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J Markham

Publications and source records attributed to J Markham.

At least 19 recordsLinked to original sources
PubMed1995

Cerebral transport and metabolism of 1-11C-D-glucose during stepped hypoglycemia.

Attempts to measure blood-to-brain glucose transport and cerebral glucose metabolism with 11C-glucose have been hampered by methods that require jugular venous sampling or do not adequately account for the efflux of labeled metabolites from the brain. We performed eight positron emission tomography studies with 1-11C-D-glucose in macaques at arterial plasma glucose concentrations of 8.43 to 1.51 mumol ml-1 (152-27 mg dl-1) using a model that includes a fourth rate constant to account for regional egress of all 11C-metabolites. Values for blood-to-brain glucose influx, cerebral glucose metabolism, and brain free glucose concentration agreed closely with values obtained in mammals by other investigators. Values for net extraction fraction corresponded closely to simultaneously measured arteriovenous values. We demonstrated that utilization of a model that includes a fourth rate constant to account for regional egress of all 11C-metabolites with positron emission tomography and 1-11C-D-glucose provides accurate measurements of blood-to-brain glucose transport and cerebral glucose metabolism in vivo without need for jugular venous sampling, even under conditions of severe hypoglycemia.

Animals↗
PubMed1995

In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. I. Theory and error analysis.

We developed a procedure for measuring pulmonary angiotensin-converting enzyme kinetics with fluorine-18 fluorocaptopril and positron emission tomography (PET). The method is based on the application of a compartmental receptor model that represents the kinetics of two species of ligand, presumably the trans and cis conformers of captopril. The input function was characterized and includes corrections for the labeled metabolites of fluorocaptopril. Application of the procedure to lung time-activity data obtained with PET produced estimates of kinetic parameters demonstrating fast kinetics for one conformer and slower kinetics for the other. Simulation studies were performed to evaluate the sensitivity of the estimated parameters to errors in the model assumptions and in measured values for variables required for analysis of the PET data. Estimates for two of the kinetic parameters, the amount of perfused unbound functional enzyme normalized to regional lung volume and the association rate constant for the trans conformer, were relatively stable even with large errors in the input data, varying < 30% from true values for all perturbations. Thus, the procedure produces reliable estimates of the kinetics of the trans conformer of captopril as well as theoretical curves that are close to the observed data.

Animals↗
PubMed1995

In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. II. Implementation and application.

We measured pulmonary angiotensin-converting enzyme (ACE) kinetics with fluorine-18 captopril and positron emission tomographic (PET) imaging in five control dogs and in five dogs after 20-30 min of left caudal lobe (LCL) hypoxic ventilation. Time-activity data obtained with PET were interpreted with a compartmental receptor model relating changes in tissue and blood activity to one another within the region. In control dogs, the mean ratio of regional blood flow (measured by PET) between left and right dorsal lung regions was 0.90 +/- 0.16 (SD) vs. 0.54 +/- 0.24 (P < 0.05) in LCL hypoxic dogs. In control dogs, the amount of perfused unbound enzyme normalized to regional extravascular water concentration (Bmax/EVLW) averaged 13.3 +/- 8.9 x 10(-6) mmol ACE/ml EVLW; the ratio of regional values between the left and right sides was 1.02 +/- 0.18. In the LCL hypoxic dogs, Bmax/EVLW was 9.7 +/- 11.3 x 10(-6) mmol/ml hypoxic lung region and the ratio was 0.47 +/- 0.31 (P < 0.05). In control dogs, the coefficient of variation for Bmax/EVLW among regions was only 19 +/- 10%, although the between-dog variation was greater (64 +/- 4%). We conclude that this completely noninvasive method appears to be a promising approach for evaluating the expression of pulmonary ACE in vivo.

Animals↗
PubMed1995

Measurement of regional pulmonary blood flow with PET.

