Interactions of quinidine and quinine and (+)- and (-)-pindolol with the organic cation/proton antiporter in renal brush border membrane vesicles.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to R J Ott.
Explore the source record for details and available documents.
Positron emission tomography (PET) has been used to measure changes in regional blood-brain barrier (BBB) permeability in patients with primary cerebral lymphoma undergoing radiotherapy and chemotherapy. The method employed is to measure the rate of wash-out of a radioactive tracer (68Ga-EDTA) from blood into brain tissue using time-sequence PET imaging. Preliminary studies carried out on patients with more common primary cerebral tumours show that time-activity data are reproducible to approximately 10%. Measurements made in 2 patients with primary cerebral lymphoma treated with initial chemotherapy showed significant changes in permeability in the region of the tumour. Within 5 weeks of the start of treatment, permeability values reached the levels of normal brain. No changes in BBB permeability in normal brain were seen immediately after radiotherapy.
Explore the source record for details and available documents.
The renal proximal tubule is responsible for the active elimination of organic cations. Studies in brush-border membrane vesicles (BBMV) suggest that active organic cation transport is mediated by an organic cation-proton antiporter. The goals of this study were to determine whether this transporter is expressed in human kidney and to elucidate its characteristics. Transport of the organic cations N1-[3H]methylnicotinamide (NMN) and [14C]tetraethylammonium (TEA) was determined by rapid filtration in BBMV of donor human kidneys. The uptake of NMN and TEA was driven against a concentration gradient by an outwardly directed proton gradient. NMN uptake was inhibited by the organic cations TEA, NMN, quinine, and cimetidine, but was not affected by p-aminohippuric acid, cephalexin, and polyamines. The electroneutral transport of NMN was characterized by a Km of 0.44 +/- 0.07 mM and a Vmax of 24.4 +/- 15.2 pmol.mg protein-1.s-1. The rate of proton efflux from BBMV increased in the presence of an inwardly directed TEA gradient. Preloading BBMV with NMN or TEA trans-stimulated the initial rate of uptake of TEA. Therefore the human proximal tubule expresses an organic cation-proton antiporter in the brush-border membrane. The antiporter is similar to that described in other mammalian species but shows some differences in its transport characteristics.
Explore the source record for details and available documents.
Nineteen patients with biopsy-proven cerebral gliomas were studied with 99mTc-HMPAO single photon emission tomography (SPECT) imaging and X-ray computed tomography (CT). The uptake of 99mTc-HMPAO was correlated with tumour size and morphology as shown by X-ray CT, and overall patient survival. It appears that uptake of 99mTc-HMPAO is associated with larger, ill-defined tumours and was an adverse factor in patient survival. In those tumours with normal or increased uptake, 99mTc-HMPAO imaging is useful in distinguishing the tumour margin from surrounding oedema.
Forty-six comparative studies were performed on 41 patients with hyperthyroidism. Clinically these comprised two groups: those with Graves' disease, and those with multinodular goitre. All patients underwent an ultrasound examination and positron emission tomography (PET) using 124I, then gamma camera pinhole imaging following their 131I therapy administration. Although the 131I pinhole imaging was not performed for diagnostic purposes, there was good correlation (78% agreement) between it and 124I PET in determining relative lobe size. Hence either imaging modality could be used as an indicator of the relative radiation dose delivered to each thyroid lobe at a macroscopic level. In terms of gland morphology the PET images corresponded well to the high resolution ultrasound images (78% agreement), unlike the pinhole images which correlated poorly (only 28% agreement). The results showed that PET imaging gives better anatomical and physiological detail than 131I pinhole imaging. In 77% of cases where the pinhole image showed a uniform distribution of radioisotope, the improved spatial resolution of the PET images revealed non-homogeneous distribution indicating a non-uniform distribution of radiation dose. Since all dosimetry calculations are based on the assumption of uniform distribution of radioiodine, this non-uniformity could possibly have important consequences in the outcome of radioiodine therapy in thyrotoxicosis.
