Biomedical subjects

J S Fleming

Publications and source records attributed to J S Fleming.

At least 55 records · Page 3Linked to original sources

PubMed1996

Standardization of a technique for BrIDA cholescintigraphy.

Calculation of ejection fraction by cholescintigraphy is a well-established technique to quantify motor function of the gallbladder. All previous cholescintigraphic studies of gallbladder emptying have exclusively used the anterior projection for gallbladder visualization. This may lead to inaccuracies because attenuation of gamma rays may vary depending on the state of gallbladder filling and body habitus. The use of geometric means may prevent these errors. In this study, 7 health volunteers were examined after the administration of 150 MBq 99Tcm-bromotrimethyl-IDA (99Tcm-BrIDA) without any stimulus and 9 volunteers ingested a maxied, fatty meal 35-40 min after BrIDA injection. Imaging was done using a dualheaded camera in a dynamic study of 140 one-minute frames. A plateau of activity was reached between 70 and 90 min post-injection of BrIDA and between 55-60% of maximal counts were achieved in the gallbladder region of interest (ROI) between 35 and 40 min. Significant emptying was seen in all nine subjects after the meal. No significant difference in ejection fraction was seen between the anterior projection and the geometric mean of the data from the anterier and posterior projections. The slope of the gallbladder filling curve from the anterior camera data was different from that obtained from the geometric mean, but the correlation coefficient was not significantly different. In conclusion, adequate counts are achieved in the gallbladder ROI 35-40 min after BrIDA injection, when the stimulus can be administered to study gallbladder emptying. There is no advantage to imaging in the anterior and posterior projections and data obtained from the anterior projection alone are adequate for gallbladder emptying studies.

Adult↗

PubMed1996

Iodine-131-metaiodobenzylguanidine dosimetry in cancer therapy: risk versus benefit.

UNLABELLED: In the treatment of neural crest tumors, such as pheochromocytoma, with[131I]MIBG, bone marrow toxicity limits the amount of administered activity and, thus, a therapeutically useful tumor dose. METHODS: We calculated tumor doses in a series of diagnostic studies with [123I]MIBG using accurate quantification of SPECT and planar scintigraphy. By extrapolating diagnostic results to therapeutic activities of [131I]MIBG, we could compare the results with whole-body doses from a series of therapies. RESULTS: The tumor dose was DT = 2.2 mGy MBq(-1) (median value of 27 measurements, range 0.04 < or = DT < or = 20 mGy MBq(-1) and the whole-body dose in a series of 16 patients undergoing 50 therapies was DWB = 0.12 +/- 0.04 mGy MBq(-1) (mean +/- s.d.). The therapeutic ratio varied between 130 to below 10 in some patients. CONCLUSION: The results were compared with published data. We found clearly skewed distribution of tumor doses, with a majority of tumors receiving only a few mGy per MBq administered activity. In some patients, however, doses did reach 20 mGy MBq(-1).

3-Iodobenzylguanidine↗

PubMed1996

Influence of collimator characteristics on quantification in SPECT.

UNLABELLED: Accurate, absolute quantification of activity in SPECT depends on the counting sensitivity of the gamma camera collimator system and on the contribution of the tail of the point spread function (PSF) that contains both scattered radiation and septal penetration. METHODS: These factors were studied for the radionuclides 99mTc, 131I and 123I on different cameras and collimators. The ability of the geometric mean line source scatter function subtraction technique to correct for the effect of the tail of the PSF was investigated in a computer simulation study with 99mTc and a physical phantom study with 123I. RESULTS: The sensitivities of 99mTc collimators were relatively constant with distance in air whereas those of 123I and 131I decreased considerably. For these radionuclides the contribution of the PSF tail was also increased as compared to 99mTc. The geometric mean line source scatter function subtraction technique was confirmed as being able to correct effectively for this factor. CONCLUSION: Collimator design affects both the fall off of sensitivity in air and the tail of the PSF. Attention to correction of these factors enables accurate quantification.