UNLABELLED: We have previously reported a method for measuring regional pulmonary blood flow (PBF) in experimental animals using 15O-water and PET. The method requires withdrawing blood from the pulmonary artery during the PET scan, so that the input function can be estimated for the one-compartment model used to analyze the data. The purpose of the present study was to modify and validate this technique for a more general use in humans. METHODS: PBF was measured after injections of 15O-water in 15 normal subjects and in five patients with reduced cardiac output. In ten of the normal subjects, PBF was also measured after the injection of 68Ga-albumin macroaggregates (MAA). In the five other normal subjects and in the cardiomyopathy patients, PBF was measured twice after two separate 15O-water administrations. The input function was estimated from a region of interest (ROI) over the right ventricle (RV), with corrections when necessary, for time delays between RV and lung tissue. RESULTS: The mean value for PBF in the normal subjects was 121 +/- 32 ml/min/100 ml lung, and was 57 +/- 33 ml/min/100 ml lung in the patients with cardiomyopathy. The correlation between PBF measured with 15O-water and PBF measured with 68Ga-MAA was r = 0.96. There was no significant difference in the mean value for PBF or the ventral-dorsal distribution of PBF when sequential measurements were made in the same individual. PBF increased in general in the ventral-dorsal direction in these supine subjects, although PBF was more evenly distributed in the cardiomyopathy patients. CONCLUSION: Measurement of regional PBF with 15O-water and PET appears to be a valid, noninvasive approach for evaluating the pulmonary perfusion pattern of humans.

Adult↗
PubMed1993

Sudden death in idiopathic dilated cardiomyopathy: role of ventricular arrhythmias.

Sudden cardiac death (SCD) is associated with idiopathic congestive cardiomyopathy (IDCM) and most commonly is due to ventricular tachyarrhythmias. The recurrence rate of SCD in the absence of specific therapy is thought to be around 20%-30% per year. Asymptomatic and symptomatic ventricular arrhythmias are common in patients with IDCM and the direct causal link of such arrhythmias with SCD in IDCM patients remains to be established. Furthermore, therapy directed at suppressing these ventricular arrhythmias has not been shown to decrease the incidence of SCD. Various approaches such as ambulatory monitoring, electrophysiological testing, signal-averaged electrocardiogram, and hemodynamics have met with variable success in identifying patients prone to SCD. Additionally, therapeutic approaches to prevent SCD in IDCM patients have produced equivocal results. This article reviews the published studies addressing the causal link of ventricular arrhythmias to sudden death in patients with IDCM and the attempts to decrease the incidence of sudden.

Arrhythmias, Cardiac↗
PubMed1992

Effects of nonideal input functions on PET measurements of pulmonary blood flow.

Regional pulmonary blood flow (rPBF) can be measured with an intravenous infusion of 15O-labeled water and positron emission tomography (PET). The current method depends on two assumptions related to the input of activity to the lung during the scan: 1) the pulmonary arterial tracer input is constant (i.e., a "step function" in shape), and 2) the scan begins at the instant of arrival of the step function. To determine the effect that departures from these assumptions might have on the measurement of rPBF, we performed a series of mathematical simulations for three different input functions: 1) a step function that arrived either 1 or 2 s before or after scan start; 2) a dispersed input function, with activity rising during the scan period; and 3) a combination of these two errors. Calculated values, based on the standard assumptions, were compared against the "known" values used in generating the simulated data. The results show that timing errors associated with starting the scan late cause an overestimation of rPBF, whereas timing errors due to low regional flow or departures from the assumed step input function both cause an underestimation of true rPBF. Thus, in actual practice, the combined errors probably partially offset one another. Except for states of truly high rPBF and low lung density, the errors remain less than 15% of the true value. We conclude that PET measurements of rPBF are not highly sensitive to these presumably common departures from the assumed pulmonary arterial input function to lung regions of interest.

Animals↗
PubMed1992

Implementation and evaluation of a two-compartment model for quantification of myocardial perfusion with rubidium-82 and positron emission tomography.

