Biomedical subjects

J S Fleming

Publications and source records attributed to J S Fleming.

At least 73 records · Page 4Linked to original sources

PubMed1993

Normal right ventricular systolic and diastolic function assessed by krypton-81m equilibrium ventriculography.

Krypton-81m equilibrium ventriculography was used to study right ventricular function in 23 healthy male volunteers. Technetium-99m lung perfusion scintigraphy was employed to subtract radionuclide activity within lung during image analysis thereby enhancing image quality. The imaging technique was used to generate a time-activity curve for the right ventricle allowing the definition of indices of normal systolic and diastolic function for the right ventricle. At rest, indices of systolic ejection and diastolic filling were comparable to those previously reported for the left ventricle. Using the imaging technique, movement artifact during exercise reduces image quality and limits accurate measurement of these indices to resting studies.

Adult↗

PubMed1993

Right ventricular function at rest and during submaximal exercise assessed by 81Krm equilibrium ventriculography in normal subjects.

81Krm equilibrium ventriculography was used to study right ventricular function in 37 healthy male volunteers. 'Anatomical' lung subtraction using 99Tcm lung perfusion scintigraphy was compared with conventional background correction in the calculation of resting right ventricular ejection fraction (RVEF). Resting RVEF was significantly greater following 'anatomical' lung subtraction than that using background correction (0.59 +/- 0.06 versus 0.55 +/- 0.05). The exercise response of the normal right ventricle was defined in 23 subjects during exercise. Right ventricular ejection fraction showed a progressive increase during graded submaximal exercise (0.55 +/- 0.05 at rest, 0.60 +/- 0.05 at 50 W and 0.66 +/- 0.05 at 100 W). Right heart 81Krm equilibrium ventriculography is well suited to the evaluation of right ventricular function at rest and during exercise. The absolute value of RVEF will however be dependent upon the method of image analysis.

Adult↗

PubMed1993

A technique for the absolute quantification of 131I radiopharmaceuticals using SPECT.

A technique is described for the quantification of the three-dimensional distribution of 131I radiopharmaceuticals using single photon emission computed tomography (SPECT). A theoretical discussion of the problems of scatter and septal penetration in 131I SPECT is presented. The correction of these effects using the geometric mean line source scatter subtraction technique and a distance varying counting sensitivity, is described. The volume and activity of objects in the SPECT dataset were assessed by segmentation using the technique of maximization of interclass variance. The technique has been examined in phantom experiments showing that volumes and activities of objects containing a uniform concentration of activity can be assessed to a precision of 7.3% (1 S.D.) and 0.32 MBq (1 S.D.) respectively. The technique has been successfully applied to patient studies using both 131I-metaiodobenzyl guanidine (MIBG) and lipiodol.

Humans↗

PubMed1993

Evaluation of a technique for the quantification of radioactivity and volume of an object using SPECT.

The technique of threshold determination using maximization of interclass variance (MIV) has been evaluated for the assessment of radioactivity and volume in single photon emission computed tomography (SPECT). The SPECT reconstruction incorporated scatter and attenuation correction using an attenuation map from computed tomographic (CT) images. The technique has been examined on a large number of phantom objects with both 99Tcm and 131I. Volume measurement of objects was performed using a variety of methods of applying the MIV technique. The standard error of volume estimation for the optimum method was 7.3 ml for 99Tcm and 15.3 ml for 131I. Activity was measured by expansion of the volume of interest representing the space occupied by the object to make allowance for limited SPECT resolution. The standard errors of the activity measurements were 0.22 MBq for 99Tcm and 0.24 MBq for 131I.

Evaluation Studies as Topic↗

PubMed1993

Right ventricular function at rest and during exercise in chronic obstructive pulmonary disease. Comparison of two radionuclide techniques.

