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PubMed2004

Validation of a new scale for the assessment of bowel preparation quality.

BACKGROUND: Bowel preparation quality scales are used to document the superiority of one preparation regime vs. another. The validity and reliability of these scales are not routinely stated in reports of studies in which the scales are used. A new colonoscopy bowel preparation scale (the Ottawa bowel preparation scale) was developed and validated prospectively. METHODS: Ninety-seven consecutive patients undergoing elective outpatient colonoscopy were entered into the study. The quality of the bowel preparation was assessed independently by two investigators who used the Ottawa scale, and the only other validated scale (Aronchick scale) that could be identified. The interobserver agreement and reliability of each scale was assessed by the Pearson correlation coefficient (r), the intraclass correlation coefficient, and regression analysis. RESULTS: The Pearson correlation coefficients were, respectively, 0.89 and 0.62 for the Ottawa and Aronchick scales (p<0.001). The values for the kappa statistic, an intraclass correlation coefficient measuring agreement over and above chance agreement, were, respectively, 0.94 and 0.77 (p<0.001). Linear regression analysis, mapping the line best describing the scatter of scores by raters, for the Ottawa scale revealed a slope of the line of 0.93 and a y intercept of 0.10. The Aronchick scale revealed a slope of 0.65 and a y intercept of 0.46. The Ottawa scale thus was closer to an identity line comparing raters (i.e., closer to a line with slope of 1.00 and y intercept of 0.00). The Ottawa scale demonstrated a right colon kappa (intraclass correlation coefficient) of 0.92: 95% CI[0.88, 0.95], a mid colon kappa (intraclass correlation coefficient) of 0.88: 95% CI[0.82, 0.92], and a rectosigmoid kappa (intraclass correlation coefficient) of 0.89: 95% CI[0.83, 0.92]. CONCLUSIONS: The Ottawa scale was validated prospectively and demonstrates high interobserver agreement and reliability, whether used as a total score or for individual colon segments.

Cathartics↗
PubMed1988

Independent determinants of systolic effectiveness: growth ability, contractility and mobility.

The left ventricle of the heart is a thick-walled chamber. In such a chamber, cavity dimensions do not express overall wall stretch, so fractional cavity-surface displacements are not ideal performance expressions, and the intercepts and slopes of relations between intensive variables (pressure, stress, resistance, viscosity) and cavity dimensions do not express wall properties. By contrast, there is a midwall isobar whose enclosed volume (Vm) does express distension and stretch, so fractional midwall-volume displacement is an ideal expression of systolic performance, and characteristics of P-Vm and sigma-Vm relations do relate consistently to wall properties. The midwall volume at average basal end-diastolic distension is calculated: Vmu = Vcu Vou (ln Vou - ln Vcu)/(Vou - Vcu), where Vcu is cavity volume and Vou is chamber volume (cavity + wall) at average basal end-diastolic distension. At other distensions, midwall volume departs from Vmu as cavity volume departs from Vcu: Vm = Vmu + Vc - Vcu. Midwall ejection fraction (Jmv) is the difference between end-diastolic midwall volume (Vmd) and end-systolic midwall volume (Vms) divided by Vmd:Jmv = (Vmd - Vms)/Vmd. It depends on preload, afterload and two tensile characteristics. The cleanest separation of tensile characteristics is not in the intercept and slope but in the amplitude and spread of the sigma-Vm relation. Amplitude (sigma su) is the height of the relation at the average basal end-diastolic distension to which the chamber is accustomed. Spread (M sigma v) is the normalized difference between x intercept (Vmx) and Vmu: M sigma v = (Vmu - Vmx)/Vmu. It is the Jmv which would occur if preload were normal and afterload were zero. These considerations give rise to a new system for expressing and evaluating systolic performance and its determinants. The system is valid for the ranges of wall/cavity ratios, P-V-curve shapes and chamber shapes seen in left ventricles.

Animals↗
PubMed1997

Effect of amiloride on suprathreshold NaCl, LiCl, and KCl salt taste in humans.

