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PubMedDate not supplied

Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers.

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin-converting enzyme (ACE). The half-life for the terminal phase (approximately 40 h) was not predictive of steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. The mean accumulation ratio was 1.38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.

Administration, Oral↗

PubMed1992

The estimation of mean nuclear volume in the diagnosis of breast carcinoma.

Sixty-two cases of breast pathology were randomly selected from the files of the Dunedin Public Hospital for evaluation of mean epithelial nuclear volume. The cases were comprised of both benign and malignant ductal epithelial disease, diagnosed in cytological smears or in histological sections. Nuclear volume in histological preparations was estimated by the stereological technique of point-line intercept measurements to derive volume-weighted mean volumes (vV). An index of the nuclear volume (Vi) of cytology smears was calculated from measurements of nuclear areas by either image analysis Vi(e) or point-line intercepts Vi(p). By all methods of analysis a clear distinction of nuclear volume was found between the benign [means for the cytology were 148 microns 3 (Vi(e)) or 246 microns 3 (Vi(p)), and 203 microns 3 (Vv) for the histology specimens] and malignant diseased cases [means for cytology: 524 microns 3 (Vi(e)) or 886 microns 3 (Vi(p)), and 587 microns 3 (vV) for the histology specimens].

Breast Neoplasms↗

PubMed1988

Ferguson plots based on absolute mobilities in polyacrylamide gel electrophoresis: dependence of linearity of polymerization conditions and application to the determination of free mobility.

In contrast to Ferguson plots based on relative mobilities, Ferguson plots of proteins in polyacrylamide gel electrophoresis based on their absolute mobilities were found to be linear under unusual polymerization conditions which yield relatively wide gel fibers and a low total fiber length per unit weight, but not under previously and commonly used conditions. These linear Ferguson plots in gels of 1, 3 and 5% crosslinking intersect at a single gel concentration between 1 and 2% T (M-point). It is postulated that the measure of free mobility of the proteins is the M-point, and not the intercept of their Ferguson plots with the mobility axis as assumed previously. This postulate abolishes the well-known paradoxical interpretation of the increase with %C of the linearly extrapolated intercept of the Ferguson plot with the log(mobility) axis (designated Yo) in terms of free mobility. The postulate is also compatible with the interpretation of the points of intersection of the Ferguson plots of oligomeric series of proteins at finite gel concentrations (designated mu-points) as their common free mobilities.

Buffers↗

PubMed2001

A discrete random effects probit model with application to the demand for preventive care.

I have developed a random effects probit model in which the distribution of the random intercept is approximated by a discrete density. Monte Carlo results show that only three to four points of support are required for the discrete density to closely mimic normal and chi-squared densities and provide unbiased estimates of the structural parameters and the variance of the random intercept. The empirical application shows that both observed family characteristics and unobserved family-level heterogeneity are important determinants of the demand for preventive care.

Analysis of Variance↗

PubMed1995

Multiple laboratory comparison of the doubly labeled water technique.

A double-blind study was conducted to determine between-laboratory variability in the doubly labeled water method for measurement of total energy expenditure in humans, and to compare the accuracy and precision of three widely-used procedures for calculating rates of carbon dioxide production from the original isotope data. Eighteen laboratories from five countries participated in the study. All laboratories were provided with five water standards containing varying amounts of 2H and 18O, and in addition 11 laboratories were provided with urine and dose specimens from one (six laboratories) or two (five laboratories) healthy elderly subjects of normal height and weight undergoing a calorimetric validation of the doubly labeled water method. The data from the five water standards were analyzed to predict between-laboratory variability in the doubly labeled water technique in all laboratories. In addition, data from the subjects were analyzed using the "slope-intercept", "2-point" and "modified" methods of calculation. The results confirm that the doubly labeled water method can be an accurate technique for the measurement of energy expenditure in adult human subjects in some laboratories. However, there was substantial between-laboratory variability in the results and some laboratories returned physiologically impossible results. There was no significant effect of calculation procedure on the accuracy of the technique in this limited comparison, although the slope-intercept procedure appeared to be more susceptible to analytical error than the other procedures. The isotope standards analyzed by participants in this study will be made available to other investigators on request.

Aged↗

PubMed1995

Validation of accuracy and precision of dual energy X-ray absorptiometry for infants.