Right ventricular function was assessed in 24 patients with COPD, at rest and during submaximal exercise, using both technetium-99m (99mTc) blood-pool and krypton-81m (81mKr) equilibrium ventriculography. Technetium-99m right ventricular ejection fraction (RVEF) at rest was lower than 81mKr RVEF (0.39 +/- 0.12 and 0.54 +/- 0.08, respectively; p < 0.001). During submaximal exercise, there was no increase in RVEF using either imaging technique. This observation contrasted with an increase in RVEF in a group of age-comparable normal subjects during modest submaximal exercise. An inability to obtain spatial separation of right heart structures using 99mTc imaging leads to a value for RVEF that is consistently lower than that measured using 81mKr ventriculography. Resting RVEF is well preserved at rest in most patients with COPD. In contrast to normal subjects, many show an inability to augment right ventricular function during exercise that may contribute to the reduced exercise capacity observed in these patients.

Aged↗

PubMed1992

Nonprostanoid prostacyclin mimetics. 2. 4,5-Diphenyloxazole derivatives.

4,5-Diphenyl-2-oxazolenonanoic acid (18b) was synthesized and found to inhibit ADP-induced aggregation of human platelets with an IC50 of 2.5 microM. Acid 18b displaced [3H]iloprost from human platelet membranes in a concentration-dependent fashion, consistent with 18b inhibiting platelet function by acting as a prostacyclin mimetic. By inserting a phenoxy ring into the side-chain moiety of 18b and systematically varying the pattern of substitution and length of the tethers, more potent inhibitors of platelet aggregation were identified. A phenoxy ring inserted centrally in the side chain proved to be the optimal arrangement but significant activity was observed when the aromatic ring was bound directly to the 2 position of the heterocycle. The meta-substituted cis-(ethenylphenoxy)acetic acid 37 is the most potent platelet aggregation inhibitor synthesized as part of this study with an IC50 of 0.18 microM. Acid 37 displaces [3H]iloprost from human platelet membranes with an IC50 of 6 nM. The trans-olefinic isomer of 37 (25p) is 72-fold weaker as an inhibitor of ADP-induced platelet aggregation, but the saturated derivative 25w (BMY 42393) is intermediate in potency. Structure-activity studies using 25w as a template focused on modification of the tethers intervening between the side-chain phenyl ring and the oxazole and carboxylate termini and substitution of the phenyl ring. These studies revealed that biological activity was sensitive to both the identity of the concatenating atoms and the pattern of ring substitution. The structure-activity relationships provide insight into the topographical relationship between the diphenylated oxazole ring and the carboxylic acid terminus that comprise the nonprostanoid prostacyclin mimetic pharmacophore.

Adenosine Diphosphate↗

PubMed1992

Nonprostanoid prostacyclin mimetics. 3. Structural variations of the diphenyl heterocycle moiety.

4,5-Diphenyl-2-oxazolenonanoic acid (2) and 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (3) were previously identified as nonprostanoid prostacyclin (PGI2) mimetics that inhibit ADP-induced aggregation of human platelets in vitro. The effects on biological activity of substitution and structural modification of the 4- and 5-phenyl rings of 3 was examined. Potency showed a marked sensitivity to the introduction of substituents to these aromatic rings and only the bis-4-methyl derivative 9j, IC50 = 0.34 microM, demonstrated enhanced potency compared to the parent structure 3, IC50 = 1.2 microM. Substitution at the ortho or meta positions of the phenyl rings, replacement by thiopheneyl or cyclohexyl moieties, or constraining in a planar phenanthrene system resulted in compounds that were less effective inhibitors of ADP-induced platelet aggregation. In contrast, variation of the heterocycle moiety revealed a much less stringent SAR and many 5- and 6-membered heterocycles were found to effectively substitute for the oxazole ring of 2 and 3. The diphenylmethyl moiety functioned as an effective isostere for 4,5-diphenylated heterocycles since 13aad showed similar platelet inhibitory activity to 3. With the exception of the 3,4,5-triphenylpyrazole derivative 13g, compounds presenting the (m-ethylphenoxy)acetic acid side chain discovered with 3 demonstrated enhanced potency compared to the analogously substituted alkanoic acid derivative. The structure-activity findings led to a refinement of a model of the nonprostanoid PGI2 mimetic pharmacophore.

Adenosine Diphosphate↗

PubMed1992

Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid, a nonprostanoid prostacyclin mimetic.

A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d), with an IC50 of 0.4 microM, was the most potent inhibitor identified in this study. Biochemical studies determined that 8d increased intraplatelet cAMP accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion. Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin (PGI2) receptor is the locus of biological action. Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet PGI2 receptor and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long. Potency depended upon both side-chain length and its topological relationship with the two phenyl rings.