Positron emission tomography offers the ability to noninvasively assess regional myocardial perfusion in absolute terms (i.e., milliliters per gram per minute). Accurate estimates have been difficult to achieve with generator-produced 82Rb because of the complex behavior of this tracer in the myocardium. The aim of the present study was to determine whether regional myocardial blood flow could be assessed quantitatively with 82Rb and positron emission tomography by using a two-compartment kinetic model. Regional perfusion in milliliters per gram per minute was estimated from dynamic tomographic scans after intravenous administration of 82Rb in 18 studies in 13 intact dogs studied without intervention, after 2 and 24 hours of induced ischemia, during reperfusion after transient occlusion, or at rest and after pharmacological hyperemia after induced coronary artery stenosis. Regional flow was estimated along with the forward and backward rates of transport (k1 and k2 [minutes-1]) after the relative volume of distribution of the first compartment was fixed to 0.53 ml/ml and the tomographic parameters, the recovery and spillover fractions, were fixed to averaged values obtained in previous studies. In 36 comparisons, estimates of regional flow with 82Rb correlated well with flow measured with concomitantly administered radiolabeled microspheres (r = 0.91, p less than 0.05) over the flow range from 0.14 to 4.25 ml/g/min. A putative index of viability, k2, increased significantly in regions with severe ischemia. The results suggest that quantification of regional myocardial perfusion is possible in centers using 82Rb for estimates of myocardial perfusion when a physiologically appropriate, two-compartment model is used.

Animals↗
PubMed1992

The effects of regional pulmonary blood flow on protein flux measurements with PET.

We used PET to evaluate whether changes in regional pulmonary blood flow (PBF) or plasma volume (PV) affect calculations of the pulmonary transcapillary escape rate (PTCER) for 68Ga-labeled transferrin. We reduced PBF in five dogs by inflating a right atrial balloon. Regional PBF decreased 25% to 174 +/- 40 ml/min/100 ml lung without a change in PV or PTCER. In eight other dogs, we decreased PBF and PV via controlled arterial hemorrhage. PBF decreased 45% to 110 +/- 33 ml/min/100 ml lung and PV decreased 22% without a change in PTCER. We also used a series of computer simulations to evaluate the effect of even greater reductions in regional PBF on PTCER calculations. These simulations showed, in support of the experimental data, that if PBF was greater than 40 ml/min/100 ml lung, PTCER could be accurately measured. However, below this level, PV was increasingly under-estimated and PTCER overestimated. The results indicate the sensitivity of the PTCER calculation to errors in the PV measurement, especially in regions of markedly reduced regional PBF.

Animals↗
PubMed1991

Diagnostic implications of spectral and temporal analysis of the entire cardiac cycle in patients with ventricular tachycardia.

BACKGROUND: Available methods for analysis of signal-averaged electrocardiograms (ECGs) have a low-positive predictive accuracy for identifying patients at risk for ventricular arrhythmias. Identification of the spectral and temporal features in ECGs that distinguish patients prone to ventricular tachycardia (VT) is a prerequisite to implementing refinements in methods that increase the diagnostic power of the signal-averaged ECG. METHODS AND RESULTS: Fast Fourier transforms and time-domain reconstructions based on inverse fast Fourier transforms were computed over the entire cardiac cycle of signal-averaged ECGs of sinus beats from 40 patients with myocardial infarction and sustained VT, 41 with infarction without VT, and 20 normal controls. Ventricular depolarization and repolarization were analyzed by procedures that obviate limited resolution due to short data segments and window functions. Spectral magnitudes of ECGs from patients in each group were compared, and the phase data were used for time-domain reconstructions to determine the temporal distributions of distinguishing frequency bands during the cardiac cycle. Magnitudes of 1-7-Hz frequencies were increased (from p less than 0.05 to p less than 0.00001), and magnitudes of 13-56-Hz and 70-128-Hz frequencies were decreased (from p less than 0.05 to p less than 0.00001) in the spectra of ECGs from patients with VT compared with patients without VT. Time-domain reconstructions demonstrated that 1-7-Hz frequencies were detectable throughout the QRS complex, ST segment, and T wave in ECGs from each group. The 13-56-Hz and 70-128-Hz frequency bands not only contributed to the terminal QRS and ST segment but were also detectable throughout the QRS complex of ECGs from patients with VT. CONCLUSIONS: Results define new spectral and temporal features in signal-averaged ECGs from patients with VT that are excluded from analysis by available techniques that limit the bandwidth or restrict interrogation to portions of the cardiac cycle. These findings provide an objective basis for developing new indexes for signal-averaged ECG analysis.

Electrocardiography↗
PubMed1990

Noninvasive quantification of regional myocardial perfusion with rubidium-82 and positron emission tomography. Exploration of a mathematical model.