The purpose of this study was to investigate normal variances in the response magnitudes of suprathreshold concentrations of NaCl, LiCl, and KCl salts and amiloride on the anterior human tongue. Random equimolar concentrations of salt solutions were delivered to spatially matched flow chambers of 20 volunteers at 3 different sessions. A cross-modal magnitude matching procedure was used to scale salt taste-intensity judgments. After each salt test, amiloride (100 microns) was delivered for 5 min and the test was repeated. At least-square regression analysis of each subjects' function between log molar concentration and log response demonstrated that every subject scaled the dynamic range of salts. There were no differences in either the mean regression or intercept among the 3 salts. Repeated-measures analysis demonstrated a statistical effect of amiloride on the before/after difference in the regression (p = 0.02) and intercept (p < 0.0001) of NaCl and LiCl functions. Postamiloride NaCl and LiCl coefficient of variance of response was increased. Amiloride had no effect on the before/after difference in the regression and intercept of KCl power functions or the variance of response. The results suggest that, after amiloride, NaCl and LiCl suprathreshold salt taste intensities are reduced, but there are individual variabilities of reduced intensity that are never completely eliminated.

Adult↗
PubMed2001

Ventilatory response to 2-h sustained hypoxia in humans.

We used two protocols to determine if hypoxic ventilatory decline (HVD) involves changes in slope and/or intercept of the isocapnic HVR (hypoxic ventilatory response, expressed as the increase in VI per percentage decrease in SaO2). Isocapnia was defined as 1.5 mmHg above hyperoxic PET(CO2). HVD was recorded in protocol I during two sequential 25 min exposures to isocapnic hypoxia (85 and 75% SaO2, n=7) and in protocol II during 14 min of isocapnic hypoxia (90% SaO2, FIO2=0.13, n=15), extended to 2 h of hypoxia with CO2-uncontrolled in eight subjects. HVR was measured by the step reduction to sequentially lower levels of SaO2 in protocol I and by 3 min steps to 80% SaO2 at 8, 14 and 120 min in protocol II. The intercept of the HVR (VI predicted at SaO2=100%) decreased after 14 and 25 min in both protocols (P<0.05). Changes in slope were observed only in protocol I at SaO2=75%, suggesting that the slope of the HVR is more sensitive to depth than duration of hypoxic exposure. After 2 h of hypoxia the HVR intercept returned toward control value (P<0.05) with still no significant changes in the HVR slope. We conclude that HVD in humans involves a decrease in hyperoxic ventilatory drive that can occur without significant change in slope of the HVR. The partial reversal of the HVD after 2 h of hypoxia may reflect some components of ventilatory acclimatization to hypoxia.

Adult↗
PubMed2002

Action-perception dissociation in response to target acceleration.

The purpose of this study was to investigate whether information about the acceleration characteristics of a moving target can be used for both action and perception. Also of interest was whether prior movement experience altered perceptual judgements. Participants manually intercepted targets moving with various acceleration, velocity and movement time characteristics. They also made perceptual judgements about the acceleration characteristics of these targets either with or without prior manual interception experience. Results showed that while aiming kinematics were sensitive to the acceleration characteristics of the target, participants were only able to perceptually discriminate the velocity characteristics of target motion, even after performing interceptive actions to the same targets. These results are discussed in terms of a two channel (action-perception) model of visuomotor control.

Acceleration↗
PubMed1979

Test of a novel method for analysis of the efficacy of antihypertensive drugs.

Diastolic blood-pressure data from 42 published studies, representing 23 anti-hypertensive drug regimens and 971 patients, were used to test the hypothesis that there is a linear relation between pretreatment diastolic pressure (P.T.D.P.) and the drug-induced fall in pressure (deltaD.P.), such that the "ideal-response line" relating these variables has a slope=1.0 and intercepts the P.T.D.P. axis at 90 mm Hg. Most of the regimens failed to show ideal behaviour; slopes of the regression lines were usually less than 1.0, and the intercepts were generally not at 90 mm Hg. Low coefficients of determination (r2) and broad 95% confidence intervals for the slopes and intercepts of the regression lines were common. Only 2 of the 23 regimens examined yielded r2 greater than 0.7, whereas 8 of the regimens exhibited r2 less than 0.25. These findings suggest a large interpatient variation in response to a given regimen. The data reported here show that what is thought to be an ideal-response relation for antihypertensive drug regimens is not observed in practice. However, the manner of presenting the data in order to test the hypothesis provides a useful method for assessing the effectiveness and variability of patient-responses to treatment.

Analysis of Variance↗
PubMed2000

Rating changes over the course of meals: what do they tell us about motivation to eat?