Adenylyl Cyclases↗

PubMed1992

Estimation of organ input function and plasma clearance from the cardiac curve in dynamic scintigraphy.

A theoretical description of the relationship between the count rate detected in the cardiac region of interest and the arterial organ input function in dynamic scintigraphy is presented. It is shown that, provided the time-activity curve for the heart is corrected for extra-cardiac and unlabelled activity, it is proportional to the arterial organ input over both the first-pass and equilibrium phases of the passage of an intravenously injected radiopharmaceutical. A practical example demonstrating the value and validity of correcting the cardiac curve in dynamic radio colloid scintigraphy is described. Estimates of the colloid clearance rate to reticuloendothelial sites using the cardiac curve without correction were significantly lower (mean 0.085/min) than those derived from the liver uptake curve (mean 0.213/min). However, corrected cardiac curve clearance rates (mean 0.225/min) were not significantly different from the liver ones. Also, the corrected cardiac curve clearance values correlated linearly with liver curve values (correlation coefficient 0.89, standard error of the estimate 0.021/min), whereas the uncorrected values showed no significant correlation. Thus, correction of the cardiac curve gave clearance rate values that were both more accurate and more precise than those obtained without correction.

Heart↗

PubMed1992

The influence of levodopa on gastric emptying in healthy elderly volunteers.

Paracetamol absorption and 99Tc-DTPA measurements have been used to determine the influence of levodopa on gastric emptying in 8 healthy elderly volunteers. In the absence of levodopa 7 subjects showed a rapid gastric emptying pattern by gamma-camera and a single major peak in the plasma concentration-time curve of paracetamol. One subject showed two rapid phases of gastric emptying separated by a period of negligible emptying and had 2 separate peaks in the paracetamol plasma concentration-time curve. In the presence of levodopa, the gamma-camera data for 6 subjects showed a pattern of gastric emptying consisting of 2 rapid phases separated by a plateau. In each case secondary peaks in the plasma concentration-time curve of paracetamol occurred about 30 min after the end of the plateau. The time to 90% emptying on the gamma scan was increased significantly from 40 min to 65 min in the presence of levodopa. Comparison of the present data with those reported previously indicates that levodopa affects gastric emptying in the both elderly and young volunteers to a similar extent.

Acetaminophen↗

PubMed1992

Humidification as an adjunct to chest physiotherapy in aiding tracheo-bronchial clearance in patients with bronchiectasis.

Humidification of inspired air or oxygen is frequently utilized by respiratory physiotherapists to relieve sputum retention. Cold water, jet nebulizing humidifiers are in widespread use but there has been no previous attempt to investigate the efficacy of this treatment. We have performed a single-blind, cross-over study to quantify the effect of humidification as an adjunct to chest physiotherapy. Seven patients with bronchiectasis completed the trial, with a mean (range) age of 51 years (41-64 years) and mean (range) percent of predicted FEV1 of 46% (29-76%). On 2 days, separated by 1 week, subjects were randomly allocated to humidification or no humidification as a precursor to an optimal chest physiotherapy regimen. A radio-aerosol of human serum albumin millimicrospheres labelled with 99mTechnetium was used to measure sputum clearance by serial gamma camera images. Serial measurements of sputum weight and FEV1 were also recorded. Humidification (30 min) was followed by postural drainage (20 min) with the subject using the forced expiration technique to assist clearance. When humidification was combined with physiotherapy there was a significant increase in total wet weight of sputum (P less than 0.05) with a median (range) increase of 6 g (-9-15.5 g); and a significant increase in total radiolabel clearance (P less than 0.05) with a median (range) increase of 8.7% (1-13%), compared to physiotherapy alone. This study demonstrates that the use of cold water, jet nebulizing humidifiers significantly increases tracheo-bronchial clearance above that of an optimal physiotherapy regimen alone in bronchiectasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Dosimetry assessment of 81Krm peripheral venous infusion studies.