Gamma Cameras↗

PubMed1996

Three-dimensional description of pulmonary deposition of inhaled aerosol using data from multimodality imaging.

UNLABELLED: Three-dimensional assessment of pulmonary deposition of inhaled aerosol may be performed using SPECT. The use of aligned anatomical images enables improved accuracy of quantification and anatomical localization of deposition. METHODS: Techniques of analyzing these data and their application to deposition studies of two nebulizer-generated aerosols (mass median diameter 1.5 and 6.5 microM respectively) in 12 normal subjects are described. The deposition data were transformed to a standard hemispherical shape and the mean distribution pattern for each aerosol evaluated. Deposition by airway generation was then calculated using a spatial model of airway morphology. The results were compared to those from planar image analysis. RESULTS: The hemispherical transform yielded considerably more qualitative information on deposition pattern. The central-to-peripheral concentration ratio between conducting and alveolated airways was 5.27 for the coarser aerosol and 2.43 for the fine. The two-dimensional spatial estimates of the ratio were 2.61 and 2.03 respectively. CONCLUSION: Analysis of multimodality imaging data considerably enhanced information on deposition compared to planar imaging. It provides new data on aerosol deposition which will be of value to physicians involved in drug inhalation therapy.

Aerosols↗

PubMed1995

Tissue-specific variation in the length of the 5' untranslated region of the beta A-inhibin mRNA in sheep.

The 5' untranslated region (UTR) of beta A inhibin mRNA was compared in a variety of sheep tissues, using primer extension. Considerable variation in the length and number of 5' extended products were noted between tissues. Specific bands were noted in ovarian follicular RNA, which were also present in samples from corpora lutea, stroma, and placental cotyledon RNA. Other extended products were observed in RNA from corpora lutea, stroma, cotyledon, pituitary, bone marrow, frontal cortex, medial basal hypothalamus, adrenal, liver, and kidney, which were not present or weakly represented in follicular RNA. Additional tissue-specific bands were noted in testis and bone marrow RNA. No specific differences in the lengths of the 5' UTR of the beta A inhibin mRNA were observed in sheep homozygous for the Booroola fecundity gene FecB, in any tissue studied. The coding region of ovine beta A inhibin cDNA was sequenced and a genetic polymorphism confirmed within or close to the ovine beta A inhibin gene. We conclude that the beta A inhibin gene is expressed widely in the sheep. Furthermore there is variation in the length of the 5' UTR of beta A inhibin mRNA between male and female gonads and other tissues, implying that expression of this gene is differentially controlled. However, the FecB mutation does not affect mRNA splicing events or the initiation site used in ovarian transcription. The mechanism by which the FecB mutation influences the amounts of beta A inhibin mRNA, follicle-stimulating hormone (FSH) secretion and ovulation rate has still to be elucidated.

Animals↗

PubMed1995

Computer simulations of human lung structures for medical applications.

Knowledge of the structure of the human lung has salient health effects applications. The clinical issues encompass: (1) aerosol therapy, the targeted delivery of inhaled particles to enhance the efficacies of pharmacologic drugs; and (2) nuclear medicine, where planar gamma camera imaging, Single Photon Emission Computer Tomography (SPECT) and Positron Emission Tomography (PET) assess the distribution patterns of radiolabeled diagnostic particles and gases. If the resolution of such images could be enhanced, medical regimens would greatly benefit. Therefore, the focused objective of our work was to develop 3-D mathematical descriptions of the complex airway networks within the lung. A Silicon Graphics workstation was used to depict the daedal structures. The computer-generated color illustrations presented herein are intended to complement medical investigation. They will assist the clinician by serving as templates for the lung and, thereby, providing a real basis for the analysis of relatively abstract images. The illustrations identify individual airways and could be of great importance to physicians in the treatment of airway diseases occurring at well defined locations (e.g. bronchogenic carcinomas). To demonstrate that computers can be actively integrated into medical research and practice we have addressed SPECT images of a subject. Computer templates will aid future clinical investigators in two major ways: (1) the interpretation of a planar gamma camera, SPECT and PET images; and (2) the design of drug testing protocols using inhalation exposures. Considering their usefulness for demonstration, the lung simulations have the potential of playing a substantive role in education.

