Biomedical subjects

R M Kessler

Publications and source records attributed to R M Kessler.

At least 37 records · Page 2Linked to original sources

PubMed1993

Evaluation of 5-[18F]fluoropropylepidepride as a potential PET radioligand for imaging dopamine D2 receptors.

This study evaluated the utility of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3 - dimethoxybenzamide ([18F]fluorpropylepidepride), [18F]5-FPrEpid, as a ligand for PET studies of cerebral dopamine D2 receptors. The in vitro affinity for the rat striatal dopamine D2 receptor, KD 138 pM, was determined by Scatchard analysis of in vitro binding to rat striatal homogenate. The apparent lipophilicity, log kw 1.6, was measured with reverse phase HPLC at pH 7.5. The receptor specificity was determined by competitive displacement of [18F]5-FPrEpid by a variety of neurotransmitter ligands. Only dopamine D2 ligands displaced [18F]5-FPrEpid with high affinity. Positron tomographic imaging studies in primates of [18F]5-FPrEpid demonstrated a stable striatal uptake of 0.02% injected dose/ml for up to 5 h after injection. The striatal: cerebellar ratio increased from 2 at 15 min, to 7 at 200 min, and to 10 at 300 min. Striatal uptake was displaceable by haloperidol (1 mg/kg) or raclopride (2.5 mg/kg) to cerebellar levels with a t1/2 of washout of 9 or 15 min. Striatal uptake was mildly susceptible to displacement by d-amphetamine (1-2 mg/kg) released endogenous dopamine; d-amphetamine administration produced a 10% h increase in the rate of striatal washout. Although uptake in the striatum is reversible, an equilibrium between receptor bound [18F]5-FPrEpid in striatum and [18F]5-FPrEpid in plasma is not reached within 5 h postinjection.

Animals↗

PubMed1993

Failure of the three compartment model to describe the pharmacokinetics in brain of a high affinity substituted benzamide.

The applicability of using the standard 3-compartment model to describe the neuropharmacokinetics of a high affinity substituted benzamide was investigated. We performed the following experiments using the [18F]-5-(3-fluoropropyl) analog of epidepride ([18F]5-FPrEpid), a potent dopamine D2 receptor antagonist: constant left ventricular infusion, first-pass clearance, varying ligand specific activity, and displacing bound ligand with varying amounts of unlabelled ligand. Taken together, the information from these experiments rigorously tests the standard 3-compartment model. The obtained data and predictions from the model of the kinetic behavior of the ligand are inconsistent. The measured and model predicted dissociation rate (measured koff = 0.065 min-1, model prediction koff = 0.007 min-1) and the equilibrium dissociation constant (measured KD = 0.14 nM, model prediction KD = 2.2 nM) differ by an order of magnitude. Furthermore, the model cannot be used to accurately estimate the receptor density. We postulate that the synapse geometry and physical relationship between receptors are necessary components of a model that describes the pharmacokinetics of [18F]5-FPrEpid.

Animals↗

PubMed1993

Pseudocoarctation of the aorta presenting as a mediastinal mass with dysphagia.

Pseudocoarctation is an uncommon anomaly thought to be caused by congenital elongation and kinking of the aorta. We report a case of pseudocoarctation of the aorta presenting as a superior mediastinal mass causing dysphagia. Aortography and echocardiography revealed dilatation of the aorta and an aneurysm below the level of the pseudocoarctation. The patient underwent operative repair of the pseudocoarctation and associated aneurysm with good symptomatic relief. Review of the literature and experience with this case demonstrate that pseudocoarctation of the aorta cannot necessarily be regarded as a benign condition. Surgical treatment is recommended for all symptomatic patients and for those with associated aneurysm formation.

Aorta, Thoracic↗

PubMed1993

Noninvasive detection of acute rejection in a new experimental model of heart transplantation.

