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PubMed1996

Comparison of the inhibitory effects of mercury and cadmium on the creatine kinase from Electrophorus electricus (L).

We have determined the effects of mercury and cadmium on the creatine kinase activity of the electric organ of Electrophorus electricus (L.) which catalyses the transphosphorylation reaction between phosphocreatine and magnesium adenosine-5'-di-phosphate and has essential sulfhydryl groups. The kinetic effects of these heavy metals, which have high affinity for sulfhydryl groups, on the creatine kinase activity were analysed with the three reaction components: phosphocreatine, adenosine-5'-di-phosphate and magnesium. The kinetic data were analysed with a non-linear regression program (Sigmaplot for Windows). Both metals inhibit creatine kinase activity in the micromolar range, mercury being a more potent inhibitor than cadmium. With phosphocreatine as substrate, mercury behaved as a mixed partial hyperbolic inhibitor, non-competitive inhibitor with adenosine-5'-di-phosphate, and with magnesium mercury behaved as a competitive inhibitor. Cadmium inhibition was shown to be of a classical competitive nature with respect to both substrates, phosphocreatine or adenosine-5'-di-phosphate, and non-competitive when magnesium was the variable in the reaction mixture. The results suggest that the binding site of mercury is at or near the phosphocreatine site, but it is not the same as adenosine-5'-di-phosphate, whereas cadmium competes with these substrates to bind at the same sulphydryl site.

Adenosine Diphosphate↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed1999

Modelling long-term persistence of hepatitis B antibodies after vaccination.

Antibody response to hepatitis B vaccination was measured in 97 institutionalized, mentally handicapped patients after a 0-, 1-, 6-month vaccination schedule. Two groups were formed at month 7 according to the antibody response, which determined whether they needed an additional vaccine dose at month 12, to achieve an antibody titre of 100 IU/liter. All residents were followed up yearly for the first 5 years, after which, they received another booster dose. Another blood sample was taken 11 years after the start of the program. A linear mixed-regression model was used to analyze the data. Random and fixed effects were included to determine the generally known risk factors and the still unknown individual characteristics that influence the titre of hepatitis B surface antibodies (anti-HBs). The mean anti-HBs titre was a function of time, type of mental retardation (Down's syndrome or other types of mental retardation), the use of antiepileptic drugs, and the additional booster at month 12. The immediate and vigorous response of the immune system to booster vaccination shows that the immunologic memory is good after primary vaccination. For the maintenance of protection, the recommendation for mentally retarded patients in institutions is vaccination of all seronegative residents as well as new entrants, after which, no additional boosters will be necessary.

Anticonvulsants↗
PubMed1995

Bioavailability of pseudoephedrine from controlled release formulations in the presence of guaifenesin in human volunteers.

A multiple-dose bioequivalence study with six healthy human volunteers was conducted. The bioavailability of an experimental controlled release tablet containing pseudoephedrine was compared with a marketed controlled release pseudoephedrine capsule in a three-way crossover study. Plasma samples, collected serially after oral drug administration, were analyzed for pseudoephedrine content using a specific HPLC method with UV detection. The bioavailability parameters, area under the concentration-time curve (AUC), maximum plasma concentration Cmax, and time to peak (Tmax) were obtained from the plasma concentration-time data. Additionally, model independent pharmacokinetic parameters were estimated. Analysis of variance of the data revealed no statistically significant differences between the test and the reference formulation. The presence of guaifenesin in the sustained release tablet did not influence pseudoephedrine bioavailability. The relative bioavailability of the tablet dosage form with respect to the capsule was found to be 100.8%. Classical and Westlake 95% confidence limits as well as the two one-sided t test, proposed by Schuirmann, and the Anderson-Hauck power analysis supported the inference that the two formulations demonstrated comparable bioavailabilty, even in the presence of guaifenesin. Using a non-linear regression program, it was found that the pharmacokinetics of pseudoephedrine followed a simple one-compartment disposition model with no lag time. Additionally, an in vitro-in vivo correlation, based on the estimation of cumulative relative fraction absorbed, was developed between the absorption of pseudoephedrine in humans and the in vitro dissolution time.