A large area multi wire proportional chamber positron camera system is under evaluation for clinical Nuclear Medicine investigation using isotopes both from the house generators (68Ga) and from remote cyclotrons (18F, 124I, 64Cu and 81Rb). Images are reconstructed using a fully three dimensional (3D) algorithm and exhibit equal resolution in all three orthogonal directions. The axial field of view of 15 cm is large enough to allow coverage of the whole brain. This paper discusses the performance of the MUP-PET system with particular emphasis on quantification and the development of an attenuation correction scheme for a large area detector system. The distribution of scattered and accidental events is investigated and observed to contribute a fairly uniform background to the image. Dead time correction factors are calculated from an analytical expression obtained by considering the various sources of dead time present in the system. Following correction for attenuation, accidentals, scattered events and dead time, reconstructed phantom images show a strong linear correlation (r = 0.998) between count density and regional isotope concentration. The extension of the methods to clinical studies is discussed.
We have designed special high-resolution, low-sensitivity collimators for a dual-headed whole-body scanner for imaging and quantifying therapy levels of iodine-131. In addition, we have used positron emission tomography (PET) with a low-cost large-area PET camera to achieve improved accuracy in the estimate to tumor mass. The physical performance of these two imaging systems is described. In order to illustrate the practical implementation of these systems for the assessment of radiation dose to normal and tumour tissue during radioiodine therapy, three clinical examples are reported, and a summary of the initial clinical results obtained from 16 patients with carcinoma of the thyroid is presented. The dose to normal thyroid remnants for patients undergoing ablation ranged from 16 to 400 Gy, while the dose to involved neck nodes ranged from 2.5 to 33 Gy for patients undergoing post-ablation radioiodine therapy. In one patient with distant metastasis in the spine, a dose of 100 Gy was achieved. The techniques described in this paper can be used to determine if sufficient activity can be accumulated in tumours to provide a therapeutic effect while minimising irradiation of normal tissues by avoiding administrations which do not provide tumouricidal radiation doses.
Explore the source record for details and available documents.
The Rutherford Appleton Laboratory clinical positron camera consists of two opposed multiwire proportional chambers (MWPCS) mounted on a rotating gantry capable of performing routine nuclear medicine studies. The system has operated since the end of 1986 with complete reliability. It has a sensitivity of 37 kcps MBq-1 cm3 per axial cm for a 20 cm diameter uniformly filled cylinder of activity. The best spatial resolution obtainable is about 6 mm, although in practice images are smoothed in order to reduce statistical noise with a corresponding decrease in resolution. Cross-plane rays are utilised during image reconstruction and the resulting three-dimensional images exhibit the same spatial resolution in three orthogonal directions over a large cylindrical field of view 15 cm high by 30 cm in diameter. The maximum data-taking rate is limited to 1.5 to 2 kcps at present due to deadtime in the read-out system. The performance of the system is described with particular reference to the problems of imaging with the large fractions of random and scattered events which are a consequence of using large-area detectors. Images of phantoms and patients are presented and proposed modifications to the camera are described.
This paper describes the potential advantages to medical diagnosis and treatment that might be obtained from the wider application of positron emission tomography as a clinical tool. Developments along the lines suggested here will require a radical change in thinking from both clinicians and the medically related scientific community in the UK and some enlightened and resourceful funding from a mixture of charitable, industrial and government sources. If these ideas are to be pursued successfully, then the work must start now on a much wider scale than is presently perceived in the UK, and close collaboration between physicists, engineers, chemists, biochemists, clinicians and industrialists is needed. Furthermore, it is imperative that the scientific developments now underway in silicon technology, parallel data processors, biochemical and pharmacological processes and even high-temperature superconductors be kept under close and constant review by those associated with the technological advancements of medicine, so that the value of such developments is rapidly transferred to applications to medicine. This must include closer relationships between academic medicine and science than is the general rule in the UK at present. In conclusion, the scenario presented here includes the installation of regional cyclotron facilities to provide a large number of institutions in the UK with positron-emitter labelled radiopharmaceuticals. Additionally, agents labelled with radionuclides from in-house generators and other already existing higher-energy cyclotrons will provide a versatile and valuable range of radiopharmaceuticals for the study of human disease. These developments must be supported by the manufacture of lower-cost positron camera systems, as suggested here, connected to high-data-rate parallel processors to provide images of body function and to determine the effects brought about by disease. These images may then be processed using algorithms based on kinetic models of the body systems to provide information about the basic biochemical and physiological processes of the body. Such a development could have a profound effect on our knowledge of human disease and on our ability to control and treat it successfully.