Detailed analysis of the pattern of change in rated appetite within a meal have proved a useful technique through which to explore appetite control. Variability in individual ratings, and technical difficulties in achieving ratings at equivalent stages of a meal, have lead to the use of curve-fitting techniques to model changes in rated appetite across a meal. These changes could best be described by a quadratic function, in which the three parameters (intercept, linear and quadratic coefficients) represented distinct influences on meal size. In normal subjects, manipulations of palatability and opioid receptor blockade and preloads of alcohol all modified the linear component of this function only, while preloading with maltodextrin reduced appetite at the start of eating (the intercept) but not the pattern of change in ratings within that meal. Thus the linear coefficient appears to measure the degree of stimulation of appetite by the sensory characteristics of the food, while the intercept reflects baseline appetite at the start of a meal. These results suggest that microstructural analyses of rating changes allow some dissociation of the factors underlying motivation to eat, and provide a novel methodology for future experimentation.

Alcohol Drinking↗
PubMed1993

Reversible vasopressin deficiency in severe hypernatremia.

Studies to assess the relationship between plasma arginine vasopressin concentration (Pavp) and plasma osmolality (Posm) were performed on an elderly patient with dementia who developed severe hypernatremia due to inadequate water intake following a debilitating hip fracture. Serum sodium concentrations were 174 and 196 mEq/L on two consecutive hospital admissions. During the second of these admissions, sequential measurements of Pavp and Posm were obtained as hypernatremia was gradually corrected. Pavp during this period was correlated with Posm (r = 0.887, P < 0.01), but was low despite the presence of hyperosmolality and volume depletion. Pavp decreased from 0.56 microU/mL to 0.18 microU/mL as Posm decreased from 396 to 338 mOsm/kg H2O. The regression line of this relationship intercepted the abscissa at 320 mOsm/kg H2O. Hypertonic sodium chloride infusion to reassess this relationship 2 days following the correction of hypernatremia increased Pavp only to 0.67 microU/mL while increasing Posm from 297 to 316 mOsm/kg H2O. Nevertheless, Pavp and Posm were significantly correlated (r = 0.937, P < 0.001). The slope of the regression line was 0.031, and Posm at the abscissal intercept was 292 mOsm/kg H2O. A similar increase in Posm from 290 to 310 mOsm/kg H2O during hypertonic sodium chloride infusion 11 days following the correction of hypernatremia increased Pavp to 1.95 microU/mL (r = 0.786, P < 0.05). The magnitude of the increase in Pavp at this time was equivalent to that previously observed in studies of normal subjects. The slope (0.048) and abscissal intercept (280 mOsm/kg H2O) of linear regression were also consistent with observations in studies of normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1997

Carotid plaque typing by multiple-parameter ultrasonic tissue characterization.

We evaluated the ability of ultrasonic tissue characterization (UTC), based on backscattered echo signals, to distinguish among the components of advanced carotid plaques. We performed spectral analysis of echo signals acquired from human carotid endarterectomy specimens in vitro to calculate three parameters of the calibrated power spectrum: slope, intercept and total power for fibrous, lipid pool and thrombus constituents of plaque. Plaque constituents were identified histologically. We evaluated classification efficacy by discriminant function analysis. Slope and intercept parameters alone provided correct classification in 92.5%, 57.6% and 72.4% of fibrous, lipid pool and thrombus plaque components, respectively. Slope, intercept and total power used in combination improved classification of the three tissue types to 93.0%, 69.7% and 81.0%. The overall proportion of correctly classified tissue regions increased from 84.5% to 88.0% by the combined use of the three parameters. The improvement in classification that occurred when we included total power as a third parameter suggests that ultrasound plaque components may not consist solely of small, randomly distributed isotropic scatterers. Our ability to identify plaque thrombi provides motivation for future studies of parameter-based imaging methods for identifying such plaque that presents an increased risk of embolic neurologic ischemic events.

Arteriosclerosis↗
PubMed2003

Quality assurance of magnetic resonance spectroscopic imaging-derived metabolic data.