There is limited information on the validity of bone mineral content measurement by dual energy X-ray absorptiometry (DXA BMC) for use in subjects with low body mass. We evaluated the accuracy and precision of DXA in piglets (body weight 886-5526 g, median 2096 g). Stepwise multiple regression analyses showed that ash weight is the major determinant of DXA BMC (adjusted r2 = 0.98, RMS residual = 3.61 g). The intercept was not significantly different from zero. DXA BMC measurements of other piglets under various clinical situations showed no significant effect from the use of cotton blanket, diaper, or positioning (prone, supine, lateral). In vivo replication of DXA BMC measurements of infants at a postnatal age of from 1-350 days showed a slope of 0.99 and high correlation coefficient (r2 = 0.99, RMS residual = 3.59 g). The intercept was not significantly different from zero, and the average coefficient of variation of duplicate DXA BMC in infants was 2.8%. We conclude that DXA BMC reliably but proportionately underestimates ash weight and is a highly precise method for measuring bone mineral status in young pediatric subjects.

Absorptiometry, Photon↗

PubMed1989

Appendix to the sulfur-cyanolysis sites of serum albumin: metabolite competition studies. Tight-binding inhibitions that yield atypical Henderson plots.

Ordinary tight-binding inhibition in steady-state enzyme systems is conveniently evaluated by means of the Henderson plot. This is a linear plotting form that has an ordinate intercept equal to the total enzyme concentration. However, there are two experimental situations that yield deviations from the common Henderson plot form. These are inhibitor binding in a separate, noninhibitory mode that depletes the concentration of free inhibitor, and partial inhibition, i.e., the retention of partial activity by the enzyme-inhibitor complex. Noninhibitory depletion results in Henderson plots with elevated ordinate intercepts. Competitive partial inhibition yields a characteristic pattern of parabolic Henderson plots.

Binding, Competitive↗

PubMed1995

Theory and practice of stereological techniques applied to the estimation of cell number and nuclear volume in the testis.

The historical background to contemporary approaches to the estimation of cell/nuclear number and volume in the testes is reviewed. The limitations of older geometric model-based approaches to the estimation of cell/nuclear number are discussed, and the need for absolute estimates of cell number rather than ratio estimates is examined. The physical and optical disector approaches to the direct estimation of numerical density and, hence, absolute cell number are presented together with data illustrating their operational efficiency in the testis. New approaches to the direct estimation of nuclear/cell volume, using the point-sampled intercept family of methods, are presented and illustrated, using the example of the Sertoli cell nucleus. The use of both classical transverse and the newer vertical section approaches is explored. Estimation of Sertoli cell/nuclear volume in the volume (point-sampled intercept procedure) and number (nucleator and rotator methods) distributions on both conventional transverse and vertical sections is discussed. The use of transverse sections of the testis is shown to produce a consistent bias in the estimation of Sertoli cell nuclear volume in 120-day-old animals, with all the estimators. Comparison of the Sertoli cell nuclear volume (measured on vertical sections) in the volume and number-weighted distribution suggests a coefficient of variation of volume in the number distribution of 0.4-0.5, suggesting either a random or stage-dependent variation in Sertoli cell nuclear size which requires further exploration.

Animals↗

PubMed1975

Elimination of 137-Cs and 59-Fe and its relationship to metabolic rates of wild small rodents.

Elimination of 137-Cs and 59-Fe by three species of wild rodents was measured in laboratory and field experiments to determine whether excretion rates of these nuclides are influenced directly by general metabolic (CO-2 production) rates. Sigmodon hispidus and Peromyscus leucopus were used in both field and laboratory experiments, and Reithrodontomys humulis was investigated only in the laboratory. Final-component biological half-lives (Tb) of 59-Fe for Sigmodon averaged 108 days in winter, 144 days in spring, and means ranged from 176 to 242 days under various laboratory conditions (ambient temperature, cold-exposure, irradiation, and chemical metabolic inhibition); for Peromyscus, values were 50 days in winter 47 days in spring, and 289 days (at ambient temperature only) in the laboratory; for Reithrodontomys mean values ranged from 121 to 178 days at different laboratory treatment levels. Biological half-lives of final-component 137-Cs elimination for Sigmodon averaged 7.5 days in winter, 7.9 days in spring, and means ranged from 7.7 to 8.6 days at the different treatment levels in the laboratory. Laboratory mean values for Reithrodontomys ranged from 3.5 to 3.9 days. For Peromyscus, Tb values averaged 3.4 days in winter, 3.6 days in spring, and 3.5 days in the laboratory. The data suggested that elimination of 59-Fe is influenced by metabolic rates of rodents in the field, but laboratory experiments were unable to demonstrate any predictable relationship. Neither did the rate of final-component 137-Cs loss from rodents appear to be influenced by metabolic rate in the laboratory or in the field. However, final-component Y-axis intercept values of 137-Cs exhibited a linear correlation with metabolic rates, and equations were derived from these intercept values to predict metabolism in the field for two species: for Sigmodon, Daily Average CO-2 Production (ml/hr/g, STP) [5.24-0.9172 (log-ea)] [0.886]; and for Reithrodontomys, = [12.51-1.80 (log-ea)] [0.886].