Administration, Inhalation↗

PubMed1995

Computer model of human lung morphology to complement SPECT analyses.

Aerosol therapy protocols could be improved if inhaled pharmacologic drugs were selectively deposited within the human lung. The targeted delivery to specific sites, such as receptors and sensitive airway cells, would enhance the efficacies of airborne pharmaceuticals. The high spatial discrimination of deposition patterns of inhaled particles can be determined via Single Photon Emission Computer Tomography (SPECT). However, major problems continue to compromise SPECT protocols. Our work focuses on two issues: how can the spatial discrimination be improved; and how are the images to be interpreted? We present a methodology, described by a mathematical model and supercomputer code, for systematically slicing through the human lung in a prescribed manner that is conducive to implementation into SPECT analyses. The lung is divided into concentric shells, or annuli, and the airway generation-by-generation composition of the respective shells determined. This identification was accomplished by superimposing the new shell structure with the 3-D branching network presented by Martonen et al. [23]. Perhaps the key aspect of the model-code is that the supercomputer is instructed to determine the 3-D spatial coordinates of each of the airways (over 16 million) of the lung with respect to the clinician-selected contours of shells within the lung.

Administration, Inhalation↗

PubMed1995

Deconvolution of planar scintigrams by maximum entropy.

Planar scintigrams are deconvolved with a point spread function using the maximum entropy method with the aim of improving image quality. The technique requires the specification of several parameters. These are related to the level of noise present in the data and our a priori knowledge of the object imaged. The performance of the technique is tested for a wide range of these parameters using images of a Williams phantom in scattering material and a figure of merit, derived from the detectability of the smallest cold spot, is calculated. For close to optimal values of the parameters a factor of two improvement in the figure is found. A processed bone image shows improved contrast and resolution. Maximum entropy processing could be used to increase image quality or allow comparable image quality with reduced imaging time or patient dose.

Bone and Bones↗

PubMed1995

The haemodynamic effects of the thromboxane A2 receptor antagonist GR32191B during cardiopulmonary bypass in the dog.

This study examined whether treatment with the specific thromboxane (TX) A2 receptor antagonist GR32191B would result in an improvement in peripheral haemodynamics during and after cardiopulmonary bypass (CPB) in anaesthetized dogs compared with animals given either saline (control) or aspirin. Following thoracotomy, heparinization and aortic cannulation, and 35 minutes before CPB, dogs received intravenously either GR32191B (15 micrograms/kg/min), saline (50 ml bolus) or aspirin (225 mg bolus) (n = 6 per group). Cardiac output (dye dilution), femoral artery blood flow (electromagnetic flowmeter), gastrocnemius muscle tissue perfusion (133Xe clearance), retinal blood flow (fluorescein angiography), and thromboxane biosynthesis (urinary excretion rates of TXB2 and the metabolite 2,3-dinor-TXB2) were measured before, during and after a standard 90 minute period of CPB at 2.4 l/min/m2 and 28 degrees C. The aspirin-treated group manifested an eightfold reduction in TXB2 excretion compared with controls, indicating a decrease in TXA2 biosynthesis. There were few haemodynamic differences between the groups, though the aspirin-treated group had better maintained muscle tissue perfusion post-CPB and significantly fewer retinal microcirculatory occlusions than GR32191B-treated animals. We conclude that specific TXA2 receptor antagonism provides no significant improvement in peripheral haemodynamics; rather aspirin provides a modest haemodynamic benefit.