PURPOSE: Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. We present a quality assurance procedure for MRSI-derived metabolic data acquired ultimately for guiding conformal radiotherapy. METHODS AND MATERIALS: An MRSI phantom filled with brain-mimicking solutions was custom-built with an insert holding eight vials containing calibration solutions of precisely varying metabolite concentrations that emulated increasing grade/density of brain tumor. Phantom metabolite ratios calculated from fully relaxed 1D, 2D, and 3D MRS data for each vial were compared with calibrated metabolite ratios acquired at 9.4 T. Additionally, 3D ratio maps were "discretized" to eight pseudoabnormality levels on a slice-by-slice basis and the accuracy of this procedure was verified. RESULTS: Regression analysis revealed expected linear relationships between experimental and calibration metabolite ratios with intercepts close to zero for the three acquisition modes. 1D MRS data agreed most with theoretical considerations (regression coefficient, b = 0.969; intercept 0.008). The 2D (b = 1.049; intercept -0.199) and 3D (correlation coefficient r(2) = 0.9978-0.7336 for five slices) MRSI indicated reduced MRS data quality in regions of degraded B(0) and B(1) homogeneity. Pseudoabnormality levels were found to be consistent with expectations within regions of adequate B(0) homogeneity. CONCLUSIONS: This simple phantom-based approach to generate baseline calibration curves for all MRS acquisition modes may be useful to identify temporal deviations from acceptable data quality in a routine clinical environment or for testing new MRS and MRSI acquisition software.

Aspartic Acid↗
PubMed1983

Determination of quinidine in serum by spectrofluorometry, liquid chromatography and fluorescence scanning thin-layer chromatography.

Quinidine is determined in serum by direct and extraction spectrofluorometry, by reflectance fluorescence scanning thin-layer chromatography (TLC), and by high-performance liquid chromatography (HPLC). Least-squares analyses of patients' sera (n = 62) analyzed first by direct fluorometry (x) and then HPLC (y) gave a slope of 0.52, an y-intercept of -0.40, a standard error of estimate of 0.65, and a correlation coefficient of 0.83. Comparison of patients' sera (n = 59) determined by extraction fluorometry (x) and then HPLC (y) gave a slope of 0.998, an y-intercept of -0.175, a standard error of estimate of 0.30, and a correlation coefficient of 0.96. Comparison of patients' sera (n = 36) by HPLC (x) and then reflectance fluorescence scanning TLC (y) gave a slope of 0.837, an y-intercept of 0.152, and a correlation coefficient of 0.94. Methaqualone and oxazepam interfere with HPLC. Within-run precision is 1.6, 1.0, 5.2 and 3.0% by direct fluorometry, extraction fluorometry, TLC and HPLC while between-run precision is 5, 3.5, 9 and 6.0%, respectively.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Intersections of mortality-rate and survival functions: model-independent considerations.

In work reported previously (Hirsch, 1995), it was shown that families of straight lines intersect at a single point if and only if the slopes of the lines are linearly related to their intercepts. This slope-intercept relation was applied to several mathematical mortality models including the Gompertz-Makeham and the Weibull. In all cases, survival functions intersected at greater ages than the corresponding mortality-rate functions. It was further demonstrated that a common point of intersection can exist for members of a family of survival functions or for members of the corresponding family of mortality-rate functions but not for both. Here the same results are obtained with respect to intersections of general model-independent survival and mortality-rate functions. The generality of the results strengthens the conclusion reached earlier that these intersections imply only the existence of a valid slope-intercept relation and have little other significance with regard to the biology of aging.

Age Distribution↗
PubMed1996

QT interval-heart rate relation during exercise in normal men and women: definition by linear regression analysis.

OBJECTIVES: This study sought to develop a regression-based method for characterization of QT interval behavior during exercise and to define the normal range of the resulting "dynamic" measures of repolarization during submaximal treadmill testing in men and women. BACKGROUND: The Bazett-corrected QT (QTc) interval during exercise has been used as a marker for ischemic disease, arrhythmogenic substrate and the long QT syndrome. However, recent studies indicate that the QTc interval is nonlinear with respect to heart rate during exercise, making the end-exercise QTc interval dependent on peak work load achieved. In contrast, the unadjusted QT interval measured from QRS onset to T wave offset (QTo) and from QRS onset to T wave peak (QTm) appears to vary linearly with heart rate during gently graded effort. METHODS: The QT interval relation to heart rate and cycle length was examined by linear regression in 50 normal men (mean age 48 years) and 30 normal women (mean age 51 years), all of whom had normal rest electrocardiograms. The QTo and QTm measurements were made from digitized lead V5 complexes averaged by computer over 20-s periods, at upright control and after seven 2-min stages of the Cornell modification of the Bruce treadmill protocol (work load equivalent to Bruce stage 3). RESULTS: For each subject, regression of QTo (ms) versus heart rate (beats/min) resulted in a slope (reflecting the "dynamic" change in QTo during effort), an adjusted intercept (reflecting QTo extrapolated to a heart rate of 60 beats/min) and a significant correlation coefficient (r) value. Under these conditions, mean +/- SD (5th to 95th percentile) values for men were -1.45 +/- 0.34 ms/beat per min (-0.90, "less dynamic" to -1.96, "more dynamic") for the slope; 403 +/- 21 ms (365 to 431) for the adjusted intercept; and -0.93 +/- 0.06 (-0.81 to -0.99) for r. Values for women were more dynamic, with a mean slope of -1.74 +/- 0.32 ms/beat per min (-1.23 to -2.18, p < 0.0005 vs. men) and higher adjusted intercept of 426 +/- 23 ms (392 to 462, p < 0.0001 vs. men) at similar strength of correlation (r = -0.95 +/- 0.06). Corresponding normal data were also tabulated for QTm behavior and QT-RR interval behavior during exercise. CONCLUSIONS: These data provide a "dynamic" definition of normal and abnormal repolarization and describe normal limits for the linear relations of the QTo and QTm intervals with respect to heart rate and cycle length during submaximal exercise in normal men and women.

