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Biomedical subjects

R E Carson

Publications and source records attributed to R E Carson.

At least 19 recordsLinked to original sources

PET imaging of opiate receptor binding in human epilepsy using [18F]cyclofoxy.

We used [18F]cyclofoxy (CF), a potent opiate antagonist with affinity for mu and kappa receptors, and the Scanditronix PC1024-7B PET scanner to study 14 patients with complex partial seizures (CPS), and 14 normal controls. Epileptic foci were localized by prolonged EEG-video monitoring. EEG was recorded continuously during each scan. Immediately before CF administration, [15O]labeled water was used to measure cerebral blood flow, and showed hypoperfusion ipsilateral to the EEG focus. Blood samples (corrected for radiolabeled metabolites) and tissue time-activity data were acquired over 90 min following bolus CF injection. Anatomic regions were outlined directly on the PET images. A kinetic model was used to derive the total volume of distribution (Vt) in each brain region. Specific binding (Vs) was determined by substracting non-specific binding (Vt) measured in a receptor-poor brain region (occipital cortex). Regions with high Vs included mesial temporal lobes, thalamus, basal ganglia, and frontal cortex. Individual patients appeared to have higher binding in temporal lobe ipsilateral to the EEG focus, but there was no asymmetry for the patients as a group in mean Vt or Vs in anterior mesial, posterior mesial, anterior lateral, posterior lateral temporal cortex, thalamus, basal ganglia, or, for Vt, in regions of low specific binding: occipital lobe, parietal lobe, cerebellum.

Adolescent

Glucose utilization in a patient with hepatoma and hypoglycemia. Assessment by a positron emission tomography.

Tumor glucose use in patients with non-islet-cell tumors has been difficult to measure, particularly in hepatoma, because of hepatic involvement by neoplasm. We studied a patient with nonhepatic recurrence of hepatoma after successful liver transplantation. Tumor tissue contained messenger RNA for insulin-like growth factor-II (IGF-II), and circulating high molecular weight components and E-peptide of IGF-II were increased. Glucose use measured by isotope dilution with [3-3H]glucose was 7.94 mg/kg fat-free mass per min, and splanchnic glucose production was 0.93 mg/kg fat-free mass per min. Glucose uptake and glucose model parameters were independently measured in tissues by positron emission tomography with 18F-fluoro-2-deoxy-D-glucose. Glucose uptake by heart muscle, liver, skeletal muscle, and neoplasm accounted for 0.8, 14, 44, and 15% of total glucose use, respectively. Model parameters in liver and neoplasm were not significantly different, and glucose transport and phosphorylation were twofold and fourfold greater than in muscle. This suggests that circulating IGF-II-like proteins are partial insulin agonists, and that hypoglycemia in hepatoma with IGF-II production is predominantly due to glucose uptake by skeletal muscle and suppression of glucose production.

Adult

In vivo imaging of insulin receptors in monkeys using 18F-labeled insulin and positron emission tomography.

We previously described a prosthetic group methodology for incorporating 18F into peptides and showed that 18F-labeled insulin (18F-insulin) binds to insulin receptors on human cells (IM-9 lymphoblastoid cells) with affinity equal to that of native insulin (1). We now report studies using 18F-insulin with positron emission tomography to study binding to insulin receptors in vivo. Positron emission tomography scans were performed in six rhesus monkeys injected with 0.3-1.4 mCi of 18F-insulin (approximately 0.1 nmol, SA 4-11 Ci/mumol). Integrity of the tracer in blood, determined by immunoprecipitation, was 94% of control for the first 5 min and decreased to 31% by 30 min. Specific, saturable uptake of 18F was observed in the liver and kidney. Coinjection of unlabeled insulin (200 U, approximately 1 nmol) with the 18F-insulin reduced liver and increased kidney uptake of the labeled insulin. Liver radioactivity was decreased by administration of unlabeled insulin at 3 min, but not 5 min, after administration of the tracer, while some kidney radioactivity could be displaced 5 min after injection. Clearance of 18F was predominantly in bile and urine. 18F-insulin is a suitable analogue for studying insulin receptor-ligand interactions in vivo, especially in the liver and kidney.

Animals

Dissociation of object and spatial visual processing pathways in human extrastriate cortex.

The existence and neuroanatomical locations of separate extrastriate visual pathways for object recognition and spatial localization were investigated in healthy young men. Regional cerebral blood flow was measured by positron emission tomography and bolus injections of H2(15)O, while subjects performed face matching, dot-location matching, or sensorimotor control tasks. Both visual matching tasks activated lateral occipital cortex. Face discrimination alone activated a region of occipitotemporal cortex that was anterior and inferior to the occipital area activated by both tasks. The spatial location task alone activated a region of lateral superior parietal cortex. Perisylvian and anterior temporal cortices were not activated by either task. These results demonstrate the existence of three functionally dissociable regions of human visual extrastriate cortex. The ventral and dorsal locations of the regions specialized for object recognition and spatial localization, respectively, suggest some homology between human and nonhuman primate extrastriate cortex, with displacement in human brain, possibly related to the evolution of phylogenetically newer cortical areas.