Animals↗

PubMed1995

Expression of gonadotrophin subunit genes in sheep that were homozygous carriers and non-carriers of the Booroola fecundity gene FecB.

Homozygous carriers (BB) of the Booroola fecundity gene FecB are characterized by high plasma concentrations of immunoreactive or biologically active FSH and, to a lesser extent, of immunoreactive LH, relative to non-carriers (++). Bovine cDNA probes for the alpha gonadotrophin, FSH beta and LH beta genes were used to investigate FecB-specific differences in the mRNA species for the gonadotrophin subunits in pituitaries obtained from ++ and BB mid-luteal phase ovary-intact ewes, ovariectomized ewes and ovary-intact or ovariectomized ewes with hypothalamic-pituitary disconnection (HPD) given the same regimen of pulsatile GnRH. No FecB-specific differences in the number or size of mRNA transcripts detected by northern blotting were noted for any of these genes. Densitometry of the northern blots revealed no significant FecB-specific differences in the relative amounts of mRNA encoding alpha gonadotrophin, FSH beta or LH beta in the pituitaries from any of the experimental groups of ++ and BB sheep. Furthermore, there were no significant FecB-specific differences in the pituitary content of FSH or LH in these animals, despite significantly higher plasma concentrations of FSH in the ovary-intact and ovariectomized HPD groups. These data show that whereas the FecB gene causes increased plasma concentrations of FSH, no consistent effects can be demonstrated on pituitary gonadotrophin content or on gonadotrophin subunit gene transcription, using northern analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

2-[3-[2-(4,5-Diphenyl-2-oxazolyl) ethyl] phenoxy] acetic acid (BMY 42393): a new, structurally-novel prostacyclin partial agonist: 1). Inhibition of platelet aggregation and mechanism of action.

BMY 42393, (2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid), is a new prostacyclin partial agonist that inhibited ADP, collagen and thrombin-induced platelet aggregation (IC50 range 0.3 - 2.0 microM). BMY 42393 stimulated platelet adenylate cyclase activity (EC50 = 25 nM), however, the maximal activation was 75-80% of that observed with maximal iloprost or PGE1. Platelets treated with BMY 42393 showed an elevation of cAMP levels and activation of cAMP-dependent protein kinase. BMY 42393 also inhibited thrombin-induced elevation of intracellular free calcium. BMY 42393 competed for radiolabeled iloprost and PGE1 binding to platelet membranes (IC50; 170 nM and 130 nM, respectively); however, it had little effect on radiolabeled PGE2, PGD2, or SQ 29548 binding. These studies indicate that BMY 42393 is a novel platelet aggregation inhibitor which acts by stimulation of platelet prostacyclin receptors to elevate platelet cAMP levels.

Adenylyl Cyclases↗

PubMed1994

2-[3-[2-(4,5-diphenyl-2-oxazolyl) ethyl] phenoxy] acetic acid (BMY 42393): 2). Oral activity and efficacy in animal models of arterial thrombosis.

The oral activity and antithrombotic efficacy of BMY 42393 was examined in ex vivo platelet aggregation studies and arterial thrombosis animal models. In a heterologous ex vivo platelet aggregation assay, ADP-induced human platelet aggregation was inhibited when washed human platelets were combined with rat platelet-poor plasma, taken from rats previously orally-dosed with BMY 42393. The IC50 for platelet aggregation inhibition was approximately 10 mg/kg. In a laser-induced thrombosis model, thrombus formation in a revascularized rabbit ear chamber was prevented in a dose-dependent fashion with an ED50 of about 2 mg/kg. A relatively long duration of anti-thrombotic activity was observed in the rabbit ear laser-induced thrombus study and the ex vivo platelet studies. Inhibition of thrombus formation was also demonstrated in a canine model of electrically-induced coronary artery thrombosis. BMY 42393 also prevented cyclic flow reductions in a monkey stenotic renal artery model. These studies indicate that BMY 42393 is orally active and capable of preventing laser and electric current-induced thrombus formation in animal models of arterial thrombosis.

