductive logic programming (ILP) have been compared to linear regression for modelling the QSAR of the inhibition of E. coli dihydrofolate reductase (DHFR) by 2,4-diamino-5-(substituted benzyl)pyrimidines, and, in the subsequent paper [Hirst, J.D., King, R.D. and Sternberg, M.J.E. J. Comput.-Aided Mol. Design, 8 (1994) 421], the inhibition of rodent DHFR by 2,4-diamino-6,6-dimethyl-5-phenyl-dihydrotriazines. Cross-validation trials provide a statistically rigorous assessment of the predictive capabilities of the methods, with training and testing data selected randomly and all the methods developed using identical training data. For the ILP analysis, molecules are represented by attributes other than Hansch parameters. Neural networks and ILP perform better than linear regression using the attribute representation, but the difference is not statistically significant. The major benefit from the ILP analysis is the formulation of understandable rules relating the activity of the inhibitors to their chemical structure.

Animals↗
PubMed1992

Relation between slow-wave frequency and spiking activity during the migrating myoelectric complex in dogs.

The quantitative relation between slow-wave periods and spiking activity was evaluated in vivo in canine small intestine during the fasted state. Experiments were performed in three conscious dogs with three bipolar electrodes, implanted respectively 10, 25 and 40 cm beyond the ligament of Treitz. Digitized electrical recordings were automatically processed for the individual slow-wave periods and spike-burst intensities using a set of computer programs developed in our laboratory. A linear correlation existed between the degree of spiking activity and the average length of the preceding slow-wave period. The slopes of the regression lines were less steep for more distal electrodes. A second series of experiments showed that an increase in the slow-wave period precedes the onset of phase 3 of the migrating myoelectric complex and that a fall in slow-wave period precedes the end of phase 3. These data show that a low slow-wave frequency is accompanied by a facilitation of spiking activity, whereas shortening of the slow-wave period is accompanied by a decrease in spike burst intensity. This relation between slow-wave period and spiking activity shows an aboral trend that may be related to intrinsic slow-wave frequency.

Animals↗
PubMed1983

The detailed physical map of the temperate phage 16-3 of Rhizobium meliloti 41.

Restriction cleavage maps for enzymes EcoRI, BamHI, PstI, PvuII, XbaI and EcoRV of Rhizobium meliloti temperate phage 16-3 have been established. Together with the earlier maps (HindIII, KpnI, HpaI, BglII) 98 restriction sites, 'evenly' distributed, have been mapped along the phage genome, including the so far unmarked silent region of the chromosome. All the restriction maps have been fitted to each other by computer optimalization. Beyond for conventional techniques a computer program (PMAP) for physical mapping of linear DNA has been employed which made the experimentation, in several cases, extremely efficient.

Bacteriophages↗
PubMed1982

Mathematical analysis of 51Cr-labelled red cell survival curves in congenital haemolytic anaemias.

The parameters of 51Cr labelled red cell survival curves were calculated in 33 patients with homozygous beta-thalassaemia, 8 with sickle-cell anaemia and 3 with s -- beta-thalassaemia, using a non-linear weighted least squares analysis computer program. In thalassaemic children the calculated parameters denote that the shortening of the mean cell life is due to early senescence alone, while there is some evidence that in thalassemic adults additional extracellular destruction mechanisms participate as well. Red cell survival curves from patients with sickle-cell anaemia and s -- beta-thalassaemia resemble each other, while their parameters indicate an initial rapid loss of radioactivity, early senescence and the presence of extracellular red cell destruction factors.

Adult↗
PubMed1984

Structure-pharmacokinetics relationship of quaternary ammonium compounds. Correlation of physicochemical and pharmacokinetic parameters.