Adult

Regional brain measurement of Bmax and KD with the opiate antagonist cyclofoxy: equilibrium studies in the conscious rat.

Brain distribution of the opiate receptor antagonist, cyclofoxy (CF), was evaluated at equilibrium in rats. A combination of i.v. injection and constant i.v. infusion was used to administer CF over a wide dose range (2.4-450 nmol/rat). Kinetic simulations and experimental results showed that this administration schedule accomplishes "true" tissue-blood equilibrium of CF within 60 min. To estimate the receptor-ligand binding parameters, we assumed that the CF concentration at the receptor site is identical to that in plasma water at equilibrium, and can be calculated from measured blood data after corrections for radiolabeled metabolites and plasma protein binding. This assumption was supported by CSF and plasma water measurements at equilibrium. Regional KD, Bmax, and a nonspecific tissue binding equilibrium constant (Keq) were estimated by fitting the tissue and plasma water concentrations to a single receptor model; the estimated values were 1.4-2.9 nM, 15-74 pmol/g of tissue, and 5.2-8.0, respectively. They are in good agreement with previous in vitro measurements (Rothman and McLean, 1988) as well as in vivo estimates from i.v. injection experiments (Sawada et al., 1990c). The conventional method to estimate the receptor-ligand binding parameters using data from cerebellum to approximate nonspecific tissue binding was found to be unacceptable. Although cerebellum is a brain region with no opiate receptors in rats, small differences in nonspecific tissue binding in different brain regions resulted in significant overestimations of KD and Bmax with this method. Receptor-active and -inactive enantiomers [[18F](-)-CF and [3H](+)-CF)] were simultaneously administered to the same animal and the receptor-bound CF concentration could be accurately measured; this method was used to estimate Bmax from a single study in a single animal and has potential for direct application in human studies using positron emission tomography.

Animals

Precision and accuracy considerations of physiological quantitation in PET.

The ability to differentiate regional patterns of flow and metabolism between various patient populations depends upon the signal-to-noise characteristics of the data. The approach chosen for producing quantitative data will affect the detection sensitivity of a method. Methods based on mathematical models can reduce intersubject variability by accounting for factors unrelated to the physiological measure of interest, in particular, differences in the input function. However, errors in the model and in the implementation of a model-based method can increase variability compared to simpler, empirical methods. Normalization of physiological measures can significantly reduce intersubject variation; however, interpretation of normalized results can be more complex. The advantages and disadvantages of various approaches for physiological quantitation are considered.

Brain

Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration.

Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow blood flow phase of diastole. Before treatment with intracarotid cisplatin, 10 patients with malignant gliomas were studied to determine whether intravascular streaming occurs after intracarotid infusion in humans, and if so, if it is reduced with DPPI. Regional cerebral blood flow (rCBF) studies were performed by intravenous injection of H2(15)O and positron emission tomography. This was followed by supra- or infraophthalmic internal carotid artery (ICA) injections of H2(15)O with either continuous infusion or DPPI. Local H2(15)O concentration in the brain was determined and the images of radiotracer distribution in the continuous infusion and DPPI studies were compared to the rCBF images. Intravascular streaming of the infusate was identified by a heterogeneous distribution of the infused H2(15)O in brain compared to rCBF. Extensive and variable intravascular streaming occurred in three patients who received infusions into the supraophthalmic segment of the ICA. Some brain areas received up to 11 times the expected radiotracer delivery, while other regions received as little as one-tenth. This streaming pattern was markedly reduced or eliminated by DPPI. In the five patients who received infraophthalmic infusions, a minimally heterogeneous distribution of the infusate was detected. The authors conclude that extensive intravascular streaming accompanies supraophthalmic ICA infusions in patients. The magnitude of streaming can be substantially reduced or eliminated with DPPI. Those who perform intra-arterial infusion should consider using DPPI to assure uniform drug delivery to brain.

Analysis of Variance

Brain glucose metabolism in noninsulin-dependent diabetes mellitus: a study in Pima Indians using positron emission tomography during hyperinsulinemia with euglycemic glucose clamp.