Adrenergic Agents↗
PubMed1991

Pharmacokinetics of ibuprofen enantiomers in dogs.

Inversion of inactive (R)-ibuprofen to active (S)-ibuprofen has been suggested to occur presystemically only. In order to investigate the site of inversion in dogs we administered both enantiomers either intravenously or intraduodenally (10 mg/kg) to adult, male beagle dogs (n = 3) in a crossover design. Plasma, urine, and bile were collected for up to 6 h and analyzed stereospecifically by HPLC, according to a previously published method. Pharmacokinetic parameters were calculated using a linear computer program. Absorption after intraduodenal administration occurred rapidly, resulting in maximum plasma concentrations 0.2 h after giving the enantiomer. Approximately 70% of the (R)-enantiomer (according to AUC) was inverted to the S-enantiomer independent of route of administration. No R-ibuprofen could be detected in plasma after (S)-ibuprofen administration. Mean residence time was found to be 2 to 3 times longer for (S)- than for (R)-ibuprofen. Total systemic clearance from plasma was twice as high for (R)- than for (S)-ibuprofen. There were no differences between plasma clearances after intravenous and intraduodenal administration. Between 8 and 17% of dose was recovered in bile [especially as free and conjugated (S)-ibuprofen] and 3-12% in urine [as (S)-ibuprofen, hydroxy- and carboxyibuprofen, free and conjugated forms]. Small amounts of (R)-ibuprofen were detected in bile after intraduodenal administration of (R)-ibuprofen only (1.8% of dose). In short, the unidirectional inversion of R-ibuprofen appears to occur systemically rather than presystemically in dogs.

Animals↗
PubMed1980

Novel deconvolution method for linear pharmacokinetic systems with polyexponential impulse response.

A novel least-squares deconvolution method for estimating the rate and the extent of drug input into the systemic circulation is presented. The method is based on a polyexponential approximation of the impulse response and a polynomial approximation of the input rate. The method, which is readily implemented on a computer using any multiple linear regression program with a zero-intercept option, is compared to two other deconvolution methods using simulated data with various degrees of random noise added. It appears to have several significant advantages. The method is applied to plasma pentobarbital level data from oral and intravenous administration. The assumptions and limitations of deconvolution methods for analyzing drug input into the blood are discussed.

Absorption↗
PubMed2003

Using splines to detect changes in PSA doubling times.

BACKGROUND: PSA doubling time (PSADT) can predict the likelihood of clinical progression in patients with biochemical relapse after surgery or radiation for prostate cancer. Changes in PSA doubling time in response to therapy may be of clinical or investigational significance. How does one estimate PSADT before and after the initiation of therapy and determine if any change is statistically significant or simply the result of random variation? These are the type of questions addressed. METHODS: Our technique uses a best-fitting spline (i.e., a broken-line approximation) to a graph of log PSA on time to estimate PSADTs before and after treatment initiation. A linear regression program is used to produce the fit and to evaluate the statistical significance of any change in PSADT. This method differs from previous methods in that it uses all the data, exploits the continuity of PSA at the time of treatment initiation, and allows one to make statistical significance statements about specific individuals. RESULTS: Our technique is illustrated with data from a pilot clinical trial using a nutritional supplement in 12 men with prostate cancer. A detailed analysis of the first patient shows how the data are handled, how two lines of computer code are sufficient to fit the spline model, and how the doubling times and statistical significance of a change are read from the computer output. In the study, 9 of 12 patients had a statistically significant increase in doubling time. Because the study is preliminary and used only to illustrate our method, no medical discussion of the study is included. The last section of the study, in part expository, is devoted to explaining the underlying principles for those who may want to know not only what to do, but why it works. CONCLUSIONS: The method presented here for determining changes in PSADT is both simple and broadly applicable. It allows the evaluation of the size and statistical significance of an observed change or increase in PSADT in response to therapy for prostate cancer. It can be done using essentially any statistical software and widely accepted statistical methods.