Animals↗

PubMed2003

Entropy evaluation using the kinetic method: is it feasible?

The kinetic method is one of the most widely used experimental techniques for the measurement of thermochemical parameters by mass spectrometry. Recently it has been realized that it can also be used to determine reaction entropies, but the validity of this approach has not been established. This Perspective evaluates kinetic method plots in cases where there is a significant entropy difference between the competing fragmentation channels (i.e. between sample and reference compounds in the dissociating cluster ion). The concept underlying this study is to calculate mass spectra theoretically, based on known thermochemical parameters and as a function of experimental conditions. This can be done accurately using the RRKM-based MassKinetics software. The resulting mass spectra are then interpreted by the kinetic method, yielding DeltaH and DeltaS values. These values are, in turn, compared with the true values used to generate the calculated mass spectra. The results show that the reaction entropy difference between sample and reference has a very large influence on kinetic method plots. This should always be considered when studying energy-dependent mass spectra (using metastable ions or low- or high-energy collision-induced dissociation (CID)), even if only DeltaH is to be determined. Kinetic method plots are not strictly linear and this becomes a serious issue in the case of small molecules showing a large entropy effect. In such cases, results obtained at a low degree of excitation are more accurate. Energy and entropy effects can be evaluated in a relatively straightforward manner: first, the apparent Gibbs energy (DeltaG(app)) and effective temperature (T(eff)) are determined from kinetic method plots (intercept and slope, respectively), obtained from experiments using various degrees of excitation. Second, the resulting DeltaG(app) is plotted against T(eff), the slope yielding DeltaS while the intercept (extrapolation to zero temperature) yields DeltaH. This data evaluation yields more accurate results than alternative methods used in the literature. The resulting DeltaH values are fairly accurate, with errors, in most cases, <4 kJ mol(-1). On the other hand, DeltaS is systematically underestimated by 20-40%. Empirically scaling DeltaS values determined by the kinetic method by 1.35 results in a DeltaS value within 20% (or 10 J mol(-1) K(-1)) of the theoretical value.

Journal Article↗

PubMed1998

Abnormalities in the stride length-cadence relation in parkinsonian gait.

The purpose of this investigation was to clarify abnormalities in the stride length-cadence relation in gait hypokinesia in Parkinson's disease (PD). A second aim was to investigate the effect of levodopa medication on the foot-step pattern. In the first experiment, 20 subjects with idiopathic PD and 20 age-, sex-, and height-matched controls performed a series of 10 m walking trials at cadence rates ranging from 40 steps/min to 180 steps/min. Cadence rates were set by an electronic metronome, and gait patterns were measured by using a footswitch stride-analyzer system. By instructing subjects to concentrate on walking in time to the metronome beat, the baseline stride length could be monitored for a range of velocities with the compensatory effects of cadence removed. Linear-regression analysis revealed that the mean slope for the regression of stride length against cadence was not different from normal in PD, although there was a statistically significant difference in mean intercept between the PD group (0.25) and the control group (0.59); [t (19) = -4.76; p = 0.0001]. The second experiment evaluated the effects of levodopa on stride-length regulation in 10 subjects with idiopathic PD on average 45 min before and after the first morning dose was administered. There was a statistically significant increase in stride length for all cadence rates from premedication to postmedication phases and the maximal stride length was achieved at higher cadence rates after medication. The slope of the regression of stride length against cadence did not alter according to medication status, although the mean intercept was significantly lower before levodopa (-0.06) compared with after levodopa (0.27); [t (9) = -3.83; p = 0.004]. These results suggest that defective scaling of stride length underlies gait disturbance in PD.

Aged↗

PubMed2003

Development of a dynamometer for measuring the isometric force of the pelvic floor musculature.

AIMS: The aim of this study was to design and develop a dynamometer providing a direct measurement of pelvic floor muscle (PFM) strength. MATERIALS AND METHODS: Two pairs of strain gauges were mounted on the moveable branch of a dynamometric speculum allowing measurements at different vaginal apertures. Linearity, repeatability, independence of the site of application of the resultant force to the lower branch of the speculum and hysteresis were tested by means of in vitro calibration studies. RESULTS: The linearity proved excellent over a range of 0-15 N with regression coefficients close to unity between imposed loads and voltage outputs. The slopes and intercepts of the regression lines were not significantly different between repeated sessions, indicating the high reliability of these in vitro measurements. The slopes and intercepts of the calibrations, using the same repertoire of loads imposed at three locations on the moving branch of the dynamometer, were not significantly different, confirming that the force measurement is independent of the site of the force application. Hysteresis was considered to be minimal. CONCLUSIONS: This study demonstrates that the dynamometer provides reliable measurements. The new device thus appears to have conceptual and measuring advantages over conventional methods and seems to be a very promising instrument for measuring pelvic floor strength.