We have shown that positron emission scintigraphy detects changes in the uptake of 18-F 2-deoxyglucose and 13-N ammonia by the acutely rejecting myocardium in a nonworking model of heterotopic heart transplantation in the rat. We developed a new working model of heterotopic heart transplantation to determine the possible relevance of these changes to clinical transplantation. Moderate aortic valvular regurgitation was produced allowing the heterotopic left ventricle to fill and eject. Rejecting allografts and nonrejecting isografts (controls) were studied 4 days after transplantation. Histologically, isografts were normal and all allografts showed mild acute rejection. Decay-corrected uptakes of 18-F 2-deoxyglucose and 13-N ammonia reflect glucose metabolism and blood flow, respectively. Values are presented as percent of injected dose per gram of tissue. Uptake of 18-F 2-deoxyglucose was higher in rejecting allografts compared with nonrejecting isografts (3.0 +/- 1.8 versus 1.1 +/- 0.4; p = 0.024). Ammonia uptake was elevated in allografts compared with isografts (2.2 +/- 0.5 versus 1.3 +/- 0.5; p = 0.023). Uptakes of 18-F 2-deoxyglucose and 13-N ammonia are higher in mildly rejecting allografts, implying increased glucose utilization and blood flow during acute rejection. These data support our earlier findings of changes in myocardial metabolism in the absence of diminishing blood flow in acutely rejecting hearts. This model may lead to a better understanding of the physiology and metabolism of acute rejection.

Animals↗

PubMed1993

High affinity dopamine D2 receptor radioligands. 3. [123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain.

Studies of [123I]epidepride uptake in rhesus monkey brain were performed using single photon tomography. Striatal uptake peaked at 0.85% of administered dose/g at 107 min post-injection, then declined slowly to 0.70% of administered dose/g at 6 h. Striatal:posterior brain ratios rose from 2 at 25 min to 6.8 at 105 min, to 15 at 4 h and to 58 at 6.4 h. [123I]Epidepride was displaced by haloperidol (0.1 and 1 mg/kg) with a half-life of washout of 55 min. Little displacement of [123I]epidepride was observed following administration of 1 or 2 mg/kg d-amphetamine, respectively, indicating [123I]epidepride is not easily displaced by endogenous dopamine. In vitro equilibrium binding studies using rat striatum revealed a KD of 46 pM and Bmax of 33 pmol/g tissue at 37 degrees C, while at 25 degrees C the KD was 25 pM and the Bmax 32 pmol/g tissue. In vitro kinetic analysis of association and dissociation curves revealed a half-life for receptor dissociation at 37 degrees C of 15 min and 79-90 min at 25 degrees C. Allowing for the temperature difference, there is good correspondence between in vivo and in vitro dissociation kinetics at 25 degrees C. Increasing in vitro incubation temperature from 25 to 37 degrees C caused a 6-fold increase in the dissociation rate, suggesting that there is a change in binding kinetics at the dopamine D2 receptor at 37 degrees C compared to in vivo binding. The results of this study indicate that [123I]epidepride is an excellent radioligand for SPECT studies of the dopamine D2 receptor in man.

Amphetamine↗

PubMed1993

Selective vulnerability of white matter during spinal cord ischemia.

The long-term effects of spinal cord ischemia were studied in 21 rats by lesion scores (LS, n = 21), somatosensory evoked potentials (SEP, n = 16), electromyographic measurements (EMG, n = 12) and histology of the spinal cord (n = 21) 48.5 +/- 57.2 days after 10- to 12-min occlusion of the thoracic aorta and subclavian arteries. All the animals were initially paraplegic with a spastic presentation but seven recovered within 2 days (group A), demonstrating low LS (3.4 +/- 1.05) normal EMGs (n = 3) and unremarkable histology. The 14 paraplegic animals presented relevant findings of the lumbar cord consisting of white matter lesions only (group B, n = 7) or white and gray matter lesions (group C, n = 7). Group B animals showed severe deficit (LS = 11.8 +/- 2.93) without denervation on EMG (n = 5) or muscle atrophy on histology. Group C animals displayed equal impairment (LS = 14.4 +/- 0.71), denervation on EMG (n = 4), and muscle atrophy. Resting motor unit activity of groups B and C were significantly different from group A (p < 0.001), while LS of groups B and C did not differ (p = 0.083). These data underscore the nature and the extent of white matter lesions during spinal cord ischemia, a finding which has generally been eclipsed by emphasis on gray matter lesions in previous studies.