Biomarkers, Tumor↗
PubMed1989

Estimation of temporal effects in treatment-induced second cancer.

Cancer chemotherapy has been remarkably successful in the treatment of several types of malignancies, but has also been demonstrated to cause leukaemia and perhaps other cancer in long-term survivors. Radiotherapy also carries a carcinogenic risk. A large case-control study of second cancer has been carried out, with the aim of quantifying the risk due to chemotherapy and radiotherapy. One of the most important goals of this study is the estimation of the temporal pattern of risk following chemotherapy. Methods are presented for modelling risk as a function of type of treatment and the interval since treatment. The methods are applications of generally available linear regression programs for epidemiological data, and could be equally well applied to studies of occupationally induced cancer.

Age Factors↗
PubMed1990

Optimal choice of prognostic variables with an application to cardiac monitoring using M-mode echocardiography.

This paper provides a methodology for the optimal choice of a subset from a large number of interrelated diagnostic variables. We use predetermined abnormal ranges for each measurement and code subjects as abnormal or normal on this basis. We present a procedure to determine the smallest subset of measurements that identifies any subject abnormal on at least one measurement. We formulate and solve the problem using integer programming. We then apply this methodology to study the use of M-mode echocardiography to determine potentially cardiotoxic side effects of chemotherapy and compare its performance to several multivariate methods. Extensions and modifications are discussed.

Child↗
PubMed1995

Location-scale cumulative odds models for ordinal data: a generalized non-linear model approach.

Proportional odds regression models for multinomial probabilities based on ordered categories have been generalized in two somewhat different directions. Models having scale as well as location parameters for adjustment of boundaries (on an unobservable, underlying continuum) between categories have been employed in the context of ROC analysis. Partial proportional odds models, having different regression adjustments for different multinomial categories, have also been proposed. This paper considers a synthesis and further generalization of these two families. With use of a number of examples, I discuss and illustrate properties of this extended family of models. Emphasis is on the computation of maximum likelihood estimates of parameters, asymptotic standard deviations, and goodness-of-fit statistics with use of non-linear regression programs in standard statistical software such as SAS.

Humans↗
PubMed1999

Evolution of protein sequences and structures.

The relationship between sequence similarity and structural similarity has been examined in 36 protein families with five or more diverse members whose structures are known. The structural similarity within a family (as determined with the DALI structure comparison program) is linearly related to sequence similarity (as determined by a Smith-Waterman search of the protein sequences in the structure database). The correlation between structural similarity and sequence similarity is very high; 18 of the 36 families had linear correlation coefficients r>/=0.878, and only nine had correlation coefficients r</=0.815. Inclusion of higher-order terms in the structure/sequence relationship improved the fit by less than 7% in 27 of the 36 families. Differences in sequence/structure correlations are distributed evenly among the four protein structural classes, alpha, beta, alpha/beta, and alpha+beta. While most protein families show high correlations between sequence similarity and structural similarity, the amount of structural change per sequence change, i.e. the structural mutation sensitivity, varies almost fourfold. Protein families with high and low structural mutation sensitivity are distributed evenly among protein structure classes. In addition, we did not detect strong correlations between structural mutation sensitivity and either protein family mutation rates or protein size. Our results are more consistent with models of protein structure that encode a protein family's fold throughout the protein sequence, and not just in a few critical residues.

Amino Acid Sequence↗
PubMed2000

Incorporating model uncertainties along with data uncertainties in microbial risk assessment.

Much research on food safety has been conducted since the National Food Safety Initiative of 1997. Risk assessment plays an important role in food safety practices and programs, and various dose-response models for estimating microbial risks have been investigated. Several dose-response models can provide reasonably good fits to the data in the experimental dose range, but yield risk estimates that differ by orders of magnitude in the low-dose range. Hence, model uncertainty can be just important as data uncertainty (experimental variation) in risk assessment. Although it is common in risk assessment to account for data uncertainty, it is uncommon to account for model uncertainties. In this paper we incorporate data uncertainties with confidence limits and model uncertainties with a weighted average of an estimate from each of various models. A numerical tool to compute the maximum likelihood estimates and confidence limits is addressed. The proposed method for incorporating model uncertainties is illustrated with real data sets.