Calibration↗

PubMed1988

The effect of age on postpneumonectomy growth in rabbits.

To assess the effect which age at pneumonectomy has on pulmonary compensatory growth, male New Zealand white rabbits underwent left pneumonectomy or sham thoracotomy at 10, 18, or 26 weeks of age. Morphometric and biochemical evaluation of the remaining lungs was carried out four weeks later. There was significant compensatory growth in terms of lung volume, weight, DNA, RNA, and protein in all three age groups. Lung volume response was incomplete, i.e., right lung volume of the experimental animals did not match the volume of both lungs of controls; other variables were not significantly different between the right lung of experimentals and both lungs of the controls. An unchanged surface area per unit volume accompanied by a stable mean linear intercept indicated that alveolar multiplication occurred in the 10 and 18 week age groups. The oldest group had significantly decreased surface area per unit volume and significantly increased mean linear intercept, suggesting an increase in the size of existing alveoli at 26 weeks of age.

Adaptation, Physiological↗

PubMed1990

Respiratory system compliance assessed by the multiple occlusion and weighted spirometer method in non-intubated healthy newborns.

In 28 healthy newborn infants (median age 3.5 days), we compared the weighted spirometer (WS) with the multiple occlusion (MO) method for measuring respiratory system compliance (Crs). The MO method was unsuccessful in 8 infants. On average the two methods gave comparable results for compliance (Crs,ws = 40.4 +/- 13.8 and Crs,MO = 45.2 +/- 10.4 mL.kPa-1) in the remaining 20 infants; however, within-individual differences were often considerable, so that the methods did not give interchangeable results. Individual pressure-volume curves almost always intercepted the volume axis below the functional residual capacity with the MO technique, compatible with dynamic elevation of end-expiratory lung volume (EEL) due to inspiratory muscle activity during expiration. A (small) negative volume intercept occurred in less than 50% of curves with the WS method; in these cases it probably reflects alinearity of the compliance curve, an alteration in laryngeal braking or in respiratory muscle control of EEL, or all of these. Both methods provide valuable means for the non-invasive determination of respiratory system compliance in newborn infants, the differences in Crs being small and of minimal physiological significance; however, for individual follow-up they should not be used interchangeably.

Female↗

PubMed1995

Functional residual capacity (FRC) measurements by plethysmography and helium dilution in normal infants.

Comparative measurements of functional residual capacity (FRC) made by plethysmography (FRCpleth) and by helium dilution (FRCHe) were obtained on 27 infants and young children without known pulmonary disease (14 males, 13 females; 4 weeks-26 months; mean age 32.2 weeks) while under chloral hydrate sedation. Clinical histories, clinical examinations, and pulmonary functions were normal for all members of the group. FRCpleth, whether measured near end expiration (EE) or near end inspiration (EI), and corrected to mean expiratory levels of at least 3 breathing cycles, was consistently and significantly greater than FRCHe. Comparative values for mean (+/- standard deviation) were FRCpleth EE, 182.0 (+/- 79.7) mL and FRCpleth El, 171.8 (+/- 77.4) mL vs. FRCHe, 154 (+/- 72.2) mL, P < 0.0001 and P < 0.005, respectively. Normalizing values by weight, FRCpleth EE was 23.8 mL/kg (+/- 5.3) vs. FRCHe, 20.2 (+/- 4.7) mL/kg, mean (+/- standard deviation). The difference between FRCpleth and FRCHe, expressed as FRCpleth - FRCHe/FRCpleth x 100, was 9% for occlusions at end inspiration and 16% for occlusions at end expiration. The following equations describe our FRC results in relation to length: In (FRCHe) = 2.74 x ln (length) - 6.53 r2 = 0.781 slope = 2.74 +/- 0.29 SE Y intercept = 6.53 +/- 1.12 SE ln (FRCPleth EI) = 2.69 x ln (length) - 6.21 r2 = 0.752 slope = 2.69 +/- 0.31 SE Y intercept = 6.21 +/- 1.29 SE The difference between FRCpleth and FRCHe was more marked when occlusions were performed at end expiration than at end inspiration.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed2005

Reporting small Delta 17O values: existing definitions and concepts.