Correlations between lipophilicity or molecular weight and some pharmacokinetic parameters such as clearance (Cl), elimination rate constant (k10), volume of distribution (V), and terminal half life (lambda z) are presented for a series of structurally related quaternary ammonium cations (QACs). The structure-pharmacokinetics relations were fitted using the computer program NONLIN and were represented by linear, parabolic or S-shaped curves. The relationship between total plasma clearance or hepatic, renal and intestinal clearance and lipophilicity for the present set of data could be described most properly by the equation Y = 1/(aXb + c), where Y stands for the logarithm of the pharmacokinetic parameters and X represents the logarithm of the values of some physicochemical parameters, such as the partition coefficient (P), the (HPLC) capacity factor k' (another lipophilicity parameter) and molecular weight (MW). On the basis of this relationship, correlations of the hepatic or intestinal clearances with the lipophilicity parameters were good (r = 0.98 and r = 0.95 respectively). Curves relating values for partition coefficients and clearance via liver and intestine (expressed relative to the most simple QAC tetramethyl ammonium) showed S-shaped correlation patterns, in contrast to the renal clearance, which correlated poorly (r = 0.54) with lipophilicity. The extent of biliary output of the organic cations shows a threshold phenomenon, sharply increasing at log P greater than 1.5 to a maximum at P greater than 2.5. This pattern was less pronounced in the case of intestinal elimination and absent in the case of renal clearance. The apparent maximum in the hepatic and intestinal clearance for the most lipophilic organic cations is probably due to limitation by organ blood-flow and/or plasma protein binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Alternative common factor models for multivariate biometric analyses.

In prior research we have shown how linear structural equation models and computer programs (e.g., LISREL) may be simply and directly used to provide alternatives for the traditional biometric twin design. We use structural equations and path models to define biometric group differences, we write traditional common-factor models in the same way, and then we take a detailed look at some alternative multivariate and biometric models. We contrast the biometric-factors covariance structure approach used by Loehlin and Vandenberg (1968), Martin and Eaves (1977), and others with the psychometric-factors approach used by McArdle et al. (1980) and others. We use the multivariate primary mental abilities data on monozygotic (MZ) and dizygotic (DZ) twins from Loehlin and Vandenberg (1968) to detail fundamental differences in model specification and results. We extend both multivariate biometric approaches using exploratory and confirmatory multiple-factor models. These comparisons show that each alternative multivariate methodology has useful features for empirical applications.

Humans↗
PubMed1996

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients.

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, non-linear mixed effect modelling with the program NON-MEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. RESULTS: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. CONCLUSION: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

Administration, Oral↗
PubMed2005

Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1,4-dihydropyridines and pyridines as multidrug resistance modulators.

PURPOSE: The aim of this study was to develop quantitative structure-activity/pharmacokinetic relationships (QSAR/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors. METHODS: Molecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca2+ channel binding. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for P-gp inhibition and QSPKR models. Cross-validation using the "leave-one-out" method was performed to evaluate the predictive performance of models. RESULTS: For Ca2+ channel binding, the MLR equation indicated a good correlation between observed and predicted values (R2 = 0.90), and cross-validation confirmed the predictive ability of the model (Q2 = 0.67). For P-gp reversal, the model obtained by PLS could account for most of the variation in P-gp inhibition (R2 = 0.76) with fair predictive performance (Q2 = 0.62). Nine structurally related 1,4-DHP drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R2 = 0.90), and cross-validation confirmed the prediction ability (Q2 = 0.69). CONCLUSION: QSAR/QSPKR models were developed, and the QSAR models were capable of identifying synthesized 1,4-DHPs and pyridines with potent P-gp inhibition and reduced Ca2+ channel binding. The QSPKR models provide insight into the contribution of electronic, steric, and lipophilic factors to the clearance of DHPs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

CADCS simulation of the closed-loop cardiovascular system.

A pulsatile simulator of the closed-loop cardiovascular system, designed to solve simulation, identification and control problems in a research and education context, is presented. Its implementation makes use of a command-driven interactive program for simulation of non-linear ordinary differential equations. The flexibility of the simulator is demonstrated by the results presented which refer to a basal steady-state circulatory condition as well as a transient induced by an abrupt change in peripheral resistance.

Blood Pressure↗
PubMed1987

Comparison of three methods of profile change prediction in the adult orthodontic patient.