Positron emission tomography (PET) centers without cyclotrons use generator-produced rubidium-82 (82Rb) for assessment of myocardial perfusion. The aim of the present study was to determine whether myocardial blood flow could be assessed quantitatively with 82Rb and PET. Because the myocardial extraction fraction of 82Rb varies inversely and nonlinearly with flow and cannot be measured conveniently with PET, we used an experimentally derived mathematical function defining the relation between single-pass extraction fraction of 82Rb and flow to obviate the necessity of measuring the extraction fraction directly. Myocardial blood flow in absolute terms (ml/g/min) was estimated from dynamic PET scans after intravenous administration of 82Rb in intact dogs and compared with flows measured with radiolabeled microspheres. In 36 comparisons in 13 dogs studied at rest, or after coronary occlusion, reperfusion, or after coronary hyperemia induced with intravenous dipyridamole, over the flow range from 0.2 to 2.0 ml/g/min, estimates of perfusion with rubidium correlated well with flows measured concomitantly with microspheres, although there was a slight underestimation of flow with rubidium (flow by 82Rb = 0.92 x flow by microspheres-0.021, r = 0.83). In general, estimates of flow in ischemic regions were less reliable than estimates for regions with normal flow. Thus, although the relation between myocardial extraction and retention of 82Rb and flow can vary under a variety of physiological and pathophysiological conditions, this study demonstrates the ability to obtain quantitative estimates of myocardial blood flow with 82Rb and PET under carefully defined conditions without measuring the extraction fraction directly.

Animals↗
PubMed1989

Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography.

Noninvasive measurement of myocardial blood flow in absolute terms (i.e., milliliters per gram per min) has been difficult to accomplish despite the intrinsically quantitative power of positron emission tomography because of the nonphysiologic nature of tracers that have been employed conventionally as well as the limited spatial resolution of currently available instruments. It was previously demonstrated that myocardial blood flow in animals can be quantitated accurately with the diffusible tracer oxygen-15-labeled water (H2(15)O) when the arterial input function and myocardial radiotracer concentration were measured directly. To extend the approach for completely noninvasive measurement of blood flow, a parameter estimation procedure was developed whereby effects of limited tomographic spatial resolution and cardiac motion were compensated for within the operational flow model. In validation studies in 18 dogs, myocardial blood flow measured with positron emission tomography after intravenously administered H2(15)O correlated closely with flow measured with concomitantly administered radiolabeled microspheres over the range of 0.29 to 5.04 ml/g per min (r = 0.95). Although regional ischemia was clearly identifiable tomographically, absolute flow could not be determined accurately in ischemic regions in four dogs because of poor count statistics related to wall thinning. Subsequently, myocardial blood flow was measured in 11 normal human subjects. Flow was homogeneous throughout the myocardium, averaged 0.90 +/- 0.22 ml/g per min at rest and increased to 3.55 +/- 1.15 ml/g per min after intravenous administration of dipyridamole. Therefore, positron emission tomography with H2 15O and the approach developed permits noninvasive measurement of myocardial blood flow in absolute terms in humans and should facilitate objective assessment of interventions designed to enhance nutritive perfusion.

Adult↗
PubMed1988

Identification of patients with sustained ventricular tachycardia by frequency analysis of signal-averaged electrocardiograms despite the presence of bundle branch block.

Previously, we have demonstrated distinguishing features in the fast Fourier transform (FFT) of signal-averaged electrocardiograms (ECGs) obtained during sinus rhythm in the absence of bundle branch block that differentiate patients with from those without sustained ventricular tachycardia (VT). The ECGs during sinus rhythm from many patients with sustained VT, however, exhibit intraventricular conduction abnormalities. Accordingly, this study was performed to determine whether the presence of bundle branch block during sinus rhythm precluded accurate identification of patients with sustained VT. Studies were performed in 28 normal subjects (group I) and 141 patients with organic heart disease grouped according to clinical characteristics. Group II comprised 40 patients without VT in whom the QRS duration during sinus rhythm was less than 120 msec. Group III included 21 patients without VT in whom the QRS duration during sinus rhythm was 120 msec or greater. Group IV comprised 43 patients with sustained VT having ECGs during sinus rhythm with QRS durations less than 120 msec. Group V included 37 patients with sustained VT in whom the QRS duration during sinus rhythm was 120 msec or greater. FFTs of the terminal QRS and ST segment of signal-averaged X, Y, and Z ECGs were computed. Transformed data were expressed as an FFT magnitude and the relative contribution and peak magnitudes of 20 to 50 Hz frequencies determined after first demonstrating that this FFT method was more appropriate, when compared with the energy spectrum, for analyzing ECG signals having a broad range of ST segment durations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Perinatal mortality and season of birth in captive wild ungulates.