Explore the source record for details and available documents.
A preliminary study of the distribution of the 99mTc complex of hexamethylpropylene amine oxime (HM-PAO) in 12 patients with brain neoplasms before, during, and after radiotherapy has been performed. Untreated brain tumors were found to exhibit a range of 99mTc-HM-PAO uptake, varying from areas of markedly increased isotope activity to photopenic areas, when compared to normal brain tissue. A ratio of 99mTc-HM-PAO tumor uptake to contralateral normal tissue uptake was calculated prior to and during radiotherapy. This ratio tended to return towards unity in lesions responding to therapy. A predictable alteration in whole brain 99mTc-HM-PAO uptake during radiotherapy was not demonstrated. Unlike the radiolabeled amines, 99mTc-HM-PAO localizes in primary tumors, probably indicating that its uptake mechanism is independent of non specific amine receptors. 99mTc-HM-PAO may be useful in the study of brain tumor physiology and response to therapy.
Standard dynamic renography procedures are used to produce time-activity curves for defined regions of interest around the kidneys. Further analysis of the acquired data using Fitted Retention and Excretion Equations (FREE) to determine single kidney glomerular filtration rate (GFR) and kidney transit time is performed at the Royal Marsden Hospital, Sutton. The disadvantage of these methods is that the renal function is assessed for the whole kidney and not on a regional basis. The aim of this study was to use parametric imaging to extend the standard analysis so that the parenchyma could be identified and analysed separately from the collecting system. The parenchyma pixel time-activity curves have shorter time-to-peak (TTP) values than the collecting system. TTP parametric images were used to set limits on the TTP values and thus define the parenchyma pixels. The time-activity curves from the parenchyma were further analysed using FREE to produce parametric images of both GFR and effective blood volume. Finally, the original dynamic data were re-analysed so that time-activity and FREE curves were generated for the parenchyma alone. A study of 15 patients (30 kidneys) showed that the extended analysis indicated parenchymal isotope clearance. By comparing the time-activity and FREE curves of the whole kidney with those from the parenchyma alone, a more useful analysis of parenchymal function was obtained. This proved to be particularly useful for patients with pelvi-ureteric junction (PUJ) obstruction.
Explore the source record for details and available documents.
Technetium-99m-labelled hexamethylpropylene amine oxime (HM-PAO) has been used to investigate tumour perfusion in 11 tumour sites in 8 patients with a variety of histologies. In 8 out of 11 instances single photon emission tomography clearly distinguished between tumour and normal tissues; in 7 cases due to increased HM-PAO uptake and in 1 due to reduced tumour uptake compared with hepatobiliary excretion of HM-PAO in adjacent normal liver. Heterogeneous uptake within individual tumour masses was observed in 3 cases. In 2 where a correlation between the pathology of excised tumour and the scan findings could be made, the findings were consistent with HM-PAO uptake in well-perfused tissue. These preliminary observations suggest that Technetium-99m-HM-PAO may be a valuable clinical technique for displaying patterns of tumour perfusion.
Measurements of the functioning volume of thyroid tissue have been made in 22 patients undergoing radioiodine therapy for thyrotoxicosis, using a prototype multiwire proportional counter positron camera. Tomographic images were produced of the distribution of 124I in the thyroid. Functioning volumes were found to be in the range 21-79 cm3 with volume errors of the order of +/- 4% to +/- 14%. Radioiodine uptake varied from 28% to 98%. Using a value of 6 days for the effective half-life of radioiodine in hyperactive thyroids, radiation doses from a standard therapy administration of 75 MBq of 131I varied from 11 to 48 Gy (compared with a recommended 50-70 Gy). In five cases PET imaging showed a non-uniform distribution of radioiodine in thyroids thought to have uniform uptake from conventional pinhole scintigraphy.