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Biomedical subjects

T Jones

Publications and source records attributed to T Jones.

At least 19 recordsLinked to original sources
PubMed1992

Isolation of cDNA clones encoding the beta isozyme of human DNA topoisomerase II and localisation of the gene to chromosome 3p24.

Topoisomerases catalyse the interconversion of topological isomers of DNA and have key roles in nucleic acid metabolism. Human cells express two distinct type II topoisomerase isozymes, designated topoisomerase II alpha (170 kDa form) and topoisomerase II beta (180 kDa form). We have isolated cDNA clones encoding the beta isozyme from a human B-cell library. The proposed coding region for the topoisomerase II beta protein is 4,863 nucleotides long and would encode a polypeptide with a calculated M(r) of 182,705. The predicted topoisomerase II beta protein sequence shows striking similarity (72% identical residues) to that of the human alpha isozyme, and homology to topoisomerase II proteins from Drosophila, yeast and bacteria. Regions of greatest amino acid sequence divergence lie at the extreme N-terminus and over a C-terminal domain comprising approximately 25% of the total protein. We have quantified the level of topoisomerase II beta mRNA in a panel of human tumour cell lines of different origin using an RNase protection assay, and compared the level to that of topoisomerase II alpha mRNA. Topoisomerase II beta mRNA was expressed in haemopoietic, epithelial and fibroblast cell lines, although to different extents, with U937 cells (promonocytic leukaemia) showing a particularly high level. There was no obvious relationship in terms of level of expression between the topoisomerase II alpha and beta genes. We have localised the gene encoding topoisomerase II beta protein to chromosome 3p24 in the human genome.

Amino Acid Sequence↗
PubMed1992

Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.

Two yeast artificial chromosomes (YACs) spanning a total distance of 1.1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5' end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.

Adenomatous Polyposis Coli↗
PubMed1992

Measurements of blood flow and exchanging water space in breast tumors using positron emission tomography: a rapid and noninvasive dynamic method.

A noninvasive dynamic method for the measurement of blood flow, using 15O-labeled water and positron emission tomography, has been developed and used to study 20 patients with breast carcinoma. The mean tumor flow was 29.8 +/- 17.0 (SE) ml/dl/min of tissue, while normal breast flow was 5.6 +/- 1.4 ml/dl/min of tissue. The exchanging water space of tissue known as the volume of distribution of the tracer (Vd) was also derived. This is defined as the volume of water in tissue that exchanges with a unit volume of water in arterial blood during the period of the study (7 min). The mean tumor Vd was 0.56 +/- 0.15 ml/ml while normal breast Vd was 0.14 +/- 0.05 ml/ml. The low value in normal breast is partly due to the high fat content of the tissue. The mean flow per unit of exchangeable volume was similar in tumor (52.8 +/- 22.0) and normal breast tissue (45.2 +/- 20.0). This suggests that the major discrepancy seen in measured values of flow between breast tumors and normal breast principally reflects the different composition of the two tissues. This method is rapid and suited for studying the reactivity of human tumor vasculature, so extending studies are being performed on animal tumors.

Adult↗
PubMed1992

The significance of a dipyridamole induced 99mTc-MIBI perfusion abnormality on single photon emission tomography: a quantitative validation with labelled water and positron emission tomography.

To relate technetium-99m 2-methoxy-isobutyl-isonitrile (99mTc-MIBI) uptake to regional myocardial blood flow (rMBF), 99mTc-MIBI single photon emission tomography (SPET) and H2(15)O positron emission tomography (PET) scans were obtained at rest and after dipyridamole infusion in six patients with single vessel coronary artery disease. 99mTc-MIBI and H2(15)O data sets were created for each segment perfused by the stenotic vessel and for a normal reference area, assigning regions on the SPET tomograms to comparable regions on the PET by similar transaxial image reconstructions. All patients demonstrated post-dipyridamole 99mTc-MIBI perfusion defects in the territories supplied by the stenotic arteries. Resting rMBF in these regions was slightly lower than that in the normal areas (0.82 +/- 0.05 vs 0.90 +/- 0.09 ml/g/min, P = NS). A 43% +/- 14% reduction in 99mTc-MIBI activity in the area at risk was coupled with on average a 60% +/- 9% reduction in post-dipyridamole rMBF compared with control regions (0.98 +/- 0.08 vs 2.52 +/- 0.51 ml/g/min, P < 0.001). Thus, SPET assessment of 99mTc-MIBI uptake tends to underestimate the perfusion contrast between areas with normal and areas with low coronary vasodilatory reserve when compared to PET. However, these findings may still not affect the clinical usefulness of 99mTc-MIBI and more extensive studies are required to confirm these results in the clinical environment.

Contrast Media↗
PubMed1992

Dipyridamole vasodilator response after human orthotopic heart transplantation: quantification by oxygen-15-labeled water and positron emission tomography.