Electrocardiography↗
PubMed1995

Determining the acuteness and stability of deep venous thrombosis by ultrasonic tissue characterization.

PURPOSE: The intent of the study was to determine whether ultrasonic tissue characterization (UTC) could indicate acuteness and stability of deep venous thrombosis (DVT) of the lower extremities. METHODS: Thrombi presenting as filling defects on color Doppler imaging in the common or superficial femoral or popliteal veins in 50 extremities in 45 patients with DVT were studied. Acute DVT was less than 4 days duration, and chronic DVT was greater than 21 days duration. UTC analysis of parameters from the normalized power spectrum of backscattered ultrasound signals from venous filling defects was performed. This spectrum approaches a straight line, and its basic parameters, slope, and Y-intercept are related to scatterer size, concentration, and the square of the scatterer-to-medium acoustic impedances. Ten of the DVT extremities were reexamined at 1 week to assess UTC changes that would indicate thrombus instability. RESULTS: Acute DVT (19 of the 50 extremities) could be distinguished from chronic DVT, mainly on the basis of significantly higher intercept values for the acute group, which were 11.6 relative decibels (dBr) higher than those of the chronic DVT group. Discriminant linear analysis of the two parameters indicated a sensitivity of 94.7% and specificity of 90.3% in correctly diagnosing acute DVT. In a small sample of 10 extremities reexamined at 1 week, acute DVT extremities showed a mean 9.4 dBr decrease in intercept values with no significant change in slope. CONCLUSIONS: UTC distinguished clinically defined acute from chronic DVT. In a small series of extremities, UTC revealed significant instability of acute thrombi in a selected patient population.

Acute Disease↗
PubMedDate not supplied

Left and right ventricular flows by Doppler echocardiography: serial measurements in patients with aortic regurgitation during exercise, cold pressor stimulation, and vasodilation.

To test the practicality of Doppler echocardiography to measure serial change, biventricular outputs were measured in 15 patients with aortic regurgitation during control periods and during interventions of bicycle exercise, cold pressor stimulation, and vasodilation. Biventricular stroke volumes were measured in 10 normal subjects for validation of methods and differed by 2.8%. Reading errors were 3.7%. Signal quality improved between the first and last observation (p less than 0.05). Velocity signals were corrected for intercept angles, which averaged 12 and 19 degrees for right heart flows and 31 and 32 degrees for the left side of the heart in all subjects. Negative correlations occurred between intercept angles and the chronologic order in which the patients were studied for left (p = 0.02) and right (p = 0.05) flows. Mean flow areas varied 9% in the left ventricle and 20% in the right ventricle. Total variability for measuring flow determined from control values was 11% to 13%. When twice the variability was used as the detectable level of change, only exercise provoked real increases in biventricular flows in the majority of patients. We conclude that serial measurements of flow by Doppler echocardiographic methods had to exceed 20% to 25% to achieve significant change. Measuring intercept angle, resolving flow area, and learning are variables that need greater emphasis.

Aortic Valve Insufficiency↗
PubMed2002

Re-assessing accumulated oxygen deficit in middle-distance runners.