To determine whether insulin or noninsulin-dependent diabetes mellitus affects brain glucose metabolism, brain glucose utilization was studied in the basal state and during hyperinsulinemic euglycemic glucose clamps in nondiabetic and diabetic Pima Indians by positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG). Glucose utilization in 75 brain areas was determined by analysis of single scans and by least squares estimation of the rate parameters for the FDG model; these data were compared to results in normal caucasian volunteers. No effect of ethnicity or diabetic status on brain glucose utilization was observed. During the hyperinsulinemic clamps (mean insulin, 11,708 +/- 3,026 pmol/L), clearance of 18FDG from blood was accelerated, and accumulation of brain radioactivity was reduced. However, glucose utilization by the brain was identical to results during sham glucose clamps (mean insulin, 204 +/- 56 pmol/L) performed in the same patients. During the studies with hyperinsulinemia, k4 (representing loss of tissue radioactivity) was increased in most brain areas (mean increase, 0.0031 +/- 0.0018 min-1; P less than 0.02). The possible mechanisms for this effect are multiple, and the physiological significance, if any, is unknown. Further studies of the effects of insulin on brain glucose metabolism are needed.

Adult

Scaling and root planing effectiveness: the effect of root surface access and operator experience.

This study investigated two variables associated with scaling and planning (S&RP): operator experience level and root surface access. One hundred and fourteen periodontally involved, single-rooted teeth designated for extraction were randomly distributed among four operators of various experience levels for either an open or closed session of S&RP. Immediately after treatment, the teeth were extracted, washed, and scored for residual calculus in a blind manner. Results showed that there was no difference in S&RP effectiveness for experience level or type of procedure in shallow (1-3 mm) pockets. However, in moderate (4-6 mm) and deep (greater than 6 mm) periodontal pockets, S&RP combined with an open flap procedure was more effective than S&RP alone for both experience levels. Also, the more experienced operators produced a significantly greater number of calculus-free root surfaces than the less experienced operators in periodontal pockets with moderate and deep probing depths. Clinical application of these results suggests that surgical access is associated with thorough surface debridement in periodontal pockets with moderate-to-advanced probing depths. However, more experienced operators could be expected to render more effective soft surface debridement.

Adult

Quantitative comparison of cerebral glucose metabolic rates from two positron emission tomographs.

The rapid progress in positron emission tomography technology has created the dilemma of how to compare data from old and new tomographs. We examined cerebral metabolic data from two scanners, with different spatial resolutions and methods of attenuation correction, to see if data from the lower resolution tomograph (ECAT II) could be "corrected" and then compared to data from the higher resolution scanner (Scanditronix PC1024-7B). Nine subjects were scanned on both tomographs after a single injection of [18F]2-fluoro-2-deoxy-D-glucose. Regional and lobar gray matter metabolic rates for glucose were obtained from comparable images from each scanner. Ratios of lobar to global gray matter metabolism also were calculated. Regression coefficients and percent differences were computed to compare ECAT II and PC1024 data. Twenty-four of the 36 regions showed significant regression slopes, and PC1024 measures of glucose utilization ranged from 30% to 120% higher than those from the ECAT II. Lobar differences between the two machines were less variable (50% to 80%), and ratios generally differed by only +/- 5%. Since there was no simple and consistent relation between regional metabolic rates on the two tomographs, an overall adjustment of regional ECAT values for comparison to PC1024 values would be impossible. A region-by-region adjustment would be necessary. On the other hand, ratios are sufficiently similar that direct comparisons could be made.

Aged

A method for postinjection PET transmission measurements with a rotating source.

A method is presented for obtaining accurate positron emission tomography transmission measurements after tracer injection. A transmission scan is performed using a rotating source immediately before or after a conventional emission scan. Sinogram windowing, which removes most scattered and random coincidences, also removes most of the emission counts contaminating the transmission measurement. Data from the emission scan can be used to subtract the remaining emission counts to produce accurate transmission measurements. For studies with moderate to low emission count rates (e.g., fluorodeoxyglucose) there is little increase in noise in the resulting attenuation correction factors. This method was tested in experiments with phantoms and a rotating source simulator and validated against conventional ring transmission measurements. Applications of the technique can significantly shorten the time between transmission and emission studies, and thereby reduce the likelihood of patient motion and increase scanning throughput.

Deoxyglucose

Examination of blood-brain barrier permeability in dementia of the Alzheimer type with [68Ga]EDTA and positron emission tomography.

Positron emission tomography with [68Ga]ethylenediaminetetraacetic acid ([68Ga]EDTA) was used to examine the integrity of the blood-brain barrier (BBB) in five patients with dementia of the Alzheimer type and in five healthy age-matched controls. Within a scanning time of 90 min, there was no evidence that measurable intravascular tracer entered the brain in either the dementia or the control group. An upper limit for the cerebrovascular permeability-surface area product of [68Ga]EDTA was estimated as 2 X 10(-6) s-1 in both groups. The results provide no evidence for breakdown of the BBB in patients with dementia of the Alzheimer type.