Animals↗

PubMed1993

Obstructive vs nonobstructive dilatation of the renal collecting system in children: distinction with duplex sonography.

OBJECTIVE: The resistive index in cortical or arcuate renal arteries of children was calculated to determine whether obstructive uropathy could be differentiated from nonobstructive dilatation. SUBJECTS AND METHODS: Kidneys (n = 176) were prospectively evaluated by using duplex Doppler sonography in patients 3 days to 20 years old. Obstruction was confirmed by renography with furosemide and/or by surgery. RESULTS: The normal resistive index was 0.57 +/- 0.06 and the normal difference in resistive indexes between kidneys was 0.03 +/- 0.02 (n = 15). Abnormal values indicative of ureteropelvic junction obstruction were defined as the normal mean +/- 2 SD (i.e., a resistive index of > or = 0.70 plus a difference in resistive indexes between kidneys of > or = 0.08). Patients with unilateral dilatation and obstruction at the ureteropelvic junction (n = 20) had a mean resistive index of 0.77 +/- 0.05 and a difference in resistive indexes between kidneys of 0.16 +/- 0.05 (p < .001 compared with patients with normal kidneys and p < .001 compared with patients with unilateral dilatation without obstruction). Patients with unilateral dilatation but without obstruction (n = 16) had a mean resistive index of 0.63 +/- 0.06 and a difference between kidneys of 0.06 +/- 0.04 (values within normal limits). The positive and negative predictive values of the obstruction criteria for unilateral collecting system dilatation were 95% and 100%, respectively. After successful surgical correction of ureteropelvic junction obstruction (n = 29), patients had a normal mean resistive index of 0.61 +/- 0.05 and a normal difference between kidneys of 0.03 +/- 0.03. Five patients examined both before and after surgery showed a statistically significant drop in the resistive index of the obstructed kidney (0.75 +/- 0.03 to 0.65 +/- 0.05, p < .05) after surgery and a small rise in the resistive index of the contralateral kidney (0.56 +/- 0.04 to 0.63 +/- 0.04, p < .02). CONCLUSION: The resistive index appears to be an effective parameter for the evaluation and follow-up of unilateral obstructive or nonobstructive ureteropelvic junction dilatation in children.

Adolescent↗

PubMed1993

Repair of atrial septal defect due to penetrating trauma.

We report a case of stab wound to the heart resulting in an atrial septal defect and perforation of the anterior leaflet of the mitral valve, which we repaired successfully 7 years after the injury. To our knowledge, repair of an atrial septal defect due to penetrating trauma has never before been reported. Investigation of possible valvular heart disease in a patient with a history of chest trauma should be aimed at identifying both intracardiac shunts and valvular abnormalities, so that a complete repair can be performed.

Echocardiography, Transesophageal↗

PubMed1993

Estimation of left ventricular mass and infarct size from nitrogen-13-ammonia PET images based on pathological examination of explanted human hearts.

The purpose of this study was to develop a technique to quantify left ventricular mass and infarct size in chronic ischemic heart disease from PET images based on correlation with pathological examination of explanted human hearts. Fourteen hearts from patients with cardiomyopathy who had 13N-ammonia scans prior to orthoptic heart transplantation were studied. Accurate estimation of the relative infarct size was possible in patients with a well-delineated, nearly transmural infarct (r = 0.93, y = 1.1x - 0.7, n = 11). Both absolute and relative infarct mass measurements on PET images correlated well with pathological measurements. We identified a population of patients with patchy interstitial or subendocardial scarring with globally reduced perfusion, for which the infarct size could not be estimated using the criteria derived for the patients with well-delineated infarcts.