Administration, Oral↗

PubMed1994

Mapping the human lung using Delaunay tessellation.

A computer protocol is (1) developed and (2) applied to the human body for medical research. Delaunay tessellation is used to derive an algorithm to describe the structure of the lung. This may be the first application of that mathematical concept to a physiological system. The lung is a complex yet systematic network of pathways described herein with cited dimensions and angles. Its terminal points are the most distal airways, alveolar sacs, defined by their (x, y, z) coordinates. We have addressed that spatial array as a set of points in 3-D space, and, visualized the physical boundary of a lung as the surface of the convex hull of that set in R3. As documented, the enveloping surface of the computer lung closely describes the outer contours of human lungs depicted in clinical studies. Therefore, the model has immediate and salient implications to problems in medicine where respiratory function and morphology have integral roles, specifically, thoracic surgery and aerosol therapy. Examples include the removal of lobes damaged by respiratory diseases such as cystic fibrosis and cancer, and the definition of lung boundaries for gamma camera, PET, and SPECT images. Importantly, the model can be varied to simulate the intersubject differences that physicians experience among a patient population. The mathematical simulations performed in this work are intended to be complementary to laboratory investigations in the medical arena. By providing accurate 3-D, quantitative descriptions of human lungs the supercomputer can be actively integrated into the clinical environment.

Algorithms↗

PubMed1994

A technique for simulation of the point spread function of a gamma camera.

A technique for simulating the point spread function (PSF) of gamma-camera images which treats primary photons and detected scattered photons separately is described. The primary photon PSF was measured at different distances in air from the camera. The scatter PSF was also assessed with different thicknesses of water between the point and the camera, and fitted to a circularly symmetric bi-exponential function. An analysis of the variation of detected scattered radiation based on the results is presented. Simulation of the PSF at a given distance from the camera and thickness of attenuating medium was then possible from the sum of the appropriate primary photon PSF corrected for attenuation and the appropriate scatter PSF. The accuracy of the technique has been studied with variation in depth, density and uniformity of thickness of the attenuating medium.

Algorithms↗

PubMed1994

Evaluation of the factors affecting the accuracy and precision of a technique for quantification of volume and activity in SPECT.

The use of the technique of maximization of interclass variance to determine the threshold level defining the volume of an object in single photon emission computed tomography (SPECT) and hence its activity has been evaluated in a variety of conditions. The influence of varying activity on volume assessment and varying volume on activity assessment were shown to be negligible. The effect of object shape for the range of shapes likely to be found in the body was also small. Non-uniformity of activity in the object caused an underestimation of volume and to a lesser extent its activity. However, with activity varying by 100% within the volume, volume was only underestimated by 10% and activity by 3%. The presence of activity surrounding the object caused an overestimation of volume which increased linearly with the relative level of surrounding activity. The object to surrounding activity concentration ratio could be estimated and therefore its effect corrected. The influence of nearby objects and methods of dealing with their effect on the technique are described. Activity concentrations in objects with uniform distribution assessed using total activity divided by total volume were shown to be more accurate than assessments from maximum voxel count rate for objects with a volume below 150 ml.

Humans↗

PubMed1994

A new method of quantification of the pulmonary regional distribution of aerosols using combined CT and SPECT and its application to nedocromil sodium administered by metered dose inhaler.