To assess coronary vasodilator reserve after orthotopic heart transplantation, regional myocardial perfusion was measured with oxygen-15-labeled water and dynamic positron emission tomography in 14 cardiac allograft recipients who were not experiencing rejection and who had no angiographic evidence of epicardial coronary sclerosis 15 to 73 months (mean +/- SD 43 +/- 19) after transplantation (group I). Twelve normal men with an average age of 31 years (group II) served as a control group. Regional perfusion was measured at rest and after the intravenous administration of 0.6 mg/kg body weight of dipyridamole. Rest regional myocardial blood flow was homogeneously distributed throughout the left ventricle and was significantly higher in transplant recipients (mean 1.16 +/- 0.26 ml/g per min [range 0.8 to 1.73] than in normal subjects (mean 0.85 +/- 0.13 ml/g per min [range 0.57 to 0.99]; p = 0.001) as was rest heart rate-systolic blood pressure product (rate-pressure product 11,255 +/- 2,540 vs. 7,073 +/- 1,306; p less than 0.001). After dipyridamole, perfusion in the transplant recipients was homogeneous and slightly lower (2.73 +/- 1.03 vs. 3.40 +/- 1.09 ml/g per min; p = NS), whereas rate-pressure product was slightly higher (12,179 +/- 2,266 vs. 10,885 +/- 1,895; p = NS) than the value in normal subjects. Dipyridamole vasodilator response (dipyridamole/rest myocardial blood flow) ranged from 1.23 to 4.92 (mean 2.50 +/- 1.13) in group I and from 2.65 to 5.45 (3.97 +/- 0.89) in group II (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

In vivo measurement of the volume of distribution of water in cerebral grey matter: effects on the calculation of regional cerebral blood flow.

The present study was undertaken to determine the apparent value for the volume of distribution of water to be used in the dynamic/integral technique for generating functional CBF images. A value of 0.86 resulted in only a minor loss of accuracy compared to the more accurate (but time-consuming) dynamic only analysis, which incorporated the regionally fitted estimates of the volume of distribution of water. In contrast to the traditionally used in vitro value of 0.95, the value of 0.86 allows for the inclusion of a significant part of the washout phase in the integral analysis, thereby producing statistically improved CBF images.

Administration, Inhalation↗
PubMed1992

Physical performance of a positron tomograph for brain imaging with retractable septa.

Performance characteristics of a new design of positron tomograph with automatically retractable septa for brain imaging have been studied. The device, consisting of block BGO detectors (8 x 8 elements per block), has a ring diameter of 76 cm and an axial FOV of 106.5 mm. The in-plane resolution is on average 5.8 mm and 5.0 mm (FWHM) for stationary and wobble sampling, respectively, over the central 18 cm of the transaxial FOV. Its unique feature is the capability of data acquisition both in the 'conventional' 2D mode (with septa) or 3D mode (septa retracted) where coincidences between any of the 16 detector rings are acquired. When scattered events are subtracted, the efficiency for a 20 cm diameter uniform cylinder increases overall by a factor of 4.8 between 2D (septa extended) and 3D modes. For a 20 cm phantom the trues/singles ratio is higher for 3D than for 2D but for a given unscattered trues rate, the randoms rate in 3D is higher. At 380 keV the scatter fraction within a 20 cm cylinder is 10% (septa extended) and 36% (retracted). In spite of the increase in scatter when septa are retracted, the increased efficiency in the 3D mode of acquisition yields distinct advantages, particularly in the many studies where tracer concentration is low and consequently where dead time and random rates are less important.

Brain↗
PubMed1992

Measurement of regional myocardial blood flow using C15O2 and positron emission tomography: comparison of tracer models.

Eight different modifications of the same single tissue compartment model to measure myocardial blood flow, based on inhalation of 15O-labelled CO2 and positron emission tomography, were assessed in both dogs and human normal volunteers. Several models provided results with the same degree of accuracy in dogs. However, a number of these models gave poorer results in humans. It was established that the model containing components for blood flow, fraction of water exchanging tissue and spill-over arterial blood volume provided the most accurate and reproducible results. This model contains inherent corrections for the limited spatial resolution of positron emission tomographs. For ease of computation, linearisation of the operational (fitting) equation was tested, but found not to be satisfactory. The left atrium was slightly better than the left ventricle for determining the arterial input function. Inclusion of the blood volume term in the fitting procedure was significantly better than subtracting blood volume prior to analysis, both in terms of accuracy and precision.

Administration, Inhalation↗
PubMed1992

Delivery of therapeutic aerosols to intubated babies.