The three-isotope tracer Delta(17)O is increasingly used in atmospheric chemistry and other research areas. Thanks to the development of isotope-ratio mass spectrometry (IRMS), delta(17)O and delta(18)O can be determined with a precision of a few 0.01 per thousand, and values for Delta(17)O may be calculated with similar precision. However, interpreting small and precisely determined Delta(17)O values as a deviation from an expected mass-dependent fractionation process is not straightforward. Several aspects are of high importance. In the present paper we review existing definitions, formulas and some other aspects of Delta(17)O reporting. One of the most confusing aspects is a variance of definitions and corresponding formulas. While Delta(17)O is traditionally defined to characterise a data point, i.e. Delta(17)O is considered as a deviation from an expected mass-fractionation line, the recently introduced definition (Miller MF. Geochim. Cosmochim. Acta 2002; 66: 188) characterises a fractionation line itself, in terms of its ordinate intercept. The formulas corresponding to this definition gives a characteristic for a specific process. When the 'traditionally defined' Delta(17)O is in use, an expected fractionation processes--the key point for Delta(17)O reporting--should be defined and parameterised with the same accuracy as intended for reporting Delta(17)O. When Delta(17)O is reported for a data point, not only a value for lambda but an ordinate intercept of a reference fractionation line should be given with high accuracy. We note that defining a single fractionation process is hardly possible for many natural compounds. For such compounds we propose to use a phenomenological reference line, namely an isotope composition range of natural sources. Next, aspects of Delta(17)O comparison and mass-balance calculations are considered. All the aspects considered for Delta(17)O may be relevant for others three-isotope tracers, e.g. Delta(33)S.

Algorithms↗

PubMed2002

Jointly modelling the relationship between survival and pulmonary function in cystic fibrosis patients.

Modelling the relationship between pulmonary function and survival in cystic fibrosis (CF) is complicated by the fact that measures of pulmonary function commonly used such as the forced expiratory volume in one second (FEV(1)) are measured with error, and patients with the poorest lung function are increasingly censored by death, that is, data are available only for the patients who have survived to the current age. We assume a linear random effects model for FEV1 per cent predicted, where the random intercept and slope of FEV(1) per cent predicted, along with a specified transformation of the age at death follow a trivariate normal distribution. We illustrate how this model can be used to describe the relationship between age at death and parameters of the individual patient's regression of FEV(1) per cent predicted versus age, such as the slope and the intercept or true value of FEV(1) per cent predicted at a given age. We also illustrate how the model provides empirical Bayes estimates of these individual parameters. In particular, we explore how the predicted value of the age at death might be used as a prognostic or severity index. The model and methods are illustrated on a cohort of 188 cystic fibrosis patients with a common genotype (homozygous for the DeltaF508 mutation), born on or after 1965 and followed at the CF Center at the Rainbow Babies and Children's Hospital, Cleveland, OH, U.S.A.

Adolescent↗

PubMedDate not supplied

On combining dose-response data from epidemiological studies by meta-analysis.

Using data from a meta-analysis of the effects of oestrogen replacement therapy on the development of breast cancer, we compared alternative methods for combining dose-response slopes from epidemiological studies. We evaluated issues related both to summarizing data from single studies and to combining results from multiple studies. Findings related to the analysis of individual dose-response studies include: (1) a method of weighing studies that gives greater influence to dose-response slopes that conform to the linear relation of relative risk to duration can lead to large differences in calculated weights as a function of non-linearity; (2) a regression model using a variable-intercept resulted in a mean dose-response slope that increased as much as threefold when compared with the values obtained with a zero-intercept model. When combining results from multiple studies, we found: (1) calculating standard errors of mean dose-response slopes by methods that allow for both among-study and within-study variability (a random-effects type model) gave values different from a method that assumes homogeneity and equal within-study precision (a fixed-effects model); (2) the random-effects model gives mean and standard error results most similar to a bootstrap resampling method as increasing heterogeneity is observed (however, this model could give biased mean estimates compared with the bootstrap method); (3) a components-of-variance model compares favourably with the bootstrap and is easier to apply than the random-effects model. Based on these findings, we recommend the use of methods which incorporate heterogeneity to guard against underestimating the standard error. However, caution is urged because bias in point estimates can occur if extreme heterogeneity is present. Two other observations affect the interpretation of data combined from multiple studies. First, inclusion into a model of quality scores assigned by blinded reviewers had little effect on the mean dose-response slope and its standard error. Second, the number of studies required to achieve desired statistical power, varies with effect size.

Analysis of Variance↗