Aged

Weighted integration method for local cerebral blood flow measurements with positron emission tomography.

A new technique called the weighted integration method for the measurement of local CBF (LCBF) in humans with positron emission tomography (PET) is presented. LCBF is calculated from weighted time integrals of the blood and tissue radioactivity curves. This method is computationally efficient and achieves nearly optimal statistical estimation of LCBF. The predicted root mean squared error of the weighted integration method is verified by simulation studies and is only 1-2% larger than the minimum possible error that can be achieved by an ideal estimation algorithm. For LCBF of greater than 30 ml/min/100 g, the weighted integration method provides reduced noise compared with the integrated projection technique, the PET autoradiographic method, and the steady-state technique. In addition, an error analysis is performed to study the sensitivity of the weighted integration method to tissue mixtures, blood sample timing errors, and changes in LCBF during the data collection period.

Brain

An SEM study of overhang removal methods.

The sonic scaler, the curet, and the reciprocating motor-driven diamond tip were evaluated by comparing the number of rough root surfaces produced by each device in recontouring overhanging root-surface margins of amalgam and composite resin restorations. Ninety extracted human teeth were restored with amalgam or composite resin so that overhangs were created. Each instrument was used to remove 30 overhangs. The root surfaces apical to the overhangs were photographed under the scanning electron microscope at a magnification of x 140 and compared by five dentists, in a single-blind manner, with two control photomicrographs of surfaces classified as rough (treated with a coarse diamond bur) or not rough (treated with a greenstone). The number of rough responses for each instrument were compared statistically. For both restorative materials, the sonic scaler produced a significantly greater number of rough responses than did the other two instruments. Similar comparisons between the curets and the diamond-tip system showed no significant differences. No differences in the number of gaps produced between restoration and tooth were noted among the instruments. Clinical ease of overhang removal was greatest for the reciprocating motor-driven diamond tip and least for the curet. The approximate time to remove an overhang from a tooth was 3 minutes for the motor-driven diamond tip, 7 minutes for the sonic scaler and 15 minutes for the curet.

Composite Resins

A noninvasive positron computed tomography technique using oxygen-15--labeled water for the evaluation of neurobehavioral task batteries.

A technique is described that provides information about relative cerebral responses to differing neurobehavioral tasks in normal subjects studied with positron computed tomography and oxygen-15-labeled water. Simulation studies demonstrate that this technique is sensitive to changes in true local CBF within a physiological range and tends to underestimate relative flow changes at high flow values (greater than 30 ml min-1 100 g-1) and to overestimate these changes for flow values of less than 25 ml min-1 100 g-1. Image acquisition times of 60 s following the arrival of oxygen-15-labeled water in the brain were the most accurate for identifying such relative changes between radioisotope administrations and were not limited by statistical noise from total image counts. Studies in normal volunteers indicate that the technique is highly reproducible, demonstrating a coefficient of variation for small (less than 2 cm2) regions of 2.98 between studies in the same state. Visual stimulation studies in normal volunteers demonstrated relative radioisotope concentration changes between control and stimulated states that are in good agreement with similar results obtained using the same stimulation paradigm but with the use of fluorodeoxyglucose to determine cerebral glucose metabolism.

Adult

Parabiotic transfer of cancer anorexia/cachexia in male rats.

To demonstrate that the anorexia and depletion of cachexia reverses on tumor removal, F344 rats underwent sarcoma resection when their food intake fell to 0 g/day. In survivors of surgery, reversal in food intake was apparent within 3 days postoperatively, followed after 2 days by gain in host weight. To detect whether the transmission of anorexia/cachexia in these tumor-bearing (TB) rats was via the circulation, four groups were studied: single non-tumor bearing (NTB); single TB; parabiotic NTB; and parabiotic TB. The measured blood exchange rate between parabiotic halves was 1.2-1.5%/min. No cachectic effect was detected in either half of the NTB parabionts. There was no evidence of sarcoma metastases in the tumor-free half of the parabiotic TB pair. All the rats associated with the presence of tumor showed cachectic effects but the degree and timing of effect varied among the three conditions, single TB, parabiotic TB half, and parabiotic tumor-free half. In all variables examined (fall in food intake, time of first fall in food intake, host weight loss, elevation of blood urea nitrogen) the severities were always in the same sequence: single TB greater than parabiotic TB half greater than parabiotic tumor-free half greater than NTB. In addition, the TB parabiotic pair had a significantly longer survival time and grew a significantly larger tumor than did the single TB animal. The parabiotic tumor had a slower initial growth rate and a slower deceleration rate than the singlet tumor. These results provide evidence for the humoral mediation of cancer-associated cachexia.

Animals