The magnitude of perinatal mortality in 50 species of captive wild ungulates born at the Zoological Society of London's collections at Regent's Park and Whipsnade between 1975 and 1985 is reviewed. Thirty-five per cent of 2471 ungulates born during this 11 year period died before six months old and most deaths occurred in the first week after birth. Similar findings have been reported at other zoos and in the wild. The seasonal distribution of births is described in 43 species. Significantly higher perinatal mortality was found in species which breed throughout the year (notably axis deer and sitatunga) than in seasonal breeders, and differences associated with system of management were apparent in some species (eg, mouflon and scimitar-horned oryx) kept at Regent's Park and Whipsnade. Considerable advances have been made in the management of captive wild ungulates in recent years but it is likely that perinatal mortality rates could be further reduced by improved management and veterinary care of the dams and neonates.

Abortion, Veterinary↗
PubMed1987

Tracer-kinetic models for measuring cerebral blood flow using externally detected radiotracers.

All tracer-kinetic models currently employed with positron-emission tomography (PET) are based on compartmental assumptions. Our first indication that a compartmental model might suffer from severe limitations in certain circumstances when used with PET occurred when we implemented the Kety tissue-autoradiography technique for measuring CBF and observed that the resulting CBF estimates, rather than remaining constant (to within predictable statistical uncertainty) as expected, fell with increasing scan duration T when T greater than 1 min. After ruling out other explanations, we concluded that a one-compartment model does not possess sufficient realism for adequately describing the movement of labeled water in brain. This article recounts our search for more realistic substitute models. We give our derivations and results for the residue-detection impulse responses for unit capillary-tissue systems of our two candidate distributed-parameter models. In a sequence of trials beginning with the simplest, we tested four progressively more detailed candidate models against data from appropriate residue-detection experiments. In these, we generated high-temporal-resolution counting-rate data reflecting the history of radiolabeled-water uptake and washout in the brains of rhesus monkeys. We describe our treatment of the data to yield model-independent empirical values of CBF and of other parameters. By substituting these into our trial-model functions, we were able to make direct comparisons of the model predictions with the experimental dynamic counting-rate histories, confirming that our reservations concerning the one-compartment model were well founded and obliging us to reject two others. We conclude that a two-barrier distributed-parameter model has the potential of serving as a substitute for the Kety model in PET measurements of CBF in patients, especially when scan durations for T greater than 1 min are desired.

Animals↗
PubMed1986

Strategies for in vivo measurement of receptor binding using positron emission tomography.

Dopaminergic ligands labeled with positron-emitting radionuclides have been synthesized for quantitative evaluation of dopaminergic binding in vivo. Two different methods, the explicit method and an operationally simplified ratio method, have been proposed for analysis of these positron emission tomographic (PET) data. The basis for both methods is the same three-compartment model. The two methods differ in the assumptions necessary for practical implementation. We have compared these two approaches using PET data obtained in our laboratory. Sequential scans and serial arterial blood samples from a baboon following intravenous injection of [18F]spiroperidol were collected. Application of the two methods to the same data yielded different values for corresponding parameters. Values calculated by the ratio method for the specific rate constant describing receptor binding varied depending upon the time after tracer injection, thus demonstrating an internal inconsistency in this approach. Tracer metabolism markedly affected the binding measurements calculated with either method and thus cannot be ignored. Our results indicate that the adoption of simplifying assumptions for operational convenience can lead to substantial errors and must be done with caution. Alternatively, we present simple new analytical solutions of the tracer conservation equations describing the complete, unsimplified three-compartment model that vastly reduce the computations necessary to implement the explicit method.

Animals↗