Potential changes in the contour of the facial profile that accompany tooth movement can be important considerations in developing an orthodontic treatment plan. The objective of this study was to compare the accuracy of three different methods of predicting horizontal soft-tissue changes. Eighty-three nongrowing, orthodontically treated patients comprised the sample. Pretreatment and posttreatment lateral cephalometric hard- and soft-tissue landmark points were digitized. A coordinate system was defined, landmark coordinates were corrected for magnification, and then hard- and soft-tissue, angular, and linear measures were calculated by computer programs developed on a DEC PDP 11/44. The accuracy of prediction of soft-tissue landmark changes was compared for three prediction methods: (1) use of ratios of means of soft-tissue changes to corresponding hard-tissue changes, (2) use of a bivariate regression equation on corresponding hard-tissue landmark changes, and (3) use of stepwise multiple regression with hard-tissue changes and initial hard- and soft-tissue facial characteristics as predictor variables. For predicting changes of four soft-tissue points, multiple regression equations were slightly more accurate than ratio of means predictions. The standard errors of the estimate ranged from 0.7 to 1.1 mm for the multiple regression predictions; these were from 0.2 to 1.4 mm lower than those obtained for ratio of means predictions. The accuracy of the bivariate regression prediction technique fell between that of the other two methods. Examination of the residuals showed that the multiple regression equations consistently underpredicted the most extreme soft-tissue facial changes.

Adolescent↗
PubMed2005

Relationship between increased levofloxacin use and decreased susceptibility of Streptococcus pneumoniae in the United States.

Increasing reports of fluoroquinolone-non-susceptible Streptococcus pneumoniae are of clinical concern. We examined the relationship between outpatient fluoroquinolone use and susceptibility of community-acquired S. pneumoniae isolates. Using multivariable general linear modeling, US SENTRY Antimicrobial Surveillance Program and Intercontinental Medical Statistics data (1997-2002) were analyzed to determine the influence of selected patient-, institution-, and geographic region-specific factors, including local fluoroquinolone usage, on the minimum inhibitory concentration (MIC) of levofloxacin against S. pneumoniae. Levofloxacin MIC50, MIC90, and MIC range (n = 384 from 26 hospitals) were 1, 1, and < or =0.5 to >4 microg/mL, respectively. Variables associated with changes in geometric mean MIC included geographical region (P < 0.0001), medical service (P = 0.0002), study year (P = 0.0006), primary diagnosis group (P = 0.02), and 2 interactions (duration of hospital stay before isolate collection by bed capacity, P = 0.06, and levofloxacin use by geographical region, P = 0.08; P < 0.001 when study year was removed from the model). MIC increased with levofloxacin use across all geographical regions, with increases of 54% and 126% in the southwest and west, respectively. In contrast to other fluoroquinolones, increased levofloxacin use, along with other variables, was associated with decreased pneumococcal susceptibility. Given the US environment of increasing pneumococcal resistance, these data may be useful in better understanding factors related to emergence of fluoroquinolone resistance.

Anti-Bacterial Agents↗
PubMedDate not supplied

Characteristics of long-term care facilities associated with standing order programs to deliver influenza and pneumococcal vaccinations to residents in 13 states.

BACKGROUND: Standing order programs (SOPs) are effective evidence-based interventions in which nurses or pharmacists are authorized to vaccinate according to an approved protocol without a physician order or examination. National rates for influenza and pneumococcal vaccination in long-term care facilities (LTCF) are far below HP2010 goals of 90%. OBJECTIVES: The aim of this study was to describe the prevalence of SOPs and other types of immunization programs in LTCFs and determine characteristics of LTCFs implementing SOPs. DESIGN: Mailed survey. SETTING: All Medicare- or Medicaid-licensed LTCFs in 13 states. PARTICIPANTS: Directors of Nursing (DONs). MEASUREMENTS: Survey collecting information on SOPs and barriers to their use in respondents' LTCF. Data from this survey were linked to the On-line Survey and Certification Administrative Record (OSCAR), a federal administrative database containing structural, staffing and other information on LTCFs. RESULTS: A total of 3,451 of 4,366 (79%) LTCFs completed surveys. Few facilities used SOPs for influenza (9%) or pneumococcal vaccination (7%). The greatest use of influenza SOPs compared with other immunization program types were seen in facilities that were government owned or owned by nonprofit entities compared with for-profit entities (15% and 10% vs. 7%; odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.4 and OR = 1.4, CI = 1.1 to 1.8, respectively); dually-certified (both Medicare- and Medicaid-certified) nursing facilities compared with distinct part skilled nursing facilities in which beds are set aside for residents with a specific payment source (11% vs. 7%; OR = 1.6, CI = 1.3 to 2.1); independent facility compared with one that is part of a multi-facility chain (10% vs. 7%; OR = 1.3, CI = 1.1 to 1.7); and lower acuity index (resident resource needs) compared with higher (10% vs. 7%; OR = 1.4, CI = 1.1 to 1.7). Findings were similar for pneumococcal vaccination SOPs. SOP use varied substantially by state (range = 0% to 23% influenza; range = 3% to 15% pneumococcal). The most frequently reported barriers to SOP use were legal concerns: liability for the facility (53%) and staff lacking legal authority (39%) to vaccinate by standing orders. CONCLUSIONS: Although LTCFs with certain characteristics used SOPs more often, overall few facilities (<10%) used SOPs to improve vaccination rates. SOP use varied by state indicating that state policies or other factors may promote or inhibit SOP use. More studies are needed to examine the causes of state-level variations in vaccination interventions and their relationships to health outcomes of residents in LTCFs. The federal government's resources to promote SOPs should focus on all LTCFs, but with a particular focus on those that are less likely to be using SOPs and that represent a large proportion of homes nationally (i.e., for-profit and chain facilities).