Colony Count, Microbial↗
PubMed2005

Association of body composition and physical activity with proximal femur geometry in middle-aged and elderly Afro-Caribbean men: the Tobago bone health study.

Osteoporotic fractures are less prevalent in African Americans than in caucasians, possibly because of differences in bone structural strength. Bone structural adaptation can be attributed to changes in load, crudely measured as lean and fat mass throughout life. The purpose of this analysis was to describe the associations of leg lean mass, total body fat mass, and hours walked per week with femoral bone mineral density (BMD) and bone geometry in a cross-sectional sample of 1,748 men of African descent between the ages of 40 and 79 years. BMD, section modulus (Z), cross-sectional area (CSA), and subperiosteal width were measured from dual energy X-ray absortiometry (DXA) scans using the hip structural analysis (HSA) program. Multiple linear regression models explained 35% to 48% of the variance in bending (Z) and axial (CSA) strength at the femoral neck and shaft. Independent of all covariates including total body fat mass, one standard deviation increase in leg lean mass was significantly associated with a 5% to 8% higher Z, CSA, and BMD (P < 0.010) at the neck and shaft. The number of hours walked per week was not a strong or consistent independent predictor of bone geometry or BMD. We have shown that weight is the strongest independent predictor of femur BMD and geometric strength although the effect appears to be mediated by lean mass since leg lean mass fraction and total body fat mass fraction had significant and opposing effects at the narrow neck and shaft in this group of middle aged and elderly men.

Absorptiometry, Photon↗
PubMed2007

Incorporating efficiency in hospital-capacity planning in Germany.

Hospital occupancy is a key metric in hospital-capacity planning in Germany, even though this metric neglects important drivers of economic efficiency, for example treatment costs and case mix. We suggest an alternative metric, which incorporates economic efficiency explicitly, and illustrate how this metric can be used in the hospital-capacity planning cycle. The practical setting of this study is the hospital capacity planning process in the German federal state of Rheinland-Pfalz. The planning process involves all 92 acute-care hospitals of this federal state. The study is based on standard hospital data, including annual costs, number of cases--disaggregated by medical departments and ICD codes, respectively--length-of-stay, certified beds, and occupancy rates. Using the developed metric, we identified 18 of the 92 hospitals as inefficient and targets for over-proportional capacity cuts. On the upside, we identified 15 efficient hospitals. The developed model and analysis has affected the federal state's most recent medium term planning cycle.

Bed Occupancy↗
PubMed1979

Recent advances in programmable pacemakers. Consideration of advantages, longevity and future expectations.

The important electrical characteristics of conventional ventricular demand pacemakers currently widely employed are unable to be altered by noninvasive means after their implantation. However, a number of domestic pacemaker manufacturers have started to introduce a new modality for atraumatic modulation of these devices, the fully programmable pacemaker system, whereby the several variables regulating pacemaker operation may be optimized on an individual basis according to need. Such programmable pacemaker functions which can be varied include rate, energy output, refractory period and sensing threshold. The indications, significance and mechanisms for control of the various function programming are delineated for physician understanding at the present time.

Arrhythmias, Cardiac↗
PubMed1993

Authentic standards for the reductive-cleavage method. The positional isomers of partially methylated and acetylated or benzoylated 1,5-anhydro-D-fucitol.

Described herein is an efficient method for the synthesis of the eight positional isomers of methylated and acetylated or benzoylated 1,5-anhydro-D-fucitol. The compounds are generated simultaneously by partial methylation of 1,5-anhydro-D-fucitol and subsequent benzoylation, and the individual isomers are obtained in pure form by high-performance liquid chromatography. Debenzoylation of the latter and acetylation yielded the desired acetates. Reported herein are the 1H NMR spectra of the benzoates and the electron-ionization mass spectra of the acetates and the tri-O-methyl derivative. Also reported for the acetates and the tri-O-methyl derivative are their linear temperature programmed gas-liquid chromatography retention indices on three different capillary columns.

Acetates↗