Calculation of S factors for 81Krm for a full range of target organs from each source organ relevant in 81Krm peripheral venous infusion imaging has been performed. Typical equilibrium activities in the source organs have been measured using quantitative planar gamma camera imaging for a generator with a mean activity at imaging time of 468 MBq eluted at 10 ml min-1. Based on the above measurements and assuming a 10 min infusion period, the mean effective dose equivalent for 81Krm infusion imaging in the assessment of right heart function in adults was found to be 0.365 mSv.

Humans↗

PubMed1992

Ovine follistatin: characterization of cDNA and expression in sheep ovary during the luteal phase of the oestrous cycle.

We have isolated ovine follistatin cDNA from an ovarian follicle cDNA library and determined its sequence. The deduced amino acid sequence of the ovine follistatin precursor is highly homologous (greater than 97%) to the porcine, human and rat follistatins. Northern analysis was used to characterize follistatin gene expression in ovaries of adult ewes, collected from days 11 to 13 of the oestrous cycle. Two major (about 2.7 kb and 1.5 kb) and one minor (about 0.5 kb) transcripts were detected in polyadenylated RNA extracted from ovarian follicles and corpora lutea. The degree of expression of the transcripts varied in the two ovarian compartments, with the 2.7 kb species predominating in the follicles and the 1.5 kb species being more abundant in the corpora lutea. No transcripts were detected in stromal tissue containing preantral follicles of less than 1 mm.

Amino Acid Sequence↗

PubMed1992

Expression of the genes for alpha inhibin, beta A inhibin and follistatin in the ovaries of Booroola ewes which were homozygotes or non-carriers of the fecundity gene FecB.

Ovine cDNA probes for the alpha and beta A inhibin subunits and for follistatin were used to investigate the mRNA species for these hormones in ovaries obtained during the luteal phase of the oestrous cycle, from Booroola ewes which were homozygous carriers (BB) or non-carriers (++) of the FecB gene. BB ewes had significantly higher concentrations of peripheral FSH and LH immunoreactivity than ++ ewes, but the peripheral inhibin immunoreactivity and ovarian inhibin and progesterone secretion rates were not significantly different between genotypes. No gene-specific differences in the number or size of mRNA transcripts detected by Northern blotting were noted for any of these genes. A single alpha inhibin mRNA species at 1.5 kb was observed in the follicle RNA from ++ and BB ovaries. Low amounts of alpha inhibin hybridization were discerned occasionally in ++ and BB stroma and also in BB, but not in ++, corpora lutea. The beta A inhibin gene was expressed only in the follicles from both ++ and BB ovaries. At least three beta A inhibin transcripts were observed; one at 7.5 kb and at least two between 1.4 and 5.0 kb. The follistatin cDNA probe detected two major transcripts at 2.7 and 1.5 kb and a minor band at 0.5 kb in both follicle and corpora lutea RNA. Densitometry of the Northern blots revealed no significant gene-specific differences in the levels of alpha inhibin and follistatin gene mRNA transcripts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Expression of the clusterin gene in the tissues of Booroola sheep which were homozygotes or non-carriers of the fecundity gene FecB.

Clusterin or sulphated glycoprotein-2 is a major component of the rete testis fluid, synthesized by the rete testis epithelial cells and Sertoli cells. Differences in the two-dimensional polyacrylamide gel electrophoresis pattern of clusterin-like proteins have been reported in rete testis fluid from Booroola rams carrying the fecundity gene FecB, when compared with that from non-carrier rams. In order to determine whether the FecB gene influences the expression of the clusterin gene, we used a rat clusterin cRNA probe to investigate mRNA species in the tissues of homozygous (BB) or non-carrier (++) Booroola sheep. Northern blots of polyadenylated RNA showed hybridization to the cRNA probe in the testis, ovarian follicles, corpora lutea and stroma, pituitary and liver. A major mRNA transcript was observed at 2.3 kb and a minor transcript in some tissues at 0.8 kb. Densitometry of the autoradiographs revealed no FecB-specific differences in the densities of the hybridization signals from ++ and BB testis or ovarian follicle, corpora lutea or stromal RNA. We conclude that the gene for ovine clusterin is expressed widely in the tissues of sheep and that its expression is not affected by the presence of the FecB gene.

Animals↗

PubMed1991

Antithrombotic activity of BMY-43351, a new imidazoquinoline with enhanced aqueous solubility.