The purpose of this study was to re-assess the accumulated oxygen deficit (AOD), incorporating recent methodological improvements i.e., 4 min submaximal tests spread above and below the lactate threshold (LT). We Investigated the Influence of the VO2 -speed regression, on the precision of the estimated total energy demand and AOD. utilising different numbers of regression points and including measurement errors. Seven trained middle-distance runners (mean +/- SD age: 25.3 +/- 5.4y, mass: 73.7 +/- 4.3kg. VO2max 64.4 +/- 6.1 mL x kg(-1) x min(-1)) completed a VO2max, LT, 10 x 4 min exercise tests (above and below LT) and high-intensity exhaustive tests. The VO2 -speed regression was developed using 10 submaximal points and a forced y-intercept value. The average precision (measured as the width of 95% confidence Interval) for the estimated total energy demand using this regression was 7.8mL O2 Eq x kg(-1) x min(-1). There was a two-fold decrease in precision of estimated total energy demand with the Inclusion of measurement errors from the metabolic system. The mean AOD value was 43.3 mL O2 Eq x kg(-1) (upper and lower 95% CI 32.1 and 54.5mL o2 Eq x kg(-1) respectively). Converting the 95% CI for estimated total energy demand to AOD or including maximum possible measurement errors amplified the error associated with the estimated total energy demand. No significant difference in AOD variables were found, using 10,4 or 2 regression points with a forced y-intercept. For practical purposes we recommend the use of 4 submaximal values with a y-intercept. Using 95% CIs and calculating error highlighted possible error in estimating AOD. Without accurate data collection, increased variability could decrease the accuracy of the AOD as shown by a 95% CI of the AOD.

Adult↗
PubMed2003

Characterization and quantification of the return map of RR intervals by Pearson coefficient in patients with acute myocardial infarction.

The return map is the plot that displays the relationship between a point and its consecutive point in a time series. This study tried to characterize and quantify the return map of RR intervals (RRI) in subjects with patent coronary arteriogram and in patients with acute myocardial infarction (AMI) by using some parameters of linear regression between RRI(n+1) and RRI(n), and compared the newly introduced parameters with the time- and frequency-domain indices of heart rate variability (HRV) obtained from the same RRI. Three quantitative measures were introduced to quantify the return map of RRI: the Pearson coefficient, slope and Y-intercept of linear regression between RRI(n+1) and RRI(n). We found that the Pearson coefficient was almost identical to the slope of linear regression, and correlated significantly and negatively with Y-intercept in controls and patients with AMI. The Pearson coefficient and the slope in patients with AMI were significantly larger while the Y-intercept was significantly smaller than those of controls. The Pearson coefficient was also found to correlate significantly and negatively with the indices of vagal modulation and positively with the indices of sympatho-vagal balance and rennin-angiotensin-aldosterone modulation in both normal controls and patients with AMI. Our results suggested that the return map of RRI could be characterized and quantified by Pearson coefficient, which was related to the autonomic nervous modulation of the subject.

Aged↗
PubMed1991

Steady-state kinetic mechanism of rat tyrosine hydroxylase.

The steady-state kinetic mechanism for rat tyrosine hydroxylase has been determined by using recombinant enzyme expressed in insect tissue culture cells. Variation of any two of the three substrates, tyrosine, 6-methyltetrahydropterin, and oxygen, together at nonsaturating concentrations of the third gives a pattern of intersecting lines in a double-reciprocal plot. Varying tyrosine and oxygen together results in a rapid equilibrium pattern, while the other substrate pairs both fit a sequential mechanism. When tyrosine and 6-methyltetrahydropterin are varied at a fixed ratio at different oxygen concentrations, the intercept replot is linear and the slope replot is nonlinear with a zero intercept, consistent with rapid equilibrium binding of oxygen. All the replots when oxygen is varied in a fixed ratio with either tyrosine or 6-methyltetrahydropterin are nonlinear with finite intercepts. 6-Methyl-7,8-dihydropterin and norepinephrine are competitive inhibitors versus 6-methyltetrahydropterin and noncompetitive inhibitors versus tyrosine. 3-Iodotyrosine, a competitive inhibitor versus tyrosine, shows uncompetitive inhibition versus 6-methyltetrahydropterin. At high concentrations, tyrosine is a competitive inhibitor versus 6-methyltetrahydropterin. These results are consistent with an ordered kinetic mechanism with the order of binding being 6-methyltetrahydropterin, oxygen, and tyrosine and with formation of a dead-end enzyme-tyrosine complex. There is no significant primary kinetic isotope effect on the V/K values or on the Vmax value with [3,5-2H2]tyrosine as substrate. No burst of dihydroxyphenylalanine production is seen during the first turnover. These results rule out product release and carbon-hydrogen bond cleavage as rate-limiting steps.

Animals↗