Aerosols of nedocromil sodium labelled with 99Tcm were delivered on 20 separate occasions to healthy male volunteers. Planar and single photon emission computerized tomography (SPECT) gamma scintigraphy were immediately performed to assess the pulmonary regional distribution of delivered aerosol. On a separate occasion volunteers were imaged using X-ray computed tomography (CT). Alignment of SPECT and CT images was performed using marked anatomical features and the anterior and lateral skin outlines. CT images provided data for attenuation correction and were used to define the anatomical lung volume. Central to peripheral (CP) ratios of deposited activity were calculated from volumes of interest in coronal and transverse sections of the right lung. These were compared with CP ratios obtained from planar images obtained immediately following aerosol inhalation. Volumetric CP ratio correlated significantly with immediate planar CP ratio (p < 0.001). Analysis of deposition in the whole right lung was performed by separating the SPECT lung data into a series of thin concentric shells centred on the entry of the right main bronchus. Measures were defined for describing the variation of deposition density and cumulative total deposition with distance from the lung centre. These showed significant correlation with planar CP ratio (p < 0.001). SPECT analysis using CT is consistent with planar measures of aerosol deposition but offers a more complete quantification of aerosol penetration and absolute deposited activity within the whole lung. It is a valuable new tool for aerosol analysis.

Administration, Inhalation↗

PubMed1994

Non-prostanoid prostacyclin mimetics. 6. Derivatives of 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid modified beta-to the oxazole ring.

2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid, 1, has been described as a non-prostanoid PGI2 mimetic that demonstrates anti-thrombotic properties of long duration in animal models of thrombosis. The effects of substitution and modification of the carbon beta-to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP-induced human platelet aggregation in vitro. Potency was sensitive to both the size of the substituent and the identity of the beta-atom. The carbamates 13c-e demonstrated IC50's of 0.28-0.36 microM and were significantly more potent than the progenitor 1, IC50 = 1.2 microM. The ethyl carbamate 13c displaced [3H]-iloprost from platelet membranes in a concentration-dependent fashion that was half maximal at 20 nM, which compares with IC50's of 171 nM for 1 and 39 nM or unlabelled iloprost. Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for PGI2, identifying 13c as a partial agonist at the platelet PGI2 receptor.

Cell Membrane↗

PubMed1993

Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid substituted alpha to the oxazole ring.

The 4,5-diphenyloxazole derivatives 2-4 were previously identified as nonprostanoid prostacyclin (PGI2) mimetics. A series of derivatives of 2-4 bearing substitutents at the carbon atom alpha to the oxazole ring were synthesized and evaluated as inhibitors of ADP-induced aggregation of human platelets in vitro. In the unsaturated series, the alpha-carbethoxy derivative 10a, evaluated as an equal mixture of geometrical isomers, inhibited platelet aggregation with an IC50 of 0.36 microM. Evaluation of the individual methyl ester derivatives (E)-9a and (Z)-9a revealed that (E)-9a was 10-fold more potent than (Z)-9a. In the saturated series, the alpha-carbomethoxy-substituted compound 12a inhibited platelet aggregation with an IC50 of 0.08 microM, 15-fold more potent than the unsubstituted prototype 2. The potency of 12a was found to be sensitive to variation of the methoxy moiety. The ethyl (12b) and isopropyl (12d) esters were less effective as were the acid 12e and a series of amides (12f-h). Other substituents introduced at this site of the pharmacophore included P(O)(OEt)2 (25), SCH3 (31a), S(O)CH3 (31b), SO2CH3 (31c), isopropyl (31d), phenyl (31f), and CH2OH (31i). However, none were significantly more potent inhibitors of platelet function than the parent compound 2. The results indicate the presence of a pocket in the PGI2 receptor protein that preferentially recognizes small, polar but uncharged substituents. The structure-activity correlates are suggestive of a hydrogen-bond interaction between a donor moiety on the PGI2 receptor and the methoxycarbonyl functionality of 12a that is sensitive to both the size of the substituent and its stereochemical presentation in this structural class of PGI2 mimetic. The ethyl ester 12b dose-dependently displaced [3H]iloprost from human platelet membranes and stimulated adenylate cyclase. However, the maximal stimulation was less than that recorded for iloprost, indicating that 12b functions as a partial agonist at the PGI2 receptor.

Adenosine Diphosphate↗