BMY-43351 is a new broad-spectrum inhibitor of platelet aggregation with greater aqueous solubility than earlier analogs from the imidazoquinoline series. This report compares the antithrombotic activity of BMY-43351 to that of two other imidazoquinolines: BMY-20844, a simply-substituted compound, and BMY-21638, a more potent ether-linked side chain analog. All of these compounds act, at least in part, via inhibition of platelet low-Km cyclic AMP phosphodiesterase. Antithrombotic activity was assessed in the rabbit ear chamber-biolaser preparation, an animal model of small vessel thrombosis, and in the canine coronary artery stenosis-occlusion model of large vessel thrombosis. BMY-43351 was found to be remarkably potent in the biolaser model, with an EDso of 0.074 mg/kg p.o. In comparison, compounds such as aspirin, ticlopidine, sulfinpyrazone, and dipyridamole demonstrate little or no activity at much higher doses, (eg. 100 mg/kg p.o.). Other inhibitors of platelet low Km cyclic AMP phosphodiesterase are active but substantially weaker than BMY-43351. Similarly, in the coronary artery stenosis-occlusion model, BMY-43351 demonstrated impressive activity, significantly inhibiting arterial thrombosis at intraduodenal doses as low as 1 micrograms/kg. The potential use of BMY-43351 as adjunct therapy in thrombolysis was suggested in a series of experiments where this drug was used in combination with a thrombolytic regimen of stretokinase plus heparin. In this experimental setting, time to reperfusion was reduced from 42 +/- 5 minutes to 11 +/- 5 minutes, and reocclusion was totally inhibited.

Animals↗

PubMed1991

Comparison of radionuclide estimation of glomerular filtration rate using technetium 99m diethylenetriaminepentaacetic acid and chromium 51 ethylenediaminetetraacetic acid.

Simultaneous measurements of the clearance rates of technetium 99m diethylenetriaminepentaacetic acid (99mTc-DTPA) and chronium 51 ethylenediaminetetraacetic acid (51Cr-EDTA) were performed in 30 patients with a range of renal function (glomerular filtration rates between 9 and 120 ml/min). Using multiple blood samples, the two clearance values correlated well (r = 0.991, standard error 3.9 ml/min), but DTPA clearance was systematically higher by 7.6%. For each radiopharmaceutical, an equation was derived to correct clearance values obtained using only plasma samples taken at 2 and 4 h for the systematic error inherent in this technique compared with analysis of the complete plasma concentration-time curve. The root mean square error remaining after application of these equations was 1.9 ml/min for both the EDTA and DTPA data. The corresponding errors obtained using the equation derived by Brochner-Mortensen for EDTA plasma clearance were 2.2 ml/min and 1.9 ml/min, respectively, these values were not significantly different from those obtained using the equations derived in this study.

Adult↗

PubMed1991

Effect of encainide, ODE, MODE, and flecainide on ADP/5-HT induced platelet aggregation and in the anesthetized dog coronary artery stenosis-occlusion model of intravascular thrombosis.

Encainide is a class 1C antiarrhythmic agent that is indicated for the treatment of life-threatening arrhythmias, such as sustained ventricular tachycardia. Furthermore, encainide possesses a moderate degree of antiserotonin activity, which was quantitated in this present study by determining displacement of [3H]spiperone binding from rat cortical 5-HT2 binding sites. The Ki for encainide in this model was 66.1 nM, compared to 2.6 nM for ketanserin. Two encainide metabolites, ODE and MODE, were also active, but were weaker than encainide. Additionally, these agents were found to inhibit platelet aggregation induced in vitro in human platelet-rich plasma by the combination of ADP and serotonin. In view of the fact that serotonin is one of a variety of humoral factors capable of activating blood platelets and has been recently implicated as playing a role in certain thrombotic syndromes, encainide, along with its two principal human metabolites, ODE and MODE, and another class 1C antiarrhythmic, flecainide, were evaluated in an in vivo model of intravascular thrombosis. Intraduodenal doses of 1 mg/kg of either encainide, ODE, or MODE significantly inhibited thrombosis in a canine model of coronary artery stenosis-occlusion.

Adenosine Diphosphate↗