Adult↗

PubMed1992

Visualization of extrastriatal dopamine D2 receptors in the human brain.

[123I]Epidepride, a potent and selective dopamine D2 radioligand, was administered to a 27 year old normal male volunteer. Single photon tomography revealed that peak striatal uptake occurred at 4 h after injection with a striatal:cerebellar ratio of 7.8 rising to over 100 at 18 h post injection. Uptake above the levels seen in cerebellum was also noted in the thalamus, pituitary, hypothalamus and temporal lobe, particularly medially. Single photon tomography with [123I]epidepride allows visualization of extrastriatal dopamine D2 receptors in man.

Adult↗

PubMed1992

Autoradiographic localization of dopamine D1 and D2 receptors in rat cerebral cortex following unilateral neurotoxic lesions.

Relative to dopaminergic innervation of cortex, dopamine D1 and D2 receptors may be located on presynaptic terminals and/or postsynaptically on cortical neurons. To assess the relative distribution of these sites, quantitative in vitro receptor autoradiography was performed following injection of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle (MFB; which lesions presynaptic DA terminals) and ibotenic acid into the prefrontal and anterior cingulate cortices (which lesions neurons whose cell bodies are intrinsic to cortex). Receptor autoradiography was performed ten days after injection of neurotoxins with [3H]SCH 23390 (a D1 probe) and [125I]epidepride (a D2 probe). Both DA receptor subtypes were found in all layers of anterior cingulate and prefrontal cortices but were concentrated in deeper layers V and VI. Ibotenic acid lesion of cortex reduced D1 and D2 receptors by 55-80%, although the concentrations of DA and its major metabolite dihydroxyphenylacetic acid (DOPAC) were unchanged. Lesion of MFB produced no significant change in D1 and D2 receptors, but was associated with a 49-52% decrease in DA and DOPAC levels relative to the contralateral side. These results suggest that the majority of D1 and D2 receptors in prefrontal and anterior cingulate cortices are located postsynaptically on neurons intrinsic to the cortex.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Noninvasive detection of heart transplant rejection with positron emission scintigraphy.

Positron emission tomography has recently been used to evaluate ischemic heart disease through changes in myocardial blood flow and carbohydrate metabolism. Positron-emitting tracers were evaluated for their ability to detect acute allograft rejection after heterotopic cardiac transplantation in the rat. Sham-operated controls, nonrejecting isografts, and rejecting allografts were evaluated. Decay-corrected uptake of 13NH3 and 18F 2-fluoro 2-deoxyglucose (FDG) reflects blood flow and glucose flux, respectively. Histologic examination of rejecting allografts documented mild rejection at 4 days and severe acute rejection by 8 days. All isografts were free from rejection. Uptake of FDG is greater in rejecting allografts than in nonrejecting isografts during both severe rejection (2.4% +/- 0.8% versus 0.7% +/- 0.4%; p less than 0.02) and mild rejection (2.1% +/- 0.6% versus 0.4% +/- 0.1%; p less than 0.02). Uptake of NH3 in severely rejected grafts is reduced compared with nonrejecting grafts (0.6% +/- 0.3% versus 1.7% +/- 1.1%; p less than 0.02). There is no difference in NH3 uptake during mild rejection (1.8% +/- 0.7% versus 1.3% +/- 0.3%; p greater than 0.05). Uptake of FDG and NH3 in native hearts of animals from all experimental groups is not significantly different from that in sham-operated controls. Glucose may be a preferred metabolic substrate during rejection. Our data support a humoral mechanism for substrate preference during transplant rejection and a potential diagnostic role for positron emission tomography.

Ammonia↗

PubMed1992

Pulmonary artery sling with severe tracheobronchial stenosis: repair in infancy by tracheal resection and pulmonary artery reimplantation.