Delivery of drug aerosols to the lungs of ventilated neonates by metered dose inhaler and spacer (Aerochamber) and ultrasonic nebuliser (Pentasonic) was assessed using sodium cromoglycate. The mean proportion of a known intratracheal dose of sodium cromoglycate excreted in the urine of four intubated infants was 37.5%. After assuming that 38% of the sodium cromoglycate aerosol reaching the neonatal lung will be excreted in the urine, three puffs (15 mg) delivered by metered dose inhaler and spacer resulted in a pulmonary dose of 258 micrograms (1.7%, n = 7). A dose of 20 mg (4 ml) sodium cromoglycate ultrasonically nebulised over five minutes into the inspiratory limb of a standard ventilator circuit produced a pulmonary dose of 257 micrograms (1.3%, n = 7). Of two in vitro lung models assessed, a combination of filter and neonatal test lung was superior to a multistage impactor in estimating the in vivo pulmonary sodium cromoglycate dose delivered by metered dose inhaler and spacer (243 micrograms v 1740 micrograms).

Aerosols↗
PubMed1992

Regional structure-function correlations in chronic obstructive lung disease measured with positron emission tomography.

BACKGROUND: Positron emission tomography, performed with isotopes of very short half life, can be used to relate local lung tissue density to local ventilation and to the ventilation:perfusion ratio. This method has been used in 10 patients with severe chronic airflow obstruction and differing values for carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO). METHODS: Ventilation (VA) and the ventilation:perfusion ratio (V/Q), lung density, and blood volume were measured regionally in a single transaxial section at mid-heart level with the patients in a supine position. Alveolar volume, extravascular tissue lung density, and perfusion (Q) were derived. Twenty five regions with abnormalities in the ventilation images were analysed. RESULTS: Tissue density showed a negative correlation with the ratio V/Q (r = 0.55) and a positive correlation with Q (r = 0.59) and blood volume (r = 0.65). In four patients with a low carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO) < 50% predicted many regions with low VA had low tissue density and normal or high V/Q. On the other hand, in four patients with TLCO and KCO > 50% predicted many regions with low VA had normal or high tissue density and low values of V/Q. The other two patients had patterns between these two extremes. Individual ratios between mean values of tissue density and V/Q had a positive correlation with KCO (% pred; r = 0.79). CONCLUSIONS: These findings link structural differences with distinctive functional patterns; they reinforce the view that bronchial inflammation or oedema predominate in some patients with chronic airflow obstruction, whereas alveolar destruction is the major feature in others.

Aged↗
PubMed1992

Preoperative prediction of the outcome of coronary revascularization using positron emission tomography.

BACKGROUND: Previous assessments of myocardial viability using positron emission tomography (PET) relied on demonstration of glucose metabolism in hypoperfused asynergic segments using the glucose analogue [18F]2-fluoro-2-deoxyglucose (FDG). Recently, it was shown that myocardial viability could be assessed by calculating the water-perfusable tissue index (PTI) for the asynergic region. PTI represents the proportion of the myocardium that is capable of rapid transsarcolemmal exchange of water and thus perfusable by water. The aim of the present study was to assess myocardial viability by PET using PTI in patients undergoing coronary revascularization. METHODS AND RESULTS: Twelve patients with chronic coronary artery disease and previous myocardial infarction were studied. Analysis of transmission (tissue density) and 15O-labeled carbon monoxide (blood pool), and 15O-labeled water (myocardial blood flow [MBF]) emission PET data enabled the simultaneous quantification of MBF (ml.min-1.g perfusable tissue-1) and PTI (gram of perfusable tissue per gram of total anatomic tissue). In addition, PET imaging with FDG after 75-g oral glucose load was performed in eight patients. Preoperative echocardiography identified 33 hypocontractile and 26 control segments. Follow-up echocardiography performed 3 to 5 months later demonstrated 26 of 33 segments with improved wall motion (recovery) and seven of 33 segments without improvement (nonrecovery). MBF in the control segments (0.97 +/- 0.22 ml.min-1.g perfusable tissue-1) was significantly higher (p < 0.001) than in both the recovery (0.73 +/- 0.18 ml.min-1.g perfusable tissue-1) and the nonrecovery (0.45 +/- 0.11 ml.min-1.g perfusable tissue-1) segments. PTI in the recovery regions (0.99 +/- 0.15) was > or = 0.7 in all cases and slightly less than in control regions (1.10 +/- 0.15, p < 0.02). FDG uptake in these regions was 92 +/- 17% (n = 13) of the uptake in control segments with normal wall motion. In the nonrecovery group, PTI was 0.62 +/- 0.06 (p < 0.02 versus control and recovery) and always < 0.7. In the one patient in whom a comparison with metabolic imaging was made, FDG uptake was 46% of the uptake in a reference region with normal wall motion. CONCLUSIONS: These data showed that contractile recovery occurred only in segments where PTI was > or = 0.7, suggesting that > or = 70% of myocardial tissue in a given asynergic segment should be perfusable by water to enable contractile recovery. There was good agreement between the PTI and FDG methods for predicting improvements in regional wall motion after revascularization. Although further studies should be performed in a larger patient group, the preliminary results are promising and suggest that PTI may be a good predictor of contractile recovery after coronary revascularization.