Aged↗
PubMed1989

A zonal model of cortical functions.

A model of cortical functions is developed with the object of simulating the observed behavior of individual neurons organized in unit circuits and functional systems of the cerebellum, the cerebrum and the hippocampal formation. The neuronal model is capable of representing refractory and potentiated states, as well as the firing and lowest resting states. The unit circuits of each system consist of all common types of cells with known synaptic connections. In the cerebral system these unit circuits are interconnected to form columns as well as zones. A new discrete neural network equation, which takes account of interactions with the extracellular field, is proposed to simulate electrical activity in these circuits. A coherent theory of cortical activity and functions is derived that accounts for many of the observed phenomena, including those associated with the development of long-term potentiation and sequential memory. Three appendices are devoted to the theory of extracellular interactions, the derivation of non-linear network equations, and a computer program to simulate learning in the cortex.

Animals↗
PubMed1988

Correlation of structure and function in glaucoma. Quantitative measurements of disc and field.

The relationship between quantitative structural measurements of the optic nerve head and quantitative measurements of the visual field in glaucoma was studied. Computerized videographic image analysis (Rodenstock Analyzer) was used to obtain cup-disc ratio, disc rim area, and cup volume in 50 glaucoma suspects and 37 glaucoma patients. The visual field indices, mean defect and loss standard deviation, were calculated from Octopus Program 32. There were statistically significant linear correlations between each of the optic nerve structural parameters and visual field mean defect and loss standard deviation. The strongest correlation was between disc rim area and visual field mean defect (r = -0.49), which are both global measures of glaucomatous damage. The correlations were not strong enough to readily allow the recognition of early nerve damage by the parameters analyzed thus far. Closer correlations may be evident if structural parameters can be found that more accurately reflect the number of surviving axons in the optic nerve head.

Female↗
PubMed2001

Investigation of a new mathematical model for compression of pharmaceutical powders.

A new compaction equation, the log-exp model: V=V(l)-w log(P)+V(e) exp(P/P(m)) is presented. The model presumes that two compaction processes: a logarithmic and an exponential decline may be active simultaneously. Using non-linear regression techniques the model gives an excellent fit to a number of model substances with wide differences in compaction behaviour. Compared to the Kawakita equation the model covers a broader range of the compaction profile. The new model and the Cooper and Eaton equation fit the data on the same level, but the parameters derived from the log-exp model seems to have more discriminative power between substances and have a close relation to the apparent plastic or brittle densification mechanism. The log-exp model has potential as a tool in estimation of the strength of agglomerated materials. A proposal for a set-up to an iterative non-linear regression calculation in a spreadsheet program is attached.

Compressive Strength↗
PubMed2002

KIR expression shapes cytotoxic repertoires: a developmental program of survival.

We hypothesize a sequential program of expression of the leukocyte-receptor complex (LRC) in CD8+T cells, associated with cellular activation and the subsequent establishment of immune homeostasis through resistance to apoptosis. This program, which is consistent with the linear development of memory CD8+ T cells, represents an ordered expression of genes during differentiation, analogous to expression of the homeobox- or globin-gene clusters. Our model not only has implications for the development and maintenance of T-cell memory but also, relates to the formation of LRC repertoires in other cell types, particularly, the development of killer-cell Ig-like receptor (KIR) repertoires in natural-killer-cell precursors.

Animals↗