Pulmonary artery sling is an unusual anomaly. The results of surgical therapy have been unsatisfactory in the past because of poor long-term left pulmonary artery patency and failure to address concomitant primary tracheobronchial stenoses. Refinement of suture materials and microsurgical techniques have allowed earlier surgical treatment of tracheal stenosis and have led to improved pulmonary artery patency rates. Intermediate results of primary one-stage repair with tracheal resection and left pulmonary artery reimplantation or translocation in early childhood have been promising. It remains to be seen whether late anastomotic tracheal stenosis will be a problem. This constitutes the first report of a case of one-stage repair with tracheal resection and left pulmonary artery reimplantation in an infant.

Anastomosis, Surgical↗

PubMed1992

Positron emission tomography imaging-directed stereotactic neurosurgery.

The diagnostic yield of stereotactic biopsies depends upon safely sampling the most representative regions of masses. Potentially, localization information presently available from CT and MR scans might be improved by considering regional levels of cerebral metabolism by PET. In 10 selected stereotactic biopsies of intracranial mass lesions, PET scans were obtained using the Siemens CTI system; the Kelly-Goerss Compass system was used as the stereotactic development platform. PET-[18F]-fluorodeoxyglucose (FDG) images provided clinically significant information by appropriately directing biopsy efforts when CT and MRI was inconclusive or misleading. PET-FDG images can be successfully incorporated into routine image-directed stereotactic surgery.

Astrocytoma↗

PubMed1991

High affinity dopamine D2 receptor radioligands. 2. [125I]epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors.

Epidepride, (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenzamide+ ++, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25 degrees C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2. Scatchard analysis of in vitro binding to striatal, medial frontal cortical, hippocampal and cerebellar membranes revealed a KD of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91-1.00 in all four regions. The IC50's for inhibition of [125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 microM to greater than 10 microM. Partial displacement of [125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to alpha 2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent KD of 9 nM. At an epidepride concentration equal to the KD for the D2 receptor, i.e. 25 pM, no striatal alpha 2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the alpha 2 site. Correlation of inhibition of [3H]spiperone and [125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site. In vitro autoradiography revealed high densities of receptor binding in layers V and VI of prefrontal and cingulate cortices as well as in striatum. In vivo rat brain uptake revealed a hippocampal:cerebellar and frontal cortical:cerebellar ratio of 2.2:1 which fell to 1.1:1 following haloperidol pretreatment. These properties suggest that [125I]epidepride is a superior radioligand for the in vitro and in vivo study of striatal and extrastriatal dopamine D2 receptors.

Animals↗

PubMed1991

High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides.

Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "Iodopride" (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, "iclopride" (KD 0.23 nM) and "itopride" (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

Animals↗

PubMed1990

Two-dimensional echocardiography and Doppler findings in cerebral arteriovenous malformations.

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Echocardiography↗

PubMed1990

Cooperative T1 and T2 effects on contrast using a new driven inversion spin-echo (DISE) MRI pulse sequence.

A pulse sequence is presented for obtaining a single image with combined T1/T2 weighting. T2 relaxation is made to increase intensity, in cooperation with the effect of T1 relaxation, by providing T2 weighting with a 90 degrees-180 degrees-90 degrees driven inversion pulse triplet in an inversion recovery method. Unlike the inversion spin-echo method having a short inversion time (TI), signals in the new driven inversion spin-echo (DISE) method need not be negative and the most T1-sensitive region of the recovery curve can be used. Selecting sensitivity to one relaxation time does not degrade the sensitivity to the other relaxation time. T1 sensitivity is thus extended to longer echo times (TE intervals). T2 sensitivity is extended to longer TI intervals, and the combined T1/T2-weighted technique with intermediate TE and TI has highly cooperative and near-maximal T1 and T2 effects on contrast. Intensity is not multiplicatively degraded by T1 and T2 weighting so that the signal-to-noise of the combined T1/T2-weighted method is high. High intensity and T1 and T2 cooperatively occur for a much wider range of relaxation times, and especially for images heavily weighted to the pathologic intermediate and long T1 and T2 regime.

Brain↗