Angioplasty, Balloon, Coronary↗
PubMed1992

Patterns of cerebral blood flow in schizophrenia.

Positron emission tomography was used to study the relationship between rCBF and symptom profiles in 30 schizophrenic patients. Factor analysis confirmed that the symptoms segregated into three syndromes--psychomotor poverty, disorganisation, and reality distortion--described previously. Analysis of the correlations between syndrome scores and rCBF revealed that each syndrome was associated with a specific pattern of perfusion in paralimbic and association cortex, and in related subcortical nuclei. The study confirmed predictions that psychomotor poverty and disorganisation are associated with altered perfusion at different loci in the pre-frontal cortex, and reality distortion with altered perfusion in the medial temporal lobe. The perfusion patterns suggest that the abnormalities of brain function underlying each of the three syndromes are not confined to single loci, but involve distributed neuronal networks.

Adult↗
PubMed1992

Low oxygen extraction fraction in tumours measured with the oxygen-15 steady state technique: effect of tissue heterogeneity.

Several reports have described decreased oxygen extraction fractions in tumours relative to those in normal tissues as measured with the oxygen-15 steady state technique and positron emission tomography. The present simulation study was carried out to assess the influence of tissue heterogeneity on these measured values. It was found that, within the range analyzed, tissue heterogeneity always resulted in underestimations of mean values of oxygen extraction fraction. It must, therefore, be concluded that the oxygen-15 steady state technique is not an accurate method for the assessment of the oxygen status of tumours. This finding should also apply to other pathological conditions, where a significant degree of tissue heterogeneity can not be excluded. More generally, this study demonstrates the need for detailed analyses of sensitivities of tracer kinetic procedures to tissue heterogeneity.

Brain Neoplasms↗
PubMed1992

Use of the left ventricular time-activity curve as a noninvasive input function in dynamic oxygen-15-water positron emission tomography.

Noninvasive recording of arterial input functions using regions of interest (ROIs) in the left ventricular (LV) chamber obviates the need for arterial cannulation in PET, but it is compromised by the limited recovery coefficient of the LV chamber and by statistical noise. In the present study, a new mathematical model has been developed, which corrects for the spillover of radioactivity both from the myocardium into the LV ROI and the blood into the myocardial ROI. The method requires the measurement of a time-activity curve in the LV chamber during the dynamic H2(15)O PET study and the measurement of the recovery coefficient of the LV ROI using a 15O-carbon monoxide (C15O) scan and venous blood sampling. This approach was successfully validated against direct measurements of the arterial input function using an on-line beta detector in five greyhounds undergoing dynamic H2(15)O PET imaging. This technique also yielded myocardial blood flow (MBF) values which were not significantly different from those obtained with the beta-probe analyses (maximum difference less than 2%), provided that the LV ROIs were sufficiently large to provide good counting statistics. When this model was not applied for large ROIs (small recovery in LV ROI), systematic overestimations in MBF compared with beta-probe analysis (e.g., a factor by 40% for a recovery coefficient of 0.7) were observed. Thus, this technique enabled the prediction of an accurate input function using the LV time-activity curve, and hence, noninvasive quantification of MBF without arterial cannulation.

Animals↗
PubMed1991

The human collagen X gene. Complete primary translated sequence and chromosomal localization.

We report on the complete primary translated sequence of human alpha 1(X) collagen, deduced from a genomic clone, and the chromosomal localization of the human collagen X gene. The primary translated product of human collagen X is encoded by two exons of 169 bp and approx. 2940 bp. The 169 bp exon encodes 15 bp of 5'-end untranslated sequence, 18 amino acid residues (54 bp) of signal peptide and 33 1/3 amino acid residues (100 bp) of the N-terminal non-collagenous domain. The 2940 bp exon encodes 4 2/3 amino acid residues (14 bp) of the N-terminal non-collagenous domain, the complete triple-helical domain of 463 amino acid residues (1389 bp), the complete C-terminal non-collagenous domain of 161 amino acid residues (483 bp) and 1054 bp of 3'-end untranslated sequence up to and including a potential cleavage/polyadenylation signal. The size of the intron separating the two exons, as estimated by partial sequencing and Southern-blot analyses, is approx. 3200 bp. By a combination of somatic cell hybrid screening and hybridization in situ the human collagen X gene (COL10A1) has been assigned to the distal end of the long arm of chromosome 6 at the locus 6q21-6q22.3.

Amino Acid Sequence↗